Preparation process of optically-pure manidipine hydrochloride for treating high blood pressure

A technology of manidipine hydrochloride and preparation process, applied in the directions of organic chemistry, organic chemistry methods, etc., can solve the problems of long time, low resolution selectivity, low yield, etc., and achieves high yield and ee value, huge The effect of economic value and broad market prospects

Inactive Publication Date: 2018-06-08
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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  • Preparation process of optically-pure manidipine hydrochloride for treating high blood pressure
  • Preparation process of optically-pure manidipine hydrochloride for treating high blood pressure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Preparation of (S)-manidipine

[0030] 4.56 g (12 mmol) of 2-(4-benzyl-1-piperazinyl) ethyl acetoacetate, 1.51 g (10 mmol) of m-nitrobenzaldehyde, and 1.21 g of methyl 3-aminocrotonate were sequentially added. (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 reaction for 2 hours. Concentrated under pressure, recrystallized from n-hexane, and dried 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] 4 g (10.5 mmol) of 2-(4-benzyl-1-piperazinyl) ethyl acetoacetate, 1.51 g (10 mmol) of m-nitrobenzaldehyde, and 1.27 g of methyl 3-aminocrotonate were sequentially added. (11mmol), (S)-BINAP 0.93g (1.5mmol), ferric chloride 0.65g (4mmol) and 50ml of 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. Concentrated, recrystallized from n-hexane, and dried 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] 4.19 g (11 mmol) of 2-(4-benzyl-1-piperazinyl) ethyl acetoacetate, 1.51 g (10 mmol) of m-nitrobenzaldehyde, and 1.38 g of methyl 3-aminocrotonate were sequentially added. (12mmol), (S)-BINAP 0.31g (0.5mmol), ferric bromide 0.59g (2mmol) and 50ml of toluene were added to the reaction vessel, the temperature was raised to 90° C. and reacted for 2 hours, concentrated under reduced pressure, and 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 high blood pressure. The preparation process comprises the following steps: a) adding 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate, m-nitrobenzaldehyde, methyl 3-aminocrotonate, (S)-BINAP, a ferric compound and a reaction solvent into a reaction vessel, and performing a reaction to obtain (S)-manidipine; and b) adding the obtained (S)-manidipine and a hydrogen chloride solution into a reactor for a reaction, after the reaction is completed, performing reduced-pressure concentration, performing recrystallization, and performing drying to obtain the optically-pure (S)-manidipine hydrochloride. According to the preparation process provided by the invention, the target product (S)-manidipine has a higher yield and ee value, and the method provided by the invention has simple operation and short reaction time, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of chiral drug synthesis, in particular to a preparation process of optically pure manidipine hydrochloride for the treatment of 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. ManidipineHydrochloride is a third-generation lipophilic calcium channel antagonist developed by Takeda Pharmaceutical Co., Ltd., Japan. The molecule of manidipine contains a chiral center, and 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 pharmaceutical form is still in the racemic form. The drug was launched in 1990 and is mainly used to treat mild to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
CPCC07B2200/07C07D211/90
Inventor 师敬利孙益东
Owner QINGDAO MUNICIPAL HOSPITAL
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