Preparation method of p-methyl cinnamic acid

A technology of p-methylcinnamic acid and p-tolualdehyde, which is applied in the field of preparation of p-methylcinnamic acid, a key intermediate of ozagrel, can solve the problems of cumbersome processing, stench, and environmental pollution, and achieve low raw material cost, Pollution reduction and high yield effects

Inactive Publication Date: 2017-05-10
山东诚汇双达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The traditional synthesis of p-methylcinnamic acid is the Perkin reaction method, that is, the reaction of p-tolualdehyde and acetic anhydride with sodium acetate as the catalyst, but the reaction temperature above 160 ° C and many side reactions are very unsuitable for industrial production
In addition, to react with p-tolualdehyde and malonic acid, pyridine and piperidine are needed as catalysts; because both catalysts have a foul smell, it is not good for the health of production personnel in the reaction and post-treatment; in addition, because It is not a reaction raw material, and the two catalysts that lead to the completion of the reaction will be discharged into the environment and pollute the environment
Patent CN102633624A discloses a method for preparing p-methyl cinnamic acid, still using p-tolualdehyde and malonic acid to react, although DBU is used as a catalyst instead of pyridine and piperidine, but because of the high price of DBU and the need for recovery and recrystallization Processing is more cumbersome

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 240 g of methanol, 81.4 g of methyl acetate, and 120 g of p-tolualdehyde into a 1 L reaction flask, pass nitrogen gas under stirring, and cool down to below 0°C. Add 56.7 g of sodium methoxide in batches, and after the addition, the temperature of the solution is slowly raised to 60~65°C. TLC monitors the completion of the reaction, concentrates to remove the solvent, adds 40g of sodium hydroxide and 300g of deionized water, reacts at 20-30°C for 2 hours, and then adjusts the pH of the solution to 1-2 with 120g of concentrated hydrochloric acid. Filtration and drying yielded 154.2 g of off-white p-methylcinnamic acid; the molar yield was 95.1%, and the liquid phase purity was 99.5%.

Embodiment 2

[0029] Add 360 g of methanol, 81.4 g of methyl acetate, and 120 g of p-tolualdehyde into a 1 L reaction flask, pass nitrogen gas under stirring, and cool down to below 0°C. Add 59.4 g of sodium methoxide in batches, and after the addition, the temperature of the solution is slowly raised to 50-60°C. TLC monitors the completion of the reaction, concentrates to remove the solvent, adds 40g of sodium hydroxide and 300g of deionized water, reacts at 20-30°C for 2 hours, and then adjusts the pH value of the solution to 1-2 with 135g of concentrated hydrochloric acid. Filtration and drying yielded 152.3 g of off-white p-methylcinnamic acid; the molar yield was 93.9%, and the liquid phase purity was 99.4%.

Embodiment 3

[0031] Add 360 g of methanol, 88.8 g of methyl acetate and 120 g of p-tolualdehyde into a 1 L reaction flask, and pass nitrogen gas under stirring for protection, and lower the temperature to below 0°C. Add 56.7 g of sodium methoxide in batches, and after the addition, the temperature of the solution is slowly raised to 50-60°C. TLC monitors the completion of the reaction, concentrates to remove the solvent, adds 40g of sodium hydroxide and 300g of deionized water, reacts at 20-30°C for 2 hours, and then adjusts the pH of the solution to 1-2 with 120g of concentrated hydrochloric acid. Filtration and drying yielded 151.6 g of off-white p-methylcinnamic acid; the molar yield was 93.5%, and the liquid phase purity was 99.6%.

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Abstract

The invention belongs to the technical field of medicine synthesis and in particular relates to a preparation method of an ozagrel key intermediate, namely p-methyl cinnamic acid. The method comprises the following steps: taking p-tolualdehyde as a raw material and alcohol as a reaction solvent; reacting under the protection of nitrogen gas and under a heating condition of sodium alcoholate and/or a sodium alcoholate alcohol solution and acetate; after reacting, concentrating until an oily product is obtained; adding an alkali solution and reacting and hydrolyzing; adding an acid for acidifying and carrying out acid regulation to obtain the p-methyl cinnamic acid. The preparation method provided by the invention has the advantages of moderate reaction conditions, simplicity in operation, high yield, high product purity, low raw material cost and the like, has the advantages of environment friendliness, greenness and environment protection, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of p-methylcinnamic acid, a key intermediate of ozagrel. Background technique [0002] p-methylcinnamic acid, CAS No. 1866-39-3, molecular formula C 10 h 10 o 2 , is the key intermediate of Ozagrel. The structural formula of p-methylcinnamic acid is as follows: [0003] . [0004] Ozagrel (Ozagrel) is the world's first marketed powerful thromboxane Az (TXAz) synthetase inhibitor, Japan's Ono and Kissei Pharmaceutical Co., Ltd. jointly researched the antithrombotic drug that was first listed in 1988; it is suitable for the treatment of acute Thrombotic cerebral infarction and cerebral infarction accompanying movement disorders, and improving cerebral vasospasm contraction and concurrent cerebral ischemia symptoms after subarachnoid hemorrhage surgery. Ozagrel is one of the varieties with the largest increase in antithrombot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/09C07C57/42
CPCC07C51/09C07C67/343C07C57/42C07C69/618
Inventor 李跃东张伟刘增强宋希军杨茂峰
Owner 山东诚汇双达药业有限公司
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