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DACLATASVIR, 达拉他韦 , Даклатасвир , داكلاتاسفير ,
Daclatasvir
Status: Launched 2014 (EU, Japan)
Originator: Bristol-Myers Squibb
Daclatasvir (USAN[1]) (formerly BMS-790052, trade name Daklinza) is a drug for the treatment of hepatitis C (HCV). It is was developed by Bristol-Myers Squibb and was approved in Europe on 22 August 2014.
Daclatasvir inhibits the HCV nonstructural protein NS5A.[2][3] Recent research suggests that it targets two steps of the viral replication process, enabling rapid decline of HCV RNA.[4]
Daclatasvir has been tested in combination regimens with pegylated interferon and ribavirin,[5] as well as with other direct-acting antiviral agents including asunaprevir[6][7][8][9] and sofosbuvir.[10][11]
It is on the World Health Organization’s List of Essential Medicines, a list of the most important medications needed in a basic health system.[12]
EUROPEAN MEDICINES AGENCY ADVISES ON COMPASSIONATE USE OF DACLATASVIR
- The first compassionate-use opinion for a hepatitis C treatment was adopted by the CHMP in October 2013.
- Sofosbuvir, which is part of this compassionate-use opinion, received a positive opinion from the CHMP recommending granting of a marketing authorisation at its November 2013 meeting.
- Daclatasvir is developed by Bristol-Myers Squibb and sofosbuvir is developed by Gilead.
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1-6-2012
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Anti-Viral Compounds
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2-13-2009
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CRYSTALLINE FORM OF METHYL ((1S)-1-(((2S)
-2-(5-(4′-(2-((2S)-1((2S)-2-((METHOXYCARBONYL)AMINO)-3-METHYLBUTANOYL)-2-PYRROLIDINYL) -1H-IMIDAZOL-5-YL)-4-BIPHENYLYL)-1H-IMIDAZOL-2-YL)-1-PYRROLIDINYL)CARBONYL) -2-METHYLPROPYL)CARBAMATE DIHYDROCHLORIDE SALT |
Synthesis
Daclatasvir dihydrochloride (Daklinza)
Daclatasvir dihydrochloride is a hepatitis C virus nonstructural 5A (NS5A) replication complex inhibitor which was first approved in Japan for the treatment of genotype 1 HCV patients who fail to respond to interferon plus ribavirin. The drug has also been approved for patients with untreated, chronic HCV who are eligible for interferon. Additionally, in Europe, daclatasvir was approved for use in combination with other products across genotype 1–4 HCV. Daclatasvir was discovered and developed by Bristol–Myers Squibb and a fascinating account describing the initiation of the program from a phenotypic screen and the medicinal chemistry strategy leading to the discovery of the compound has been recently reported.80 Daclatasvir has been prepared via two different routes81,82 and the process route is outlined in Scheme 11.83 Bromination of commercial 4,40-diacetylbiphenyl (58) gave 4,40-bis(bromoacetyl)biphenyl 59 in 82% yield. Alkylation of NBoc- L-proline (60) with 59 gave diester 61 which was treated with ammonium acetate to effect cyclization of the bis-ketoester to provide bis-imidazole 62 in 63% yield for the two steps. Acidic removal of the Boc protecting groups followed by recrystallization provided bis-pyrrolidine 63 in high yield. Acylation of 63 with N-(methoxycarbonyl)- L-valine (64) using N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide(EDC) and 1-hydroxybenxotriazole hydrate (HOBT) provided declatasvir. The dihydrochloride salt was prepared and treated with Cuno Zet Carbon followed by crystallization from acetone
to give daclatasvir dihydrochloride (IX) in 74% yield.
80 Belema, M.; Meanwell, N. A. J. Med. Chem. 2014, 57, 5057.
81. Bachand, C.; Belema, M.; Deon, D. H.; Good, A. C.; Goodrich, J.; James, C. A.;
Lavoie, R.; Lopez, O. D.; Martel, A.; Meanwell, N. A.; Nguyen, V. N.; Romine, J.
L.; Ruediger, E. H.; Snyder, L. B.; St. Laurent, D. R.; Yang, F.; Langley, D. R.;
Wang, G.; Hamann, L. G. WO Patent 2008021927A2, 2008.
82. Belema, M.; Nguyen, V. N.; Bachand, C.; Deon, D. H.; Goodrich, J. T.; James, C.
A.; Lavoie, R.; Lopez, O. D.; Martel, A.; Romine, J. L.; Ruediger, E. H.; Snyder, L.
B.; St Laurent, D. R.; Yang, F.; Zhu, J.; Wong, H. S.; Langley, D. R.; Adams, S. P.;
Cantor, G. H.; Chimalakonda, A.; Fura, A.; Johnson, B. M.; Knipe, J. O.; Parker, D.
D.; Santone, K. S.; Fridell, R. A.; Lemm, J. A.; O’Boyle, D. R., 2nd; Colonno, R. J.;
Gao, M.; Meanwell, N. A.; Hamann, L. G. J. Med. Chem. 2014, 57, 2013.
83. Pack, S. K.; Geng, P.; Smith, M. J.; Hamm, J. WO Patent 2009020825A1, 2009.
PATENT
EXAMPLES
A 1 L, 3-neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple, was charged with 20 g (83.9 mmol, 1 equiv) 1,1′-(biphenyl-4,4′-diyl)diethanone, 200 mL CH2Cl2 and 8.7 mL (27.1 g, 169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir under nitrogen for about 20 hours under ambient conditions. The resulting slurry was charged with 200 mL CH2Cl2 and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25° C. over 1 hour and allowed to stir at 20-25° C. for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL CH2Cl2. The product was dried under vacuum at 60° C. to yield 27.4 g (69.2 mmol, 82%) of the desired product : 1H NMR (400 MHz, CDCl3) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); 13C NMR (100 MHz, CDCl3) 6 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm−1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C16H12Br2O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53 HRMS calcd for C16H13Br2O2 (M+H; DCI+): 394.9282. Found: 394.9292. mp 224-226° C.
A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Compound 2, 22.8 g (105.9 moles, 2.10 equiv) 1-(tert-butoxycarbonyl)-L-proline and 200 mL acetonitrile. The slurry was cooled to 20° C. followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25° C. and allowed to stir for 3 hours. The resulting clear, organic solution was washed with 3×100 mL 13 wt % aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume=215 mL) by vacuum distillation until there was less than 0.5 vol % acetonitrile.
The toluene solution of Compound 3 was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100° C. The mixture was allowed to stir at 95-100° C. for 15 hours. After reaction completion, the mixture was cooled to 70-80° C. and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol % aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature >50° C. The rich organic phase was charged with 80 mL of 5 vol % aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature >50° C. The resulting biphasic solution was split while maintaining a temperature >50° C. and the rich organic phase was washed with an additional 80 mL of 5 vol % aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature >60° C., 64 mL methanol was charged. The resulting slurry was heated to 70-75° C. and aged for 1 hour. The slurry was cooled to 20-25° C. over 1 hour and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:methanol. The product was dried under vacuum at 70° C., resulting in 19.8 g (31.7 mmol, 63%) of the desired product: 1H NMR (400 MHz, DMSO-d6) δ 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); 13C NMR (100 MHz, DMSO-d6) δ 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm−1) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C36H45N6O4 (M+H; ESI+): 625.3502. Found: 625.3502. mp 190-195° C. (decomposed).
To a 250 mL reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Compound 4 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous HCl. The temperature was increased to 50° C. and agitated at 50° C. for 5 hours. The resulting slurry was cooled to 20-25° C. and held with agitation for about 18 hours. Filtration of the slurry afforded a solid which was washed successively with 100 mL 90% methanol/water (V/V) and 2×100 mL of methanol. The wet cake was dried in a vacuum oven at 50° C. overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.
Recrystallization of Compound 5
To a 250 mL reactor equipped with a nitrogen line and an overhead stirrer, 17.8 g of Compound 5 from above was charged followed by 72 mL methanol. The resulting slurry was agitated at 50° C. for 4 hours, cooled to 20-25° C. and held with agitation at 20-25° C. for 1 hour. Filtration of the slurry afforded a crystalline solid which was washed with 60 mL methanol. The resulting wet cake was dried in a vacuum oven at 50° C. for 4 days to yield 14.7 g (25.7 mmol, 82.6%) of the purified product: 1H NMR (400 MHz, DMSO-d6) δ 10.5-10.25 (br, 2H), 10.1-9.75 (br, 2H), 8.19 (s, 2H), 7.05 (d, J=8.4, 4H), 7.92 (d, J=8.5, 4H), 5.06 (m, 2H), 3.5-3.35 (m, 4H), 2.6-2.3 (m, 4H), 2.25-2.15 (m, 2H), 2.18-1.96 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 156.6, 142.5, 139.3, 128.1, 127.5, 126.1, 116.9, 53.2, 45.8, 29.8, 24.3; IR (KBr, cm−1) 3429, 2627, 1636, 1567, 1493, 1428, 1028. Anal calcd for C26H32N6Cl4: C, 54.75; H, 5.65; Cl, 24.86; Adjusted for 1.9% water: C, 53.71; H, 5.76; N, 14.46; Cl, 24.39. Found: C, 53.74; H, 5.72; N, 14.50; Cl, 24.49; KF=1.9. mp 240° C. (decomposed).
A 1 L jacketed flask equipped with a nitrogen line and an overhead stirrer was sequentially charged with 100 mL acetonitrile, 13.69 g (89.4 mmol, 2.5 equiv) hydroxybenzotriazole hydrate, 15.07 g (86 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 16.46 g (85.9 mmol, 2.4 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 100 mL acetonitrile. The resulting solution was agitated at 20° C. for 1 hour and charged with 20.4 g (35.8 mmol, 1 equiv) of purified Compound 5. The slurry was cooled to about 0° C. and 18.47 g (142.9 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10° C. The solution was slowly heated to 15° C. over 3 hours and held at 15° C. for 12 hours. The resulting solution was charged with 120 mL 13 wt % aqueous NaCl and heated to 50° C. for 1 hour. After cooling to 20° C., 100 mL of isopropyl acetate was added. The biphasic solution was filtered through a 0.45 μm filter and the mixture split. The rich organic phase was washed with 2×240 mL of a 0.5 N NaOH solution containing 13 wt % NaCl followed by 120 mL 13 wt % aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation with a target volume of 400 mL. The resulting hazy solution was cooled to 20° C. and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 140 mL. While maintaining a temperature of 50° C., 66.4 mL (82.3 mmol, 2.3 equiv) of 1.24M HCl in ethanol was added. The mixture was then charged with 33 mg (0.04 mmol, 0.001 equiv) of seed crystals of Compound (I) (see preparation below) and the resulting slurry was stirred at 50° C. for 3 hours. The mixture was cooled to 20° C. over 1 hour and aged at that temperature for an additional 22 hours. The slurry was filtered and the wet cake was washed with 100 mL of 2:1 acetone:ethanol. The solids were dried in a vacuum oven at 70° C. to give 22.15 g (27.3 mmol, 76.3%) of the desired product.
A solution of Compound (I) was prepared by dissolving 3.17 g of Compound (I) from above in 22 mL methanol. The solution was passed through a 47 mm Cuno Zeta Carbon® 53SP filter at ˜5 psig at a flow rate of ˜58 mL/min. The carbon filter was rinsed with 32 mL of methanol. The solution was concentrated down to 16 mL by vacuum distillation. While maintaining a temperature of 40-50° C., 15.9 mL acetone and 5 mg of seed crystals of Compound (I) (see procedure below) were added. The resulting slurry was then charged with 32 mL acetone over 30 minutes. The slurry was held at 50° C. for 2 hours, cooled to 20° C. over about 1 hour and held at 20° C. for about 20 hours. The solids were filtered, washed with 16 mL 2:1 acetone:methanol and dried in a vacuum oven at 60° C. to give 2.14 g (67.5%) of purified Compound (I):
1H NMR (400 MHz, DMSO-d6, 80° C.): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97-4.11 (m, 2 H), 3.74-3.90 (m, 2 H), 3.57 (s, 6 H), 2.32-2.46 (m, 2 H), 2.09-2.31 (m, 6 H), 1.91-2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H);
13C NMR (75 MHz, DMSO-d6): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7;
IR (neat, cm−1): 3385, 2971, 2873, 2669, 1731, 1650.
Anal. Calcd for C40H52N8O6Cl2: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267° C. (decomposed).
Preparation of Seed Crystals of Compound (I)
A 250 mL round-bottom flask was charged with 6.0 g (10.5 mmol, 1 equiv) Compound 5, 3.87 g (22.1 mmol, 2.1 equiv) N-(methoxycarbonyl)-L-valine, 4.45 g (23.2 mmol, 2.2 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.289 g (2.14 mmol, 0.2 equiv) 1-hydroxybenzotriazole, and 30 mL acetonitrile. The resulting slurry was then charged with 7.33 mL (42.03 mmol, 4 equiv) diisopropylethylamine and allowed to stir at 24-30° C. for about 18 hours. The mixture was charged with 6 mL of water and heated to 50° C. for about 5 hours. The mixture was cooled and charged with 32 mL ethyl acetate and 30 mL water. The layers were separated and the rich organic layer was washed with 30 mL of 10 wt % aqueous NaHCO3, 30 mL water, and 20 mL of 10 wt % aqueous NaCl. The rich organic layer was then dried over MgSO4, filtered, and concentrated down to a residue. The crude material was then purified via flash chromatography (silica gel, 0-10% methanol in dichloromethane) to provide the free base of Compound (I).
The free-base of Compound (I) (0.03 g) was dissolved in 1 mL isopropanol at 20° C. Anhydrous HCl (70 μL, dissolved in ethanol, approximately 1.25M concentration) was added and the reaction mixture was stirred. To the solution was added methyl tert-butyl ether (1 mL) and the resulting slurry was stirred vigorously at 40° C. to 50° C. for 12 hours. The crystal slurry was cooled to 20° C. and filtered. The wet cake was air-dried at 20° C. A white crystalline solid (Form N-2 of Compound (I)) was obtained.
Clip
Daclatasvir synthesis: WO2009020828A1
Procedure:
Step a: A 1 L, 3 -neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple, was charged with 20 g (83.9 mmol, 1 equiv) 1,1′-(biphenyl-4,4′-diyl)diethanone, 200 mL Dichloromethane and 8.7 mL (27.1g, 169.3 mmol, 2.02 equiv) bromine. The mixture was allowed to stir under nitrogen for about 20 hours under ambient conditions. The resulting slurry was charged with 200 mL Dichloromethane and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25 0C over 1 hour and allowed to stir at 20-25 0C for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL Dichloromethane. The product was dried under vacuum at 60 0C to yield 27.4 g (69.2 mmol, 82%) of the desired product: 1H NMR (400 MHz, CDCl3) d 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); 13C NMR 100 MHz, CDCl3) d 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm-1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C16H12Br2O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd for C16H12Br2O2 (M + H; DCI+): 394.9282. Found: 394.9292. mp 224-226 0C.
Step b: A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Compound 2, 22.8 g (105.9 moles, 2.10 equiv) 1-(tert-butoxycarbonyl)-L-proline and 200 mL acetonitrile. The slurry was cooled to 20 0C followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25 0C and allowed to stir for 3 hours. The resulting clear, organic solution was washed with 3 x 100 mL 13 wt% aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume = 215 mL) by vacuum distillation until there was less than 0.5 vol% acetonitrile.
Step c: The toluene solution of Compound 3 was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100 0C. The mixture was allowed to stir at 95-100 0C for 15 hours. After reaction completion, the mixture was cooled to 70- 80 0C and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol% aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature > 50 0C. The rich organic phase was charged with 80 mL of 5 vol% aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature > 50 0C. The resulting biphasic solution was split while maintaining a temperature > 50 0C and the rich organic phase was washed with an additional 80 mL of 5 vol% aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature > 60 0C, 64 mL methanol was charged. The resulting slurry was heated to 70-75 0C and aged for 1 hour. The slurry was cooled to 20-25 0C over 1 hour and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:methanol. The product was dried under vacuum at 70 0C, resulting in 19.8 g (31.7 mmol, 63%) of the desired product: 1H NMR (400 MHz, DMSO-^) d 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); 13C NMR (100 MHz, DMSO-?fe) d 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm-1) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C36H45N6O4 (M + H; ESI+): 625.3502. Found: 625.3502. mp 190-195 0C (decomposed).
Step d: To a 250 mL reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Compound 4 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous HCl. The temperature was increased to 50 0C and agitated at 50 0C for 5 hours. The resulting slurry was cooled to 20-25 0C and held with agitation for about 18 hours. Filtration of the slurry afforded a solid which was washed successively with 100 mL 90% methanoI/water (WV) and 2 x 100 mL of methanol. The wet cake was dried in a vacuum oven at 50 0C overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.
CUT PASTE…….WO2009020825
Preparation of Compound (I)
A 1 L jacketed flask equipped with a nitrogen line and an overhead stirrer was sequentially charged with 100 mL acetonitrile, 13.69 g (89.4 mmol, 2.5 equiv) hydroxybenzotriazole hydrate, 15.07 g (86 mmol, 2.4 equiv) N-(methoxycarbonyl)- L-valine, 16.46 g (85.9 mmol, 2.4 equiv) l-(3-dimethyaminopropyl)-3- ethylcarbodiimide hydrochloride and an additional 100 mL acetonitrile. The resulting solution was agitated at 20 0C for 1 hour and charged with 20.4 g (35.8 mmol, 1 equiv) of purified Compound 7. The slurry was cooled to about 0 0C and 18.47 g (142.9 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10 0C. The solution was slowly heated to 15 0C over 3 hours and held at 15 0C for 12 hours. The resulting solution was charged with 120 mL 13 wt% aqueous NaCl and heated to 50 0C for 1 hour. After cooling to 20 0C, 100 mL of isopropyl acetate was added. The biphasic solution was filtered through a 0.45 μm filter and the mixture split. The rich organic phase was washed with 2 x 240 mL of a 0.5 Ν NaOH solution containing 13 wt% NaCl followed by 120 mL 13 wt% aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation with a target volume of 400 mL. The resulting hazy solution was cooled to 20 0C and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 140 mL. While maintaining a temperature of 50 0C, 66.4 mL (82.3 mmol, 2.3 equiv) of 1.24M HCl in ethanol was added. The mixture was then charged with 33 mg (0.04 mmol, 0.001 equiv) of seed crystals of Compound (I) (see preparation below) and the resulting slurry was stirred at 50 0C for 3 hours. The mixture was cooled to 20 0C over 1 hour and aged at that temperature for an additional 22 hours. The slurry was filtered and the wet cake was washed with 100 mL of 2: 1 acetone:ethanol. The solids were dried in a vacuum oven at 70 0C to give 22.15 g (27.3 mmol, 76.3%) of the desired product.
Alternative Preparation of Compound (I)
A jacketed reactor equipped with a mechanical agitator, a thermocouple and a nitrogen inlet was sequentially charged with 10 L acetonitrile, 0.671 kg (4.38 moles, 2.50 equiv) 1-hydroxybenzotriazole, 0.737 kg (4.21 moles, 2.40 equiv) N- (methoxycarbonyl)-L-valine and 0.790 kg (4.12 moles, 2.35 equiv) l-(3- dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was agitated at 200C for 1 hour, cooled to 5 0C and charged with 1 kg (1.75 moles, 1.00 equiv) Compound 7. While maintaining a temperature < 10 0C, 0.906 kg (7.01 moles, 4 equiv) diisopropylethylamine was added. The mixture was heated to 15-20 0C over 2 hours and agitated for an additional 15 hours. After the reaction was complete, the mixture was washed once with 6.0 L 13 wt% aqueous NaCl, twice with 6.1 L (6.12 moles, 3.5 equiv) 1.0 M aqueous NaOH containing 13 wt% NaCl and once with 6.0 L 13 wt% aqueous NaCl. Water was then removed from the rich organic solution via azeotropic distillation. The mixture was cooled to 20 0C, agitated for 1 hour and filtered. The rich organic solution was then solvent exchanged into EtOH via vacuum distillation to a target volume of 5 L. While maintaining a temperature of 50 0C, 3.2 L (4.0 moles, 2.3 equiv) 1.25M HCl in EtOH was charged. The mixture was seeded with 1.6 g Compound (I) (see preparation below) and agitated at 50 0C for 3 hours. The resulting slurry was cooled to 20 0C and agitated for at least 3 hours. The product was collected by filtration and washed with 5 L 2: 1 acetone:
EtOH to give 1.29 kg (ca. 90 wt% product) of wet crude product. A reactor equipped with an overhead agitator, nitrogen inlet and thermocouple was charged with 1.11 kg of the above crude product and 7 L methanol. The resulting solution was treated with Cuno Zeta Carbon (TM) 55SP. The carbon was washed with 15 L MeOH and the combined filtrate and wash was concentrated down to 4 L via vacuum distillation. The concentrated solution was charged with 5 L acetone and seeded with 1.6 g Compound (I) (see preparation below) while maintaining a temperature of 50 0C. An additional 10 L acetone was charged and the resulting slurry was stirred at 50 0C for 3 hours. The slurry was cooled to 20 0C and allowed to agitate at 200C for 3 hours. The product was collected by filtration, washed with 5 L 2: 1 acetone: EtOH and dried under vacuum at 50-60 0C to give 0.900 kg (1.11 moles, 74% adjusted) of Compound (I)-
Carbon Treatment and Recrystallization of Compound (I) A solution of Compound (I) was prepared by dissolving 3.17 g of Compound (I) from above in 22 mL methanol. The solution was passed through a 47mm Cuno Zeta Carbon 53SP filter at ~5 psig at a flow rate of~58mL/min. The carbon filter was rinsed with 32 mL of methanol. The solution was concentrated down to 16 mL by vacuum distillation. While maintaining a temperature of 40-50 0C, 15.9 mL acetone and 5 mg of seed crystals of Compound (I) (see procedure below) were added. The resulting slurry was then charged with 32 mL acetone over 30 minutes. The slurry was held at 50 0C for 2 hours, cooled to 20 0C over about 1 hour and held at 20 0C for about 20 hours. The solids were filtered, washed with 16 mL 2: 1 acetone:methanol and dried in a vacuum oven at 60 0C to give 2.14 g (67.5%) of purified Compound (I):
1H NMR (400 MHz, DMSO-έfc, 80 0C): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97 – 4.11 (m, 2 H), 3.74 – 3.90 (m, 2 H), 3.57 (s, 6 H), 2.32 – 2.46 (m, 2 H), 2.09 – 2.31 (m, 6 H), 1.91 – 2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H);
13C NMR (75 MHz, DMSO-έfc): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7;
IR (neat, cm“1): 3385, 2971, 2873, 2669, 1731, 1650.
Anal. Calcd for C40H52N8O6Cl2: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267 0C (decomposed).
Characteristic diffraction peak positions (degrees 2Θ + 0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKa) with a spinning capillary with 2Θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7
Daclatasvir faces problems in USA
The US-FDA in 2014 issued a complete response letter for NS5A inhibitor daclatasvir saying it was unable to approve the drug because the marketing application was for its use in tandem with asunaprevir, an NS3/NS4A protease inhibitor discontinued in the US by BMS for commercial reasons. Daclatasvir is already on the market in Europe-where it is sold as Daklinza-and also in Japan where it was approved alongside asunaprevir in July as the country’s first all-oral HCV therapy. However, a delay in the large US market is clearly a major setback for BMS’ ambitions in hepatitis therapy.
To make the matter worse, US FDA has rescinded breakthrough therapy designation status from Bristol-Myers Squibb for Daclatasvir for the treatment of hepatitis C virus infection in Feb 2015.
PAPER
Makonen, B.; et. al. Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir. J Med Chem 2014, 57(5), 2013–2032.
http://pubs.acs.org/doi/abs/10.1021/jm401836p
PATENT
http://www.google.com/patents/WO2008021927A2?cl=en
Example 24-23
methyl ((lS)-l-(((2S)-2-(5-(4′-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-
1 -pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate
A 50 mL flask equipped with a stir bar was sequentially charged with 2.5 mL acetonitrile, 0.344 g (2.25 mmol, 2.5 equiv) hydroxy benzotriazole hydrate, 0.374 g (2.13 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 0.400 g (2.09 mmol, 2.4 equiv) 1 -(3 -dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 2.5 mL acetonitrile. The resulting solution was agitated at 20 0C for 1 hour and charged with 0.501 g (0.88 mmol, 1 equiv) Example A-le-4. The slurry was cooled to about 0 0C and 0.45 g (3.48 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10 0C. The solution was slowly heated to 15 0C over 3 hours and held at 15 0C for 16 hours. The temperature was increased to 20 0C and stirred for 3.25 hours. The resulting solution was charged with 3.3 g of 13 wt% aqueous NaCl and heated to 50 0C for 1 hour. After cooling to 20 0C, 2.5 mL of isopropyl acetate was added. The rich organic phase was washed with 2 x 6.9 g of a 0.5 N NaOH solution containing 13 wt% NaCl followed by 3.3 g of 13 wt% aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation to a target volume of 10 mL. The resulting hazy solution was cooled to 20 0C and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 3 mL. 1.67 mL (2.02 mmol, 2.3 equiv) of 1.21 M HCl in ethanol was added. The mixture was then stirred at 25 0C for 15 hours. The resulting slurry was filtered and the wet cake was washed with 2.5 mL of 2: 1 acetone:ethanol. The solids were dried in a vacuum oven at 50 0C to give 0.550 g (0.68 mmol, 77 %) of the desired product.
RecrystalHzation of Example 24-23
A solution of Example 24-23 prepared above was prepared by dissolving 0.520 g of the above product in 3.65 mL methanol. The solution was then charged with 0.078 g of type 3 Cuno Zeta loose carbon and allowed to stir for 0.25 hours. The mixture was then filtered and washed with 6 ml of methanol. The product rich solution was concentrated down to 2.6 mL by vacuum distillation. 7.8 mL acetone was added and allowed to stir at 25 0C for 15 h. The solids were filtered, washed with 2.5 mL 2: 1 acetone:ethanol and dried in a vacuum oven at 70 0C to give 0.406 g (57.0%) of the desired product as white crystals: 1H NMR (400 MHz, OMSO-d6, 80 0C): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97 – 4.11 (m, 2 H), 3.74 – 3.90 (m, 2 H), 3.57 (s, 6 H), 2.32 – 2.46 (m, 2 H), 2.09 – 2.31 (m, 6 H), 1.91 – 2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H); 13C NMR (75 MHz, DMSO- d6): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7; IR (neat, cm“1): 3385, 2971, 2873, 2669, 1731, 1650. Anal. Calcd for C40H52N8O6Cl2: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267 0C (decomposed). Characteristic diffraction peak positions (degrees 2Θ ± 0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKa) with a spinning capillary with 2Θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7
PAPER
Bioorganic & Medicinal Chemistry Letters (2015), 25(16), 3147-3150
http://www.sciencedirect.com/science/article/pii/S0960894X15005995
Scheme 1.
Synthetic route for the preparation of the target compounds 8a–8y. Reagents and conditions: (a) Br2, CH2Cl2, rt, overnight, 86%; (b) N-Boc-l-proline, MeCN, Et3N, rt, 2 h, 98%; (c) NH4OAc, toulene, 130 °C, 15 h, 85%; (d) 6 N HCl, MeOH, 50 °C, 4 h, 87%; (e) HATU, N-(methoxycarbonyl)-l-valine, DIPEA, rt, 14 h, 83%; (f) RCOCl, TEA, CH2Cl2, rt, 3 h, 64–87%.
Dimethyl((2S,2’S)-((2S,2’S)-2,2′-(5,5′-([1,1′-biphenyl]-4,4′-diyl)bis(1H-imidazole-
5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-
diyl))dicarbamate 7……………FREE BASE
To a solution of 5 (90 mg, 0.181 mmol), N-me-thoxycarbonyl-l-valine 6 (92 mg,0.525 mmol) and DIPEA (0.18 mL, 1.03 mmol) in DMF (5 mL) was added HATU(165.5 mg, 0.434 mmol). The resulting reaction was allowed to stir at room temperature for 15 h, the reaction mixture was filtered and the residue was partitioned between EtOAc and H2O, The aqueous phase was extracted with EtOAc, and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; 5% Methanol /CH2Cl2) to
afford 7 (0.11 g, 83 %)as white solid.
1H NMR (DMSO-d6, 500 MHz) δ: 11.56 (s, 2H), 7.69-7.48 (m, 8H), 7.26-7.03 (m, 4H), 5.24-5.05 (m, 2H), 4.09-4.04 (m, 2H), 3.85-3.75 (m, 4H), 3.58 (s, 6H), 2.24-1.98 (m, 10H), 0.87 (d, J = 3.6 Hz, 12H).
Anal. calcd. (%) for C40H50N8O6: C 65.02, H 6.82, N 15.17; found: C 65.20, H 6.79, N 15.31.
ESI-MS m/z: 739.5 (M+H)+.
NMR PREDICT
1H NMR PREDICT
13C NMR PREDICT
COSY PREDICT
Patents
http://www.who.int/phi/implementation/ip_trade/daclatasvir_report_2014_09-02.pdf
Click on images to view
Click on images to view
Click on images to view
http://www.who.int/phi/implementation/ip_trade/daclatasvir_report_2014_09-02.pdf
Click on images to view
Click on images to view
Click on images to view
 |
|
| Names | |
|---|---|
| IUPAC name
Methyl [(2S)-1-{(2S)-2-[4-(4’-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-pyrrolidinyl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}-3-methyl-1-oxo-2-butanyl]carbamate
|
|
| Other names
BMS-790052
|
|
| Identifiers | |
1009119-64-5  |
|
| ATC code | J05AX14 |
| ChEBI | CHEBI:82977 |
| ChEMBL | ChEMBL2023898 ChEMBL2303621 |
| ChemSpider | 24609522 |
| Jmol-3D images | Image |
| Properties | |
| C40H50N8O6 | |
| Molar mass | 738.89 g·mol−1 |
CLIP 1
Australian Government, National Measurement Institute
REFERENCE MATERIAL ANALYSIS REPORT
HPLC: Instrument: Shimadzu Binary pump LC-20AB, SIL-20 A HT autosampler
Column: X-Bridge C-18, 5.0 m (4.6 mm x 150 mm)
Column oven: 40 °C
Mobile Phase: A = Milli-Q water buffered at pH 10 with NH4
+ -OAc; B = MeCN
Gradient 0 min 35% B; 0-15 min 35% B; 15-18 min 35-75% B; 18-23 min 75% B.
Flow rate: 1.0 mL/min
Detector: Shimadzu SPD-M20A PDA operating at 310 nm
Relative peak area response of main component:
Initial analysis: Mean = 99.2%, s = 0.01%
Thermogravimetric analysis: Non volatile residue < 0.2% mass fraction . The volatile
content (e.g. organic solvents and/or water) could not be determined by
thermogravimetric analysis.
Karl Fischer analysis: Moisture content 0.6% mass fraction
QNMR: Instrument: Bruker Avance-III-500
Field strength: 500 MHz Solvent: DMSO-d6 (2.50 ppm)
Internal standard: Potassium hydrogen maleate (98.8% mass fraction)
Initial analysis: Mean (0.86 ppm) = 98.2%, s = 0.2%
LC-MS: Instrument: Thermo Scientific Dionex UltiMate 3000 Degasser,
Column: ZORBAX RRHD SB-C8, 2.1 x 50 mm, 1.8 μm (Agilent, 857700-906)
Column temp: 30.0 °C
Solvent system: Mobile phase A: 10 mM ammonium formate, 0.01% (v/v) formic acid in Milli-Q® water.
Mobile phase B: 0.01% (v/v) formic acid in acetonitrile.
Gradient from 90% A to 100% B
Flow rate: 0.25 mL/min
Sample prep: 2 mg/mL in MeOH with trace of formic acid
Injection volume: 10 L
Ionisation mode: Electrospray positive ion
Capillary voltage: 4.5 kV
Capillary temp: 360ºC Desolvation gas temperature: 300 ºC
Cone gas flow rate: 10 (arbitrary unit) Desolvation gas flow rate: 70 (arbitrary unit)
The retention time of daclatasvir is reported along with the major peak in the mass spectrum. The latter is reported as a mass/charge ratio.
9.98 min: 739.39545 (M+H+) m/z
HS-GC-MS: Instrument: Agilent 6890/5973/G1888
Column: DB-624, 30 m x 0.25 mm I.D. x 1.4 μm
Program: 50 C (5 min), 7 C/min to 120 C, 15 °C/min to 220 °C (8.3 min)
Injector: 150 C Transfer line temp: 280 C
Carrier: Helium, 1.2 mL/min Split ratio: 50/1
Solvents detected: Ethyl acetate
TLC: Conditions: Kieselgel 60F254. Ethyl acetate : methanol (95/5)
Single spot observed, Rf = 0.18. Visualisation with UV at 254 nm
The TLC was performed on the liberated free base.
IR: Instrument: Bruker Alpha FT-IR
Range: 4000-400 cm-1, neat
Peaks: 1723, 1697, 1643, 1523, 1439, 1235, 1099, 1024 cm-1
1H NMR: Instrument: Bruker Avance III 500
Field strength: 500 MHz Solvent: DMSO-d6 (2.50 ppm)
Spectral data: 0.77 (6H, d, J = 6.7 Hz), 0.83 (6H, d, J = 6.7 Hz), 2.01 (2H, m), 2.07 (2H, m), 2.12-2.27 (4H, m), 2.38 (2H, m), 3.54 (6H, s), 3.84 (2H, m), 3.97 (2H, m), 4.12 (2H, t, J = 7.7 Hz), 5.18 (2H, t, J = 7.0 Hz), 7.31 (2 N-H, d, J = 8.5 Hz), 7.94 (4H, d, J = 8.4 Hz), 7.99 (4H, d, J = 8.4 Hz), 8.16 (2H, s) ppm
Ethyl acetate estimated at 0.6% mass fraction was observed in the 1H NMR
13C NMR: Instrument: Bruker Avance III 500
Field strength: 126 MHz Solvent: DMSO-d6 (39.5 ppm)
Spectral data: 17.8, 19.6, 25.0, 29.0, 31.2, 47.3, 51.6, 52.9, 58.0, 115.1, 125.9, 126.6, 127.3, 131.8, 139.2, 149.4, 157.0, 171.1 ppm
Melting point: > 250 oC
Microanalysis: Found: C = 59.0%; H = 6.5%; N = 13.7% (August 2015)
Calc: C = 59.2%; H = 6.5%; N = 13.8% (Calculated for C40H50N8O6.2HCl)
REFERENCE
Australian NMI NATA Certification Daclatasvir – FixHepC
https://fixhepc.com/images/coa/NMI-NATA-Daclatasvir-Certification.pdf
Oct 7, 2015 – Compound Name: Daclatasvir dihydrochloride … Note: The assigned stereochemistry of this sample of daclatasvir has not …. Melting point:.
CLIP 2
Full Text Article – European Journal of Pharmaceutical and Medical …
Nov 28, 2016 – Daclatasvir dihydrochloride (DCLD) is a new drug …. DSC thermogram of daclatasvirdihydrochloriderealed drug melting point at 273.600C as …
CLIP 3
DCV dihydrochloride (anhydrous) is a white to yellow, non hygroscopic powder which is highly soluble in water (>700mg/mL). Solubility is higher at low pH. In aqueous buffers over the physiological pH range (pH 1.2-6.8) solubility is very low (4mg/mL to 0.004 mg/mL) due to the slow formation of the less soluble hydrated form. Water content in the drug substance is adequately controlled by in process tests. The desired anhydrous crystalline form of DCV dihydrochloride (N-2) is consistently produced and has been shown to not change on storage.
[DOC]AusPAR Daclatasvir dihydrochloride – Therapeutic Goods Administration
https://www.tga.gov.au/sites/default/…/auspar-daclatasvir–dihydrochloride-151214.do…
Dec 14, 2015 – Australian Public Assessment Report for daclatasvir dihydrochloride …. Figure 1:Chemical structure of daclatasvir dihydrochloride. …… 24 weeks is based on a selected literaturereview mostly of studies in patients with GT-1.
CLIP 4
The structure of the active substance has been confirmed by UV, IR, Raman and 1 H and 13C NMR spectroscopy, MS spectrometry, and crystal X-Ray diffraction.
Daclatasvir is a white to yellow crystalline non-hygroscopic powder. It is freely soluble in water, dimethyl sulfoxide, methanol; soluble in ethanol (95%); practically insoluble in dichloromethane, tetrahydrofuran, acetonitrile, acetone and ethyl acetate.
Daclatasvir is a chiral molecule with four stereocenters (1,1’, 2, 2;) in the S configuration. The synthetic strategy and process design such as starting material and reagent selection, process parameters, and in-process controls ensure the desired configuration at each of the four chiral centers. In addition, the established control strategy minimizes epimerization and eliminates other diastereomeric impurity formation in each step.
Polymorphism has been observed for daclatasvir hydrochloride. Although two neat crystalline dihydrochloride salts, N1 and N-2 have been identified in screening studies, it has been confirmed that the form N-2 is the thermodynamically most stable polymorph and only this form produced by the proposed synthetic process.
Manufacture, characterisation and process controls
Daclatasvir dihydrochloride is synthesised in three main steps using three commercially available well defined starting materials with acceptable specifications. The synthesis involves an alkylation and formation of the imidazole ring, a coupling reaction and the formation of the hydrochloride salt.
As mentioned above, the synthetic process has been designed to ensure the correct configuration at each of the four chiral centres is achieved. In addition, it has been demonstrated that the stereogenic centres do not epimerize during normal or stressed processing conditions.
The manufacturing process has been developed using a combination of conventional univariate studies and elements of QbD such as risk assessment.
The characterisation of the active substance and its impurities are in accordance with the EU guideline on chemistry of new active substances. Potential and actual impurities were well discussed with regards to their origin and characterised. Adequate in-process controls are applied during the synthesis. The specifications and control methods for intermediate products, starting materials and reagents have been presented.
The active substance specification includes tests for: appearance, colour, identity (IR/Raman, HPLC), assay (HPLC), impurities (HPLC), residual solvents (GC), HCl content (titration), total inorganic impurities (ICP-MS), and particle size (laser light scattering). The absence of a test for chiral purity in the active substance specification has been adequately justified based on the stereochemical control during the synthetic process and demonstration that there is no epimerization during normal or stressed processing conditions. Similarly, since the N-2 form of daclatasvir hydrochloride is the thermodynamically most stable polymorph and, is consistently produced by the synthetic process and remained unchanged during storage under long-term or accelerated conditions, this parameter is not included in the specification
CLIP5
SEE
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206843Orig1s000ChemR.pdf
CLIP6
Daclatasvir dihydrochloride
References
- 1 Statement on a Nonproprietary Name Adopted by the USAN Council
- 2 Gao, Min; Nettles, Richard E.; Belema, Makonen; Snyder, Lawrence B.; Nguyen, Van N.; Fridell, Robert A.; Serrano-Wu, Michael H.; Langley, David R.; Sun, Jin-Hua; O’Boyle, Donald R., II; Lemm, Julie A.; Wang, Chunfu; Knipe, Jay O.; Chien, Caly; Colonno, Richard J.; Grasela, Dennis M.; Meanwell, Nicholas A.; Hamann, Lawrence G. (2010). “Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect”. Nature 465 (7294): 96–100. doi:10.1038/nature08960. PMID 20410884.
- 3 Bell, Thomas W. (2010). “Drugs for hepatitis C: unlocking a new mechanism of action”. ChemMedChem 5 (10): 1663–1665. doi:10.1002/cmdc.201000334. PMID 20821796.
- 4 Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Guedj, J et al. Proceedings of the National Academy of Sciences. February 19, 2013.
- 5 AASLD: Daclatasvir with Pegylated Interferon/Ribavirin Produces High Rates of HCV Suppression. Highleyman, L. HIVandHepatitis.com. 6 December 2011.
- 6Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1. Lok, A et al. New England Journal of Medicine. 366(3):216-224. January 19, 2012.
- 7“Bristol-Myers’ Daclatasvir, Asunaprevir Cured 77%: Study”. Bloomberg. Apr 19, 2012.
- 8AASLD: Daclatasvir plus Asunaprevir Rapidly Suppresses HCV in Prior Null Responders. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
- 9High rate of response to BMS HCV drugs in harder-to-treat patients – but interferon-free prospects differ by sub-genotype. Alcorn, K. Aidsmap.com. 12 November 2012.
- 10AASLD 2012: Sofosbuvir + Daclatasvir Dual Regimen Cures Most Patients with HCV Genotypes 1, 2, or 3. Highleyman, L. HIVandHepatitis.com. 15 November 2012.
- 11Mark Sulkowski et al. (January 16, 2014). “Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection”. New England Journal of Medicine. doi:10.1056/NEJMoa1306218.
- 12“www.who.int” (PDF).
| WO2004005264A2 * | 7 Jul 2003 | 15 Jan 2004 | Axxima Pharmaceuticals Ag | Imidazole compounds for the treatment of hepatitis c virus infections |
| WO2008021927A2 * | 9 Aug 2007 | 21 Feb 2008 | Squibb Bristol Myers Co | Hepatitis c virus inhibitors |
| WO2008021928A2 * | 9 Aug 2007 | 21 Feb 2008 | Squibb Bristol Myers Co | Hepatitis c virus inhibitors |
| WO2008021936A2 * | 9 Aug 2007 | 21 Feb 2008 | Squibb Bristol Myers Co | Hepatitis c virus inhibitors |
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FDA Approves Olysio (simeprevir) for Hepatitis C Virus
Simeprevir
Inhibits HCV NS3/4A protease.
MEDIVIR … originator
launched 2013
923604-59-5 CAS
C38H47N5O7S MF
749.93908 MW
IUPAC standard name
(1R, 4R, 6S, 15R, 17R)-N-(cyclopropanesulfonyl) -17 – ({7-methoxy-8-methyl-2-[4 – (propan-2-yl) -1,3-thiazol-2 -yl] quinolin-4-yl} oxy)-13-methyl-2 ,14-dioxo-3 ,13-diazatricyclo [13.3.0.0 4 , 6 ] octadec-7-ene-4-carboxamide
IUPAC traditional name
(1R, 4R, 6S, 15R, 17R)-N-(cyclopropanesulfonyl) -17 – {[2 – (4-isopropyl-1 ,3-thiazol-2-yl)-7-methoxy-8-methylquinolin-4- yl] oxy}-13-methyl-2 ,14-dioxo-3 ,13-diazatricyclo [13.3.0.0 4 , 6 ] octadec-7-ene-4-carboxamide
- Olysio
- Simeprevir
- TMC 435
- TMC 435350
- TMC-435
- TMC435
- TMC435350
- UNII-9WS5RD66HZ
November 22, 2013 — The U.S. Food and Drug Administration approved Olysio (simeprevir), a new therapy to treat chronic hepatitis C virus infection.
OLYSIO™ is the first once-daily protease inhibitor approved for the treatment of chronic hepatitis C in a combination antiviral regimen for adults with compensated liver disease
Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with the hepatitis C virus have no symptoms of the disease until liver damage becomes apparent, which may take several years. Most of these people then go on to develop chronic hepatitis C. Some will also develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with the hepatitis C virus
Hepatitis C virus (HCV) infections affect approximately 3 percent of the worldwide population and often lead to cirrhosis and hepatocellular carcinoma. The standard therapy of pegylated- interferon and ribavirin induces serious side effects and provides viral eradication in less than 50% of patients. Combination therapy of HCV including ribavirin and interferonare currently is the approved therapy for HCV. Unfortunately, such combination therapy also produces side effects and is often poorly tolerated, resulting in major clinical challenges in a significant proportion of patients. Numerous direct acting agents (DAAs) have been or are being developed for treatment of HCV, such as telaprevir and boceprevir (both received MA approved in 2011 for use with interferon and ribavirin based therapy), however direct acting agents are linked to increased toxicity of treatment, the emergence of resistance, and to date do not provide a standard of care which is interferon free. The combination of direct acting agents can also result in drug-drug interactions. To date, no HCV therapy has been approved which is interferon free. There is therefore a need for new combination therapies which have reduced side effects, and interferon free, have a reduced emergence of resistance, reduced treatment periods and/or and enhanced cure rates.
Simeprevir (formerly TMC435) is an experimental drug candidate for the treatment of hepatitis C. It is being developed byMedivir and Johnson & Johnson‘s pharmaceutical division Janssen Pharmaceutica and is currently in Phase III clinical trials.[1]
Simeprevir is a hepatitis C virus protease inhibitor.[2]
Simeprevir is being tested in combination regimens with pegylated interferon alfa-2a and ribavirin,[3] and in interferon-free regimens with other direct-acting antiviral agents including daclatasvir[4] and sofosbuvir [5]
Simeprevir has been launched in 2013 in Japan by Janssen Pharmaceutical (JP) for use in combination with pegylated interferon (Peg-IFN) and ribavirin for the treatment of genotype 1 chronic hepatitis C virus (HCV) patients who are treatment naïve, prior non responders or relapsed following treatment with Peg-IFN with or without ribavirin. In 2013, the product has also been approved in the U.S. by Medivir and Janssen R&D Ireland for the oral treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non-pegylated) with ribavirin.
The drug candidate was originally developed at Medivir, which was acquired by Janssen R&D Ireland in 2012. In November 2004, Medivir entered into a license and research collaboration agreement with Tibotec, a Johnson & Johnson subsidiary, for the discovery and development of orally active protease inhibitors of the NS3/4A protease of HCV. In 2011, a codevelopment agreement between Pharmasset (now Gilead Sciences) and Tibotec was signed for the treatment of chronic hepatitis C (HCV) in combination with PSI-7977. Also in 2011, fast track designation was received in the U.S. for the treatment of chronic hepatitis C (CHC) genotype-1 infection.
In 2011, Tibotec Therapeutics, Division of Centocor Ortho Biotech Products, L.P. announced that it had changed its name to Janssen Therapeutics, Division of Janssen Products, LP.
“Hepatitis C is a complex disease and Janssen is committed to working with the HCV community, caregivers, and health care systems to address this global epidemic,” said Gaston Picchio, Hepatitis Disease Area Leader, Janssen Research & Development. “We are pleased that the FDA has granted simeprevir Priority Review, as it is a significant step forward in making this therapy available to physicians and their hepatitis C patients.”
Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide.
Following initial acute infection, a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytopathic. Chronic hepatitis can progress to liver fibrosis leading to cirrhosis, end- stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations. This and the number of patients involved, has made HCV the focus of considerable medical research. Replication of the genome of HCV is mediated by a number of enzymes, amongst which is HCV NS3 serine protease and its associated cofactor, NS4A. NS3 serine protease is considered to be essential for viral replication and has become an attractive target for drug discovery.
Current anti-HCV therapy is based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. Not only does this therapy result in a limited efficacy in that only part of the patients are treated successfully, but it also faces significant side effects and is poorly tolerated in many patients. Hence there is a need for further HCV inhibitors that overcome the disadvantages of current HCV therapy such as side effects, limited efficacy, poor tolerance, the emergence of resistance, as well as compliance failures.
Various agents have been described that inhibit HCV NS3 serine protease. WO05/073195 discloses linear and macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 with a central cyclopentyl moiety. Amongst these, the macrocyclic derivatives are attractive by overcoming one or more of the disadvantages of current anti-HCV therapy
(I) simeprevir
The compound of formula (I) is an inhibitor of the Hepatitis C virus (HCV) serine protease and is described in WO 2007/014926, published on 8 February 2007. This compound overcomes several of the disadvantages of current anti-HCV therapy and in particular shows pronounced activity against HCV, has an attractive pharmacokinetic profile, and is well-tolerated. Following the synthesis procedure described in Example 5 of WO 2007/014926, an amorphous solid form is obtained.
It now has been found that the compound of formula (I) can be converted into crystalline forms, which can advantageously be used as active ingredients in anti-HCV therapy. To that purpose, these crystalline forms are converted into pharmaceutical formulations.
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SIMEPREVIR
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OLYSIO (simeprevir) is an inhibitor of the HCV NS3/4A protease.
The chemical name for simeprevir is (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2[[2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy]-5-methyl-4,14-dioxo2,3,3a,4,5,6,7,8,9,11a,12,13,14,14atetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide. Its molecular formula is C38H47N5O7S2 and its molecular weight is 749.94. Simeprevir has the following structural formula:
 |
Simeprevir drug substance is a white to almost white powder. Simeprevir is practically insoluble in water over a wide pH range. It is practically insoluble in propylene glycol, very slightly soluble in ethanol, and slightly soluble inacetone. It is soluble in dichloromethane and freely soluble in some organic solvents (e.g., tetrahydrofuran and N,N-dimethylformamide).
OLYSIO (simeprevir) for oral administration is available as 150 mg strength hard gelatin capsules. Each capsule contains 154.4 mg of simeprevir sodium salt, which is equivalent to 150 mg of simeprevir. OLYSIO (simeprevir) capsules contain the following inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate and sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904).
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Synthesis
Example 1 : preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl- quinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[ 13.3.0.04‘6]octadec-7-ene- 4-carboxylic acid (16)
Synthesis of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (6) Step 1 : synthesis of Λ/-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline (2)
1 2
Triethylamine (42.4 mL, 302 mmol) was added to a suspension of 3-methoxy-2- methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 mL). A clear solution was obtained. Then, dppa (65.4 mL, 302 mmol) in toluene (100 mL) was slowly added. After 1 h at room temperature, the reaction mixture was successively heated at 500C for 0.5 h, at 700C for 0.5 h then at 1000C for 1 h. To this solution, t-BuOH (30.5 g, 411 mmol) in toluene (40 mL) was added at 1000C and the resulting mixture was refluxed for 7h. The solution was cooled to room temperature then successively washed with water, 0.5 N HCl, 0.5 N NaOH and brine, dried (Na2SO4), and evaporated to give 67 g of the target product: m/z = 237 (M)+.
_2: synthesis of 3-methoxy-2-methylaniline (3)
TFA (40.7 mL, 548 mmol) was added to a solution of jV-(teτt-butyloxycarbonyl)- 3-methoxy-2-methylaniline, in dichloro methane (500 mL). After 2 h at room temperature, TFA (40.7 mL, 548 mmol) was added and the resulting mixture was stirred at room temperature overnight. Then, volatiles were evaporated. The residue was triturated with toluene (100 mL) and diisopropylether (250 mL), filtered off and washed with diisopropyl ether (100 mL) to give 56.3 g of the title product as a TFA salt: m/z = 138 (M+H)+. The TFA salt was transformed to the free aniline by treatment with NaHCO3.
Step 3: synthesis of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (4)
A solution Of BCl3 (1.0 M, 200 mL, 200 mmol) in CH2Cl2 was slowly added under nitrogen to a solution of 3-methoxy-2-methylaniline (26.0 g, 190 mmol) in xylene (400 mL). The temperature was monitored during the addition and was kept below 100C. The reaction mixture was stirred at 5°C for 0.5 h. Then, dry acetonitrile (13 mL, 246 mmol) was added at 5°C. After 0.5 h at 5°C, the solution was transferred into a dropping funnel and slowly added at 5°C to a suspension OfAlCl3 (26.7 g, 200 mmol) in CH2Cl2 (150 mL). After 45 min at 5°C, the reaction mixture was heated at 700C under a nitrogen stream. After evaporation Of CH2Cl2, the temperature of the reaction mixture reached 65°C. After 12 h at 65°C, the reaction mixture was cooled at 00C, poured onto ice (300 g), and slowly heated to reflux for 7h. After 2 days at room temperature, 6 N NaOH (50 mL) was added. The pH of the resulting solution was 2-3. The xylene layer was decanted. The organic layer was extracted with CH2Cl2. The xylene and CH2Cl2 layers were combined, successively washed with water, IN NaOH, and brine, dried (Na2SO4) and evaporated. The residue was triturated in diisopropyl ether at O0C, filtered off and washed with diisopropylether to give 13.6 g (40 %) of the title product as a yellowish solid: m/z = 180 (M+H)+.
Step 4: synthesis of 2′-[[(4-isopropylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3 ‘- methylacetophenone (5)
A solution of the compound 4 (18.6 g, 104 mmol) in dioxane (50 rnL) was added under nitrogen to a suspension of 4-isopropylthiazole-2-carbonyl chloride in dioxane (250 rnL). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution of NaHCOs and AcOEt, organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was triturated in diisopropyl ether, filtered off and washed with diisopropyl ether to give 30.8 g (90 %) of the title product 5.
Step 5: synthesis of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinoline (6)
Potassium tert-butoxide (21.8 g, 195 mmol) was added to a suspension of the compound 5 (30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixtures was heated at 1000C overnight. Then, the reaction mixture was cooled at room temperature and diluted with ether (100 mL). The precipitate was filtered off and washed with Et2O to give a powder (fraction A). The mother liquor was concentrated in vacuo, triturated in ether, filtered off, and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 mL). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with HCl IN. The precipitate was filtered off, washed with water and dried. Then, the solid was triturated in diisopropyl ether, fϊltered off and dried to give 26 g (88%) of the compound 6 as a brownish solid: m/z = 315 (M+H)+.
Synthesis of (hex-5-enyl)(methyl)amine (8)
O CF,
FX N Br’ N O NH
H 7
(a) Sodium hydride (1.05 eq) was slowly added at 00C to a solution of JV-methyl- trifluoro-acetamide (25 g) in DMF (140 mL). The mixture was stirred for Ih at room temperature under nitrogen. Then, a solution of bromohexene (32,1 g) in DMF
(25 mL) was added dropwise and the mixture was heated to 700C for 12 hours. The reaction mixture was poured on water (200 mL) and extracted with ether (4 x 50 mL), dried (MgSO4), filtered and evaporated to give 35 g of the target product 7 as a yellowish oil which was used without further purification in the next step.
(b) A solution of KOH (187.7 g) in water (130 mL) was added dropwise to a solution of 7 (35 g) in methanol (200 mL). The mixture was stirred at room temperature for
12 hours. Then, the reaction mixture was poured on water (100 mL) and extracted with ether (4 x 50 mL), dried (MgSO4), filtered and the ether was distilled under atmospheric pressure. The resulting oil was purified by distillation under vacuum (13 mm Hg pressure, 500C) to give 7,4 g (34 %) of the title product 8 as a colourless oil: 1H-NMR (CDCl3): δ 5.8 (m, IH), 5 (ddd, J = Yl 2 Hz, 3.5 Hz, 1.8 Hz, IH), 4.95 (m, IH), 2.5 (t, J = 7.0 Hz, 2H), 2.43 (s, 3H), 2.08 (q, J= 7.0 Hz, 2H), 1.4 (m, 4H), 1.3 (br s, IH).
Preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxyl- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[ 13.3.0.04‘6loctadec-7-ene-4-carboxylic acid (16)
3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid 9 (500 mg, 3.2 mmol) in 4 mL DMF was added at 00C to HATU (1.34 g, 3.52 mmol) and JV-methylhex-5-enylamine (435 mg, 3.84 mmol) in DMF (3 mL), followed by DIPEA. After stirring for 40 min at 00C, the mixture was stirred at room temperature for 5 h. Then, the solvent was evaporated, the residue dissolved in EtOAc (70 rnL) and washed with saturated NaHCOs (IO mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated NaCl (20 mL), dried (Na2SO4), and evaporated. Purification by flash chromatography (EtO Ac/petroleum ether, 2:1) afforded 550 mg (68%) of the target product 10 as a colorless oil: m/z = 252 (M+H)+.
A solution of LiOH (105 mg in 4 mlof water) was added at 00C to the lactone amide 10. After Ih, the conversion was completed (HPLC). The mixture was acidified to pH 2 – 3 with IN HCl, extracted with AcOEt, dried (MgSO4), evaporated, co-evaporated with toluene several times, and dried under high vacuum overnight to give 520 mg (88%) of the target product 11: m/z = 270 (M+H)+.
The l-(amino)-2-(vinyl)cyclopropanecarboxylic acid ethyl ester hydrochloride 12
(4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added to 11 (8.14 g,
30.2 mmol). The mixture was cooled in an ice bath under argon, and then DMF (100 mL) and DIPEA (12.5 mL, 11.5 mmol) were successively added. After 30 min at 00C, the solution was stirred at room temperature for an additional 3 h. Then, the reaction mixture was partitioned between EtOAc and water, washed successively with 0.5 N HCl (20 mL) and saturated NaCl (2 x 20 mL), and dried (Na2SO4). Purification by flash chromatography (AcOEt/CH2Cl2/Petroleum ether, 1 :1 :1) afforded 7.41 g (60%) of the target product 13 as a colorless oil: m/z = 407 (M+H)+.
DIAD (1.02 niL, 5.17 mmol) was added at -15°C under nitrogen atmosphere to a solution of 13 (1.5 g, 3.69 mmol), quinoline 6 (1.39 g, 4.43 mmol) and triphenyl- phosphine (1.26 g, 4.80 mmol) in dry THF (40 mL). After 4.5 h, at -15°C, the reaction mixture was partitioned between ice-cold water and AcOEt, dried (Na2SO4) and evaporated. The crude material was purified by flash column chromatography (gradient of petroleum AcOEt/CH2Cl2, 1 :9 to 2:8) to give 1.45 g (56 %) of the target product 14: m/z = 703 (M+H)+.
A solution of 14 (1.07 g, 1.524 mmol) and Hoveyda-Grubbs 1st generation catalyst (33 mg, 0.03 eq) in dried and degassed 1 ,2-dichloroethane (900 mL) was heated at 75°C under nitrogen for 12 h. Then, the solvent was evaporated and the residue purified by silica gel chromatography (25% EtOAc in CH2Cl2). 620 mg (60%) of pure macrocycle 15 were obtained, m/z = 674 (M+H)+. 1H NMR (CDCl3): 1.18-1.39 (m, 12H), 1.59 (m, IH), 1.70-2.08 (m, 5H), 2.28 (m, IH), 2.38 (m, IH), 2.62 (m, 2H), 2.68 (s, 3H), 2.83 (m, IH), 3.06 (s, 3H), 3.19 (sept, J= 6.7 Hz, IH), 3.36 (m, IH), 3.83 (m, IH), 3.97 (s, 3H), 4.09 (m, 2H), 4.65 (td, J= 4 Hz, 14 Hz, IH), 5.19 (dd, J= 4 Hz,
10 Hz, IH), 5.31 (m, IH), 5.65 (td, J= 4 Hz, 8 Hz, IH), 7.00 (s, IH), 7.18 (s, IH), 7.46
(d, J= 9 Hz, IH), 7.48 (s, IH), 8.03 (d, J= 9 Hz, IH).
A solution of lithium hydroxide (1.65 g, 38.53 mmol) in water (15 rnL) was added to a stirred solution of ester 15 (620 mg, 0.920 mmol) in THF (30 mL) and MeOH (20 mL). After 16 h at room temperature, the reaction mixture was quenched with NH4Cl sat., concentrated under reduced pressure, acidified to pH 3 with HCl IN and extracted with CH2Cl2, dried (MgSO4) and evaporated to give 560 mg (88%) of carboxylic acid 16. m/z = 647 (M+H)+. 1H NMR (CDCl3): 1.11-1.40 (m, 8H), 1.42-1.57 (m, 2H), 1.74 (m, 2H), 1.88-2.00 (m, 2H), 2.13 (m, IH), 2.28 (m, IH), 2.40 (m, IH), 2.59 (m, 2H), 2.67 (s, 3H), 2.81 (m, IH), 2.97 (s, 3H), 3.19 (m, IH), 3.31 (m, IH), 3.71 (m, IH), 3.96 (s, 3H), 4.56 (dt, J= 4 Hz, 12 Hz, IH), 5.23 (m, 2H), 5.66 (m, IH), 7.01 (s, IH), 7.10 (s, IH), 7.22 (d, J= IO Hz, IH), 7.45 (s, IH), 8.00 (d, J= 10 Hz, IH).
Example 2: Preparation of Λ/-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl- quinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[ 13.3.0.04‘6]octadec-7-ene- 4-carbonyll(cvclopropyl)sulfonamide (17) SIMEPREVIR
A solution of the compound 16 (560mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 500C for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 17, which is the compound of formula (I) SIMEPREVIR , as a white powder: m/z = 750 (M+H)+.
1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, IH), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, IH), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J= 13 Hz, IH), 5.04 (t, J= 11 Hz, IH), 5.37 (m, IH), 5.66 (m, IH), 6.21 (s, IH), 7.02 (s, IH), 7.22 (d, J= IO Hz, IH), 7.45 (s, IH), 7.99 (d, J= 10 Hz, IH), 10.82 (broad s, IH).
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SYNTHESIS
Example 4: preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl- quinolin-4-yloxy] – 13 -methyl-2, 14-dioxo-3 , 13 -diazatricyclo[ 13.3.0.04‘6]octadec-7-ene- 4-carboxylic acid (46) FREE ACID
Synthesis of 4-hvdroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (36) Step 1: synthesis of iV-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline (32)
31 32
Triethylamine (42.4 mL, 302 mmol) was added to a suspension of 3-methoxy-2- methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 mL). A clear solution was obtained. Then, dppa (65.4 mL, 302 mmol) in toluene (100 mL) was slowly added. After 1 h at room temperature, the reaction mixture was successively heated at 50°C for 0.5 h, at 70°C for 0.5 h then at 100°C for 1 h. To this solution, t-BuOH (30.5 g, 411 mmol) in toluene (40 mL) was added at 100°C and the resulting mixture was refluxed for 7h. The solution was cooled to room temperature then successively washed with water, 0.5 N HCl, 0.5 N NaOH and brine, dried (Na2SO4), and evaporated to give 67 g of the target product: m/z = 237 (M)+.
Step 2: synthesis of 3-methoxy-2-methylaniline (33)
TFA (40.7 mL, 548 mmol) was added to a solution of iV-(tert-butyloxycarbonyl)-3- methoxy-2-methylaniline, in dichloromethane (500 mL). After 2 h at room temperature, TFA (40.7 mL, 548 mmol) was added and the resulting mixture was stirred at room temperature overnight. Then, volatiles were evaporated. The residue was triturated with toluene (100 mL) and diisopropylether (250 mL), filtered off and washed with diisopropyl ether (100 mL) to give 56.3 g of the title product as a TFA salt: m/z = 138 (M+H)+. The TFA salt was transformed to the free aniline by treatment with NaHCO3.
Step 3: synthesis of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (34)
A solution OfBCl3 (1.0 M, 200 mL, 200 mmol) in CH2Cl2 was slowly added under nitrogen to a solution of 3-methoxy-2-methylaniline (26.0 g, 190 mmol) in xylene (400 mL). The temperature was monitored during the addition and was kept below 10°C. The reaction mixture was stirred at 5°C for 0.5 h. Then, dry acetonitrile (13 mL, 246 mmol) was added at 5°C. After 0.5 h at 5°C, the solution was transferred into a dropping funnel and slowly added at 5°C to a suspension OfAlCl3 (26.7 g, 200 mmol) in CH2Cl2 (150 mL). After 45 min at 5°C, the reaction mixture was heated at 70°C under a nitrogen stream. After evaporation Of CH2Cl2, the temperature of the reaction mixture reached 65°C. After 12 h at 65°C, the reaction mixture was cooled at 0°C, poured onto ice (300 g), and slowly heated to reflux for 7h. After 2 days at room temperature, 6 N NaOH (50 mL) was added. The pH of the resulting solution was 2-3. The xylene layer was decanted. The organic layer was extracted with CH2Cl2. The xylene and CH2Cl2 layers were combined, successively washed with water, IN NaOH, and brine, dried (Na2SO4) and evaporated. The residue was triturated in diisopropyl ether at O0C, filtered off and washed with diisopropylether to give 13.6 g (40 %) of the title product as a yellowish solid: m/z = 180 (M+H)+.
Step 4: synthesis of 2′-[[(4-isopropylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3 ‘- methylacetophenone (35)
A solution of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (18.6 g, 104 mmol) in dioxane (50 mL) was added under nitrogen to a suspension of 4-isopropylthiazole-2- carbonyl chloride in dioxane (250 mL). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution OfNaHCO3and AcOEt, organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was triturated in diisopropyl ether, filtered off and washed with diisopropyl ether to give 30.8 g (90 %) of the title product 35.
Step 5: synthesis of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinoline (36)
Potassium tert-butoxide (21.8 g, 195 mmol) was added to a suspension of 2′-[[(4-iso- propylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3′-methylacetophenone (35, 30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixtures was heated at 100°C overnight. Then, the reaction mixture was cooled at room temperature and diluted with ether (100 mL). The precipitate was filtered off and washed with Et2O to give a powder (fraction A). The mother liquor was concentrated in vacuo, triturated in ether, filtered off, and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 mL). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with HCl IN. The precipitate was filtered off, washed with water and dried. Then, the solid was triturated in diisopropyl ether, filtered off and dried to give 26 g (88%) of the title product 36 as a brownish solid: m/z = 315 (M+H)+.
Synthesis of (hex-5-enyl)(methyl)amine (38)
Sodium hydride (1.05 eq) was slowly added at 0°C to a solution of iV-methyltrifluoro- acetamide (25 g) in DMF (140 mL). The mixture was stirred for Ih at room temperature under nitrogen. Then, a solution of bromohexene (32,1 g) in DMF (25 mL) was added dropwise and the mixture was heated to 70°C for 12 hours. The reaction mixture was poured on water (200 mL) and extracted with ether (4 x 50 mL), dried (MgSO4), filtered and evaporated to give 35 g of the target product 37 as a yellowish oil which was used without further purification in the next step.
Step B:
A solution of potassium hydroxide (187.7 g) in water (130 mL) was added dropwise to a solution of 37 (35 g) in methanol (200 mL). The mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was poured on water (100 mL) and extracted with ether (4 x 50 mL), dried (MgSO4), filtered and the ether was distilled under atmospheric pressure. The resulting oil was purified by distillation under vacuum (13 mm Hg pressure, 50°C) to give 7,4 g (34 %) of the title product 38 as a colourless oil: 1H-NMR (CDCl3): δ 5.8 (m, IH), 5 (ddd, J= 17.2 Hz, 3.5 Hz, 1.8 Hz, IH), 4.95 (m, IH), 2.5 (t, J= 7.0 Hz, 2H), 2.43 (s, 3H), 2.08 (q, J= 7.0 Hz, 2H), 1.4 (m, 4H), 1.3 (br s, IH).
Preparation of 17-r2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxyl-
13-methyl-2,14-dioxo-3,13-diazatricvclori3.3.0.04‘6loctadec-7-ene-4-carboxylic acid
£46}
3-Oxo-2-oxa-bicyclo[2.2.1]heptane-5-carboxylic acid 39 (500 mg, 3.2 mmol) in 4 mlDMF was added at 0°C to HATU (1.34 g, 3.52 mmol) and iV-methylhex-5- enylamine (435 mg, 3.84 mmol) in DMF (3 mL), followed by DIPEA. After stirring for 40 min at 0°C, the mixture was stirred at room temperature for 5 h. Then, the solvent was evaporated, the residue dissolved in EtOAc (70 mL) and washed with saturated NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated NaCl (20 mL), dried (Na2SO4), and evaporated. Purification by flash chromatography (EtOAc/petroleum ether, 2:1) afforded 550 mg (68%) of the target product 40 as a colorless oil: m/z = 252 (M+H)+.
A solution of LiOH (105 mg in 4 mlof water) was added at 0°C to the lactone amide 40. After Ih, the conversion was completed (HPLC). The mixture was acidified to pH 2 – 3 with IN HCl, extracted with AcOEt, dried (MgSO4), evaporated, co-evaporated with toluene several times, and dried under high vacuum overnight to give 520 mg (88%) of the target product 41: m/z = 270 (M+H)+.
The l-(amino)-2-(vinyl)cyclopropanecarboxylic acid ethyl ester hydrochloride 42 (4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added to 41 (8.14 g, 30.2 mmol). The mixture was cooled in an ice bath under argon, and then DMF (100 mL) and DIPEA (12.5 mL, 11.5 mmol) were successively added. After 30 min at 0°C, the solution was stirred at room temperature for an additional 3 h. Then, the reaction mixture was partitioned between EtOAc and water, washed successively with 0.5 N HCl (20 mL) and saturated NaCl (2 x 20 mL), and dried (Na2SO4). Purification by flash chromatography (AcOEt/CH2Cl2/Petroleum ether, 1:1:1) afforded 7.41 g (60%) of the target product 43 as a colorless oil: m/z = 407 (M+H)+.
DIAD (1.02 mL, 5.17 mmol) was added at -15°C under nitrogen atmosphere to a solution of 43 (1.5 g, 3.69 mmol), quinoline 36 (1.39 g, 4.43 mmol) and triphenyl- phosphine (1.26 g, 4.80 mmol) in dry THF (40 mL). After 4.5 h, at -15°C, the reaction mixture was partitioned between ice-cold water and AcOEt, dried (Na2SO4) and evaporated. The crude material was purified by flash column chromatography (gradient of petroleum AcOEt/CH2Cl2, 1 :9 to 2:8) to give 1.45 g (56 %) of the target product 44: m/z = 703 (M+H)+.
A solution of 44 (1.07 g, 1.524 mmol) and Hoveyda-Grubbs 1st generation catalyst (33 mg, 0.03 eq) in dried and degassed 1,2-dichloroethane (900 mL) was heated at 75°C under nitrogen for 12 h. Then, the solvent was evaporated and the residue purified by silica gel chromatography (25% EtOAc in CH2Cl2). 620 mg (60%) of pure macrocycle 45 were obtained, m/z = 674 (M+H)+. 1H NMR (CDCl3): 1.18-1.39 (m, 12H), 1.59 (m, IH), 1.70-2.08 (m, 5H), 2.28 (m, IH), 2.38 (m, IH), 2.62 (m, 2H), 2.68 (s, 3H), 2.83 (m, IH), 3.06 (s, 3H), 3.19 (sept, J= 6.7 Hz, IH), 3.36 (m, IH), 3.83 (m, IH), 3.97 (s, 3H), 4.09 (m, 2H), 4.65 (td, J= 4 Hz, 14 Hz, IH), 5.19 (dd, J= 4 Hz, 10 Hz, IH), 5.31 (m, IH), 5.65 (td, J= 4 Hz, 8 Hz, IH), 7.00 (s, IH), 7.18 (s, IH), 7.46 (d, J= 9 Hz, IH), 7.48 (s, IH), 8.03 (d, J= 9 Hz, IH).
Step F
A solution of lithium hydroxide (1.65 g, 38.53 mmol) in water (15 mL) was added to a stirred solution of ester 45 (620 mg, 0.920 mmol) in THF (30 mL) and MeOH (20 mL). After 16 h at room temperature, the reaction mixture was quenched with NH4Cl sat., concentrated under reduced pressure, acidified to pH 3 with HCl IN and extracted with CH2Cl2, dried (MgSO4) and evaporated to give 560 mg (88%) of carboxylic acid 46. m/z = 647 (M+H)+. 1H NMR (CDCl3): 1.11-1.40 (m, 8H), 1.42-1.57 (m, 2H), 1.74 (m, 2H), 1.88-2.00 (m, 2H), 2.13 (m, IH), 2.28 (m, IH), 2.40 (m, IH), 2.59 (m, 2H), 2.67 (s, 3H), 2.81 (m, IH), 2.97 (s, 3H), 3.19 (m, IH), 3.31 (m, IH), 3.71 (m, IH), 3.96 (s, 3H), 4.56 (dt, J= 4 Hz, 12 Hz, IH), 5.23 (m, 2H), 5.66 (m, IH), 7.01 (s, IH), 7.10 (s, IH), 7.22 (d, J= 10 Hz, IH), 7.45 (s, IH), 8.00 (d, J= 10 Hz, IH).
Example 5: Preparation of JV-ri7-r2-(4-isopropylthiazole-2-yl)-7-methoxy-8- methylquinolin-4- yloxyl – 13 -methyl-2, 14-dioxo-3 , 13 -diazatricyclol“ 13.3.0.04‘6loctadec- 7-ene-4-carbonyll (cvclopropyPsulfonamide (47) SIMEPREVIR
A solution of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]- 13-methyl-2, 14-dioxo-3, 13-diazatricyclo[l 3.3.0.04,6]octadec-7-ene-4-carboxylic acid 46 (560mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50°C for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2CI2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2CI2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 47 SIMEPREVIR as a white powder: m/z = 750 (M+H)+.
1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, IH), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, IH), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J= 13 Hz, IH), 5.04 (t, J= 11 Hz, IH), 5.37 (m, IH), 5.66 (m, IH), 6.21 (s, IH), 7.02 (s, IH), 7.22 (d, J= 10 Hz, IH), 7.45 (s, IH), 7.99 (d, J= 10 Hz, IH), 10.82 (broad s, IH).
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REFERENCES
- “Medivir Announces That Simeprevir (TMC435) Data Will Be Presented at the Upcoming AASLD Meeting”. Yahoo News. October 1, 2012. Retrieved November 6, 2012.
- Lin, TI; Lenz, O; Fanning, G; Verbinnen, T; Delouvroy, F; Scholliers, A; Vermeiren, K; Rosenquist, A et al. (2009). “In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor”. Antimicrobial agents and chemotherapy 53 (4): 1377–85. doi:10.1128/AAC.01058-08. PMC 2663092. PMID 19171797.
|displayauthors=suggested (help) - “Phase 3 Studies Show Simeprevir plus Interferon/Ribavirin Cures Most Patients in 24 Weeks”. hivandhepatitis.com. December 27, 2012.
- Medivir announces TMC435 in an expanded clinical collaboration. Medivir. 18 April 2012.
- Results from a phase IIa study evaluating Simeprevir and Sofosbuvir in prior null responder Hepatitis C patients have been presented at CROI. 6 March 2013.
- TMC-435350
Drugs Fut 2009, 34(7): 545 - Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350
Bioorg Med Chem Lett 2008, 18(17): 4853 - Synthesis of enantiomerically pure trans-3,4-substituted cyclopentanols by enzymatic resolution
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PATENTS
- WO 2008092954
- WO 2007014926
- WO 2008092955
- WO 2000009543
- CN 102531932
- WO 2013061285
- WO 2011113859
- WO 2013041655
| WO2010097229A2 * | 26 Feb 2010 | 2 Sep 2010 | Ortho-Mcneil-Janssen Pharmaceuticals Inc | Amorphous salt of a macrocyclic inhibitor of hcv |
| WO2013037705A2 * | 7 Sep 2012 | 21 Mar 2013 | Fovea Pharmaceuticals | Aniline derivatives,their preparation and their therapeutic application |
| WO2005073195A2 * | 28 Jan 2005 | 11 Aug 2005 | Per-Ola Johansson | Hcv ns-3 serine protease inhibitors |
| WO2007014926A1 * | 28 Jul 2006 | 8 Feb 2007 | Tibotec Pharm Ltd | Macrocyclic inhibitors of hepatitis c virus |
The compound ritonavir, and pharmaceutically acceptable salts thereof, and methods for its preparation are described in WO94/14436. For preferred dosage forms of ritonavir, see US6,037, 157, and the documents cited therein: US5,484, 801, US08/402,690, and WO95/07696 and WO95/09614. Ritonavir has the following formula:
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