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Production method of azelnidipine intermediate

A technology of azeldipine and a production method, applied in the direction of organic chemistry and the like, can solve the problems of difficult purification, poor purity, complicated operation, etc., and achieve the effects of improving product yield and purity, reducing production cost, and shortening reaction cycle.

Inactive Publication Date: 2016-09-21
XUCHANG HAOFENG CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this operation is loaded down with trivial details, and purity is poor, is not easy to purify, is difficult to obtain solid product, and productive rate is low, has a strong impact on the quality of final product, and production cost is greatly increased; Yield and quality of Dipin intermediates, etc.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1 A kind of production method of Azedipine intermediate

[0025] A kind of production method of Azedipine intermediate, comprises the following steps:

[0026] (1) Esterification reaction: a. Under the protection of inert gas, slowly add xyleneamine, epichlorohydrin and organic solvent into the reaction kettle and mix them in proportion. The stirring time is 2 hours, and the temperature is controlled at 80°C;

[0027] b, drop cyanoacetic acid and N,N-dicyclohexylcarbodiimide to continue the reaction for 3h;

[0028] c, after the reaction is completed, cool, filter with suction, wash the filtrate with water, and prepare solvent A for subsequent use;

[0029] (2) Pinner response:

[0030] a. Use a pump with a flow rate of 100ml / min to add solvent A into the microreactor and heat to 220°C;

[0031] b. Slowly add dehydrated ethanol and dichloromethane dropwise to the microreactor, and the stirring time is 3h;

[0032] c. Pass in liquid nitrogen, cool to 15°C,...

Embodiment 2

[0041] Embodiment 2 A kind of production method of Azelnidipine intermediate

[0042] A kind of production method of Azedipine intermediate, comprises the following steps:

[0043] (1) Esterification reaction: a. Under the protection of inert gas, slowly add xyleneamine, epichlorohydrin and organic solvent into the reaction kettle and mix them in proportion. The stirring time is 2-8 hours, and the temperature is controlled at 90°C;

[0044] b, drop cyanoacetic acid and N,N-dicyclohexylcarbodiimide to continue the reaction for 4h;

[0045] c, after the reaction is completed, cool, filter with suction, wash the filtrate with water, and prepare solvent A for subsequent use;

[0046] (2) Pinner response:

[0047] a. Use a pump with a flow rate of 150ml / min to add solvent A into the microreactor and heat to 240°C;

[0048] b. Slowly add dehydrated ethanol and dichloromethane dropwise to the microreactor, and the stirring time is 3-5h;

[0049] c, feed liquid nitrogen, cool to 2...

Embodiment 3

[0058] Embodiment 3 A kind of production method of Azelnidipine intermediate

[0059] A kind of production method of Azedipine intermediate, comprises the following steps:

[0060](1) Esterification reaction: a. Under the protection of inert gas, slowly add xyleneamine, epichlorohydrin and organic solvent into the reaction kettle and mix them in proportion. The stirring time is 8 hours, and the temperature is controlled at 100°C;

[0061] b, drop cyanoacetic acid and N,N-dicyclohexylcarbodiimide to continue the reaction for 5h;

[0062] c, after the reaction is completed, cool, filter with suction, wash the filtrate with water, and prepare solvent A for subsequent use;

[0063] (2) Pinner response:

[0064] a. Use a pump with a flow rate of 200ml / min to add solvent A into the microreactor and heat to 260°C;

[0065] b. Slowly add dehydrated ethanol and dichloromethane dropwise to the microreactor, and the stirring time is 5h;

[0066] c. Pass in liquid nitrogen, cool to 25...

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Abstract

The invention discloses a production method of an azelnidipine intermediate. The production method comprises the following steps of 1 an esterification reaction; 2 a Pinner reaction, wherein a solvent A is added into a microreactor through a pump with the flow velocity of 100-200 ml / min, heating is conducted until the temperature is 220 DEG C-260 DEG C, absolute ethyl alcohol and dichloromethane are slowly and dropwise added into the microreactor, stirring is conducted for 3-5 h, liquid nitrogen is introduced, cooling is conducted until the temperature is 15 DEG C-25 DEG C, dry hydrogen chloride gas is introduced for 2-6 h, the microreactor is sealed, stirring is conducted for 20-30 h, and mixed liquid B is prepared for standby application; 3 a neutralization reaction; 4 an amidine generation reaction, wherein the azelnidipine intermediate-3-amino-3-aminoproionic acid-1-(diphenylmethyl)-3-azetidinyl ester acetate compound is obtained. According to the production method, the temperature state of a reaction system and the usage quantity of the reactants in all the steps are strictly controlled, synthesis of the intermediate is stable, the product yield is increased, the product purity is improved, side reactions are decreased, the purpose sof reducing the production cost and shortening the reaction cycle are achieved, and the production method is more suitable for industrialized large-scale production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a production method of an azedipine intermediate. Background technique [0002] Azelnidipine (azelnidipine) is a new type of dihydropyridine calcium channel blocker jointly developed by Sankyo and Ube Industries of Japan. It was approved to be marketed in Japan in late May 2003 under the trade name of Calblock. Azedipine has a selective blocking effect on the calcium channel of arterial smooth muscle cells, it can dilate blood vessels, reduce peripheral vascular resistance and arterial pressure, and is widely used clinically for mild or moderate essential hypertension, renal impairment with hypertension and treatment of severe hypertension. Compared with dihydropyridine calcium channel blockers such as nicardipine and nifedipine, azedipine has the advantages of high selectivity, strong and long-lasting antihypertensive effect, and little impact on the heart; at ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04
CPCC07D205/04
Inventor 邢远
Owner XUCHANG HAOFENG CHEM TECH
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