Preparation method of manidipine intermediate 2-(4-diphenylmethyl piperazinyl)ethyl acetoacetate

A technology of ethyl acetoacetate and benzhydrylpiperazine, which is applied in the field of preparation of manidipine intermediate 2-ethyl acetoacetate, achieves the effects of mild reaction, high yield and high safety

Inactive Publication Date: 2013-10-16
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The technical problem to be solved in the present invention is to provide a preparation method of manidipine intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate, which has mild reaction, hi

Method used

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  • Preparation method of manidipine intermediate 2-(4-diphenylmethyl piperazinyl)ethyl acetoacetate

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Experimental program
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Effect test

Embodiment 1

[0019] A kind of preparation method of manidipine intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate, comprises the steps:

[0020] (1) Add 9.7g (0.405mol) of sodium hydride to 500mL of toluene, heat up to 90°C, add dropwise 100g (0.337mol) of 1-benzhydryl-4-(2-hydroxyethyl)piperene The toluene (300mL) solution of oxazine was stirred for about 30min, and then 52.68g (51.19ml, 0.405mol) ethyl acetoacetate was added dropwise, and reacted at this temperature for 5 hours;

[0021] (2) After the obtained reaction solution was concentrated under reduced pressure, it was extracted with ethyl acetate (500mL×3) and saturated brine, the organic phases were combined, dried, and concentrated to obtain an oil, which was dissolved in 600mL of dichloromethane , then pass hydrogen chloride gas, stir and crystallize, and filter to obtain a white solid;

[0022] (3) The obtained white solid was dissolved in 20 times the volume of water, and 30% potassium hydroxide aqueous solution was ...

Embodiment 2

[0024] A kind of preparation method of manidipine intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate, comprises the steps:

[0025] (1) Add 72.82g (1.348mol) of sodium methylate to 800mL of dichloromethane, heat up to 40°C, and add 200g (0.674mol) of 1-benzhydryl-4-(2-hydroxyethyl) dropwise. ) dichloromethane (400mL) solution of piperazine, after stirring for about 30min, add dropwise 52.68g (102.38ml, 0809mol) ethyl acetoacetate, react at this temperature for 8 hours;

[0026] (2) After the obtained reaction solution was concentrated under reduced pressure, it was extracted with ethyl acetate (800mL×3) and saturated brine, the organic phases were combined, dried, and concentrated to obtain an oil, which was dissolved in 600mL of dichloromethane , then pass hydrogen chloride gas, stir and crystallize, and filter to obtain a white solid;

[0027] (3) Dissolve the gained white solid in 20 times the volume of water, add dropwise 30% potassium hydroxide aqueous solution t...

Embodiment 3

[0029] (1) Add 121.10g (0.876mol) of potassium carbonate to 800mL of toluene, heat up to 90°C, and dropwise add 130g (0.438mol) of 1-benzhydryl-4-(2-hydroxyethyl)piperene The toluene (300mL) solution of oxazine was stirred for about 30min, and then 79.02g (66.55ml, 0.526mol) ethyl acetoacetate was added dropwise, and reacted at this temperature for 6 hours;

[0030] (2) After the obtained reaction solution was concentrated under reduced pressure, it was extracted with ethyl acetate (500mL×3) and saturated brine, the organic phases were combined, dried, and concentrated to obtain an oil, which was dissolved in 600mL of dichloromethane , then pass hydrogen chloride gas, stir and crystallize, and filter to obtain a white solid;

[0031] (3) Dissolve the obtained white solid in 20 times the volume of water, add 30% potassium hydroxide aqueous solution dropwise under stirring conditions until the pH is 10-11, place it at 4°C for a period of time, suction filter, and dry to obtain 1...

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Abstract

The invention discloses a preparation method of a manidipine intermediate 2-(4-diphenylmethyl piperazinyl)ethyl acetoacetate. According to the invention, alkali is adopted as a catalyst. In an organic solvent, 1-diphenylmethyl-4-(2-hydroxyethyl)piperazine is adopted as a raw material, and is subjected to trans-esterification by using ethyl acetoacetate. Through reduced-pressure concentration extraction, the material is purified with a salt-forming and freeing method, such that the 2-(4-diphenylmethyl piperazinyl)ethyl acetoacetate is obtained. According to the method provided by the invention, the application of diketene with defects of high tearing property, high toxicity, low flash point, and easy explosion is avoided. The reaction is mild, safety is high, and yield is high. The method is more suitable for industrialized productions.

Description

technical field [0001] The invention relates to the technical field of production of pharmaceutical intermediates, in particular to a preparation method of manidipine intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate. Background technique [0002] At present, 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...

Claims

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Application Information

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