A kind of preparation technology of optically pure manidipine hydrochloride for treating hypertension

A manidipine hydrochloride, preparation technology, applied in the direction of organic chemistry, organic chemical methods, etc., can solve the problems of long time, low yield, high cost, etc., and achieve high ee value, simple operation, and short reaction time.

Inactive Publication Date: 2021-02-12
QINGDAO MUNICIPAL HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the yield of this method is not high, and the resolution selectivity is not high. To obtain a high-purity photoactive product for medicine, it must be resolved several times to achieve
[0005] However, due to the problems of low efficiency, long time and high cost in chemical splitting, industrial application is still difficult

Method used

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  • A kind of preparation technology of optically pure manidipine hydrochloride for treating hypertension
  • A kind of preparation technology of optically pure manidipine hydrochloride for treating hypertension

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Preparation of (S)-manidipine

[0030] Sequentially add 4.56g (12mmol) of 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate, 1.51g (10mmol) of m-nitrobenzaldehyde, and 1.21g of methyl 3-aminocrotonate (10.5mmol), (S)-BINAP 0.62g (1mmol), ferric chloride 0.4g (2.5mmol) and 50ml N,N-dimethylformamide were added to the reaction vessel, and the temperature was raised to 100°C for 2 hours to react. Concentrate under reduced pressure, recrystallize from n-hexane, and dry to obtain 4.68 g of (S)-manidipine, with a yield of 78.4% and an ee value of 99.37%.

Embodiment 2

[0032] Preparation of (S)-manidipine

[0033] Sequentially add 4g (10.5mmol) of 2-(4-benzhydryl-1-piperazinyl) ethyl acetoacetate, 1.51g (10mmol) of m-nitrobenzaldehyde, and 1.27g of methyl 3-aminocrotonate (11mmol), (S)-BINAP 0.93g (1.5mmol), ferric chloride 0.65g (4mmol) and 50ml N,N-dimethylformamide were added to the reaction vessel, the temperature was raised to 110°C and the reaction was carried out for 4 hours, and the pressure was reduced Concentrate, recrystallize from n-hexane, and dry to obtain 4.55 g of (S)-manidipine, with a yield of 76.2% and an ee value of 99.33%.

Embodiment 3

[0035] Preparation of (S)-manidipine

[0036] Sequentially add 4.19g (11mmol) of 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate, 1.51g (10mmol) of m-nitrobenzaldehyde, and 1.38g of methyl 3-aminocrotonate (12mmol), (S)-BINAP 0.31g (0.5mmol), ferric bromide 0.59g (2mmol) and 50ml of toluene were added to the reaction vessel, heated to 90°C for 2 hours, concentrated under reduced pressure, recrystallized from n-hexane, After drying, 4.66 g of (S)-manidipine was obtained, with a yield of 78.1% and an ee value of 99.67%.

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Abstract

The invention discloses a preparation process of optically pure manidipine hydrochloride for treating hypertension. The preparation process comprises the following steps: a) preparing 2-(4-benzhydryl-1-piperazinyl) ethyl acetoacetate Ester, m-nitrobenzaldehyde, 3-aminocrotonate methyl ester, (S)-BINAP, ferric iron compound and reaction solvent are added in reaction vessel and react to obtain (S)-manidipine; b) gaining (S) )-manidipine and hydrogen chloride solution are added in the reactor to react, and the reaction is completed, concentrated under reduced pressure, recrystallized, and dried to obtain optically pure (S)-manidipine hydrochloride. The target product (S)-manidipine of the preparation process provided by the present invention has higher yield and ee value, and the method of the present invention is simple to operate, has short reaction time, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chiral drug synthesis, and in particular relates to a preparation process of optically pure manidipine hydrochloride for treating hypertension, in particular to a preparation process of (S)-manidipine. Background technique [0002] As we all know, chirality is one of the essential properties of nature. Most drugs are composed of chiral molecules, and the enantiomers of chiral molecules often have significantly different biological activities. Manidipine Hydrochloride is a third-generation lipophilic calcium channel antagonist developed by Takeda Pharmaceutical Co., Ltd., Japan. Containing a chiral center in the manidipine molecule, it has been reported that the activity of the (S) configuration isomer of manidipine is 30 times that of the (R) configuration, and 2 times that of the racemate. The current drug form is still the racemic form. The drug was launched in 1990 and is mainly used to treat mild to moderate ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
CPCC07B2200/07C07D211/90
Inventor 王滨薛克增师敬利孙益东
Owner QINGDAO MUNICIPAL HOSPITAL
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