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Method of preparing zofenopril calcium

A technology of zofenopril calcium and phenylthio group, which is applied in the field of preparation of zofenopril calcium, can solve the problems of high raw material cost, increased product cost, complicated operation and the like, and achieves the effects of easy operation and low cost

Inactive Publication Date: 2007-08-08
GUANGDONG BANGMIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The synthesis method of zofenopril calcium is described in detail in U.S. Patent US4316906 and Chinese Patent ZL99810517.1, but the technical scheme disclosed in the above-mentioned patents has complex operations in the condensation reaction and the preparation of zofenopril potassium salt. The lack of high raw material cost increases the product cost of industrial production

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  • Method of preparing zofenopril calcium
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] (1) Take 84g of N-acetyl-hydroxyproline and 150ml of anhydrous methanol, stir to dissolve, 16.58g of p-toluenesulfonic acid, react, add solid sodium bicarbonate to adjust pH=7, filter the filtrate and add anhydrous sulfuric acid Sodium-dried, filtered, concentrated and distilled to remove the solvent to obtain 85 g of a light yellow oily substance, namely N-acetyl-L-hydroxyproline methyl ester (intermediate (1)), with a yield of 93.6%.

[0026] (2) Take 84.2 g of intermediate (1) and 150 ml of pyridine, add 102.6 g of p-toluenesulfonyl chloride, stir to precipitate a white solid, add 50 ml of water to dissolve the solid, extract with 75 ml of dichloromethane × 3 times, combine the organic layers, Wash with water twice in turn. The organic layer was dried and filtered, and the solvent was evaporated to obtain 107.6 g of a yellow-brown oily substance, that is, N-acetyl-trans-4-p-toluenesulfonyl-L-hydroxyproline methyl ester (intermediate (2)), and the yield was 70.0%.

...

Embodiment 2

[0035] (1) Take 840g of N-acetyl-hydroxylamine and 1.5L of anhydrous methanol, stir to dissolve, add 165.8g of p-toluenesulfonic acid, stir at room temperature for 48h, add sodium bicarbonate to adjust pH=7, filter, and then Add anhydrous sodium sulfate to dry, filter, and distill off the solvent to obtain 866 g of light yellow oily intermediate (1), with a yield of 96%.

[0036] (2) Take 842g of intermediate (1) and 1500ml of pyridine, add 1026g of p-toluenesulfonyl chloride, stir to have a white solid precipitate out, add 500ml of water to dissolve the solid, extract with 750ml of dichloromethane × 3 times, combine the organic layers, and use Washed twice with water; the organic layer was dried and filtered with anhydrous sodium sulfate, and the solvent was evaporated to obtain 1086 g of yellow-brown oil intermediate (2), with a yield of 70.7%.

[0037] (3) Get 1500ml of absolute ethanol and add it to a dry reaction vessel, slowly add 215g of chopped metal sodium in batches,...

Embodiment 3

[0045] (1) Take 840g of N-acetyl-hydroxyproline and 1.5L of anhydrous methanol, stir to dissolve, add 165.8g of p-toluenesulfonic acid, stir at room temperature for 48h, add sodium bicarbonate to adjust the pH to 7, filter, and refill the filtrate Add anhydrous sodium sulfate to dry, filter, and distill off the solvent to obtain 848 g of light yellow oil intermediate 1) with a yield of 94%.

[0046] (2) Take 842g of intermediate (1) and 1500ml of pyridine, add 1026g of p-toluenesulfonyl chloride, stir to have a white solid precipitate out, add 500ml of water to dissolve the solid, extract with 750ml of dichloromethane × 3 times, combine the organic layers, and use Wash twice. The organic layer was dried and filtered with anhydrous sodium sulfate, and the solvent was evaporated to obtain 1109 g of yellow-brown oily intermediate (2). The yield was 72.2%.

[0047] (3) Take 1500ml of absolute ethanol and add it to a dry reaction vessel, slowly add 215g of chopped metal sodium in ...

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Abstract

The invention discloses a making method of zonfenpuli calcium, which comprises the following steps: adopting N-aceto-L-hydroxyproline as raw material; esterifying with carbinol; sulfonating through p-toluene sulfonyl chloride; substituting by benzene sulfenyl; hydrolyzing through alkaline; reacting to generate salt; obtaining cis-4-benzene sulfenyl-L-proline hydrochlorate; reacting with (s)-3-(benzoyl sulfuric group)-2-methyl propionyl chloride; obtaining the product.

Description

technical field [0001] The invention relates to a preparation method of zofenopril calcium. Background technique [0002] Zofenopril calcium is a white or off-white polymorphic powder, odorless, insoluble in water, insoluble in ethanol, methanol, ether, ethyl acetate and other organic solvents; its chemical name is: (cis)-1- [(2S)-3-(Benzoylthio)-2-methylpropionyl]-4-phenylthio-L-proline calcium salt, the structural formula is as follows: [0003] [0004] Zofenopril calcium is mainly used as an antihypertensive drug, which has therapeutic and preventive effects on acute myocardial infarction, can significantly reduce the recurrence rate and mortality of acute myocardial infarction, and has important clinical value. [0005] The synthesis method of zofenopril calcium is described in detail in U.S. Patent US4316906 and Chinese Patent ZL99810517.1, but the technical scheme disclosed in the above-mentioned patents has complex operations in the condensation reaction and the ...

Claims

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Application Information

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IPC IPC(8): C07D207/16
Inventor 陈建明李崇伟
Owner GUANGDONG BANGMIN PHARMA
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