Method for preparing canagliflozin intermediate 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene

Patent metadata

Field	Value
Publication number	US-9951036-B2
Application number	US-201515308456-A
Country	US
Kind code	B2
Filing date	Jun 19, 2015
Priority date	Jul 18, 2014
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

Provide in the present invention is a method for preparing canagliflozin intermediate 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene. The method comprises a compound, shown as formula (II), of (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophene-2-yl]ketone being reduced under the action of a directly used borane solution or borane locally produced by reacting alkali metal borohydride with a Lewis acid in a suitable solvent and at a suitable temperature, so as to obtain the compound of formula (I) of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene. The preparation method avoids the use of expensive reductive agents and guarantees the complete conversion of raw materials, wherein the post-treatment is simple, the purity of product obtained is high, the reaction yield is high, in the preparation method is simple and convenient, and can easily be used in industry.

First claim

The invention claimed is:

1. A method for preparing a compound of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene shown as formula I, comprising the steps of:
subjecting a compound of (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophene-2-yl]methanone shown as formula II

to a reduction reaction under the effect of a borane to obtain the compound of formula I,

wherein the reduction reaction is performed in an inert solvent selected from ethers or haloalkanes, and wherein the ether is selected from tetrahydrofuran or dimethyltetrahydrofuran, and the haloalkane is selected from dichloromethane, trichloromethane, or 1,2-dichloromethane.

2. The method according to claim 1 , characterized in that, as the borane, a borane solution can be used directly or a borane produced in situ can be used.

3. The method according to claim 1 , characterized in that, the reduction reaction is performed at a temperature of −20 to 85 ° C.

4. The method according to claim 2 , characterized in that, the borane produced in situ is obtained by the reaction of an alkali metal borohydride and a Lewis acid, wherein the alkali metal is selected from sodium or potassium.

5. The method according to claim 4 , characterized in that, the alkali metal borohydride is selected from sodium borohydride, potassium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.

6. The method according to claim 4 , characterized in that, the Lewis acid is selected from aluminium trichloride, trifluoroacetic acid or boron trifluoride diethyl etherate solution.

Assignees

• Zhejiang Huahai Pharm Co Ltd
• Shanghai Syncores Tech Inc Ltd
• Zhejiang Huahai Pharm Co Ltd

Inventors

• Liao Wenjing
• Guo Xiaowen
• Huang Luning
• Gu Eric

Classifications

• C07D333/12 Primary

  Radicals substituted by halogen atoms or nitro or nitroso radicals · CPC title