阅读说明：本技术 一种二氢吡啶类化合物的制备方法 (Preparation method of dihydropyridine compound ) 是由 方亚辉 姚凌燕 于 2019-09-19 设计创作，主要内容包括：本发明涉及一种二氢吡啶类化合物的制备方法,该方法以化合物II原料,在甲烷磺酸中进行脱甲基反应,制备得到二氢吡啶类化合物I。与现有技术相比,本发明所用脱保护试剂原料易得,反应及后处理简便,对环境污染小,适合工业生产；本发明收率高,产品质量稳定,成本低,操作简单,适合降压药丁酸氯维地平关键中间体的工业化制备。(The invention relates to a preparation method of dihydropyridine compounds, which uses compound II as raw material to perform demethylation reaction in methane sulfonic acid to prepare dihydropyridine compounds I. Compared with the prior art, the method has the advantages that the used deprotection reagent is easy to obtain raw materials, the reaction and the post-treatment are simple and convenient, the environmental pollution is small, and the method is suitable for industrial production; the method has the advantages of high yield, stable product quality, low cost and simple operation, and is suitable for the industrial preparation of the key intermediate of the antihypertensive agent clevidipine butyrate.)

1. A preparation method of dihydropyridine compounds is characterized in that a compound II raw material is subjected to demethylation reaction in methane sulfonic acid to prepare dihydropyridine compounds I;

2. the method for preparing dihydropyridines according to claim 1, wherein the reaction temperature is 60 to 80 ℃ and the reaction time is 3 to 4 hours.

3. The method for preparing dihydropyridines according to claim 2 wherein the reaction temperature is 80 ℃ and the reaction time is 3 h.

4. The process according to claim 1, wherein the weight ratio of methanesulfonic acid to compound II is 1-4: 1.

5. The process according to claim 1, wherein the weight ratio of methanesulfonic acid to compound II is 2: 1.

6. The method of claim 1, further comprising the steps of cooling, filtering, washing, and drying after the demethylation reaction.

7. The method for preparing dihydropyridine compounds according to claim 6, wherein the temperature is reduced to 5 to 10 ℃ after the demethylation reaction.

8. A process for preparing dihydropyridines according to claim 6 wherein the washing is with cold methane sulfonic acid.

Technical Field

The invention relates to the technical field of chemical pharmacy, in particular to a preparation method of dihydropyridine compounds.

Background

Clevidipine butyrate (Clevidipine butyrate), chemically known as 4- (2 ', 3' -dichlorophenyl) -2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid methyl (butyryloxymethyl) ester (compound 1), was developed by the Company medicinal Company and was approved by the U.S. FDA on 8.1.2008 on the market. The product has the advantages of rapid action, rapid elimination of effect, incremental dosage, accurate control of blood pressure, no accumulation in vivo, and low adverse side effect. The antihypertensive drug is the first antihypertensive drug for intravenous injection in foreign countries in the last decade, is suitable for treating hypertension under the condition that oral preparations are not suitable or are not desired to be used, and also has application in the aspect of treating acute blood pressure rise after cardiac surgery.

Wherein the compound I is a key intermediate of clevidipine butyrate.

Patent CN101759631A reports that 2, 3-dichlorobenzaldehyde (2), methyl aminocrotonate (4) and cyanoethyl acetoacetate (3) are mixed to perform one-pot Hantzsch reaction, 2-cyanoethyl is removed by alkali to prepare a key intermediate I, and the key intermediate I reacts with chloromethyl n-butyrate under alkaline conditions to prepare clevidipine butyrate. Although the route is short, the yield is low, and the high-purity clevidipine butyrate can be obtained by repeated recrystallization.

Patent CN103242221A uses compound VII and compound VIII as starting materials, and performs a cyclization reaction in a solvent to obtain intermediate IX, and removes a protecting group from compound IX in an organic solvent to obtain compound I. The compound VII in the route is expensive and has low total yield.

Patent CN101602710A discloses a process for preparing compound I by direct selective hydrolysis of demethylation with intermediate II. But the method has obvious defects, a large amount of acid and alkali alcohol solution is used in the hydrolysis process, the treatment capacity of the waste solvent is large, the environment is not protected, and the yield of the deprotection step is not high.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a preparation method of dihydropyridine compounds.

The purpose of the invention can be realized by the following technical scheme:

a preparation method of dihydropyridine compound, which comprises the steps of carrying out demethylation reaction on compound II raw material in methane sulfonic acid to prepare dihydropyridine compound I;

the reaction formula is as follows:

as a preferable technical scheme of the invention, the reaction temperature is 60-80 ℃, and the reaction time is 3-4 h.

As a preferable technical scheme of the invention, the reaction temperature is 80 ℃, and the reaction time is 3 h.

As a preferred technical scheme of the invention, the weight ratio of the methane sulfonic acid to the compound II is 1-4: 1.

As a preferred embodiment of the present invention, the weight ratio of methanesulfonic acid to compound II is 2: 1.

As a preferable technical scheme of the invention, the method also comprises the steps of cooling, filtering, washing and drying after the demethylation reaction.

As the preferable technical scheme of the invention, the temperature is reduced to 5-10 ℃ after the demethylation reaction.

As a preferred technical scheme of the invention, the washing adopts cold methane sulfonic acid washing.

Compared with the prior art, the invention has the following beneficial effects:

(1) in the reaction process, methane sulfonic acid is used as a deprotection reagent and a solvent, the addition amount is small, the methane sulfonic acid is filtered and removed after the reaction is finished, no redundant waste solvent is generated, and the method is economical and environment-friendly.

(2) The reagent used for removing the protecting group is cheap and easy to obtain, the operation is convenient, the post-treatment is simple, the cost is low, the environmental pollution is small, and the method is suitable for industrial production.

The invention has the advantages of high yield, stable product quality, low cost and simple operation, is suitable for the industrial preparation of the key intermediate I of clevidipine butyrate, and has novel, creative, practical and scientific progress in the synthetic route and the preparation method.

Detailed Description

A preparation method of dihydropyridine compound, which comprises the steps of carrying out demethylation reaction on compound II raw material in methane sulfonic acid to prepare dihydropyridine compound I;

the reaction formula is as follows:

preferably, the reaction temperature is 60-80 ℃, and the reaction time is 3-4 h.

Preferably, the reaction temperature is 80 ℃ and the reaction time is 3 h.

Preferably, the weight ratio of methane sulfonic acid to compound II is 1-4: 1.

Preferably, the weight ratio of methane sulfonic acid to compound II is 2: 1.

Preferably, the method further comprises the steps of cooling, filtering, washing and drying after the demethylation reaction.

Preferably, the temperature is reduced to 5-10 ℃ after the demethylation reaction.

Preferably, the washing is with cold methane sulphonic acid.

The present invention will be described in detail with reference to specific examples.