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Preparation method for manidipine intermediate 2-(4-diphenylmethyl piperazine)ethyl acetoacetate

A technology of ethyl acetoacetate and benzhydrylpiperazine, which is applied in the field of preparation of manidipine intermediate 2-ethyl acetoacetate, can solve the problem that the reaction yield is not too high, prone to explosion, Difficult to control and other problems, to achieve the effect of high purity and safe reaction process

Inactive Publication Date: 2017-03-22
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the high toxicity of the raw material diketene, this traditional preparation process has a strong lachrymatory property, and its flash point is 33.89 ° C, which causes the risk of explosion at a slightly higher temperature, which is difficult to control and makes industrialization difficult. In order to solve the above Technical problem, a kind of preparation method of 2-(4-benzhydrylpiperazine) ethyl acetoacetate is provided in the application number 2013102381412, but its reaction yield is still not too high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] This example provides a kind of preparation method of manidipine intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate, and its steps are as follows:

[0014] 1) Add 300ml of chloroform to a 500ml reactor, then add 13.5g (0.337mol) of solid sodium hydroxide, heat up to 70°C, and then use chloroform to dissolve 100g (0.337mol) of 1-diphenylmethane Base-4-(2-hydroxyethyl)piperazine was dissolved, stirred for 30 minutes, 65.75g (0.505mol) ethyl acetoacetate was added dropwise, and the reaction was kept for 5 hours;

[0015] 2) Concentrate the obtained reaction solution under reduced pressure, extract with ethyl acetate (500mL×3) and saturated brine, combine the organic phases, dry and concentrate to obtain an oil, and dissolve the obtained oil in 600 mL of acetic acid ethyl ester, then pass hydrogen chloride gas, stir and crystallize, and filter with suction to obtain a white solid;

[0016] 3) Dissolve the obtained white solid in 20 times the volume of water, add dr...

Embodiment 2

[0018] This example provides a kind of preparation method of manidipine intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate, and its steps are as follows:

[0019] 1) Add 600ml of chloroform to a 1000ml reactor, then add 40.4g (1.011mol) of solid sodium hydroxide, heat up to 80°C, and then use chloroform to dissolve 200g (0.674mol) of 1-diphenylmethane Base-4-(2-hydroxyethyl)piperazine was dissolved, stirred for 30min, 131.5g (1.011mol) ethyl acetoacetate was added dropwise, and the reaction was kept for 5 hours;

[0020] 2) Concentrate the obtained reaction solution under reduced pressure, extract with ethyl acetate (800mL×3) and saturated brine, combine the organic phases, dry and concentrate to obtain an oily substance, and dissolve the obtained oily substance in 600 mL acetic acid ethyl ester, then pass hydrogen chloride gas, stir and crystallize, and filter with suction to obtain a white solid;

[0021] 3) Dissolve the obtained white solid in 20 times the volume o...

Embodiment 3

[0023] This example provides a kind of preparation method of manidipine intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate, and its steps are as follows:

[0024] 1) Add 300ml of chloroform to a 500ml reactor, then add 16.17g (0.404mol) of solid sodium hydroxide, heat up to 70°C, and then use chloroform to dissolve 100g (0.337mol) of 1-diphenylmethane Base-4-(2-hydroxyethyl)piperazine was dissolved, stirred for 30 minutes, 87.67g (0.674mol) ethyl acetoacetate was added dropwise, and the reaction was kept for 5 hours;

[0025] 2) Concentrate the obtained reaction solution under reduced pressure, extract with ethyl acetate (500mL×3) and saturated brine, combine the organic phases, dry and concentrate to obtain an oil, and dissolve the obtained oil in 600 mL of acetic acid ethyl ester, then pass hydrogen chloride gas, stir and crystallize, and filter with suction to obtain a white solid;

[0026] 3) Dissolve the obtained white solid in 20 times the volume of water, add d...

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Abstract

The invention discloses a preparation method for a manidipine intermediate 2-(4-diphenylmethyl piperazine)ethyl acetoacetate, wherein the method comprises the following specific processes: adding an alkali catalyst into a reaction vessel containing an organic solvent, heating to make the temperature rise to 60-90 DEG C, then dissolving 1-diphenylmethyl-4-(2-hydroxyethyl)piperazine with trichloromethane, dropwise adding the dissolved 1-diphenylmethyl-4-(2-hydroxyethyl)piperazine into the reaction vessel, dropwise adding ethyl acetoacetate while stirring, carrying out heat preservation reaction until the reaction is completed, and carrying out reduced pressure concentration, extraction and purification of the reaction solution to obtain 2-(4-diphenylmethyl piperazine)ethyl acetoacetate. The method has the advantages of mild and safe whole reaction process and less impurity, the purity of the obtained product is as high as 99.5% or more, the yield is 99% or more, and the method is suitable for industrialized production.

Description

technical field [0001] The invention relates to the preparation of chemical medicine intermediates, in particular to a preparation method of manidipine intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate. Background technique [0002] Manidipine is widely used in cardiovascular diseases, and its hydrochloride is a new generation of dihydropyridine calcium ion dual channel antagonist with good clinical effect and significant antihypertensive effect. However, when preparing manidipine hydrochloride intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate, there are environmental pollution, raw materials that are difficult to store, and easy to explode, which affects large-scale industrial production. [0003] The traditional process generally uses 1-benzhydryl-4-(2-hydroxyethyl)piperazine as the starting material, and the intermediate 2-(4-benzhydrylpiperazine)ethyl is obtained through acylation with diketene acetoacetate. Such as patents EP94159, WO8304023, EP138...

Claims

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Application Information

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IPC IPC(8): C07D295/088
CPCC07D295/088
Inventor 赵金召张梅彭学东闫勇义
Owner ZHANG JIA GANG VINSCE BIO PHARM
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