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FALDAPREVIR

801283-95-4

(1R,2S)-1-{[(2S,4R)-4-[{8-bromo-7-methoxy-2-[2-(2-methylpropanamido)-1,3-thiazol-4-yl]quinolin-4-yl}oxy]-1-[(2S)-2-{[(cyclopentyloxy)carbonyl]amino}-3,3-dimethylbutanoyl]pyrrolidine-2-carboxamido]-2-ethenylcyclopropane-1-carboxylic acid

Boehringer Ingelheim (Originator)

BI-201335 is an HCV NS3 protease inhibitor awaiting approval in the E.U. by Boehringer Ingelheim for the treatment of chronic hepatitis C, in combination with pegylated Interferon and ribavirin.

Faldaprevir (formerly BI 201335) is an experimental drug for the treatment of hepatitis C. It is being developed by Boehringer-Ingelheim and is currently in Phase III trials.[1]

Faldaprevir is a hepatitis C virus protease inhibitor.

Faldaprevir is being tested in combination regimens with pegylated interferon and ribavirin, and in interferon-free regimens with other direct-acting antiviral agents including BI 207127.

Data from the SOUND-C2 study, presented at the 2012 AASLD Liver Meeting, showed that a triple combination of faldaprevir, BI 207127, and ribavirin performed well in HCV genotype 1b patients.[2] Efficacy fell below 50%, however, for dual regimens without ribavirin and for genotype 1a patients.

Phase II clinical trials are also ongoing for the treatment of patients with chronic genotype-1a hepatitis C virus (HCV) infection, in combination with PPI-668 and BI-207127.

In 2007, fast track designation was assigned to the compound in the U.S. for the treatment of chronic genotype-1 hepatitis C (HCV).

Protease inhibitors that are active against NS3/4a are a fertile area of research, not least because of the early promise shown by the two already-approved agents

Faldaprevir

Protease inhibitors that are active against NS3/4a are a fertile area of research. Boehringer Ingelheim’s compound faldaprevir is currently in Phase III trials.1 In one 24-week trial in 429 treatment-naïve patients with genotype-1 hepatitis C infection, subjects were given standard peg-interferon and ritonavir therapy plus placebo, or standard therapy plus either 120mg or 240mg of faldaprevir either with or without a three day lead-in of standard therapy alone, or standard therapy plus the higher dose of faldaprevir.

ADDN LIT

Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335)

J Med Chem 2010, 53(17): 6466

WO 2010033444

WO 2004103996

US6323180 Aug 5, 1999 Nov 27, 2001 Boehringer Ingelheim (Canada) Ltd Hepatitis C inhibitor tri-peptides
US7514557 * May 23, 2005 Apr 7, 2009 Boehringer Ingelheim International Gmbh Process for preparing acyclic HCV protease inhibitors
US7585845 * May 20, 2004 Sep 8, 2009 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US20050020503 * May 20, 2004 Jan 27, 2005 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US20120059033 Mar 9, 2011 Mar 8, 2012 Boehringer Ingelheim International Gmbh Crystalline Salts of a Potent HCV Inhibitor
USRE40525 Sep 30, 2005 Sep 30, 2008 Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor tri-peptides
WO2000009543A2 Aug 9, 1999 Feb 24, 2000 Boehringer Ingelheim Ca Ltd Hepatitis c inhibitor tri-peptides
WO2004087741A1 Mar 25, 2004 Oct 14, 2004 Boehringer Ingelheim Int Crystalline phases of a potent hcv inhibitor
WO2004103996A1 May 19, 2004 Dec 2, 2004 Boehringer Ingelheim Int Hepatitis c inhibitor compounds
WO2011112761A1 Mar 10, 2011 Sep 15, 2011 Boehringer Ingelheim International Gmbh Crystalline salts of a potent hcv inhibitor

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US8232293

Figure US08232293-20120731-C00011

EXAMPLES Example 1 Preparation of Quinoline Starting Material Compound 11

Figure US08232293-20120731-C00006

Step 1

The dianion of amide 1 (prepared exactly as described above, from 1.00 g amide 1) was cooled to −78° C., then 2.19 mL perfluorooctyl bromide (8.46 mmol, 1.75 eq.) was added dropwise via syringe over 5 minutes. The dark-colored reaction mixture was then placed in a −10° C. bath. After two hours, 10 mL 1N HCl was cautiously added, and the mixture extracted with EtOAc (2×25 mL), dried (MgSO4), and the solvents removed in vacuo. The residue was then chromatographed on silica gel eluting with 4:1 Hexane:EtOAc to give 1.13 g bromoamide 5 (81%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 8.12 (br s, 1H), 8.04 (dd, J=1.3, 8.4 Hz, 1H), 7.24 (t, J=8.3 Hz, 1H), 6.63 (dd, J=1.3, 8.3 Hz, 1H), 3.87 (s, 3H), 1.33 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 176.57 (s), 155.74 (s), 136.98 (s), 128.34 (d), 113.63 (d), 106.86 (d), 103.07 (s), 56.26 (q), 40.20 (s), 27.45 (q).

Step 2

0.25 g bromoamide 5 (0.87 mmol, 1 eq.), 2.0 mL con. HCl (24 mmol, 28 eq.), and 1.0 mL diglyme were heated at 100° C. for 24 hours. The mixture was then cooled and filtered (product). The filtrate was evaporated in vacuo using H2O to azeotropically remove all solvents. The residue was triturated with EtOAc to cause precipitation of additional product, which was also filtered. The combined solids were dried to give 0.16 g (77%) of bromoaniline 6.HCl as a light brown solid. 1H NMR (400 MHz, CDCl3) δ: 7.09 (t, J=8.1 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 6.47 (d, J=8.1 Hz, 1H), 3.84 (br s, 2H), 3.77 (s, 3H).

Step 3

Bromoanisidine.HCl (5.73 g, 24.0 mmol), Aluminumtrichloride (3.52 g) and chlorobenzene (15.0 mL) are charged into an oven dried 100 mL three necked flask at rt (temperature rise to 30° C.). The resulting mixture is then stirred for 10 min then cooled to 0-5° C. followed by slow addition of acetonitrile (1.89 mL, 36.0 mmol) followed by addition of BCl(2.82 g), transferred as gas (or liquid) into the reaction mixture, keeping the temperature below 5° C. The resulting mixture is then stirred at rt for 20 min then heated to 85-100° C. for 16 h. HPLC indicate completion of the reaction (SM<0.5% at 220 nm). The mixture is cooled down to 50° C. then Toluene (15 mL) was added followed by slow addition of IPA (11.1 mL) then slow addition of water (32 mL) at 50° C. The resulting mixture stirred for additional 2 h at this temperature then 3 g Celite was added and the stirred mixture cooled to rt. Filtration then wash of the organic fraction with water 1×15 mL, 2×15 m: 5% NaHCO3, 1×15 mL water then concentration under reduced pressure provided 3.92-4.4 g of the desired product in 68-72% isolated yield. 1H NMR (400 MHz, CDCl3) δ: 7.72 (d, J=9.0 Hz, 1H), 7.1 (br s, 2H), 6.28 (d, J=9.1 Hz, 1H), 3.94 (s, 3H), 2.55 (s, 3H).

Step 4

Oxalyl chloride (8.15 mL) is added dropwise to the cold mixture (10±5° C.) of Thiazole acid 8 (20.18 g) is dissolved in THF (300 mL) and DMF (300 μL) over a period of ˜5 min keeping the internal temperature at 10±5° C. The reaction mixture becomes yellow and homogenous. The cooling bath is removed and the mixture is allowed to reach ambient temperature over a period of ˜30 min. Gas evolution is observed. The mixture is stirred at ambient temperature for 30 min to 1 hour. A solution of aniline 7 (19.8 g), DMAP (140 mg) and THF (35 mL) was added at 10±5° C. Et3N (13.2 mL) was added in portions at 10±5° C. over a period of 10 min. The ice bath was removed and mixture was heated to 65±2° C. and stirred overnight (18 h). The mixture was allowed to reach ambient temperature, diluted with EtOAc (150 mL) and washed with water (150 mL). NaHCO3(5%, 225 mL) was added to the organic portion and the mixture was stirred at ambient temperature for 30 min. The organic portion was concentrated under reduced pressure at approx. 40° C. EtOAc (150 mL) was added to the resulting material and the residual water was removed and the mixture was concentrated under reduced pressure at approx. 40° C. (to azeotrope water). EtOAc (94 mL) was added and the resulting slurry was stirred for 2-6 h and filtered. The solid was washed with EtOAc (30 mL) followed by heptane (30 mL) and air dried for 1 h to give the desired product in 70% yield.

1H NMR (400 MHz, CDCl3) δ: 1.32 (d, 6H, J=7.8 Hz), 2.58 (s, 3H), 2.65-2.72 (m, 1H), 3.98 (s, 3H), 6.83 (d, 1H, J=8.7 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.86 (s, 1H), 8.98 (bs, 1H), 10.13 (bs, 1H).

Step 5

In a 2 L flask was placed potassium t-butoxide (112 g). Dry DME was added at room temperature (exothermic: temperature went up to 35° C.). The resultant solution was heated to ca. 80° C., and amide (88 g) was added in 10 portions slowly so temperature was kept between 80-85° C. Upon completion, reaction mixture was stirred at 85° C. for 2 hours. Solid precipitated during the reaction. HPLC analysis indicated that the reaction was completed at this point (conversion: 100%). The reaction mixture was cooled to room temperature and then to 10° C. with a cool bath. Aqueous 2N HCl solution (ca. 500 ml) was added slowly so temperature was kept under 25° C. to quench the reaction mixture. pH was adjusted to 4-5. About 100 ml of water was added (Note: amount of water may need adjustment to facilitate filtration), and the resulting suspension was stirred at room temperature for 5-10 hours. Product was isolated by filtration, washing with THF and drying under vacuum. Yield: 81 g, 96% yield.

1H-NMR (400 M Hz, DMSO-d6): 1.14 (6H, d, J=6.8 Hz, i-Pr), 2.48 (1H, hept., J=6.8 Hz, i-Pr), 3.99 (3H, s, MeO), 6.75 (1H, s, H-3), 7.24 (1H, d, J=8.5 Hz, H-6), 8.10 (1H, d, J=8.5 Hz, H5), 8.22 (1H, s, H-5′), 9.87 (1H, s, OH), 12.40 (1H, s, amide NH).

Step 6

In a 100 ml flask was placed starting material quinoline (4.22 g) and dioxane (40 ml). POCl(4.6 g) was added, and the mixture was heated to 75° C. After 2 hours, HPLC showed the reaction finished (99.7% conversion). Reaction mixture was cooled to room temperature, and then poured to 100 ml saturated NaHCOsolution and 20 ml EtOAc. The resulting suspension was stirred for 3 hours. Product was isolated by filtration, washing with EtOAc and drying under vacuum. Yield: 4.0 g, 90.9%.

1H-NMR (400 M Hz, CDCl3): 1.14 (6H, d, J=6.8 Hz, i-Pr), 2.76 (1H, hept., J=6.8 Hz, i-Pr), 4.05 (3H, s, MeO), 7.68 (1H, d, J=8.5 Hz, H-6), 8.07 (1H, s, H-3), 8.13 (1H, s, H-5′), 8.20 (1H, d, J=8.5 Hz, H5), 12.30 (1H, s, amide NH).

Example 2 Preparation of Dipeptide Acid Compound 13 Starting Material

Figure US08232293-20120731-C00007

A 250 mL 3-neck flask with a thermocouple, nitrogen inlet, and magnetic stir bar was charged with N-cyclopentyloxy carbonyl-tert-L-leucine (20.0 g, 82.2 mmol, 1.0 eq.), 1-hydroxy-benzotriazole (12.73 g, 90.42 mmol, 1.1 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.33 g, 90.42 mmol, 1.1 eq.) The flask was purged with nitrogen, and the stiffing started. Anhydrous DMF (62 mL) was added to the flask and the mixture was stirred for 20 minutes at room temperature (about 24° C.). The reaction was mildly exothermic, the internal temperature rose to 29° C. Solid trans-4-hydroxyproline methyl ester HCl (14.93 g, 82.2 mmol, 1.0 eq) was added to the reaction in one portion. Using a syringe, diisopropyl ethyl amine (14.36 mL, 82.2 mmol, 1.0 eq) was added to the reaction dropwise over 25 min. The internal temperature rose to 34.5° C. from 29° C. The reaction was stirred for 1.75 h, forming 12. The reaction was then quenched with 0.1 M HCl (100 mL), the internal temperature rose to 34° C. The reaction was extracted three times with 75 mL of ethyl acetate, and the organic layers were combined. The organic layer was washed with 75 mL H2O, and 2×75 mL of sat. NaHCO3. The organic layer (about 235 mL) was transferred to a 500 mL flask fitted with a mechanical stirrer, shortpath distillation head, internal and external thermocouples, and distilled to minimal stirrable volume under house vacuum (˜110 mm Hg) below 35° C. internal temperature with an oil bath temperature of 40° C. To this crude mixture of 12 was then added tetrahydrofuran (150 mL) and it was distilled to minimum stirrable volume. Tetrahydrofuran (100 mL) was added to the flask, and it was again distilled to minimum stirrable volume. The distillation head was replaced with an addition funnel. Tetrahydrofuran, (100 mL) and methanol (50 mL) were added to the flask, and the solution stirred for about 15 minutes. A 3.2 M solution of LiOH (77 mL, 246.6 mmol, 3 eq.) was charged to the addition funnel, and added over 45 minutes. The temperature rose from 22° C. to 29° C., and the reaction mixture became slightly cloudy. The mixture was cooled in a cold water bath, then the reaction was quenched by slow (45 min.) addition of 4 M HCl (58-65 mL) to adjust the pH to 3.5, causing a slight increase in temperature to 27° C. The flask was fitted with a distillation head, and the methanol and tetrahydrofuran were removed by distillation at reduced pressure, with a bath temperature of 40° C., internal temperature below 30° C. The mixture was extracted twice with 150 mL of MTBE. The MTBE solution was concentrated at reduced pressure, (350 mmHg) to minimum stirrable volume. 50 mL of MTBE was added, it was removed by distillation, internal temp below 35° C. The reaction was a clear viscous liquid, 20 mL of MTBE was added, the mixture was heated to 50° C., solution was clear, the oil bath was turned off, and the solution cooled to rt, ˜24° C. over 1.5 h. To the resultant slurry was then added 60 mL MTBE, stirred 2 h, then the slurry was filtered, using ˜20 mL MTBE to transfer the mixture. The solid was then dried under vacuum at 35° C. to constant weight, 16.4 g (52%), to give the ⅓ MTBE solvate compound 13 as a colorless solid, m.p. 117-124° C.; αD=−58.6 (c 2.17, MeOH); 1H NMR (400 MHz, DMSO, major rotamer reported) δ: 6.76 (d, J=9.3 Hz, 1H), 5.15 (s, 1H), 4.92 (m, 1H), 4.31 (br s, 1H), 4.26 (t, J=8.3 Hz, 1H), 4.19 (d, J=9.3 Hz, 1H), 3.63 (m, 2H), 3.06 (s, 1H, (MTBE)), 2.08 (m, 1H), 1.87-1.48 (m, 9H), 1.09 (s, 3H, (MTBE)), 0.92 (s, 9H).

Example 3 Preparation of Tripeptide Acid Compound 16 Starting Material

Figure US08232293-20120731-C00008

In a 25 ml flask 14 was dissolved in 3 ml DMF. HOBt (149 mg, 1.1 mmol), EDC (211 mg, 1.1 mmol), 13 (290 mg, 1.0 mmol) and i-Pr2NEt (129 mg, 1.0 mmol) were added in the given order at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 15 ml aqueous NaHCOand extracted with ethyl acetate (20 ml). The organic layer was washed with HCl (0.5 N, 2×10 ml) and saturated aqueous NaHCO(10 ml). After removal of solvent by rotary evaporation, 15 was obtained as a white solid. 0.46 g (95% yield). 1H-NMR (400 M Hz, CDCl3): 0.96 (s, 9H), 1.35 (1H, dd, J=3.0, 4.5 Hz), 1.45-1.90 (m, 9H), 1.77 (1H, dd, J=3.0, 4.0 Hz), 2.00-2.09 (1H, m), 2.45-2.52 (1H, m), 3.02 (1H, br), 3.50 (1H, dd, J=11.0, 3.0 Hz), 3.58 (3H, s), 3.99 (1H, d, J=11.0 Hz), 4.18 (1H, d, J=9.0 Hz), 4.43 (1H, br), Hz), 4.63 (1H, t, J=8.0 Hz), 4.93-5.00 (1H, m), 5.04 (1H, dd, J=10.5, 2.0 Hz), 5.20 (1H, d, J=18.0 Hz), 5.20-5.25 (1H, m), 5.65-5.77 (1H, ddd, J=18.0, 10.5, 2.0 Hz), 7.78 (1H, br) ppm.

320 mg ester 15 (0.667 mmol, 1 eq.) was dissolved in 6.7 mL THF+3.4 mL MeOH at ambient temperature under N2. To this solution was then added 3.34 mL 1.6 M LiOH (5.34 mmol, 8 eq.) dropwise over 5 minutes. After 1.5 hours, the solvents were removed in vacuo, and the residue diluted with 15 mL EtOAc+10 mL sat’d NaCl, then 1N HCl was added until pH 3.45 was reached. The phases were separated and the aqueous phase reextracted with 15 mL EtOAc. The combined EtOAc layers were washed with H2O (1×50 mL), dried (MgSO4), and the solvents removed in vacuo to give an oil. The oil was azeotroped with MTBE (1×15 mL), and the residue dried under high vacuum to give 320 mg of 16 (100%) as a colorless foam. Exact mass calc’d for C23H35N3O7: 465.25. Found (ES−): 464.29; 1H NMR (400 MHz, DMSO, major rotamer reported) δ: 12.40 (br s, 1H), 8.49 (s, 1H), 6.77 (d, J=8.2 Hz, 1H), 5.71 (m, 1H), 5.22-4.85 (m, 4H), 4.36-4.10 (m, 3H), 3.80-3.21 (m, 4H), 2.00-1.42 (m, 11H), 0.92 (s, 9H).

Example 4 Dipeptide SNAr Approach to Amorphous Compound (1)

Figure US08232293-20120731-C00009

SNAr Protocol 1: A 100 mL 3-neck round bottom flask was charged with 1.93 g 13 (5.00 mmol, 1 eq.), then evacuated/Ar filled (3×), then 17.0 mL DMSO was added via syringe to give a clear, colorless solution. The flask was again evacuated/Ar filled (3×), then 2.53 g t-BuOK (22.5 mmol, 4.5 eq.) was added neat, at once. An exotherm to a maximum of 31.5° C. was observed. The flask was evacuated/Ar filled (3×), then stirred under house vacuum (˜60 mm) for one hour, and some foaming (-t-BuOH) was observed. The vacuum was relieved to Ar, then 2.20 g 11 (5.00 mmol, 1 eq.) was added neat, at once. An exotherm to 28.6° C. was observed. The flask was evacuated/Ar filled (3×), then stirred under house vacuum protected from light at ambient temperature. After 6.5 h the vacuum was relieved to Ar and a sample removed for HPLC, which showed <2% unreacted 11. The flask was then cooled in a cold water bath to 18° C., and 1.72 mL glacial HOAc (30 mmol, 6 eq.) was then added via syringe over ˜10 minutes. An exotherm to 20.5° C. was observed. The mixture was stirred for 10 minutes, then added dropwise over 15 minutes into a second flask containing a well-stirred solution of 30 mL pH 3.5H2O (˜0.001M HCl) at 18° C., causing a precipitate to form immediately, and giving an exotherm to 21.0° C. 2.0 mL DMSO was used to wash the residue into the aqueous mixture, followed by a wash of 5.0 mL ˜0.001M HCl. The resulting suspension was stirred for 15 minutes, then 30 mL of a 1:1 mixture of EtOAc:MTBE was added, and the mixture agitated vigorously for 15 minutes. Agitation was stopped and the phases were allowed to separate. Rapid phase separation and formation of 2 clear phases with no rag layer was seen. The lower aqueous phase was then reextracted with 30 mL of 1:1 EtOAc:MTBE (same fast separation), and the organic extracts were combined and saved. The aqueous phase was discarded as waste.

The organic solution was then washed with H2O (3×30 mL), again all extractions gave rapid separation of phases and no rag layer, then the EtOAc was distilled to minimal stirrable volume. The residue was then azeotroped with 30 mL THF (2×), again distilling to minimal stirrable volume. The resultant slurry of crude 18 was used immediately in the peptide coupling. Exact mass calc’d for C34H42BrN5O8S: 759.19. Found (MS−): 757.92.

SNAr Protocol 2: 1.00 g 13 (2.59 mmol, 1 eq.) and 1.35 g 11 (2.59 mmol, 1 eq.) were charged to a dry flask. The flask was then evacuated/Ar filled (3×), then 10 mL dry DMSO was added via syringe. The flask was again evacuated/Ar filled (3×), then cooled to 19° C. with a cold water bath. To this mixture was then added a 2M solution of KDMO/heptane (5.71 mL, 11.7 mmol, 4.5 eq.) dropwise over 30 minutes. After six hours, HPLC showed the reaction as complete. The reaction was quenched with 0.89 mL HOAc (6 eq.), and added slowly to 25 mL stirring H2O, causing a precipitate to form. The mixture was then extracted with IPAc (2×25 mL). The combined IPAc phases were washed with H2O (1×25 mL), dried (MgSO4), and the solvents removed in vacuo to give a solid, which was azeotroped with MeCN (1×25 mL), and then diluted with heptane to give a slurry. The slurry was filtered and dried to give 1.80 g 18 (91%).

Peptide Coupling Protocol 1: To the THF slurry of crude 18 from SNAr Protocol 1 (taken as 5.00 mmol, 1 eq.) under Ar at ambient temperature in a flask protected from light was added 1.72 g 14 (5.5 mmol, 1.1 eq.) and 25 mL THF. The solution was then cooled to 5° C. under Ar, then 0.958 mL DIEA (5.50 mmol, 1.1 eq.) was added dropwise via syringe over 5 minutes. 5 minutes after the DIEA addition was completed, 0.85 g HOBT hydrate (6.00 mmol, 1.2 eq.), and 1.05 g EDC (5.50 mmol, 1.1 eq.) was then added neat, at once. The flask was then removed from the cold bath and the resultant mixture was then stirred at ambient temperature under Ar for 4 hours. A sample was withdrawn for HPLC which showed <2% unreacted 18 remained. The mixture was cooled to 5° C., then 40 mL 0.1N HCl was added dropwise via addition funnel over 5 minutes, followed by 40 mL EtOAc. The mixture was well agitated for 15 minutes, then agitation was stopped and the phases were allowed to separate. The lower aqueous phase was then reextracted with 40 mL EtOAc and the organic phases were combined and saved. The aqueous phase was discarded as waste. The organic solution was then washed with H2O (1×40 mL), sat’d NaHCO(2×40 mL), and again H2O (1×40 mL), then distilled to minimal stirrable volume. The residue was then azeotroped with MTBE (2×40 mL), and again distilled to minimal stirrable volume. The residue was dried under high vacuum to give 4.70 g of crude 19 as an orange solid, with HPLC purity of 78.3%. This material was then chromatographed on silica gel eluting with 2:1 EtOAc:Hexane to give 3.01 g (68% over 2 steps) pure 19 as a yellow powder. Exact mass calc’d for C41H51BrN6O9S: 882.26, MS+: 883.30. 1H NMR (400 MHz, DMSO, major rotamer reported) δ: 12.32 (s, 1H), 8.69 (s, 1H), 8.14 (d, J=9.2 Hz, 1H), 8.03 (s, 1H), 7.45 (s, 1H), 7.33 (d, J=9.4 Hz, 1H), 6.97 (d, J=8.6 Hz, 1H), 5.65 (m, 1H), 5.40 (s, 1H), 5.20 (dd, J=1.5, 17 Hz, 1H), 5.06 (dd, J=1.6, 10.2 Hz, 1H), 5.56 (s, 1H), 4.46 (m, 1H), 4.37 (d, J=9 Hz, 1H), 4.08 (m, 1H), 3.99 (s, 3H), 3.90 (m, 1H), 3.56 (s, 3H), 2.81 (m, 1H), 2.51 (m, 1H), 2.25 (m, 1H), 2.07 (m, 1H), 1.70-1.32 (m, 7H), 1.30 (m, 3H), 1.15 (d, J=8.1 Hz, 6H), 0.95 (s, 9H).

Peptide Coupling Protocol 2: A 5 L 4-neck RBF fitted with mech. stirrer, addition funnel, and thermocouple was charged with 69.57 g 14 (222 mmol, 1.3 eq.), then evacuated/Ar filled (3×). To this was then added a 200 mL THF solution of 18 (contains 129.85 g 171 mmol, 1 eq.), then 523 mL THF was charged to bring the final THF volume to 1 L. The mixture was then cooled to 4.0° C. under Ar. 38.67 mL DIEA (222 mmol, 1.3 eq.) was then added dropwise via addition funnel over 10 minutes, as the internal temperature fell to 2.4° C. The mixture was aged 5 minutes, then 29.98 g HOBT H2O (222 mmol, 1.3 eq.) was added, followed by 42.57 g EDC (222 mmol, 1.3 eq.). The internal temperature was then 3.6° C. The bath was then removed. The internal temperature rose to 20.5° C. over 90 minutes. 4 h after the EDC addition was completed, HPLC showed the reaction was complete. The mixture was cooled to 4.0° C., then 750 mL 0.1N HCl was added over 30 minutes via addition funnel, giving an exotherm to 9.5° C. To this mixture was then added 250 mL sat’d NaCl, followed by 1 L IPAc. After 5 min. vigorous stirring, the mixture was added to a separatory funnel, and the phases were separated. The lower aq. phase was then reextracted with 500 mL IPAc, and the IPAc phases combined. These were then washed successively with H2O (1×1 L), sat’d NaHCO(1×1 L), and then H2O (1×1 L). The mixture was then mech. stirred for 12 h to precipitate quinoline 7. The mixture was then filtered through a medium-fritted funnel, and the filtrate distilled until minimal stirrable volume was reached. The residue was then azeotroped with MTBE (2×400 mL), and again distilled to minimal stirrable volume. The residue was dried under high vacuum to give 128 g of 19 as a yellow solid, with HPLC purity of 89%.

140 mg 19 (0.158 mmol, 1 eq.) was dissolved in 1.6 mL THF+0.80 mL MeOH at ambient temperature under N2. To this solution was then added 0.79 mL 1.6 M LiOH (1.27 mmol, 8 eq.) dropwise over 5 minutes. After 1.5 h, the organic solvents were removed in vacuo, and the residue diluted with 10 mL EtOAc+10 mL sat’d NaCl. The pH was then adjusted to 5.75 with 1N HCl. The mixture was agitated vigorously for one hour, then the phases were separated. The aqueous phase was reextracted with 10 mL EtOAc. The combined EtOAc phases were then washed with H2O (2×25 mL), dried (MgSO4, and the solvents removed in vacuo to give 125 mg of Compound (1) (91%) as an amorphous yellow powder.

Example 5 Tripeptide SNAr Approach to Amorphous Compound (1)

Figure US08232293-20120731-C00010

233 mg tripeptide acid 16 (0.50 mmol) was charged to a flask, then the flask was evacuated/Ar filled (3×). 1.7 mL DMSO was then added, and the mixture evacuated/Ar filled (3×). The mixture was then cooled in a cold water bath, then 317 mg t-BuOK (2.82 mmol, 5.63 eq.) were added. The flask was again evacuated/Ar filled (3×), then stirred under 60 mm vacuum for one hour. 220 mg quinoline 11 (0.50 mmol, 1 eq.) was then added, and the flask evacuated/Ar filled (3×), then stirred under 60 mm vacuum in the dark at ambient temperature for 3 hours. 0.30 mL HOAc was then added, then the resulting solution was added to 25 mL 0.001 M HCl, causing a precipitate to form. The slurry was filtered, washing the solids with 25 mL H2O. The solid was dried under Nfor 2 hours, then chromatographed on silica gel eluting with EtOAc to give 226 mg (52%) of Compound (1) as an amorphous yellow solid.

Additional methods for preparing amorphous Compound (1) can be found in U.S. Pat. Nos. 6,323,180, 7,514,557 and 7,585,845, which are herein incorporated by reference.

Example 6 Preparation of Type A of Compound (1)

Amorphous Compound (1) (Batch 7, 13.80 g) was added to a 1000 ml three neck flask. Absolute ethanol (248.9 g) was added to the flask. While stirring, the contents of the flask were heated at 60 degrees C./hr to ˜74 degrees C. (Solids do not dissolve at 74 degrees C.). Water (257.4 g) was then added linearly over 4 hr to the resulting slurry while stirring and maintaining the temperature at 74 degrees C. After the water addition was complete, the temperature was reduced linearly to ambient temperature at 8 degrees C./hr and then held at ambient temperature for 6 hrs while stiffing. The resulting solids were collected by filtration and washed with 50 ml of 1/1 (w/w) EtOH/Water. The wet solids were dried on the funnel for 30 minutes by sucking Nthrough the cake. (XRPD analysis on this sample indicates that the pattern is similar to the EtOH solvate). The solids were then dried at 65-70 degrees C. under vacuum (P=25 in Hg) and a nitrogen bleed for 1.5 hr. The resulting solids (12.6 g, 95.5% corrected yield) were confirmed by XRPD as being Type A Compound (1).

The unique XRPD pattern and DSC curve of Type A Compound (1) is shown in FIGS. 1 and 2.

Example 7 Preparation of the Sodium Salt of Compound (1)—Method 1

2.1 g of amorphous sodium salt of Compound (1) and 8.90 g of acetone was added to a vial and stirred at ambient temperature for 3 hr. The slurry was filtered off mother liquors and the resulting solids were dried for 20 minutes under nitrogen flow for 20 minutes. 1.51 g of crystalline sodium salt of Compound (1) as solids was collected.

Example 8 Preparation of the Sodium Salt of Compound (1)—Method 2

15.6 g of Type A of Compound (1), 175 ml of acetone and 3.6 ml of water was added to a 250 ml reactor and heated to 53 degrees C. to dissolve the solids. 900 ul of 10.0 N NaOH was added to reactor and the solution was seeded with Type A. The seeded solution was stirred at 53 degrees C. for 10 minutes. A second 900 ul portion of 10.0 N NaOH was added and the system was stirred at 53 degrees C. for 30 minutes over which a slurry developed. The slurry was cooled to 19 degrees C. at a cooling rate of 15 degrees C. per hour and held overnight at 19 degrees C. The final resulting slurry was filtered and the wet solids were washed with 15 ml of acetone. Dried solids for 1 hr at 52 degrees C. under vacuum with a nitrogen flow and then exposed the solids to lab air for one hour. Collected 12.1 g of Compound (1) crystalline sodium salt solids.

Example 11 Preparation of the Sodium Salt of Compound (1)—Method 5

At room temperature a solution of sodium ethoxide in ethanol (21 weight %; 306 ml) was added to a solution of Compound (1) (745 g) in THF (2000 ml) and water (76.5 ml) while stiffing. After stiffing for 30 minutes, the mixture was filtered and the filter was washed with THF (85 ml). The resulting solution was warmed to 65° C. and treated with filtered butyl acetate (6640 ml, optionally pre-warmed to 65° C.) within 30 minutes. Seeding crystals (0.50 g) were added, and the mixture was stirred at 65° C. for 2 hours, while crystallization starts after about 30 minutes. The suspension was cooled to 50° C. within 1 hour and stirred at this temperature for an additional hour. The title compound was isolated by filtration, washed with filtered butyl acetate (765 ml, optionally pre-warmed to 50° C.) and dried at 65° C. for about 16 h giving Compound (1) crystalline sodium salt (˜725 g).

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

http://medcheminternational.blogspot.in/p/vir-series-hep-c-virus.html

Patent Filing date Publication date Applicant Title
US8399484 Sep 16, 2009 Mar 19, 2013 Boehringer Ingelheim International Gmbh Combination therapy for treating HCV infection
US8530497 Mar 9, 2011 Sep 10, 2013 Boehringer Ingelheim International Gmbh Crystalline salts of a potent HCV inhibitor
WO2013144193A1 Mar 27, 2013 Oct 3, 2013 Boehringer Ingelheim International Gmbh Combination therapy for treating hcv infection in specific patient subgenotype sub-population

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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