Doravirine, MK-1439

Phase 3 drug, Uncategorized Comments Off

Jul 182016

Image for unlabelled figure

Doravirine, MK-1439……….. AN ANTIVIRAL

3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydro-3-pyridinyl}oxy)benzonitrile

Benzonitrile, 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]-

3-chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile

(3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile)

1338225-97-0 CAS

MF C17H11ClF3N5O3
MW 425.7 Merck Sharp & Dohme Corp

Merck Frosst Canada Ltd. INNOVATOR

Jason Burch, Bernard Cote, Natalie Nguyen,Chun Sing Li, Miguel St-Onge, Danny Gauvreau,

Reverse transcriptase inhibitor

UNII:913P6LK81M

Originator Merck & Co
Class Antiretrovirals; Nitriles; Pyridones; Small molecules; Triazoles
Mechanism of Action Non-nucleoside reverse transcriptase inhibitors

Phase III HIV-1 infections

Most Recent Events

16 Jul 2016 No recent reports of development identified for phase-I development in HIV-1-infections(Monotherapy, Treatment-naive) in Germany (PO, Tablet)
01 Jun 2016 Merck Sharp & Dohme completes a phase I pharmacokinetics trial in subjects requiring methadone maintenance therapy in USA (PO, Tablet) (NCT02715700)
01 May 2016 Merck completes a phase I trial in severe renal impairment in USA (NCT02641067)

SYNTHESIS COMING………

WO 2015084763

CONTD………………………

SPECTRAL DATA

19F DMSOD6

13C NMR DMSOD6

1H NMR DMSOD6

3-chloro-5-((2-oxo-1-((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile.

1H NMR (400 MHz, DMSO-d6) δ 11.47 (br. s., 1H), 11.40 (s, 1H), 7.93 (d, J = 7.3 Hz, 1H), 7.75 (t, J =1.5 Hz, 1H), 7.58 (dd, J = 1.2, 2.3 Hz, 1H), 7.51 (t, J = 2.1 Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 5.02 (s, 2H)

13C NMR (101 MHz, DMSO-d6) δ 157.25, 156.20, 155.97, 142.52, 140.09 (q, JC-F = 2.0 Hz), 137.74,134.97, 130.17 (q, JC-F = 31.2 Hz), 126.53, 121.70 (q, JC-F = 274.7 Hz), 121.16, 118.37, 116.96, 113.70,99.96 (q, JC-F = 4.0 Hz), 44.90

19F NMR (376 MHz, DMSO-d6) δ -62.24 (s, 1F)
HRMS [M + H]+ for C16H10ClF3N5O3 calcd, 412.0419; found, 412.0415.
mp 148.46-156.11 °C

REF Org. Process Res. Dev., Article ASAP, DOI: 10.1021/acs.oprd.6b00163

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00163

Doravirine (MK-1439) is a non-nucleoside reverse transcriptase inhibitor under development by Merck & Co. for use in the treatment of HIV/AIDS. Doravirine demonstrated robust antiviral activity and good tolerability in a small clinical study of 7-day monotherapy reported at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013. Doravirine appeared safe and generally well-tolerated with most adverse events being mild-to-moderate.^[2]^[3]

Highly active antiretroviral therapy (HAART) is the standard of care for the treatment of HIV infection. Typically, this protocol recommends the combination of two nucleoside reverse-transcriptase inhibitors (NRTIs) with either a non-nucleoside reverse-transcriptase inhibitor (NNRTI), a ritonavir-boosted protease inhibitor or an integrase inhibitor.

NNRTI-based combinations have become first-line therapy mainly because of their demonstrated efficacies, convenient dosing regimen and relatively low toxicities. These inhibitors block the polymerase activity of the HIV reverse transcriptase by binding to an allosteric hydrophobic pocket adjacent to the active site. Efavirenz (1, ) is a first generation NNRTI that has been conveniently co-formulated with NRTIs tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) as a once-a-day fixed-dose combination (Atripla®). Although recommended for the therapy of treatment-naïve patients, efavirenz suffers from neurocognitive side effects, teratogenicity and exacerbation of hyperlipidemia. Moreover, the low barrier to genetic resistance of first generation NNRTIs led to the emergence of resistant viruses bearing mutations K103N and Y181C in patients failing therapy.

: Figure .

Structures of marketed and lead NNRTIs.

Second generation NNRTIs etravirine (2) and rilpivirine (3) efficiently suppress the replication of the K103N resistant mutants as shown by an improved activity in cell culture assays . Etravirine (200 mg, bid) is approved for use in treatment-experienced adult patients with multi-drug resistance. With an improved pharmacokinetic profile, the close analog rilpivirine (25 mg, qd) was recently approved for use in treatment-naïve patients. Phase III data reveal that at the 96-week point, a rilpivirine/truvada® combination was better tolerated than efavirenz/truvada®. However, the virologic failure rate was twice as high for rilpivirine (14%) than it was for efavirenz (8%). For patients with viral load greater than 500,000 copies/mL, the response rate is 62% (rilpivirine) versus 81% (efavirenz). As a result, rilpivirine is not recommended for treating HIV patients with viral load >500,000 copies/mL. This difference in treatment durability could be explained by the much higher ratio of trough concentration over the antiviral activity for efavirenz versus rilpivirine.

Investigational next-generation, non-nucleoside reverse transcriptase inhibitor (NNRTI), at the 21^st Conference on Retroviruses and Opportunistic Infections (CROI). Interim data demonstrating potent antiretroviral (ARV) activity for four doses (25, 50, 100 and 200 mg) of once-daily, oral doravirine in combination with tenofovir/emtricitabine in treatment-naïve, HIV-1 infected adults after 24 weeks of treatment were presented during a late-breaker oral session. Based on these findings as well as other data from the doravirine clinical program, Merck plans to initiate a Phase 3 clinical trial program for doravirine in combination with ARV therapy in the second half of 2014.

“Building on our long-standing commitment to the HIV community, Merck continues to evaluate new candidates we believe have the potential to make a meaningful difference in the lives of HIV patients,” said Daria Hazuda, Ph.D., vice president, Infectious Diseases, Merck Research Laboratories. “We look forward to advancing doravirine into Phase 3 clinical trials in the second half of 2014.”

Doravirine Clinical Data

This randomized, double-blind clinical trial examined the safety, tolerability and efficacy of once-daily doravirine (25, 50, 100 and 200 mg) in combination with once-daily tenofovir/emtricitabine versus efavirenz (600 mg), in treatment-naïve, HIV-1 infected patients. The primary efficacy analysis was percentage of patients achieving virologic response (< 40 copies/mL).

At 24 weeks, doravirine doses of 25, 50, 100, and 200 mg showed virologic response rates consistent with those observed for efavirenz at a dose of 600 mg. All treatment groups showed increased CD4 cell counts.

		Proportion of Patients with Virologic Response at 24 weeks (95% CI)		Mean CD4 Change from Baseline (95% CI)
Treatment*	Dose (mg)	n/N	% <40 copies/mL	cells/μL
Doravirine	25	32/40	80.0 (64.6, 90.9)	158 (119, 197)
	50	32/42	76.2 (60.5, 87.9)	116 (77, 155)
	100	30/42	71.4 (55.4, 84.3)	134 (100, 167)
	200	32/41	78.0 (62.4, 89.4)	141 (96, 186)
Efavirenz	600	27/42	64.3 (48.0, 78.4)	121 (73, 169)
Missing data approach:		Non-completer = Failure		Observed Failure

*In combination with tenofovir/emtricitabine

The incidence of drug-related adverse events was comparable among the doravirine-treated groups. The overall incidence of drug-related adverse events was lower in the doravirine-treated groups (n=166) than the efavirenz-treated group (n=42), 35 percent and 57 percent, respectively. The most common central nervous system (CNS) adverse events at week 8, the primary time point for evaluation of CNS adverse experiences, were dizziness [3.0% doravirine (overall) and 23.8% efavirenz], nightmare [1.2% doravirine (overall) and 9.5% efavirenz], abnormal dreams [9.0% doravirine (overall) and 7.1% efavirenz], and insomnia [5.4% doravirine (overall) and 7.1% efavirenz].

Based on the 24-week data from this dose-finding study, a single dose of 100 mg doravirine was chosen to be studied for the remainder of this study, up to 96 weeks.

About Doravirine

DORAVIRINE

Doravirine, also known as MK-1439, is an investigational next-generation, NNRTI being evaluated by Merck for the treatment of HIV-1 infection. In preclinical studies, doravirine demonstrated potent antiviral activity against HIV-1 with a characteristic profile of resistance mutations selected in vitro compared with currently available NNRTIs. In early clinical studies, doravirine demonstrated a pharmacokinetic profile supportive of once-daily dosing and did not show a significant food effect.

Merck’s Commitment to HIV

For more than 25 years, Merck has been at the forefront of the response to the HIV epidemic, and has helped to make a difference through our proud legacy of commitment to innovation, collaborating with the community, and expanding global access to medicines. Merck is dedicated to applying our scientific expertise, resources and global reach to deliver healthcare solutions that support people living with HIV worldwide.

About Merck

Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

PATENT

WO 2014089140

The compound 3 -chloro-5-( { 1 – [(4-methyl-5 -oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 – yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile has the following chemical structure.

Anhydrous 3 -chloro-5-( { 1 – [(4-methyl-5 -oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 -yl)methyl] -2-oxo-4- (trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile is known to exist in three crystalline forms – Form I, Form II and Form III. The differential scanning calorimetry (DSC) curve for crystalline anhydrous Form II shows an endotherm with an onset at 230.8° C, a peak maximum at 245.2°C, and an enthalpy change of 3.7 J/g, which is due to polymorphic conversion of anhydrous Form II to anhydrous Form I, and a second melting endotherm with an onset at 283.1°C, a peak maximum at 284.8°C, and an enthalpy change of 135.9 J/g, due to melting of Anhydrous Form I. Alternative production and the ability of this compound to inhibit HIV reverse transcriptase is illustrated in WO 201 1/120133 Al, published on October 6, 201 1, and US 201 1/0245296 Al, published on October 6, 201 1, both of which are hereby incorporated by reference in their entirety.

The process of the present invention offers greater efficiency, reduced waste, and lower cost of goods relative to the methods for making the subject compounds existing at the time of the invention. Particularly, the late stage cyanation and methylation steps are not required.

The following examples illustrate the invention. Unless specifically indicated otherwise, all reactants were either commercially available or can be made following procedures known in the art. The following abbreviations are used:

EXAMPLE 1

Step 1

1 2

3-(Chloromethyl)-l-(2-methoxypropan-2-yl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (2): A

100 ml round bottom flask equipped with stir bar and a nitrogen inlet was charged with 1 (5 g, 33.9 mmol) and (lS)-(+)-10-camphorsulfonic acid (0.39 g, 1.694 mmol) at ambient temperature. After 2,2-dimethoxy propane (36.0 g, 339 mmol) was charged at ambient temperature, the resulting mixture was heated to 45°C. The resulting mixture was stirred under nitrogen at 45°C for 18 hours and monitored by HPLC for conversion of the starting material (< 5% by HPLC). After the reaction was completed, the batch was taken on to the next step without further workup or isolation. ‘H NMR (CDCI₃, 500 MHz): 4.45 (s, 2H), 3.35 (s, 3H), 3.21 (s, 3H), 1.83 (s, 6H).

Step 2

3-Fluoro-l-((l-(2-methoxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl)-4-(trifluoromethyl)pyridin-2(lH)-one (3): A mixture of 2 (100 mg, 93.1% purity, 0.49 mmol), pyridone (1 17 mg, 97.6% purity, 0.49 mmol) and K2CO₃ (82 mg, 0.59 mmol) in DMF (0.5 ml) was aged with stirring at ambient temperature for 3h. After the reaction was completed, the batch was taken on to the next step without further work up or isolation.

Step 3

3-Chloro-5-((l-((l-(2-methoxypropan-2-yl)-4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl)-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (4): To a mixture of compound 3 in DMF (reaction mixture from the previous step) was added 3-chloro-5- hydroxybenzonitrile (1.77 g, 1 1.5 mmol) at ambient temperature. The resulting mixture was then heated to 95-100°C and held for 20 hours.

Upon completion (typically 18-20 hours), the reaction was cooled to room temperature, diluted with ethyl acetate and washed with water. The aqueous cut was back extracted with ethyl acetate. The organic layers were combined and then concentrated to an oil. MeOH (80 ml) was added and the resulting slurry was taken on to the next step. ^XH NMR (CDC1₃, 500 MHz): 7.60 (d, IH), 7.42 (s, IH), 7.23 (s, IH), 7.12 (s, IH), 6.56 (d, IH), 5.14 (s, 2H), 3.30 (s, 3H), 3.22 (s, 3H), 1.82 (s, 6H).

Step 4

4 5

3-Chloro-5-((l-((4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)-2-oxo-4- (trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (5): To a solution of 4 (5.74 g., 1 1.53 mmol) in MeOH (from previous step) was added concentrated hydrochloric acid (lml, 12.18 mmol) at ambient temperature. The resulting mixture was agitated for 1 hour at room temperature.

The resulting solids were collected by filtration and dried under a nitrogen sweep, providing 5 as a white solid (2.63 g, 46% yield): ^XH NMR (DMSO, 400 MHz): 1 1.74 (S, IH), 7.92 (d, IH), 7.76 (s, IH), 7.61 (s, IH), 7.54 (s, IH), 6.69 (d, IH), 5.15 (s, 2H), 3.10 (s, 3H)

EXAMPLE 2

Step 1

Phenyl methylcarbamate: 40% Aqueous methylamine (500 g, 6.44 mol) was charged to a 2 L vessel equipped with heat/cool jacket, overhead stirrer, temperature probe and nitrogen inlet. The solution was cooled to -5 °C. Phenyl chloroformate (500.0 g, 3.16 mol) was added over 2.5 h maintaining the reaction temperature between -5 and 0 °C. On complete addition the white slurry was stirred for lh at ~0 °C.

The slurry was filtered, washed with water (500 mL) and dried under 2 sweep overnight to afford 465g (96%> yield) of the desired product as a white crystalline solid; 1H NMR (CDCI₃, 500 MHz): δ 7.35 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 4.95 (br s, 1H), 2.90 (d, J = 5 Hz, 3H).

Step 2

2-(2-Hydroxyacetyl)-N-methylhydrazinecarboxamide: Part A: Phenyl methylcarbamate (300 g, 1.95 mol) was charged to a 2 L vessel with cooling jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. IPA (390 mL) was added at 23 °C. Hydrazine hydrate (119 g, 2.33 mol) was added and the slurry heated to 75 °C for 6 h.

The slurry was filtered and washed with IPA (600 mL). The cake was dried under 2 sweep to afford 241.8g (81% yield) of the desired product as a white crystalline solid: ^XH NMR (D₂0, 500 MHz): δ 4.11 (s, 2H), 2.60 (s, 3H).

Step 3

3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 2-(2-Hydroxyacetyl)-N- methylhydrazinecarboxamide (130 g @ ~95wt%, 0.84 mol), w-propanol (130 mL) and water (130 mL) were charged to a 1 L vessel with jacket, overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. Sodium hydroxide (pellets, 16.8 g, 0.42 mol) was added and the slurry warmed to reflux for 3h. The reaction mixture was cooled to 20 °C and the pH adjusted to 6.5 (+/- 0.5) using cone hydrochloric acid (28.3 mL, 0.34 mol). Water was azeotropically removed under vacuum at 40-50 °C by reducing the volume to -400 mL and maintaining that volume by the slow addition of n-propanol (780 mL). The final water content should be <3000 ug/mL. The resultant slurry (~ 400 mL) was cooled to 23 °C and heptane (390 ml) was added. The slurry was aged lh at 23 °C, cooled to 0 °C and aged 2h. The slurry was filtered, the cake washed with 1 :2 n-PrOH/heptane (100 mL) and dried to provide 125g (85% yield) of an off- white crystalline solid. The solid is ~73 wt% due to residual inorganics (NaCl): ‘H NMR (CD₃OD, 500 MHz): δ 3.30 (s, 3H), 4.46 (s, 2H).

Step 4

3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (1): A mixture of 3- (Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (54 g, at 73wt%, 307 mmol) in ethyl acetate (540 mL) was stirred at 45 °C. SOCI2 (26.9 mL, 369 mmol) was added over 30-45 min and aged at 50 °C for 2h. Monitor reaction progress by HPLC. On complete reaction (>99.5% by area at 210nm.), the warm suspension was filtered and the filter cake (mainly NaCl) was washed with ethyl acetate (108 mL). The combined filtrate and wash were concentrated at 50-60 °C under reduced pressure to approximately 150 mL. The resulting slurry was cooled to -10 °C and aged lh. The slurry was filtered and the filter cake washed with ethyl acetate (50 mL). The cake was dried under 2 sweep to afford 40. lg (86% yield) of the desired product as a bright yellow solid: ‘H NMR (CD₃OD, 500 MHz): δ 3.30 (s, 3H), 4.58 (s, 2H).

EXAMPLE 3

3-fluoro-4-(trifluoromethyl)pyridin-2(lH)-one (2): To a 250 ml round bottom flask equipped with overhead stirring and a nitrogen inlet was added a mixture of sulfuric acid (24.31 ml, 437 mmol) and water (20.00 ml). To this was added 2,3-difluoro-4-(trifluoromethyl)pyridine (6.83 ml, 54.6 mmol) and the mixture was heated to 65 °C and stirred for 4 h. By this time the reaction was complete, and the mixture was cooled to room temperature. To the flask was slowly added 5M sodium hydroxide (43.7 ml, 218 mmol), maintaining room temperature with an ice bath. The title compound precipitates as a white solid during addition. Stirring was maintained for an additional lh after addition. At this time, the mixture was filtered, the filter cake washed with 20 mL water, and the resulting white solids dried under nitrogen. 3-fluoro-4- (trifluoromethyl)pyridin-2(lH)-one (2) was obtained as a white crystalline solid (9.4g, 51.9 mmol, 95 % yield): ¾ NMR (CDC1₃, 400 MHz): 12.97 (br s, 1H), 7.36 (d, 1H), 6.44 (m, 1H).

EXAMPLE 4

Step 1 – Ethyl Ester Synthesis Experimental Procedure;

Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (A): A 1L round bottom flask equipped with overhead stirring was charged with 3-chloro-5-hydroxybenzonitrile (50.0 g, 98 wt% purity, 319 mmol) and 15% aqueous DMF (200 mL DMF + 35.5 mL FLO). To the resulting solution was added diisopropylethylamine (61.3 mL, 99.0% purity, 1.1 equiv) and ethyl 2-bromoacetate (35.7 g, 98% purity, 1.15 equiv) at ambient temperature. The resulting solution was warmed to 50°C under nitrogen and aged for 12 h. Upon completion of the reaction the batch was cooled to 0- 5°C. To the clear to slightly cloudy solution was added 5% seed (3.8g, 16.0 mmol). H₂0 (64.5mL) was added to the thin suspension via syringe pump over 3h while maintaining the temp at 0-5 °C. Additional FLO (200mL) was added over lh while maintaining the temp at 0-5 °C. The final DMF/FLO ratio is 1 : 1.5 (10 vol). The resulting slurry was typically aged lh at 0-5 °C. The batch was filtered and the cake slurry washed with 2: 1 DMF/water (150 mL, 3 vol), followed by water (200 mL, 4 vol). The wet cake was dried on the frit with suction under a nitrogen stream at 20-25 °C; note: heat must not be applied during drying as product mp is 42 °C. The cake is considered dry when H₂0 is <0.2%. Obtained 73.4 g ethyl ester as a light tan solid, 96% yield (corrected), 99.5 LCAP: ^XH NMR (CDC1₃, 400 MHz) δ = 7.29 (s, 1H), 7.15 (s, 1H), 7.06 (s, 1H), 4.67 (s, 2H), 4.32 (q, 2H), 1.35 (t, 3H) ppm. Step 2 – Pyridone Synthesis

Synthetic Scheme; batch

TEA, TFAA, 10 °C;

then MeOH, rt

[isolated solid, A] [PhMe exit stream, B]

[PhMe/MeOH solution, C] [PhMe/MeOH/NH₃ solution, D] [isolated solid, E]

Experimental Procedures;

Aldol Condensation, Ester A to Diene C

(2E/Z,4E)-Ethyl 2-(3-chloro-5-cyanophenoxy)-5-ethoxy-3-(trifluoromethyl)penta-2,4- dienoate (C): Ester A (25.01 g, 104.4 mmol, 1.00 equiv) was charged to toluene (113.43 g, 131 mL, 5.24 vol) and 4-ethoxy-l, l, l-trifluoro-3-buten-2-one (26.43 g, 157.2 mmol, 1.51 equiv) was added.

The flow reactor consisted of two feed solution inlets and an outlet to a receiving vessel. The flow reactor schematic is shown in Figure 1.

The ester solution was pumped to one flow reactor inlet. Potassium tert-pentoxide solution was pumped to the second reactor inlet. Trifluoroacetic anhydride was added continuously to the receiver vessel. Triethylamine was added continuously to the receiver vessel. The flow rates were: 13 mL/min ester solution, 7.8 mL/min potassium tert-pentoxide solution, 3.3 mL/min trifluoroacetic anhydride and 4.35 mL/min triethylamine.

Charged toluene (50 mL, 2 vol) and potassium trifluoroacetate (0.64 g, 4.21 mmol, 0.04 equiv) to the receiver vessel. The flow reactor was submerged in a -10 °C bath and the pumps were turned on. The batch temperature in the receiver vessel was maintained at 5 to 10 °C throughout the run using a dry ice/acetone bath. After 13.5 min the ester solution was consumed, the reactor was flushed with toluene (10 mL) and the pumps were turned off.

The resulting yellow slurry was warmed to room temperature and aged for 4.5 h. Charged methanol (160 mL) to afford a homogeneous solution which contained 81.20 area percent diene C by HPLC analysis.

The solution of diene C (573 mL) was used without purification in the subsequent reaction. Cyclization, Diene C to E

3-Chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (E): To a solution of diene C in PhMe/MeOH (573 mL; 40.69 g, 104.4 mmol theoretical C) was charged methanol (25 mL, 0.61 vol). Ammonia (32 g, 1.88 mol, 18 equiv based on theoretical C) was added and the solution was warmed to 60 °C. The reaction was aged at 60 °C for 18 h. The temperature was adjusted to 35-45 °C and the pressure was decreased maintain a productive distillation rate. The batch volume was reduced to -300 mL and methanol (325 mL, 8 vol) was charged in portions to maintain a batch volume between 250 and 350 mL. The heating was stopped and the system vented. The resulting slurry was cooled to room temperature and aged overnight.

The batch was filtered and the cake washed with methanol (3x, 45 mL). The wet cake was dried on the frit with suction under a nitrogen stream to afford 18.54 g of a white solid: ^XH NMR (DMSO-i/₆, 500 MHz): δ 12.7 (br s, 1H), 7.73 (t, 1H, J= 1.5 Hz), 7.61-7.59 (m, 2H), 7.53 (t, 1H, J= 2.0 Hz), 6.48 (d, 1H, J= 7.0 Hz) ppm.

Step 3 – Chlorination, Alkylation and Isolation of 3-Chloro-5-({l-[(4-methyl-5-oxo-4,5-dihydro- lH-l,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile

3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 3-(Hydroxymethyl)-4-methyl-lH- l,2,4-triazol-5(4H)-one (1.638 kg of 68wt%, 8.625 mol) and N-methylpyrrolidinone (8.9 L) was charged into a 30 L vessel. The suspension was aged for lOh at ambient temperature. The slurry was filtered through a 4L sintered glass funnel under 2 and the filter cake (mainly NaCl) was washed with NMP (2.23 L). The combined filtrate and wash had a water content of 5750 μg/mL. The solution was charged to a 75L flask equipped with a 2N NaOH scrubber to capture off-gasing vapors. Thionyl chloride (0.795 L, 10.89 mol) was added over lh and the temperature rose to 35 °C. HPLC analysis indicated that the reaction required an additional thionyl chloride charge (0.064 L, 0.878 mol) to bring to full conversion. The solution was warmed to 50 °C, placed under vacuum at 60 Torr (vented to a 2N NaOH scrubber), and gently sparged with subsurface N2 (4 L/min). The degassing continued for lOh until the sulfur dioxide content in the solution was <5 mg/mL as determined by quantitative GC/MS. The tan solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP weighed 13.0 kg and was assayed at 9.63 wt% providing 1.256 kg (97% yield).

3-chloro-5-((l-((4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)-2-oxo-4- (trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile: To a 75L flask was charged a 9.63wt% solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP (1 1.6 kg, 7.55 mol), 3 -chloro-5 -((2-oxo-4-(trifluoromethyl)- 1 ,2-dihydropyridin-3 -yl)oxy)benzonitrile (2.00 kg, 6.29 mol), NMP (3.8 L) and 2-methyl-2-butanol (6.0 L). To the resulting suspension was slowly added N,N-diisopropylethylamine (4.38 L, 25.2 mol) over 4h. The reaction was aged 18h at ambient temperature. The reaction is considered complete when HPLC indicates <1% 3 -chloro-5 -((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile remaining. The tan solution was quenched with acetic acid (1.26 L, 22.0 mol) and aged at ambient temperature overnight. The tan solution was warmed to 70 °C. Water (2.52 L) was added and the batch was seed with anhydrate Form II (134 g). The thin suspension was aged lh at 70 °C. Additional water (14.3 L) was added evenly over 7 h. The slurry was aged 2h at 70 °C and then slowly cooled to 20 °C over 5 h. The slurry was filtered and washed with 2 : 1 NMP/water (6 L), followed by water washes (6 L x 2). The filter cake was dried over a 2 sweep to give 2.53 kg (85% yield – corrected) of a white solid that was confirmed to be crystalline Form II by X-ray powder detraction analysis.

PATENT

WO 2015084763

The following scheme is an example of Step 3A.

EXAMPLE 1

Step 1

_{c| 0}. h CH3NH3 Me._NA₀.Ph

The slurry was filtered, washed with water (500 mL) and dried under a nitrogen sweep overnight to afford 465g (96% yield) of the desired product as a white crystalline solid; ^XH NMR (CDCI₃, 500 MHz): δ 7.35 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 4.95 (br s, 1H), 2.90 (d, J = 5 Hz, 3H).

Step 2

Part B: On complete reaction (>99% conversion by HPLC), IPA (810 mL) and glycolic acid (222 g, 2.92 mol) were added and the mixture stirred at 83-85 °C for 10-12 h. The reaction mixture was initially a clear colorless solution. The mixture was seeded with product (0.5 g) after 4h at 83-85 °C. The slurry was slowly cooled to 20 °C over 2h and aged for lh. Seed was used to advance the crystallization, but the crystalline product can be precipitated and isolated without seed by allowing the solution to age at 83-85 °C for 4 hours.

The slurry was filtered and washed with IPA (600 mL). The cake was dried under a nitrogen sweep to afford 241.8g (81% yield) of the desired product as a white crystalline solid: ^XH NMR (D₂0, 500 MHz): δ 4.11 (s, 2H), 2.60 (s, 3H).

Step 3

azeotropically removed under vacuum at 40-50 °C by reducing the volume to -400 mL and maintaining that volume by the slow addition of n-propanol (780 mL). The final water content was <3000 ug/mL. The resultant slurry (~ 400 mL) was cooled to 23 °C and heptane (390 ml) was added. The slurry was aged lh at 23 °C, cooled to 0 °C and aged 2h. The slurry was filtered, the cake washed with 1 :2 n-PrOH/heptane (100 mL) and the filter cake was dried under a nitrogen sweep to provide 125g (85% yield) of an off-white crystalline solid. The solid was -73 wt% due to residual inorganics (NaCl): ¾ NMR (CD₃OD, 500 MHz): δ 3.30 (s, 3H), 4.46 (s, 2H).

Step 4

3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (1): A mixture of 3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (54 g, at 73wt%, 307 mmol) in ethyl acetate (540 mL) was stirred at 45 °C. SOCl₂ (26.9 mL, 369 mmol) was added over 30-45 min and aged at 50 °C for 2h. The reaction progress was monitored by HPLC. On complete reaction (>99.5% by area at 210nm), the warm suspension was filtered and the filter cake (mainly NaCl) was washed with ethyl acetate (108 mL). The combined filtrate and wash were concentrated at 50-60 °C under reduced pressure to approximately 150 mL. The resulting slurry was cooled to – 10 °C and aged lh. The slurry was filtered and the filter cake washed with ethyl acetate (50 mL). The cake was dried under a nitrogen sweep to afford 40. lg (86% yield) of the desired product as a bright yellow solid: ^XH NMR (CD₃OD, 500 MHz): δ 3.30 (s, 3H), 4.58 (s, 2H).

EXAMPLE 2

Step 1 – Ethyl Ester Synthesis

Experimental Procedure;

Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (A): A 1L round bottom flask equipped with overhead stirring was charged with 3-chloro-5-hydroxybenzonitrile (50.0 g, 98 wt% purity, 319 mmol) and 15% aqueous DMF (200 mL DMF + 35.5 mL Η₂0). To the resulting solution was added diisopropylethylamine (61.3 mL, 99.0% purity, 1.1 equiv) and ethyl 2-bromoacetate (35.7 g, 98% purity, 1.15 equiv) at ambient temperature. The resulting solution was warmed to 50°C under nitrogen and aged for 12 h. Upon completion of the reaction the batch was cooled to 0-5°C. To the clear to slightly cloudy solution was added 5% seed (3.8g, 16.0 mmol). H₂0 (64.5mL) was added to the thin suspension via syringe pump over 3h while maintaining the temperature at 0-5 °C. Additional H₂0 (200mL) was added over lh while maintaining the temp at 0-5 °C. The final DMF/H₂0 ratio is 1 : 1.5. The resulting slurry was aged lh at 0-5 °C. The batch was filtered and the cake slurry washed with 2: 1 DMF/water (150 mL), followed by water (200 mL). The wet cake was dried on the frit with suction under a nitrogen stream at 20-25 °C. The cake is considered dry when H₂0 is <0.2%. Obtained 73.4 g ethyl ester as a light tan solid, 96% yield: ^XH NMR (CDC1₃, 400 MHz) δ = 7.29 (s, 1H), 7.15 (s, 1H), 7.06 (s, 1H), 4.67 (s, 2H), 4.32 (q, 2H), 1.35 (t, 3H) ppm. Seed was used to advance the crystallization, but the crystalline product can be precipitated and isolated without seed by allowing the solution to age at 0-5 °C for at least about 2 hours.

Step 2 – Pyridone Synthesis

Synthetic Scheme;

Experimental Procedures;

Aldol Condensation

(2E/Z,4E)-Ethyl 2-(3-chloro-5-cyanophenoxy)-5-ethoxy-3-(trifluoromethyl)penta-2,4-dienoate (C): Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (25.01 g, 104.4 mmol, 1.00 equiv) was charged to toluene (113.43 g, 131 mL) and 4-ethoxy-l, l,l-trifluoro-3-buten-2-one (26.43 g, 157.2 mmol, 1.51 equiv) was added.

The flow reactor consisted of two feed solution inlets and an outlet to a receiving vessel. The flow reactor schematic is shown in Figure 1.

The ester solution was pumped to one flow reactor inlet. Potassium tert-amylate solution was pumped to the second reactor inlet. Trifluoroacetic anhydride was added continuously to the receiver vessel. Triethylamine was added continuously to the receiver vessel.

The flow rates were: 13 mL/min ester solution, 7.8 mL/min potassium tert-amylate solution, 3.3 mL/min trifluoroacetic anhydride and 4.35 mL/min triethylamine.

Charged toluene (50 mL) and potassium trifluoroacetate (0.64 g, 4.21 mmol, 0.04 equiv) to the receiver vessel. The flow reactor was submerged in a -10 °C bath and the pumps were turned on. The batch temperature in the receiver vessel was maintained at 5 to 10 °C throughout the run using a dry ice/acetone bath. After 13.5 min the ester solution was consumed, the reactor was flushed with toluene (10 mL) and the pumps were turned off.

The resulting yellow slurry was warmed to room temperature and aged for 4.5 h. Charged methanol (160 mL) to afford a homogeneous solution which contained 81.20 LCAP diene .

The solution of diene (573 mL) was used without purification in the subsequent reaction.

Cyclization

3-Chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (E): To a solution of diene in PhMe/MeOH (573 mL; 40.69 g, 104.4 mmol theoretical) was charged methanol (25 mL). Ammonia (32 g, 1.88 mol, 18 equiv based on theoretical) was added and the solution was warmed to 60 °C. The reaction was aged at 60 °C for 18 h. The temperature was adjusted to 35-45 °C and the pressure was decreased to maintain a productive distillation rate. The batch volume was reduced to -300 mL and methanol (325 mL) was charged in portions to maintain a batch volume between 250 and 350 mL. The heating was stopped and the system vented. The resulting slurry was cooled to room temperature and aged overnight.

The batch was filtered and the cake washed with methanol (3x, 45 mL). The wet cake was dried on the frit with suction under a nitrogen stream to afford 18.54 g of a white solid: ^XH NMR (DMSO-ifc, 500 MHz): δ 12.7 (br s, 1H), 7.73 (t, 1H, J= 1.5 Hz), 7.61-7.59 (m, 2H), 7.53 (t, 1H, J= 2.0 Hz), 6.48 (d, 1H, J= 7.0 Hz) ppm.

Step 3 – Chlorination, Alkylation and Isolation of 3-Chloro-5-({l-[(4-methyl-5-oxo-‘ dihydro-lH-l,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl}oxy)benzonitrile

3-(Chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one: 3-(Hydroxymethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one (1.638 kg of 68wt%, 8.625 mol) and N-methylpyrrolidinone (8.9 L) was charged into a 30 L vessel. The suspension was aged for lOh at ambient temperature. The slurry was filtered through a 4L sintered glass funnel under 2 and the filter cake (mainly NaCl) was washed with NMP (2.23 L). The combined filtrate and wash had a water content of 5750 μg/mL. The solution was charged to a 75L flask equipped with a 2N NaOH scrubber to capture off-gasing vapors. Thionyl chloride (0.795 L, 10.89 mol) was added over lh and the temperature rose to 35 °C. HPLC analysis indicated that the reaction required an additional thionyl chloride charge (0.064 L, 0.878 mol) to bring to full conversion. The solution was warmed to 50 °C, placed under vacuum at 60 Torr (vented to a 2N NaOH scrubber), and gently sparged with subsurface nitrogen (4 L/min). The degassing continued for lOh until the sulfur dioxide content in the solution was <5 mg/mL as determined by quantitative GC/MS. The tan solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP weighed 13.0 kg and was assayed at 9.63 wt% providing 1.256 kg (97% yield).

3-chloro-5-((l-((4-methyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile: To a 75L flask was charged a 9.63wt% solution of 3-(chloromethyl)-4-methyl-lH-l,2,4-triazol-5(4H)-one in NMP (1 1.6 kg, 7.55 mol), 3-chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile (2.00 kg, 6.29 mol), NMP (3.8 L) and 2-methyl-2-butanol (6.0 L). To the resulting suspension was slowly added N,N-diisopropylethylamine (4.38 L, 25.2 mol) over 4h. The reaction was aged 18h at ambient temperature. The reaction is considered complete when HPLC indicated <1% 3-chloro-5-((2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)oxy)benzonitrile remaining. The tan solution was quenched with acetic acid (1.26 L, 22.0 mol) and aged at ambient temperature overnight. The tan solution was warmed to 70 °C. Water (2.52 L) was added and the batch was seeded with anhydrate Form II (134 g)(procedures for making anhydrate Form II are described in WO2014/052171). The thin suspension was aged lh at 70 °C. Additional water (14.3 L) was added evenly over 7 h. The slurry was aged 2h at 70 °C and then slowly cooled to 20 °C over 5 h. The slurry was filtered and washed with 2 : 1 NMP/water (6 L), followed by water washes (6 L x 2). The filter cake was dried under N2 to give 2.53 kg (85% yield) of a white solid that was confirmed to be crystalline Form II of the title compound by X-ray powder detraction analysis.

EXAMPLE 3

Ethyl 2-(3-chloro-5-cyanophenoxy)acetate (A):

70%

Step 3

Three step one pot sequence

Steps 1 and 2:

To an oven dried 250mL round bottom flask was added sodium 2-methylpropan-2-olate (12.85 g, 134 mmol) and BHT (0.641 g, 2.91 mmol) then added DMF (30mL). After lOmin, a light yellow solution resulted. 2-Phenylethanol (7.66 ml, 63.9 mmol) was added and the solution exothermed to 35 °C. The light yellow solution was warmed to 55 °C and then a solution of 3,5-dichlorobenzonitrile (10 g, 58.1 mmol) in DMF (15mL) was added over 2h via syringe pump. The resulting red-orange suspension was aged at 55-60 °C. After 2h, HPLC showed >98% conversion to the sodium phenolate.

Step 3:

The suspension was cooled to 10 °C, then ethyl 2-bromoacetate (8.70 ml, 78 mmol) was added over lh while maintaining the temperature <20 °C. The resulting mixture was aged at ambient temperature. After lh, HPLC showed >99% conversion to the title compound.

Work-up and isolation:

To the suspension was added MTBE (50mL) and H₂0 (50mL) and the layers were separated. The organic layer was washed with 20% aq brine (25mL). The organic layer was assayed at 12.5g (90% yield). The organic layer was concentrated to -38 mL, diluted with hexanes (12.5mL) and then cooled to 5 °C. The solution was seeded with 0.28g (2 wt%) of crystalline ethyl 2-(3-chloro-5-cyanophenoxy)acetate and aged 0.5h at 5 °C to give a free flowing slurry. Hexane (175mL) was added to the slurry over lh at 0-5 °C. The slurry was filtered at 0-5 °C, washed with hexane (50 mL) and dried under a nitrogen sweep to give 9.8g (70% yield) of the title compound as a white crystalline solid. Seed was used to advance the crystallization, but the crystalline product can be precipitated and isolated without seed by allowing the solution to age at 0-5 °C for at least about 2 hours.

Paper

Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses
Bioorg Med Chem Lett 2014, 24(3): 917

http://www.sciencedirect.com/science/article/pii/S0960894X13014546

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.

Full-size image (16 K)

Full-size image (10 K)

Scheme 1.

Reagents and conditions: (a) K₂CO₃, NMP, 120 °C; (b) KOH, tert-BuOH, 75 °C; (c) Zn(CN)₂, Pd(PPh₃)₄, DMF, 100 °C.

Scheme 3.

Reagents and conditions: (a) K₂CO₃, DMF, −10 °C; (b) MeI or EtI, K₂CO₃, DMF.

36 IS DORAVIRINE

PATENT

WO 2011120133

http://www.google.com/patents/WO2011120133A1?cl=en

Scheme I depicts a method for preparing compounds of Formula I in which hydroxypyridine 1-1 is alkylated with chlorotriazolinone 1-2 to provide 1-3 which can be selectively alkylated with an alkyl halide (e.g., methyl iodide, ethyl iodide, etc.) to afford the desired 1-4. Scheme I

Scheme II depicts an alternative route to compounds of the present invention, wherein fluorohydroxypyridine II-l can be alkylated with chlorotriazolinone II-2 to provide the alkylated product II-3 which can be converted to the desired II-5 via nucleophilic aromatic substitution (S] fAr) using a suitable hydroxyarene II-4.

Scheme II

Hydroxypyridines of formula I-l (Scheme 1) can be prepared in accordance with Scheme III, wherein a SNAr reaction between pyridine III-l (such as commercially available 2- chloro-3-fluoro-4-(trifluoromethyl)pyridine) and hydroxyarene H-4 can provide chloropyridine III-2, which can be hydrolyzed under basic conditions to the hydroxypyridine I-l. Scheme III

Another method for preparing hydroxypyridines of formula I-l is exemplified in Scheme IV, wherein S Ar coupling of commercially available 2-chloro-3-fluoro-4- nitropyridone-N-oxide IV-1 with a suitable hydroxyarene II-4 provides N-oxide IV-2, which can first be converted to dihalides IV-3 and then hydro lyzed to hydroxypyridine IV-4. Further derivatization of hydroxypyridine IV-4 is possible through transition metal-catalyzed coupling processes, such as Stille or boronic acid couplings using a PdL_n catalyst (wherein L is a ligand such as triphenylphosphine, tri-tert-butylphosphine or xantphos) to form hydroxypyridines IV-5, or amination chemistry to form hydroxypyridines IV-6 in which R2 is N(RA)RB.

Scheme IV

IV-1

– – Scheme V depicts the introduction of substitution at the five-position of the hydroxypyridines via bromination, and subsequent transition metal-catalyzed chemistries, such as Stille or boronic acid couplings using PdL_n in which L is as defined in Scheme IV to form hydroxypyridines V-3, or amination chemistry to form hydroxypyridines V-4 in which R3 is N(RA)RB.

Scheme V

As shown in Scheme IV, fiuorohydroxypyridines II-l (Scheme II) are available from the commercially available 3-fluoroypridines VI- 1 through N-oxide formation and rearrangement as described in Konno et al., Heterocycles 1986, vol. 24, p. 2169.

Scheme VI

The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention.

The term “room temperature” in the examples refers to the ambient temperature which was typically in the range of about 20°C to about 26°C.

EXAMPLE 1

3-Chloro-5-({ l-[(4-methyl-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-3-yl)methyl]-2-oxo-4- (trifluoromethyl)-l ,2-dihydropyridin-3-yl}oxy)benzonitrile (1-1)

Step 1(a):

A mixture of the 3-bromo-5-chlorophenol (3.74 g; 18.0 mmol), 2-chloro-3-fluoro- 4-(trifluoromethyl)pyridine (3.00 g; 15.0 mmol) and 2CO3 (2.49 g; 18.0 mmol) in NMP (15 mL) was heated to 120°C for one hour, then cooled to room temperature. The mixture was then diluted with 250 mL EtOAc and washed with 3 x 250 mL 1 :1 H20:brine. The organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by ISCO CombiFlash (120 g column; load with toluene; 100:0 to 0:100 hexanes:CH2Cl2 over 40 minutes) provided title compound (1-2) as a white solid. Repurification of the mixed fractions provided additional title compound. lH NMR (400 MHz, CDCI3): δ 8.55 (d, J = 5.0 Hz, 1 H); 7.64 (d, J = 5.0 Hz, 1 H);

7.30 (s, 1 H); 6.88 (s, 1 H); 6.77 (s, 1 H).

3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2-ol (1-3)

To a suspension of 3-(3-bromo-5-chlorophenoxy)-2-chloro-4- (trifluoromethyl)pyridine (1-2; 3.48 g; 8.99 mmol) in ^lBuOH (36 mL) was added KOH (1.51 g; 27.0 mmol) and the mixture was heated to 75°C overnight, at which point a yellow oily solid had precipitated from solution, and LCMS analysis indicated complete conversion. The mixture was cooled to room temperature, and neutralized by the addition of -50 mL saturated aqueous NH4CI. The mixture was diluted with 50 mL H2O, then extracted with 2 x 100 mL EtOAc. The combined organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by ISCO CombiFlash (120 g column; dry load; 100:0 to 90: 10 CH2Cl2:MeOH over 40 minutes) provided the title compound (1-3) as a fluffy white solid. lH NMR (400 MHz, DMSO): δ 12.69 (s, 1 H); 7.59 (d, J = 6.9 Hz, 1 H); 7.43 (t, J = 1.7 Hz, 1 H); 7.20 (t, J = 1.9 Hz, 1 H); 7.13 (t, J = 2.0 Hz, 1 H); 6.48 (d, J = 6.9 Hz, 1 H).

3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile (1-4)

To a suspension of 3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2-ol (1-3; 3.25 g; 8.82 mmol) in NMP (29 mL) was added CuCN (7.90 g; 88 mmol) and the mixture was heated to 175°C for 5 hours, then cooled to room temperature slowly. With increased fumehood ventilation, 100 mL glacial AcOH was added, then 100 mL EtOAc and the mixture was filtered through Celite (EtOAc rinse). The filtrate was washed with 3 x 200 mL 1 : 1 H20:brine, then the organic extracts were dried (Na2S04) and concentrated in vacuo.

Purification by ISCO CombiFlash (120 g column; dry load; 100:0 to 90:10 CH2Cl2:MeOH over 40 minutes), then trituration of the derived solid with Et20 (to remove residual NMP which had co-eluted with the product) provided the title compound (1-4). lH NMR (400 MHz, DMSO): δ 12.71 (s, 1 H); 7.75 (s, 1 H); 7.63-7.57 (m, 2 H); 7.54 (s, 1 H); 6.49 (d, J = 6.9 Hz, 1 H).

Step 1(d): 5-(chloromethyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (1-5)

The title compound was prepared as described in the literature: Cowden, C. J.; Wilson, R. D.; Bishop, B. C; Cottrell, I. F.; Davies, A. J.; Dolling, U.-H. Tetrahedron Lett. 2000, 47, 8661.

3 -chloro-5 -( { 2-oxo- 1 – [(5 -oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 -yl)methyl] – 4- (trifiuoromethyl)- 1 ,2-dihydropyridin-3 -yl } oxy)benzonitrile (1-6)

A suspension of the 3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3- yl]oxy}benzonitrile (1-4; 2.00 g; 6.36 mmol), 5-(chloromethyl)-2,4-dihydro-3H-l,2,4-triazol-3- one (1-5; 0.849 g; 6.36 mmol) and K2CO3 (0.878 g; 6.36 mmol) in DMF (32 mL) was stirred for 2 hours at room temperature, at which point LCMS analysis indicated complete conversion. The mixture was diluted with 200 mL Me-THF and washed with 150 mL 1 : 1 : 1 H20:brine:saturated aqueous NH4CI, then further washed with 2 x 150 mL 1 : 1 H20:brine. The aqueous fractions were further extracted with 150 mL Me-THF, then the combined organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by ISCO CombiFlash (80 g column; dry load; 100:0 to 90:10 EtOAc:EtOH over 25 minutes) provided the title compound (1-6) as a white solid. lH NMR (400 MHz, DMSO): δ 1 1.46 (s, 1 H); 1 1.39 (s, 1 H); 7.93 (d, J = 7.3 Hz, 1 H); 7.76 (s, 1 H); 7.58 (s, 1 H); 7.51 (s, 1 H); 6.67 (d, J = 7.3 Hz, 1 H); 5.02 (s, 2 H).

Step 1(f): 3 -chloro-5 -( { 1 – [(4-methyl-5-oxo-4,5 -dihydro- 1 H- 1 ,2,4-triazol-3 -yl)methyl] -2- oxo-4-(trifluoromethyl)- 1 ,2-dihydropyridin-3 -yl } oxy)benzonitrile (1 -1 )

A solution of 3-chloro-5-({2-oxo-l -[(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl)methyl]- 4-(trifluoromethyl)-l ,2-dihydropyridin-3-yl}oxy)benzonitrile (1-6; 2.37 g; 5.76 mmol) and K2CO3 (0.796 g; 5.76 mmol) in DMF (58 mL) was cooled to 0°C, then methyl iodide (0.360 mL; 5.76 mmol) was added. The mixture was allowed to warm to room

temperature, and stirred for 90 minutes, at which point LCMS analysis indicated >95%

conversion, and the desired product of -75% LCAP purity, with the remainder being unreacted starting material and 6/s-methylation products. The mixture was diluted with 200 mL Me-THF, and washed with 3 x 200 mL 1 : 1 H20:brine. The aqueous fractions were further extracted with 200 mL Me-THF, then the combined organic extracts were dried (Na2S04) and concentrated in vacuo. The resulting white solid was first triturated with 100 mL EtOAc, then with 50 mL THF, which provided (after drying) the title compound (1-1) of >95% LCAP. Purification to >99% LCAP is possible using Prep LCMS (Max-RP, 100 x 30 mm column; 30-60% CH₃CN in 0.6% aqueous HCOOH over 8.3 min; 25 mL/min). lH NMR (400 MHz, DMSO): δ 1 1.69 (s, 1 H); 7.88 (d, J = 7.3 Hz, 1 H); 7.75 (s, 1 H); 7.62 (s, 1 H); 7.54 (s, 1 H); 6.67 (d, J = 7.3 Hz, 1 H); 5.17 (s, 2 H); 3.1 1 (s, 3 H). EXAMPLE 1A

3-Chloro-5-({ l-[(4-methyl-5-oxo-4,5-dihydro-lH-l ,2,4-triazol-3-yl)methyl]-2- (trifluoromethyl)-l ,2-dihydropyridin-3-yl}oxy)benzonitrile (1-1)

Step lA(a): 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine (1A-2)

A mixture of the 3-chloro-l-iodophenol (208 g; 816.0 mmol), 2-chloro-3-fluoro-

4-(trifluoromethyl)pyridine (155 g; 777.0 mmol) and K2CO3 (161 g; 1 165.0 mmol) in NMP (1.5 L) was held at 60°C for 2.5 hours, and then left at room temperature for 2 days. The mixture was then re-heated to 60°C for 3 hours, then cooled to room temperature. The mixture was then diluted with 4 L EtOAc and washed with 2 L water + 1 L brine. The combined organics were then washed 2x with 500 mL half brine then 500 mL brine, dried over MgS04 and concentrated to afford crude 1A-2. lH NMR (500 MHz, DMSO) δ 8.67 (d, J = 5.0 Hz, 1 H), 7.98 (d, J = 5.0 Hz, 1 H), 7.63-7.62 (m, 1 H), 7.42-7.40 (m, 1 H), 7.22 (t, J = 2.1 Hz, 1 H).

Step lA(b): 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine (1A-3)

To a suspension of 3-(3-chloro-5-iodophenoxy)-2-chloro-4- (trifluoromethyl)pyridine (1A-2; 421 g, 970 mmol) in t-BuOH (1 L) was added KOH (272 g, 4850 mmol) and the mixture was heated to 75°C for 1 hour, at which point HPLC analysis indicated >95% conversion. The t-BuOH was evaporated and the mixture diluted with water (7mL/g, 2.4L) and then cooled to 0°C, after which 12N HC1 (~240mL) was added until pH 5. This mixture was then extracted with EtOAc (20mL/g, 6.5L), back extracted with EtOAc 1 x 5mL/g (1.5L), washed 1 x water:brine 1 : 1 (l OmL/g, 3.2L), 1 x brine (lOmL/g, 3.2L), dried over MgS04, filtered and concentrated to afford a crude proudct. The crude product was suspended in MTBE (2.25 L, 7mL/g), after which hexanes (1 L, 3 mL/g) was added to the suspension over ten minutes, and the mixturen was aged 30minutes at room temperature. The product was filtered on a Buchner, rinsed with MTBE hexanes 1 :2 (2 mL/g = 640 mL), then hexanes

(640mL), and dried on frit to afford 1A-3. lH NMR (400 MHz, acetone-d6): δ 11.52 (s, 1 H); 7.63 (d, J = 7.01 Hz, 1 H); 7.50-7.48 (m, 1 H); 7.34-7.32 (m, 1 H); 7.09-7.07 (m, 1 H); 6.48 (d, J = 7.01 Hz, 1 H).

Step lA(c): 3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile (1-4)

A solution of 3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridin-2-ol (1A-3; 190 g; 457 mmol) in DMF (914 mL) was degassed for 20 minutes by bubbling N2, after which CuCN (73.7 g; 823 mmol) was added, and then the mixture was degassed an additional 5 minutes. The mixture was then heated to 120°C for 17 hours, then cooled to room temperature and partitioned between 6 L MeTHF and 2 L ammonium buffer (4:3: 1 = NH4CI

sat/water/NH-iOH 30%). The organic layer washed with 2 L buffer, 1 L buffer and 1 L brine then, dried over MgS04 and concentrated. The crude solid was then stirred in 2.2 L of refluxing

MeCN for 45 minutes, then cooled in a bath to room temperature over 1 hour, aged 30 minutes, then filtered and rinsed with cold MeCN (2 x 400mL). The solid was dried on frit under N2 atm for 60 hours to afford title compound 1-4. lH NMR (400 MHz, DMSO): δ 12.71 (s, 1 H); 7.75 (s, 1 H); 7.63-7.57 (m, 2 H); 7.54 (s, 1 H); 6.49 (d, J = 6.9 Hz, 1 H).

Steps lA(d) and lA(e)

The title compound 1-1 was then prepared from compound 1-4 using procedures similar to those described in Steps 1(d) and 1(e) set forth above in Example 1.

Patent

WO-2014052171

Crystalline anhydrous Form II of doravirine, useful for the treatment of HIV-1 and HIV-2 infections. The compound was originally claimed in WO2008076223. Also see WO2011120133. Merck & Co is developing doravirine (MK-1439), for the oral tablet treatment of HIV-1 infection. As of April 2014, the drug is in Phase 2 trials.

CLIPS

The next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine (formerly MK-1439) showed potent antiretroviral activity and good tolerability in combination with tenofovir/FTC (the drugs in Truvada) in a dose-finding study presented at the 21stConference on Retroviruses and Opportunistic Infections (CROI) last week in Boston.

NNRTIs are generally well tolerated and well suited for first-line HIV treatment, but as a class they are susceptible to resistance. Pre-clinical studies showed that Merck’s doravirine has a distinct resistance profile and remains active against HIV with common NNRTI resistance mutations including K103N and Y181C.

As reported at last year’s CROI, doravirine reduced HIV viral load by about 1.3 log in a seven-day monotherapy study. Doravirine is processed by the CYP3A4 enzyme, but it is neither a CYP3A4 inducer nor inhibitor, so it is not expected to have major drug interaction concerns.

Javier Morales-Ramirez from Clinical Research Puerto Rico reported late-breaking findings from a phase 2b study evaluating the safety and efficacy of various doses of doravirine versus efavirenz (Sustiva) for initial antiretroviral therapy.

This study included 208 treatment-naive people living with HIV from North America, Europe and Asia. More than 90% were men, 74% were white, 20% were black and the median age was 35 years. At baseline, the median CD4 cell count was approximately 375 cells/mm³ and 13% had received an AIDS diagnosis. Study participants were stratified by whether their viral load was above (about 30%) or below 100,000 copies/ml; median HIV RNA was approximately 4.5 log₁₀.

Morales-Ramirez reported 24-week results from part 1 of the study, which will continue for a total of 96 weeks. In this part, participants were randomly allocated into five equal-sized arms receiving doravirine at doses of 25, 50, 100 or 200mg once daily, or else efavirenz once daily, all in combination with tenofovir/FTC.

At 24 weeks, 76.4% of participants taking doravirine had viral load below 40 copies/ml compared with 64.3% of people taking efavirenz. Response rates were similar across doravirine doses (25mg: 80.0%; 50mg: 76.2%; 100mg: 71.4%; 200mg: 78.0%). More than 80% of participants in all treatment arms reached the less stringent virological response threshold of <200 copies/ml.

Both doravirine and efavirenz worked better for people with lower pre-treatment viral load in an ad hoc analysis. For people with <100,000 copies/ml at baseline, response rates (<40 copies/ml) ranged from 83 to 89% with doravirine compared with 74% with efavirenz. For those with >100,000 copies/ml, response rates ranged from 50 to 91% with doravirine vs 54% with efavirenz.

Median CD4 cell gains were 137 cells/mm³ for all doravirine arms combined and 121 cells/mm³for the efavirenz arm.

Doravirine was generally safe and well tolerated. People taking doravirine were less than half as likely as people taking efavirenz to experience serious adverse events (3.0% across all doravirine arms vs 7.1% with efavirenz) or to stop treatment for this reason (2.4 vs 4.8%). Four people taking doravirine and two people taking efavirenz discontinued due to adverse events considered to be drug-related.

The most common side-effects were dizziness (3.6% with doravirine vs 23.8% with efavirenz), abnormal dreams (9.0 vs 7.1%), diarrhoea (4.8 vs 9.5%), nausea (7.8 vs 2.4%) and fatigue (6.6 vs 4.8%). Other central nervous system (CNS) adverse events of interest included insomnia (5.4 vs 7.1%), nightmares (1.2 vs 9.5%) and hallucinations (0.6 vs 2.4%). Overall, 20.5% of people taking doravirine reported at least one CNS side-effect, compared with 33.3% of people taking efavirenz.

People taking doravirine had more favourable lipid profiles and less frequent liver enzyme (ALT and AST) elevations compared with people taking efavirenz.

The researchers concluded that doravirine demonstrated potent antiretroviral activity in treatment-naive patients, a favourable safety and tolerability profile, and fewer drug-related adverse events compared with efavirenz.

Based on these findings, the 100mg once-daily dose was selected for future development and will be used in part 2 of this study, a dose-confirmation analysis that will enrol an additional 120 participants.

In the discussion following the presentation, Daniel Kuritzkes from Harvard Medical School noted that sometimes it takes longer for viral load to go down in people who start with a high level, so with further follow-up past 24 weeks doravirine may no longer look less effective in such individuals.

Reference

Morales-Ramirez J et al. Safety and antiviral effect of MK-1439, a novel NNRTI (+FTC/TDF) in ART-naive HIV-infected patients. 21^st Conference on Retroviruses and Opportunistic Infections, Boston, abstract 92LB, 2014.

Merck Moves Doravirine Into Phase 3 Clinical Trials

Wednesday Mar 19 | Posted by: roboblogger | Full story: EDGE

Earlier this month, at the 21st Conference on Retroviruses and Opportunistic Infections , Merck indicated plans to initiate a Phase 3 clinical trial program for doravirine in combination with ARV therapy in the second half of 2014.

PAPER

A Robust Kilo-Scale Synthesis of Doravirine

Louis-Charles Campeau^*^†^‡, Qinghao Chen^†, Danny Gauvreau^‡, Mélina Girardin^‡, Kevin Belyk^†, Peter Maligres^†,Guoyue Zhou^∥, Chaozhan Gu^∥, Wei Zhang^∥, Lushi Tan^†, and Paul D. O’Shea^‡

^† Process Research and Development, Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, New Jersey 07065,United States

^‡ Process Research and Development, Merck Frosst Center for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada

^∥ WuXi AppTec Co., Ltd., No. 1 Building, No. 288 FuTe ZhongLu, WaiGaoQiao Free Trade Zone, Shanghai 200131, China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00163, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00163

*E-mail: [email protected].

Doravirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in phase III clinical trials for the treatment of HIV infection. Herein we describe a robust kilo-scale synthesis for its manufacture. The structure and origin of major impurities were determined and their downstream fate-and-purge studied. This resulted in a redesign of the route to introduce the key nitrile functionality via a copper mediated cyanation which allowed all impurities to be controlled to an acceptable level. The improved synthesis was scaled to prepare ∼100 kg batches of doravirine to supply all preclinical and clinical studies up to phase III. The synthesis affords high-quality material in a longest linear sequence of six steps and 37% overall yield.

PAPER

Highly Efficient Synthesis of HIV NNRTI Doravirine

Donald R. GauthierJr.^*, Benjamin D. Sherry^*, Yang Cao, Michel Journet, Guy Humphrey, Tetsuji Itoh, Ian Mangion, and David M. Tschaen

Department of Process Chemistry, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States

Org. Lett., 2015, 17 (6), pp 1353–1356

DOI: 10.1021/ol503625z

Publication Date (Web): March 09, 2015

*E-mail: [email protected]., *E-mail: [email protected].

Gauthier, D. R., Jr.; Sherry, B. D.; Cao, Y.; Journet, M.; Humphrey, G.; Itoh, T.; Mangion, I.; Tschaen, D. M.Org. Lett. 2015, 17, 1353, DOI: 10.1021/ol503625z………..http://pubs.acs.org/doi/full/10.1021/ol503625z

http://pubs.acs.org/doi/pdf/10.1021/ol503625z

The development of an efficient and robust process for the production of HIV NNRTI doravirine is described. The synthesis features a continuous aldol reaction as part of a de novo synthesis of the key pyridone fragment. Conditions for the continuous flow aldol reaction were derived using microbatch snapshots of the flow process.

Doravirine (1). A 75 L flask was charged a 9.63 wt% solution of 16 in NMP (11.6kg, 7.55 mol). Charged 10(2.00 kg, 6.29 mol), NMP
(3.8 L) and 2-methyl-2-butanol (6.0 L). To theresulting suspension was slowly added N,N-diisopropylethylamine (4.38 L, 25.2 mol) over 4 h. The reaction was aged for 18 h at ambient temperature. The tan solution was quenched with acetic acid (1.26 L, 22.0 mol) and aged at ambient temperature overnight. The tan solution was warmed to 70 °C. Water (2.52 L) was added and the batch was seeded with crystalline 1 (134 g) to induce crystallization. The thin suspension was aged 1 h at 70 °C. Additional water (14.3 L)
was added over 7 h. The slurry was aged for 2 h at 70 °C and slowly cooled to 20 °C over 5 h. The slurry was filtered and washed with 2:1 NMP/water (6 L), followed by water (6 L x 2). The filter cake was dried under nitrogen to give 2.53 kg (85% yield) of 1 as a white solid.

Characterization Data : 1H NMR (DMSO-d6, 500 MHz): δ 3.11 (s,3H), 5.17 (s, 2H), 6.66 (d, 1H, J = 7.4 Hz), 7.52 (m, 1H), 7.61 (dd, 1H, J = 2.4, 1.3 Hz), 7.74 (dd, 1H, J = 1.8, 1.4Hz), 7.89 (d, 1H, J = 7.4 Hz), 11.68 (s, 1H) ppm.

13C NMR (DMSO-d6, 125.7 MHz): δ 26.7, 43.3, 100.2, 113.6,116.8, 118.4, 121.1, 121.6, 126.5, 129.9, 134.9, 137.3, 140.1, 143.2, 155.0, 156.0, 157.2 ppm.

19F NMR (DMSO-d6,470.5 MHz): δ -62.3 ppm.

HMRS (ESI) calcd for C17H12N5O3F3Cl [M+H]+ 426.0581, found 426.0588.

13C NMR

1H NMR

US20100034813 *	8 Nov 2007	11 Feb 2010	Yi Xia	Substituted pyrazole and triazole compounds as ksp inhibitors
US20100256181 *	14 Nov 2008	7 Oct 2010	Tucker Thomas J	Non-nucleoside reverse transcriptase inhibitors
US20110245296 *		6 Oct 2011	Jason Burch	Non-nucleoside reverse transcriptase inhibitors

Reference
1	*	COWDEN ET AL.: “A new synthesis of 1,2,4-triazolin-5-ones: application to the convergent synthesis of an NK1 antagonist.“, TETRAHEDRON LETTERS, vol. 41, no. 44, 2000, pages 8661 – 8664, XP004236142

Patent ID	Date	Patent Title
US2015329521	2015-11-19	PROCESS FOR MAKING REVERSE TRANSCRIPTASE INHIBITORS
US9150539	2015-10-06	Crystalline form of a reverse transcriptase inhibitor
US2015232447	2015-08-20	CRYSTALLINE FORM OF A REVERSE TRANSCRIPTASE INHIBITOR
US2013296382	2013-11-07	NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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References

Collins, Simon; Horn, Tim. “The Antiretroviral Pipeline.” (PDF). Pipeline Report. p. 10. Retrieved 6 December 2015.
Safety and Antiviral Activity of MK-1439, a Novel NNRTI, in Treatment-naïve HIV+ Patients. Gathe, Joseph et al. 20th Conference on Retroviruses and Opportunistic Infections. 3–6 March 2013. Abstract 100.
CROI 2013: MK-1439, a Novel HIV NNRTI, Shows Promise in Early Clinical Trials. Highleyman, Liz. HIVandHepatitis.com. 6 March 2013.

Doravirine
Systematic (IUPAC) name

3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydro-3-pyridinyl}oxy)benzonitrile
Clinical data
Routes of administration	Oral^[1]
Legal status
Legal status	Investigational New Drug
Identifiers
CAS Number	1338225-97-0
ATC code	none
PubChem	CID 58460047
ChemSpider	28424197
UNII	913P6LK81M
KEGG	D10624
ChEMBL	CHEMBL2364608
Synonyms	MK-1439
PDB ligand ID	2KW (PDBe, RCSB PDB)
Chemical data
Formula	C₁₇H₁₁ClF₃N₅O₃
Molar mass	425.75 g/mol

//////////Doravirine, MK-1439, 1338225-97-0 , Merck Sharp & Dohme Corp, Reverse transcriptase inhibitor, ANTIVIRAL, Non-nucleoside reverse transcriptase, HIV, Triazolinone, Pyridone, Inhibitor,

Supporting Info

AND

Supporting Info

Cn1c(n[nH]c1=O)Cn2ccc(c(c2=O)Oc3cc(cc(c3)Cl)C#N)C(F)(F)F

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

PATENTS, Uncategorized Comments Off

Jul 182016

New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd

FOR Cancer; Parasitic infection; Plasmodium falciparum infection; Viral infection

WO-2016110874

KUMAR, Ashok; (IN).
SINGH, Dharmendra; (IN).
MAURYA, Ghanshyam; (IN).
WAKCHAURE, Yogesh; (IN)

Dr. Ashok Kumar, President – Research and Development (Chemical) at IPCA LABORATORIES LTD

IPCA LABORATORIES LIMITED [IN/IN]; 48, Kandivli Industrial Estate, Charkop, Kandivali (West), Mumbai 400067 (IN)

Novel process for preparing artemisinin or its derivatives such as dihydroartemisinin, artemether, arteether and artesunate. Also claims novel intermediates of artemesinin such as artemisinic acid or dihydroartemisinic acid. Discloses the use of artemisinin or its derivatives, for treating malaria, cancer, viral and parasitic infections.

In July 2016, Newport Premium™ reported that IPCA was capable of producing commercial quantities of artemether, arteether and artesunate; and holds an inactive US DMF for artemether since February 2009. In July 2016, IPCA’s website lists artemether, arteether and artesunate under its products and also lists artemether and artesunate as having EDMF and WHO certificates. The assignee also has Canada HPFB certificate for artemether.

The Central Drug Research Institute (CDRI) in collaboration with IPCA is developing CDRI-97/78 (1,2,4 trioxane derivative), a synthetic artemisinin substitute for treating drug resistant Plasmodium falciparum infection. In July 2016, CDRI-97/78 was reported to be in phase 1 clinical development. IPCA in collaboration with CDRI was also investigating CDRI-99/411, a synthetic artemisinin substitute for treating malaria; but its development had been presumed to have been discontinued; however, this application’s publication would suggest otherwise.

Writeup

Artemisinin is an active phytoconstituent of Chinese medicinal herb Artemisia annua, useful for the treatment of malaria. Generally, artemisinin/artemisinic acid is obtained by extraction of the plant, Artemisia annua. The plant Artemisia annua was first mentioned in an ancient Chinese medicine book written on silk in the West Han Dynasty at around 200 B.C. The plant’s anti-malarial application was first described in a Chinese pharmacopeia, titled “Chinese Handbook of Prescriptions for Emergency Treatments,” written at around 340 A.D.

Artemisinin being poorly bioavailable limits its effectiveness. Therefore semisynthetic derivatives of artemisinin such as artesunate, dihydroartemisinin, artelinate, artemether, arteether have been developed to improve the bioavailability of Artemisinin.

Artemisinin and its derivatives – dihydroartemisinin, artemether, arteether, and artesunate being a class of antimalarials compounds used for the treatment of uncomplicated, severe complicated/cerebral and multi drug resistant malaria. Additionally, there are research findings that artemisinin and its derivatives show anti-parasite, anti-cancer, and anti-viral activities.

Dihydroartemisinin Artesunate

The content of Artemisinin in the plant Artemisia annua varies significantly according to the climate and region/geographical area where it is cultivated. Further, the extraction methods provide artemisinin or artemisinic acid from the plant in very poor yields and therefore not sufficient to accommodate the ever-growing need for this important drug. Consequently, widespread use of these valuable drugs has been hampered due to the low availability of this natural product. Therefore, research has focused on the syntheses of this valuable drug in a larger scale to meet the increasing global demand and accordingly ample literature is available on the synthesis of artemisinin or its derivatives, but no commercial success being reported / known till date.

Artemisinin can be prepared synthetically from its precursors such as artemisinic acid or dihydroartemisinic acid according to literature methods known to skilled artisans. For example, dihydroartemisinic acid can be converted to artemisinin by a combination of photooxidation and air-oxidation processes as described in U.S. Patent No. 4,992,561.

Amorphadiene is an early starting material for synthesis of Artemisinic acid or dihydroartemisinic acid, which is an important intermediate for producing Artemisinin commercially, and WO2006128126 reported a preparation method as mentioned in scheme- 1.

acid

In accordance with the scheme 1, the amorphadiene is treated with di(cyclohexyl)borane ( δΗι ΒΗ followed by reaction with H2O2 in presence of NaOH to obtain the amorph-4-ene 12-ol which is further oxidized to dihydroartemisinic acid using CrCb/ifcSC^. The formation of amorph-4-ene 12-ol is taking place via epoxidation of the exocyclic double bond. However, the reported yields of this synthesis are very low, making it unviable to produce artemisinic acid at a cheaper cost than natural extraction, for commercial use.

Amorpha -4, 11-diene

A similar method is published in, WO2009088404, for synthesis of dihydroartemisinic acid through preparation of amorph-4-ene-12-ol via epoxide formation, albeit, predominantly at exo position by reacting the amorpha-4,11-diene with H2O2 in presence of porphyrin catalyst (TDCPPMnCl). During reaction, epoxidation also occurred at endo position leading to formation of Amorphadiene- 4,5- epoxide that remain as impurity. The formed exo epoxide (amorphadiene – 11, 12 – epoxide) is further reduced to get amorph- 4-ene 12-ol and then converted to dihydroartemisinic acid and finally converted into artemisinin.

Amorphadiene-11,12-epoxide

This process involves expensive & industry unfriendly reagents. Moreover, desired stereo isomers were obtained only in poor yields, because several purification steps were needed to get desired stereo isomers leading to escalated production/operational costs.

Therefore there remains a need in the art to improve the yield of Dihydroartemisinic acid, which could potentially reduce the cost of production of Artemisinin and/or its derivatives. Consequently it is the need of the hour to provide a synthetic and economically viable process to meet the growing worldwide demand by improving the process for Artemisinin and/or its derivatives to obtain them in substantially higher yields with good purity by plant friendly operations like crystallization/extractions rather than column chromatography/other cost constraint procedures.

Therefore, the object of the invention is to prepare Artemisinic acid of formula-II, Dihydroartemisinic acid of formula-IIa, Artemisinin and its derivatives through Amorphadiene- 4,5- epoxide.

DHAA methyl ester

Scheme 2

Method 4 (From compound of formula IV (R = CI)):

In the 4-neck round bottom flask was charged Diphenyl sulfoxide (23.8 g), NaHC03 (32.96 g) and DMSO (80 ml) at 30^°C. Further a solution of compound of formula IV (R = CI) (10 g) in DMSO (20 ml) was charged to the reaction mass at 30^°C followed by heating and maintaining the temperature for 40 hours at 80^°C till completion. DMSO was distilled out under vacuum. The reaction mass was cooled followed by charging water

(100 ml) and toluene (100 ml) to the reaction mass with stirring for 30 minutes at 28^°C. The layers were separated out and aqueous layer was back extracted with toluene (2 X 100 ml). The organic layer was washed with water (100 ml) and saturated brine solution (100 ml). Solvent was distilled out under vacuum at 50^°C, and the crude mass degassed under vacuum at 50-55^°C. IPA (40 ml) was charged to the mass. Simultaneous addition of hydrazine hydrate (65% in aqueous solution) (3.8 g) and hydrogen peroxide (50% in aqueous solution) (2.5 ml) was done at 30-32^°C over a period of 3.25 hours. After completion, reaction mass was cooled up to 5-10^°C and water (100ml) was added to the reaction mass. The pH of the reaction mass was adjusted to 3.8 with dilute 8% aqueous HC1 (24 ml) at 10^°C. Ethyl acetate (60 ml) was added to the reaction mass at 10^°C and stirred for 15 minutes at 15-20^°C. The layers were separated. Aqueous layer was back extracted with ethyl acetate (2 X 20 ml). The combined organic layer was washed with 10%) sodium metabisulfite solution (50 ml), water (50 ml) and saturated brine solution (50 ml). The organic layer was distilled out under vacuum at 45^°C and the obtained crude mass was degassed at 50-55^°C. To this was added DME (40 ml), Biphenyl (0.9 g) and Li-metal (1.63 g) and the reaction mass was maintained for 10 hours at 80-85^°C till reaction completion. The reaction mass was cooled up to 0-5^°C followed by drop wise addition of water within one hour, and the reaction stirred for two hours at 20-25^°C. Toluene (35 ml) was charged with stirring and layers were separated. The aqueous layer was washed with toluene (35 ml) and the combined toluene layer was washed with water (20 ml). The combined aqueous layer was again washed with toluene (20 ml). The aqueous layer was cooled to 10-15^°C and pH adjusted to 3.5-4 with dilute 16% aqueous HC1. MDC (50 ml) was charged and stirred 30 minutes at 20-25^°C followed by separation of layers. The aqueous layer extracted with MDC (25 ml) and the combined MDC layer was washed with water (50 ml), then with saturated NaCl solution (25 ml). The solvent was distilled out under vacuum at 40-45^°C and the crude mass (Purity: 70-80%>) was degassed at 65-70°C. The crude product (10 g) was dissolved in ethyl acetate (200 ml). 10%> aqueous NaOH (100 ml) was charged to the reaction mass and stirred one hour at 20^°C followed by layer separation. Again 10%> aqueous NaOH (100ml) was added to the organic layer, stirred for 30 minutes and layers were separated out. The pH of the combined NaOH solution wash was adjusted to 4.0 with dilute 16%> aqueous HC1 at 5-10^°C under stirring. Ethyl acetate (850 ml) was charged to aqueous acidic mass, stirred 30 minutes and layers were separated out. The aqueous layer was back extracted with ethyl acetate (2 X 30 ml) and the combined organic layer was washed with water (100 ml) and saturated brine (50 ml). The organic layer was dried over sodium chloride, solvent was distilled out under vacuum and the purified mass was degassed under vacuum at 50-55^°C to obtain Dihydroartemisinic acid (Purity: 90-95%).

b) Methyl ester of Dihydroartemisinic acid:

To a clear solution of Dihydroartemisinic acid (40 g) dissolved in MDC (120 ml) was added thionyl chloride (SOCh) (14.85 ml) at 10±2°C and reaction mass was heated to reflux temperature 40±2°C. After the completion of reaction, solvent was distilled out and excess SOCh was removed under reduced pressure. The resulting concentrated mass of acid chloride was dissolved in MDC (200 ml). In another RBF was taken triethylamine (30.6 ml) and methanol (120 ml). To this solution was added above acid chloride solution at 30±2°C and maintained till completion of reaction. To the reaction mass was added water (400 ml) and organic layer was separated. The aqueous layer was washed with MDC and mixed with main organic layer and the combined organic layer was back washed with water till neutral pH. Then organic layer was concentrated to give methyl ester of Dihydroartemisinic acid as a brown color oily mass.

Weight: 41.88 gm

Yield = 98%

c) Artemisinin:

Methyl ester of dihydroartemisinic acid (67.7 g) was dissolved in methanol (338 ml). To this solution was added Sodium molybdate (29.5 g), 50% hydrogen peroxide (147.3 g) was added at 30±2°C and reaction was maintained for 3-4 hours. After completion of reaction was added water (300 ml) and MDC (300 ml) to the reaction mass. The organic layer was separated and aqueous layer washed with MDC (100 ml). The combined organic layer was concentrated to 475 ml containing hydroperoxide intermediate and directly used for next stage reaction. In another RBF containing MDC (475 ml) was added benzene sulfonic acid (1.27 g) and Indion resin (6.7 g). This heterogeneous solution was saturated with oxygen by passing O2 gas for 10 min at 0±2°C. To this was added previous stage hydroperoxide solution at same temperature with continuous 02 gas purging within 30-40 minutes. The oxygen gas was passed at same temp for 4 hours and temperature raised to 15±2°C with continued passing of oxygen for 5 hours. The

mixture was stirred at 25-30°C for 8-10 hours followed by filtration of resin. The filtrate was washed with water (200 ml X 3) and the combined aqueous layer back washed with MDC (50 ml). The combined organic layer was concentrated to give crude Artemisinin. Weight: 54 gm

Yield= 70.7%

Purification of Artemisinin:

Crude Artemisinin (10 g) was dissolved in ethyl acetate (25 ml) at 45-50°C. The solution was cooled to 30-35°C followed by addition of n-Hexane (100 ml). The material was isolated, stirred for 2 hours, filtered and vacuum dried at 45°C.

Weight: 4 gm

Yield: 40%

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, [email protected], +91 9323115463 India

////////New Patent, WO 2016110874, Artemisinin , IPCA Laboratories Ltd, malaria, Cancer, Parasitic infection, Plasmodium falciparum infection, Viral infection, artemether artemisinin, artemotil, artenimol, artesunate,

RG 6080

phase 1, Uncategorized Comments Off

Jul 152016

RG-6080

Sulfuric acid, mono[(1R,2S,5R)-2-[[(2-aminoethoxy)amino]carbonyl]-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester

A β-lactamase inhibitor potentially for the treatment of bacterial infections.

RG-6080; FPI-1459; OP-0595

CAS No. 1452458-86-4

Molecular Formula	C₉ H₁₆ N₄ O₇ S
Formula Weight	324.31

Originator Fedora Pharmaceuticals
Developer Meiji Seika Pharma
Class Antibacterials; Azabicyclo compounds
Mechanism of Action Beta lactamase inhibitors

Phase IBacterial infections

Most Recent Events

13 Jan 2015 OP 0595 licensed to Roche worldwide, except Japan ,
30 Nov 2014 Meiji Seika Pharma completes a phase I trial in Healthy volunteers in Australia (NCT02134834)
01 May 2014 Phase-I clinical trials in Bacterial infections (in volunteers) in Australia (IV)

SYNTHESIS

WO 2015046207,

CONTD…………………..

CONTD………………………………..

Patent

WO 2015053297

The novel heterocyclic compound in Japanese Patent 4515704 (Patent Document 1), preparation and shown for their pharmaceutical use, sodium trans-7-oxo-6- (sulfooxy) as a representative compound 1,6-diazabicyclo [3 .2.1] discloses an octane-2-carboxamide (NXL104). Preparation in regard to certain piperidine derivatives which are intermediates Patent 2010-138206 (Patent Document 2) and JP-T 2010-539147 (Patent Document 3) are shown at further WO2011 / 042560 (Patent Document 4) NXL104 to disclose a method for producing the crystals.

　In Patent 5038509 (Patent Document 5) (2S, 5R) -7- oxo -N- (piperidin-4-yl) -6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane – 2- carboxamide (MK7655) is shown, discloses the preparation of certain piperidine derivatives with MK7655 at Patent 2011-207900 (Patent Document 6) and WO2010 / 126820 (Patent Document 7).

　The present inventors also disclose the novel diazabicyclooctane derivative represented by the following formula (VII) in Japanese Patent Application 2012-122603 (Patent Document 8).

Patent Document 1: Japanese Patent No. 4515704 Pat
Patent Document 2: Japanese Patent Publication 2010-138206 Pat
Patent Document 3: Japanese patent publication 2010-539147 Pat
Patent Document 4: International Publication No. WO2011 / 042560 Patent
Patent Document 5: Japanese Patent No. 5038509 Pat
Patent Document 6: Japanese Patent Publication 2011-207900 Pat
Patent Document 7: International Publication No. WO2010 / 126820 Patent
Patent Document 8: Japanese Patent application 2012-122603 Pat.

[Chemical formula 1] (In the formula, R ³ are the same as those described below)

Reference Example
5 of 5 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
Formula 43]

step 1 tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate 　(IV-1)(2S, 5R)-6-(benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxylic acid (4 .30g, dehydrated ethyl acetate (47mL) solution of 15.56mmol) was cooled to -30 ℃, isobutyl chloroformate (2.17g, washing included dehydration ethyl acetate 1mL), triethylamine (1.61g, washing included dehydration ethyl acetate 1 mL), successively added dropwise, and the mixture was stirred 1 hour at -30 ° C.. To the reaction solution tert- butyl 2-dehydration of ethyl acetate (amino-oxy) ethyl carbamate (3.21g) (4mL) was added (washing included dehydration ethyl acetate 1mL), raising the temperature over a period of 1.5 hours to 0 ℃, It was further stirred overnight. The mixture of 8% aqueous citric acid (56 mL), saturated aqueous sodium bicarbonate solution (40 mL), sequentially washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to 5 mL, up to 6mL further with ethanol (10 mL) It was replaced concentrated. Ethanol to the resulting solution (3mL), hexane the (8mL) in addition to ice-cooling, and the mixture was stirred inoculated for 15 minutes. The mixture was stirred overnight dropwise over 2 hours hexane (75 mL) to. Collected by filtration the precipitated crystals, washing with hexane to give the title compound 5.49g and dried in vacuo (net 4.98 g, 74% yield). HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 50/50, 1.0 mL / min, UV 210 nm, Retweeted 4.4 min; ¹ H NMR (400 MHz, CDCl ₃ ) [delta] 1.44 (s, 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 3.03 (br.d., J = 11.6 Hz , 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 5.44 (br. . s, 1H), 7.34-7.48 (yd, 5H), 9.37 (Br.S., 1H); MS yd / z 435 [M + H] ⁺ .

Step 2

tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate
(V-1) tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl ] carbonyl} amino) oxy] ethyl} carbamate (3.91 g, to a methanol solution (80 mL) of 9.01mmol), 10% palladium on carbon catalyst (50% water, 803 mg) was added, under hydrogen atmosphere and stirred for 45 minutes . The reaction mixture was filtered through Celite, after concentrated under reduced pressure to give 3.11g of the title compound (quantitative).
HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 75/25, 1.0 mL / min, UV 210 nm, Retweeted 3.9 from min; ¹ H NMR (400 MHz, CD ₃ OD) [delta] 1.44 (s, 9H) , 1.73-1.83 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (br.dd., J = 15.0, 7.0 Hz, 1H), 3.03 (d, J= 12.0 Hz, 1H), 3.12 (br.d., J = 12.0 Hz, 1H), 3.25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS M / Z 345 [M Tasu H] ^Tasu .

Step 3
Tetrabutylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate
(VI-1) tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct 2-yl] carbonyl} amino) oxy] ethyl} carbamate (3.09g, in dichloromethane (80mL) solution of 8.97mmol), 2,6- lutidine (3.20mL), sulfur trioxide – pyridine complex (3 .58g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into half-saturated aqueous sodium bicarbonate solution, washed the aqueous layer with chloroform, tetrabutylammonium hydrogen sulfate to the aqueous layer and (3.47 g) chloroform (30 mL) was added and stirred for 10 minutes. The aqueous layer was extracted with chloroform, drying the obtained organic layer with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound 5.46g (91% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 80/20, 1.0ML / Min, UV210nm, RT 2.0 Min; ¹ H NMR (400 MHz, CDCl ₃ ) Deruta 1.01 (T, J = 7.4 Hz, 12H), 1.37-1.54 (m , 8H), 1.45 (s, 9H), 1.57-1.80 (m, 9H), 1.85-1.98 (m, 1H), 2.14-2.24 (m, 1H), 2.30- 2.39 (m, 1H), 2.83 (d, J = 11.6 Hz, 1H), 3.20-3.50 (m, 11H), 3.85-3.99 (m, 3H), 4.33-4.38 (m, 1H), 5.51 (br s , 1H), 9.44 (Br.S., 1H); MS yd / z 425 [M-Bu ₄ N + 2H] ⁺ .

Step 4 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
tetra butylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (5.20g, 7.82mmol) in dichloromethane (25mL) solution of ice-cold under trifluoroacetic acid (25mL), and the mixture was stirred for 1 hour at 0 ℃. The reaction mixture was concentrated under reduced pressure, washed the resulting residue with diethyl ether, adjusted to pH7 with aqueous sodium bicarbonate, subjected to an octadecyl silica gel column chromatography (water), after freeze drying, 1.44 g of the title compound obtained (57% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 99/1, 1.0ML / Min, UV210nm, RT 3.1 Min; ¹ H NMR (400 MHz, D ₂O) Deruta 1.66-1.76 (M, 1H), 1.76-1.88 (m, 1H ), 1.91-2.00 (m, 1H), 2.00-2.08 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 3.15 (t, J = 5.0 Hz , 2H), 3.18 (br d , J = 12.0 Hz, 1H), 3.95 (dd, J = 7.8, 2.2 Hz, 1H), 4.04 (t, J = 5.0 Hz, 2H), 4.07 (dd, J = 6.4 3.2 Hz &, 1H); MS yd / z 325 [M + H] ⁺ .

PATENT

WO 2015046207

Example
64 tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy ] ethyl} carbamate (V-1)
[of 124]

tert- butyl {2 – [({[(2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl } carbamate (example 63q, net 156.42g, 360mmol) in methanol solution (2.4L) of 10% palladium carbon catalyst (50% water, 15.64g) was added, under an atmosphere of hydrogen, stirred for 1.5 hours did. The catalyst was filtered through celite, filtrate was concentrated under reduced pressure until 450mL, concentrated to 450mL by adding acetonitrile (1.5 L), the mixture was stirred ice-cooled for 30 minutes, collected by filtration the precipitated crystals, washing with acetonitrile, and vacuum dried to obtain 118.26g of the title compound (net 117.90g, 95% yield). Equipment data of the crystals were the same as those of the step 2 of Reference Example 3.

Example
65 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VI-1)
[of 125]

　tert- butyl {2 – [({[(2S, 5R) -1,6- -6- hydroxy-7-oxo-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (example 64,537.61g, 1.561mol) in acetonitrile (7.8L) solution of 2,6-lutidine (512.08g), sulfur trioxide – pyridine complex (810.3g) was added, at room temperature in the mixture was stirred overnight. Remove insolubles and the mixture was filtered, the filtrate concentrated to 2.5 L, diluted with ethyl acetate (15.1L). The mixture was extracted with 20% phosphoric acid 2 hydrogencarbonate aqueous solution (7.8L), the resulting aqueous layer into ethyl acetate (15.1L), added tetrabutylammonium hydrogen sulfate (567.87g), was stirred for 20 min. The organic layer was separated layers, dried over anhydrous magnesium sulfate (425 g), after filtration, concentration under reduced pressure, substituted concentrated tetrabutylammonium tert- butyl with dichloromethane (3.1L) {2 – [({[(2S, 5R ) -7-oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate was obtained 758g (net 586.27g, Osamu rate 84%).

　The tetra-butyl ammonium salt 719g (net 437.1g, 0.656mol) in dichloromethane (874mL) solution was cooled to -20 ℃, dropping trifluoroacetic acid (874mL) at 15 minutes, 1 the temperature was raised to 0 ℃ It was stirred time. The reaction was cooled to -20 ° C. was added dropwise diisopropyl ether (3.25L), and the mixture was stirred for 1 hour the temperature was raised to 0 ° C.. The precipitate is filtered, washed with diisopropyl ether to give the title compound 335.36g of crude and vacuum dried (net 222.35g, 99% yield).

　The title compound of crude were obtained (212.99g, net 133.33g) and ice-cold 0.2M phosphate buffer solution of pH5.3 mix a little at a time, alternating between the (pH6.5,4.8L). The solution was concentrated under reduced pressure to 3.6L, it was adjusted to pH5.5 at again 0.2M phosphate buffer (pH6.5,910mL). The solution resin purification (Mitsubishi Kasei, SP207, water ~ 10% IPA solution) is subjected to, and concentrated to collect active fractions, after lyophilization, to give the title compound 128.3 g (96% yield). Equipment data of the crystals were the same as those of step 3 of Reference Example 3.

PATENT

US 20140288051

WO 2014091268

WO 2013180197

US 20130225554

///////////RG-6080, 1452458-86-4, FPI-1459, OP-0595, , β-lactamase inhibitor, bacterial infections, Fedora parmaceuticals, Meiji Seika Pharma

Chemistry in Water

Uncategorized Comments Off

Jul 152016

Chemistry in Water

Isley et al. reported the use of the nonionic amphiphile TPGS-750-M (2 wt %) in water to facilitate nucleophilic aromatic substitution reactions (S_NAr) with oxygen, nitrogen, and sulfur nucleophiles. The team eliminated the use of dipolar aprotic organic solvents traditionally required for S_NAr reactions, such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP).

Moderate to high yields at ambient or slightly elevated temperatures (up to 45 °C) were observed, and a diverse substrate scope with respect to thermal stability was established. The team additionally demonstrated the ability to recycle the water/micelle mixture by extracting the product with organic solvent. Recycling of the aqueous media resulted in improving the E-factor and reducing aqueous waste ( Org. Lett. 2015, 17,4734−4737).

, Supporting Info

Nucleophilic Aromatic Substitution Reactions in Water Enabled by Micellar Catalysis

Nicholas A. Isley^†, Roscoe T. H. Linstadt^†, Sean M. Kelly^†, Fabrice Gallou^‡, and Bruce H. Lipshutz^*^†

^† Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States

^‡ Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland

Org. Lett., 2015, 17 (19), pp 4734–4737

DOI: 10.1021/acs.orglett.5b02240

*E-mail: [email protected].

Wang et al. described the development of a copper-catalyzed hydroxylation of aryl halides in water. The syntheses of phenols generally require the use of energy intensive and/or harsh reaction conditions which can impact the substrate scope. This methodology utilized a hydroxylated phenanthroline ligand to improve solubility in water. Optimization of this method through screening resulted in the selection of copper(I) oxide (Cu₂O) as the copper source and tetrabutyl-ammonium hydroxide (TBAOH) at 110 °C. The TBAOH was proposed to function as both phase transfer catalyst and nucleophile, resulting in high yields and excellent selectivity toward phenol versus biphenyl ether.

The scope of this method with substituted aryl halides was demonstrated, affording excellent yields and high selectivity for para-substituted electron-rich and electron-deficient aryl bromides, as well as meta-substituted bromo-halides. Functional groups such as carboxyl and hydroxyl groups were also tolerated. The team additionally demonstrated a one-pot synthesis of either alkyl aryl ethers or benzofuran by trapping the in situ generated phenol with an alkyl bromide or through intramolecular cyclization ( Green Chem. 2015, 17, 3910−3915).

Graphical abstract: Copper-catalyzed hydroxylation of aryl halides: efficient synthesis of phenols, alkyl aryl ethers and benzofuran derivatives in neat water

Copper-catalyzed hydroxylation of aryl halides: efficient synthesis of phenols, alkyl aryl ethers and benzofuran derivatives in neat water

Yangxin Wang,^a^b Chunshan Zhou^a and Ruihu Wang*^a

*Corresponding authors

^aState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
E-mail: [email protected]

^bUniversity of Chinese Academy of Sciences, Beijing, China

Green Chem., 2015, 17, 3910-3915
DOI: 10.1039/C5GC00871A , supporting info,

An efficient catalytic protocol for hydroxylation of aryl halides in water is proposed to prepare phenols, ethers and benzofuran derivatives.

A thorough study of environmentally friendly hydroxylation of aryl halides is presented. The best protocol consists of hydroxylation of different aryl bromides and electron-deficient aryl chlorides by water solution of tetrabutylammonium hydroxide catalyzed by Cu₂O/4,7-dihydroxy-1,10-phenanthroline. Various phenol derivatives can be obtained in excellent selectivity and great functional group tolerance. This methodology also provides a direct pathway for the formation of alkyl aryl ethers and benzofuran derivatives in a one-pot tandem reaction.

Jung et al. reported the use of a continuous flow reactor to synthesize propargylamines in an atom economic fashion using stoichiometric quantities of reagents, water as solvent, and generating only CO₂ and water as byproducts. The team exploited the use of a pressurized tube reactor to achieve temperatures above the boiling point of water, enabling excellent yields (≥88%) and reasonable residence time (2 h).

This procedure improved the atom economy of previously reported methods for this transformation by eliminating the use of transition metal catalysts and excess of reagents. The substrate scope was demonstrated for multiple alkynyl carboxylic acids and secondary amines ( Tetrahedron. Lett. 2015, 56, 4697−4700).

Tetrahedron Letters

Volume 52, Issue 36, 7 September 2011, Pages 4697–4700

Basic alumina supported tandem synthesis of bridged polycyclic quinolino/isoquinolinooxazocines under microwave irradiation

Department of Chemistry, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India

Wang et al. reported the synthesis of an easily accessible diammonium functionalized Ru-alkylidene complex capable of ring-closing metathesis (RCM) and cross metathesis (CM) reactions in water. The NHBoc penultimate intermediate was isolated as an air-stable, nonhygroscopic Ru-alkylidene complex. Acidic cleavage of the Boc groups with trifluoroacetic acid (TFA) in dichloromethane generated the diammonium catalyst as a green solid after removal of volatiles under reduced pressure. The diammonium catalyst (5 mol %) achieved modest to high conversion to cyclic RCM products in D₂O at ambient to elevated temperatures (up to 80 °C). Lowering the catalyst loading to 0.1 mol % established a turnover number (TON) of >900.

Homocoupling of allyl alcohol and long chain alkenylammonium salts provided the desired diammonium cross products in high yield/conversion. Short chain alkenyl-ammonium salts were poor substrates for the CM reaction.

Catalyst deactivation was attributed to the ammonium:free amine equilibration in water followed by Lewis basic nitrogen coordination to the Ru-center (Green Chem. 2015, 17, 3407−3414).

A simple and practical preparation of an efficient water soluble olefin metathesis catalyst

Zhen J. Wang,^a W. Roy Jackson^a and Andrea J. Robinson*^a

*Corresponding authors

^aSchool of Chemistry, Monash University, Clayton 3800, Australia
E-mail: [email protected]

Green Chem., 2015,17, 3407-3414

DOI: 10.1039/C5GC00252D, supp info

The same research group additionally reported the divergent functionalization of L-tyrosine to generate a family of tyrosine-derived Ru-alkylidene RCM catalysts. This common ligand precursor approach was utilized to successfully create not only a hydrophilic/water-soluble PEG Ru-alkylidene, but a hydrophobic alkane Ru-alkylidene for solvent-free catalysis and a solid-phase supported Ru-alkylidene to access a potentially recyclable precatalyst system.

The PEG Ru-alkylidene complex displayed poor solubility in water at 40 °C under ultrasonication, providing the desired model RCM product in only 25% conversion. >95% conversion was achieved by utilizing a 1:1 water–MeOH solvent system at 40 °C with 2.5 mol % catalyst loading. It was rationalized in the Green Chemistry report (vide supra) that functionalization of the benzylidene ligand to increase aqueous solubility may be problematic due to the dissociation of the labile ligand during the catalytic cycle, whereas functionalization of nondissociating NHC ligand could sustain the desired solubility throughout the reaction.

The hydrophobic alkane Ru-alkylidene provided solvent-free RCM and CM products in high conversion. The solid-phase Ru-alkylidene also provided the desired RCM products in high conversion and demonstrated stable performance after multiple catalyst recovery/reuse operations. Sustained leaching of Ru metal into the reaction media was monitored and observed for the recycled solid-phase catalyst method. However, this iterative loss of metal did not negatively impact conversion ( J. Org. Chem. 2015, 80, 7205−7211).

Divergent Approach to a Family of Tyrosine-Derived Ru−Alkylidene Olefin Metathesis Catalysts

Authors	Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson
Published	Journal of Organic Chemistry
Graphical abstract
Abstract	A simple and generic approach to access a new family of Ru−alkylidene olefin metathesis catalysts with specialized properties is reported. This strategy utilizes a late stage, utilitarian Hoveyda-type ligand derived from tyrosine, which can be accessed via a multigram-scale synthesis. Further functionalization allows the catalyst properties to be tuned, giving access to modified second-generation Hoveyda−Grubbs-type catalysts. This divergent synthetic approach can be used to access solid-supported catalysts and catalysts that function under solvent-free and aqueous conditions.
Citation	Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson, J. Org. Chem., 2015, 80(14), 7205–7211
Pdf	Article
Doi	10.1021/acs.joc.5b01091

Bhowmick et al. published a review “Water: the most versatile and nature’s friendly media in asymmetric organocatalyzed direct aldol reactions”. This review addressed the various types of organocatalysts based on (1) l-proline, (2) 4-hydroxy-l-proline, (3) amino acid derivatives, (4) enzymes, and (5) other miscellaneous catalysts applied to the aldol reaction in aqueous media. In general, the intermolecular asymmetric aldol reaction has been shown to perform poorly in pure aqueous media and is typically performed in organic solvents such as DMF, DMSO, etc.

However, structural modifications to l-proline and 4-hydroxy-l-proline have generated catalysts capable of asymmetric aldol reactions in aqueous media.

Examples provided in this review highlight (a) instances of enhanced reactivity using water as a solvent, cosolvent, or additive, (b) formation of enzyme mimics that use hydrophobic forces to reinforce substrate/catalyst binding, (c) the use of aqueous media to interrogate proposed transition state geometries, and (d) the pH dependence of organocatalyzed aldol reactions. Limitations presented in the review include (a) substrate specific catalyst activities, (b) multistep/low-yielding synthesis of the organocatalysts, (c) slow catalysis rate in pure aqueous media, (d) high catalyst loading, and (e) poor to moderate selectivity (Tetrahedron: Asymmetry 2015, 26, 1215−1244).

Tetrahedron: Asymmetry

Volume 26, Issues 21–22, 1 December 2015, Pages 1215–1244

Tetrahedron: Asymmetry Report Number 159

Water: the most versatile and nature’s friendly media in asymmetric organocatalyzed direct aldol reactions

Division of Organic Synthesis, Department of Chemistry, Visva-Bharati (A Central University), Bolpur, West Bengal 731 235, India

Hot water’s ability to promote unexpected reactions without any other reagents or catalysts.

Chinese and Japanese chemists have highlighted hot water’s ability to promote unexpected reactions without any other reagents or catalysts. The work should expand our understanding of how to harness the physicochemical properties of water to potentially replace more complex reagents and catalysts.

Above its critical point at 374°C and 218atm the properties of water change quite dramatically, explains Hiizu Iwamura from Nihon University in Tokyo. But even below that point, as water is heated, hydrogen bonding and hydrophobic interactions are disrupted. ‘This means that organic compounds get more soluble and salts become insoluble in hot pressurised water,’ Iwamura says. Dissociation of water into hydroxide (OH^–) and hydronium (H₃O⁺) ions also increases, he adds, so there are higher concentrations of these ions available to act as catalysts for reactions.

Iwamura was synthesising triaroylbenzene molecules for a previous project on molecular magnets, using base-catalysed Michael addition reactions, when he first became interested in whether the reactions might work in water. He teamed up with a chemical engineer colleague, Toshihiko Hiaki, who is more familiar with working at the required temperatures and pressures. Together, they found that 4-methoxy-3-buten-2-one could be transformed into 1,3,5-triacetylbenzene in pressurised water at 150°C, with no other additives (see reaction scheme).¹

Meanwhile, Jin Qu and her team at Nankai University in Tianjin have been investigating water-promoted reactions at lower temperatures, without the need for pressurised vessels, which Qu says is more accessible for many researchers and makes monitoring reactions easier. ‘In 2008, one of my students found he could hydrolyse epoxides in pure water at 60°C, in 90% yields,’ she explains. ‘At first I thought it was not very interesting, just a hydrogen-bonding effect, but as we found more examples I got more interested.’

More than a thermal effect

When Qu’s team hydrolysed an epoxide made from (-)-α-pinene, they found that at room temperature they got (-)-sobrerol, the product they expected. But at 60°C or higher, the sobrerol began to racemise, giving a mixture of the (+)- and (-)-forms (see reaction scheme). ‘We couldn’t understand why this was happening at first,’ says Qu, but eventually it became clear that the allylic alcohol group in the sobrerol, which is much less reactive than the epoxide in pinene, was also being hydrolysed. The same reactions happen at room temperature if acid is added, Qu says, but don’t happen in propanol or other alcoholic and hydrogen-bonding solvents heated to the same temperatures, so it is not simply a thermal effect.

Qu points out that these observations, along with those of Iwamura’s team, show that molecules that might usually be considered unreactive in water can undergo useful transformations. And these reactions can take place without other reagents or solvents, which would create extra waste streams. Also, owing to the decreased solubility of the organic product molecules when the solutions are cooled back to room temperature, they are often easy to purify as well.

Iwamura suggests that there are many other simple acid- and base-catalysed reactions that might be suitable for reacting in hot water. However, reactions with thermally unstable molecules, or those requiring delicate selectivity, are unlikely to be so effective at higher temperatures, he adds. He also makes a distinction between Qu’s work – in which the water molecules are directly involved in the reaction – and his own group’s, in which the water acts as the reaction medium and provides the catalyst. ‘Our reaction did not take place in water heated at reflux,’ Iwamura adds.

However, Hiaki points out that the potential environmental benefits of reduced waste streams will have little impact on industrial chemistry if the reactions remain confined to batch processes. ‘High temperature and pressure is detrimental for the scale up to commercial chemical plants,’ he says. For that reason, the team is developing a flow microreactor system that should be more industry compatible.REFERENCES, 1 T Iwado et al, J. Org. Chem., 2012, DOI: 10.1021/jo301979p, 2 Z-B Xu and J Qu, Chem. Eur. J., 2012 DOI: 10.1002/chem.201202886

Hydration: A process which adds water.

In this hydration reaction, 1-methyl cyclohexene (an alkene) is reacted with aqueous H₃O⁺ (formed from water and a strong acid such as H₂SO₄), resulting in Markovnikov addition of water across the pi bond. The product is an alcohol.

Syn, anti-Markovnikov addition of water to an alkene can be achieved via a hydroboration-oxidation reaction.

–to be added–		–to be added–
CuSO₄ (anhydrous)		CuSO₄ ^. 5 H₂O

Anhydrous CuSO₄ (colorless) absorbs water vapor from the air, hydrating it to CuSO₄ ^. 5 H₂O (copper sulfate pentahydrate; blue).

///////////Chemistry in Water

Besifloxacin hydrochloride (Besivance)

Uncategorized Comments Off

Jul 132016

Besifloxacin

SS 734, BOL 303224A, ISV-403

MW 430.301, MF C₁₉H₂₁ClFN₃O₃

141388-76-3 CAS

7-[(3R)-3-aminoazepan-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

(R)-(+)-7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(R) -7- (3- amino-hexahydro-azepin -1H- mushroom-1-yl) -8-chloro-1-cyclopropylmethyl -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

Synthesis of the molecule (R)-(+)-7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is disclosed in U.S. Pat. No. 5,447,926,

Besifloxacin is a fourth generation fluoroquinolone-type opthalmic antibiotic for the treatment of bacterial conjunctivitis. FDA approved on May 28, 2009. by Bausch & Lomb, for the treatment of non-viral bacterial conjunctivitis

Besifloxacin, (+)-7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride, developed by SS Pharmaceutical (SSP) Co.Ltd. was a fourth-generation fluoroquinolone antibiotic . Besifloxacin hydrochloride eye drop was used to treat bacterial conjunctivitis caused by aerobic and facultative Gram-positive microorganisms and aerobic and facultative Gram-negative microorganisms

Besifloxacin (INN/USAN) is a fourth-generation fluoroquinolone antibiotic. The marketed compound is besifloxacin hydrochloride. It was developed by SSP Co. Ltd., Japan, and designated SS734. SSP licensed U.S. and European rights to SS734 for ophthalmic useto InSite Vision Incorporated (OTCBB: INSV) in 2000. InSite Vision developed an eye drop formulation (ISV-403) and conducted preliminary clinical trials before selling the product and all rights to Bausch & Lomb in 2003.^[1]

The eye drop was approved by the United States Food and Drug Administration (FDA) on May 29, 2009 and marketed under the trade name Besivance.^[2]

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Besivance	suspension	6 mg/mL	ophthalmic	Bausch & Lomb Incorporated	2009-05-28	Not applicable
Besivance	suspension	0.6 %	ophthalmic	Bausch & Lomb Inc	2010-01-27	Not applicable
Besivance	suspension	6 mg/mL	ophthalmic	Physicians Total Care, Inc.	2011-07-13	Not applicable

405165-61-9 CAS

Besifloxacin Hydrochloride

Besifloxacin hydrochloride is a fourth-generation fluoroquinolone antibiotic.
IC50 Value:
Target: Antibacterial
Besifloxacin has been found to inhibit production of pro-inflammatory cytokines in vitro. Besifloxacin is a novel 8-chloro-fluoroquinolone agent with potent, bactericidal activity against prevalent and drug-resistant pathogens.besifloxacin is the most potent agent tested against gram-positive pathogens and anaerobes and is generally equivalent to comparator fluoroquinolones in activity against most gram-negative pathogens. Besifloxacin demonstrates potent, broad-spectrum activity, which is particularly notable against gram-positive and gram-negative isolates that are resistant to other fluoroquinolones and classes of antibacterial agents.

Clinical Information of Besifloxacin Hydrochloride

Product Name	Sponsor Only	Condition	Start Date	End Date	Phase	Last Change Date
Besifloxacin Hydrochloride	Bucci Laser Vision Institute	Bacterial infection	31-MAY-11	31-DEC-11	Phase 4	05-JUN-13
	Bucci Laser Vision Institute		31-MAY-11	31-DEC-11	Phase 4	03-JUN-13
	Innovative Medical Services		30-SEP-10	31-OCT-12	Phase 4	11-SEP-13
	Ophthalmology Consultants, Ltd	Cataract	30-SEP-10	28-FEB-11	Phase 4	11-SEP-13
	University of Louisville	Blepharitis	31-AUG-11	31-OCT-11	Phase 4	01-DEC-11

Pharmacodynamics

Besifloxacin is a fluoroquinolone that has a broad spectrum in vitro activity against a wide range of Gram-positive and Gram-negativeocular pathogens: e.g., Corynebacterium pseudodiphtheriticum, Moraxella lacunata, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus hominis, Streptococcus mitis, Streptococcus oralis, Streptococcus pneumoniae and Streptococcus salivarius. Besifloxacin has been found to inhibit production of pro-inflammatory cytokines in vitro.^[3] The mechanism of action of besifloxacin involves inhibition of two enzymes which are essential for the synthesis and replication of bacterial DNA: the bacterialDNA gyrase and topoisomerase IV.

Medical Use

Besifloxacin is indicated in the treatment of bacterial conjunctivitis caused by sensitive germs,^[4] as well as in the prevention of infectious complications in patients undergoing laser therapy for the treatment of cataracts.^[5]^[6]

Adverse Effects

During the treatment, the most frequently reported ocular adverse reaction was the appearance of conjunctival redness (approximately 2% of patients). Other possible adverse reactions, reported in subjects treated with besifloxacin were: eye pain, itching of the eye, blurred vision, swelling of the eye or eyelid.

MORE SYNTHESIS COMING, WATCH THIS SPACE…………………..

PATENT

WO 2010111116

https://www.google.com/patents/WO2010111116A1?cl=en

PATENT

CN 104592196

https://www.google.com/patents/CN104592196A?cl=en

The method comprises performing condensation reaction of 1-cyclopropyl-6,7-dichloro-1,4-dihydro-4-oxy-3-quinoline carboxylic acid with (R)-3-aminohexahydroazepine in the presence of org. base in org. solvent I at 45°C-solvent b.p. temp. under refluxing, washing with acid, vacuum concg. to obtain (R)-7-(3-amino-hexahydro-1H-azepine-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxy-3-quinoline carboxylic acid, dissolving in 5-10 fold org. solvent II, reacting with thionyl chloride at 0-40°C, and vacuum concg. to obtain (R) -7- (3- amino-hexahydro-azepin -1H- mushroom-1-yl) -8-chloro-1-cyclopropylmethyl -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride

Preparation method of the present invention provides hydrochloride Besifloxacin, comprising the steps of:

(1), in three _6 flask of 1-cyclopropyl, 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 10g of acetonitrile added 100mL, was added (R ) -3-amino-hexahydro-aza mushroom 4.73g and 7.2mL of triethylamine was heated at reflux for 5h TLC plate detection point, the reaction was complete spin dry plus 100mL dissolved in chloroform and then 200mL 1M hydrochloric acid and washed twice with saturated brine The organic phase to pH 4-6, the organic phase was poured into the jar and dried to obtain the single (R) -7- (3- amino-hexahydro-azepin -1H- leather-yl) cyclopropyl-6 -1_ fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid in chloroform solution; spin-dried to give (R) -7- (3- amino-hexahydro-azepin -1H- leather-yl) cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

(2), obtained in the previous step (R) -7- (3_ atmosphere atmosphere -1H- gas hybrid group six leather-1-yl) cyclopropyl-6-fluoro-1,4 _1_ dihydro-4-oxo-3-quinolinecarboxylic acid in chloroform solution was cooled to 0 ° C, was slowly added dropwise under constant stirring 18mL S0C12, temperature does not exceed 5 ° C added, the mixture was stirred at 0 ° C after 2h l to room temperature, TLC detection, after completion of the reaction was evaporated to dryness to column chromatography to give (R) -7- (3- amino-hexahydro-azepin -1H- mushroom-1-yl) -8-chloro-1-cyclopropylmethyl -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride 5. 12g.

PATENT

US 20110144329

https://www.google.com/patents/US20110144329

EXAMPLE 1Preparation of Besifloxacin Free Base Solid

Besifloxacin free base was prepared from besifloxacin hydrochloride addition salt.

An amount of about 5 g of besifloxacin HCl (HCl addition salt of besifloxacin made, for example, by the method of U.S. Pat. No. 5,447,926; which is incorporated herein by reference in its entirety) was added to about 750 ml of water. The besifloxacin HCl was allowed to dissolve in said water. Twenty milliliters of 1N NaOH solution were added slowly to the besifloxacin aqueous solution while stirring (final pH 10.2). Besifloxacin free base started to precipitate. Eight milliliters of 1N HCl solution were added slowly while stirring (final pH of 9.7). The resulting mixture was allowed to mix for 2 hours while besifloxacin free base continued to precipitate. At the end of 2 hours, the precipitated besifloxacin free base was filtered through a Millipore type RA 1.2 μm filter. The besifloxacin free base thus collected was dried in a vacuum oven at room temperature. 4.35 g of besifloxacin free base was recovered.

FIG. 1 shows a UV absorption spectrum of besifloxacin free base starting material of Example 1.

FIG. 3 shows an IR spectrum of free base starting material of Example 1.

PATENT

https://www.google.com/patents/CN103044397A?cl=en

Example 6 (R) -7_ (3- amino-hexahydro–1H- diazepan-1-yl) -8_ chloro-1-cyclopropyl-6-fluoro-1,4- Hydrogen oxo – quinoline-3-carboxylic acid (Besifloxacin). [0021] The reaction vessel was added chloroform (50ml) as a reaction solvent, in the case of a solid material was added with stirring (III) (3. 59g, O. Olmol), until the intermediate (III) is completely dissolved, was added dropwise under ice- chlorosulfonic acid, stirred for I hour under ice-cooling, gradually warmed to room temperature, stirred for 6 hours, and then reacted at reflux temperature for 6 hours. After completion of the reaction by TLC, the reaction solution was cooled to 0 ° C, white solid was precipitated, filtered, washed with a small amount of dichloromethane to give a crude product besifloxacin (3. 65g, 93. 01%). [0022] Example 7 (R) -7_ (3- amino-hexahydro–1H- diazepan-1-yl) -8_ chloro-1-cyclopropyl-6-fluoro-1,4- Hydrogen oxo – quinoline-3-carboxylic acid (Besifloxacin). [0023] The reaction vessel was added chloroform (50ml) as a reaction solvent, in the case of a solid material was added with stirring (III) (3. 59g, 0. Olmol), until the intermediate (III) is completely dissolved, was added dropwise under ice- chlorosulfonic acid was stirred for I hour under ice-cooling, gradually warmed to room temperature, stirred for 6 hours, and then reacted at reflux temperature for 12 hours. After completion of the reaction by TLC, the reaction solution was cooled to 0 ° C, the precipitated white solid was filtered , washed with a little dichloromethane to give Besifloxacin crude (3. 05g, 77. 22%).

PAPER

Molbank 2013, 2013(2), M801; doi:10.3390/M801

Short Note

(R)-7-(Azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid Hydrochloride

Zhengjun Xia, Zaixin Chen * and Shuitao Yu

http://www.mdpi.com/1422-8599/2013/2/M801

Supplementary File 3:Support Information (PDF, 340 KB)

Download PDF [188 KB, 27 May 2013; original version 22 May 2013]

R&D Center, Jiangsu Yabang Pharmaceutical Group, Changzhou 213200, China

In this paper (R)-7-(azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1was isolated and identified as the N-substituted regioisomer of besifloxacin, which has been synthesized from the reaction of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 3 with (R)-tert-butyl 3-aminoazepane-1-carboxylate 2in acetonitrile as solvent in 37% yield. The chemical structure of compound 1 was established on the basis of ¹H-NMR, ¹³C-NMR, mass spectrometry data and elemental analysis

REGIOMER OF BESIFLOXACIN

BESIFLOXACIN

References

“InSite Vision Reaches Agreement to Sell ISV-403 to Bausch & Lomb” (Press release). InSite Vision. 2003-12-19. Retrieved 2009-08-15.
“Bausch & Lomb Receives FDA Approval of Besivance, New Topical Ophthalmic Antibacterial for the Treatment of Bacterial Conjunctivitis (“Pink Eye”)” (Press release). Bausch & Lomb. 2009-05-29. Retrieved 2009-05-29.
Zhang JZ, Ward KW (January 2008). “Besifloxacin, a novel fluoroquinolone antimicrobial agent, exhibits potent inhibition of pro-inflammatory cytokines in human THP-1 monocytes”. J. Antimicrob. Chemother. 61 (1): 111–6. doi:10.1093/jac/dkm398. PMID 17965029.
Malhotra R, Ackerman S, Gearinger LS, Morris TW, Allaire C (December 2013). “The safety of besifloxacin ophthalmic suspension 0.6 % used three times daily for 7 days in the treatment of bacterial conjunctivitis”. Drugs in R&D 13 (4): 243–52. doi:10.1007/s40268-013-0029-1. PMC 3851703. PMID 24142473. Retrieved 2015-01-06.
Majmudar PA, Clinch TE (May 2014). “Safety of besifloxacin ophthalmic suspension 0.6% in cataract and LASIK surgery patients”. Cornea33 (5): 457–62. doi:10.1097/ICO.0000000000000098. PMC 4195578. PMID 24637269. Retrieved 2015-01-06.
Nielsen SA, McDonald MB, Majmudar PA (2013). “Safety of besifloxacin ophthalmic suspension 0.6% in refractive surgery: a retrospective chart review of post-LASIK patients”. Clinical Ophthalmology (Auckland, N.Z.) 7: 149–56. doi:10.2147/OPTH.S38279. PMC 3552478. PMID 23355771. Retrieved 2015-01-06.

CLIPS

Besifloxacin hydrochloride (Besivance) Besifloxacin is a fourth-generation fluoroquinolone antibiotic which is marketed as besifloxacin hydrochloride. It was originally developed by the Japanese firm SSP Co. Ltd and designated SS734. SSP then licensed U.S. and European rights of SS734 for ophthalmic use to InSite Vision, Inc., in 2000, who then developed an eye drop formulation (ISV-403) and conducted preliminary clinical trials before selling the product and all rights to Bausch & Lomb in 2003.

The eye drop was approved by the United States Food and Drug Administration (FDA) on May 29, 2009 and marketed under the trade name Besivance.24a

Besifloxacin has been found to inhibit production of pro-inflammatory cytokines in vitro. The synthesis of besifloxacin commences with commercially available ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate (13, Scheme3).24b

Condensation of this ketoester with triethyl orthoformate resulted in a mixture of vinylogous esters 14. Substitution with cyclopropanamine converts 14 to the vinylogous amide 15 as an unreported distribution of cis- and trans-isomers. This mixture was treated with base at elevated temperature to give 16.

Presumably, the trans-isomer isomerizes to the cis-isomer, which subsequently undergoes an intramolecular nucleophilic aromatic substitution with concomitant saponification to construct quinolone acid 16.

Quinolone 16 is then subjected to another nucleophilic substitution involving readily available iminoazepine 17 and the displacement reaction proceeds regioselectively to furnish the atomic framework of besifloxacin (18).

Acidic methanolysis of 18 at elevated temperature gave besiflozacin (III).

24. (a) Bertino, J. S.; Zhang, J.-Z. Expert Opin. Pharmacother. 2009, 10, 2545; (b) Harms, A. E.; Arul, R.; Soni, A. K. U.S. 2009561283 A1, 2009.

US5447926 *	Sep 16, 1994	Sep 5, 1995	Ss Pharmaceutical Co., Ltd.	Quinolone carboxylic acid derivatives

Citing Patent	Filing date	Publication date	Applicant	Title
CN104458945A *	Nov 27, 2014	Mar 25, 2015	广东东阳光药业有限公司	Separation and measurement method of besifloxacin hydrochloride and isomer of besifloxacin hydrochloride

CN102659761A *	Apr 27, 2012	Sep 12, 2012	常州亚邦制药有限公司	Method for preparing besifloxacin hydrochloride
US5385900 *	Nov 8, 1993	Jan 31, 1995	Ss Pharmaceutical Co., Ltd.	Quinoline carboxylic acid derivatives

Reference
1	*	黄山等: “克林沙星的 2, 4, 5-三氟苯甲酸路线合成“, 《中国医药工业杂志》, vol. 31, no. 8, 31 December 2000 (2000-12-31)

Citing Patent	Filing date	Publication date	Applicant	Title
CN103709100A *	Dec 31, 2013	Apr 9, 2014	南京工业大学	Preparation method of 8-chloroquinolone derivatives

Besifloxacin
Systematic (IUPAC) name


7-[(3R)-3-Aminoazepam-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Clinical data
Trade names	Besivance
AHFS/Drugs.com	Monograph
MedlinePlus	a610011
License data	US FDA: Besifloxacin
Routes of administration	Ophthalmic
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	141388-76-3
ATC code	S01AE08 (WHO)
PubChem	CID 10178705
ChemSpider	8354210
UNII	BFE2NBZ7NX
ChEMBL	CHEMBL1201760
Chemical data
Formula	C₁₉H₂₁ClFN₃O₃
Molar mass	393.84 g·mol⁻¹

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US5,447,926	No	1995-09-05	2012-09-05
US5447926	No	1996-04-13	2016-04-13
US6,685,958	No	2004-02-03	2021-06-20
US6,699,492	No	2004-03-02	2019-03-31
US6685958	No	2001-06-29	2021-06-29
US6699492	No	1999-03-31	2019-03-31
US8415342	No	2010-11-07	2030-11-07
US8481526	No	2011-01-09	2031-01-09
US8604020	No	2010-03-12	2030-03-12
US8937062	No	2009-11-13	2029-11-13

O’Brien TP: Besifloxacin ophthalmic suspension, 0.6%: a novel topical fluoroquinolone for bacterial conjunctivitis. Adv Ther. 2012 Jun;29(6):473-90. doi: 10.1007/s12325-012-0027-7. Epub 2012 Jun 20. [PubMed:22729919 ]
Proksch JW, Granvil CP, Siou-Mermet R, Comstock TL, Paterno MR, Ward KW: Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans. J Ocul Pharmacol Ther. 2009 Aug;25(4):335-44. doi: 10.1089/jop.2008.0116. [PubMed:19492955 ]
Besifloxacin Hydrochloride

[1]. Wang Z, Wang S, Zhu F, Chen Z, Yu L, Zeng S. Determination of enantiomeric impurity in besifloxacin hydrochloride by chiral high-performance liquid chromatography with precolumn derivatization. Chirality. 2012 Jul;24(7):526-31. doi: 10.1002/chir.22042.
Abstract
Besifloxacin hydrochloride is a novel chiral broad-spectrum fluoroquinolone developed for the treatment of bacterial conjunctivitis. R-besifloxacin hydrochloride is used in clinics as a consequence of its higher antibacterial activity. To establish an enantiomeric impurity determination method, some chiral stationary phases (CSPs) were screened. Besifloxacin enantiomers can be separated to a certain extent on Chiral CD-Ph (Shiseido Co., Ltd., Japan), Chiral AGP, and Crownpak CR (+) (Daicel Chemical IND., Ltd., Japan). However, the selectivity and sensitivity were both unsatisfactory on these three CSPs. Therefore, Chiral AGP, Chiral CD-Ph, and Crownpak CR (+) were not used in the enantiomeric impurity determination of besifloxacin hydrochloride. The separation of enantiomers of besifloxacin was further performed using a precolumn derivatization chiral high-performance liquid chromatography method. 2,3,4,6-Tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate was used as the derivatization reagent. Besifloxacin enantiomer derivates were well separated on a C(18) column (250 × 4.6 mm, 5 μm) with a mobile phase that consisted of methanol-KH(2)PO(4) buffer solution (20 mM; pH 3.0) (50:50, v/v). Selectivity, sensitivity, linearity, accuracy, precision, stability, and robustness of this method were all satisfied with the method validation requirement. The method was suitable for the quality control of enantiomeric impurity in besifloxacin hydrochloride.

[2]. Hussar DA. New drugs: golimumab, besifloxacin hydrochloride, and artemether/lumefantrine. J Am Pharm Assoc (2003). 2009 Jul-Aug;49(4):570-4.

[3]. Nafziger AN, Bertino JS Jr. Besifloxacin ophthalmic suspension for bacterial conjunctivitis. Drugs Today (Barc). 2009 Aug;45(8):577-88.
Abstract
Besifloxacin hydrochloride ophthalmic suspension 0.6% (Besivance) is a recently approved fluoroquinolone for the topical treatment of bacterial conjunctivitis. The drug is rapidly bactericidal against common bacterial pathogens causing conjunctivitis, i.e., coagulase-negative Staphylococcus, Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae as well as against other less common organisms. In addition to being a potent agent against Gram-positive and Gram-negative pathogens including those resistant to other fluoroquinolones, besifloxacin has balanced DNA gyrase and topoisomerase IV activity, which should slow the development of resistance. Topical administration achieves high sustained concentrations in human tears and good ocular tissue penetration in animals while demonstrating an excellent safety profile. Besifloxacin’s pharmacokinetic and pharmacodynamic characteristics meet the criteria for successful eradication of many Gram-positive and Gram-negative bacteria while demonstrating minimal systemic exposure. The biochemical properties, achievement of target pharmacokinetic/pharmacodynamic goals and the restriction of besifloxacin to topical ophthalmic use should result in slower development of bacterial resistance, making besifloxacin a new, appealing option for empiric therapy in acute bacterial conjunctivitis.

[4]. Proksch JW, Ward KW. Ocular pharmacokinetics/pharmacodynamics of besifloxacin, moxifloxacin, and gatifloxacin following topical administration to pigmented rabbits. J Ocul Pharmacol Ther. 2010 Oct;26(5):449-58.
Abstract
PURPOSE: The purpose of this investigation was to evaluate the ocular pharmacokinetic/pharmacodynamic (PK/PD) relationship for besifloxacin, moxifloxacin, and gatifloxacin using rabbit ocular PK data, along with in vitro minimum inhibitory concentration (MIC90) values against methicillin- and ciprofloxacin-resistant Staphylococcus aureus (MRSA-CR) and Staphylococcus epidermidis (MRSE-CR).METHODS: Rabbits received a topical instillation of Besivance? (besifloxacin ophthalmic suspension, 0.6%), Vigamox (moxifloxacin hydrochloride ophthalmic solution, 0.5% as base), or Zymar (gatifloxacin ophthalmic solution, 0.3%), and ocular tissues and plasma were collected from 4 animals/treatment/collection time at 8 predetermined time intervals during the 24h after dosing. Ocular levels of each agent were measured by LC/MS/MS, and PK parameters (Cmax, Tmax, and AUC????) were determined. AUC????/MIC?? ratios were calculated for tears, conjunctiva, cornea, and aqueous humor using previously reported MIC??values for MRSA-CR and MRSE-CR.RESULTS: All of the fluoroquinolones tested demonstrated rapid penetration into ocular tissues after a single instillation. Besifloxacin demonstrated the highest exposure in tear fluid, while exposure in conjunctiva was comparable for all 3 compounds. Peak concentrations of all fluoroquinolones in aqueous humor were at or below ~1g/mL. In comparison with their MIC??values against MRSE-CR and MRSA-CR, besifloxacin achieved an AUC????/MIC?? ratio of ~800 in tears, compared with values of ≤10 for moxifloxacin and gatifloxacin. In cornea, conjunctiva, and aqueous humor, the AUC????/MIC?? ratios were <10 for all compounds. However, in these tissues AUC????/MIC?? ratios for besifloxacin were 1.5- to 38-fold higher than moxifloxacin and gatifloxacin….

[5]. Comstock TL, Paterno MR, Usner DW, Pichichero ME. Efficacy and safety of besifloxacin ophthalmic suspension 0.6% in children and adolescents with bacterial conjunctivitis: a post hoc, subgroup analysis of three randomized, double-masked, parallel-group, multicenter clinical trials. Paediatr Drugs. 2010 Apr 1;12(2):105-12. doi: 10.2165/11534380-000000000-00000.
Abstract
BACKGROUND: Acute conjunctivitis is the most frequent eye disorder seen by primary care physicians and one that often affects children. Besifloxacin is a new topical fluoroquinolone, the first chlorofluoroquinolone, for the treatment of bacterial conjunctivitis.OBJECTIVE: To examine the efficacy and safety of besifloxacin ophthalmic suspension 0.6% in patients aged 1-17 years with bacterial conjunctivitis.METHODS: This was a post hoc analysis of a subgroup of pediatric patients aged 1-17 years who had participated in three previously reported, randomized, double-masked, parallel-group, multicenter, clinical trials evaluating the safety and efficacy of besifloxacin in the treatment of bacterial conjunctivitis. The studies were conducted in a community setting (clinical centers). All three clinical trials included children (aged > or = 1 year) with a clinical diagnosis of bacterial conjunctivitis in at least one eye, based on the presence at baseline of grade 1 or greater purulent conjunctival discharge and conjunctival injection, and pin-hole visual acuity of at least 20/200 in both eyes for verbal patients. Two trials were vehicle controlled; the third trial was comparator controlled (moxifloxacin hydrochloride ophthalmic solution 0.5% as base). In all studies, besifloxacin ophthalmic suspension 0.6% was administered as one drop in the affected eye(s) three times daily, at approximately 6-hourly intervals, for 5 days. The main outcome measures were clinical resolution and microbial eradication at visit 2 (day 4 +/- 1 in one study; day 5 +/- 1 in the other two studies) and visit 3 (day 8 or 9). Data from the two vehicle-controlled studies were combined for the assessments to provide greater statistical power.RESULTS: This analysis included 815 pediatric patients aged 1-17 years (447 with culture-confirmed bacterial conjunctivitis). Clinical resolution was significantly greater (p < 0.05) in the besifloxacin group than in the vehicle group at both visit 2 (53.7% vs 41.3%) and visit 3 (88.1% vs 73.0%). Similarly, microbial eradication was significantly higher with besifloxacin than with vehicle at visit 2 (85.8% vs 56.3%) and visit 3 (82.8% vs 68.3%). No significant differences in clinical resolution and microbial eradication were noted between besifloxacin and moxifloxacin. Besifloxacin was well tolerated, with similar incidences of adverse events in the besifloxacin, vehicle, and moxifloxacin groups.CONCLUSION: Besifloxacin ophthalmic suspension 0.6% was shown to be safe and effective for the treatment of bacterial conjunctivitis in children and adolescents aged 1-17 years.

///////Besifloxacin hydrochloride, Besivance, Besifloxacin, SS734, 141388-76-3, 405165-61-9, BOL 303224A, ISV-403, Bausch & Lomb, treatment of non-viral bacterial conjunctivitis

Fc1c(c(Cl)c2c(c1)C(=O)C(\C(=O)O)=C/N2C3CC3)N4CCCC[C@@H](N)C4

Febuxostat

Uncategorized Comments Off

Jul 102016

Febuxostat

Febuxostat; 144060-53-7; Uloric; Adenuric; Tei 6720; 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid;
Molecular Formula:	C₁₆H₁₆N₂O₃S
Molecular Weight:	316.37484 g/mol

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid

Febuxostat is a thiazole derivative and inhibitor of XANTHINE OXIDASE that is used for the treatment of HYPERURICEMIA in patients with chronic GOUT.

CAS 144060-53-7

2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid
2-(3-Cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid
FBX
Febugood
Feburic
Febutaz
TMX 67
Zurig

Febuxostat (INN; trade names Adenuric in Europe and New Zealand, Uloric in the US, Goturic in Latin America, Feburic in Japan) is a drug that inhibits xanthine oxidase, thus reducing production of uric acid in the body. It is used in the treatment of chronicgout and hyperuricemia.

Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998. Teijin partnered the drug with TAP Pharmaceuticals in the US and Ipsen in Europe. Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008, Takeda obtained FDA approval in February 2009, and Teijin obtained approval from the Japanese “Pharmaceuticals and Medical Devices Agency” in 2011.

Medical uses

Febuxostat is used to treat chronic gout and hyperuricemia.^[2] National Institute for Health and Clinical Excellence concluded that febuxostat is more effective than standard doses of allopurinol, but not more effective than higher doses of allopurinol.^[2]

Uloric 40 mg tablet

Febuxostat is in the US pregnancy category C; there are no adequate and well-controlled studies in pregnant women.^[3]

Side effects

The adverse effects associated with febuxostat therapy include nausea, diarrhea, arthralgia, headache, increased hepatic serum enzyme levels and rash.^[3]^[4]

Drug interactions

Febuxostat is contraindicated with concomitant use of theophylline and chemotherapeutic agents, namely azathioprine and 6-mercaptopurine, because it could increase blood plasma concentrations of these drugs, and therefore their toxicity.^[3]^[5]

Mechanism of action

Febuxostat is a non-purine-selective inhibitor of xanthine oxidase.^[3] It works by non-competitively blocking the molybdenum pterincenter which is the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine andxanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid. Febuxostat inhibits both oxidized as well as reduced form of xanthine oxidase because of which febuxostat cannot be easily displaced from the molybdenum pterin site.^[4]

History

Febuxostat was discovered by scientists at the Japanese pharmaceutical company Teijin in 1998.^[6] Teijin partnered the drug withTAP Pharmaceuticals in the US and Ipsen in Europe.^[7]^[8]^[9]

Ipsen obtained marketing approval for febuxostat from the European Medicines Agency in April 2008,^[10] Takeda obtained FDA approval in February 2009,^[11]^[12] and Teijin obtained approval from the Japanese authorities in 2011.^[13] Ipsen exclusively licensed its European rights to Menarini in 2009.^[14] Teijin partnered with Astellas for distribution in China and southeast Asia.^[15]^[16]

Society and culture

Cost

In the UK, NICE has found that febuxostat has a higher cost/benefit ratio than allopurinol and on that basis recommended febuxostat as a second-line drug for people who cannot use allopurinol.^[2]

Trade names

Febuxostat is marketed as Adenuric in Europe and New Zealand, Uloric in the US, Goturic and Goutex in Latin America, Feburic in Japan, and is generic in several countries and is available by many names in those countries.^[1]

Febuxostat (Formula I) is an inhibitor of xanthine oxidase, which was discovered by the Japanese company Teijin Pharma Ltd and it is indicated for use in the treatment of hyperuricemia and chronic gout. Its chemical name is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl- l,3-thiazole-5-carboxylic acid. It is marketed under the brand names Adenuric in Europe, Feburic in Japan and Uloric in USA and Canada.

In EP0513379B1 Febuxostat is prepared from 4-hydroxy-3-nitrobenzaldehyde, according to the following scheme.

This particular process suffers from major drawbacks. Not only it is very long, including seven steps from the starting material to the final product, but, most importantly, it employs the use of cyanides, which are extremely toxic reagents. Cyanide salts are likely to generate hydrocyanide, which sets a high amount of risk in an industrial scale process.

In Japanese patent JP06345724A(JP2706037B) the intermediate ethyl ester of Febuxostat is prepared from p-cyano-nitrobenzene, in three steps. Febuxostat may, then, be prepared by alkaline hydrolysis, according to prior art.

MeCSNH,

The use of extremely toxic potassium cyanide makes this process unsuitable for manufacturing purposes.

Route A

In Japanese patent JP3202607B Febuxostat ethyl ester is prepared, according to the above scheme, through two similar routes. Route A uses flash column chromatography for the purification of the hydroxylamine reaction product, while Route B suffers from low yield and the use of chlorinated solvents for recrystallization. In addition, the reaction solvent is, in both cases, formic acid which causes severe skin burns and eye damage to humans. Formic acid is also corrosive towards metal-based materials of construction (MOC), like stainless steel and nickel alloys, limiting the options, essentially, to glass reactors or vessels. The drawbacks of using this solvent are also related to the high volumes of formic acid required per batch, which hinder the waste treatment.

In CN101723915B focus is made to the improvement of the hydroxylamine reaction. Formic acid is replaced with dimethylformamide (DMF) and other solvents. However, according to widely used organic chemistry textbooks, such as March’s Advanced Organic Chemistry, pi 287, 6^th edition, M. B. Smith and J. March, ISBN 0-471-72091-7, the mechanism of the reaction involves the formation of an oxime, upon the action of hydroxylamine, which further dehydrates to form a nitrile, with the aid of a suitable reagent, for example formic acid, or acetic anhydride. In the absence of such a reagent, it is expected that the reaction will, at least, not lead to completion, thereby leading to low yields and undesired impurity levels, namely the intermediate oxime. Such impurities, arising from the reactions of the process and which exhibit similar structure of the desired product, are often difficult to remove with common industrial techniques, e.g. crystallization.

In WO2010142653A1 the intermediate Febuxostat ethyl ester is prepared from 4-cyanophenol, through a five-step process. Febuxostat can be prepared from its respective ethyl ester via alkaline hydrolysis, as in the previous case.

1: patents US5614520 febuxostat synthetic process:

2: Patent JP1994329647 febuxostat synthesis

PATENT

https://www.google.com/patents/CN102936230A?cl=en

Gout occurs because the body produces too much uric acid and renal clearance capacity decreased, uric acid accumulation in the body, leading to urate crystals deposited in the joints and organs. Therefore, it means the treatment of gout usually taken to be: to promote uric acid excretion and suppression of uric acid, and the use of appropriate measures to improve symptoms. Uric acid formation and purine metabolism, the final step in the purine metabolism, hypoxanthine generation xanthine xanthine oxidoreductase (XOR) effect, further generate uric acid, inhibit the activity of the enzyme can effectively reduce uric acid production. Febuxostat is currently the world’s newly developed XOR inhibitors, which act by highly selective to the oxidase, reduce uric acid synthesis, reduce uric acid levels, so as to effectively treat the disease ventilation.

Compared with the traditional treatment of gout drug allopurinol, febuxostat has obvious advantages: (1) allopurinol reduced the XOR only inhibit rather than febuxostat of oxidized and reduced form are XOR significant inhibition, thus reducing the role of uric acid, which is more powerful and lasting; (2) Since allopurinol is a purine analogue, the inevitable result of the purine and other activity related to the impact of pyridine metabolism. So allopurinol treatment should be repeated large doses of the drug to maintain a high level. Which also brought serious or even fatal adverse reactions due to drug accumulation due.Instead of febuxostat non-purine XOR inhibitors, so it has better security.

Document TMX-67. Drugs Fut2001, 26, I, 32, and EP0513379, US5614520, W09209279, public

The detailed preparation febuxostat. Using 3-nitro-4-hydroxybenzaldehyde as the starting material is first reacted with hydroxylamine hydrochloride, to give 3-nitro-4-hydroxybenzonitrile. In effect then HCl, reaction with thioacetamide to give 3-nitro-4-hydroxy-thiobenzamide. Closed loop then reacted with 2-chloro ethyl acetoacetate to give 2- (3_ nitro-4-hydroxyphenyl) methyl-5-thiazolyl -4_ carboxylic acid ethyl ester. Followed by potassium carbonate effect, isobutane is reacted with bromo, to give 2- (3_ nitro-4-isobutyloxyphenyl) -4-methyl-5-carboxylic acid ethyl ester. Under the catalytic action of palladium on carbon, hydrogen reduction to give 2- (3-amino-4-isobutyloxyphenyl) -4-methyl-5-thiazole carboxylic acid ethyl ester. Followed by diazotization with sodium nitrite occur, was added cuprous cyanide and potassium cyanide, to give 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid ethyl ester. Finally, under the effect of the hydrolysis of sodium hydroxide, to give the product 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl – thiazole-5-carboxylic acid, to obtain febuxostat.The process route is as follows:

This route in the preparation of febuxostat, there are many disadvantages: raw 3-nitro-4-hydroxybenzaldehyde in the country is difficult to buy; requires the use of palladium-carbon catalytic hydrogenation reaction under the factory equipment higher requirements, there is a certain danger; the cyano preparation, the need to use sodium nitrite diazotization, could easily lead to corrosion of equipment; the cyano preparation, the need to use toxic cyanide copper, potassium cyanide, pollution, higher risk.

Document JP1994329647, JP1998045733, US3518279 reported another synthesis of febuxostat

Methods. From 4-hydroxy-thiobenzamide as a starting material, and the cyclization reaction to give ethyl 2-bromo-acetyl occurred

2- (4_ hydroxyphenyl) -4_ methyl-5-carboxylic acid ethyl ester in polyphosphoric acid effect, HMTA (hexamethylene tetramine) reacts with 2- (3_ aldehyde – 4-hydroxyphenyl) methyl-5-thiazolyl -4_ carboxylic acid ethyl ester. Then two cases: the first case, the effect of potassium carbonate, is reacted with isobutane to give bromo-2- (4-isobutyloxyphenyl 3_ aldehyde) -4_-methyl-5- thiazole carboxylic acid ethyl ester, and then reacted with hydroxylamine hydrochloride to give 2- (3_-cyano-4-isobutyloxyphenyl) -4_-methyl-5-thiazole carboxylic acid ethyl ester; second case is the first with hydroxylamine hydrochloride to give 2- (3_ cyano-4-hydroxyphenyl) methyl-5-thiazolecarboxylic -4_ carboxylic acid ethyl ester, and then under the effect of potassium carbonate, and reacted with isobutane to give bromo-2- (3 _-cyano-4-isobutyloxyphenyl) -4-methyl-5-carboxylic acid ethyl ester.

Finally, under the effect of the hydrolysis of sodium hydroxide, to give the product 2- (3_-cyano-4-isobutyloxyphenyl) -4_ methyl – thiazole-5-carboxylic acid, i.e., to obtain febuxostat . The process route is as follows:

This synthesis route febuxostat process, since the introduction of aldehyde HMTA in PPA (polyphosphoric acid) effect. So there are a lot of phosphorus wastewater, serious environmental pollution, but also because PPA has great viscosity, and therefore difficult to stir the production, operation is extremely inconvenient.

Document Heterocyclesl998, 47,2,857 JP1994345724 also reported the synthesis method of febuxostat, using p-nitrophenyl-carbonitrile as a starting material in the reaction with potassium cyanide in DMSO solvent, and then the carbonate lower potassium catalyzed reaction of isobutane and brominated 1,3-cyano-4-diisobutoxybenzene ether. By reaction with thioacetamide to afford

3-cyano-4-isobutyloxyphenyl thiobenzamide. Under heating, and 2-chloro ethyl acetoacetate, ring closure reaction occurs to give 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-carboxylic acid ethyl ester, and finally hydrolysis under the effect of sodium hydroxide, to give the product 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl – thiazole-5-carboxylic acid, to obtain febuxostat.

The present invention febuxostat new technology system, comprising the steps of:

(1) 2-hydroxy-5-cyano – NaSH reacted with benzaldehyde to give 4-hydroxy-3- aldehyde thiobenzamide;

(2) the step (I) to give 4-hydroxy-3-aldehyde thiobenzamide reaction with ethyl 2-halo-acetyl, closed

Ring to give 2- (3-aldehyde-4-hydroxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole;

X is a halogen, preferably Cl or Br;

(3) the step (2) to give 2- (3-aldehyde-4-hydroxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole with hydroxylamine in formic acid in the reaction solution to give 2- (3- cyano-4-hydroxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole;

(4) The step (3) to give 2- (3-cyano-4-hydroxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole isobutane with halo effect in potassium carbonate, to give 2- (3-aldehyde-4-isobutyloxyphenyl) -4-methyl-5-ethoxycarbonyl thiazole;

(5) in step (4) to give 2- (3-aldehyde-4-isobutyloxyphenyl) -4-methyl-5-ethoxycarbonyl-thiazol-off hydrolyzable ester group, to obtain a non-Tendon Disposition Tanzania.

[0011] Scheme of the method is as follows:

X is halogen, may be Cl, Br;

Preparation 5 febuxostat Example

To a 500ml reaction flask was added 200ml of absolute ethanol, the product of Step 4 was added with stirring (60g, O. 174mol),

5% sodium hydroxide was added 100ml. Stirring heated to 40 degrees, until it is completely dissolved. 40 degrees heat, reaction 4h. The reaction by TLC tracking. After completion of the reaction, the reaction solution was added 10% hydrochloric acid to adjust the pH to 3, the precipitated solid was filtered. And dried to give a pale yellow solid. Dried over anhydrous recrystallized from methanol to give 31. 2g of white crystals, yield 56.7%.

TLC monitoring of the reaction. Eluent: petroleum ether / ethyl acetate = 3: 1 Melting point:. 201 · 7 ~202 30C (literature value 201 ~202 ° C)

1H-NMR δ:. 1 01 (m, 6H), 2.06 (m, lH), 2.57 (m, 3 H), 3.96 (d, 2H), 7.30 (d, lH), 8.13 (m, 1H), 8. 19 (d, 1H);

MS (m / z):. 316 O (M +)

Infrared detection: 3550-3400cm_1; 2961, 2933,2874; 2227cm_1; 1680U604U511cm_1; 1425cm_1; 1296U283CHT1;

Elemental analysis for C, Η, N, S purified product actual measurement of the content of C, H, N, S content: C:. 60 57%, H:. 5 32%, N:. 8 86%, S: 10. 16%; theoretical value: In C16H16N203S calculated C: 60 74%, H: 510%, N: 885%, S: 1014%..

CLIP

Facile OnePot Transformation of Arenes into Aromatic Nitriles …

onlinelibrary.wiley.com

Facile OnePot Transformation of Arenes into Aromatic Nitriles under MetalCyanideFree Conditions

Patent

http://www.google.com/patents/WO2011141933A2?cl=en

The present invention relates to an improved process for the preparation of anti- hyperuricemia drug 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5- carboxylic acid (commonly known as Febuxostat) and its pharmaceutically acceptable salts, represented by the following structural formula- 1.

Formula- 1

Further, the present invention provides novel amine salts of compound of formula- 1 and its process for the preparation.

The present invention also provides a novel process for the preparation of crystalline forms A, B and G of Febuxostat. Febuxostat is an inhibitor of xanthine oxidase that is indicated for use in the treatment of hyperuricemia and gout.

Febuxostat was approved by the European Medicines and the U.S. Food and Drug Administration. Febuxostat is marketed by Takeda Pharmaceuticals with the brand names Adenuric (EU) and Uloric (US).

Background of Invention:

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid was first disclosed in US 5614520. The disclosed process comprises of reacting the ethyl 2-[4- hydroxy-3-nitrophenyl]-4-methyl-5-thiazolecarboxylate with 1 -bromo-2-methylpropane in the presence of potassium carbonate in dimethyl formamide provides ethyl 2-[4-(2- methylpropoxy)-3-nitrophenyl]-4-methyl-5-thiazole carboxylate which is reduced with Pd/C and the obtained compound is treated with sodium nitrite in water and followed by a mixture of cuprous cyanide and potassium cyanide provides ethyl 2-[4-(2- methylpropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylate. The obtained ethyl 2- [3-cyano-4-(2-methylpropoxy)phenyl)-4-methyl-5-thiazolecarboxylate was hydrolyzed by treating with aqueous sodium hydroxide in a mixture of ethanol and tetrahydrofuran provides 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid having melting range of 238 – 239°C with the yield of 33%. The above process utilizes Pd/C, which is difficult to handle in the laboratory, hence it is not recommended on large scale. However, the yield and purity were also not satisfactory. The said process involves more number of steps, hence there is a need to produce the process for the preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid with less number of steps.

Heterocycles, 1998, Vol. 47, No. 2, 857-864 disclosed a process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid which comprises of reacting 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile in the presence of hydrochloric acid with thioacetamide in dimethyl formamide provides 4-(2- methylpropoxy)-3-cyanobenzthioarnide. It was reacted with ethyl 2-chloroacetoacetate in ethanol provides ethyl 2-[4-(2-methylpropoxy)-3-nitrophenyl]-4-methyl-5-thiazole carboxylate which is further hydrolyzed with aqueous sodium hydroxide solution in a mixture of tetrahydrofuran and ethanol provides 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid with the yield of 35% which on further recrystallized from acetone provides a colorless crystals having the melting range of 201 – 202°C. However the yield and purity were not satisfactory. JP10-045733 disclosed a process for the preparation of 2-[3-cyano-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid which comprises of reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate with hydroxyl amine in 2011/000328 presence of formic acid and sodium formate provide ethyl 2-(3-cyano-4-hydroxyphenyl)-4- methylthiazole-5-carboxylate. The obtained compound was reacted with l-bromo-2- methylpropane in presence of potassium carbonate provides ethyl 2-[3-cyano-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate, which on further hydrolysis with aq sodium hydroxide provides 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid.

2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid produced by the above processes contains 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid as an impurity. So there is a need for the purification to get the highly pure 2-[3-cyano-4-(2-methylpropoxy) phenyI]-4-methylthiazole-5-carboxylic acid.WO2011141933

In general, febuxostat prepared by the reported processes contain impurities like amide impurity, ethyl ester impurity and methyl ester impurity etc. It is important that any pharmaceutical compound or intermediate should free of impurities or if present they must be limited to the maximum level set by ICH guidelines. The purification technique of by recrystallisation of the compound from a suitable solvent such as the recrystallisation of febuxostat as disclosed in Heterocycles, Vol. 47, No. 2, 1998 does not yields the desired purity. Hence it is necessary to have an alternate purification technique for the preparation of highly pure febuxostat.

In the aforementioned processes using aqueous sodium hydroxide for hydrolyzation of ethyl 2-[4-(2-methylpropoxy)-3-nitrophenyl]-4-methyl-5-thiazole carboxylate, which lead to the formation of impurities such as ethyl ester impurity, methyl ester impurity, amide impurity and high polar impurities. Hence there is a need to develop a process for the preparation of highly pure febuxostat with high yield.

The crystalline forms A, B, C, D and G of febuxostat and their preparation were first disclosed in US 6225474. However as on date, there is no alternative processes were reported in the prior art for preparing the said polymorphs. Henceforth, there is a need to develop a novel process for the preparation of said crystalline polymorphs.

In view of the foregoing, there is a necessity for the improved process which overcome the problems of prior art and to produce the highly pure 2-[3-cyano-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid with high yield.

Advantages of Present Invention:

• Avoids the usage of Pd/ C .

• Provides the highly pure 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5- thiazole carboxylic acid with high yield.

• Controls the impurities (such as methyl impurity, ethyl impurity, amide impurity and high polar impurities) levels to meet the ICH guidelines.

• Provides a novel process for the preparation of crystalline forms A, B and G of 2-[3- cyano-4-(2 -methylpropoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid.

· Provides a novel and improved processes for the preparation of 4-(2-methylpropoxy)- 1,3 -benzene dicarbonitrile and also provides a simplest process for the purification of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole carboxylic acid.

• Eco-friendly process.

• Uses simple, milder reagents which are easier to handle and use in large scale.

WO2011141933

Formula-6 ForrauIa-

Scheme-II:

Scheme-Ill:

Example 8: Preparation of Febuxostat (Formula-1)

A mixture of compound of formula-5 (50 g), sodium hydroxide (23.25 g), tetrahydrofuran (250 ml) and water (13 ml) was heated to 60-65°C and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C and quenched it with water. The reaction mixture was stirred for 1 hour at 25-30°C. A solution of hydrose (2.5 g) in water (25 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes. The p^H of the reaction mixture was adjusted to 1.3 with hydrochloric acid. The reaction mixture was extracted thrice with ethylacetate, washed with water and the organic layer was dried with sodium sulfate. Carbon (2.5 g) was added to the organic layer and stirred for 30 minutes. The reaction mixture was filtered through hyflow bed and washed with ethylacetate. Distilled off the solvent completely from the obtained filtrate to get the solid. Ethyl acetate (200 ml) was added to the obtained solid and heated to reflux temperature and stirred for 30 minutes. The reaction mixture was cooled to 25-30°C, filtered the solid obtained and washed with ethyl acetate. Acetone (250 ml) was added to the wet solid obtained, heated to 55-60°C and stirred for 15 minutes. Water (250 ml) was added to the reaction mixture and stirred for 2 hours. The obtained solid was filtered, washed with aqueous acetone and then dried to get the title compound. Yield: 38 grams.

Example 9: Preparation of Febuxostat (Formula-1)

A mixture of compound of formula-5 (50 g), sodium hydroxide (23.25 g), tetrahydrofuran (250 ml) and water (13 ml) was heated to 60-65°C and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C and quenched it with water. The reaction mixture was stirred for 1 hour at 25-30°C. A solution of hydrose (2.5 g) in water (25 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes. The p^H of the reaction mixture was adjusted to 1.3 with hydrochloric acid. The compound was extracted thrice with ethyl acetate, washed with water and the organic layer was dried with sodium sulfate. Carbon (2.5 g) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was filtered through hyflow bed and washed with ethylacetate. Distilled off the solvent completely from the obtained filtrate to get the solid. Acetone (250 ml) was added to the solid obtained, heated to 55-60°C and stirred for 15 minutes. Water (250 ml) was added to the reaction mixture and stirred for 45 minutes . Cooled the reaction mixture to 25-30°C and stirred for 30 minutes, further to 0-5 °C and stirred for 2 hours. The obtained solid was filtered, washed with aqueous acetone and then dried. Ethylacetate (200 ml) was added to the obtained solid and heated to reflux temperature and stirred for 30 minutes. The reaction mixture was cooled to 25-30°C. Filtered the solid, washed with ethyl acetate and then dried to get the pure title compound. Yield: 39 grams

Example 10: Preparation of ethyl 2-[3-formyl-4-(2-methyIpropoxy) phenyl]-4- methylthiazole-5-carboxylate compound of formula-12.

To a stirred solution of ethyl 2-[3-formyl-4-hydroxyphenyl]-4-methylthiazole-5- carboxylate (10 gms) in dimethylformamide (40 ml) added potassium carbonate (9.78 gms) and potassium iodide (2.35 gms). Heated the reaction mixture to 70 – 75°C and stirred for 30 minutes. To the above reaction added a solution of l-bromo-2- methylpropane (9.72 gms) in dimethyl formamide (10 ml) and stirred for 5 hours. Cooled the reaction mixture to 25°C, quenched with water and stirred for one hour. Filtered the precipitated solid and dried the material to get the title compound. Yield: 9 gms.

Example 11: Preparation of ethyl 2-[3-cyano-4-(2-methyIpropoxy) phenyl]-4- methyIthiazoIe-5-carboxylate compound of formuIa-5.

To the solution of ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylate compound of formula-12 (10 gms) in formic acid (40 ml) was added hydroxylamine hydrochloride (2.38 gms) and sodium formate (2.35 gms).

Stirred the reaction mixture for 10 minutes. Heated the reaction mixture to 100°C and stirred for four hours at same temperature. Cooled the reaction mixture to 25 °C and quenched with water. Stirred the reaction mixture for 10 hours, filtered the precipitated solid and washed with water. Dried the material to get the title compound. Yield: 10 gms. Take the dry material, added 30 ml of ethyl acetate and heated to reflux temperature. Stirred the reaction mixture for 30 minutes at reflux temperature. Cooled the reaction mixture to 25°C and filtered the precipitated solid. Dry the material to get the title compound as a pure material. Yield: 8.5 gms.

http://www.google.com/patents/WO2011141933A2?cl=en

Clip

synthesis describes synthesis of febuxostat (I) from 4-hydroxybenzonitrile (II) in six stages. The synthesis shown is a short, concise route and does not require use of poisonous reagents such as KCN (14). Compound II was converted to 4-hydroxybenzothioamide (III) with 85% yield using NaHS in the presence of hydrated magnesium chloride as Lewis acid. Intermediate III, on cyclization with ethyl-2-chloroacetoacetate, gave thiazole ester (IV) with quantitative yield. In these two stages, the source of potential impurities was identified as an ortho isomer (i.e., 2-hydroxybenzonitrile), which can lead to Impurity VIII and subsequently to Impurity IX . Impurities VIII and IX can be controlled in starting material II with appropriate specification.

Figure 2: Impurities identified during the various stages of synthesis of febuxostat.

The ortho formylation of hydroxyl compound IV by using Duff condition (hexamine/TFA) gave aldehyde V (15). The major impurity identified in this reaction was dialdehyde X. Although we have used only 1.0 equivalence of hexamine with respect to Compound IV, the dialdehyde X impurity was formed to a 5-10% ratio in only 2.5 h. It is, therefore, impossible to get rid of this impurity during the reaction, and only effective recrystallization will eliminate it. Impurity X was minimized (≤ 2%) by recrystallization using IPA/H₂O (3:5) to get aldehyde V with 50% yield and & #8805; 97% HPLC purity.

Aldehyde V, on alkylation with isobutyl bromide in the presence of potassium carbonate base, gave compound VI with 90% yield. In this stage, Impurities XI and XII were alkylations of carryover Compound IV and dialdehyde, respectively. Two more isomeric impurities n-butyl-aldehyde XIII and 1-methyl propyl-aldehyde XIV were also identified in this stage. Both isomeric impurities can be controlled with appropriate specification for isobutyl bromide. The reaction of Compound VI with hydroxylamine hydrochloride and sodium formate in formic acid at reflux temperature gave Compound VII with 85% yield. Impurities XIII and XIV will also carry forward to impurities n-butyl-nitrile XV and 1-methyl propyl-nitrile XVI, respectively.

In the final step, Compound VII was hydrolyzed using sodium hydroxide in a MeOH:THF:H2O (1:1:1) solvent combination to yield febuxostat (85%). During saponification, methyl ester Impurity XVII was identified via trans-esterification. Its hydrolysis was comparatively slower than its ethyl isomer VII. One way to avoid Impurity XVII is to replace methanol with ethanol. Carryover impurities XI, XV, and XVI were also hydrolyzed to their respective acid derivatives impurities XVIII, XIX, and XX. However, the acid derivatives of impurities X and XII were unexpectedly absent as impurities. It is believed that, because they were present in low concentrations during workup, they were eliminated in the mother liquor. Two additional impurities, amide XXI and diacid XXII, formed by the side reaction of the febuxostat nitrile group with sodium hydroxide, were identified during saponification. The amide XXI and diacid XXII impurities can be controlled by using appropriate equivalence of sodium hydroxide and controlled reaction time. Febuxostat, on acetone recrystallization and seed Crystal A at 45°C, gave pure febuxostat with 75% yield.

http://www.pharmtech.com/investigation-various-impurities-febuxostat

References

Drugs.com Drugs.com international names for febuxostat Page accessed June 25, 2015
Febuxostat for the management of hyperuricaemia in people with gout (TA164) Chapter 4. Consideration of the evidence
Uloric label Updated February, 2009.
Love BL, Barrons R, Veverka A, Snider KM (2010). “Urate-lowering therapy for gout: focus on febuxostat”. Pharmacotherapy 30 (6): 594–608. doi:10.1592/phco.30.6.594.PMID 20500048.
Ashraf Mozayani; Lionel Raymon (2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science+Business Media.
Teijin Febuxostat Story Page accessed June 25, 2015
Tomlinson B. Febuxostat (Teijin/Ipsen/TAP). Curr Opin Investig Drugs. 2005 Nov;6(11):1168-78. PMID 16312139
Bruce Japsen for the Chicago Tribune. August 17, 2006. FDA puts gout treatment on hold
Note: TAP Pharmaceuticals was a joint venture between Abbott Laboratories and Takedathat was dissolved in 2008 per this press release: Takeda, Abbott Announce Plans to Conclude TAP Joint Venture
“Adenuric (febuxostat) receives marketing authorisation in the European Union” (PDF). Retrieved 2008-05-28.
“Uloric Approved for Gout”. U.S. News and World Report. Retrieved 2009-02-16.
Teijin and Takeda. February 14, 2009 Press release: ULORIC® (TMX-67, febuxostat) Receives FDA Approval for the Chronic Management of Hyperuricemia in Patients with Gout
Teijin. January 21, 2011 Press release: TMX-67 (febuxostat) Approved in Japan
Genetic Engineering News. October 2009. Menarini to Market Takeda/Ipsen Gout Therapy in 41 European Countries
First Word Pharma. April 1st, 2010 Teijin Pharma and Astellas Pharma enter into agreement for marketing rights of TMX-67 in China and Hong Kong
Research Views. Aug 11 2011 Teijin Pharma Enters Into Distribution Agreement With Astellas Pharma For Febuxostat

Febuxostat is an inhibitor of xanthine oxidase, and was developed by Teijin pharma. This compound is known as a new drug that is effective against gout and hyperuricemia, and it has been 40 years since the last time a drug of this kind of drug was developed.

Febuxostat has therefore gained a lot of popularity and it has already been accepted as a drug in Europe, USA, Korea and Japan. The synthesis of this molecule have been reported in patents by Teijin pharma as shown below.^[1,2]

Recently, Itami group was reported the rapoid synthesis of febxostat by using Ni-catalyzed direct coupling of azoles and arylhalides^[3]

References

Sorbera, L.A.; Castaner, J.; Rabasseda, X.; Revel, L.; TMX-67. Drugs Fut 2001, 26, 1, 32

[1] Hasegawa, M.; A facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile. Heterocycles 1998, 47, 2, 857. [2] Hasegawa, M.; Hasegawa, M.; Komoriya, K. (Teijin Ltd.); Cyano cpds. and their preparation method. JP 1994345724 . [3] “Nickel-Catalyzed Biaryl Coupling of Heteroarenes and Aryl Halides/Triflates”

Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733-1736. DOI: 10.1021/ol9001587

Ni-based catalytic systems for the arylation of heteroarenes with aryl halides and triflates have been established. Ni(OAc)2/bipy is a general catalyst for aryl bromides/iodides, and Ni(OAc)2/dppf is effective for aryl chlorides/triflates. Thiazole, benzothiazole, oxazole, benzoxazole, and benzimidazole are applicable as heteroarene coupling partners. A rapid synthesis of febuxostat, a drug for gout and hyperuricemia, is also demonstrated.

A CLIP

A final example of a thiazole containing drug is given in the novel xanthine oxidase inhibitor febuxostat (359, Uloric) which was approved by the FDA in 2009. This inhibitor works by blocking xanthine oxidase in a non-competitive fashion. Consequently, the amount of the oxidation product uric acid is reduced. Thus it is an efficient treatment for hyperuricemia in gout. In order to prepare febuxostat first a synthesis of the noncommercial 4-isobutoxy-1,3-dicyanobenzene building block (363), has to be conducted. An elegant way of achieving this was shown through the reaction of 4-nitrocyanobenzene (360) with potassium cyanide in dry DMSO followed by quenching with isobutyl bromide under basic conditions (Scheme 70). It is suggested that a Meisenheimer-complex intermediate 361 is initially formed, which after rearomatisation, undergoes nucleophilic aromatic substitution of the nitro group by the DMSO solvent [107]. Upon hydrolysis and O-alkylation the desired 4-isobutoxy-1,3-dicyanobenzene (363) is obtained in good overall yield. Subsequently, the less hindered nitrile is converted to the corresponding thioamide 365 in an intriguing reaction using thioacetamide (364). The thiazole ring is then formed by condensation with chloroacetoacetate 366 followed by ester hydrolysis (Scheme 70).

107 Hasegawa, M. Heterocycles 1998, 47, 857–864. doi:10.3987/COM-97-S(N)89

Paper | Special issue | Vol 47, No. 2, 1998, pp.857-864

DOI: 10.3987/COM-97-S(N)89

■ A Facile One-Pot Synthesis of 4-Alkoxy-1,3-benzenedicarbonitrile

Masaichi Hasegawa

*Teijin Institute, Bio-Medical Research, Asahigaoka 4-3-2, Hino, Tokyo 191, Japan

Abstract

2-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxlic acid (TEI-6720) was prepared. The introduction of cyano group to 4-nitrobenzonitrile with KCN in dry DMSO followed by quenching with alkyl halide afforded the key intermediates, 4-alkoky-1,3-benzenedicarbonitriles, in good yield. The reaction was completed in dry DMSO, while no reaction occurred in dry DMF. This observation can be suggested by the participation of DMSO in the reaction.

PDF (208KB)

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-7-57#S70

A CLIP

Synthesis and characterization of process-related impurities of an anti-hyperuricemia drug-Febuxostat

Venkateswara Rao Vallu,$ Krunal Girishbhai Desai, Sandip Dhaya Patil, Rajendra Agarwal, Pratap Reddy Padi and Mahesh Reddy Ghanta

*Process Research Laboratory-I, Research & Development Centre, Macleods Pharmaceuticals Ltd, G-2, Mahakali Caves Road, Shantinagar, Andheri (East), Mumbai, Maharastra, India

$Department of Chemistry, Pacific University, Pacific Hills, Airport Road, Pratap Nagar Extension, Debari, Udaipur, Rajasthan, India _____________________________________________________________________

Der Pharma Chemica, 2014, 6(3):300-311 (http://derpharmachemica.com/archive.html)

http://derpharmachemica.com/vol6-iss3/DPC-2014-6-3-300-311.pdf

Synthesis of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (1) [10] A solution of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (1 tech grade, 5.0 g, 0.015 mol.) in methanol (50.0 mL) was heated the reaction mass at 60-65°C till clear solution was obtained. Water (50.0 mL) was added drop wise into reaction mass with in 30.0 min. at 60-65°C. Resultant white crystalline solid was filtrated, Mahesh Reddy Ghanta et al Der Pharma Chemica, 2014, 6 (3):300-311 _____________________________________________________________________________ 302 www.scholarsresearchlibrary.com washed with water (10.0 mL) and dried in vacuum tray drier at 50-55°C under vacuum to give

2-(3-cyano-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (1). Yield: 95.0 % (4.75 g)

mp 239°C. Purity by HPLC: 99.74 % (10.2 min. retention time),

Anal. Calcd for C16H16N2O3S: C, 60.74; H, 5.10; N, 8.85. Found: C, 60.70; H, 5.11; N, 8.87 %;

IR (KBr) υmax (in cm−1): 3834.61, 3742.03, 3680.30, 3556.85, 3456.55, 2962.76, 2877.89, 2661.85, 2546.12, 2353.23, 2229.79, 2168.06, 2029.18, 1921.16, 1790.00, 1674.27, 1604.83, 1512.24, 1427.37, 1381.08, 1280.78, 1172.76, 1118.75, 1010.73, 918.15, 833.28, 771.55, 725.26, 648.10, 524.66, 462.93; 1H NMR (300 MHz, CDCl3 or DMSO-d6) δH (in ppm): 1.00-1.02 (d, 6H, (CH3)2-CH-), 2.49-2.50 (m, 1H, (CH3)2-CH-), 3.97-3.99 (d, 2H, -CH-CH2−), 7.33–8.25 (d, dd, 3H, Ar-H), 2.64 (s, 3H, -CH3), 13.39 (s, 1H, -COOH);

13C NMR (300 MHz, DMSO–d6) δC (in ppm) (Positiona ): 166.3 (l), 162.9 (p), 162.2 (n), 159.6 (e), 133.1 (g), 131.6 (i), 125.5 (m), 123.0 (h), 115.5 (k), 114.0 (f), 101.7 (j), 75.2 (d), 27.7 (b), 18.8 (a, c), 17.1 (o);

MS m/z (%) (70 eV): m/z =317.0 (100.0 %) [M+1], 318.0 (16.0 %) [M+2], 403.0 (63.0 %), 512.0 (47.0 %), 482.0 (46.0 %), 405.0 (27.0 %), 468.0 (25.0 %), 570.0 (24.0 %).

PATENT

WO 2012066561

https://www.google.com/patents/WO2012066561A1?cl=en

As per the present invention, hydroxylamine hydrochloride is added to compound of Formula-Ill in presence of a polar aprotic solvent like DMSO, DMA, ACN or DMF. To this reaction mixture acetyl halides or sulfonyl chlorides are added and temperature raised to 70 -80 °C. Acetyl halides are selected from acetyl bromide or acetyl chloride. Sulfonyl chlorides are selected from methane sulfonyl chloride or para toluene sulfonyl chloride. To this reaction mixture a base selected from alkali metal carbonates like potassium carbonate or sodium carbonate, preferably potassium carbonate and alkyl halide selected from isobutyl bromide is successively added. The reaction mass is washed with water and compound of Formula-II is isolated. In one embodiment the present invention provides, process for the preparation of Febuxostat comprising the steps of:

a) reacting the compound of Formula-III(a) with hydroxylamine hydrochloride in presence of organic solvent;

Formula-III(a)

b) adding acyl halides or sulfonyl chlorides to the reaction mixture;

c) optionally isolating compound of Formula- IV (a)

Formula-IV(a)

d) reacting with isobutyl bromide in presence of base;

e) isolating the compound of Formula-II(a); and

FormuIa-II(a)

f) hydrolyzing the compound of Formula-II(a) to get Febuxostat.

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art. Experimental procedure:

Example – 1: Preparation of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyI thiozole -5-carboxylate

A mixture of 10. Og of Ethyl -2-(3-formyl-4-hydroxy phenyl)-4-methyl thiozole -5- carboxylate and 2.85 g of hydroxylamine hydrochloride were stirred for 30 minutes in 40 g of Dimethyl sulfoxide. To this reaction mixture 3.3 grams of acetyl chloride was added and stirred at 70 -80°C for 2-3 hours. Reaction mass was cooled to room temperature and to this 19 g of potassium carbonate and 19 g of isobutyl bromide was added successively. The reaction mass was stirred for 5 hours at 70-80°C. Reaction mass was diluted with 200 ml of purified water. The reaction mass was filtered and washed with purified water to give 10.0 g of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxyltae (yield 84.0%)

Example – 2: Preparation of Ethyl-2-(3-cyano-4-hydroxyphenyl)-4-methyl thiozole – 5-carboxylate

A mixture of 10. Og of Ethyl-2-(3-formyl-4-hydroxy phenyl)-4-methyl thiozole -5- carboxylate and 2.85 g of hydroxylamine hydrochloride were stirred for 30 minutes in 30 g of Dimethylformamide. To this reaction mixture 3.3 grams of acetyl chloride was added and stirred at 90°C for 2-3 hours. Reaction mass was cooled to room temperature and diluted with 100 ml of water and stir for 2 hours. The reaction mass was filtered and washed with purified water to give 10.0 g of Ethyl-2-(3-cyano-4-hydroxy phenyl)-4- methyl thiozole -5-carboxyltae (yield 99.0%).

Example – 3: Preparation of Ethyl 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylate

A mixture of 10. Og of Ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole -5- carboxylate, 30 g of NMP, 9.6 g of potassium carbonate and 7.2 g of isobutyl bromide were stirred for 3 hours at 90°C. Reaction mass was diluted with 100 ml of purified water. The reaction mass was filtered and washed with purified water and ethanol to give 10.5 g of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxyltae (yield 88.0%). Example – 4: Preparation of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5- carboxylic acid

A mixture of 10. Og of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5- carboxyltae, 2.0g of sodium hydroxide was heated at 45-60°C in 75 ml of aqueous methanol for 1 hour. Reaction mass was cooled to ambient temperature and pH adjusted to 2.0 to 2.5 with dilute hydrochloric acid and precipitated crystal was collected by filtration to give 8.8g of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid (yield 95.8%).

Example – 5-13: Preparation of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole – 5-carboxylic acid

The above compound was prepared by following the procedure as disclosed in Example- 4, using the below listed solvents instead of aqueous methanol.

Example – 14: Preparation of pure 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid

10.0 g of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid was dissolved in 100 ml of ethanol at reflux temperature. After dissolution reaction mass was cooled and precipitated crystal was collected by filtration to give 9.6 g of pure 2-(3- cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid (yield 96%).

PATENT

KR 201603732

PATENT

WO 2015018507

https://www.google.com/patents/WO2015018507A2?cl=en

EXPERIMENTAL

of compound of formula lib

Dissolve 14.14g of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula III) in 55 ml dimethylformamide, at ambient temperature. Add 40g of potassium carbonate, along with 15.9 ml isobutyl bromide. Heat the reaction to 75-80 °C and stir for 4 hours. Cool to 25-30 °C, while 165 ml process water is added. Further cool to 0-5 °C and stir for 30 minutes at this temperature. Filter off the precipitated solid and wash the filter cake with 55 ml process water. The wet cake is dried under vacuum at 40 °C for 7 hours, to furnish 16.43 g of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula lib).

of compound of formula Illb

In a 25 mL round-bottomed flask charge under stirring at 25-30 °C, 1.0 g (2.88 mmol) of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate in 3.0 mL dimethylformamide. Add 34 mg (0.19 mmol) copper acetate under stirring at 25-30 °C. Flush with oxygen (0₂) and add 0.66 ml (34.92 mmol) 25% aqueous ammonia. Flush again with 0₂. Heat the reaction mixture to 80-82 °C overnight. Check the progress of the reaction by TLC (cyclohexanerethyl acetate 3:1). Cool reaction mass to 25-30 °C. Add 25mL ethyl acetate and 25mL brine at the reaction mass, separate organic layer and extract aqueous layer twice with 25mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate till dry. The residue is purified with column chromatography (cyclohexane:ethyl acetate 9:1). afforded 0.754g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula Illb) Yield: 75.4%.

EXAMPLE 3: Preparation of compound of formula Illb

In a 25 mL round-bottomed flask charge under stirring at 25-30 °C, 0.17 g (0.49 mmol) of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate in 2.5 mL tetrahydrofuran. Add 2.9 mL (153.43 mmol) 25% aqueous ammonia, under stirring at 25-30 °C. Add 137 mg (0.54 mmol) iodine (I₂) to the reaction mass, stir the reaction mixture at 25-30 °C for 15-30 min. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 3:1). Starting material is consumed. Add 2.5 mL 5% w/v aqueous sodium thiosulfate Na₂S₂0₃ and 15mL ethyl acetate at the reaction mass, separate organic layer and extract twice aqueous layer with 15mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate till dry. 0.158g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula Illb) are collected.

EXAMPLE 4: Preparation of Febuxostat

In a 100 ml 2-neck round-bottomed flask charge 2.407g of ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methylhiazole-carboxylate in 20ml tetrahydrofuran under stirring, at 25-35 °C, 0.748g of sodium hydroxide and heat reaction mass to 60-65 °C for approximately 8 hrs. Check the progress of the reaction by TLC (cyclohexane:ethyl acetate 3:1). Cool reaction mass to 0-5 °C and add 50 ml process water keeping temperature within 0-5 °C. Adjust pH to 1-2 with 4.5 ml 6 N hydrochloric acid, keeping temperature within 0-5 °C. Warm up reaction mass to 25-30 °C and stir reaction mass at the above temperature for 15 min. Filter off the precipitated solid through Buchner funnel under reduced pressure, spray wash with 2 ml process water and suck dry for 20-30 min. Transfer the crude solid in a 50 ml round-bottomed flask, charge 12 ml process water and 12 ml acetone at 25-30°C. Heat the reaction mass to 50-60 °C for 60 min. Cool down reaction mass to 0-5 °C and stir for 60 min at the above temperature. Filter off the precipitated solid though Buchner funnel under reduced pressure, spray wash with 2 ml of a 1 : 1 mixture of acetone and process water and suck dry for 30-45 min. Dry under vacuum at 60 °C. 1.821g of (compound I) Febuxostat are collected, Purity: 82.6%, Yield: 0.62w/w.

on of compound of formula Ilia

In a 50 mL round-bottomed flask charge under stirring 0.5g (1.72 mmol) of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate in 8.6 mL THF, at 25-30 °C. Add 10.3 mL (544.94 mmol) 25% aqueous ammonia, under stirring at 25-30 °C. Add 480 mg (1.89 mmol) iodine (I₂) to the reaction mass, stir the reaction mixture at 25-30 °C for 15-30 min. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 1 :1). Starting material is consumed. Add 8.6 mL 5% w/v aqueous thiosulfate and 40 mL ethyl acetate at the reaction mass, separate organic layer and extract aqueous layer twice with 40 mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate to dryness. Purification of the residue with column chromatography (cyclohexane: ethyl acetate 3: 1) afforded 0.213 g of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula Ilia). Yield : 42.6%.

EXAMPLE 6: Preparation of compound Illb

Dissolve 2.2 g of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula VI) in 7 ml dimethylformamide and to this mixture add 6.6 g of potassium carbonate and 3.14 g of isobutyl bromide. Stir the reaction at 75 °C for 15 hours and then cool to 40 °C. Add 15 ml process water and cool to 0-5 °C. Filter the precipitated solid off and wash with 15 ml process water, which, after drying, affords 2.28 g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula Illb).

EXAMPLE 7: Preparation of compound I (Febuxostat)

In a 100 ml 2-neck round-bottomed flask charge 2.131 g of ethyl-2(3-cyano-4-isobutoxyphenyl)-4-methylhiazole-carboxylate, 64 ml methanol and 2.5 ml process water are added under stirring at 25-35 °C. Add 1.718 g potassium carbonate and heat reaction mass to reflux for approximately 2-3 hrs. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 3:1). Cool reaction mass to 20-25 °C. Concentrate solvent at below 40 °C. To the residue add 43 ml process water, 21 ml ethyl acetate and stir for 30 min at 25-35 °C. Separate layers and transfer aqueous layer in a 100 ml round-bottomed flask. Adjust pH to 2.3-2.7 with 25 ml 1 N hydrochloric acid, at 25-35 °C. Warm up reaction mass to 40 °C and stir reaction mass at this temperature for 60-90 min. Cool down reaction mass to 25-35 °C. Filter off the precipitated solid through Buchner funnel under reduced pressure, spray wash with 5 ml process water and suck dry for 30-45 min. Dry under vacuum at 60 °C. 1.708g of (compound I) Febuxostat are collected, Purity: 86.7%, Yield: 0.69w/w.

EXAMPLE 8: Preparation of Febuxostat crystalline form III

In a 250 mL round-bottomedflask charge under stirring at 25-30 °C 10 g of crude 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (Febuxostat) in 200 mL ethyl acetate. Heat reaction mass to reflux and stir for 30 min. Cool reaction mass to 25-30°C. Warm again reaction mass and partially distill off solvent from the reaction mass at temperature below 40 °C under reduced pressure. Cool reaction mass to 25-30°C. Filter off the precipitated solid through Buchner funnel under reduced pressure and spray wash with 10 mL ethyl acetate. Dry under vacuum at 60°C. 8.5 g of Febuxostat are collected. Yield: 85 % w/w. XRPD of crystalline compound is in accordance with the one reported in Chinese patent CN101412700B.

PATENT

CN 104418823

https://www.google.com/patents/CN104418823A?cl=zh

Figure CN104418823AD00042

PATENT

CN 103588723

https://www.google.com/patents/CN103588723A?cl=zh

Chinese patent CN1275126 described by the Japanese company Teijin invention relates febuxostat Form A, B, C, D, G, and six kinds of amorphous and crystalline preparation method, reported in the literature Form A relatively stable . The method used is a solvent of methanol and water, patent phase diagram (Figure 7 Zone I) can be obtained in anhydrous crystalline Form A (hereinafter referred to as “Form A”), the mixing process by a temperature and the formation of methanol and water to determine the composition of the solvent, and the need to add a certain amount of Form a as a seed crystal to induce precipitation of crystals to control crystallization conditions are very harsh, operable range is very small, easy to form methanol solvate, hydrate or stable crystalline type C, to obtain reproducible single crystal type a low, it is difficult to achieve industrial production, and no mention of the preparation of Form a yield and purity in this patent.

[0011]

[0012] Chinese patent CN102267957A invention discloses a method for preparing febuxostat Form A, the solvent is preferably acetone, dissolved into 25 ~ 40 ° C was allowed to stand, when there began to crystallize when stirred for 20 to 40 minutes, then placed in -15 ~ 0 ° C to continue the crystallization of 8 to 10 hours. The crystallization process need to well below zero, when industrial mass production, resulting in high production costs, is not conducive to industrial production, the process yield up to 95.4%.

[0013] Chinese patent CN101139325 of Example 7 discloses the preparation of Form A with acetone method, although the process is simple, but the yield is low, only 50%.

[0014] Although the Chinese patent CN101684108A isopropyl alcohol as a solvent is disclosed a method for preparing crystalline form, the crystalline form of preparation is used to cool and heat a phased manner was allowed to stand, the crystallization temperature, long crystallization time, about 30 hours, the yield is low, and its products are not crystalline Form A.

[0015] In addition, Chinese patent CN101525319A, CN101805310, CN101926795A, CN101926794, W02012020272A2 are disclosed ethanol as a solvent or aqueous ethanol as a solvent preparation methods, and its products are crystalline ethanol solvate.

[0016] World Patent W02011139886A2 discloses the use of a mixed solvent of alcohol, and its products are not obtained polymorph A0

PAPER

Letters in Organic Chemistry (2015), 12(3), 217-221

Synthesis of the Major Metabolites of Febuxostat

Author(s): Xiao Long Li, Rui Qiu, Wei Li Wan, Xu Cheng, Li Hai and Yong Wu

Affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

Graphical Abstract:

Abstract:

Total synthesis of three Febuxostat metabolites, named 67M-1, 67M-2, and 67M-4,is described in this article. Through condensation of the key intermediate compound A with different side chains, and then oxidation and hydrolysis, we obtained three target compounds with an overall yield of 19.5%-28.0%.

VOLUME: 12
ISSUE: 3
Page: [217 – 221]
Pages: 5
DOI: 10.2174/1570178612666150108000805, http://www.eurekaselect.com/127479/article

ULORIC (febuxostat) is a xanthine oxidase inhibitor. The active ingredient in ULORIC is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C₁₆H₁₆N₂O₃S.

The chemical structure is:

Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 205°C to 208°C.

LORIC tablets for oral use contain the active ingredient, febuxostat, and are available in two dosage strengths, 40 mg and 80 mg. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate. ULORIC tablets are coated with Opadry II, green.

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WO2015018507A3 *	Jul 30, 2014	Oct 22, 2015	Pharmathen S.A.	A novel process for the preparation of febuxostat
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WO2011031409A1 *	Aug 12, 2010	Mar 17, 2011	Teva Pharmaceutical Industries Ltd.	Processes for preparing febuxostat
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CN102229581A *	Nov 15, 2010	Nov 2, 2011	邹巧根	Preparation method for febuxostat intermediate
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CN101497589A *	Feb 26, 2009	Aug 5, 2009	沈阳药科大学	Method for synthesizing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-carboxylate
CN101863854A *	Jun 29, 2010	Oct 20, 2010	沈阳药科大学	Synthesis method of 2-(3-cyan-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid
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WO2014009817A1 *	Mar 19, 2013	Jan 16, 2014	Alembic Pharmaceuticals Limited	Pharmaceutical composition of febuxostat
WO2014057461A1	Oct 10, 2013	Apr 17, 2014	Ranbaxy Laboratories Limited	Process for the preparation of crystalline form g of febuxostat

Febuxostat
Systematic (IUPAC) name

2-(3-cyano-4-isobutoxyphenyl)-4-methyl- 1,3-thiazole-5-carboxylic acid
Clinical data
Trade names	Uloric, Adenuric, Atenurix, Feburic, Goturic, Goutex. Generic in several countries.^[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a609020
License data	EU EMA: Adenuric US FDA: Febuxostat
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Oral
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	~49% absorbed
Protein binding	~99% to albumin
Metabolism	via CYP1A2, 2C8, 2C9,UGT1A1, 1A3, 1A9, 2B7
Biological half-life	~5-8 hours
Excretion	Urine (~49% mostly as metabolites, 3% as unchanged drug); feces (~45% mostly as metabolites, 12% as unchanged drug)
Identifiers
CAS Number	144060-53-7
ATC code	M04AA03 (WHO)
PubChem	CID 134018
IUPHAR/BPS	6817
DrugBank	DB04854
ChemSpider	118173
UNII	101V0R1N2E
KEGG	D01206
ChEMBL	CHEMBL1164729
Chemical data
Formula	C₁₆H₁₆N₂O₃S
Molar mass	316.374 g/mol

/////////Febuxostat, 144060-53-7, Uloric, Adenuric, Tei 6720, thiazole derivative, inhibitor of XANTHINE OXIDASE, treatment of HYPERURICEMIA, chronic GOUT, FBX, Febugood, Feburic, Febutaz, TMX 67, Zurig

CC1=C(SC(=N1)C2=CC(=C(C=C2)OCC(C)C)C#N)C(=O)O

Mastoparan

Uncategorized Comments Off

Jul 082016

Mastoparan, Peptide (H-INLKALAALAKKIL-NH₂)

IUPAC Condensed

H-Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-xiIle-Leu-NH2

LINUCS

[][L-Leu-NH2]{[(1+2)][L-xiIle]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Ala]{[(1+2)][L-Leu]{[(1+2)][L-Ala]{[(1+2)][L-Ala]{[(1+2)][L-Leu]{[(1+2)][L-Ala]{[(1+2)][L-Lys]{[(1+2)][L-Leu]{[(1+2)][L-Asn]{[(1+2)][L-Ile]{}}}}}}}}}}}}}}

Sequence

INLKALAALAKKXL

HELM

PEPTIDE1{I.N.L.K.A.L.A.A.L.A.K.K.[*N[C@H](C(=O)*)C(C)CC |$_R1;;;;;_R2;;;;$|].L.[am]}$$$$

Mastoparan

Ile – Asn – Leu – Lys – Ala – Leu – Ala – Ala – Leu – Ala – Lys – Lys – Ile – Leu -NH₂

(2S)-N-[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-2-[[(2S,3S)-2-amino-3-methylpentanoyl]amino]butanediamide

Mastoparan; Mast cell degranulating peptide (Vespula lewisii); NSC351907; CAS 72093-21-1;
Molecular Formula:	C₇₀H₁₃₁N₁₉O₁₅
Molecular Weight:	1478.90744 g/mol

18: PN: WO0181408 SEQID: 37 claimed protein
18: PN: WO2010069074 SEQID: 16 claimed protein
L-Leucinamide, L-isoleucyl-L-asparaginyl-L-leucyl-L-lysyl-L-alanyl-L-leucyl-L-alanyl-L-alanyl-L-leucyl-L-alanyl-L-lysyl-L-lysyl-L-isoleucyl-
Mastoparan 1

NSC 351907

Description

Mastoparan (Vespula lewisii) has been shown to cause an increase in the production of Arachidonic Acid (sc-200770) catalyzed by PLA2 from porcine pancreas and bee venom. This compound also displays toxicity by regulating G proteins via mimicking of G-protein-coupled receptors. Additionally, Mastoparan has been reported as a stimulator of insulin release by pancreatic islets, which acts through GTP-binding proteins and PLA2. In other experiments, this agent has demonstrated the ability to cause exocytosis of rat peritoneal mast cells and also stimulate the accumulation of inositol phosphates in hepatocytes. Additionally, Mastoparan has been noted to act as a mitogen in Swiss 3T3 cells and stimulate pertussis toxin-sensitive Arachidonate release without phosphoinositide breakdown. Mastoparan (Vespula lewisii) is an inhibitor of CaM. Mastoparan (Vespula lewisii) is an activator of Heterotrimeric G Protein and PLA2.

Technical Information

Physical State:	Solid
Derived from:	Synthetic. Originally isolated from wasp venom (Vespula lewisii)
Solubility:	Soluble in water (2.6 mg/ml), and 100% ethanol.
Storage:	Store at -20° C
Refractive Index:	n²⁰_D 1.53
IC50:	Na+,K+-ATPase: IC₅₀ = 7.5 µM

Mastoparan is a peptide toxin from wasp venom. It has the chemical structure Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2.^[2]

The net effect of mastoparan’s mode of action depends on cell type, but seemingly always involves exocytosis. In mast cells, this takes the form of histamine secretion, while in platelets and chromaffin cells release serotonin and catecholamines are found, respectively. Mastoparan activity in the anterior pituitary gland leads to prolactin release.

In the case of histamine secretion, the effect of mastoparan takes place via its interference with G protein activity. By stimulating theGTPase activity of certain subunits, mastoparan shortens the lifespan of active G protein. At the same time, it promotes dissociation of any bound GDP from the protein, enhancing GTP binding. In effect, the GTP turnover of G proteins is greatly increased by mastoparan. These properties of the toxin follow from the fact that it structurally resembles activated G protein receptors when placed in a phospholipid environment. The resultant G protein-mediated signaling cascade leads to intracellular IP₃ release and the resultant influx of Ca²⁺.

In an experimental study conducted by Tsutomu Higashijima and his counterparts, mastoparan was compared to melittin, which is found in bee venom.^[2] Mainly, the structure and reaction to phosphate was studied in each toxin. Using Circular Dichroism (CD), it was found that when mastoparan was exposed to methanol, an alpha helical form existed. It was concluded that strong intramolecular hydrogen bonding occurred. Also, two negative bands were present on the CD spectrum. In an aqueous environment, mastoparan took on a nonhelical, unordered form. In this case, only one negative band was observed on the CD spectrum. Adding phosphate buffer to mastoparan resulted in no effect.

Melittin produced a different conformational change than mastoparan. In an aqueous solution, melittin went from a nonhelical form to an alpha helix when phosphate was added to the solution. The binding of melittin to the membrane was believed to result fromelectrostatic interactions, not hydrophobic interactions.

Infections caused by multidrug resistant bacteria are currently an important problem worldwide. Taking into account data recently published by the WHO, lower respiratory infections are the third cause of death in the world with around 3.2 million deaths per year, this number being higher compared to that related to AIDS or diabetes mellitus [1]. It is therefore important to solve this issue, although the perspectives for the future are not very optimistic. During the last 30 years an enormous increase has been observed of superbugs isolated in the clinical setting, especially from the group called ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) which show high resistance to all the antibacterial agents available [2]. We will focus on Acinetobacter baumannii, the pathogen colloquially called “iraquibacter” for its emergence in the Iraq war. It is a Gram-negative cocobacillus and normally affects people with a compromised immune system, such as patients in the intensive care unit (ICU) [3] and [4]. Together with Escherichia coliand P. aeruginosa, A. baumannii are the most common cause of nosocomial infections among Gram-negative bacilli. The options to treat infections caused by this pathogen are diminishing since pan-drug resistant strains (strains resistant to all the antibacterial agents) have been isolated in several hospitals [5]. The last option to treat these infections is colistin, which has been used in spite of its nephrotoxic effects [6]. The evolution of the resistance of A. baumannii clinical isolates has been established by comparing studies performed over different years, with the percentage of resistance to imipenem being 3% in 1993 increasing up to 70% in 2007. The same effect was observed with quinolones, with an increase from 30 to 97% over the same period of time[7]. In Spain the same evolution has been observed with carbapenems; in 2001 the percentage of resistance was around 45%, rising to more than 80% 10 years later [8]. Taking this scenario into account, there is an urgent need for new options to fight against this pathogen. One possible option is the use of antimicrobial peptides (AMPs) [9],[10] and [11], and especially peptides isolated from a natural source [12]. One of the main drawbacks of using peptides as antimicrobial agents is the low stability or half-life in human serum due to the action of peptidases and proteases present in the human body[13], however there are several ways to increase their stability, such as using fluorinated peptides [14] and [15]. One way to circumvent this effect is to study the susceptible points of the peptide and try to enhance the stability by protecting the most protease labile amide bonds, while at the same time maintaining the activity of the original compound. Another point regarding the use of antimicrobial peptides is the mechanism of action. There are several mechanisms of action for the antimicrobial peptides, although the global positive charge of most of the peptides leads to a mechanism of action involving the membrane of the bacteria [16]. AMPs has the ability to defeat bacteria creating pores into the membrane [17], also acting as detergents [18], or by the carpet mechanism [19]. We have previously reported the activity of different peptides against colistin-susceptible and colistin-resistant A. baumannii clinical isolates, showing that mastoparan, a wasp generated peptide (H-INLKALAALAKKIL-NH₂), has good in vitro activity against both colistin-susceptible and colistin-resistant A. baumannii [20]. Therefore, the aim of this manuscript was to study the stability of mastoparan and some of its analogues as well as elucidate the mechanism of action of these peptides.

Paper

European Journal of Medicinal Chemistry

Volume 101, 28 August 2015, Pages 34–40

Research paper

Sequence-activity relationship, and mechanism of action of mastoparan analogues against extended-drug resistantAcinetobacter baumannii

^a ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic – Universitat de Barcelona, Barcelona, Spain
^b Biomedical Institute of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
^c Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
^d Department of Clinical Microbiology, CDB, Hospital Clinic, School of Medicine, University of Barcelona, Barcelona, Spain
^e Department of Organic Chemistry, University of Barcelona, Barcelona, Spain

http://www.sciencedirect.com/science/article/pii/S0223523415300933

doi:10.1016/j.ejmech.2015.06.016

Highlights

•The most susceptible position of mastoparan is the peptide bond between isoleucine and asparagine.
•The positive charge present in the N-terminal play an important role in the antimicrobial activity of the peptides.
•Mastoparan and its enantiomer version exhibit a mechanism of action related to the membrane disruption of bacteria.
•Three of the mastoparan analogues synthesized have good activity against highly resistant Acinetobacter baumannii.
•Two of the active analogues showed a significant increase in the human serum stability compared to mastoparan.

Abstract

The treatment of some infectious diseases can currently be very challenging since the spread of multi-, extended- or pan-resistant bacteria has considerably increased over time. On the other hand, the number of new antibiotics approved by the FDA has decreased drastically over the last 30 years. The main objective of this study was to investigate the activity of wasp peptides, specifically mastoparan and some of its derivatives against extended-resistant Acinetobacter baumannii. We optimized the stability of mastoparan in human serum since the specie obtained after the action of the enzymes present in human serum is not active. Thus, 10 derivatives of mastoparan were synthetized. Mastoparan analogues (guanidilated at the N-terminal, enantiomeric version and mastoparan with an extra positive charge at the C-terminal) showed the same activity against Acinetobacter baumannii as the original peptide (2.7 μM) and maintained their stability to more than 24 h in the presence of human serum compared to the original compound. The mechanism of action of all the peptides was carried out using a leakage assay. It was shown that mastoparan and the abovementioned analogues were those that released more carboxyfluorescein. In addition, the effect of mastoparan and its enantiomer against A. baumannii was studied using transmission electron microscopy (TEM). These results suggested that several analogues of mastoparan could be good candidates in the battle against highly resistant A. baumannii infections since they showed good activity and high stability.

Graphical abstract

References

PDB: 2CZP; Todokoro Y, Yumen I, Fukushima K, Kang SW, Park JS, Kohno T, Wakamatsu K, Akutsu H, Fujiwara T (August 2006). “Structure of Tightly Membrane-Bound Mastoparan-X, a G-Protein-Activating Peptide, Determined by Solid-State NMR”. Biophys. J. 91 (4): 1368–79. doi:10.1529/biophysj.106.082735. PMC 1518647. PMID 16714348.
Higashijima T, Uzu S, Nakajima T, Ross EM (May 1988). “Mastoparan, a peptide toxin from wasp venom, mimics receptors by activating GTP-binding regulatory proteins (G proteins)”. J. Biol. Chem. 263 (14): 6491–4. PMID 3129426.

Reference

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- WHO’s First Global Report on Antibiotic Resistance Reveals Serious, Worldwide Threat to Public Health
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- An increasing threat in hospitals: multidrug resistant Acinetobacter baumannii
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- The Acinetobacter baumannii oxymoron: commensal hospital dweller turned pan-drug-resistant menace
- Front. Microbiol., 23 (3) (2012), p. 148
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- Therapeutic options for Acinetobacter baumannii infections: an update
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- In vitro activity of 18 antimicrobial agents against clinical isolates of Acinetobacter spp. Multicenternational study GEIH-REIPI-Ab 2010
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- The human beta-defensin-3, an antibacterial peptide with multiple biological functions
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- L.M. Gottler, A. Ramamoorthy
- Structure, membrane orientation, mechanism, and function of pexiganan–a highly potent antimicrobial peptide designed from magainin
- Biochim. Biophys. Acta, 1788 (2009), pp. 1680–1686
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- Efficacy of six frog skin-derived antimicrobial peptides against colistin-resistant strains of theAcinetobacter baumannii group
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Patent IDDatePatent TitleUS20160672612016-03-10SERCA INHIBITOR AND CALMODULIN ANTAGONIST COMBINATION

Mastoparan
Solution structure of mastoparan from Vespa simillima xanthoptera.^[1]
Identifiers
Symbol	Mastoparan_2
Pfam	PF08251
InterPro	IPR013214
TCDB	1.C.32
OPM superfamily	160
OPM protein	2czp

///////Peptide, Antimicrobial peptide, Mastoparan, Acinetobacter baumannii, NSC351907, 72093-21-1, NSC 351907

CCC(C)C(C(=O)NC(CC(=O)N)C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(C)C(=O)NC(CC(C)C)C(=O)NC(C)C(=O)NC(C)C(=O)NC(CC(C)C)C(=O)NC(C)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(CC(C)C)C(=O)N)N

Eldecalcitol, an active vitamin D3 analog used to treat osteoporosis

Uncategorized Comments Off

Jul 072016

Eldecalcitol

(1S,2S,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-2-(3-hydroxypropoxy)-4-methylidenecyclohexane-1,3-diol

(1R,2R,3R,5Z,7E)-2-(3-Hydroxypropyloxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol

AC1O5QQ2; CAS 104121-92-8; AN-3697; ED 71, Edirol^®
Molecular Formula:	C₃₀H₅₀O₅
Molecular Weight:	490.715 g/mol

APPROVED JAPAN , 2011-01-21, Chugai (Originator) , Roche,Taisho Toyama

Eldecalcitol was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on January 21, 2011. It was developed by Chugai Pharmaceutical (a member of Roche) and marketed as Edirol^® by Chugai Pharmaceutical and Taisho.

Eldecalcitol is an orally active vitamin D analogue leading to greater absorption of bind calcium. It is usually used to treat osteoporosis.

Edirol^® is available as capsule for oral use, containing 0.5 μg or 0.75 μg of free Eldecalcitol, and the recommended dose is 0.75 μg once daily.

ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis. ED-71, effectively and safely increased lumbar and hip bone mineral density (BMD) in osteoporotic patients who also received vitamin D3 supplementation.

Eldecalcitol is a drug used in Japan for the treatment of osteoporosis.^[1] It is an analog of vitamin D.^[2] Osteoporosis is a common bone disease among the older generation, with an estimated prevalence of over 200 million people.^[1] This condition often results in bone fractures due to abnormally low bone mass density, and is a leading cause of disability, especially among developed countries with longer average life spans. Osteoporosis is more common in women than with men.

Eldecalcitol

Discovery

Chugai Pharmaceutical/Roche are the originators of the medicinal drug eldecalcitol through Taisho Pharmaceutical Holdings and Chugai Pharmaceutical. The trade name of eldecalcitol is Edirol, and its Chemical Abstracts Service (CAS) registry number is 104121-92-8. Eldecalcitol was approved for use in Japan on January 2011. The approval came from the Japanese Ministry of Health, Labor, and Welfare for the objective of a treatment for osteoporosis.^[3]

Effects

Clinical trials have suggested that eldecalcitol, a vitamin D analog, has strong effects to reduce calcium reabsorption into the body from bones, therefore increasing bone mineral density, and to increase calcium absorption in intestines.^[4] In animals, eldecalcitol inhibits the activity of osteoclasts for the function to reduce bone degradation for calcium, while still able to maintain osteoblast function so as to not hinder bone formation.^[5] Unlike other vitamin D analogs, eldecalcitol does not significantly suppress parathyroid hormone levels, promising a better treatment for osteoporosis in comparison to other medications.^[6] Bone mineral density increases with eldecalcitol use, in addition to strengthening bone structure. This occurs due to the function of the eldecalcitol drug, which decreases bone reabsorption as observed through a bone reabsorption marker. Bone geometry assessments show that eldecalcitol increases cortical bone area in patients with osteoporosis more so than other vitamin D analogs, such as alfacalcidol. There was also the maintenance of thickness of cortical bone mass, strongly indicating that eldecalcitol improves the strength and mass of bone, specifically cortical bone structure.^[7] Adverse effects of eldecalcitol include an increase in blood and urinary calcium levels. Abnormally high levels of calcium can lead to problems associated with hypercalcemia.

Treatment for Osteoporosis

Eldecalcitol can be used for the treatment of hypocalcaemia or osteoporosis. Calcium absorption increases with the presence of eldecalcitol by the body, occurring in the intestines, which is useful for those who have low calcium levels. Eldecalcitol is more often used due to its effects to treat osteoporosis. In the aging population, the bone matrix becomes weakened through untreated osteoporosis. This leads to an increased risk of severe fractures that include spinal and hip fractures in addition to vertebral and wrist fractures. This creates a burden on the health care system due to a decline in the quality of life for the individuals that suffer from this condition. Some risk factors leading to the predisposition of developing osteoporosis are previous incidents of bone fractures and a reduction in bone mineral density.^[1] These factors expectantly increase as age increases. Bone health is reliant on maintaining physiologically needed levels of calcium, where the body constantly maintains this calcium homeostasis through osteoblast and osteoclast activity. Osteoblast activity serves this function of maintaining appropriate calcium levels by depositing calcium in bones when blood calcium levels are above normal. In contrast, osteoclasts break down bone tissue to increase blood calcium levels if they are low.^[8] This activity is performed after absorption of calcium by the body, which requires the actions of vitamin D. The active metabolite of vitamin D, calcitriol, performs its function through interactions with the calcitriol receptor. This nuclear hormone receptor is responsible for calcium absorption which, in turn, is involving in bone depletion and formation. The new analogs of vitamin D, such as eldecalcitol, are observed to have stronger effects in preventing bone loss, fractures, and falls in comparison to calcitriol.^[9] Eldecalcitol is even more effective than its counterpart alfacalcidol, another vitamin D analog. Studies have shown eldecalcitol is more effective than alfacalcidol in preventing vertebral and wrist fractures, and even falls, with osteoporotic patients with vitamin D insufficiencies.^[10] Eldecalcitol is also more effective at preventing fractures than vitamin D and calcium supplements.^[1] Eldecalcitol increases calcium absorption for vitamin D deficient patients, and therefore could be used for osteoporosis treatment for all age groups.

Pharmacology

Analogs of vitamin D are being explored intensely for their regulatory effects on calcium metabolism with the purpose of treating osteoporosis, a skeletal disease associated with low bone mass and deterioration of bone tissue. Vitamin D is imperative for absorption of calcium to maintain bone strength.

Mechanism of Action

Eldecalcitol is an orally administered drug to patients, which binds to vitamin D receptors and binding protein for the goal of achieving greater specificity to bind calcium for its absorption. This greater affinity is 2.7-fold that of the active vitamin D form of calcitriol. Eldecalcitol is readily absorbed into the body, with a long elimination half-life of over eight hours, reaching maximum absorption in 3.4 hours.^[1]

Dosage

Eldecalcitol is present in the form of pills for oral administration. In preclinical models with healthy male volunteers, oral doses of eldecalcitol ranged from 0.1 to 1.0 micrograms once daily to show an increase in bone mineral density.^[11] Preclinical trials show improvements for doses at 0.5 and 0.75 micrograms, which are the recommended dosage amounts for the Edirol product as approved by the Japanese Ministry of Health, Labor, and Welfare for treating osteoporosis.^[3]

Chemistry

The class of eldecalcitol is a vitamin D3 derivative. This molecule has a molecular weight of 490.71 grams per mole. The eldecalcitol analog of calcitriol, contains a hydroxypropyl group in the lower cyclohexane ring. The synthesis of eldecalcitol incorporates two units assembled together. The IUPAC names include (3S, 4S, 5R)-oct-1-en-7-yne-3,4,5-triol that is fused to a bicyclic system, (R)-6-((1R, 3aR, 7aR, E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)-2-methylheptan-2-ol. The assembly process includes a Diels-Alder reaction to give the fully protected eldecalcitol. In order to get the parent molecule, the hydroxyl groups have to be deprotected. The chemistry of eldecalcitol allows for its binding 2.7-fold more potently than calcitriol. In addition, some vitamin D derivatives have been known to inhibit the serum parathyroid hormone. Eldecalcitol only weakly inhibits the serum parathyroid hormone, making it an even more appealing medicinal drug for its physiological uses in the treatment of osteoporosis.^[3] Animal studies of eldecalcitol, in ovariectomized rats, show improvements in bone mass while lowering bone reabsorption to demonstrate its effectiveness in osteoporosis treatment.^[5]

PAPER

Heterocycles, Vol 92, No. 6, 2016, pp.1013-1029
Published online, 22nd March, 2016

DOI: 10.3987/REV-16-840

https://www.heterocycles.jp/newlibrary/payments/form/24714/fulltext

■ Diverse and Important Contributions by Medicinal Chemists to the Development of Pharmaceuticals: An Example of Active Vitamin D3 Analog, Eldecalcitol

Noboru Kubodera*

*International Institute of Active Vitamin D Analogs, 35-6, Sankeidai, Mishima, Shizuoka 411-0017, Japan

Abstract

Presented herein are diverse and important contributions by medicinal chemists to different stages of pharmaceutical development. The conceptual elements reviewed, which are intended for young chemists who engage in drug discovery research, draw upon the author’s experience in developing eldecalcitol, an active vitamin D3 analog used to treat osteoporosis. The review covers exploratory research for a lead candidate compound; process development for practical manufacturing; and synthesis of other compounds relevant to the program, such as tritiated compounds, postulated metabolites, and miscellaneous analogs for mode of action studies.

PAPER

Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D₃], an analog of calcitriol (1α,25-dihydroxyvitamin D₃), possesses a hydroxypropoxy substituent at the 2β-position of calcitriol. Eldecalcitol has potent biological effects on bone disease such as osteoporosis. The marketing of eldecalcitol has very recently started in Japan. In consideration of this, we have been investigating practical synthesis of eldecalcitol for industrial-scale production. Eldecalcitol was initially synthesized in a linear manner. The 27-step linear sequence was, however, suboptimal due to its lengthiness and low overall yield (ca. 0.03%). Next, we developed a convergent approach based on the Trost coupling reaction, in which the A-ring fragment (ene-yne part obtained in 10.4% overall yield) and the C/D-ring fragment (bromomethylene part obtained in 27.1% overall yield) are coupled to produce the triene system of eldecalcitol (15.6%). Although the overall yield of the convergent synthesis was better than that of the linear synthesis, significant improvements were still necessary. Therefore, additional biomimetic studies were investigated. Process development for the practical production of eldecalcitol is described herein.

http://ar.iiarjournals.org/content/32/1/303/F3.expansion.html

Convergent synthesis of eldecalcitol (5) by coupling A-ring fragment 37 with C/D-ring fragment 40. Reagents and conditions: a: HO(CH₂)₃OH/t-BuOK, 120°C. b: t-BuCOCl/pyridine/CH₂Cl₂, rt. c: H₂/Pd(OH)₂/MeOH, rt. d: Me₂C(OMe)₂/TsOH/acetone, rt. e: DMSO/(COCl)₂/CH₂Cl₂, −60°C. f: CH₂=CHMgBr/THF, −60°C. g: t-BuCOCl/Et₃N/DMAP/CH₂Cl₂, rt. h: 1 M HCl/MeOH, rt. i: Ph₃P/DEAD/benzene, reflux. j: LiC ≡ CTMS/BF₃-OEt₂, −78°C. k: 10 N NaOH/MeOH, rt. l: TBSOTf/Et₃N/CH₂Cl₂, 0°C. m: TESOTf/Et₃N/CH₂Cl₂, 0°C. n: O₃/CH₂Cl₂/MeOH, −78°C then NaBH₄/MeOH, −78°C. o: NMO/TPAP/4Ams/CH₂Cl₂, rt. p: Ph₃P⁺CH₂BrBr⁻/NaHMDS/ THF, −60°C to rt. q: (dba)₃Pd₂-CHCl₃/PPh₃/Et₃N/toluene, reflux. r: TBAF/THF/toluene, reflux.

Industrial synthesis of alfacalcidol (4) and biomimetic synthesis of eldecalcitol (5) from cholesterol (42). Reagents and conditions: a: [Al(Oi-Pr)₃]/cyclohexanone. b: DDQ/AcOEt. c: NaOEt/EtOH. d: NaBH₄/MeOH/THF. e: Ac₂O/DMPA/pyridine, rt. f: NBS/AIBN/n-hexane, reflux. g: γ-collidine/toluene, reflux. h: KOH/MeOH, rt. i: PTAD/CH₂Cl₂, rt. j: TBSCl/imidazole. k: MCPBA/CH₂Cl₂. l: DMI, 140°C. m: TBAF/THF. n: NaBH₄/EtOH. o: 400 W high pressure mercury lamp/THF, 0°C then reflux without mercury lamp. p: HO(CH₂)₃OH/t-BuOK, 110°C. q: Microbial 25-hydroxylation.

ROUTE1

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3. Drug Evaluation Research 2011, 34, 224-229.

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Reference：1. Bioorg. Med. Chem. 1998, 6, 2517-2523.

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No.	Major Technical Classification	Publication No.	Patent No.	Legal Status	Filling Date	Estimated Expiry Date
1	Preparation	CN85108857A	CN1008368B	Granted/expired	1985/12/4	2005/12/4
2	Crystal	CN1223639A	CN1216861C	Granted	1997/6/16	2017/6/16
3	Preparation	CN1637017A	CN1276927C

Patent ID	Date	Patent Title
US7927613	2011-04-19	Pharmaceutical co-crystal compositions
US7323580	2008-01-29	CRYSTALS OF A VITAMIN D DERIVATIVE AND A METHOD FOR THE PREPARATION THEREOF
US7235679	2007-06-26	Crystals of a vitamin D derivative and a method for the preparation thereof
EP0924199	2006-05-10	CRYSTALS OF VITAMIN D DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
US2005009794	2005-01-13	Crystals of a vitamin D derivative and a method for the preparation thereof
US6831183	2004-12-14	Crystals of a vitamin D derivative and a method for the preparation thereof
US6448421	2002-09-10	CRYSTALS OF VITAMIN D DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF

Eldecalcitol
Systematic (IUPAC) name

(1S,2S,3S,5Z,7E)-2-(3-Hydroxypropoxy)-9,10-secocholesta-5,7,10-triene-1,3,25-triol
Clinical data
Trade names	Edirol
Identifiers
CAS Number	104121-92-8
ATC code	None
PubChem	CID 6438982
ChemSpider	4943418
Chemical data
Formula	C₃₀H₅₀O₅
Molar mass	490.715 g/mol

///////////eldecalcitol, active vitamin D3 analog, treat osteoporosis, AC1O5QQ2, 104121-92-8, AN-3697, ED 71, ED-71, Edirol^{®, PMDA, JAPAN}

O[C@H]1CC(\C(=C)[C@H](O)[C@H]1OCCCO)=C\C=C2/CCC[C@]3([C@H]2CC[C@@H]3[C@H](C)CCCC(O)(C)C)C

CC(CCCC(C)(C)O)C1CCC2C1(CCCC2=CC=C3CC(C(C(C3=C)O)OCCCO)O)C

Discovery and development of natural product oridonin-inspired anticancer agents

Uncategorized Comments Off

Jul 072016

Natural products have historically been, and continue to be, an invaluable source for the discovery of various therapeutic agents. Oridonin, a natural diterpenoid widely applied in traditional Chinese medicines, exhibits a broad range of biological effects including anticancer and anti-inflammatory activities. To further improve its potency, aqueous solubility and bioavailability, the oridonin template serves as an exciting platform for drug discovery to yield better candidates with unique targets and enhanced drug properties. A number of oridonin derivatives (e.g. HAO472) have been designed and synthesized, and have contributed to substantial progress in the identification of new agents and relevant molecular mechanistic studies toward the treatment of human cancers and other diseases. This review summarizes the recent advances in medicinal chemistry on the explorations of novel oridonin analogues as potential anticancer therapeutics, and provides a detailed discussion of future directions for the development and progression of this class of molecules into the clinic.

Highlights

Oridonin displays significant anticancer activities via multi-signaling pathways.

Recent advances in medicinal chemistry of oridonin-like compounds are presented.

The article summarizes the SAR and mechanism studies of relevant drug candidates.

The milestones and future direction of oridonin-based drug discovery are discussed.

European Journal of Medicinal Chemistry

Volume 122, 21 October 2016, Pages 102–117

Review article

Discovery and development of natural product oridonin-inspired anticancer agents

^a Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States
^b Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States

SEE http://www.sciencedirect.com/science/article/pii/S0223523416304937

doi:10.1016/j.ejmech.2016.06.015

////////Natural product, Oridonin, Diterpenoids, Anticancer agents, Drug discovery, Chemical biology,

Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): A review

Uncategorized Comments Off

Jul 062016

Highlights

Modification of BHT has a significant multivariate effect on antioxidant efficiency.

BDE is the key to rational design and development of antioxidants.
Antioxidant performance of BHT is mainly depending on 13 very crucial parameters.
MPAO is a promising way to increase antioxidant and pharmacological activities.

Abstract

Hindered phenols find a wide variety of applications across many different industry sectors. Butylated hydroxytoluene (BHT) is a most commonly used antioxidant recognized as safe for use in foods containing fats, pharmaceuticals, petroleum products, rubber and oil industries. In the past two decades, there has been growing interest in finding novel antioxidants to meet the requirements of these industries. To accelerate the antioxidant discovery process, researchers have designed and synthesized a series of BHT derivatives targeting to improve its antioxidant properties to be having a wide range of antioxidant activities markedly enhanced radical scavenging ability and other physical properties. Accordingly, some structure–activity relationships and rational design strategies for antioxidants based on BHT structure have been suggested and applied in practice. We have identified 14 very sensitive parameters, which may play a major role on the antioxidant performance of BHT. In this review, we attempt to summarize the current knowledge on this topic, which is of significance in selecting and designing novel antioxidants using a well-known antioxidant BHT as a building-block molecule. Our strategy involved investigation on understanding the chemistry behind the antioxidant activities of BHT, whether through hydrogen or electron transfer mechanism to enable promising anti-oxidant candidates to be synthesized.

European Journal of Medicinal Chemistry

Volume 101, 28 August 2015, Pages 295–312

Review article

Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): A review

^aNanotechnology & Catalysis Research Centre, (NANOCAT), University of Malaya, Block 3A, Institute of Postgraduate Studies Building, 50603 Kuala Lumpur, Malaysia
^bDepartment of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
^cDivision of Human Biology, Faculty of Medicine, International Medical University, 57000 Kuala Lumpur, Malaysia
^dDrug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
http://www.sciencedirect.com/science/article/pii/S022352341530101X

doi:10.1016/j.ejmech.2015.06.026