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Preparation method of (S)-manidipine

A technology of manidipine and resolving agent, applied in the field of preparing S-type manidipine, achieving the effects of low equipment requirements, simple unit operation, and high product purity

Active Publication Date: 2016-03-30
YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no report at present to obtain the method of (S)-manidipine by splitting

Method used

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  • Preparation method of (S)-manidipine
  • Preparation method of (S)-manidipine
  • Preparation method of (S)-manidipine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: preparation manidipine free base

[0041] Weigh 12 g of sodium hydroxide and add 18 mL of water to prepare a 40% aqueous sodium hydroxide solution, which is cooled in an ice bath.

[0042] Weigh manidipine hydrochloride (20.5 g) into a three-neck flask (500 mL) equipped with mechanical stirring and ice-bath cooling, and then add water (100 mL). Start the stirring, and add the pre-prepared ice-cold 40% sodium hydroxide solution dropwise into the three-neck flask cooled by the ice bath. Ethyl acetate (90 mL) was added during the dropwise addition. After adding all the lye, stop stirring and let stand to separate layers. Take the aqueous phase to measure the pH to 11-12, and separate the liquids. The aqueous phase was extracted twice with ethyl acetate (30 mL×2), and the combined organic phases were washed once with water (50 mL) and saturated sodium chloride solution (50 mL). Then, the organic phase was dried over anhydrous sodium sulfate (15 g) for 2 ho...

Embodiment 2

[0043] Embodiment 2: D-(+)-tartaric acid resolution preparation (S)-manidipine

[0044] Take the manidipine free base (610 mg) prepared in Example 1, add a mixed solvent of acetone and n-heptane (10.0 mL, acetone:n-heptane=2:1) ​​to dissolve. Then, D-(+)-tartaric acid (150 mg) was added into the reaction bottle with stirring, the solution was clear, and then a white solid precipitated out. After continuing to stir for 2 hours, filter and wash the filter cake with a small amount of solvent (acetone:n-heptane=1:1). Then, the obtained filter cake was dried in a vacuum oven at 45° C. for 2 hours to obtain a white solid.

[0045]The obtained white solid was added to 15 mL of ice water, then 15 mL of ethyl acetate was added, and then 40% sodium hydroxide solution was added dropwise to adjust the pH of the aqueous phase to 11-12, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with 15 mL of water...

Embodiment 3

[0046] Example 3: Preparation of (S)-manidipine by resolution of D-(+)-dibenzoyltartaric acid

[0047] Take the manidipine free base (610 mg) prepared in Example 1, add methanol and n-heptane mixed solvent (10.0 mL, methanol:n-heptane=2:1) ​​to dissolve. Then, D-(+)-dibenzoyltartaric acid (358 mg) was added into the reaction flask with stirring, the solution was clear, and then a white solid precipitated out. After continuing to stir for 2 hours, filter and wash the filter cake with a small amount of solvent (methanol:n-heptane=1:1). Then, the obtained filter cake was dried in a vacuum oven at 45° C. for 2 hours to obtain a white solid.

[0048] The obtained white solid was added to 15 mL of ice water, then 15 mL of ethyl acetate was added, and then 40% sodium hydroxide solution was added dropwise to adjust the pH of the aqueous phase to 11-12, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (3×10 mL), the organic phases were combined, wash...

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Abstract

The invention relates to a preparation method of (S)-manidipine. Particularly, racemic manidipine free alkali is taken as a raw material, a resolving agent is used, and (S)-manidipine free alkali with optical activity is obtained with a chemical salting-out method. According to the preparation method, the yield is high, the process is simple to operate, the cost is lower, and (S)-manidipine is suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of resolution of compounds. It specifically relates to a method for preparing S-type manidipine by splitting racemic manidipine free base. Background technique [0002] Manidipine hydrochloride is an effective drug for the treatment of hypertension, which was launched in Japan in 1990. Its chemical name is 3,5-pyridinedicarboxylic acid 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-2-[4-(diphenylmethyl)- 1-Piperazinyl]ethyl methyl ester dihydrochloride. Molecular formula C 35 h 38 N 4 o 6 , the structural formula is as shown in formula (I): [0003] [0004] Manidipine contains one chiral center and has two enantiomers. It is reported that the activity of the S-isomer of manidipine is 30 times that of the R-form and 2 times that of the racemate. There is no report on the method of obtaining (S)-manidipine by splitting. [0005] The racemic compound with a single chiral center contains two enantiomers,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90A61P9/12C07B57/00
CPCC07B57/00C07B2200/07C07D211/90
Inventor 刘伟刘玉海闫瑞卿何艳杨伟秋王芳谢艳方于宝辉王海盛刘文东闫利颖
Owner YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA
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