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Method for synthesizing Zofenopril

A technology of zofenopril calcium and a synthesis method, which is applied in the field of drug synthesis and can solve problems such as difficulty in refining, insoluble calcium salts and the like

Inactive Publication Date: 2009-02-25
YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Judging from the report of the above-mentioned method three, this method is milder than the first two conditions, and the operation is more convenient, but there are still defects, because calcium salts are difficult to dissolve in both organic solvents and inorganic solvents, so it is difficult to Refining, in order to ensure product quality, it is necessary to refine in the step of zofenopril potassium salt

Method used

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  • Method for synthesizing Zofenopril
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  • Method for synthesizing Zofenopril

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0095] Example 1 (synthesis of N-acetyl-L-hydroxyproline methyl ester):

[0096] Raw materials and proportioning (see Table 1)

[0097] Table 1

[0098]

[0099]

[0100] operate:

[0101] Add 600g of N-acetyl-hydroxyproline and 1000ml of anhydrous methanol into a 3000ml three-neck flask, stir for 45min to dissolve, then add 120g of p-toluenesulfonic acid, stir at room temperature for 48h, TLC (see below for the method) to detect the end point, raw materials The point basically disappears as the end point. Add solid sodium bicarbonate to adjust pH=7, filter, add anhydrous Na to the filtrate 2 SO 4 Dry, filter, concentrate under reduced pressure at 50°C to remove the solvent, add the oily residue to acetone, stir and mix, and a white precipitate precipitates out, filter, wash the solid with acetone, and concentrate the filtrate to obtain 605 g of a light yellow oil (Intermediate 1). 93.2%

example 2

[0102] Synthesis of Example 2 (N-acetyl-trans-4-tosyl-L-hydroxyproline methyl ester)

[0103] Raw materials and proportioning (see Table 2)

[0104] Table 2

[0105]

[0106] operate:

[0107] Put 602g of intermediate (1) and 1200ml of pyridine in a 3000ml dry three-neck flask, stir in an ice bath for 30min, add 735g of p-toluenesulfonyl chloride in batches at (0-10°C), stir to form a solid, and store in the refrigerator Stand overnight, add 600ml of water to dissolve the solid, extract with 800ml of dichloromethane x 3 times, combine the organic layers, and wash with dichloromethane, water, 2mol / l HCL, saturated sodium bicarbonate, and water twice each. The organic layer was dried and filtered, and the solvent was evaporated to obtain 928 g of a reddish-brown oil (Intermediate 2), with a yield of 84.5%.

example 3

[0108] Synthesis of Example 3 (N-acetyl-cis-4-phenylthio-L-proline methyl ester)

[0109] Raw materials and proportioning (see Table 3)

[0110] table 3

[0111]

[0112]

[0113] operate:

[0114] Add 3000ml of absolute ethanol into a dry 5000ml three-neck flask, stir, and slowly add 103g of chopped metal sodium in batches under ice-bath cooling, add 450g of thiophenol after dissolving, stir for 1h, and cool down in a water bath to At room temperature, add 926 g of intermediate (2) at one time, and stir overnight at room temperature (the temperature should not be too high). Ethanol was evaporated under reduced pressure, 1000ml of water and 1000mL of dichloromethane were added to the residue to dissolve the solid, the organic layer was separated, and the aqueous phase was extracted with 1000ml of dichloromethane, the organic layers were combined, washed twice with water, and anhydrous Na 2 SO 4 After drying, filtering, and distilling off th...

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Abstract

The invention provides a method for synthetizing Zofenopril Calcium salt, which takes N-acetyl-L-oxyproline as raw materials; the N-acetyl-L-oxyproline and methanol are esterified, paratoluensulfonyl chloride is sulphonated, and thiophenyl is substituted; the obtained product is hydrolyzed to be freeacid by alkali, and (cis form)-4-thiophenyl-L-proline hydrochloride is further obtained by hydrochloric acid deacetylation reaction; in addition, (S)-3-(benzoyl sulfhydryl group)-2-methylpropanoic acid reacts with thionyl chloride, and (S)-3-(benzoyl sulfhydryl group)-2-methyl propionyl chloride which then reacts with the (cis form)-4-thiophenyl-L-proline hydrochloride, so that Zofenopril freeacid is obtained; the Zofenopril freeacid is firstly made into sylvite, and then refined and purified to be calcium salt, so that the termination product is obtained. The materials of the method of the invention is easily obtained, the process route is simple, and the reaction conditions are mild; therefore, the method is easy to operate and suitable for commercial process.

Description

technical field [0001] The invention relates to drug synthesis, in particular to a method for synthesizing zofenopril calcium salt. Background technique: [0002] zofenopril calcium [0003] 【English name】Zofenopril calcium. [0004] 【Chinese chemical name】(4S)-1-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-phenylthio-L-proline calcium [0005] 【English chemical name】(4S)-1-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L-proline calcium salt [0006] [structural formula] [0007] [0008] Zofenopril calcium is the first third-generation long-acting angiotensinase inhibitor containing a sulfhydryl group, which is used for the treatment of mild to moderate essential hypertension, and for acute myocardial infarction with or without symptoms within 24 hours, blood Hemodynamically stable patients not receiving thrombolytic therapy. [0009] Regarding the synthetic method of zofenopril calcium, according to relevant literature reports, zofenopril calcium salt has m...

Claims

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Application Information

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IPC IPC(8): C07D207/16
Inventor 马文宁周庆武甘益民唐开勇
Owner YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA
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