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Synthesis method of 4-bromobenzo[b]thiophene

A synthesis method and thiophene technology, which are applied in the field of synthesis of 4-bromobenzo[b]thiophene, can solve the problems of unfavorable large-scale industrial production, cumbersome operation, and low product yield, and achieve large-scale industrial production and yield. The effect of high efficiency and good product quality

Active Publication Date: 2020-02-21
苏州诚和医药化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The decarboxylation process of this synthetic method needs to add a large amount of copper powder, and high temperature heating (185-195°C) is required in the reaction process, and the product yield is low (37%), which not only causes environmental pollution, but also is cumbersome to operate, which is not conducive to large-scale industrial production

Method used

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  • Synthesis method of 4-bromobenzo[b]thiophene
  • Synthesis method of 4-bromobenzo[b]thiophene
  • Synthesis method of 4-bromobenzo[b]thiophene

Examples

Experimental program
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Effect test

Embodiment 1

[0025] The synthesis of 4-bromobenzo [b] thiophene comprises the following steps:

[0026] S1: Add 150ml of DMF, 7.2g (0.18mol) of sodium hydroxide, 20g (0.10mol) of 2-bromo-6-fluorobenzaldehyde into a 250ml reaction flask, stir, and add dropwise at a temperature of 10-15°C 12.5g (0.10mol) of bromomethylmercaptan, add and keep warm for 2 hours, recover most of the acetone under negative pressure, add 200ml of water, extract with 100ml*3 ethyl acetate, combine organic layers, add 10g of magnesium sulfate to dry, filter, The mother liquor was concentrated to dryness to obtain 22.3 g of oil, with a yield of 86%.

[0027] S2: Add 100ml of toluene to 24.2g (0.092mol) of the above-mentioned oil, add 25g (0.095mol) of triphenylphosphine while stirring, heat up to 60°C and reflux for 2 hours, cool to room temperature, and filter to obtain 41.2g of quaternary phosphonium salt , yield 84%.

[0028] S3: Add 200ml of DMF and 3.74g (0.094mol) of sodium hydrogen to a 500ml reaction flask ...

Embodiment 2

[0031] The synthesis of 4-bromobenzo [b] thiophene comprises the following steps:

[0032] S1: Add 150ml of acetone, 25g (0.18mol) of potassium carbonate, 20g (0.10mol) of 2-bromo-6-fluorobenzaldehyde into a 250ml reaction flask, stir and raise the temperature to 30-35°C, then add methyl chloride dropwise at this temperature 8.1g (0.10mol) of mercaptan, add and keep warm for 4 hours, recover most of the acetone under negative pressure, add 200ml of water, extract with 100ml*3 ethyl acetate, combine the organic layers, add 10g of magnesium sulfate to dry, filter, and concentrate the mother liquor to After drying, 24.2 g of oil was obtained, with a yield of 93%.

[0033] S2: Add 100ml of toluene to 24.2g (0.092mol) of the above-mentioned oil, add 25g (0.095mol) of triphenylphosphine while stirring, heat up to 110°C and reflux for 4 hours, cool to room temperature, and filter to obtain 44.4g of quaternary phosphonium salt , yield 91%.

[0034] S3: Add THF 200ml, sodium hydrogen...

Embodiment 3

[0037] The synthesis of 4-bromobenzo [b] thiophene comprises the following steps:

[0038] S1: Add THF 150ml, sodium carbonate 18.9g (0.18mol), 2-bromo-6-fluorobenzaldehyde 20g (0.10mol) into a 250ml reaction flask, stir, the temperature is 75-80°C, add chlorine dropwise at this temperature Add 8.1g (0.10mol) of methyl mercaptan, keep it warm for 6 hours, recover most of the acetone under negative pressure, add 200ml of water, extract with 100ml*3 ethyl acetate, combine the organic layers, add 10g of magnesium sulfate to dry, filter, and the mother liquor Concentrate to dryness to obtain 23.3 g of oil, yield 89%.

[0039] S2: Add 100ml of toluene to 24.2g (0.092mol) of the above-mentioned oil, add 25g (0.095mol) of triphenylphosphine while stirring, heat up to 140°C and reflux for 6 hours, cool to room temperature, and filter to obtain 41.2g of quaternary phosphonium salt , yield 86%.

[0040]S3: Add 200ml of DMF and 3.74g (0.094mol) of sodium hydrogen to a 500ml reaction fl...

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Abstract

The invention discloses a novel synthesis method of 4-bromobenzo[b]thiophene. 2-bromo-6-fluorobenzaldehyde used as a raw material and chloro or bromo methyl-mercaptan undergo an etherification reaction to obtain 2-chloro(bromo) methylether-6-bromobenzaldehyde, then a Wittig reaction is carried out to obtain a target compound 4-bromobenzo[b]thiophene, and the crude product is refined and purified to obtain the high-purity product. The method has the advantages of mild reaction conditions, easiness in industrial production, good quality and high yield of the product, environmental friendliness and the like.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a synthesis method of 4-bromobenzo[b]thiophene. [0002] technical background [0003] 4-Bromobenzo[b]thiophene is an important intermediate of ebiprazole, a drug for the treatment of schizophrenia. The traditional synthetic method is to use 2-bromo-6-fluorobenzaldehyde as raw material, and thioglycolic acid in DMF solvent to obtain 4-chlorobenzo[b]thiophene-2-carboxylic acid by cyclization, and then in quinoline / copper powder system Decarboxylation at high temperature gives 4-chlorobenzo[b]thiophene. Chinese patents CN101374834B / CN104736530A are all synthesized by this method, and the reaction equation is as follows: [0004] [0005] The decarboxylation process of this synthesis method needs to add a large amount of copper powder, and high temperature heating (185-195 ° C) is required in the reaction process, and the product yield is low (37%), which not only causes environ...

Claims

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Application Information

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IPC IPC(8): C07D333/54
CPCC07D333/54
Inventor 陈晓强方欢
Owner 苏州诚和医药化学有限公司
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