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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
DR ANTHONY MELVIN CRASTO Ph.D
DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues,
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Cellular proliferation IC507–32 nM against EGFRm+ NSCLC cells
547 nM against A431 cell with WT EGFR
Ongoing, not currently recruiting
Phase I/II (NCT01526928)
Recruiting
Phase III (NCT02322281, TIGER-3)
SYNTHESIS COMING……….
Evaluate safety, PK and efficacy of previously treated NSCLC patients, Compare the efficacy of oral single agent versus single agent cytotoxic chemotherapy in patients with EGFRm+ NSCLC after failure of at least 1 previous EGFR-directed TKI and at least 1 line of platinum-containing doublet therapy. Compare the safety and efficacy of CO-1686 versus erlotinib as first line treatment of patients with EGFRm+ NSCLC
Rociletinib (CO-1686): Rociletinib is an orally administered irreversible inhibitor currently in several clinical trials targeting both the activating EGFR mutations and the acquired T790M resistance mutation while sparing WT EGFR. It is a potent inhibitor of EGFR T790M/L858R double mutant with a kinact/Ki of 2.41 × 105 M−1 s−1. It has a 22-fold selectivity over WT EGFR (kinact/Ki of 1.12 × 104 M−1 s−1). In NSCLC cell lines containing EGFR mutations, rociletinib demonstrates the following cellular pEGFR IC50: 62 nM in NCI-1975 (L858R/T790M), 187 nM in HCC827 (exon 19 deletion), 211 nM in PC9 (exon 19 deletion). In cell lines expressing WT EGFR, cellular pEGFR IC50 are: >4331 nM in A431, >2000 nM in NCI-H1299, and >2000 nM in NCI-H358.
Rociletinib displayed good oral bioavailability (65%) and long half-life when dosed at 20 mg/kg in female Nu/Nu mice. In tumor bearing mice when rociletinib was dosed orally once daily as a single agent, the compound showed dose-dependent tumor growth inhibition in various EGFR-mutant models. In NCI-H1975 as well as in patient-derived LUM 1868 lines expressing the EGFR T790M/L858R double mutation that are erlotinib-resistant models, rociletinib caused tumor regressions at 100 mg/kg/d. In the HCC827 xenograft model that expresses the del-19 activating EGFR mutation, rociletinib showed antitumor activity that was comparable with erlotinib and the second-generation EGFR TKI, afatinib. The wild-type sparing feature of rociletinib was further demonstrated through its minimal inhibition (36%) of tumor growth in the A431 xenograft model that is dependent on WT EGFR for proliferation.
In a Phase I/II study (TIGER-X), rociletinib was administered to patients with EGFR mutated NSCLC who had disease progression during treatment with a previous line of EGFR TKI therapy.The Phase I trial was a dose escalation study to assess safety, side-effect profile and pharmacokinetic properties of rociletinib, and the Phase II trial was an expansion arm to evaluate efficacy. T790M positivity was confirmed before enrollment in the Phase II portion. At the dose of 500 mg BID, the objective response rate in 243 centrally confirmed tissues from T790M positive patients was 60% and the disease control rate was 90%. The estimated overall median PFS at the time of the publication (May 2015) was 8.0 months among all centrally confirmed T790M positive patients. Rociletinib also showed activity in centrally confirmed T790M negative patients with the overall response rate being 37%. The common dose-limiting adverse event was grade 3 hyperglycemia occurring in 17% of patients at a dose of 500 mg BID. Grade 3 QTc prolongation was observed in 2.5% of the patients at the same dose. Treatment-related adverse events leading to drug discontinuation was seen in only 2.5% of patients at 500 mg BID.
In a 25 mL 3-neck RBF previously equipped with a magnetic stirrer, Thermo pocket and CaCl2 guard tube, N-Boc-l,3-diaminobenzene (0.96 g) and n-butanol (9.00 mL) were charged. Reaction mixture was cooled to 0 °C. 2,4-Dichloro-5-trifluoromethylpyrimidine (1.0 g) was added dropwise to the above reaction mixture at 0 °C. The DIPEA (0.96 mL) was dropwise added to the above reaction mixture at 0 °C and the reaction mixture was stirred for 1 hr at 0 °C to 5 °C. Finally the reaction mixture was allowed to warm to room temperature. Reaction mixture was stirred for another 4 hrs at room temperature. Completion of reaction was monitored by TLC using hexane: ethyl acetate (7: 3). The solid precipitated out was filtered off and washed with 1-butanol (2 mL). Solid was dried under reduced pressure at 40 °C for 1 hr. ^-NMR (DMSO-d6, 400 MHz) δ 1.48 (S, 9 H), 7.02 (m, 1 H), 7.26 (m, 2 H), 7.58 (S, 1 H), 8.57 (S, 1 H), 9.48 (S, 1 H), 9.55 (S, 1 H).
Step 2:
To the above crude (3.1 g) in DCM (25 mL) was added TFA (12.4 mL) slowly at 0 °C. The reaction mixture was allowed to warm to room temperature. Reaction mixture was stirred for another 10 min at room temperature. The crude was concentrated under reduced pressure.
Step 3:
The concentrated crude was dissolved in DIPEA (2.0 mL) and DCM (25 mL), and then cooled to -30 °C. To the reaction mixture was slowly added acryloyl chloride (0.76 g) at -30 °C. The reaction mass was warmed to room temperature stirred at room temperature for 1.0 hr. The reaction was monitored on TLC using hexane: ethyl acetate (7:3) as mobile phase. Reaction got completed after 1 hr. 1H-NMR (DMSO-d6, 400 MHz) δ 5.76 (dd, J = 2.0, 10.0 Hz, 1 H), 6.24 (dd, J = 2.0, 17.2 Hz, 1 H), 6.48 (m, 1 H), 7.14 (d, J = 8.8 Hz, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.94 (S, 1 H), 8.59 (S, 1 H), 9.60 (S, 1 H), 10.26 (S, 1 H).
EXAMPLE 3
Compound 1-4 N- henylamino)-5-
(trifluor mide)
Using 2-methoxy-4-(4-acteylpiperazinyl)aniline and intermediate 1 in Example 1, the title compound 1-4 was prepared as described in Example 2. 1H-NMR (DMSO-d6, 400 MHz) δ 10.2 (S, 1 H), 8.2 (br, 1 H), 8.30 (S, 1 H), 7.73 (br, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.26 (J = 8.2 Hz, 1 H), 7.14 (be, 1 H), 6.60 (S, 1 H), 6.42 (dd, J = 11.4, 16.9 Hz, 1 H), 6.24 (d, J = 16.9 Hz, 1 H), 5.75 (d, J = 11.4 Hz, 1 H), 3.76 (S, 3 H), 3.04 (br, 4 H), 2.04 (S, 3 H); calculated mass for C27H28F3N7O3 : 555.2, found: 556.2 (M+H+).
SOLID FORMS OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR
References
A.O. Walter, R.T.T. Sjin, H.J. Haringsma, K. Ohashi, J. Sun, K. Lee, A. Dubrovskiy, M. Labenski, Z. Zhu, Z. Wang, M. Sheets, T. St. Martin, R. Karp, D. van Kalken, P. Chaturvedi, D. Niu, M. Nacht, R.C. Petter, W. Westlin, K. Lin, S. Jaw-Tsai, M. Raponi, T. Van Dyke, J. Etter, Z. Weaver, W. Pao, J. Singh, A.D. Simmons, T.C. Harding, A. Allen, Cancer Disc., 3 (2013), p. 1404
////Rociletinib, CO-1686, Clovis, Third generation, covalent EGFR inhibitors, AVL-301, CNX-419
CAS 1776112-90-3
Chemical Formula: C18H22FN9O2
Exact Mass: 415.188
Recruiting, Phase I/II (NTC02349633)
Epidermal growth factor receptor antagonists
Antineoplastics
Non-small cell lung cancer
Dose escalation study to evaluate safety, PK, PD and efficacy in advanced EGFRm+ NSCLC
02 May 2015Phase-I clinical trials in Non-small cell lung cancer (Metastatic disease, Second-line therapy or greater) in USA (PO) (NCT02349633)
05 Feb 2015Pfizer plans a phase I trial for Non-small cell lung cancer (Second-line therapy or greater) in USA (NCT02349633)
05 Jan 2015Preclinical trials in Non-small cell lung cancer in USA (PO)
SYNTHESIS COMING…………
PF-06747775 is an orally available inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. EGFR T790M inhibitor PF-06747775 specifically binds to and inhibits EGFR T790M, a secondarily acquired resistance mutation, which prevents EGFR-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. Compared to some other EGFR inhibitors, PF-06747775 may have therapeutic benefits in tumors with T790M-mediated drug resistance.
for the oral treatment of patients with locally advanced or metastatic EGFR mutant (del19 or L858R) non-small cell lung cancer
Kinetic mechanism for two-step covalent inhibition of EGFR
A suspension of 6-chloro-2-fluoro-9H-purine (5.49 g, 31.8 mmol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (6.60 g, 40.34 mmol, 1.26 eq), and N,N-diisopropylethylamine (16.6 mL, 95.5 mmol, 3.00 eq) in DMSO (31.8 mL) was stirred at ambient temperature for 19 hr. The reaction mixture was then concentrated in vacuo at 50° C., poured into water (250 mL), and stirred vigorously at 0° C. for 1 hr. The resulting solids were filtered off, washed with ice cold water (20 mL), and dried for 16 hr at 50° C. to give the title compound (7.26 g, 87% yield, 96% purity) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3H). m/z (APCI+) for C10H11FN7O 264.2 (M+H)+.
Step 2: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl -9H-purin-6-amine
To a vigorously stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (7.25 g, 27.5 mmol, 1.00 eq) and potassium carbonate (7.61 g, 55.1 mmol, 2.00 eq) in 1,4-dioxane (92.0 mL), was added dimethyl sulfate (2.90 mL, 30.3 mmol, 1.10 eq) in a dropwise manner over 3 min. After 4 hr, additional portions of 1,4-dioxane (50.0 mL), potassium carbonate (3.80 g, 27.5 mmol, 1.00 eq), and dimethyl sulfate (1.00 mL, 10.4 mmol, 0.30 eq) were added to the reaction mixture. After a further 16 hr, the reaction mixture was concentrated in vacuo, diluted with water (120 mL), and stirred at ambient temperature for 1 hr. The resulting solids were filtered, washed with water (20 mL), and dried for 16 hr at 60° C. to give the title compound (6.42 g, 84% yield, >95% purity) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H) 3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C11H13FN7O 278.2 (M+H)+.
Step 3: Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol -4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide
To a stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (554 mg, 2.00 mmol, 1.00 eq) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (500 mg, 2.10 mmol, 1.05 eq) in DMSO (4.2 mL) was added N,N-diisopropylethylamine (0.83 mL, 5.00 mmol, 2.50 eq). The reaction mixture was then heated at 100° C. for 16 hr, cooled to ambient temperature, diluted with THF (4 mL), and treated with potassium tert-butoxide (4.00 mL, 1 M in THF, 2.00 eq). After 1 hr, an additional portion of potassium tert-butoxide (0.50 mL, 1 M in THF, 0.25 eq) was added to the reaction mixture. After a further 1 hr, the reaction mixture was poured into phosphate buffer (50 mL, pH=7) and water (50 mL), and extracted with ethyl acetate (5×40 mL). The combined organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. This crude product was then dissolved in ethyl acetate (40 mL) at 60° C. and then treated with heptanes (20 mL), at which point the solution became cloudy and was allowed to cool to ambient temperature and then to 0° C. After 16 hr at 0° C., the resulting solids were filtered and dried at ambient temperature to give the title compound (620.5 mg, 75% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C18H23FN9O2 416.3 (M+H)+.
Example 7A
(Scheme F): Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide
A mixture of xylene, (1.2 L), benzylamine (120 g, 1.10 mol, 1.0 eq) and L-(+)-tartaric acid (173 g, 1.15 mol, 1.05 eq) were heated at 135° C. for 12 hr (flask jacket temperature). Upon reaction completion, the mixture was cooled to 65° C. and MeOH (120 mL, 1 vol) was added. The resulting mixture was stirred for 1 hr and the resulting suspension was cooled to 20° C. followed by the addition of EtOAc (480 mL). Stirring was continued at 10° C. for 2 hr. The crude product was isolated by filtration and washed with EtOAc (120 mL) and dried on the filter. The crude product was then taken up in MeOH (480 mL) and heated at a gentle reflux for 1 hr, then cooled to 20° C. and granulated for 1 hr. The suspension was filtered and the precipitate washed with MeOH (240 mL) and dried to give the title compound (191 g, 864 mmol, 79%) as a white granular solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.30 (m, 2H) 7.30-7.22 (m, 3 H) 6.32 (br. s., 1 H) 4.59 (d, J=14.8 Hz, 1 H) 4.53 (d, J=14.8 Hz, 1 H) 4.40 (br. D., J=4.3 Hz, 2 H). m/z (EI+) for C11H11NO4 221.0 (M)+.
Preparation Step 2A: Preparation of (3S,4S)-1-benzylpyrrolidine-3,4-diol
To a mixture of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (44 g, 199 mmol, 1.0 eq) and THF (176 mL) at 20° C. (vessel jacket temperature) was added borane-tetrahydrofuran complex (1.0 mol/L) in THF (800 mL, 800 mmol, 1.0 mol/L, 4.0 eq) at a rate to maintain the temperature between 20° C. and 25° C. Over 1 hr, the jacket temperature was ramped to 60° C. and then held for 1 hr. Upon completion, the reaction was cooled to 30° C. and quenched by the slow dropwise addition of MeOH (97 mL, 12 eq) to the mixture at a rate to control off gassing. The reaction mixture was then heated to reflux and concentrated to a low stir volume. The reaction solvent THF was then replaced by a constant volume displacement with MeOH (total of 1.5 L). Once the THF content had been reduced to less than 1 wt %, MeOH was replaced by a constant volume displacement with EtOAc (total of 1.5 L) to reduce the MeOH content to less than 1 wt %. The total volume of EtOAc was then readjusted to about 250 mL (6 vol) and then cooled to 5° C. to crystallize the product. The desired product was isolated by filtration, washed with cold EtOAc (88 mL) and dried to give title compound (27.0 g, 140 mmol, 70%). A second crop of product was isolated by concentration of the combined filtrate and cake wash to half volume, which was then cooled to 5° C., filtered and washed with cold EtOAc (50 mL) to afford additional title compound (4.5 g, 23 mmol, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.26 (m, 4 H) 7.25-7.20 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.57 (d, J=13.0 Hz, 1 H) 3.46 (d, J=13.0 Hz, 1 H) 2.74 (dd, J=9.4, 5.9 Hz, 2 H) 2.30 (dd, J=9.4, 4.4 Hz, 2 H). m/z (EI+) for C11H15NO2 194.2 (M+H)+.
Preparation Step 3A: Preparation of (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ6-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester
To a 5 L jacketed reactor (Reactor 1) was added 1,4-dioxane (1.8 L), (3S,4S)-1-benzylpyrrolidine-3,4-diol (180 g, 0.932 mol, 1.0 eq) and TEA (792 mL, 5.68 mol, 6.1 eq) and the resulting mixture stirred at 10° C.
To a 2 L jacketed reactor (Reactor 2) was added 1,4-dioxane (1.6 L) and chlorosulfonyl isocyanate (596 g, 2.80 mol, 3.0 eq) and the resulting solution was cooled to 10° C. A solution of tert-butanol (211 g, 2.85 mol, 3.05 eq) in 1,4-dioxane (180 mL) was added over 45 min while maintaining the temperature between 10° C. and 20° C., and the resulting solution was then stirred for 15 min at 10° C.
The solution in Reactor 2 was transferred to Reactor 1 over 50 min while controlling the internal temperature of Reactor 1 from 10° C. to 20° C. Once the addition was complete, the jacket temperature was warmed at 20° C. and the resulting mixture was stirred for 16 hr. When UPLC analysis confirmed that the bis-alkylated intermediate was fully formed (target <3% mono-alkylated intermediate), the entire batch was filtered and the filtrate was sent into a clean reactor. The residual TEA-HCl cake was washed with dioxane (300 mL) and the wash was combined with the filtrate. The resulting dioxane solution was then heated to 80° C. and held for 3 hr. After sampling for reaction completion (<1% intermediate remaining), the batch was distilled (pot temp=80° C.) under partial vacuum (400 mbar) to less than half volume. The reaction mixture was diluted with EtOAc (2 L) and washed twice with water (2×2 L). The mixture was then washed with 0.5 N sodium bicarbonate (2 L) and then dried over sodium sulfate (360 g, 2 wt eq) and filtered into a clean dry reactor. The EtOAc solution was concentrated under partial vacuum to about 400 mL total volume resulting in the formation of a thick slurry. The mixture was cooled to 0° C. and stirred for 1 hr and then filtered and washed with cold EtOAc (200 mL) and then dried in a vacuum oven at 40° C. to give 173 g of the title compound. A second crop of product was isolated by concentrating the filtrate and then cooling, granulating and filtering to give an additional 28.4 g of the desired product. In total, the title compound was isolated in 61% yield (201 g, 568 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.37-7.29 (m, 4 H) 7.29-7.23 (m, 1 H) 5.36 (dd, J=7.3, 3.8 Hz, 1 H) 4.79-4.73 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.70 (d, J=13.4 Hz, 1 H) 3.62 (d, J=13.4 Hz, 1 H) 3.13-2.99 (m, 2 H) 2.48-2.40 (m, 2 H) 1.46 (s, 9 H). m/z (EI+) for C16H22N2O5S 355.2 (M+H)+.
Preparation Step 4A: Preparation of (3R,4R)-1-benzyl-4-fluoropyrrolidin-3-amine bis-tosylate
A solution of 1M tetrabutylammonium fluoride in THF (1.27 L, 1.27 mol, 2.5 eq) and (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ6-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester (180 g, 0.508 mol, 1.0 eq) were heated at 60° C. (jacket temperature) for 2 hr. Upon reaction completion, the mixture was partially distilled under vacuum to remove the THF. After concentration to a low stir volume, THF was displaced with EtOAc (2×500 mL). After again reducing to a low stir volume, EtOAc (3.6 L) and p-toluenesulfonic acid monohydrate (396 g, 2.10 mol, 4.1 eq) were charged and heated at 80° C. for 2 hr. The mixture was cooled to 10° C. over 1.5 hr and then granulated at 10° C. for 2 hr. The solid product was filtered and washed with EtOAc (2×900 mL) and dried at 50° C. in a vacuum oven for 12 hr. The title compound was isolated as an air stable crystalline solid in 83% yield (231 g, 419 mmol). 1H NMR (400 MHz, D2O) δ ppm 7.69-7.61 (m, 4 H) 7.56-7.42 (m, 5 H) 7.36-7.29 (m, 4 H) 5.65-5.49 (m, 1 H) 4.47 (br. s., 2H) 4.37-4.23 (m, H) 4.15 (ddd, J=12.8, 8.2, 1.4 Hz, 1 H) 3.88 (dd, J=19.1, 1.2 Hz, 1 H), 3.74 (ddd, J=33.2, 14.0, 5.5 Hz, 1 H) 3.44 (dd, J=12.8, 8.2 Hz, 1 H) 2.34 (s, 6 H). m/z (EI+) for C11H15FN2 194.8 (M+H)+.
A suspension of 1,1′-carbonyldiimidazole (73.0 g, 441 mmol, 1.1 eq) in acetonitrile (3.3 L) was stirred at 20° C. until a clear solution was obtained. 3-(methylsulfonyl)propanoic acid (67.0 g, 440 mmol, 1.1 eq) was then added and the mixture was stirred at 25° C. for 3 hr. (3R,4R)-1-benzyl-4-fluoropyrrolidin-3-amine bis-tosylate (220 g, 400 mmol, 1.0 eq) was added and the mixture was stirred at 25° C. for 16 hr resulting in a fine white slurry. The solids were filtered off and the byproduct cake washed with acetonitrile (600 mL). The acetonitrile solution was then concentrated to a low stir volume and then taken up in EtOAc (2.0 L) and washed with 1 N aqueous sodium bicarbonate (1.3 L). The aqueous layer was back extracted with EtOAc (500 mL) and the combined EtOAc layers were washed with water (1.0 L). The resulting EtOAc solution was distilled to remove about 2.0 L of distillate and then displaced with 2-propanol under atmospheric conditions until the internal temperature rose to 78° C. while maintaining a total volume of 2 L. The batch was then cooled to 20° C. and granulated at 20° C. for 12 hr resulting in product crystallization. The desired product was isolated by filtration and the cake washed with 2-propanol (600 mL), then dried in an oven at 40° C. under reduced pressure for 12 hr. The title compound (108 g, 308 mmol) was isolated in 77% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (br. d., J=7.0 Hz, 1 H) 7.37-7.29 (m, 4 H) 7.29-7.23 (m, 1 H) 4.90 (ddt, J=53.4, 5.3, 2×1.7 Hz, 1 H) 4.25 (dddd, J=26.4, 13.9, 7.0, 1.4 Hz, 1 H) 3.61 (d, J=13.2 Hz, 1 H) 3.57 (d, J=13.2 Hz, 1 H) 3.36-3.28 (m, 2 H) 3.03 (dd, J=9.3, 7.5 Hz, 1 H) 2.97 (s, 3 H) 2.80 (dd, J=24.0, 11.6 Hz, 1 H) 2.66 (ddd, J=30.6, 11.6, 5.3 Hz, 1 H) 2.57 (td, 2×7.7, 1.4 Hz, 2 H) 2.18 (dd, J=9.4, 6.7 Hz, 1 H). m/z (EI+) for C15H21FN2O3S 329.7 (M+H)+.
To a Parr reactor was added N-((3R,4R)-1-benzyl-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (86.5 g, 263 mmol, 1.0 eq), palladium hydroxide (20% on carbon, 2.59 g, 3.69 mmol, 3 wt/wt %) and MeOH (430 mL). The reactor was purged three times with nitrogen (50 psi) and then purged three times with hydrogen (20 psi). The reactor was heated at 50° C. and then pressurized to 50 psi while stirring at 1200 rpm. The material was hydrogenated for 7 hr and then cooled to 20° C. and purged with nitrogen. The mixture was filtered to remove the catalyst and the cake was washed with MeOH (173 mL). The combined filtrate and wash were concentrated to about 200 mL followed by addition of MTBE (200 mL) and then concentrated to a low stir volume. Additional MTBE (200 mL) was added and the resulting slurry granulated at 20° C. for 16 hr. The desired product was isolated by filtration, washed with MTBE (300 mL) and then dried in an oven at 40° C. for 12 hr. The title compound was isolated in 90% yield (53.3 g, 224 mmol) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (br. d., J=6.8 Hz, 1 H) 4.96-4.78 (m, 1 H) 4.14-4.01 (m, 1 H) 3.32 (dd, J=8.0, 7.3 Hz, 2 H) 3.13 (dd, J=11.8, 6.8 Hz, 1 H) 3.01-2.93 (m, 1 H) 2.98 (s, 3 H) 2.88 (d, J=3.0 Hz, 1 H) 2.60 (br. s., 1 H) 2.5 7-2.52 (m, 3 H). m/z (EI+) for C8H15FN2O3S 239.1 (M+H)+.
Step 1: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine
A suspension of 6-chloro-2-fluoro-9H-purine (88% potency, 5.90 kg, 30.20 mol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (98% potency, 5.55 kg, 33.22 mol, 1.10 eq), and sodium bicarbonate (10.1 kg, 120.81 mol, 4.00 eq) in EtOAc (106 L) was stirred at 50° C. for 12 hr. The reaction mixture was then cooled to 20° C., granulated for 1 hr, filtered, and the solids were washed with EtOAc (18 L) and dried on the filter. The crude product was charged back into the reactor and suspended in water (106 L) and stirred at 35° C. for 2 hr. The resulting slurry was cooled to 20° C. and the desired product was isolated by filtration and the cake was washed with water (30 L) and then with EtOAc (30 L) and dried for 16 hr at 50° C. to give the title compound (6.26 kg, 23.8 mol, 79% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3 H). m/z (APCI+) for C10H11FN7O 264.2 (M+H)+.
Step 2: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine
To a 100 L reactor fitted with a caustic scrubber was added 2-methyltetrahydrofuran (44.0 L), 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (2.20 kg, 8.36 mol, 1.00 eq) and potassium phosphate tribasic (7.10 kg, 33.43 mol mmol, 4.00 eq). The resulting mixture was stirred at 5° C. and dimethyl sulfate (1.42 kg, 11.28 mol, 1.35 eq) was added and the resulting mixture was stirred at 5° C. for 1 hr. The reaction was warmed from 5° C. to 15° C. over 2 hr and then held at 15° C. for 20 hr. The reaction mixture was cooled to 5° C. and quenched with water (44.0 L) while maintaining the internal temperature below 10° C. The mixture was then heated at 50° C. for 2 hr and then cooled to 10° C. and granulated for 2 hr. The product was isolated by filtration and washed with water (11.0 L) and then with 2-methyltetrahydrofuran (11.0 L). The cake was dried under vacuum at 40° C. for 8 hr to give the title compound (1.99 kg, 7.18 mol, 86% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H)3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C11H13FN7O 278.2 (M+H)+.
Step 3: Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide
To a 200 L Hastelloy reactor heated to 40° C. was added sulfolane (22.4 L) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (4.03 kg, 16.9 mol, 1.05 eq) and stirred the resulting mixture until all solids were dissolved. To this solution was added 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (4.47 kg, 16.1 mol, 1.00 eq) and N,N-diisopropylethylamine (8.50 L, 48.7 mol, 3.0 eq) and the mixture heated at 115° C. for 16 hr. The reaction mixture was cooled to 30° C., and a solution of potassium hydroxide (2.26 kg, 40.3 mol, 2.5 eq) in water (44.7 L) was added. After stirring for 4 hr, the reaction mixture was cooled to 20° C., water (44.7 L) was added and the resulting mixture granulated for 12 hr. The crude product was isolated on a Nutsche filter and washed with water (27 L) and then dried under nitrogen on the filter. The reactor was cleaned and then charged with water (35.8 L) and acetone (53.6 L). The crude product cake was charged back into the reactor and heated to 60° C. until all of the solids had dissolved. The batch was then cooled to 40° C. and then transferred into a speck free 100 L reactor via an in-line 10 μm filter. The 200 L reactor, line and filter were rinsed with acetone (5 L) and sent into the 100 L reactor. The batch was concentrated with the jacket temperature set at 70° C. under partial vacuum until the acetone content reduced to 5 wt %, as determined by gas chromatography head space. The batch was then cooled to 20° C. and granulated for 4 hr. The product was filtered, washed with water (18 L) and dried in a vacuum oven at 55° C. for 8 hr. The title compound (3.942 kg, 9.49 mol, 59%) was isolated as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C18H23FN9O2 416.3 (M+H)+.
Summary of 1st generation and 2nd generation EGFR inhibitors
REFERENCES
Planken, S.; Murray, B. W.; Lafontaine, J.; Weinrich, S.; Hemkens, M.; Kath, J. C.; Nair, S. K.; Johnson, T. O.; Cheng, H.; Sutton, S. C.; Zientek, M.; Yin, M. -J.; Solowiej, J.; Nagata, A.; Gajiwala, K. Abstracts of Papers, 249th ACS National Meeting & Exposition, Denver, CO, United States, March 22–26, 2015; MEDI-248
PROCESS, SYNTHESISComments Off on Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling
Mar232016
Herein, the first continuous cross-dehydrogenative homocoupling of an unactivated arene using oxygen as sole oxidant is reported. Employing microreactor technology which enables the use of elevated temperatures and pressures leads to a boost of the catalytic reaction. Hence, a major reduction in reaction time is achieved. Due to the significance as precursor for MOFs as well as high-tech and high-value polymers, the study focused on the production of 3,4,3′,4′-tetramethyl-biphenyl.
Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling
Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands
MONOCLONAL ANTIBODIESComments Off on Dipeptide-Based Metabolic Labeling of Bacterial Cells for Endogenous Antibody Recruitment
Mar232016
The number of antibiotic-resistant bacterial infections has increased dramatically over the past decade. To combat these pathogens, novel antimicrobial strategies must be explored and developed. We previously reported a strategy based on hapten-modified cell wall analogues to induce recruitment of endogenous antibodies to bacterial cell surfaces. Cell surface remodeling using unnatural single d-amino acid cell wall analogues led to modification at the C-terminus of the peptidoglycan stem peptide. During peptidoglycan processing, installed hapten-displaying amino acids can be subsequently removed by cell wall enzymes. Herein, we disclose a two-step dipeptide peptidoglycan remodeling strategy aimed at introducing haptens at an alternative site within the stem peptide to improve retention and diminish removal by cell wall enzymes. Through this redesigned strategy, we determined size constraints of peptidoglycan remodeling and applied these constraints to attain hapten–linker conjugates that produced high levels of antibody recruitment to bacterial cell surfaces.
Dipeptide-Based Metabolic Labeling of Bacterial Cells for Endogenous Antibody Recruitment
ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
UCB; For the treatment of partial onset seizures related to epilepsy, Approved February 2016
Brivaracetam, the 4-n-propyl analog of levetiracetam, is a racetam derivative with anticonvulsant properties.[1][2] Brivaracetam is believed to act by binding to the ubiquitous synaptic vesicle glycoprotein 2A (SV2A).[3] Phase II clinical trials in adult patients with refractory partial seizures were promising. Positive preliminary results from stage III trials have been recorded,[4][5] along with evidence that it is around 10 times more potent[6] for the prevention of certain types of seizure in mouse models than levetiracetam, of which it is an analogue.
On 14 January 2016, the European Commission,[7] and on 18 February 2016, the USFDA[8] approved brivaracetam under the trade name Briviact (by UCB). The launch of this anti-epileptic is scheduled for the first quarter of that year. Currently, brivaracetam is still not approved in other countries like Australia, Canada and Switzerland.
Brivaracetam was approved by European Medicine Agency (EMA) on Jan 14, 2016 and approved by the U.S. Food and Drug Administration (FDA) on Feb 18, 2016. It was developed and marketed as Briviact® by UCB in EU/US.
Brivaracetam is a selective high-affinity synaptic vesicle protein 2A ligand, as an adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in adult and adolescent patients from 16 years of age with epilepsy.
Briviact® is available in three formulations, including film-coated tablets, oral solution and solution for injection/infusion. And it will be available as 10 mg, 25 mg, 50 mg, 75 mg and 100 mg film-coated tablets, a 10 mg/ml oral solution, and a 10 mg/ml solution for injection/infusion. The recommended starting dose is either 25 mg twice a day or 50 mg twice a day, depending on the patient’s condition. The dose can then be adjusted according to the patient’s needs up to a maximum of 100 mg twice a day. Briviact can be given by injection or by infusion (drip) into a vein if it cannot be given by mouth.
European Patent No. 0 162 036 Bl discloses compound (S)-α-ethyl-2-oxo-l- pyrrolidine acetamide, which is known under the International Non-proprietary Name of Levetiracetam.
Levetiracetam
Levetiracetam is disclosed as a protective agent for the treatment and prevention of hypoxic and ischemic type aggressions of the central nervous system in European patent EP 0 162 036 Bl. This compound is also effective in the treatment of epilepsy.
The preparation of Levetiracetam has been disclosed in European Patent No. 0 162 036 and in British Patent No. 2 225 322.
International patent application having publication number WO 01/62726 discloses 2-oxo-l -pyrrolidine derivatives and methods for their preparation. It particularly discloses compound (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-l-yl] butanamide known under the international non propriety name of brivaracetam.
Brivaracetam
International patent application having publication number WO 2005/121082 describes a process of preparation of 2-oxo-l -pyrrolidine derivatives and particularly discloses a process of preparation of (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxo-pyrrolidin-l- yl]butanamide known under the international non propriety name of seletracetam.
Seletracetam
Kenda et al., in J. Med. Chem. 2004, 47, 530-549, describe processes of preparation of 2-oxo-l -pyrrolidine derivatives and particularly discloses compound 1-((1S)-I- carbamoyl-propyl)-2-oxo-pyrrolidone-3-carboxylic acid as a synthetic intermediate.
WO2005028435
CLIPS
Find better ways to make old and new epilepsy drugs. J. Surtees and co-inventors disclose alternative processes for making active pharmaceutical ingredients (APIs) that are used to treat epilepsy and seizures. One compound that can be prepared by their processes is the established drug levetiracetam (1, Figure 1), marketed under the trade name Keppra. Because 1 is now off-patent, there is obvious interest in new drugs.
The inventors also claim that seletracetam (2) and brivaracetam (3) (Figure 2) can be prepared by their processes. These drugs are apparently much more active than 1.
All of the drugs are used as single isomers, so a stereoselective synthesis is desirable. The inventors describe two routes for preparing the molecules; the first, shown in Figure 1, is the synthesis of 1 by the reaction between pyrrolidone (4) and chiral bromo amide 5 in the presence of a base. GC analysis showed that the conversion is 40.3% and that the product contains 51% of the (S)-enantiomer and 49% of the (R)-isomer. No details of their separation are given, although the use of chiral HPLC is discussed.
The same reaction is used to prepare derivative 6 of 1. Compound 7 is prepared from the corresponding hydroxy ester and then condensed with 4 to give 6. Chiral HPLC showed that the product is a mixture of 89.3% (S)-enantiomer 6 and 10.7% of its (R)-isomer.
The inventors do not describe the detailed preparation of 2, but they report that acid 8 is prepared in 41% yield from pyrrolidone 9 and acid 10 in the presence of NaH (Figure 2). Ammonolysis of 8 produces 2; no reaction details are provided.
In a reaction similar to the preparation of 8, acid 11 is prepared from 10 and pyrrolidone 12. The product is isolated in 77% yield and can be converted to 3 by ammonolysis. Again, no details are provided for this reaction.
The second route for preparing the substituted pyrrolidones does not start with simple pyrrolidones and is the subject of additional claims. The route involves a cyclization reaction, shown in Figure 3. The preparation of enantiomer 13 begins with the reaction of racemic salt 14 and optically pure bromo ester 15. This step produces intermediate 16, isolated as a yellow oil. The crude material is treated with 2-hydroxypyridine (2-HP) to cyclize it to 17. This ester is hydrolyzed to give acid 18. Conversion to 13 is carried out by adding ClCO2Et, followed by reaction with liquid NH3 in the presence of K2CO3. The overall yield of 13 is 32%.
This route is also used to prepare levetiracetam (1) by treating 5 with the HCl salt of amino ester 19 to give 20, recovered as its HCl salt in 49% yield. The salt is basified with Et3N and treated with 2-HP to cyclize it to 1, initially isolated as an oil. GC analysis showed 100% conversion, and chiral HPLC showed that the product contains 98.6% (S)-isomer and 1.4% (R)-isomer.
The inventors also prepared 1 and its (R)-enantiomer 21 by using a similar reaction scheme with alternative substrates to 5. Figure 4 outlines the route, which starts from protected hydroxy amide 22 and amino ester 23. When the reaction is carried out in the presence of Cs2CO3, the product is (R)-enantiomer24, which is used without purification to prepare 21 by treating it with 2-HP. Chiral HPLC showed that the product is 94% (R) and 6% (S).
When the reaction between 22 and 23 is run with K2CO3, the product is (S)-enantiomer 25. This is used to prepare 1, but the product contains only 79% (S)-isomer.
The inventors do not comment on the apparent stereoselectivity of the carbonate salts in the reaction of 22 with 23. This is an intriguing finding and worthy of investigation. (UCB S.A. [Brussels]. US Patent 8,338,621
SYNTHESIS
PATENT
WO2005028435
Example 1: Synthesis of (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide 1.1 Synthesis of (2S)-2-aminobutyramide free base
1800 ml of isopropanol are introduced in a 5L reactor. 1800 g of (2S)-2- aminobutyramide tartrate are added under stirring at room temperature. 700 ml of a 25% aqueous solution of ammonium hydroxide are slowly added while maintaining the temperature below 25°C. The mixture is stirred for an additional 3 hours and then the reaction is allowed to complete at 18°C for 1 hour. The ammonium tartrate is filtered. Yield : 86%.
1.2 Synthesis of 5-hydroxy-4-n-propyl-furan-2-one
Heptane (394 ml) and morpholine (127.5 ml) are introduced in a reactor. The mixture is cooled to 0°C and glyoxylic acid (195 g, 150 ml, 50w% in water) is added. The mixture is heated at 20°C during 1 hour, and then valeraldehyde (148.8 ml) is added . The reaction mixture is heated at 43°C during 20 hours. After cooling down to 20CC, a 37 % aqueous solution of HCl (196.9 ml) is slowly added to the mixture, which is then stirred during 2 hours.
After removal of the heptane phase, the aqueous phase is washed three times with heptane. Diisopropyl ether is added to the aqueous phase. The organic phase is removed, and the aqueous phase further extracted with diisopropyl ether (2x). The diisopropyl ether phases are combined, washed with brine and then dried by azeotropic distillation. After filtration and evaporation of the solvent, 170g of 5- hydroxy-4-n-propyl-furan-2-one are obtained as a brown oil. Yield: 90.8 %
1.3 Synthesis of (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide and (2S)-2-((4S)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide
(S, R) (S, S) The (2S)-2-aιninobutyrarnide solution in isopropanol containing 250 g obtained as described here above is dried by azeotropic distillation under vacuum. To the dried (2S)-2-am obutyraιnide solution is added 5-hydroxy-4-n-propyl-furan-2-one (290 g) between 15°C and 25 °C; the mixture is heated to 30 °C and kept for at least 2 hours at that temperature. Acetic acid (1, 18 eq.), Pd/C catalyst (5 w/w%; Johnson Matthey 5% Pd on carbon – type 87L) are then added and hydrogen introduced into the system under pressure. The temperature is kept at 40 °C maximum and the H2 pressure maintained between 0,2 bar and 0,5 bar followed by stirring for at least 20 hours following the initial reaction. The solution is then cooled to between 15 °C and 25 °C and filtered to remove the catalyst. The solution of product in isopropanol is solvent switched to a solution of product in isopropyl acetate by azeotropic distillation with isopropyl acetate. The organic solution is washed with aqueous sodium bicarbonate followed by a brine wash and then filtered. After recristallisation, 349 g of (2S)-2-((4R)-2- oxo-4-n-propyl-l-pyrrolidinyl)butanamide and (2S)-2-((4S)-2-oxo-4-n-propyl-l- pyιτolidinyl)butanamide are obtained (Yield: 82.5%).
1.4 Preparation of (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide The chromatographic separation of the two diastereoisomers obtained in 1.3 is performed using of (CHIRALPAK AD 20 um) chiral stationary phase and a 45/55 (volume /volume) mixture of n-heptane and ethanol as eluent at a temperature of 25 + 2°C. The crude (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide thus obtained is recristallised in isopropylacetate, yielding pure (2S)-2-((4R)-2-oxo-4-n-propyl-l- pyrrolidinyl)butanamide (Overall yield: 80%) .
Example 2: Synthesis of (2S)-2-((4R)-2-oxo-4-n-propyl-l-pyrrolidinyl)butanamide
Example 1 is repeated except that in step 1.1 a solution of (2S)-2- aminoburyramide.HCl in isopropanol is used (27.72 g, 1.2 equivalent), which is neutralised with a NHs/isopropanol solution (3,4-3,7 mol/L). The resulting ainmonium chloride is removed from this solution by filtration and the solution is directly used for reaction -with 5-hydroxy-4-n-propyl-furan-2-one (23.62 g, 1.0 equivalent) without intermediate drying of the (2S)-2-aminobutyramide solution. Yield after separation of the two diastereoisomers and recristallisation: approximately 84%.
3.a. Synthesis of (S) and (R) 2-((R)-2-oxo-4-propyl-pyrrolidin-l-yl)-butyric acid methyl ester fVIaa*) and (Wlab)
(VIaa) (VIab) A slurry of 60% sodium hydride suspension in mineral oil (0.94g, 23.4 mmol) in tetrahydrofuran (30 mL) is cooled at 0°C under a nitrogen atmosphere. A solution of substantially optically pure (R)-4-propyl-pyrrolidin-2-one (Ilia) (2g, 15.7 mmol) in tetrahydrofuran (2 mL) is added over a 15 minutes period. The reaction mixture is stirred 10 min at 0°C then a solution of methyl-2-bromo-butyric acid methyl ester (V) (3.69g, 20.4 mmol) in tetrahydrofuran (2mL) was added over a 20 minutes period. The reaction mixture is stirred at O0C until maximum conversion of starting material and the reaction mixture is then allowed to warm to room temperature and diluted with water (20 mL). Tetrahydrofuran is removed by evaporation and the residue is extracted with isopropyl acetate (20 ml + 10 mL). The combined organic layers are dried on anhydrous magnesium sulfate and evaporated to afford 3g (13.2 mmol, 86 %) of a mixture of epimers of compound (Via), as a mixture respectively of epimer (VIaa) and epimer (VIab). 1H NMR(400 MHz, CDCI3) of the mixture of epimers (VIaa) and (VIab) : δ = 4.68
HPLC (GRAD 90/10) of the mixture of epimers (VIaa) and (VIab): retention time= 9.84 minutes (100 %)
GC of the mixture of epimers (VIaa) and (VIab): retention time = 13.33 minutes (98.9 %)
MS of the mixture of epimers (VIaa) and (VIab) (ESI) : 228 MH+
3.b. Ammonolysis of compound of the mixture of (VIaa) and (VIab)
(VIaa) (VIab) (I) (VII)
A solution of (VIaa) and (VIab) obtained in previous reaction step (1.46g, 6.4 mmol) in aqueous ammonia 50 % w/w (18 mL) at 00C is stirred at room temperature for 5.5hours. A white precipitate that appears during the reaction, is filtered off, is washed with water and is dried to give 0.77g (3.6 mmol, yield = 56 %) of white solid which is a mixture of brivaracetam (I) and of compound (VII) in a 1 :1 ratio.
HPLC (GRAD 90/10) of the mixture of (I) and (VII) retention time= 7.67 minutes (100 %)
Melting point of the mixture of (I) and (VII) = 104.90C (heat from 400C to 1200C at 10°C/min)
Compounds (I) and (VII) are separated according to conventional techniques known to the skilled person in the art. A typical preparative separation is performed on a 11.7g scale of a 1 :1 mixture of compounds (I) and (VII) : DAICEL CHIRALPAK® AD 20 μm, 100*500 mm column at 300C with a 300 mL/minutes debit, 50 % EtOH – 50 % Heptane. The separation affords 5.28g (45 %) of compound (VII), retention time = 14 minutes and 5.2Og (44 %) of compounds (I), retention time = 23 minutes.
3c. Epimerisation of compound of (2RV2-((R)-2-oxo-4-propyl-pyπOlidin-l-ylV butyramide (VID
Compound (VII) (200 mg, 0.94 mmol) is added to a solution of sodium tert- butoxide (20 mg, 10 % w/w) in isopropanol (2 mL) at room temperature. The reaction mixture is stirred at room temperature for 18h. The solvent is evaporated to afford 200 mg
(0.94 mmol, 100 %) of a white solid. Said white solid is a mixture of brivaracetam (I) and of (VII) in a ratio 49.3 / 50.7.
5h. Synthesis of brivaracetam and (V) A suspension of (Id) and (Ie) (0.6 g, 2.3 mmol) in MIBK (10 mL) is heated at
120°C for 6 hours. The resulting solution is concentrated and separated on chromatography column (Silicagel 600.068-0.200 mm, cyclohexane/EtOAc : 10/90) to give 0.13 g of brivaracetam (0.6 mmol, 26 %, ee = 94 %) and (V).
Clinical trial number NCT00464269 for “Double-blind, Randomized Study Evaluating the Efficacy and Safety of Brivaracetam in Adults With Partial Onset Seizures” at ClinicalTrials.gov
On Friday, March 18, the U.S. Food and Drug Administration approved Anthim (obiltoxaximab) injection to treat inhalational anthrax in combination with appropriate antibacterial drugs. Anthim is also approved to prevent inhalational anthrax when alternative therapies are not available or not appropriate.
Inhalational anthrax is a rare disease that can occur after exposure to infected animals or contaminated animal products, or as a result of an intentional release of anthrax spores. It is caused by breathing in the spores of the bacterium Bacillus anthracis. When inhaled, the anthrax bacteria replicate in the body and produce toxins that can cause massive and irreversible tissue injury and death. Anthrax is a potential bioterrorism threat because the spores are resistant to destruction and can be spread by release in the air.
“As preparedness is a cornerstone of any bioterrorism response, we are pleased to see continued efforts to develop treatments for anthrax,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in FDA’s Center for Drug Evaluation and Research.
Anthim is a monoclonal antibody that neutralizes toxins produced by B. anthracis. Anthim was approved under the FDA’s Animal Rule, which allows efficacy findings from adequate and well-controlled animal studies to support FDA approval when it is not feasible or ethical to conduct efficacy trials in humans.
Anthim’s effectiveness for treatment and prophylaxis of inhalational anthrax was demonstrated in studies conducted in animals based on survival at the end of the studies. More animals treated with Anthim lived compared to animals treated with placebo. Anthim administered in combination with antibacterial drugs resulted in higher survival outcomes than antibacterial therapy alone.
The safety of Anthim was evaluated in 320 healthy human volunteers. The most frequently reported side effects were headache, itching (pruritus), upper respiratory tract infections, cough, nasal congestion, hives, and bruising, swelling and pain at the infusion site.
Anthim carries a Boxed Warning alerting patients and health care providers that the drug can cause allergic reactions (hypersensitivity), including a severe reaction called anaphylaxis. Anthim should be administered in settings where patients can be monitored and treated for anaphylaxis. However, given that anthrax is a very serious and often deadly condition, the benefit of Anthim for treating anthrax is expected to outweigh this risk.
Anthim was developed by Elusys Therapeutics, Inc. of Pine Brook, New Jersey, in conjunction with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority.
Obiltoxaximab is a monoclonal antibody designed for the treatment of exposure to Bacillus anthracis spores (etiologic agent ofanthrax).[1]
The efficacy of ANTHIM for treatment and prophylaxis of inhalational anthrax was demonstrated in multiple studies in the cynomolgus macaque and NZW rabbit models of inhalational anthrax. These studies tested the efficacy of ANTHIM compared to placebo and the efficacy of ANTHIM in combination with antibacterial drugs relative to the antibacterial drugs alone. The primary endpoint was survival following challenge with B. anthracis.
Two studies in NZW rabbit and two studies in cynomolgus macaques evaluated treatment with ANTHIM 16mg/kg IV single dose compared to placebo in animals with systemic anthrax. Treatment with ANTHIM alone resulted in statistically significant improvement in survival relative to placebo in both species. Survival rates were 93% and 62% with ANTHIM compared to 0 placebo survivors in rabbits, and 47% and 31-35% survival with ANTHIM compared to 6% or 0% placebo survival in macaques.
ANTHIM administered in combination with antibacterial drugs (levofloxacin, ciprofloxacin and doxycycline) for the treatment of systemic inhalational anthrax disease resulted in higher survival outcomes than antibacterial therapy alone in multiple studies where ANTHIM and antibacterial therapy was given at various doses and treatment times.
ANTHIM administered as prophylaxis resulted in higher survival outcomes compared to placebo in multiple studies where treatment was given at various doses and treatment times. ANTHIM administered as prophylaxis resulted in higher survival outcomes compared to placebo in multiple studies where treatment was given at various doses and treatment times. In one study, cynomolgus macaques were administered ANTHIM 16 mg/kg at 18 hours, 24 hours or 36 hours after exposure. Survival was 6/6 (100%) at 18 hours, 5/6 (83%) at 24 hours, and 3/6 (50%) at 36 hours. Another cynomolgus macaque study evaluated ANTHIM 16 mg/kg administered 72, 48 or 24 hours prior to exposure. Survival was 100% at all three time points (14/14, 14/14, 15/15, respectively) at day 56 (end of study).
Elusys Therapeutics
Elusys Therapeutics, Inc., a private company based in Pine Brook, NJ, is focused on the development of antibody therapeutics for the treatment of infectious disease.
In November 2015, Elusys was awarded a $45M delivery order from the U.S. government to produce ANTHIM® for the U.S. Strategic National Stockpile (SNS), the U.S. government’s repository of critical medical supplies for public health emergency preparedness. Elusys has received grants and contracts from the USG totaling over $240 million to support ANTHIM’s development.
In March 2016, ANTHIM (obiltoxaximab) Injection, the company’s monoclonal antibody (mAb) anthrax antitoxin, received approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with inhalational anthrax due toBacillus anthracis in combination with appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax due to B. anthracis when alternative therapies are not available or not appropriate. ANTHIM should only be used for prophylaxis when its benefit for prevention of inhalational anthrax outweighs the risk of hypersensitivity and anaphylaxis. The effectiveness of ANTHIM is based solely on efficacy studies in animal models of inhalational anthrax. There have been no studies of the safety or pharmacokinetics (PK) of ANTHIM in the pediatric population. Dosing in pediatric patients was derived using a population PK approach. ANTHIM does not have direct antibacterial activity. ANTHIM should be used in combination with appropriate antibacterial drugs. ANTHIM is not expected to cross the blood-brain barrier and does not prevent or treat meningitis.
Company
Elusys Therapeutics Inc.
Description
High-affinity humanized mAb against the Bacillus anthracis protective antigen that inhibits binding of anthrax toxins
Molecular Target
Bacillus anthracis protective antigen
Mechanism of Action
Antibody
Therapeutic Modality
Biologic: Antibody
Latest Stage of Development
Approved
Standard Indication
Anthrax
Indication Details
Treat and prevent anthrax infection; Treat anthrax infection
Regulatory Designation
U.S. – Fast Track (Treat and prevent anthrax infection);
U.S. – Orphan Drug (Treat and prevent anthrax infection)
PROCESS, spectroscopy, SYNTHESISComments Off on Phytochemical compounds or their synthetic counterparts? A detailed comparison of the quantitative environmental assessment for the synthesis and extraction of curcumin
Mar212016
Green Chem., 2016, 18,1807-1818 DOI: 10.1039/C6GC00090H, Paper
Elisabetta Zerazion, Roberto Rosa, Erika Ferrari, Paolo Veronesi, Cristina Leonelli, Monica Saladini, Anna Maria Ferrari
LCA of the synthesis of curcumin and its direct conventional and microwave assisted extractions fromCurcuma longa L. were compared.
Phytochemical compounds or their synthetic counterparts? A detailed comparison of the quantitative environmental assessment for the synthesis and extraction of curcumin
aDipartimento di Scienze e Metodi dell’Ingegneria, Università degli Studi di Modena e Reggio Emilia, via Amendola 2, 42100 Reggio Emilia, Italy
bDipartimento di Ingegneria “Enzo Ferrari”, Università degli Studi di Modena e Reggio Emilia, via Pietro Vivarelli 10, 41125 Modena, Italy E-mail: [email protected] Fax: +390592056243 Tel: +390592056224
c
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Modena e Reggio Emilia, via Campi 103, 41125 Modena, Italy
Green Chem., 2016,18, 1807-1818
DOI: 10.1039/C6GC00090H
Natural compounds represent an extremely wide category to be exploited, in order to develop new pharmaceutical strategies. In this framework, the number of in vitro, in vivo and clinical trials investigating the therapeutic potential of curcumin is exponentially increasing, due to its antioxidant, anti-inflammatory and anticancer properties. The possibility to obtain this molecule by both chemical synthesis and extraction from natural sources makes the environmental assessments of these alternative production processes of paramount importance from a green chemistry perspective, with the aim, for both industries and academia, to pursue a more sustainable development. The present work reports detailed and quantitative environmental assessments of three different curcumin production strategies: synthesis, conventional Soxhlet-based extraction (CE) and microwave-assisted extraction (MAE). The chemical synthesis of curcumin, as recently optimized by the authors, has been firstly evaluated by using the EATOS software followed by a complete “cradle to the grave” study, realized by applying the Life Cycle Assessment (LCA) methodology. The life cycles of CE and MAE were then similarly assessed, considering also the cultivation of Curcuma longa L., the production of the dried rhizomes as well as their commercialization, in order to firstly investigate the widely claimed green character of MAE with respect to more conventional extraction procedures. Secondly, the results related to the two different extraction strategies were compared to those obtained by the chemical synthesis of curcumin, with the aim to determine its greenest preparation procedure among those investigated. This work represents the first example of an environmental assessment comparison between different production strategies of curcumin, thus smoothing the way towards the highly desirable establishment of environmentally friendly rankings, comprising all the existing alternatives to the chemical synthesis of a target chemical compound.
PROCESS, SYNTHESISComments Off on A pot-economical and diastereoselective synthesis involving catalyst-free click reaction for fused-triazolobenzodiazepines
Mar212016
Green Chem., 2016, Advance Article DOI: 10.1039/C6GC00497K, Communication
Xiaofeng Zhang, Sanjun Zhi, Wei Wang, Shuai Liu, Jerry P. Jasinski, Wei Zhang
A pot-economical synthesis involving two [3 + 2] cycloadditions for diastereoselective synthesis of novel triazolobenzodiazepine-containing polycyclic compounds
aCentre for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, USA E-mail: [email protected]
bJiangsu Key Laboratory for the Chemistry of Low-Dimensional Materials, Huaiyin Normal University, Huaian, PR China
cSchool of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an, PR China
dDepartment of Chemistry, Keene State College, Keene, USA
Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC00497K
A pot-economical synthesis involving sequential [3 + 2] cycloadditions of an azomethine ylide and an azide–alkyne (click reaction) has been developed for diastereoselective synthesis of novel triazolobenzodiazepine-containing polycyclic compounds. A new example of catalyst-free click chemistry of non-strained alkynes is also disclosed
Green Chem., 2016, Advance Article DOI: 10.1039/C6GC00370B, Paper
Xu Jiang, Faliang Gou, Fengjuan Chen, Huanwang Jing
Bisimidazole-functionalized cobaltoporphyrin acted as efficient bifunctional catalysts to facilitate the synthesis of cyclic carbonates from epoxides and CO2.
aState Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering Lanzhou University, Gansu 730000, PR China
bState Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences, Taiyuan 030001, P R China E-mail: [email protected]
Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC00370B
A series of innovative bisimidazole-functionalized porphyrin cobalt(III) complexes have been devised, synthesized and characterized using NMR, MS and elemental analysis. These homogeneous catalysts were applied to the cycloaddition of epoxides and carbon dioxide without organic solvent and co-catalyst. It was found that the performance of the catalysts deeply relies on their structural features. The alkoxyl chain length of the linkage and the imidazole position relative to the phenyl rings of porphyrin evidently affects the catalyst activities. [5,15-Di(3-((8-imidazolyloctyl)oxy)phenyl)porphyrin] cobalt(III) chloride (J-m8) and [5,15-di(2-((6-imidazolylhexyl)oxy)phenyl)porphyrin] cobalt(III) chloride (J-o6) demonstrated excellent activity under optimal reaction conditions. Synchronously, a preliminary kinetic investigation of this reaction was carried out using three catalysts and illustrated the activation energies of cyclic carbonate formation. Furthermore, a tri-synergistic catalytic mechanism has been carefully proposed in light of the features of the new catalysts and experimental results.
References [1] L. Jin, H. Jing, T. Chang, X. Bu, L. Wang and Z. Liu, J. Mol. Catal. A: Chem., 2007, 261, 262. [2] X. Jiang, F. Gou and H. Jing, J. Catal., 2014, 313, 159. [3] B. Li, L. Zhang, Y. Song, D. Bai and H. Jing, J. Mol. Catal. A: Chem., 2012, 363– 364, 26.
///Cycloaddition of epoxides, CO2 catalyzed, bisimidazole-functionalized porphyrin cobalt(III) complexes
A novel spherical cellulose adsorbent with amide and sulphinate groups was used for a first reduction of trichloroacetic acid(TCAA) and a subsequent adsorption of generated species, haloacetic acids. The removal mechanism involved TCAA reduction by sulphinate groups and the adsorption of the haloacetic acids through electrostatic interaction with amide group. Investigation of product formation and subsequent disappearance reveals that the reduction reactions proceed viasequential hydrogenolysis, and transform to acetate ultimately. Adsorption of haloacetic acids was ascertained by low chloride mass balances(89.3%) and carbon mass balances(75.1%) in solution. The pseudo-first-order rate constant for TCAA degradation was (0.93±0.12) h-1. Batch experiments were conducted to investigate the effect of pH value on the reduction and adsorption process. The results show that the reduction of TCAA by sulphinate groups requires higher pH values while the electrostatic attraction of haloacetic acids by amino group is favorable in more acidic media.
Trichloroacetic Acid Removal by a Reductive Spherical Cellulose Adsorbent
LIN Chunxiang1,3, TIAN Chen1, LIU Yifan1,3, LUO Wei1, ZHU Moshuqi1, SU Qiaoquan1, LIU Minghua1,2,3
1. College of Environment & Resources, Fuzhou 350108, P. R. China;
2. State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350108, P. R. China;
3. Key Laboratory of Eco-materials Advanced Technology(Fuzhou University), Fujian Province University, Fuzhou 350108, P. R. China
LIN Chunxiang,TIAN Chen,LIU Yifan等. Trichloroacetic Acid Removal by a Reductive Spherical Cellulose Adsorbent[J]. CHEMICAL RESEARCH IN CHINESE UNIVERSITIES, 2016, 32(1): 95-99.
