Method for preparing zofenopril calcium

A zofenopril calcium and compound technology, applied in the field of medicinal chemistry, can solve the problems of difficult dissolution and refinement of calcium salts

Inactive Publication Date: 2014-07-23
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, Zofenopril potassium salt needs to be refined

Method used

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  • Method for preparing zofenopril calcium
  • Method for preparing zofenopril calcium
  • Method for preparing zofenopril calcium

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0056] Preparation of Example 1 N-acetyl-L-hydroxyproline methyl ester (compound 1):

[0057] Raw materials and proportioning (see Table 1)

[0058] Table 1

[0059]

[0060] operate:

[0061] Add 1732g of N-acetyl-L-hydroxyproline and 2500ml of anhydrous methanol into a 5000ml reaction kettle, stir for 45min to dissolve, then add 380g of p-toluenesulfonic acid, stir at room temperature for 48h, TLC (using silica gel GF254 thin-layer plate, two Chloromethane / ethyl acetate / methanol=1 / 5 / 0.2 developer, phosphomolybdic acid color) detection end point, the raw material point basically disappears as the end point. Add solid sodium bicarbonate to adjust pH=7~8, filter, add anhydrous Na to the filtrate 2 SO 4 Dry, filter, concentrate under reduced pressure at 40-50°C to remove the solvent, add the oily residue to 4000ml of acetone, stir and mix, a white precipitate precipitates out, filter, wash the solid with acetone, and concentrate the filtrate to obtain 1960g of light yel...

example 2

[0062] Preparation of Example 2 (N-acetyl-trans-4-p-toluenesulfonyl-L-hydroxyproline methyl ester) (compound 2)

[0063] Raw materials and proportioning (see Table 2)

[0064] Table 2

[0065]

[0066] operate:

[0067] Put 1960g of the crude product of compound (1) (calculated as 1872g effective amount) and 2700ml of pyridine in a 5000ml dry reaction kettle, stir for 30min under ice bath, add 2288g of p-toluenesulfonyl chloride in batches at 0-10°C, and add After completion, the temperature was naturally raised to 15-25°C for 12 hours, and solids were precipitated. TLC (using silica gel GF254 thin-layer plate, dichloromethane / ethyl acetate / methanol=1 / 5 / 0.2 developer, iodine color development) detection end point, The raw material point basically disappears as the end point. Add 5600ml of water to dissolve the solid, extract with 3600ml of dichloromethane x 3 times, combine the organic layers, wash with 2mol / l hydrochloric acid 4 times, water once, saturated sodium bic...

example 3

[0068] The preparation of example 3 thiophenol

[0069] Raw materials and proportioning (see Table 3)

[0070] table 3

[0071]

[0072] operate:

[0073] Under strong ventilation conditions, add 3750g of sodium thiophenate aqueous solution (≥40%) into a 20L clean reactor, and add about 2500mL of 20% dilute hydrochloric acid to the system under stirring conditions to adjust to acidic (pH=1 ~2), complete, continue to stir at room temperature for 30min. After standing still, the lower aqueous phase was separated, the organic phase was washed three times with saturated brine, the organic layer was dried over anhydrous sodium sulfate for more than 10 h, and the solid was removed by filtration to obtain 1218 g of a light-colored oily liquid with a yield of 97%. Concentrated treatment of hazardous waste: Combine all water phases, and the washing liquid when cleaning the reactor or other equipment that has been in contact with thiophenol with ethanol or acetone, soak in 40% sod...

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Abstract

The invention provides a method for preparing zofenopril calcium. N-acetyl-L-oxyproline is adopted as a raw material. The method includes: a step of subjecting the N-acetyl-L-oxyproline and methanol to esterification, subjecting the obtained product and paratoluensulfonyl chloride to sulfonation, and subjecting the obtained product and thiophenol prepared from a sodium thiophenolate solution to thiophenyl substitution; a step of hydrolyzing the obtained product into an free acid by utilization of an alkali, performing recrystallization for purification, and performing deacetylation with hydrochloric acid to obtain (cis)-4-thiophenyl-L-proline hydrochloride; a step of reacting (S)-3-(benzoyl sulfhydryl)-2-methylpropanoic acid with thionyl chloride to obtain (S)-3-(benzoyl sulfhydryl)-2-methyl propionylchloride; a step of reacting the (S)-3-(benzoyl sulfhydryl)-2-methyl propionylchloride with the (cis)-4-thiophenyl-L-proline hydrochloride to obtain the free acid zofenopril; and a step of forming a potassium salt, purifying and reacting with a calcium chloride to obtain a calcium salt, thus obtaining a final product zofenopril calcium. The method has characteristics of easily available raw materials, simple preparation method, mild conditions, easy control, reasonable monitoring points in the preparation process, effective removal and control of impurities, capability of producing the final product with the needed crystal form preferentially in a high ratio, suitability for industrial production and large application value.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a preparation method of medicine, in particular to a preparation method of zofenopril calcium, an angiotensinase inhibitor. 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] According to relevant literature reports, Zofen...

Claims

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Application Information

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IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 王文丰闫雪峰高苇姚书扬李京华
Owner YANGZIJIANG PHARMA GROUP SHANGHAI HAINI PHARMA
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