Synthesis method of 4-chlorothiophene-2-carbonyl derivative

A synthesis method, the technology of chlorothiophene, applied in the direction of organic chemistry, etc., can solve the problems of high post-processing cost, low yield, strong combustion support, etc., and achieve the effects of easy post-processing and purification, reduced production procedures, and mild reaction conditions

Active Publication Date: 2019-02-22
上海毕得医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is highly toxic and highly combustible because of the addition of chlorine, which pollutes the environment and is potentially dangerous.
In addition, the poor control of the chlorine equivalent leads to the presence of dichlorine by-products, which need to be re-reduced by iron powder acetic acid to obtain 4-chlorothiophene-2-carbonyl derivatives. This is a two-step reaction, which increases the reaction process, and the cost of post-treatment is high. The rate is not high, and there are problems in both economic benefits and environmental impacts

Method used

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  • Synthesis method of 4-chlorothiophene-2-carbonyl derivative
  • Synthesis method of 4-chlorothiophene-2-carbonyl derivative
  • Synthesis method of 4-chlorothiophene-2-carbonyl derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Synthesis of 2-acetyl-4-chlorothiophene

[0036]

[0037] The reaction formula is shown in formula (II). Dissolve 200g of 2-acetylthiophene Sm1 (1eq) in 2L of dichloromethane, add 147.3g of trichloroisocyanuric acid Sm2 (0.4eq), and slowly divide at 10-15°C. 1060 g of aluminum trichloride (5 eq) was added in batches and the addition was completed within 2 hours. Then react at 10-15°C for 2 hours, TLC detects that the reaction is complete, pour the reaction solution into 2L of ice-cold 1M hydrochloric acid solution, extract with dichloromethane, dry the organic phase with sodium sulfate, concentrate and distill to obtain 210g of 2-acetyl-4- Chlorothiophene, the yield is 82.48%, and the proton nuclear magnetic spectrum is as figure 1 shown.

Embodiment 2

[0038] Embodiment 2: the synthesis of 2-formyl-4-chlorothiophene

[0039]

[0040] The reaction formula is shown in formula (III). Dissolve 50g of 2-formylthiophene Sm1 (1eq) in 500ml of dichloromethane, add 41.5g of trichloroisocyanuric acid Sm2 (0.4eq), and slowly 297 g of aluminum trichloride (5 eq) were added in portions over 1 hour. Then react at 10-15°C for 2 hours, TLC detects that the reaction is complete, pour the reaction solution into 500ml of ice-cold 1M hydrochloric acid solution, extract with dichloromethane, dry the organic phase with sodium sulfate, concentrate and distill to obtain 53g of 2-formyl-4- Chlorothiophene, the yield is 81.09%, and the proton nuclear magnetic spectrum is as figure 2 shown.

Embodiment 3

[0041] Embodiment 3: the synthesis of 4-chlorothiophene-2-carboxylic acid

[0042]

[0043] The reaction formula is shown in formula (IV). Dissolve 20g of thiophene-2-carboxylic acid Sm1 (1eq) in 200ml of dichloromethane, add 14.5g of trichloroisocyanuric acid Sm2 (0.4eq), and slowly Add 104.1g of aluminum trichloride (5eq) in batches and complete the addition within 30min. Then react at 10-15°C for 2 hours, TLC detects that the reaction is complete, wash the reaction solution into 200ml of ice-cold 1M hydrochloric acid solution, extract with dichloromethane, dry the organic phase with sodium sulfate, concentrate and beat with PE to obtain 20.4g of 4-chlorothiophene-2 -Formic acid, the yield is 80.4%, and the proton nuclear magnetic spectrum is as image 3 shown.

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Abstract

The invention discloses a synthesis method of a 4-chlorothiophene-2-carbonyl derivative. A thiophene-2-carbonyl derivative is used as a raw material and reacts with symclosene and aluminum trichloride, and liquid separation and concentration are performed to obtain the 4-chlorothiophene-2-carbonyl derivative. The synthesis method adopts one-step reaction, the yield is not lower than 80%, the production process is decreased while the yield is improved, and the cost is reduced; the used raw materials and reagents are easy to obtain, reaction conditions are mild, post-treatment and purification is easy to operate, and large-scale production can be achieved.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of 4-chlorothiophene-2-carbonyl derivatives. Background technique [0002] Thiophene derivatives are more effective than phenyl homologues when used in antibiotics, and are widely used in anti-inflammatory analgesics and antibiotics. Among them, 4-chlorothiophene-2-carbonyl derivatives are also used in cardiovascular drugs, blood lipid-lowering drugs, Organic intermediates of various pharmaceutical products such as ulcer drugs, platelet aggregation inhibitors, cardiovascular relaxants, thrombin, 5-lipoxygenase inhibitors, etc. [0003] At present, the synthetic method of 4-chlorothiophene-2-carbonyl derivatives mainly uses thiophene-2-carbonyl derivatives to react under the action of aluminum trichloride in carbon tetrachloride solution by chlorine gas to obtain 4-chlorothiophene-2- The mixture of carbonyl derivati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/22C07D333/38
CPCC07D333/22C07D333/38
Inventor 陈华郦荣浩康治军
Owner 上海毕得医药科技股份有限公司
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