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Isomer impurities in bulk pharmaceutical chemicals of enalapril maleate and synthesis method of isomer impurities

A technology of enalapril and enantiomers, applied in the field of isomer impurities and their synthesis, can solve the problems of teratogenicity, no disclosure of enalapril maleate enantiomeric impurities and the like

Active Publication Date: 2019-08-13
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the 1960s, pregnant women took a drug called "Thalidomide" which led to the tragedy of "Seal". "Thalidomide-Thalidomide" has two structures, L- and D-. Reduces early pregnancy reactions in pregnant women, but its chiral partner (dextrorotary) is teratogenic
[0012] The prior art only discloses the degradation impurities of enalapril maleate, but does not disclose enalapril maleate enantiomer impurities, and enalapril maleate is the key product of our company. Now, in accordance with the requirements of the Food and Drug Administration for the consistency evaluation of generic drugs, it is necessary to study the enantiomers in the raw material drug of enalapril maleate

Method used

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  • Isomer impurities in bulk pharmaceutical chemicals of enalapril maleate and synthesis method of isomer impurities
  • Isomer impurities in bulk pharmaceutical chemicals of enalapril maleate and synthesis method of isomer impurities
  • Isomer impurities in bulk pharmaceutical chemicals of enalapril maleate and synthesis method of isomer impurities

Examples

Experimental program
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Effect test

Embodiment 1

[0052] Example 1: Compound I and Compound II are condensed to prepare Compound III

[0053] Dissolve 30g of N-tert-butoxycarbonyl-D-alanine (I) and 33g of D-proline benzyl ester in 300ml of dichloromethane, then add 32g of HOBT and 41g of N,N-diiso Propylamine, stir, cool down to 0~10 ℃, add 46g EDCI in batches, after adding, keep warm for 1 hour, raise to room temperature to react to complete, add water to wash, separate liquid, the organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 68g The oily substance was purified by column chromatography to obtain compound III 37g oily substance, the yield was 62%.

Embodiment 2

[0054] Example 2: Compound III was removed from Boc to prepare compound IV

[0055] Dissolve 37 g of compound III in 370 ml of ethyl acetate, stir, add 74 ml of ethyl acetate hydrochloride dropwise, stir at room temperature until complete deprotection, precipitate a solid, filter, wash with ethyl acetate, and dry to obtain product IV 17.9 g as a white solid. The rate was 58.2%.

Embodiment 3

[0056] Example 3: Reductive amination of compound IV with ethyl 2-oxo-4-phenylbutanoate (V) to prepare compound IV

[0057] Add 17g of product IV to 170ml of absolute ethanol, stir, add 8.5g of anhydrous sodium acetate and 13.6g of ethyl 2-oxo-4-phenylbutyrate (V), cool to 0~5℃, dropwise A solution of 6.8 g of sodium cyanoborohydride dissolved in 34 ml of absolute ethanol was added, and the dropwise addition was completed. After the reaction was incubated for 1 hour, the reaction was returned to room temperature to complete the reaction. After the reaction was completed, the ethanol was concentrated under reduced pressure, 200 ml of dichloromethane was added, washed with 100 ml of saturated sodium bicarbonate solution, and concentrated under reduced pressure to obtain a crude oily product, which was purified by dichloromethane:methanol 10:1 column chromatography to obtain compound VI 17.8g , the yield is 70.5%.

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Abstract

The invention provides isomer impurities in bulk pharmaceutical chemicals of enalapril maleate and a preparing method of the isomer impurities. N-t-butyloxycarboryl-D-alanine (a compound I) and D-proline benzyl ester (II) are subjected to a condensation acylation reaction to prepare an intermediate compound III, then Boc deprotection is conducted to obtain an intermediate compound IV, the intermediate IV and ethyl 2-oxo-4-phenylbutyrate (V) are subjected to reductive amination to obtain a compound VI, then the compound VI is subjected to hydrogenation to remove benzyl groups, then a mixture ofenalapril enantiomers (TM1) and diastereoisomers (TM2), and then the enalapril enantiomers (TM1) and diastereoisomers (TM2) are obtained through preparative chromatographic separation.

Description

technical field [0001] The invention relates to the technical field of bulk drugs, in particular to a kind of isomer impurities in enalapril maleate bulk drugs and a synthesis method thereof. Background technique [0002] Most of the major parts of biological macromolecules that constitute living systems exist in the form of one enantiomer. At the molecular level, biological systems are chiral environments composed of biological macromolecules, and the enzymes and cell surface receptors of organisms are chiral. When chiral drug enantiomers enter the organism, they will be recognized and matched as different molecules by the chiral environment. Enantiomers have stereoselectivity in pharmacodynamics, pharmacokinetics, and toxicology. [0003] In recent years, the development of chiral drugs has been rapid. Among the drugs being developed by major pharmaceutical companies, the proportion of monorotation is increasing year by year. Among the listed drugs, in 1986, hyaluronic ...

Claims

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Application Information

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IPC IPC(8): C07K5/062C07K1/06C07K1/02C07K1/22G01N33/68
CPCC07K5/06026G01N33/68G01N2410/00Y02P20/55Y02P20/54
Inventor 唐井元杨晓勇马贯军
Owner CHANGZHOU PHARMA FACTORY
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