Schering Corporation

Basf Aktiengesellschaft

Merck Sharp + Dohme Corp.

Schering-plough Corporation

George S K Wong

Jeonghan Park

Weidong Tong

Juergen Weber

Ramani R Raghavan

Anantha R Sudhakar

Minzhang Chen

Hong-Chang Lee

Jennifer Ann Vance

George G Wu

Frank Xing Chen

Xiaojing Yang

Nanfei Zou

Jeffrey Manning Eckert

Daw-long Albert Kwok

David Jieh-Shyh Tsai

Eugene John Vater

Ingyu Jeon

Peter C Nirchio

Maria M Tamarez

Tetsuo Iwama

Paitoon Rashatasakhon

Nolan C Erickson

William W Leong

Suhan Tang

Bosco D'Sa

Christopher Nielsen

Tong Gan

This disclosure relates to novel processes useful in the purification of keto-amide, ketone and aldehyde compounds, which are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease and have application in the treatment of conditions caused by HCV. The processes of this disclosure relate to purification via a bisulfite adduct. In particular, this disclosure relates to processes useful in the purification of the keto-amide compound of Formula I, (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]-amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide: 

Bisulfite purification of an alpha-keto amide

The present invention provides for a process for preparing racemic methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate, its corresponding salt: (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate di-p-toluoyl-D-tartaric acid ('D-DTTA') salt or a (1S,2R,5R)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate di-p-toluoyl-L-tartaric acid salt ('L-DTTA') in a high enantiomeric excess. This invention also provides for a process for preparing a (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate dibenzoyl-D-tartaric acid (&#x201c;D-DBTA&#x201d;) salt or a (1S,2R,5R)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate L-tartaric acid (&#x201c;L-DBTA&#x201d;) salt in a high enantiomeric excess. Further, this invention provides a process for preparing intermediates II, IIB, III, IV, IV salt, V, VI, and VII.

Process for the preparation of 6,6-dimethyl-3-azabicyclo-[3.3.0]-hexane compounds and enantiomeric salts thereof

The present invention relates also to a process for the preparation of intermediate compounds useful in preparing the compounds of Formula (I) using the process of Scheme (II). 

Process for preparing (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

In one embodiment, the present application relates to a process of making a compound of formula I. and to certain intermediate compounds that are made within the process of making the compound of formula I.

[object Object]

The present invention provides for a process for preparing racemic methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate, its corresponding salt: (2S, 3R, 4S)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate di-p-toluoyl-D-tartaric acid ('D-DTTA') salt or a (2R, 3S, 4R)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate di-p-toluoyl-L-tartaric acid salt ('L-DTTA') in a high enantiomeric excess. This invention also provides for a process for preparing a (2S, 3R, 4S)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate dibenzoyl-D-tartaric acid (&#x201c;D-DBTA&#x201d;) salt or a (2R, 3S, 4R)-methyl 6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylate L-tartaric acid (&#x201c;L-DBTA&#x201d;) salt in a high enantiomeric excess. Further, this invention provides a process for preparing intermediates II, IIB, III, IV, IV salt, V, VI, and VII.

Process for the preparation of 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds and enantiomeric salts thereof

Process and intermediates for the preparation of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylates for salts thereof

In one embodiment, the present invention describes the synthesis of (4-bromophenyl) (4-piperidyl)methanone-(Z)-O-ethyloxime and its acid salts, and similar compounds, in high stereochemical purity.

Synthesis of (4-bromophenyl)(4-piperidyl)methanone-(Z)-O-ethyloxime and salts

In one embodiment, the present invention describes the synthesis of (4-bromophenyl) (4-piperidyl)methanone-(Z)&#x2014;O-ethyloxime and its acid salts, and similar compounds, in high stereochemical purity.

Synthesis of (4-bromopnenyl)(4-piperidyl)methanone-(Z)-O-ethyloxime and salts

In one embodiment, the present invention describes the synthesis of 4-&lsqb;(Z)-(4-bromophenyl)(ethoxyimino)methyl&rsqb;-1&prime;-&lsqb;(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl&rsqb;-4&prime;-methyl-1,4&prime;-bipiperidine, and intermediates therefor from easily available starting materials by a simple route.

Synthesis of 4-&lsqb;(Z)-4-bromophenyl)(ethoxyimino) methyl&rsqb;-1'-&lsqb;(2,4-dimethyl-1-oxido-3-pyridinyl)carbony)&rsqb;-4'-methyl-1,4-&prime;bipiperidine

Process for the preparation of 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone and an intermediate useful therefore

Growing community of inventors

Summit, NJ, United States of America

George S K Wong