Trademarks: Daklinza
Molecular Formula: C40H50N8O6
CAS Registry Number: 1214735-16-6; 1009119-65-6 (dihydrochloride)
CAS Name: methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
Molecular Weight: 738.88
SMILES:CC(C)C(C(=O)N1CCCC1C2=NC=C(N2)C3=CC=C(C=C3)C4=CC=C(C=C4)C5=CN=C(N5)C6CCCN6C(=O)C(C(C)C)NC(=O)OC)NC(=O)OC
InChI Key: FKRSSPOQAMALKA-CUPIEXAXSA-N
InChI: InChI=1S/C40H50N8O6/c1-23(2)33(45-39(51)53-5)37(49)47-19-7-9-31(47)35-41-21-29(43-35)27-15-11-25(12-16-27)26-13-17-28(18-14-26)30-22-42-36(44-30)32-10-8-20-48(32)38(50)34(24(3)4)46-40(52)54-6/h11-18,21-24,31-34H,7-10,19-20H2,1-6H3,(H,41,43)(H,42,44)(H,45,51)(H,46,52)/t31-,32-,33-,34-/m0/s1
Activity: Treatment of Hepatitis C; HCV Drug; Treatment of HCV; Inhibitor of NS5A
Status: Launched 2014 (EU, Japan)
Originator: Bristol-Myers Squibb
Daclatasvir synthesis: WO2009020828A1
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
less than 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.
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.
References:
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.
References:
1. Kim, S.; et. al. 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. WO2009020828A1
2. Makonen, B.; et. al. Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir. J Med Chem 2014, 57(5), 2013–2032.
3. ClinicalTrials Phase III Daclatasvir + Sofosbuvir in Cirrhotic Subjects and Subjects Post-liver Transplant (ALLY 1). Trial ID Number NCT02032875 (AI444-215).
4. ClinicalTrials Phase III HIV/HCV Co-Infection Daclatasvir (DCV) + Sofosbuvir (SOF) (ALLY 2). Trial ID Number NCT02032888 (AI444-216).
5. ClinicalTrials Phase III Daclatasvir + Sofosbuvir for Genotype 3 Chronic HCV (ALLY 3). Trial ID Number NCT02032901 (AI444-218).
2. Makonen, B.; et. al. Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir. J Med Chem 2014, 57(5), 2013–2032.
3. ClinicalTrials Phase III Daclatasvir + Sofosbuvir in Cirrhotic Subjects and Subjects Post-liver Transplant (ALLY 1). Trial ID Number NCT02032875 (AI444-215).
4. ClinicalTrials Phase III HIV/HCV Co-Infection Daclatasvir (DCV) + Sofosbuvir (SOF) (ALLY 2). Trial ID Number NCT02032888 (AI444-216).
5. ClinicalTrials Phase III Daclatasvir + Sofosbuvir for Genotype 3 Chronic HCV (ALLY 3). Trial ID Number NCT02032901 (AI444-218).
