865466-24-6 Usage
Uses
Used in Pharmaceutical Industry:
(1R,2S,5S)-N-[(1S)-1-[(Cyclopropylamino)oxoacetyl]pentyl]-3-[(2S)-2-[[[[[1-[[(1,1-dimethylethyl)sulfonyl]methyl]cyclohexyl]amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide is used as a pharmaceutical agent for the treatment of hepatitis C virus (HCV). It functions as an NS3/4A protease inhibitor, specifically targeting genotype 1 HCV and demonstrating a rapid and steady decline in HCV-RNA levels in both previously treated and treatment-naive patients when used in combination with ritonavir and PEG-IFN-α. This combination leads to a significant percentage of patients achieving undetectable HCV-RNA levels after a second period of treatment.
Additionally, (1R,2S,5S)-N-[(1S)-1-[(Cyclopropylamino)oxoacetyl]pentyl]-3-[(2S)-2-[[[[1-[[(1,1-dimethylethyl)sulfonyl]methyl]cyclohexyl]amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide has shown activity against HCV mutations that are resistant to other treatments, such as boceprevir and telaprevir. The unique activity of this drug can be attributed to its critical electrophilic α-keto-amide "warhead," which covalently reacts with an HCV NS3 protease active-site serine residue involved in the HCV viral replication process. The development of (1R,2S,5S)-N-[(1S)-1-[(Cyclopropylamino)oxoacetyl]pentyl]-3-[(2S)-2-[[[[1-[[(1,1-dimethylethyl)sulfonyl]methyl]cyclohexyl]amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide was pursued as a single-diastereomer, second-generation HCV protease inhibitor, providing improved in vitro potency and pharmacokinetic profile over the structurally related antiviral drug boceprevir.
After the R-Pharm pharmaceutical group obtained the license to manufacture (1R,2S,5S)-N-[(1S)-1-[(Cyclopropylamino)oxoacetyl]pentyl]-3-[(2S)-2-[[[[1-[[(1,1-dimethylethyl)sulfonyl]methyl]cyclohexyl]amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide from Merck in 2012, further development was realized through collaborations with Schering-Plough and Texas Liver Institute.
Synthesis
A kilogram-scale synthetic route to narlaprevir has been
reported and proceeds strategically through the union of urea
45, bicyclic amine intermediate 46, and amine salt 48 . Preparation of urea 45 begins with commercial
cyclohexanecarboxylic acid methyl ester (40), which was
treated with freshly prepared LDA and TMSCl in THF to
provide silyl enol ether 41. This intermediate was
immediately reacted with commercial 2-[(chloromethyl)thio]-
2-methylpropane (42) under Lewis acid conditions (ZnBr2) to
provide ester 43 in 58% yield over the two-step process.17,19 A
solution of crude 43 was subjected to saponification conditions
(NaOH, H2O, MeOH) and sulfide oxidation with oxone in
DCM/MeOH, leading to the target sulfone 44 in 65% yield.
From 44, a Curtius rearrangement delivered an isocyanate
intermediate that could be trapped with L-tert-leucine, forming
the desired urea 45 in 53% over the two-step sequence.17,19
Coupling 45 with commercially available bicyclic amine 46
under peptide coupling conditions (EDC, HOBt, NMM) led to
the desired amide in 79% yield, which was then saponified with
aqueous NaOH in 2-methyltetrahydrofuran (2-MeTHF) to
provide acid intermediate 47 (84% yield). This intermediate
was coupled with amine salt 48 with EDC and HOBt, providing the penultimate
intermediate to narlaprevir. Completion of the synthesis relied
upon installation of the essential α-keto-amide functionality,
which was accomplished by α-hydroxy amide oxidation using
TEMPO-catalyzed conditions. A final recrystallization from
acetone/water completed synthesis of narlaprevir (IV) in 83%
yield. It is worth noting that this overall route was used to generate >1 kg of narlaprevir and required no chromatographic
separation steps.Amine salt 48 was prepared by first subjecting commercially
available pentanal (49) to Knoevenagel condensation conditions
using malonic acid followed by conversion of the
resulting acid to the corresponding t-butyl ester 50 by reaction
with H2SO4 and isobutylene. The key
transformation for establishing the requisite stereocenter in
intermediate 48 relied on an asymmetric conjugate addition of
a bis-protected lithiated amine followed by enolate trap with an
electrophilic source of oxygen. In practice, treatment of α-
methyl-N-(phenylmethyl)-(αS)-benzenemethanamine (51)
with n-hexyllithium resulted in stereoselective 1,4-addition to
enone 50. Subjection of lithium enolate intermediate 52 to
(1S)-(+)-(10-camphorsulfonyl)oxaziridine (53) then furnished
the α-hydroxyl group and delivered the syn-amino alcohol
derivative 54 in 81% yield for the two-step protocol. tert-Butyl
ester removal was realized by exposure of 54 to TFA in warm
toluene. Subsequent coupling of the resulting acid with
cyclopropylamine (55) utilizing EDC and HOBt conditions
provided cyclopropyl amide 56 in 71% yield from 54. Finally,
hydrogenolytic removal of the benzyl groups from the β-amine
followed by subjection of the product to refluxing HCl
provided amine salt 48 in 83% yield.19a
references
[1]. arasappan a, bennett f, bogen s l, et al. discovery of narlaprevir (sch 900518): a potent, second generation hcv ns3 serine protease inhibitor. acs medicinal chemistry letters, 2010, 1(2): 64-69.[2]. tong x, arasappan a, bennett f, et al. preclinical characterization of the antiviral activity of sch 900518 (narlaprevir), a novel mechanism-based inhibitor of hepatitis c virus ns3 protease. antimicrobial agents and chemotherapy, 2010, 54(6): 2365-2370.[3]. wang h, geng l, chen b z, et al. computational study on the molecular mechanisms of drug resistance of narlaprevir due to v36m, r155k, v36m+ r155k, t54a, and a156t mutations of hcv ns3/4a protease. biochemistry and cell biology, 2014, 92(5): 357-369.
Check Digit Verification of cas no
The CAS Registry Mumber 865466-24-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 8,6,5,4,6 and 6 respectively; the second part has 2 digits, 2 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 865466-24:
(8*8)+(7*6)+(6*5)+(5*4)+(4*6)+(3*6)+(2*2)+(1*4)=206
206 % 10 = 6
So 865466-24-6 is a valid CAS Registry Number.
865466-24-6Relevant articles and documents
ENANTIO- AND STEREO-SPECIFIC SYNTHESES OF β-AMINO-α- HYDROXY AMIDES
-
, (2011/02/24)
Processes useful for the preparation of a Compound of Formula I: Formula (I). Intermediates useful for the preparation of the compound of Formula I, and processes useful for preparing said intermediates are disclosed.
Discovery of narlaprevir (SCH 900518): A potent, second generation HCV NS3 serine protease inhibitor
Arasappan, Ashok,Bennett, Frank,Bogen, Stephane L.,Venkatraman, Srikanth,Blackman, Melissa,Chen, Kevin X.,Hendrata, Siska,Huang, Yuhua,Huelgas, Regina M.,Nair, Latha,Padilla, Angela I.,Pan, Weidong,Pike, Russell,Pinto, Patrick,Ruan, Sumei,Sannigrahi, Mousumi,Velazquez, Francisco,Vibulbhan, Bancha,Wu, Wanli,Yang, Weiying,Saksena, Anil K.,Girijavallabhan, Viyyoor,Shih, Neng-Yang,Kong, Jianshe,Meng, Tao,Jin, Yan,Wong, Jesse,McNamkra, Paul,Prongay, Andrew,Madison, Vincent,Piwinski, John J.,Cheng, Kuo-Chi,Morrison, Richard,Malcolm, Bruce,Tong, Xiao,Ralston, Robert,Njoroge, F. George
scheme or table, p. 64 - 69 (2010/12/29)
Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (～10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.
