Methods and intermediates for the preparation of (4bS,5aR)-12-cyclohexyl-N-(N,N-dimethylsulfamoyl)-3-methoxy-5a-((1R,5S)-3-methyl-3,8-diazabicyclo [3.2.1]octane-8-carbonyl)-4b,5,5a,6-tetrahydrobenzo [3,4]cyclopropa[5,6]azepino[1,2-A]indole-9-carboxamide

Patent metadata

Field	Value
Publication number	US-9556204-B2
Application number	US-201314414475-A
Country	US
Kind code	B2
Filing date	Jul 16, 2013
Priority date	Jul 18, 2012
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The present invention provides methods and intermediates for the preparation of (1aR,12bS)-8-cyclohexyl-11-fluoro-N-((1-methylcyclopropyl)sulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide (formula I), including pharmaceutically acceptable salts. The compound has activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.

First claim

We claim:

1. A method for preparing the compound

comprising amidation of the compound

followed by crystallization.

2. The method of claim 1 further comprising the coupling of

to generate the compound

3. The method of claim 2 further comprising the coupling of the compound

with the compound

to generate the compound

4. The method of claim 3 further comprising the reduction of the compound

to generate the compound

5. The method of claim 4 further comprising the cyclopropanation and hydrolysis of the compound

to generate the compound

6. A method for the preparation of the compound

from indole-6-carboxylic acid comprising converting the acid moiety to the dimethylacylsulfonamide moiety followed by coupling to cyclohexanone and reduction.

7. A method for the preparation of the compound

from 6-bromoindole comprising coupling and reduction with cyclohexanone followed by transitional metal catalyzed conversion to the dimethylacylsulfonamide with CO and dimethylsulfamide.

8. The salt compound

9. The salt compound

Assignees

• Bristol Myers Squibb Co

Inventors

• Delmonte Albert J
• Natalie Jr Kenneth J
• Fraunhoffer Kenneth J
• Risatti Christina Ann
• Hang Chao
• Gao Zhinong
• Davulcu Akin H
• Hu Wenhao

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07C69/757

  having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] in the acid moiety · CPC title

• C07D209/08

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07C211/27

  having amino groups linked to the six-membered aromatic ring by saturated carbon chains · CPC title

• C07C67/343

  by increase in the number of carbon atoms · CPC title