ONL 1204 a small molecule peptide for Treatment of retinal detachment

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Feb 172016

ONL 1204

CAS 1349038-53-4

(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[2-[(3R)-3-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxybutanoyl]amino]acetyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-2-oxopiperidin-1-yl]acetyl]amino]-4-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]propanoic acid

His-His- Ile-Tyr-Leu-Gly-Ala-Val-Asn-Tyr-Ile-Tyr-NH2

ONL Therapeutics Inc.

Fas receptor (CD95)

Peptide, Retinal detachment, OPTHALMIC DRUGS

C71 H100 N18 O16, 1461.66

L-Histidyl-L-histidyl-L-isoleucyl-L-tyrosyl-L-leucylglycyl-L-alanyl-L-valyl-L-asparaginyl-L-tyrosyl-L-isoleucyl-L-tyrosinamide

RFVTGHFXGL YPA

ORPHAN DRUG DESIGNATION DATA

His-His- Ile-Tyr-Leu-Gly-Ala-Val-Asn-Tyr-Ile-Tyr-NH2

01/13/2016

Treatment of retinal detachment

ONL Therapeutics, Inc
1600 Huron Parkway
Second Floor
Ann Arbor, Michigan 48109…….http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=501215

ONL1204, ONL’s lead therapeutic candidate, is a first-in-class small molecule peptide designed to protect key retinal cells, including photoreceptors, against the apoptosis (programmed cell death) that occurs in a range of retinal diseases and conditions. It is this death of these retinal cells that is the root cause of vision loss and the leading cause of blindness.

Researchers have shown that ONL1204 effectively inhibits the Fas pathway; one of the body’s primary mechanisms for inducing programmed cell death (apoptosis). Specifically, the compound’s activity inhibits the Fas receptor, blocks the activation of the Fas pathway, and prevents the apoptosis cascade which results in the death of key retinal cells, including photoreceptor.

While initial development efforts for ONL1204 are focused on retinal detachment, preclinicalin vivo data, along with a growing body of literature, support potential application in age-related macular degeneration (AMD) and other chronic retinal diseases. Combined, the estimated market for the initial indications that ONL plans to target is >$12 billion globally.

ONL Therapeutics, Inc., a biopharmaceutical company developing novel therapies for preserving sight in a range of retinal diseases, today announced that the United States Food and Drug Administration (FDA) has granted orphan drug designation to ONL1204 for the treatment of retinal detachment. ONL1204 is a novel, first-in-class small molecule peptide designed to protect key retinal cells, including photoreceptors, from cell death that occurs in a range of retinal diseases and conditions. Death of these retinal cells is the root cause of vision loss and the leading cause of blindness. ONL expects to advance ONL1204 into clinical trials for retinal detachment patients in 2016.

Retinal detachment occurs when the retina is separated from the underlying layer of cells called the retinal pigment epithelium (RPE). The RPE provides nutritional support to the highly-active photoreceptors in the retina. When there is a detachment, the photoreceptors no longer receive these nutrients and undergo cell death processes that dramatically impact a patient’s vision. Retinal detachments occur in approximately 50,000 people each year in the United States and affect people of all ages, although risk increases as people reach fifty years of age.

Patients experiencing a retinal detachment are normally treated by surgical reattachment of the retina to reconnect the photoreceptors with the RPE and prevent additional loss of vision. However, these procedures do not address the photoreceptor death and vision loss, which can be significant, that occurs prior to surgery. ONL1204 will be delivered to patients upon diagnosis and is intended to block photoreceptor cells from dying until surgery can be completed.

“When retinal detachments involve the center of vision called the macula, more than a third of patients have final best corrected vision of 20/60 or worse after successful surgery,” said David Zacks, M.D., Ph.D., co-founder and chief science officer of ONL Therapeutics. “Those are truly poor outcomes from successful surgeries. We are very pleased the FDA has recognized this need and that ONL is the only company to have received an orphan designation for this disease. It reinforces our belief that ONL1204 can play a key role in preventing vision loss in these patients by protecting their photoreceptors.”

The FDA’s Orphan Drug Designation program provides certain incentives for companies developing therapeutics to treat rare diseases or conditions that affect less than 200,000 individuals in the US. A drug candidate and its developer must meet several key criteria in order to qualify for, and obtain, orphan drug status. Once a drug has received orphan drug designation, the developer qualifies for a range of benefits, including federal grants, tax credits, reduction in certain regulatory fees, and the potential for seven years of market exclusivity for the drug following FDA marketing approval.

About ONL Therapeutics

ONL Therapeutics (ONL) is a biopharmaceutical company committed to protecting and improving the vision of patients with retinal disease. By advancing a novel breakthrough technology designed to protect key retinal cells from Fas-mediated cell death, ONL is pioneering an entirely new approach to preserving sight. The death of key retinal cells is the root cause of vision loss and leading cause of blindness, and is implicated in a wide range of retinal diseases, including retinal detachment and both the wet and dry forms of age related macular degeneration (AMD).

read

FDA grants orphan status for ONL Therapeutics’ ONL1204 to treat retinal detachment
The US Food and Drug Administration (FDA) has granted orphan drug designation for ONL Therapeutics’ first-in-class small molecule peptide, ONL1204, for the treatment of retinal detachment.

see,………https://newdrugapprovals.org/2016/02/17/onl-1204-a-small-molecule-peptide/

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CC(C)CC(C(=O)NC(CC1=CC=C(C=C1)O)C(=O)N2CCCC2C(=O)NC(C)C(=O)O)NC(=O)CN3CCCC(C3=O)NC(=O)C(CC4=CC=CC=C4)NC(=O)C(CC5=CN=CN5)NC(=O)CNC(=O)C(C(C)O)NC(=O)C(C(C)C)NC(=O)C(CC6=CC=CC=C6)NC(=O)C(CCCN=C(N)N)N

C[C@@H](CC)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(=O)N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](Cc3cncn3)N)Cc4cncn4)[C@@H](C)CC)C(C)C)C(=O)N[C@@H](Cc5ccc(O)cc5)C(N)=O

BENFOTIAMINE

Uncategorized Comments Off

Feb 142016

Benfotiamine

S-[(Z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-phosphonooxypent-2-en-3-yl] benzenecarbothioate

Benphothiamine; Betivina; Biotamin; Neurostop; Nitanevril;22457-89-2

C₁₉H₂₃N₄O₆PS
MW:	466.447882 g/mol

Benfotiamine (rINN, or S-benzoylthiamine O-monophosphate) is a synthetic S-acyl derivative of thiamine (vitamin B1).

It has been licensed for use in Germany since 1993 under the trade name Milgamma. (Combinations with pyridoxine or cyanocobalamin are also sold under this name.) It is prescribed there for treating sciatica and other painful nerve conditions.^[1]

It is marketed as a medicine and/or dietary supplement, depending on the respective Regulatory Authority.^{[citation needed]}

Uses

Benfotiamine is primarily marketed as an antioxidant dietary supplement. In a clinical study with six patients, benfotiamine lowered AGE by 40%.^[2]

Benfotiamine may be useful for the treatment of diabetic retinopathy, neuropathy, and nephropathy however “Most of the effects attributed to benfotiamine are extrapolated from in vitro and animal studies. Unfortunately apparent evidences from human studies are scarce and especially endpoint studies are missing. Therefore additional clinical studies are mandatory to explore the therapeutic potential of benfotiamine in both diabetic and non-diabetic pathological conditions”.^[3] It is thought that treatment with benfotiamine leads to increased intracellular thiamine diphosphate levels,^[3] a cofactor of transketolase. This enzyme directs advanced glycation and lipoxidation end products (AGE’s, ALE’s) substrates to the pentose phosphate pathway, thus reducing tissue AGEs.^[4]^[5]^[6]^[7]^[8]

Pharmacology

After absorption, benfotiamine can be dephosphorylated by cells bearing an ecto-alkaline phosphatase to the lipid-soluble S-benzoylthiamine.^[9] Benfotiamine should not be confused with allithiamine, a naturally occurring thiamine disulfide derivative with a distinct pharmacological profile.^[10]

PATENT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=48F4CE7167F2EB243FBAF807987983D5.wapp1nB?docId=WO2014059702&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

The Benfotiamine, disclosed in US pat. no. 19623064000 US english names: S-benzoylthiamine O-monophosphate common name: Benfotiamine, chemical name: S − 2-[ [ (2-methyl-4-amino-5-pyrimidinyl) methyl ]-propionylamino ]-5-phosphonato-2-pentene-3-thiol benzoate, formula C 19 H 23 N 406 PS molecular weight 466.45 the following structural formula:

Chemical composition of the same species, in various physico-chemical conditions, crystallization into two or more different structure of the crystalline phenomenon, also referred to as polymorphs or homogeneous an image drug polymorph is a common phenomenon of drug discovery, drug quality is an important factor. Various polymorphs have different physical properties such as appearance, melting point, hardness, dissolution rate, chemical stability, mechanical stability, etc. differences, these differences in the physical properties of the sometimes affect the stability of the drug, bioavailability, even the drug availability. Thus, in drug development, it should be fully considered drug poly-type problems, the type of study and control in drug development of significant research content.

The benfotiamine, vitamin B 1 lipid-soluble derivatives, improved water-soluble vitamins B1 low bioavailability of disadvantages, increased blood and tissues. Thiamine concentration, thereby enhancing efficacy. The primary application to the following aspects (1) for thiamine deficiency disease prevention and treatment; (2) vitamin B 1 demand increases, from the food uptake is not sufficient make-up, fatigue, hyperthyroidism, gestation, lactation, vigorous manual labor, etc.); (3) for the treatment of non-l 酒性 lopinavir, grams of brain disease; (4) for the treatment of foot disease; (5) for the disease, the speculative and thiamine deficiency and metabolic disorders associated with treatment, such as: neuropathic pain; muscle pain, joint pain ; Peripheral-inflammatory, peripheral nerve

The paralysis; myocardial metabolism disorders, constipation, gastrointestinal motility dysfunction. The benfotiamine as vitamin B 1 supplemental agents have been in the united states, japan, europe, etc worldwide market. Recent studies have shown that, benfotiamine in diabetic peripheral neuropathy and retinopathy of significant therapeutic effect. In addition, our studies, benfotiamine may also be applied to the prevention and treatment of alzheimer’s disease, and aging.

Alzheimer’s disease (Altheimer’s disease, AD) is a cognitive, behavioral disorders is the primary clinical manifestations progressive neurodegenerative diseases, an age-related disorders, with age, their prevalence is a significant rise. 我国 the number of people in excess of 600 million AD patients, it is contemplated that in 2050 worldwide by the year AD patient may exceed 3000 million people as the medical scientific development, severe affect human health, mortality is a leading significant diseases such as cancer, stroke, cardiovascular disease, exhibit a decrease in mortality year by year, and AD mortality the rendering large increase in . In addition, alzheimer’s disease course long, the disabling rate is high, thus, alzheimer’s disease will be the 21 st century threaten both human diseases the most serious. It is estimated that worldwide by the year AD 2010 for medical costs up to 6040 of millions of dollars, the same global of the gross national product of 1%

China and the USA, the world there have been the following two classes of drugs approved for AD treatment: cholinesterase inhibitors and N-methyl D-aspartate (NMDA) receptor antagonist are both improved AD patient symptoms, slow disease progression does not prevent or reverse the progression of a disease. The benfotiamine by inhibiting the sugar synthase kinase -3 (Glycogen synthase kinase -3, GSK -3) activity, decrease in brain beta-amyloid protein (beta-amyloid, alpha beta) the deposition and tau protein phosphorylation, reduce alzheimer’s disease, pathological damage.

Presently available, benfotiamine primarily in the form of tablets and powders is administered in the form of, all formulations are not related to the benfotiamine feedstock form has not yet been the benfotiamine crystalline be systematically studied, the present US pat. no. first for benfotiamine of systematic study of various forms, illustrating different form benfotiamine characteristics and their feasibility. As a pharmaceutical agent

PATENT

http://www.google.com/patents/CN103772432A?cl=en

Example 1:

Was added to the reaction kettle 4000kg polyphosphoric acid, heated to 100 ~ 120 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range 8 hours, was added water quenching 3000kg off after the reaction, the temperature was raised to 80-90 ° C hydrolysis of 10 hours; cooled to room temperature, was added to the kettle 5000kg trioctylamine mixture of methyl tert-butyl ether = WPA / 1/1; aqueous phase 5000kg methanol to precipitate a solid, centrifuged to obtain a monoester 1200kg vitamin BI phosphoric acid crude; the 1200kg Vitamin `prime BI phosphate monoester crude in 6000kg water mixed beating, down to O ~ 5 ° C, dropping liquid in this temperature range adjusting the PH value of the base system to 12.0 ~ 14.0; PH after adjustment to ensure that the reactor temperature 10 ~ 25 ° C within 1200kg of benzoyl chloride was added dropwise, after the addition is complete heat the reaction to completion; filtered and the filtrate adjust PH from 3.5 to 4.0 precipitated solid was isolated and dried to give a white solid 1200kg, namely benfotiamine. Yield: 77.38%, Purity: 98.70% ο

Example 2:

Was added to the reaction kettle 5000kg polyphosphoric acid, heated to 80 ~ 100 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range 6 hours, was added water quenching 5000kg off after the reaction was heated to reflux for 5 hours hydrolysis; cooled to room temperature, the autoclave was added to the mixture was extracted twice 4000kg trioctylamine / methyl tert-butyl ether = 1/1; aqueous phase 6000kg ethanol precipitation The solid obtained by centrifugation vitamin BI phosphate monoester 1200kg crude; after 1200kg vitamin BI crude phosphate monoester product mixing beating in 6000kg water, down to O ~ 5 ° C, solution of caustic soda adjust PH value system in this temperature range to 10.0 ~ 12.0; PH adjusting finished, to ensure the reactor temperature 10 ~ 25 ° C within 1200kg of benzoyl chloride was added dropwise, after the addition is complete heat the reaction to completion; filtered, the solid was filtered, the filtrate was adjusted to 3.5 ~ PH value 4.0 precipitated solid was isolated and dried to give a white solid 1250kg, namely benfotiamine. Yield: 80.61%, Purity: 98.50% ο

Example 3:

After the reactor was added 3000kg polyphosphoric acid, heated to 90 ~ 110 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after the insulation in this temperature range for 5 hours, 5000kg of water quenching off after the reaction, the temperature was raised to 90-100 ° C hydrolysis 5 hours; cooled to room temperature, was added to the kettle 5000kg trioctylamine methyl tert-butyl ether mixture was extracted twice = / 1/1; aqueous phase Join 7000kg acetone precipitate a solid, mono- 1230kg centrifuged to obtain crude vitamin BI phosphoric acid; vitamin BI after 1200kg crude phosphate monoester product mixing beating in 6000kg water, down to O ~ 5 ° C, solution of caustic soda adjusted within this temperature range System PH value to 11.0 ~ 13.0; PH after adjustment to ensure that the temperature of the reactor was added dropwise within 10 ~ 25 ° C within 1200kg benzoyl chloride, and after the addition is complete heat to the completion of the reaction; filtered, the filtrate was adjusted to 3.5 PH value to 4.0 precipitated solid was isolated and dried to give a white solid 1240kg, namely benfotiamine. Yield: 79.96%, Purity: 98.50% ο

Example 4

Was added to the reaction kettle 4000kg polyphosphoric acid, heated to 100 ~ 120 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range for 4 hours, water quenching 8000kg off after the reaction, the temperature was raised to 90 – 110 ° C hydrolysis seven hours; cooled to room temperature, was added to the kettle 4000kg trioctylamine / methyl tert-butyl ether mixture was extracted phosphoric = 1/1; aqueous phase 6000kg methanol precipitated solid was centrifuged to give 1200kg vitamin BI phosphate monoester crude; the 1200kg vitamin BI phosphate monoester crude 6000kg water were mixed after beaten, cooled to O ~ 5 ° C, caustic soda was added dropwise at this temperature adjustment range of the system PH value to 9.0 ~ 11.0; PH adjustment finished, the reactor temperature to ensure solution of 10 ~ 25 ° C within 1200kg benzoyl chloride, and after the addition is complete heat to the completion of the reaction; filtered, the filtrate was adjusted to PH value

3.5 to 4.0 precipitated solid was isolated and dried to give a white solid 1260kg, namely benfotiamine. Yield: 81.24%, Purity: 98.70% ο

Example 5

Was added to the reaction kettle 5000kg polyphosphoric acid, heated to 110 ~ 130 ° C, the vitamin BI 1000kg batches added to the reaction dad, add after kept at this temperature range for 3 hours, water quenching 10000kg off after the reaction, the temperature was raised to 110 – 120 ° C under reflux for 3 hours hydrolysis; cooled to room temperature, the mixture was extracted phosphoric acid was added to the kettle 3000kg trioctylamine / methyl tert-butyl ether = 1/1; aqueous phase `6000kg ethanol was added to precipitate a solid, obtained by centrifugation 1200kg vitamin BI phosphate monoester crude; after 1200kg vitamin BI phosphate monoester crude mixing beating in 6000kg water, down to O ~ 5 ° C, solution of caustic soda in this temperature range adjusting the PH value of the system to the 8.0 ~ 10.0; PH adjusting finished, 1200kg of benzoyl chloride was added dropwise to ensure the kettle temperature within 10 ~ 25 ° C, after the addition is complete heat the reaction to completion; filtered, the filtrate was adjusted to PH value 3.5 to 4.0 precipitated solid was isolated and dried to give a white solid 1230kg, namely benfotiamine. Yield: 79.31%, purity: 98.60% ο

PATENT

Figure CN102911208AD00041

http://www.google.com/patents/CN102911208A?cl=en

Example I: Phosphorus oxychloride 15. 33g (O. Imol) was added to the water 10. 8mL, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 26. 53g (O. lmol), warmed to 50 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 91.36%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, the 0_5 ° C under stirring, monitoring the reaction solution and pH changes, the pH value is stable, does not change when the reaction liquid PH, stirring was continued for I hour the reaction, the solution was adjusted to pH 3. 5-4. 0, suction filtration to give 33. 58g benfotiamine white solid. Yield 71.9%.

MP: 164-165 ° C; H1 NMR (400MHz, CDCl3): 2.18 (s, 3H), 2.56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4.. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, J = I. 5, 1H), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

Example 2: Phosphorus oxychloride 15. 33g (O. lmol) was added to a 7. 2mL of water, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 21. 23g (O. OSmol), warmed to 60 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 92.37%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, stirred at 0-5 ° C, and monitoring the pH of the reaction solution changes, stable pH, the reaction solution PH does not change when the stirring was continued for I hour the reaction, the solution pH adjusted to 3. 5-4. 0, suction filtration to give 27. 69g benfotiamine white solid. Yield 74.2%.

MP: 164-165 ° C; H1 NMR (400MHz, CDCl3):.. 2.18 (s, 3H), 2 56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, / = 1. 5, 1H ), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

Example 3: Phosphorus oxychloride 15. 33g (O. lmol) was added to a 3. 6mL of water, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 15. 92g (O. 06mol), warmed to 70 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 93.23%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, stirred at 0-5 ° C, and monitoring the pH of the reaction solution changes, stable pH, the reaction solution PH does not change when the stirring was continued for I hour the reaction, the solution pH adjusted to 3. 5-4. 0, filtration, benfotiamine was a white solid 23. 71g. Yield 84.7%.

MP: 164-165 ° C; H1 NMR (400MHz, CDCl3): 2.18 (s, 3H), 2.56 (s, 3H), 2 58 (t, / = 6 7,2H.), 4.. 33 (t, / = 6.7,2H), 4. 83 (s, 2H), 7. 44 (m, 2H), 7. 57 (dd, / = 7. 3, / = 1. 5, 1H), 7. 60 (m, 2H), 7. 70 (s, 1H), 8. 67 (s, 1H).

Example 4: Phosphorus oxychloride 15. 33g (O. lmol) was added to a 7. 2mL of water, placed in an ice bath with stirring O. 5 hours was added portionwise thiamine 10. 62g (O. 04mol), warmed to 80 ° C followed by stirring for 2 hours, cooled to room temperature to obtain a solution of phosphorus thiamine, thiamine HPLC phosphorus content of 95.26%, adjusted with 15% NaOH solution to pH 8_9 the solution was added 28. Ilg (O. 2mol) benzoyl chloride, stirred at 0-5 ° C, and monitoring the pH of the reaction solution changes, stable pH, the reaction solution PH does not change when the stirring was continued for I hour the reaction, the solution pH adjusted to 3. 5-4. 0, filtration, benfotiamine was a white solid 15. 22g. Yield 85.2%.

PATENT

http://www.google.com/patents/CN103724374A?cl=en

Synthesis I) thiamine monophosphate hydrochloride

In the reaction flask was added phosphate, thiamine hydrochloride, phosphorous pentoxide was added and stirred to dissolve, controlling the reaction temperature to complete the reaction thiamine hydrochloride, was added and stirring was continued after dropwise addition of concentrated hydrochloric acid hydrolysis of purified water was added dropwise acetone crystallization dropwise at raising grain, filtration, washed with acetone crystal, vacuum drying intermediates thiamine monophosphate hydrochloride;

2) Synthesis of crude benfotiamine

In the reaction flask thiamine monophosphate hydrochloride, dissolved in purified water, sodium hydroxide was added dropwise to adjust the pH to alkaline and steady, benzoyl chloride, sodium hydroxide was added dropwise while controlling alkaline pH, to control the temperature of the reaction pH remained stable, the end of the reaction, concentrated hydrochloric acid was added and extracted twice with ethyl acetate, the aqueous phase of sodium hydroxide was added dropwise until the pH is acidic, crystal seeding planting, filtration, purified water and acetone crystal, vacuum drying crude benfotiamine;

References

1 “BBC news story: Back pain drug ‘may aid diabetics'”. BBC News. 18 February 2003.
2
J Lin, A Alt, J Liersch, RG Bretzel, M Brownlee (May 2000). “Benfotiamine Inhibits Intracellular Formation of Advanced Glycation End Products in vivo” (PDF). Diabetes. 49 (Suppl1) (A143): 583.
3
Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A (2010). “The multifaceted therapeutic potential of benfotiamine”. Pharmacol Res 61 (6): 482–8. doi:10.1016/j.phrs.2010.02.008. PMID 20188835.
4
Since AGEs are the actual agents productive of diabetic complications, in theory, if diabetic patients could block the action of AGEs completely by benfotiamine, strict blood sugar control, with its disruption of lifestyle and risks to health and life by severe hypoglycemic episodes, could be avoided, with revolutionary implications for the treatment of diabetes. Hammes, HP; Du, X; Edelstein, D; Taguchi, T; Matsumura, T; Ju, Q; Lin, J; Bierhaus, A; Nawroth, P; Hannak, D; Neumaier, M; Bergfeld, R; Giardino, I; Brownlee, M (2003). “Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy”. Nat Med 9 (3): 294–299. doi:10.1038/nm834.
5
Stirban A, Negrean M, Stratmann B; et al. (2007). “Adiponectin decreases postprandially following a heat-processed meal in individuals with type 2 diabetes: an effect prevented by benfotiamine and cooking method”. Diabetes Care 30 (10): 2514–6. doi:10.2337/dc07-0302. PMID 17630265.
6
Stracke H, Hammes HP, Werkmann D; et al. (2001). “Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats”. Exp. Clin. Endocrinol. Diabetes 109 (6): 330–6. doi:10.1055/s-2001-17399. PMID 11571671.
7
Stirban A, Negrean M, Stratmann B; et al. (2006). “Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes”. Diabetes Care 29 (9): 2064–71. doi:10.2337/dc06-0531. PMID 16936154.
8
Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ (2003). “Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine”. Diabetes 52 (8): 2110–20. doi:10.2337/diabetes.52.8.2110. PMID 12882930.
9
Yamazaki, M (1968). “Studies on the absorption of S-benzoylthiamine O-monophosphate : (I) Metabolism in tissue homogenates”. Vitamins 38 (1): 12–20.
10

Volvert, M.L.; Seyen, S.; Piette, M.; Evrard, B.; Gangolf, M.; Plumier, J.C.; Bettendorff, L. (2008). “Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives”. BMC Pharmacology 8 (1): 10. doi:10.1186/1471-2210-8-10. PMC 2435522. PMID 18549472.

External links

BBC news story (2003): Back pain drug ‘may aid diabetics’

CN101654464A *	Jul 28, 2009	Feb 24, 2010	湖北华中药业有限公司;湖北制药有限公司	Method for synthesizing vitamin B1 phosphatic monoester
CN102766163A *	Jun 29, 2012	Nov 7, 2012	暨明医药科技（苏州）有限公司	Synthesis method of phosphate monoester of vitamin B1
CN102911208A *	Sep 25, 2012	Feb 6, 2013	同济大学	Method for synthesizing benfotiamine
CA682778A *		Mar 24, 1964	Sankyo Kabushiki Kaisha	S-benzoylthiamine o-monophosphate and a process for preparing the same
US3507854 *	Apr 7, 1965	Apr 21, 1970	Sankyo Co	Process for preparing thiamine derivatives

CN103772432A *	Jan 3, 2014	May 7, 2014	湖北瑞锶科技有限公司	Production method of benfotiamine
CN103772432B *	Jan 3, 2014	Jan 20, 2016	湖北瑞锶科技有限公司	一种苯磷硫胺的生产方法

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PYRAZOLE-AMIDE COMPOUNDS AND PHARMACEUTICAL USE THEREOF [US2014296315]	2014-03-14	2014-10-02

Patent	Submitted	Granted
HYDRATE AND CRYSTAL OF FLUORENE COMPOUNDS [US2014296316]	2014-03-14	2014-10-02
Cysteine Peptide-Containing Health Drink [US2014302171]	2012-10-11	2014-10-09
Delaying the Progression of Diabetes [US2014303079]	2012-05-08	2014-10-09
FIBRONECTIN BASED SCAFFOLD DOMAIN PROTEINS THAT BIND TO MYOSTATIN [US2014309163]	2014-05-12	2014-10-16
METHODS AND COMPOSITIONS FOR CORRECTION OF ORGAN DYSFUNCTION [US2014274957]	2014-03-13	2014-09-18
COMPOUNDS FOR IMPROVED VIRAL TRANSDUCTION [US2014234278]	2012-09-28	2014-08-21
TOPICAL DERMAL DELIVERY COMPOSITIONS USING SELF ASSEMBLING NANOPARTICLES WITH CETYLATED COMPONENTS [US2014234428]	2013-02-15	2014-08-21
Polymeric Hyperbranched Carrier-Linked Prodrugs [US2014243254]	2012-08-10	2014-08-28
ENCAPSULATED OILS [US2014023688]	2013-07-12	2014-01-23
COMPOSITIONS, KITS AND METHODS FOR NUTRITION SUPPLEMENTATION [US2014023751]	2013-09-27	2014-01-23

Benfotiamine
Systematic (IUPAC) name


S-[2-{[(4-Amino-2-methylpyrimidin-5-yl)methyl] (formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate
Clinical data
Trade names	Milgamma
AHFS/Drugs.com	International Drug Names
Legal status	OTC
Routes of administration	Oral
Identifiers
CAS Number	22457-89-2
ATC code	A11DA03
PubChem	CID 3032771
ChemSpider	2297665
UNII	Y92OUS2H9B
ChEBI	CHEBI:41039
ChEMBL	CHEMBL1491875
Synonyms	S-Benzoylthiamine O-monophosphate
Chemical data
Formula	C₁₉H₂₃N₄O₆PS
Molar mass	466.448 g/mol

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O=P(O)(O)OCCC(/SC(=O)c1ccccc1)=C(/N(C=O)Cc2cnc(nc2N)C)C

WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LTD, New patent

PATENTS, Uncategorized Comments Off

Feb 082016

(S) – propylene glycol and water, 1: 1 crystalline complex

PATENT

WO2016018024, CRYSTALLINE COMPOSITE COMPRISING DAPAGLIFLOZIN AND METHOD FOR PREPARING SAME

HANMI FINE CHEMICAL CO., LTD. [KR/KR]; 59, Gyeongje-ro, Siheung-si, Gyeonggi-do 429-848 (KR)

KIM, Ki Lim; (KR).
PARK, Chulhyun; (KR).
LEE, Jaeheon; (KR).
CHANG, Young-kil; (KR)

The present invention relates to a crystalline composite comprising dapagliflozin and a method for preparing the same. More specifically, the present invention provides a novel crystalline composite comprising dapagliflozin, which is an SGLT2 inhibitor, and a preparing method capable of economically preparing the novel crystalline composite at high purity.

long period of time, there is a problem with secretion of insulin in diabetes is a problem with the function of insulin, or the two compounds problems of the disease that is to say maintaining a high blood sugar. Insulin helps the one that sends glucose into cells in order to replace the nutrients such as glucose that is in a hormone secreted by the beta cells of the pancreas blood into energy. However, if there is insufficient action of insulin, glucose accumulates in the blood does not enter the cell and cause the muscles and blood sugar, sugar in the urine is out. When these two long-standing high blood sugar will cause a number of microvascular complications. Not cut due to such complications, such as may result in blindness.

Worldwide diabetes has become one of the major causes of death in adults, an increasing number of diabetes patients may sharply with the increase of obesity population.

In diabetic patients SGLT2 (Sodium-Glucose linked transporter 2) selective inhibition of significant gastrointestinal side effects without increasing the emissions of glucose in the urine, thereby improving insulin sensitivity and delay the onset of diabetes complications by the normalization of plasma glucose can be there.

Bristol-to US Patent No. 6,515,117 of Myers Squibb Company of formula It discloses a binary) to dapa glyphs.

[Formula 1]

While preparing the material of Formula 1 in the above patent, the desired compound was obtained as an oil form, here was added to the chloroform under vacuum to reprocess getting the desired compound as a solid in a viscous that contains ethyl acetate. Compounds of the formula I obtained by the above method of production must be carried out the purification using a column, etc. because it can not remove the impurities of the desired compound, which is not suitable as an industrial method.

In addition, Bristol-to the US Patent 7,919,598 of Myers Squibb Company No. discloses a compound of formula 2.

[Formula 2]

Compounds of Formula 2 are the compounds of formula 1, (S) – propylene glycol and water, 1: 1 crystalline complex: 1. The compound of Formula 2 can be conveniently used in medicine to use by crystallizing the compound of formula 1 with low crystallinity and are also useful in the purification of the compounds of formula (I).

However, the compound of formula 2 is (S), the price is very expensive – and the use of propylene glycol, which results in increasing the production cost. This is very disadvantageous In the eyes of people with diabetes need to take the long-term.

In addition, European Patent No. 2597090 of Sandoz is disclosed of the formula monohydrate. Of the formula monohydrate is then stirred as a compound of the sugar alcohol and the formula of the glycol, glycerol, arabitol, xylitol, etc. in water obtained the seed (seed), by using this discloses a method for preparing the monohydrate in water, and have.

However, the European patent is described that the hydrate should be obtained stirred for three days at low temperature in order to obtain after obtaining the actual seed crystals, although not yield is mentioned is expected to be very low. For this reason, because of the situation in the research and development of novel crystalline complexes THE dapa glyphs are continually required.

Best Mode for Carrying out the Invention

Hereinafter, the present invention will be described in detail.

Crystalline complex according to the invention is for lowering the production cost by obtaining a product of high purity without the need for further purification, it has the structure of formula (3).

[Formula 3]

The crystalline complex is in the X- ray diffraction pattern of 9.7, 17.3, 20.0, 20.4, and may comprise a characteristic peak at a 2θ of 21.4 ± 0.2 °, preferably 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 43.9 ± 0.2 °, and can include a peak at 2θ of teukjeongjik, it may be most preferably having a powder X-ray diffraction pattern is shown in Fig.

It was confirmed that the heat-absorption peak appears at about 163 ℃, to refer to the thermal analysis by; (DSC differential scanning calorimetr) The crystalline complex is differential scanning calorimetry of FIG.

The crystalline complex is the measured moisture content in accordance with the Karl-Fischer method can be 2-5%, preferably be 2.1 ~ 3.5%.

In addition, the present invention includes a mixture of 1), mannitol and the solvent to prepare a mannitol solution; 2) preparing an alcohol solution by mixing the alcohol with the glyph dapa gin; 3) mixing the mannitol solution and the alcohol solution, heating to 50 ~ 100 ℃; And 4) cooling the heated solution to 0 ~ 15 ℃ provides a method for preparing the crystalline complex comprising the steps of obtaining a composite having a crystalline structure of Formula 3.

It describes a method for producing crystalline complex according to the present invention;

Step 1: Mannitol solution prepared

Step 1 of the manufacturing method according to the present invention is a step in which a mixture of mannitol and a solvent to prepare a mannitol solution.

The mannitol is suitable for the manufacture of a therapeutic agent for diabetes to be taking a long period of time as a material that is widely used like medicine, food, with high stability and low price. Furthermore, mannitol is used in reducing the edema by osmotic action, and thus the material to promote diuresis. This is mannitol is determined to be helpful to the action Qin dapa glyphs used as SGLT-2 inhibitors.

The mannitol is typically so long that can be purchased and / or synthesis is not particularly limited, preferably the D- mannitol, L- and D · mannitol may include one or more of the group consisting of L- mannitol , and it can be most preferably D- Magny-tolyl.

The solvent as long as it can dissolve the mannitol is not particularly limited, and may preferably be water.

The Mani mixing ratio of the toll and the solvent. If the amount that can be dissolve the mannitol, the solvent is not particularly restricted, the preferably mannitol and solvent 1: 8-20 weight ratio or 1: 1 may be mixed with 10 to 15 weight .

Step 2: Preparation of an alcohol solution

Step 2 of the manufacturing method according to the invention by mixing the alcohol with Jean dapa glyph is a step for preparing the alcoholic solution.

In the glyph binary dapa may be prepared by the method described in commercially available, and arc carried US Patent 6,515,117 example G.

The alcohol is long as it can dissolve the THE dapa glyph is not particularly limited, preferably the C ₁ ~ C ₄ alcohol may comprise at least one of (a lower alcohol), and most preferably ethanol .

The dapa If the mixing ratio of the pictures and alcohol as a glyph is content that can be dissolved in THE dapa glyph to alcohol is not particularly limited, preferably the gin alcohol dapa glyphs 1: 3-8 or 1: a volume ratio of 6-7 It may be mixed.

Step 3: heat-up phase

Step 3 of the manufacturing method according to the present invention is a step in which the mani mixing and heating the solution and the alcohol solution toll.

The step is a process for producing a crystalline complex containing THE dapa glyphs included in mannitol as an alcohol solution that is included in the mannitol solution, the mixing ratio of the mixed solution and the alcohol solution is mannitol and the pro pageul a binary 1: 0.5-2 or 1: it is preferable to mix in 1.0 to 1.5 molar ratio.

The heating may preferably be carried out at 50 ~ 100 70 ~ 90 ℃ or ℃.

Step 4: obtained crystalline complexes

Step 4 according to the present invention is by cooling the heated solution to obtain a crystalline complex having the structure of Formula 3.

The cooling is preferably at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃.

Further, according to the embodiment of the present invention, in order to improve the speed of determining the crystalline complex to be obtained, the cooling after seeding may further include a (seeding) and further comprising cooling. The further cooling can preferably be carried out at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃ for 5 to 24 hours, or 7 ~ 15 hours.

The production method of the present invention as described above, dapa glyphs to binary and mannitol for the crystalline complex has the advantage that can be produced in more than 99.0% pure without further purification, including, of high purity at a low manufacturing cost crystalline It has the advantage of producing the composite.

Mode for the Invention

Hereinafter the present invention will be described in more detail by examples. However, these examples are for the purpose of illustrating the invention by way of example, but the scope of the present invention is limited to these Examples.

Example 1. Preparation of the crystalline complex

The D- mannitol 0.98g (5.4mmol) was dissolved in purified water to prepare a mannitol 12㎖. On the other hand, amorphous THE dapa glyphs (purity:> 94%, U.S. Patent No. 6,515,117 prepared by the method described in of Example G) was dissolved in 2g (4.9mmol) in ethanol to give the alcohol 13 ㎖ solution. After the mannitol solution at room temperature to give the mixed solution is added to the alcohol solution. The mixed solution was heated under reflux for 3 hours so that the 80 ℃. After the cooling the solution obtained through the reflux slowly to 10 ℃ for 2 hours and then added to camp in the dapa glyph to 4 wt% solution total weight compared to the seeding (seeding) for 12 hours at 200 rpm at 4 ℃ cooling and stirring was added. After Buchner funnel (Buchner funnel) and filtered with a filter paper 55 ㎜ and dried for 8 hours under nitrogen and 20 ℃ to obtain a crystalline complex 1.3g (45%).

Experimental Example 1. Structural analysis

Nuclear magnetic resonance spectrum (NMR) (400MHz FT-NMR Spectrometer (Varian, 400-MR)) of a crystalline complex obtained in Example 1 by using ¹ yielded a H NMR spectrum, and the results, and in Fig. 1 It exhibited.

¹ H NMR (400㎒, DMSO-d ₆ ): δ 7.37-7.35 (d, 1H), 7.32-7.31 (d, 1H), 7.24-7.21 (dd, 1H), 7.10-7.08 (d, 2H), 6.83-6.81 (d, 2H), 4.97-4.95 (dd, 2H), 4.84-4.83 (d, 1H), 4.48-4.44 (t, 1H), 4.42-4.40 (d, 1H), 4.34-4.31 (t , 1H), 4.14-4.12 (d, 1H), 4.02-3.92 (m, 5H), 3.71-3.67 (m, 1H), 3.67-3.58 (m, 1H), 3.56-3.52 (t, 1H), 3.46 -3.35 (m, 3H), 3.28-3.07 (m, 4H), 1.31-1.27 (t, 3H)

The ^first through the results of 1 H NMR, and also, to the structure of a crystalline complex obtained in Example 1, it was confirmed that the formula (4).

[Formula 4]

Experimental Example 2. OK crystalline crystalline complexes

By performing an X-ray diffraction analysis and differential scanning calorimetry, it was confirmed that crystal form of the crystalline complex obtained in Example 1. More specifically, Diffraction Extensible Resource Descriptor (Brucker, USA) for use with X-ray diffraction (XRD) to perform, and differential scanning calorimetry (Differential scanning calorimeter; METTLER TOLEDO, Swiss) for use by differential scanning calorimetry (DSC) It was performed. Results of X-ray diffraction analysis results in Figure 1, the differential scanning calorimetry are shown in Fig.

Results of X-ray diffraction analysis, the crystalline complex according to an embodiment of the present invention exhibited a characteristic peak at 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 2θ of 43.9 ° .

Experimental Example 3. HPLC analysis

To a crystalline complex obtained in Example 1 under the conditions of Table 1 and Table 2 it was carried out to HPLC (high performance liquid chromatography) analysis.

TABLE 1

column	Ascentis Express RP-Amide 4.6mm × 150mm (diameter × height), 2.7㎛ (Aldrich)
The mobile phase	_{A: Formic acid 1mL/1000mL in H 2 OB: Formic acid 1mL/1000mL in Acetonitrile (ACN)}
Test Solution	Acetonitrile Test specimen 5mg / 10mL in 50% (ACN)
Column temperature	25 ℃
Wavelength detector	UV, 220nm
Dose	3 ㎕
Flow rate	0.7 mL / min
Operating hours	40 min

Table 2

Gradient systems
Time (min)	Mobile phase A (%)	Mobile phase B (%)
0	75	25
0-25	35	65
25-26	30	70
26-29	30	70
29-35	75	25
35-40	75	25

As described above, the results of the HPLC analysis, the crystalline complex of Example 1, it was confirmed that the purity of 99% or more. In addition, the crystalline complex of Example 1, it was confirmed that the water content measured by Karl-Fischer method of 2.9%.

Claims

To a crystalline complex comprising a dapa THE glyph having the structure of formula 3: [Formula 3]

According to claim 1, wherein said crystalline complex is in the X- ray diffraction pattern of 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4, and the characteristic peaks at 2θ of 43.9 ± 0.2 ° containing crystalline complexes.

According to claim 1, wherein said crystalline complex is the measured moisture content in accordance with the Karl-Fischer method which is characterized in that 2 to 5%, the crystalline complex.

1) preparing a mannitol solution by mixing mannitol (mannitol) and the solvent 2) a mixture of binary (dapagliflozin) and alcohol in dapa glyph for preparing an alcohol solution; 3) wherein the mannitol solution and the alcohol mixing the solution and heated to 50 ~ 100 ℃; And 4) the production method to cool the heated solution to 0 ~ 15 ℃ comprising the step of obtaining a polycrystalline composite having a structure of formula (3), a crystalline complex: [Formula 3]

[Claim 5]

According to claim 4, wherein the solvent is the production of water, the crystalline complex.

According to claim 4, wherein the alcohol is a C ₁ ~ C _4, a method of producing a crystalline complex comprising at least one kind of alcohol.

According to claim 6, wherein the alcohol is ethanol, the method of the crystalline complex prepared.

According to claim 4, wherein the mixing ratio by the spirit and mannitol dapa glyph is 1: 0.5 to 2 mole ratio, the method of producing a crystalline complex.

FIGURES

Figure 1 illustrates a X- ray diffraction spectrum of the crystalline complex in accordance with an embodiment of the present invention.

2 is a result of the differential scanning calorimetry of the crystalline complexes (DSC) in accordance with an embodiment of the present invention.

3 is of the crystalline complex in accordance with an embodiment of the present invention ¹ shows the H-NMR measurement results.

[Figure 1]

[Figure 2]

[Figure 3]

CEO, YOUNG KIL CHANG

/////////WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LT, NEW PATENT

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Facts, Growth, and Opportunities in Industrial Biotechnology

Uncategorized Comments Off

Jan 132016

The revolution in synthetic biology has enabled innovative manufacture of biofuels and the development of biological processes for the manufacture of bulk and fine chemicals. This short review gives some examples of recent progress.

Facts, Growth, and Opportunities in Industrial Biotechnology

Rina Singh

Industrial Biotechnology and Environmental, Biotechnology Industry Organization (BIO), 1201 Maryland Avenue, SW, Suite 900, Washington, DC 20024, United States

Org. Process Res. Dev., 2011, 15 (1), pp 175–179

DOI: 10.1021/op100312a

Publication Date (Web): December 7, 2010

This article is part of the Biocatalysis special issue.

http://pubs.acs.org/doi/abs/10.1021/op100312a

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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

MONITORING FLUORINATIONS……Selective direct fluorination for the synthesis of 2-fluoromalonate esters

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Jan 022016

Graphical abstract: Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters .

Optimisation and real time reaction monitoring of the synthesis of 2-fluoromalonate esters by direct fluorination using fluorine gas is reported. An assessment of green metrics including atom economy and process mass intensity factors, demonstrates that the one-step selective direct fluorination process compares very favourably with established multistep processes for the synthesis of fluoromalonates.

image file: c5gc00402k-s2.tif .

Scheme 2 Synthetic routes to 2-fluoromalonate esters.

There are three realistic, low-cost synthetic strategies available for the large scale manufacture of diethyl 2-fluoromalonate ester (Scheme 2) which involve reaction of ethanol with hexafluoropropene (HFP), halogen exchange (Halex)and selective direct fluorination processes. Other syntheses of fluoromalonate esters using electrophilic fluorinating agents such as Selectfluor™ are possible, but are not sufficiently commercially attractive to be considered for manufacture on the large scale.

A growing number of patents utilising fluoromalonate as a substrate for the synthesis of a range of biologically active systems have been published For example, Fluoxastrobin (Fandango®), a fungicide marketed by Bayer CropScience that has achieved global annual sales of over €140 m since its launch in 2005, and TAK-733, an anti-cancer drug candidate, employ 2-fluoromalonate esters as the key fluorinated starting material (Scheme 1).

Scheme 1 2-Fluoromalonate esters used in the synthesis of Fluoxastrobin and TAK-733.

Before a comparison of the green metrics between the three possible, economically viable large scale processes for the synthesis of fluoromalonate esters (Scheme 2) could be carried out, some primary goals for the optimisation of the process were targeted: complete conversion of the starting material is essential because it can be difficult to separate the starting material from the desired monofluorinated product by simple distillation; fluorine gas usage should be minimised because neutralisation of excess reagent could potentially generate significant amounts of waste; reduction in volumes of solvents used to reduce waste streams and overall intensification of the fluorination process and replacement and/or reduction of all environmentally harmful solvents used.

Conventional batch direct fluorination reactions of malonate esters were carried out in glassware vessels by introduction of fluorine gas, as a 10% or 20% mixture in nitrogen (v/v), at a prescribed rate via a gas mass flow controller into a solution of malonate ester and copper nitrate catalyst in acetonitrile using equipment described previously.

To better understand the relationship between fluorine gas introduction and rate of conversion, real time IR spectroscopic monitoring of the reaction was chosen as the most suitable technique. The use of the ReactIR technique was enabled by a sufficient difference in the carbonyl group stretching frequencies (1734 cm⁻¹ for diethyl malonate and 1775 cm⁻¹ for diethyl 2-fluoromalonate) and provided an in situ reaction profile (Fig. 1).


	Fig. 1 IR spectra of the fluorination reaction at 0% (light blue), 50% (dark blue) and 100% (red) conversions.

The real time reaction monitoring (Fig. 1 and 2) revealed that the reaction begins instantly upon initiation of fluorine introduction and the reaction conversion is directly proportional to the amount of fluorine gas passed into the reaction vessel. When the intensity of the fluoromalonate carbonyl peak (1775 cm⁻¹) reached a maximum, the introduction of fluorine gas was stopped and the crude reaction mixture was analysed by ¹H and ¹⁹F NMR spectroscopy. Complete conversion of the starting material was observed and diethyl fluoromalonate was formed with 93% selectivity after introducing 1.1 equivalents of fluorine into the reaction mixture. The small excess of fluorine explains the unexpectedly small amount of difluorinated side products B and C (4.5 and 2.5% respectively) which were the major impurities (6.5 and 9% respectively) when larger excess of fluorine gas (1.8 eq.) was used.


	Fig. 2 In situ monitoring of the fluorination of diethyl malonate.

The effect of concentration of fluorine in nitrogen, reaction temperature, copper nitrate catalyst loading and concentration of malonate substrate in acetonitrile were varied to optimise the fluorination process (Table 1). Additionally, reactions described in Table 1 allowed an assessment of various factors that have a major influence on the environmental impact of the process such as solvent usage, reaction temperature and the amount and composition of waste generated. In each case 20 mmol (3.20 g) of diethyl malonate was used as substrate and the isolated mass balance of crude material obtained after work-up was recorded along with the conversion of starting material and yield of fluorinated products (Table 1).

Table 1 Fluorination of diethyl malonate ester using fluorine gas catalysed by Cu(NO₃)₂·2.5H₂O


Entry no.	T/°C	C _malonate (mol L⁻¹)	Catalyst (mol%)	F ₂ in N₂ (% v/v)	Conversion (¹H NMR)	A/B/C ratio (¹⁹F NMR)	Isolated weight
1	0–5	1.0	10	10	100%	93.5/4.5/2	3.37 g
2	0–5	1.5	10	10	100%	94/4/2	3.30 g
3	0–5	1.0	5	10	97%	95/4/1	3.53 g
4	0–5	1.0	2.5	10	82%	95/4/1	3.51 g
5	RT	1.0	10	10	56%	97.5/1.5/1	3.33 g
6	0–5	1.0	10	15	85%	97.5/1.5/1	3.47 g
7	0–5	1.0	10	20	100%	94/3/3	3.50 g
8	0–5	2.0	5	20	52%	92/5/3	3.40 g

In all cases, small quantities of side products were formed which were identified by ¹⁹F NMR and these originate from two different processes: 3,3-difluoromalonate is produced from enolisation of diethyl fluoromalonate which is much slower than enolisation of the diethyl malonate substrate, while the fluoroethyl fluoromalonate is postulated to form via an electrophilic process.

The data in Table 1 suggest that the concentration of the malonate ester substrate in acetonitrile has no apparent effect on the outcome of the reaction although solvent is required for these reactions because diethyl malonate does not dissolve the catalyst. Additionally, the use of high dielectric constant media, such as acetonitrile, have been found to be beneficial for the control of selectivity of electrophilic direct fluorination processes. For convenience, a 1.5 M concentration of malonate in acetonitrile was chosen as the optimal conditions which is approximately 5 mL solvent per 1 mL of diethyl malonate.

The concentration of fluorine gas, between 10–20% v/v in nitrogen, does not affect the selectivity of the reaction and the quality of the product either, as exemplified by the product mixtures obtained from reactions 1, 2 and 7 which have identical compositions. In contrast, carrying out fluorination reactions at room temperature rather than cooling the reaction mixture to 0–5 °C leads to increased catalyst decomposition which results in an insoluble copper species that on occasion blocked the fluorine gas inlet tube. In addition, without cooling, the exothermic nature of this fluorination reaction led to a slight reaction temperature increase (from 20 to 29 °C in a small scale laboratory experiment) resulting in loss of some solvent and some decomposition of the catalyst and product degradation.

Lowering the concentration of the copper nitrate catalyst led to a significantly slower reaction as would be expected and required the use of a larger excess of fluorine gas to enable sufficiently high conversion. For example, the reaction proceeded in the presence of only 2.5 mol% catalyst, but in this case 40% excess fluorine was required to reach 100% conversion.

Typical literature work-up procedures for direct fluorination reactions involve pouring the reaction mixture into 3 to 5 volumes of water and extracting the resulting mixture three times with dichloromethane. The combined organic fraction is typically washed with water, saturated sodium bicarbonate solution and dried over sodium sulfate before evaporation of the solvent to give the crude reaction product. We sought to improve the work-up to enable recycling of the reaction solvent and substitute the use of environmentally harmful dichloromethane in the reaction work-up stage. Upon completion of fluorine gas addition, acetonitrile was evaporated for reuse and then the residue was partitioned between ethyl acetate and water, the organic phase was washed with water, saturated Na₂CO₃ solution and saturated brine and dried prior to evaporation under reduced pressure. Modification of the workup procedure in this manner enables the recovery of acetonitrile and ethyl acetate and significantly reduces the amount of aqueous waste generated. When direct reuse of the recovered acetonitrile was attempted, a copper containing precipitate was formed presumably because of the high HF content of the solvent (0.63 M by titration). Therefore, before reuse of the solvent, HF must be removed. Stirring the recovered reaction solvent with solid Na₂CO₃ lowered the acid content to an acceptable level (0.04 M) and when a second fluorination reaction was carried out in the recovered, neutralised acetonitrile, no change in the fluorination reaction profile was observed.

Upon completion of these optimisation studies, selective fluorination reactions of malonate esters were scaled up to 40 g scale in the laboratory without experiencing any change in product profile. Isolation of significant quantities of monofluoromalonate A crude product (99% yield, 95% purity) was achieved which could be used in the subsequent cyclisation processes described below without further purification or, if high purity material was required, could be purified by fractional vacuum distillation (bp. 102–103 °C, 18 mbar) to produce 99% pure material in 77% yield.

Related malonate esters were also subjected to direct fluorination using the optimised conditions established above. In the case of di-tert-butyl malonate, fluorination was carried out on 12 g scale. 100% conversion was reached after the introduction of 1.2 equivalents of fluorine gas and the desired product was isolated in 96% yield. The purity of the crude product was higher than 97% by ¹H and ¹⁹F NMR spectroscopy without any further purification and as expected, the only side product was the 2,2-difluorinated product (Scheme 3).


	Scheme 3 Fluorination of di-methyl and di-tert-butyl malonates.

Diethyl fluoromalonate large scale fluorination

Diethyl malonate (40.0 g, 0.25 mol) and copper nitrate hydrate (Cu(NO₃)₂·2.5H₂O; 5.81 g, 25 mmol) were dissolved in acetonitrile (200 mL) and placed in 500 mL fluorination vessel, cooled to 0–5 °C and stirred at 650 rpm using an overhead stirrer. After purging the system with N₂ for 5 minutes, fluorine gas (20% v/v in N₂, 80 mL min⁻¹, 265 mmol) was introduced into the mixture for 6 hours and 30 minutes. The reactor was purged with nitrogen for 10 minutes, the solvent removed in vacuo and the residue partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase was extracted once more with ethyl acetate (50 mL) and the combined organic layers were washed with saturated NaHCO₃ (25 mL) and brine (20 mL). After drying over sodium sulfate, the solvent was evaporated to leave diethyl 2-fluoromalonate (44.4 g, 99% yield, 95% purity) as a light yellow, transparent liquid. This crude product was distilled to afford high purity fluoromalonate (34.7 g, 77% yield, 99%+ purity) as a colourless liquid, bp. 102–103 °C (18 mbar), (lit.: 110–112 °C, 29 mbar), spectroscopic data as above………N. Ishikawa, A. Takaoka and M. K. Ibrahim, J. Fluorine Chem., 1984, 25, 203–212 CrossRef CAS.

PAPER

REF

http://pubs.rsc.org/en/content/articlehtml/2015/gc/c5gc00402k

http://pubs.rsc.org/en/Content/ArticleLanding/2015/GC/c5gc00402k#!divAbstract

DOI: 10.1039/C5GC00402K (Paper) Green Chem., 2015, 17, 3000-3009

Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters†

Antal Harsanyi and Graham Sandford *
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK. E-mail: graham.sandford@durham.ac.uk

Received 19th February 2015 , Accepted 17th March 2015

First published on the web 17th March 2015

Paper

Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters

Antal Harsanyi^a and Graham Sandford*^a

*Corresponding authors

^aDepartment of Chemistry, Durham University, South Road, Durham, UK
E-mail: graham.sandford@durham.ac.uk

Green Chem., 2015,17, 3000-3009

DOI: 10.1039/C5GC00402K

A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions

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Nov 032015

An immobilised monolithic iridium hydrogen transfer catalyst has been developed for use in flow based processing. The monolithic construc thas been used for several redox reductions demonstrating excellent recyclability, good turnover numbersand high chemical stability giving negligible metal leaching over extended periods of use.

A FlowSyn Auto-LF system was employed to automatically process a library of 40 aldehydes and ketones.

Maria Victoria Rojo,*a Lucie Guetzoyana and Ian. R. Baxendale Org. Biomol. Chem., 2015, 13, 1768

An immobilised iridium hydrogen transfer catalyst has been developed for use in flow based processing by incorporation of a ligand into a porous polymeric monolithic flow reactor. The monolithic construct has been used for several redox reductions demonstrating excellent recyclability, good turnover numbers and high chemical stability giving negligible metal leaching over extended periods of use.

Graphical abstract: A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions

Maria Victoria Rojo,*^a Lucie Guetzoyan^a and Ian. R. Baxendale^a^b

*Corresponding authors

^aDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
E-mail: mavirm@hotmail.com

^bDepartment of Chemistry, University of Durham, South Road, Durham, UK

Org. Biomol. Chem., 2015,13, 1768-1777
DOI: 10.1039/C4OB02376E

http://pubs.rsc.org/en/content/articlelanding/2015/ob/c4ob02376e#!divAbstract

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Tafluprost

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Oct 252015

isopropyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]-3,5-dihydroxycyclopentyl}hept-5-enoate,

propan-2-yl (E)-7-[2-[(E)-3,3-difluoro-4-phenoxybut-1-enyl]-3,5-dihydroxycyclopentyl]hept-5-enoate

Molecular Formula: C₂₅H₃₄F₂O₅

Molecular Weight: 452.531266

Drug: Zioptan
Generic molecule: tafluprost
Company: Merck
Approval date: Feb. 10, 2012

The scoop: Merck says this is the first (get ready for a mouthful) preservative-free prostaglandin analog ophthalmic solution and is for treating elevated eye pressure in some patients with the most common form of glaucoma. Merck sells the ointment in the U.S. and most of Europe, while it licensed it to Japanese drugmaker Santen in Japan, Germany and northern Europe.

Tafluprost (trade names Taflotan, marketed by Santen Pharmaceutical Co. and Zioptan, by Merck (U.S.)) is a prostaglandin analogue used topically (as eye drops) to control the progression of glaucoma and in the management of ocular hypertension. It reduces http://en.wikipedia.org/wiki/Intraocular_pressure”; rel=”nofollow”>intraocular pressure by increasing the outflow of aqueous fluid from the eyes.^[1]^[2]

Taflotan contains 15 µg/ml Tafluprost. Taflotan sine is a preservative-free, single-dose formulation containing 0.3 ml per dose.^[3]

tafluprost_PG

Tafluprost
Systematic (IUPAC) name

isopropyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]-3,5-dihydroxycyclopentyl}hept-5-enoate
Clinical data
Trade names	Saflutan, Taflotan, Tapros, Zioptan
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	C (US)
Legal status	℞-only (US)
Routes	Topical (eye drops)
Identifiers
CAS number	209860-87-7
ATC code	S01EE05
PubChem	CID 6433101
ChemSpider	8044182
UNII	1O6WQ6T7G3
ChEBI	CHEBI:66899
ChEMBL	CHEMBL1963683
Chemical data
Formula	C₂₅H₃₄F₂O₅
Mol. mass	452.531266 g/mol

Chemical structure for AC1O5FKL

Links

Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
Santen Home Page
Gelbe Liste (in German)

Its synthesis from compound Corey aldehyde and HWE (Hormer-Wadsworth-Emmons) reagent 1 generates trans olefin 2 , 2 and fluorination reagent 3 hydrolysis reaction 4 , lactone 4 with DIBAL reduction to give the ring hemiacetal 5 , 5 and Wittig reagent 6 cis olefin reaction after esterification with isopropyl iodide Tafluprost.

……………………….

http://www.google.st/patents/WO2013118058A1?cl=en

European Patent No. 8509621 discloses a process for the preparation of tafluprost. In the first step, (3afl,4fl,5fl,6aS)-4-formyl-2-oxohexahydro-2 — cyclopenta[b]furan-5-ylbenzoate (CTAF 1 (i)) is condensed with dimethyl (2-oxo-3- phenoxypropyl)-phosphonate in the presence of lithium chloride and triethylamine, to provide (3aft,4F?,5F?,6aS)-2-oxo-4-((£)-3-oxo-4-phenoxybut-1 -en-1 -yl)hexahydro-2H- cyclopenta[b]-furan-5-ylbenzoate (CTAF1 ). In the second step, CTAF 1 is reacted with morpholinosulfurtrifluoride to provide (3aH,4H,5H,6aS)-4-((£)-3,3-difluoro-4- phenoxybut-1 -en-1 -yl)-2-oxohexahydro-2 –cyclopenta-[b]furan-5-yl benzoate (CTAF2). CTAF 2 is debenzoylated by potassium carbonate in methanol, to provide (3aH,4H,5H,6aS)-4-((£)-3,3-difluoro-4-phenoxybut-1 -en-1 -yl)-5-hydroxyhexahydro-2H- cyclopenta[b]furan-2-one(CTAF 3), which is further reduced by diisobutyl aluminum hydride (DIBALH) to provide (3af?,4f?,5f?,6aS)-4-((£)-3,3-difluoro-4-phenoxybut-1 -en-1 – yl) hexahydro-2H-cyclopenta[b]furan-2,5-diol (CTAF 4). CTAF 4 is then treated with (4- carboxybutyl)triphenylphosphonium bromide, in the presence of potassium bis(trimethylsilyl)amide in THF, to provide (Z)-7-((1 f?,2f?,3f?,5S)-2-((£)-3,3-difluoro-4- phenoxybut-1 -en-1 -yl)-3,5-dihydroxycyclopentyl)hept-5-enoic acid (“tafluprost free acid,” CTAF5), which is reacted with isopropyl iodide in the presence of DBU to provide (Z)- isopropyl 7-((1 F?,2F?,3F?,5S)-2-((£)-3,3-difluoro-4-phenoxybut-1 -en-1 -yl)-3,5-dihydroxy- cyclopentyl)hept-5-enoate (“tafluprost,” CTAF 6). The reaction sequence is summarized in Scheme 1 .

CTAF 1(i)

CTAF 1 CTAF 2

U.S. Patent Application Publication No. 2010/0105775A1 discloses amino acid salts of prostaglandins. The application also discloses a process for the preparation of prostaglandins, comprising forming an amino acid salt of a prostaglandin and converting the amino acid salt to the prostaglandin.

EXAMPLE 1 : Preparation of CTAF 1

CTAF1(i)

CTAF1

To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.217 g, 5.429 mmol) in THF (5 ml_) was added a solution of dimethyl (2-oxo-3- phenoxypropyl)phosphonate(1 .21 g, 4.705 mmol) in THF (2 ml_), over 15 minutes at 0- 5°C under a nitrogen atmosphere. The mixture was warmed to 25-35 , 0.5 M zinc chloride solution in THF (9.4 ml_, 4.705 mmol) was added over 10 minutes, and then the mixture was stirred for 15 minutes at 25-35^<€. CTAF1 (i) (3af?,4F?,5F?,6aS)-4-formyl-2- oxohexahydro-2 –cyclopenta[b]furan-5-yl benzoate (1 g) in dichloromethane (10 ml_) was added over 5 minutes at 25-35 °C. The temperature was raised to 35-40 °C and the mixture was stirred for 2hours under a nitrogen atmosphere. The mixture was cooled to 15°C and the reaction was quenched by adding acetic acid (0.2 mL), followed by adding saturated ammonium chloride solution (10 mL), and further stirring for 15 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were evaporated under reduced pressure below 50°C. The crude product was purified by column chromatography on silica gel (100-200 mesh) with 30% ethyl acetate in hexane, to afford the title compound (0.9 g, 61 %yield).

EXAMPLE 2: Preparation of CTAF 2

CTAF1 CTAF2

To a stirred solution of CTAF1 (5 g, 0.0123 mol) in dichloromethane (100 mL) was added diethylaminosulfurtrifluoride (13 mL, 0.09841 mol) at 0-5 °C under a nitrogen atmosphere. The temperature was raised to 25-35 °C and maintained for 24 hours under a nitrogen atmosphere at the same temperature. The mass was slowly added into a saturated sodium bicarbonate solution (75 mL) at 0-5 °C. Temperature was raised to 25- 35 °C, the layers were separated, and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with water (25mL) and dried over sodium sulfate (5 g). The organic layer was evaporated to dryness under reduced pressure below 40 °C. The crude product was purified by column chromatography on silica gel (100-200 mesh) with 30% ethyl acetate in hexane, to afford the title compound (4.2 g, 79% yield). EXAMPLE 3: Preparation of CTAF 4

CTAF 2 CTAF 4

CTAF 2 (2.30 g, 5.37 mmol) was dissolved in toluene (25 mL) and the solution was cooled to -65 °C under nitrogen. Diisobutyl aluminum hydride (1 .5 M in toluene, 1 1 .8 mL, 17.7mmol) was added over 15 minutes at -61 to -65 . The mixture was stirred for 3hours and then the reaction was quenched by adding methanol (1 .5 mL). Sulfuric acid (1 M, 25 mL) was added and the temperature rose to -20°C during the addition. Methyl t-butyl ether (MTBE) (10 mL) was added and the mixture was allowed to warm to room temperature. The organic phase was separated and the aqueous phase was extracted with MTBE (2x 10 mL). The combined organic phase was washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL), and then brine (10 mL). The washes were back-extracted with MTBE (10 mL). The combined organic phases were dried with magnesium sulfate, filtered, and evaporated to give a colourless oil (2.20 g). The crude product was chromatographed on silica (60 g), eluting with a mixture of ethyl acetate and heptane (2:1 by volume), and then with ethyl acetate, to give CTAF 4 as a colourless oil (1 .71 g, 97% yield).

EXAMPLE 4: Preparation of CTAF 2

CTAF1 CTAF2

To a stirred solution of CTAF1 (20 g, 0.0492 mol) in dichloromethane(400 mL) was added diethylaminosulfurtrifluoride (52 mL, 0.393 mol) at 0-10°C under a nitrogen atmosphere. The temperature was raised to 25-35 and maintained for 96hours under a nitrogen atmosphere at that temperature. The mass was slowly added to a saturated NaHCOs solution (600 mL) at 0-10°C. The mixture was heated to 25-35 ^<€ and filtered through aCelite bed. The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layer was washed with 10% NaCI solution (100 mL) and evaporated to dryness under reduced pressure below 40°C. The residue was purified by column chromatography on silica gel (100-200 mesh) with 30% ethyl acetate in hexane.

Column purified material was dissolved in MTBE (80 mL) at 40°C and stirred for 30 minutes at that temperature. Diisopropyl ether (160 mL) was added at 35-40 and stirring continued for 30 minutes at 35-40 . Cooled the mass to 5-15°C and stirred for 30 minutes at that temperature. The solid was filtered, washed with a mixture of MTBE and diisopropyl ether (DIPE) (1 :2 by volume, 60 mL), and dried at 40°C under vacuum, to afford pure CTAF2 (12.0 g, 57% yield).

EXAMPLE 5: Preparation of CTAF 5

(4-Carboxybutyl)triphenylphosphonium bromide (10.32 g, 23.3 mmol, 4 eq) was suspended in THF (20 mL) under a nitrogen atmosphere and cooled to 5°C. NaHMDS solution (1 M in THF, 46.6 mL, 46.6 mmol, 8 eq) was added over 10 minutes. The red/orange mixture was stirred for 30 minutes. A solution of CTAF 4 (1 .90 g, 5.82 mmol) in THF (10 mL) was added over 30 minutes at 0-3 . The mixture was stirred for 1 .5hours and then the reaction was quenched by adding water (30 mL) and the masswas warmed to room temperature. The aqueous phase was separated and the organic phase was washed with water (20 mL). The combined aqueous phases were washed with MTBE (30 mL). The organic phases up to this point were discarded. The aqueous phase was acidified with 2M hydrochloric acid (14 mL, to pH 3-4) and extracted with ethyl acetate (2×30 mL). The combined ethyl acetate layers were washed with brine (20 mL), dried with magnesium sulfate, filtered, and evaporated under reduced pressure to give CTAF 5 asa yellow oil (8.60 g).

A 2.96 g sample was removed and the remainder (5.64 g) was chromatographed on silica (30 g) eluting with ethyl acetate to give purified CTAF 5 (1 .41 g) asa yellow oil. NMR analysis showed approximately 90% purity, remainder triphenyl phosphine oxide.

EXAMPLE 6: Preparation of CTAF 5 DCHA salt

CTAF 5 CTAF 5 DCHA sa t

CTAF5 (1 1 .72 g, 90% purity, 25.7 mmol, containing 1 .4% trans isomer) was dissolved in acetone (60 mL). Dicyclohexylamine (4.66 g, 25.7 mmol) was added and the mixture was stirred at room temperature overnight. The solid was filtered and washed with acetone (6 mL), then dried to give the DCHA salt (12.93 g, 85% yield, 0.29% trans-isomer).

A sample (7.03 g) was further purified by recrystallisation. It was dissolved in hot acetone (30 mL) and cooled to room temperature with stirring. The mixture was stirred for 3 hours, filtered and the solid was washed with acetone (3 mL) and dried to give a white solid (6.41 g, 91 % recovery, 0.1 1 % trans-isomer).

A PXRD pattern of the product is shown as Fig. 1 , obtained using copper Ka radiation. In the drawing, the y-axis is intensity units and the x-axis is the 2-theta angle, in degrees. EXAMPLE 7: Pre aration of CTAF 6

CTAF 5 DCH A sa l ^ I AI- O

CTAF 5 DCHA salt (5.80 g, 9.80 mmol) was suspended in ethyl acetate (20 mL). Sulfuric acid (1 M, 20 mL) was added and the mixture was stirred until a clear solution was obtained. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), dried with magnesium sulfate, filtered, and evaporated. The residue was dissolved in acetone (40 mL) and charged into a jacketed vessel at 30°C. 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (8.95 g, 58.8 mmol) was added, then 2- iodopropane (10.0 g, 58.8 mmol) was added, and the mixture was stirred for 20hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (30 mL) and aqueous potassium dihydrogen orthophosphate (8 g) in water (50 mL). The organic phase was separated and the aqueous was extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine (20 mL), dried with magnesium sulfate, filtered and evaporated to give a yellow oil (4.83 g). The crude product was chromatographed on silica (130 g), eluting with a mixture of ethyl acetate and heptane (2:1 by volume), to give CTAF 6 (3.98 g, 90% yield) as a colorless oil.

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

MAVATREP, JNJ 39439335,

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Oct 252015

Mavatrep; UNII-F197218T99; Mavatrep (USAN); JNJ-39439335; 956274-94-5;

2-(2-(2-(2-(4-trifluoromethylphenyl)vinyl)-1H-benzimidazol-5-yl)phenyl)propan-2-ol

(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

Phase I Musculoskeletal pain; Pain

01 Mar 2013 Janssen Research and Development completes a phase I trial in Japanese and Caucasian adult male volunteers in the US (NCT01631487)
01 Mar 2013 Janssen completes enrolment in its phase I trial for Pain (in volunteers) in the USA (NCT01631487)
05 Feb 2013 Janssen Research and Development initiates enrolment in a phase I trial for Pain (Japanese and Caucasian volunteers) in USA (NCT01631487)

Originator Johnson & Johnson Pharmaceutical Research & Development
Developer Janssen Research & Development
Class Analgesics; Benzimidazoles; Small molecules
Mechanism of Action TRPV1 receptor antagonists

ChemSpider 2D Image | Mavatrep | C25H21F3N2O

PHASE 1 Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Public title:	A Clinical Study to Investigate the Effect on Pain Relief of a Single Dose of JNJ-39439335 in Patients With Chronic Osteoarthritis Pain of the Knee

http://clinicaltrials.gov/ct2/show/NCT01006304
http://apps.who.int/trialsearch/trial.aspx?trialid=NCT00933582

http://www.ama-assn.org/resources/doc/usan/mavatrep.pdf SEE STRUCTURE IN THIS FILE

MAVATREP IS JNJ-39439335
—

(E)-2-(2-(2-(4-(trifluoromethyl)styryl)-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol hydrochloride

956282-89-6 CAS NO OF HCl SALT

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00271, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00271

The process development of Mavatrep (1), a potent transient receptor potential vanilloid-1 (TRPV1) antagonist, is described. The two key synthetic transformations are the synthesis of (E)-6-bromo-2-(4-(trifluoromethyl)styryl)1H-benzo[d]imidazole (4) and the Suzuki coupling of 4 with 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (5). Compound 1a was prepared in four chemical steps in 63% overall yield.

http://www.google.st/patents/US20110190344

CLICK ON IMAGE FOR CLEAR VIEW

Example 10 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol(Cpd 18)

Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

[0278]

A solution of 4-trifluoromethylbenzaldehyde (7.7 mL, 57.7 mmol), malonic acid (12.0 g, 115.4 mmol), 0.567 μL piperidine (5.75 mmol) in 30 mL of pyridine was stirred at 70° C. for 18 h. The reaction solution was cooled to room temperature. Water (300 mL) was added and the resulting mixture was acidified to pH 4 (litmus) using concentrated hydrochloric acid to give a precipitate. The solid was filtered, and washed with water until the filtrate was neutral. The solid product was dried in vacuo to give the title Compound 10a as a white powder (11.2 g, 90%). ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 12.60 (bs, 1H), 7.92 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz), 7.66 (d, 1H, J=16.0 Hz), 6.70 (d, 1H, J=16.0 Hz).
[0000]

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

[0279]

A solution of Compound 10a (20.6 g, 95.4 mmol) in anhydrous methylene chloride (200 mL) was treated with oxalyl chloride (16.6 mL, 190 mmol) and “3 drops” of anhydrous dimethylformamide. The resulting solution was stirred at room temperature under an argon atmosphere for 18 h. The solvent was concentrated to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b as a solid, which was used without further purification in the next step.
[0280]

To a solution of 4-bromo-benzene-1,2-diamine (16.1 g, 86.7 mmol) in acetic acid (100 mL) was added dropwise a solution of Compound 10b (assumed 95.4 mmol) in acetic acid (100 mL). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and a mixture of ethyl acetate and hexanes 3:7 (500 mL) was added. The mixture was triturated at room temperature for 3 h to give a precipitate. The solid was filtered, and dried in vacuo to give the title Compound 10c (23.2 g, 73%). ¹H NMR (400 MHz, DMSO-d₆/CDCl₃) δ (ppm): 8.45 (d, 1H, J=16.7 Hz), 7.84-7.90 (m, 1H), 7.74 (d, 2H, J=8.3
[0281]

Hz), 7.56-7.62 (m, 3H), 7.50-7.52 (m, 1H), 7.34 (d, 1H, 16.7 Hz).
[0000]

Step C. 2-(2-bromo-phenyl)-propan-2-ol

[0282]

To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol) in 120 mL of anhydrous ether under Argon at 0° C. was slowly added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the internal temperature of the mixture was below 20° C. A white suspension resulted, and the mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice-water bath. To the reaction mixture was very slowly added hydrochloric acid (400 mL, 0.5 M). The pH of the final mixture was adjusted to less than about 6 with few drops of 2M hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined and dried over magnesium sulfate. The organic fraction was filtered, and the filtrate was concentrated to yield the title compound as a pale yellow liquid, which was distilled under vacuum to afford the title Compound 10d as a colorless liquid (16.9 g, 82%, b.p. about 65-70° C./0.3 mmHg). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.67 (dd, 1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H, J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br s, 1H), 1.76 (s, 6H).
[0000]

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

[0283]

To a solution of n-BuLi (166 mL, 2.6 M, 432 mmol) in 200 mL of THF at −78° C. under argon was slowly added a solution of Compound 10d (42.2 g, 196 mmol) in 60 mL of THF at a rate that the internal temperature remained below −70° C. The mixture was stirred at −75° C. for 2 h. To the reaction mixture was then added triisopropylborate (59 mL, 255 mmol) in three portions. The mixture was allowed to warm slowly to room temperature overnight. The mixture was then cooled to 0° C., and was carefully quenched with dilute hydrochloric acid (250 mL, 2N). The mixture was then stirred at room temperature for 1 h. The pH of the mixture was checked and adjusted to acidic using additional 2N HCl if prophetic. The two layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined, and dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a pale yellow oil. The residue was then diluted with ethyl acetate (400 mL) and, washed with 1N sodium hydroxide solution (150 mL×3). The basic aqueous layers were combined and acidified with 2N HCl. The clear solution turned cloudy when the acid was added. The mixture was extracted with ether (150 mL×3). The organic layers were combined and dried with magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to yield the title Compound 10e as a colorless oil (26.2 g, 82%) which was used without further purification in the next step. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.00 (s, 1H), 7.66 (dm, 1H, J=7.3 Hz), 7.45 (dt, 1H, J=1.1, 7.7 Hz), 7.40 (dm, 1H, J=7.6 Hz), 7.31 (dt, 1H, J=1.2, 7.1 Hz), 1.44 (s, 6H).
[0000]

Step E. (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

[0284]

To a mixture of Compound 10e (11.7 g, 71 mmol), Compound 10c (19.9 g, 54 mmol), sodium carbonate (46 g, 435 mmol) and PdCl₂(dppf).CH₂Cl₂(8.9 g, 11 mmol) in a 1 L round bottom flask equipped with water condenser was added 400 mL of anhydrous DME and 200 mL of water. The mixture was evacuated and filled with Argon three times. The mixture was heated to 100° C. for 20 h. The mixture was then cooled to room temperature. The biphasic system was transferred to a 1 L separatory funnel and the two layers were separated. The organic layer was washed with brine (2×300 mL). The aqueous layers were combined and extracted with ethyl acetate once (about 300 mL). The organic layers were combined, dried with sodium sulfate, and filtered. The volume of the filtrate was reduced to about 170 mL under reduced pressure. The mixture was then filtered through a pad of silica gel and the pad was washed with ethyl acetate until the filtrate did not contain any product. After concentration, a light pink/beige solid was obtained. The solid was triturated with 50 mL ethyl acetate, and the mixture was heated to 85° C. for 5 min. The mixture was slowly cooled to r.t., then cooled at 0° C. for 0.5 h. The mixture was filtered, and the solid was washed with cold ethyl acetate twice, and dried under vacuum at 40° C. to yield the title Compound 18 as a light beige solid (7.58 g, 33%). RP-HPLC 95% pure.
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.73 (m, 1H,), 7.90 (d, 2H, J=8.2 Hz), 7.85 (dd, 1H, J=8.0, 0.6 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.74 (d, 1H, J=16.8 Hz), 7.59-7.47 (m, 1H), 7.41 (s, 1H), 7.37-7.32 (m, 2H), 7.21 (dt, 1H, J=1.2, 7.4 Hz), 7.06 (s, 1H), 7.02 (d, 1H, J=7.4 Hz), 4.85 (s, 1H), 1.21 (s, 6H).
Mass Spectrum (LCMS, APCI pos.) Calcd. For C₂₅H₂₁F₃N₂O: 423.2 (M+H). Found 423.3.
m.p. (uncorr.) 250-251° C.

Example 10.1 Scale Up Preparation of (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Cpd 18) Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

[0286]

A 2-L 4-neck round bottom flask equipped with an air condenser/argon inlet, mechanical stirrer, thermocouple and a stopper was charged with 4-(trifluoromethyl)benzaldehyde (250 g, 196.2 mL, 1.44 mol), malonic acid (302.6 g, 2.87 mol), and pyridine (750 mL). An exotherm developed (about 38-40° C.), which was maintained for 30 min. Piperidine (14.202 mL, 143.58 mmol) was then added to the reaction and a second exotherm developed (T_maxabout 42° C. after about 10 min.). The reaction was stirred for 30 min and then heated to 60° C. for 18 h (overnight). The reaction appeared to be complete by TLC, and was cooled to about 40° C., diluted into water (2 L; done to prevent reaction freezing), cooled to room temperature, and further diluted with water (4 L, 6 L total). The slurry was acidified to pH=2.0-3.0 with concentrated hydrochloric acid (about 675-700 mL). The material was stirred for 30 min., and a white solid was collected by filtration. The filter cake was washed with water until the filtrate was neutral (pH about 5.5-6, 2.5 L), air-dried in a Buchner funnel for 2 h, and then further dried in a vacuum oven at 60° C. overnight to provide 300.5 g (96%) of the title Compound 10a as a white solid.

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

[0287]

To a 5-L 4-neck round bottom flask equipped with a magnetic stirrer, argon inlet-argon outlet to a carbonate scrub, two stoppers, and a room temperature water bath was charged with 4-(trifluoromethyl)cinnamic acid (315 g, 1.46 mol) and dichloromethane (3.15 L) to give a slurry. To the slurry was added oxalyl chloride (151.71 mL, 1.75 mol) and DMF (1.13 mL, 14.57 mmol). Upon addition of DMF, gas evolution commenced, and the reaction was continued for about 3 h during which time a solution developed. When the reaction was complete (LC-MS), it was concentrated to dryness to give 342.4 g of 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b (>100%) as a yellow oily solid.
[0288]

A 5-L 4-neck round bottom flask equipped with mechanical stirrer, thermocouple, air condenser with argon inlet, and a stopper was charged with 4-bromo-benzene-1,2-diamine (244 g, 1.27 mol) and acetic acid (2.13 L). To this solution was added a solution of Compound 10b (327 g, 1.39 mol) in toluene (237 mL). After this addition, the temperature spiked to 45° C. in about 30 seconds and then subsided. The reaction was then heated to 90° C. for 16 h (overnight). The reaction was cooled to 40° C., and poured into a mixed solution of EtOAc and heptane (about 1:3, 5.75 L) and a precipitate occurred. The resulting slurry was stirred for 3 h, and the solid was collected by filtration, washed with EtOAc:heptane (1:3, 3 L), and then dried in a vacuum oven (60° C.) to give 324.3 g (65%) of the title Compound 10c as a partial acetate salt.

Step C. 2-(2-bromo-phenyl)-propan-2-ol

[0289]

A 12-Liter 4-neck flask equipped with a thermocouple, condenser, septum, addition funnel and overhead mechanical stirrer under argon was charged with methyl-2-bromobenzoate (226.5 g, 1.05 mol) and THF (1.6 L, 19.66 mol). The mixture was cooled to a temperature between 2 and 5° C. with stirring and held for 30 min. To the solution was slowly added methyl magnesium bromide in diethyl ether (3M, 1.05 L; 3.15 mol) via the addition funnel at a rate to maintain the reaction temperature below 15° C. An exotherm was observed during the addition, the reaction temperature warmed from 3 to 15° C. The addition of 1.05 L Grignard was complete in 4 h (approximate feed rate was 4.17 mL/min). The reaction mixture appeared to be off-white/yellow slurry. The reaction was allowed to warm to room temperature and stirred overnight (15 h). The reaction was sampled by HPLC/TLC and showed no starting material present. The ice bath was again applied to the reaction flask and a 0.5 M HCl solution (4.5 L; 2.25 mol) was slowly added over a period of 2 h. The temperature increased dramatically from 0 to 15° C. After the quench was complete, the reaction was stirred at room temperature for 30 min. Additional 2 N HCl (500 mL; 1.00 mol) was slowly added to maintain a pH less than 6. MTBE (1 L) was added to help with the phase split. The reaction was stirred at room temperature for 1 to 2 h to dissolve the solid material into the aqueous phase (most likely Mg(OH)₂which is very basic). The pH must be checked and adjusted with additional acid when necessary. The phases were separated and the aqueous layer was washed with an additional 1 L MTBE (2×500 mL). The organic phases were combined, washed with NaHCO₃solution (2×300 mL), dried over MgSO₄, filtered and the filtrate was concentrated under vacuum to yield the title Compound 10d (220.83 g, 97.48% yield) as a clear yellow oil.

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

[0290]

A 12-Liter 4-neck round bottom flask equipped with a thermocouple, condenser, addition funnel and overhead mechanical stirrer under dry Argon was charged with anhydrous THF, (3 L) and chilled to −70 to −78° C. via a dry ice/acetone bath. n-Butyl lithium (2.5N in hexanes, 860 mL, 2.15 mol) was slowly added via addition funnel. An exotherm was observed as the temperature rose from −78 to −70° C. To the addition funnel was added a solution of Compound 10d (220 g, 979.97 mmol) in anhydrous THF (1 L). The 2-(2-bromophenyl)propan-2-ol solution was slowly added to the n-BuLi solution. The addition took 90 min in order to maintain a reaction temperature below −70° C. After the addition was complete, the reaction mixture was stirred at −70 to −75° C. for 30 min. The triethylborate (230 mL, 1.35 mol) was quickly added in 3 portions at −70° C. An exotherm was observed, the batch temperature rose from −70 to −64° C. The reaction was stirred at −70° C. and slowly warmed to room temperature over night. After the reaction was cooled to 0-5° C., the reaction was slowly quenched with 2 M HCl (1 L, 2.00 mol) added via the addition funnel while maintaining the batch temperature 0-5° C. The reaction mixture was stirred for 1 h. The aqueous phase pH was 9-10. The pH was then adjusted to acidic (4-5) with 2 M HCl (200 mL). The two phases were separated and the aqueous layer was extracted with MTBE (2×500 mL). The combined organic phases were dried with anhydrous magnesium sulfate. The solution was filtered and concentrated to yield a yellow oil. The yellow oil was diluted with MTBE (1.5 L) and washed with 1M NaOH (3×500 mL). The product containing basic aqueous phases were combined and acidified with 2 M HCl (800 mL) (the clear solution turns turbid with the addition of acid). After stirring the turbid solution for 15 min (pH=4-5) (Note 1), it was extracted with MTBE (2×500 mL). The organic phases were combined and dried over MgSO₄. The solution was filtered and the filtrate was concentrated to yield the title Compound 10e as a clear yellow oil (121.78 grams, 77% yield).

Step E. (E)-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

A 5-L 4-neck flask equipped with a thermocouple controller, condenser, overhead mechanical stirrer, Firestone Valve® and a nitrogen inlet/outlet was charged with dimethoxyethane (2 L), DI water (1 L) and sodium carbonate (230.9 g, 2.18 mol). The solution was degassed and purged with N₂three times. Compound 10e (71.7 g, 0.35 mol) and Compound 10c (100.0 g, 0.27 mol) were added to the degassed solution. The solution was degassed and purged with N₂three times. PdCl₂(dppf) (44.48 g, 54.4 mmol) was added to the solution, and the solution was degassed and purged with N₂three times. The resulting two-phase suspension was heated to reflux for 18 h, and then cooled to room temperature. The reaction mixture was transferred to a 12-L separatory funnel, and the layers were separated. The organic layer was washed with brine (1 L). The two aqueous layers were combined and extracted with EtOAc (1 L). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated to an oil. Two separate 100 g coupling reactions were combined and purified by chromatography in 10 successive chromatography runs on an ISCO preparative chromatography system (10×1.5 Kg SiO2, 5 column volumes of EtOAc, 250 mL/min flow rate). The combined fractions were transferred to two 22 L 4-neck round bottom flasks, and Silicycle Si-thiol functionalized silica gel (2 g) was added to each solution. The solutions were warmed to 40° C. and aged for 1 h. The solutions were filtered thru a medium glass funnel and washed with EtOAc (4 L) and combined. The filtrate was evaporated to a semi solid, which was transferred to a 2 L round bottom flask, to which EtOAc (0.4 L) was added. The resulting white precipitate slurry was cooled to −5° C. and stirred for 1 h. The slurry was filtered and washed twice with cold EtOAc (100 mL). The solids were dried in a vacuum oven at 40° C. for 40 h to afford 84.0 g (36.5% yield, 98.8 area % purity) of the title Compound 18 as a white solid. Anal. Calcd for C₂₅H₂₁N₂OF₃.0.04% H₂O.0.15 mol MeOH: C, 70.48; H, 5.14: N, 6.42; F, 13.06 Found: C, 70.54; H, 4.83: N, 6.18; F, 13.33

Example 10.2 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol monosodium salt (Cpd 18)

A 5-L 4-neck flask equipped with a thermocouple controller, an overhead mechanical stirrer, and a nitrogen inlet/outlet was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (125.0 g, 0.510 mol) and MeOH (1.25 L). A solution of sodium methoxide in methanol (0.5 M, 592 mL, 0.3 mol) was added. The reaction was heated to 65° C. for 30 min and all solids dissolved. The solution was cooled and evaporated to dryness. The foam was collected by scraping it out of the flask. The solids were placed in vacuum oven for 24 h at 40° C. to afford 139 g (about 100% isolated yield) of the title Compound 18 monosodium salt as a yellowish solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.80-7.84 (m, 3H), 7.74 (d, 2H, J=8.59 Hz), 7.65 (d, 1H, J=16.4 Hz), 7.40-7.44 (m, 2H), 7.25-7.37 (m, 2H), 7.16-7.20 (m, 1H), 7.01-7.05 (m, 1H), 6.84-6.87 (m, 1H), 1.23 (s, 6H). Mass Spectrum (LCMS, APCI pos.) Calcd. For C₂₅H₂₁F₃N₂O: 423.2 (M+H). Found 423.3. m.p. (uncorr.) 258-259° C.

Example 10.3 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol hydrochloride salt (Cpd 18)

A 250-mL separatory funnel was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (1.0 g, 2.4 mmol) and EtOAc (20 mL). Aqueous HCl (1M, 20 mL) was added to the white slurry, and the separatory funnel was shaken. The solid product quickly dissolved, and a white precipitate started to form. The organic layer was transferred to a 100 mL round bottom flask equipped with a magnetic stir bar, and was stirred for 2 h. The thick slurry was filtered, rinsed with EtOAc (2×5 mL), and put into a vacuum oven at 40° C. for 36 h to afford 0.95 g (87.5%) of the title Compound 18 hydrochloride salt.

US7951829

Patent	Submitted	Granted
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190344]	2011-08-04
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190364]	2011-08-04
Benzimidazole Modulators of VR1 [US7951829]	2007-11-08	2011-05-31

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Chemical synthesis of IL-10 cytokine 90% cheaper than bioproduction, Provepep

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Oct 152015

Chemical synthesis of IL-10 cytokine 90% cheaper than bioproduction, Provepep

By Dan Stanton+, 08-Oct-2015

Chemical synthesis of peptides and proteins can be done at a tenth of the cost of bioproduction says French chemistry specialist Provepep.

http://www.in-pharmatechnologist.com/Product-Categories/APIs-active-pharmaceutical-ingredients/Chemical-synthesis-of-IL-10-90-cheaper-than-bioproduction-Provepep

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An introduction to the Prequalification of Active Pharmaceutical Ingredients

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Sep 052015

An introduction to the Prequalification of Active Pharmaceutical Ingredients

The WHO Prequalification of Medicines Programme (PQP) facilitates access to quality medicines through assessment of products and inspection of manufacturing sites. Since good-quality active pharmaceutical ingredients (APIs) are vital to the production of good-quality medicines, PQP has started a pilot project to prequalify APIs.

WHO-prequalified APIs are listed on the WHO List of Prequalified Active Pharmaceutical Ingredients. The list provides United Nations agencies, national medicines regulatory authorities (NMRAs) and others with information on APIs that have been found to meet WHO-recommended quality standards. It is believed that identification of sources of good-quality APIs will facilitate the manufacture of good-quality finished pharmaceutical products (FPP) that are needed for procurement by UN agencies and disease treatment programmes.

Details of the API prequalification procedure are available in the WHO Technical Report Series TRS953, Annex 4. Key elements of this document are given below.

What is API prequalification?

API prequalification provides an assurance that the API concerned is of good quality and manufactured in accordance with WHO Good Manufacturing Practices (GMP).

API prequalification consists of a comprehensive evaluation procedure that has two components: assessment of the API master file (APIMF) to verify compliance with WHO norms and standards and assessment of the sites of API manufacture to verify compliance with WHO GMP requirements.

Prequalification of an API is made with specific reference to the manufacturing details and quality controls described in the APIMF submitted for assessment. Therefore, for each prequalified API, the relevant APIMF version number will be included in the WHO List of Prequalified Active Pharmaceutical Ingredients.

Steps in the process

The WHO prequalification procedure for medicines and active pharmaceutical ingredients

Steps API prequalification

Initially, an application is screened to determine whether it is covered by the relevant expression of interest (EOI). It is also screened for completeness; in particular, the formatting of the submitted APIMFs is reviewed. Once the application has been accepted, a WHO reference number is assigned to it.

A team of assessors then reviews the submitted APIMF, primarily at bimonthly meetings in Copenhagen. Invariably, assessors raise questions during assessment of the APIMF that require revision of the information submitted and/or provision of additional information, and/or replacementof certain sections within the APIMF. Applicants are contacted to resolve any issues raised by the assessors.

It is important that any prequalified API can be unambiguously identified with a specific APIMF. Therefore, once any and all issues regarding its production have been resolved, the applicant will be asked to submit an updated APIMF that incorporates any changes made during assessment. The version number of the revised and up-to-date APIMF will be included on the WHO List of Prequalified Active Pharmaceutical Ingredients, to serve as a reference regarding the production and quality control of that API.

For APIMFs that have already been accepted in conjunction with the prequalification of an FPP, full assessment is generally not required. Such APIMFs are reviewed only for key information and conformity with administrative requirements. Nonetheless, a request for further information may be made, to ensure that the APIMF meets all current norms and standards; PQP reserves the right to do so.

An assessment is also undertaken of WHO GMP compliance at the intended site(s) of API manufacture. Depending on the evidence of GMP supplied by the applicant, this may necessitate on-site inspection by WHO. If a WHO inspection is conducted and the site is found to be WHO GMP-compliant, the API will be recommended for prequalification. Additionally, a WHO Public Inspection Report (WHOPIR) will be published on the PQP web site.

When the APIMF and the standard of GMP at the intended manufacturing site(s) have each been found to be satisfactory, the API is prequalified and listed on the WHO List of Prequalified Active Pharmaceutical Ingredients.

The successful applicant will also be issued a WHO Confirmation of Active Pharmaceutical Ingredient Prequalification document. This document contains the accepted active ingredient specifications and copies of the assay and related substances test methodology. This document may be provided by the API manufacturers to interested parties at their discretion.

Maintenance of API prequalification status

Applicants are required to communicate to WHO any changes that have been made to the production and control of a WHO-prequalified API. This can either be in the form of an amendment, or as a newly-issued version of the APIMF. It is the applicant’s responsibility to provide WHO with the appropriate documentation (referring to relevant parts of the dossier), to prove that any intended or implemented change will not have or has not had a negative impact on the quality of the prequalified API. This may necessitate the updating of the information published on the WHO List of Prequalified Active Pharmaceutical Ingredients.

The decision to prequalify an API is based upon information available to WHO at that time, i.e. information in the submitted APIMF, and on the status of GMP at the facilities used in the manufacture and control of the API. The decision to prequalify an API is subject to change, should new information become available to WHO. For example, if serious safety and/or quality concerns arise in relation to a prequalified API, WHO may suspend the API until the investigative results have been evaluated by WHO and the issues resolved, or delist the API in the case of issues that are not resolved to WHO’s satisfaction.

Who can participate?

Any manufacturer of any active pharmaceutical ingredient (API) that is included on an Invitation to Submit an Expression of Interest for Product Evaluation can submit an application for product evaluation.

If an applicant is acting on behalf of a manufacturer, the actual manufacturer(s) of the API and any contract manufacturers, must be clearly listed in the cover letter

To manufacturers of medicinal products

The vision of the WHO Prequalification of Medicines Programme (PQP) is of a world in which good-quality medicines are available to all those who need them. PQP facilitates access to good-quality medicines through assessment of products and inspection of manufacturing facilities. Since good-quality active pharmaceutical ingredients (APIs) are vital to the production of good-quality medicines, PQP has started a project to prequalify APIs.

APIs that meet assessment criteria will be added to the WHO List of Prequalified Active Pharmaceutical Ingredients. Manufacturers and National Regulatory Authorities (NRAs) can use the List to help them identify APIs of assured quality, while UN agencies and others can use the List to supplement the information found on the WHO List of Prequalified Medicines Products.

The issuing of an invitation to submit an expression of interest (EOI) is the first step in the prequalification process. Each invitation is developed in consultation with WHO disease programmes, other UN agencies (including UNAIDS and UNICEF) and UNITAID. The 1st Invitation to manufacturers of APIs to submit a request for an evaluation of an API was issued in October 2010.

The current EOI is:

8 ^th invitation to manufacturers of APIs to submit an EOI for product evaluation

In applying for evaluation of an API, manufacturers are requested to submit a covering letter, application form, API master file (APIMF), site master file (SMF), and evidence of current GMP certification to PQP. Thereafter, PQP will undertake a comprehensive evaluation of the APIMF and review the GMP status of the manufacturing site(s). In some cases, PQP will request additional information and may also inspect the manufacturing site(s).

Prequalification of Active Pharmaceutical Ingredients (APIs) – Procedural Guidance

Any applicant who is unclear over any aspect of the API prequalification procedure should contact PQT prior to submission, since incorrect submissions will be rejected.

read at

http://apps.who.int/prequal/