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Novel method for preparing esmolol hydrochloride optical isomer

A technology for esmolol hydrochloride and optical isomers, which is applied in the field of preparation of esmolol hydrochloride optical isomers, can solve the problems of high cost, low yield, unsuitability for industrialized large-scale production and the like, and achieves mild conditions, Easy to use effect

Inactive Publication Date: 2010-11-24
南京海辰药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Method C uses more expensive chiral organic carboxylic acids, and the yield is low
The above three methods are not suitable for the needs of industrialized mass production

Method used

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  • Novel method for preparing esmolol hydrochloride optical isomer
  • Novel method for preparing esmolol hydrochloride optical isomer
  • Novel method for preparing esmolol hydrochloride optical isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]Add 50kg of DMF and 8kg of methyl p-hydroxyphenylpropionate into a dry 100L enamel reaction kettle. After stirring and dissolving, add 0.22kg of 60% NaH in batches at room temperature. Toluenesulfonic acid (S)-glycidyl ester 10.1kg, after adding, continue to react at room temperature, after TLC (ethyl acetate: sherwood oil=1: 10) detection reaction finishes, the reaction solution is poured into the container prepared in advance. 250kg of ice water in a 500L enamel reactor, fully stirred, and then extracted with dichloromethane (100kg×2). The organic layer was dried over anhydrous sodium sulfate, then placed in a 300L enamel reaction kettle and concentrated to dryness under reduced pressure to obtain (S)-methyl 4-glycidoxy phenylpropionate. Add 80kg of methanol and 5.2kg of isopropylamine to the reaction kettle, and react at room temperature. TLC (ethyl acetate:petroleum ether=1:10) showed that after the completion of the reaction, the solvent was recovered under reduced...

Embodiment 2

[0042] Add 50kg of DMF and 8kg of methyl p-hydroxyphenylpropionate into a dry 100L enamel reaction kettle. After stirring and dissolving, add 0.22kg of 60% NaH in batches at room temperature. Toluenesulfonic acid (R)-glycidyl ester 10.1kg, after adding, continue to react at room temperature, after TLC (ethyl acetate: sherwood oil=1: 10) detection reaction finishes, the reaction solution is poured into the container prepared in advance. 250kg of ice water in a 500L enamel reactor, fully stirred, and then extracted with dichloromethane (100kg×2). The organic layer was dried over anhydrous sodium sulfate, then placed in a 300L enamel reaction kettle and concentrated to dryness under reduced pressure to obtain (S)-methyl 4-glycidoxy phenylpropionate. Add 80kg of methanol and 5.2kg of isopropylamine to the reaction kettle, and react at room temperature. TLC (ethyl acetate:petroleum ether=1:10) showed that after the completion of the reaction, the solvent was recovered under reduce...

Embodiment 3

[0045] Add 300g of DMF and 80g of methyl p-hydroxyphenylpropionate into a dry 1L three-necked reaction flask. After stirring and dissolving, add 21.3g of 60% NaH in batches at room temperature. Nitrobenzenesulfonic acid (S)-glycidyl ester 126g, after adding, continue to react at room temperature, TLC (ethyl acetate: sherwood oil=1: 10) detects after reaction finishes, and reaction solution is poured into 1.5kg ice water, Stir well, then extract with dichloromethane (300g×2). The organic layer was dried over anhydrous sodium sulfate, and then concentrated to dryness to obtain (S)-methyl 4-glycidoxyphenylpropionate. 500 g of methanol and 52 g of isopropylamine were added to the raffinate, and the mixture was reacted at room temperature. TLC (ethyl acetate:petroleum ether=1:10) showed that after the reaction was completed, the solvent was recovered under reduced pressure to dryness, then 100 g of methyl acetate was added to the raffinate, the temperature was lowered to below 10°...

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Abstract

The invention provides a novel method for preparing an esmolol hydrochloride optical isomer, which comprises the following steps of: preparing alkoxide by adding an alkali into para hydroxybenzene methyl propionate in an anhydrous aprotic polar solvent; then carrying out condensation with the alkoxide and a (S)-glycidol derivative or a (R)-glycidol derivative to prepare an intermediate; preparing optically active esmolol hydrochloride by aminolysis of isopropyl amine and hydrogen chloride salifying; and refining the optically active esmolol hydrochloride to obtain (S)-esmolol hydrochloride or (R)-esmolol hydrochloride. The method has the advantages of simple and convenient operation, higher product purity and suitability for big industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a novel preparation method of esmolol hydrochloride optical isomers. Background technique [0002] Esmolol Hydrochloride (CAS: 81161-17-3) is a β-receptor blocker widely used clinically in the treatment of cardiovascular diseases. It acts quickly and has definite curative effect. Its chemical name: methyl 4-[2-hydroxy-3-(isopropylamino)propoxy]phenylpropionate hydrochloride, molecular formula: C 16 h 25 NO 4 · HCl, molecular weight: 331.83. [0003] The method for preparing esmolol hydrochloride optical isomers mainly contains following three kinds so far: [0004] A: WO8703583 discloses that chiral propylidene glycerol is used as a starting material, and it is prepared by acylation to ester, etherification, hydrolysis, chlorination, cyclization, and finally amination to salt. The route is as follows: [0005] [0006] B: In addition, US4990668 discloses that sodium phe...

Claims

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Application Information

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IPC IPC(8): C07C217/36C07C213/08
Inventor 冯明声韩爱霞倪桃冒宜兰姚晓敏曹于平姚其正郑文艳张璐
Owner 南京海辰药业股份有限公司
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