New process

Patent metadata

Field	Value
Publication number	US-2016200672-A1
Application number	US-201615077344-A
Country	US
Kind code	A1
Filing date	Mar 22, 2016
Priority date	Sep 16, 2010
Publication date	Jul 14, 2016
Grant date	—

Abstract

A process for the preparation of a compound of formula (I):

which is useful as an intermediate in the preparation of pharmaceutically active compounds.

First claim

1 . A process for the preparation of a cyclohexanecarbonitrile derivative of formula (I):

wherein R 1 is a (C 1 -C 8 )alkyl, comprising adding a Grignard reagent to the cyclohexanecarbonitrile of formula (II):

in the presence of an alkylating agent.

2 . A process according to claim 1 , wherein the coupling reaction is carried out in the presence of a secondary amine.

3 . A process according to claim 2 , wherein R 1 is pent-3-yl.

4 . A process according claim 1 further comprising the preparation of a cyclohexanecarboxylic acid derivative of formula (IV):

wherein R 1 is as defined in claim 1 , comprising:
a) hydrolysing the cyclohexanecarbonitrile derivative of formula (I) in claims 1 :

to obtain a cyclohexanecarboxylic acid amide derivative of formula (III):

and
b) further hydrolysing the compound of formula (III) to obtain the compound of formula (IV).

5 . A process according to claim 4 , further comprising the step of reacting the compound of formula (IV) as defined in claim 4 with a halogenating agent in the presence of a tri-(C 1 -C 5 )alkylamine, to obtain compound of formula (V):

wherein R 1 is as defined in claim 4 and X is I, Br, Cl or F.

6 . A process according to claim 5 , further comprising the step of using the compound of formula (V) in claim 5 , to acylate a compound of the formula VI′:

to obtain a compound of formula VI:

wherein R 1 is as defined in claim 5 .

7 . A process according to claim 6 further comprising the step of reducing the compound of formula VI as defined in claim 6 with a reducing agent to obtain a compound of formula VII:

wherein R 1 is as defined in claim 6 .

8 . A process according to claim 7 further comprising the step of acylating the compound of formula VII as defined in claim 7 with R 4 C(O)X′, wherein X′ is I, Br, Cl or F, to obtain a compound of formula VIII:

wherein R 4 is a (C 1 -C 8 )alkyl and R 1 is as defined in claim 7 .

9 . A process according to claim 1 , wherein the coupling reaction is followed by a mineral acid quenching with hydrofluoric acid, hydrochloric acid, boric acid, acetic acid, formic acid, nitric acid, phosphoric acid or sulfuric acid.

10 . A process according to claim 1 , wherein the coupling reaction is followed by a hydrochloric acid quenching.

11 . A process according to claim 1 , wherein a nonprotic solvent is present.

12 . A process according to claim 11 , wherein the nonprotic solvent is tetrahydrofuran.

13 . A process according to claim 1 , wherein the alkylating agent is 1-halo-CH 2 R 1 or a sulfonate ester of R 1 CH 2 —OH wherein R 1 is defined in claim 1 .

14 . A process according to claim 1 , wherein the alkylating agent is 1-halo-2-ethylbutane.

15 . A process according to claim 1 , wherein the alkylating agent is 2-ethyl-1-butanol.

16 . A process according to claim 1 , wherein the alkylating agent is 1-bromo-2-ethylbutane.

17 . A process according to claim 1 , wherein the Grignard reagent is a (C 1 -C 6 )alkyl-magnesium-halide, phenyl-magnesium-halide, heteroaryl-magnesium-halide or a (C 3 -C 6 )cycloakyl-magnesium-halide.

18 . A process according to claim 1 , wherein the Grignard reagent is methylmagnesiumchloride.

19 . A process according to claim 2 , wherein the secondary amine is diethylamine or diisopropylamine.

20 . A process according to claim 2 , wherein the secondary amine is diethylamine.

21 . A process according to claim 2 , wherein the secondary amine is in a catalytic amount.

22 . A process according to claim 2 , wherein 0.01 to 0.5 equivalents of the secondary amine is used.

23 . A process according to claim 2 , wherein the process is continuous.

24 . A process according to claim 8 , wherein the compound of formula VIII is S-[2-([[1-(2-ethylbutyl)-cyclohexyl]-carbonyl]amino)phenyl]2-methylpropanethioate.

Assignees

• Hoffmann La Roche

Inventors

• Harnett Gerard John
• Hayes John
• Reents Reinhard
• Smith Dennis A
• Walsh Andrew

Classifications

• C07C327/30

  having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups · CPC title

• C07C319/22

  of hydropolysulfides or polysulfides · CPC title

• C07C253/30 Primary

  by reactions not involving the formation of cyano groups · CPC title

• C07C51/08

  from nitriles · CPC title

• C07C51/60

  by conversion of carboxylic acids or their anhydrides {or esters, lactones, salts} into halides with the same carboxylic acid part · CPC title