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The preparation method of 2-(2-chloro-1-ethylene) hydrazide methyl formate

A technology of methyl hydrazide formate and chloroacetonitrile, which is applied in the field of synthesis of the antiemetic drug aprepitant intermediate 2-methyl hydrazide formate, can solve the problems of low purity, high energy consumption, and long time consumption, and achieve The effect of high yield and simple operation

Inactive Publication Date: 2015-10-28
深圳万乐药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Actual experimental results show that the product properties obtained by this method are not good, the purity is low, and highly toxic chloroacetonitrile and other unreacted raw materials are likely to remain, which affects the purity of subsequent products. High consumption, not suitable for industrial production

Method used

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  • The preparation method of 2-(2-chloro-1-ethylene) hydrazide methyl formate

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Under nitrogen protection, 50 g (0.67 mol) of chloroacetonitrile and 200 ml of methanol were successively added into a 1000 ml three-necked flask, and cooled to 0 °C. Dissolve 1g of sodium methoxide in 50ml of methanol and slowly drop it into the reaction flask. After the dropwise addition was completed, the mixture was raised to room temperature and stirred for 30 minutes. 1.06 ml of glacial acetic acid were added, and then a solution of 39 g (0.43 mol) of methyl carbazate in 250 ml of methanol was added dropwise to the resulting mixture. After the dropwise addition was complete, stirring was continued for 30 minutes.

[0024] Concentrate the reaction solution under reduced pressure until it is nearly dry, add 1000ml of acetone, stir and beat at room temperature for 30min, filter to obtain a light yellow solid, and dry the solid at 50°C with air blowing to obtain 70.1g of 2-(2-chloro-1-ethylidene)hydrazide formic acid methyl Esters, yield: 93.1%, HPLC purity 99.8%. ...

Embodiment 2

[0026] Under nitrogen protection, 50 g (0.67 mol) of chloroacetonitrile and 200 ml of methanol were successively added into a 1000 ml three-necked flask, and cooled to 0 °C. Dissolve 1g of sodium methoxide in 50ml of methanol and slowly drop it into the reaction flask. After the dropwise addition was completed, the mixture was raised to room temperature and stirred for 30 minutes. 1.06 ml of glacial acetic acid were added, and then a solution of 39 g (0.43 mol) of methyl carbazate in 250 ml of methanol was added dropwise to the resulting mixture. After the dropwise addition was complete, stirring was continued for 30 minutes.

[0027] Concentrate the reaction solution under reduced pressure until nearly dry, add 500ml of acetone, stir and beat at room temperature for 2 minutes, filter to obtain a light yellow solid, and dry the solid at 50°C with air blast to obtain 69.5g of 2-(2-chloro-1-ethylidene)hydrazide formic acid Methyl ester, yield: 93.0%, HPLC purity 99.5%.

Embodiment 3

[0029] Under nitrogen protection, 50 g (0.67 mol) of chloroacetonitrile and 200 ml of methanol were successively added into a 1000 ml three-necked flask, and cooled to 0 °C. Dissolve 1g of sodium methoxide in 50ml of methanol and slowly drop it into the reaction flask. After the dropwise addition was completed, the mixture was raised to room temperature and stirred for 30 minutes. 1.06 ml of glacial acetic acid were added, and then a solution of 39 g (0.43 mol) of methyl carbazate in 250 ml of methanol was added dropwise to the resulting mixture. After the dropwise addition was complete, stirring was continued for 30 minutes.

[0030] Add 500ml of acetone dropwise to the above reaction solution, stir while adding dropwise, continue to stir and crystallize at -10~0°C after the dropwise addition, start to crystallize after 1h, keep stirring for 40~60min, filter to obtain a light yellow solid, solid Air-dried at 50°C to obtain 38.1 g of methyl 2-(2-chloro-1-ethylene)hydrazide ...

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Abstract

The invention provides a method for preparing a method for preparing an aprepitant intermediate 2-(2-chloro-1-ethidene)hydrazide methyl formate. The method comprises the following steps: carrying out a condensation reaction between chloroacetonitrile and methyl hydrazinocarboxylate in a methanol / sodium methylate reaction solution by virtue of catalysis of glacial acetic acid, and performing after-treatment purification on the reaction solution by adopting acetone. The operation is simple, the purity of the obtained product is over 99%, and the method is high in yield and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing an antiemetic drug aprepitant intermediate 2-(2-chloro-1-ethylidene)hydrazide methyl formate. Background technique [0002] Aprepitant (English name aprepitant), chemical name 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy ]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, approved by FDA in 2003 The first neurokinin 1 (NK-1) receptor blocker approved for marketing blocks the action of substance P by binding to NK-1 receptors (mainly present in the central nervous system and its periphery). This product can pass through the blood-brain barrier and occupy the NK-1 receptors in the brain, with selectivity and high affinity, but very low affinity for NK-2 and NK-3 receptors. At the same time, this product has a low affinity to the targets (such as dopamine receptors and 5HT receptors) of other drugs used to trea...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C281/04
Inventor 蔡敏英李瑞远黄金林李昌希井绪文袁庆张广明
Owner 深圳万乐药业有限公司
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