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Method for preparing Canagliflozin intermediate 2-(4-fluoro-phenyl) thiophene

A technology of fluorophenyl and intermediates, applied in the field of preparation of canagliflozin intermediate 2-thiophene, which can solve the problems of high cost, complex operation industry, and high equipment requirements

Inactive Publication Date: 2016-11-30
ZHEJIANG YONGTAI TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Aiming at the cost and operation problems in the prior art, the present invention provides a kind of preparation method of the canagliflozin intermediate 2-(4-fluorophenyl) thiophene that can realize industrialized production, solves the preparation method cost in the prior art High, complex operation industry, high equipment requirements, etc., and the method of this application can obtain high product purity in a simple and easy-to-achieve industrialization method, and can also achieve relatively high yields in scaled-up industrial production

Method used

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  • Method for preparing Canagliflozin intermediate 2-(4-fluoro-phenyl) thiophene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 1.1 Format response

[0032] In a 1000ml four-necked flask under nitrogen protection, 14 grams (0.58 mol) of magnesium flakes, 40 grams of THF, and 1 gram of 2-bromothiophene were put in and stirred. At around 30°C, the reaction begins to initiate. (bubbles are generated, and the temperature naturally rises to 35-45°C). The temperature was lowered to 30°C with cold water, and a mixture of 81 g (0.5 mol) of 2-bromothiophene (0.5 mol) and 160 g of THF was started dropwise, and the dropwise addition was completed in about two hours. During the dropping process, the temperature is controlled at about 30°C. After dropping, keep warm at 30°C for 30-60 minutes, take a sample, and the raw material 2-bromothiophene <0.5% is qualified. Finish. Seal and set aside.

[0033] 1.2 Coupling reaction

[0034] In another 1000ml four-neck flask. Under nitrogen protection, 40 grams of THF and 93 grams (0.53 mol) of p-fluorobromobenzene were added. Stir on. Throw in 0.9 g (0.005 mo...

Embodiment 2

[0038] 2.1 Format response

[0039] In a 1000ml four-necked flask under nitrogen protection, 28 grams (0.116 mol) of magnesium flakes, 80 grams of THF, and 2 grams of 2-bromothiophene were put into the flask and stirred. At about 30°C, the reaction starts to occur (bubbles are generated, and the temperature naturally rises to 35-45°C). The temperature was lowered to 30°C with cold water, and a mixture of 162 g (1.0 mol) of 2-bromothiophene (1.0 mol) and 320 g of THF was started dropwise, and the dropwise addition was completed in about two hours. During the dropping process, the temperature is controlled at about 30°C. After dropping, keep warm at 30°C for 30-60 minutes, take a sample, and the raw material 2-bromothiophene <0.5% is qualified. Finish. Seal and set aside.

[0040] 2.2 Coupling reaction

[0041]In another 2000ml four-neck flask. Under nitrogen protection, 40 grams of THF and 187 grams (1.05 mol) of p-fluorobromobenzene were added. Stir on. Throw in 1.8 gr...

Embodiment 2

[0044] Example 2 is actually very similar to the reaction conditions of Example 1. The main reason is that Example 2 doubles the reaction of Example 1, and when the purity is basically close, the yield has a relatively large increase.

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Abstract

The invention relates to a method for preparing Canagliflozin intermediate 2-(4-fluoro-phenyl) thiophene. The method comprises a step (1) of causing 2-bromothiophene to react with magnesium chips in a THF solvent to generate 2-thienyl magnesium bromide ringer solution; a step (2) of causing 2-thienyl magnesium bromide ringer solution and p-fluoro bromo benzene to undergo catalytic Kumada coupling reaction under the conditions of taking a nickel or palladium complex as a catalyst, and obtaining 2-(4-fluoro-phenyl) thiophene. According to the method, the product is good in quality and high in yield, reaction conditions are mild, and the method is simple to operate and easy to industrialize.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates, and relates to a preparation method of a canagliflozin intermediate 2-(4-fluorophenyl)thiophene suitable for actual industrial production. Background technique [0002] Canagliflozin is a SGLT2 inhibitor developed by Johnson & Johnson. It was approved by the US FDA in March 2013 for the treatment of type 2 diabetes in adults. It is safe to take, well tolerated, and has obvious weight loss effects and good blood sugar control. [0003] There are many reports on the synthesis of canagliflozin intermediate 2-(4-fluorophenyl)thiophene. Patent WO2002026706 reports that p-fluorophenylboronic acid is coupled with 2-bromothiophene under palladium catalyst. The yield is high, but the reaction needs to first make p-fluorophenylboronic acid from p-fluorobromobenzene, and a palladium catalyst is used, which is expensive. [0004] The patent US201000099883 reports four synthetic routes of 2-(4-fl...

Claims

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Application Information

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IPC IPC(8): C07D333/12
CPCC07D333/12
Inventor 邵鸿鸣王雷林娇华
Owner ZHEJIANG YONGTAI TECH CO LTD
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