Method for preparing optically pure cis apovincaminic acid ester

A vincristate, optical purity technology, applied in organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve problems such as separation and removal of product purification difficulties

Active Publication Date: 2012-07-11
CHEDOM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of these methods can only achieve moderate to slightly high stereoselectivity, involving the recovery of chiral sources or chiral ligands, the separation and removal of heavy metals, etc. will also cause difficulties in the purification of products

Method used

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  • Method for preparing optically pure cis apovincaminic acid ester
  • Method for preparing optically pure cis apovincaminic acid ester
  • Method for preparing optically pure cis apovincaminic acid ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]Preparation of D-cis-vincine methyl ester: at room temperature, add acetone 2500mL and racemic cis-vincine to a 5.0L three-necked bottle equipped with mechanical stirring, thermometer and spherical condenser 336.4 g (1.00 mol) of methyl ester, and slowly drop into it a solution of 394.1 g (1.10 mol) of L-dibenzoyl tartaric acid and 1000 mL of acetone, and stir while adding. After the addition, continue to control the temperature and stir the reaction, the solid gradually precipitates, and continue to stir for 2.0h. After filtering, the obtained crystals were washed with cold acetone (150mL×2), and dried under reduced pressure at 40-50°C for 3.0h to obtain 316.1g of dextro-apovincine methyl ester L-dibenzoyl tartrate, with a yield of 45.5 %, melting point 142°C (decomposition).

[0033] The obtained d-vincine methyl ester L-dibenzoyl tartrate was added to a mixture of 2500 mL of dichloromethane and 2000 mL of ice water, and the pH was adjusted to 9.0 with 25% ammonia wat...

Embodiment 2

[0037] Preparation of D-cis-vincine methyl ester: at room temperature, add acetonitrile 2000mL and racemic cis-vincine in turn to a 5.0L three-necked flask equipped with mechanical stirring, thermometer and spherical condenser 336.4 g (1.00 mol) of methyl ester, and slowly drop into it a solution of 394.1 g (1.10 mol) of L-dibenzoyl tartaric acid and 1000 mL of acetonitrile, stirring while adding. After the addition, continue to control the temperature and stir the reaction, the solid gradually precipitates, and continue to stir for 2.0h. After filtering, the obtained crystals were washed with cold acetonitrile (150mL×2), and dried under reduced pressure at 40-50°C for 3.0h to obtain 319.6g of dextro-apovincine methyl ester L-dibenzoyl tartrate, with a yield of 46.0 %, melting point 142°C (decomposition).

[0038] According to the method described in Example 1, 10% sodium carbonate solution was used instead of ammonia water to neutralize, release and crystallize the separated...

Embodiment 3

[0042] Preparation of D-cis-Apo-vincine methyl ester: At room temperature, add acetonitrile 1600mL, methanol 200mL and racemic cis-Apo Add 336.4 g (1.00 mol) of vinblastine methyl ester, and slowly drop into it a solution of 394.1 g (1.10 mol) of L-dibenzoyl tartaric acid and 1000 mL of acetonitrile, stirring while adding. After the addition, continue to control the temperature and stir the reaction, the solid gradually precipitates, and continue to stir for 2.0h. After filtration, the obtained crystals were washed with cold acetonitrile (150mL×2), and dried under reduced pressure at 40-50°C for 3.0h to obtain 284.8g of dextro-apovincine methyl ester L-dibenzoyl tartrate, with a yield of 41.0 %, melting point 142°C (decomposition).

[0043] According to the method described in Example 1, 10% potassium carbonate solution was used instead of ammonia water to neutralize, release and crystallize the separated and purified D-apovincine methyl ester L-dibenzoyl tartrate. Obtain 12...

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Abstract

The invention relates to a method for preparing optically pure enantiomers of racemic cis apovincaminic acid ester from the racemic cis apovincaminic acid ester. Chiral resolving agent R*-COOH reacts with the racemic cis apovincaminic acid ester to generate a corresponding salt; the salt is resolved according to the difference of the salt solubility of two enantiomers; the salt is neutralized, released and finally recrystallized, purified and enriched in the optical purity to prepare one signal enantiomer with high optical purity; in addition, because appropriate resolving agent and resolving solvent are used, a mother solution can be concentrated and resolved to obtain a salt of another enantiomer, wherein the salt has high chemical purity and high optical purity; and the salt is neutralized, released and refined to obtain another enantiomer with high-purity. The example of directly obtaining two optically pure enantiomers of a raceme to be resolved by using the same resolving agent is rare, and particularly it is the first time that the racemic cis apovincaminic acid ester including vinpocetine is resolved. The resolving operation is simple and efficient. The racemic cis apovincaminic acid ester is resolved by using the method to obtain the vinpocetine, thus another method of preparing the racemic cis apovincaminic acid ester including the vinpocetine is invented.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a method for preparing optically pure enantiomers from racemic cis-apo vincate esters. Background technique [0002] D-cis-vinpocetine ethyl ester is Vinpocetine (1), the chemical name is (3α, 16α)-ivorine-14-carboxylate ethyl ester, which was successfully developed by Gedeon Richter Company in Hungary in the 1970s The cerebral circulation metabolism improving agent, first listed in 1978, has been widely used in ischemic hypertensive encephalopathy, cerebral arteriosclerosis, cerebral ischemia, intermittent cerebral blood flow insufficiency, cerebral vasospasm, early cerebral palsy Treatment of arterial endarteritis, cerebral thrombosis, cerebral embolism, vertigo aphasia, Meniere's syndrome, and has been proven to improve memory, vision and hearing in the elderly. Vinpocetine is a derivative of natural ivory amine-vincamine (eburnamine-vincamine) alkalo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D461/00C07B57/00
Inventor 张宝富林桂清
Owner CHEDOM PHARMA
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