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Preparation method of perindopril impurity K

A perindopril and impurity technology, which is applied in the field of preparation of perindopril impurity K, can solve the problems of less disclosure of the synthesis process, and achieve the effect of simple operation and reasonable process design

Pending Publication Date: 2022-04-26
SHENZHEN SUNGENING BIO-MEDICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the synthesis process of perindopril impurity is seldom disclosed, and the preparation method of perindopril impurity K involved in the present invention has not yet been reported; as we all know, the purity of the drug directly affects its quality, and the corresponding analysis is established by directional preparation of the target impurity It is of great significance to effectively control the quality of raw materials and their related preparations

Method used

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  • Preparation method of perindopril impurity K

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] (1) Dissolve compound I (5.2g, 20mmol), N-tert-butoxycarbonyl-L-alanine (4.15g, 22mmol) in DCM (100ml), then add HOBT (2.97g, 22mmol) and DCC (4.12g, 20mmol) was reacted at room temperature overnight. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was extracted by adding saturated sodium bicarbonate solution (150ml) and DCM (100ml×3). Dry over sodium sulfate and concentrate to obtain compound II.

[0023] (2) Compound II (8.6g, 20mmol) was dissolved in DCM (40ml), cooled to 0°C, and then TFA (10ml) was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature, and the reaction was continued for 4h, and the reaction solution was concentrated. Saturated sodium bicarbonate (150ml) and DCM (100ml×3) were added to the residue for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain compound III.

[0024]...

Embodiment 2

[0026] (1) Dissolve compound Ⅰ (5.2g, 20mmol), N-tert-butoxycarbonyl-L-alanine (4.15g, 22mmol) in DCM (100ml), then HATU (11.4g, 30mmol), react at room temperature Overnight, after the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was extracted by adding saturated sodium bicarbonate solution (150ml) and DCM (100ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain compound II.

[0027] (2) Dissolve compound II (8.6g, 20mmol) in DCM (40ml), cool to 0°C, then slowly add 2M dioxane hydrochloride (30ml) dropwise, after the addition is complete, warm up to room temperature, and continue the reaction for 4h , the reaction solution was concentrated, saturated sodium bicarbonate (150ml) and DCM (100ml×3) were added to the residue for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain compound III.

[0028] (3) Dissol...

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Abstract

The invention relates to a preparation method of a perindopril impurity K. The invention finds that an intramolecular ring-closed compound IV can be generated when a compound III is subjected to hydrogenation debenzylation, and the ratio of converting the compound III into the compound IV is relatively high under the condition of relatively high temperature, so that the compound IV can be directly prepared from the compound III by utilizing the phenomenon; the method is short in route, simple in process and easy to operate, and the prepared perindopril impurity K can provide a test sample for perindopril research and has important research value in drug process impurity research and clinical pharmacokinetic research.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation method of impurity K of perindopril. Background technique [0002] Perindopril, as a thiol-free angiotensin-converting enzyme inhibitor, was first listed in France in 1989; it can prevent the decapeptide angiotensin I from being converted into an octapeptide angiotensin II (vasoconstrictor), and prevent the Kinins (vasodilators) are degraded to inactive peptides. In addition, it not only has the characteristics of other ACE inhibitors, but also has a longer duration of action, fewer side effects, and better tolerance. It is the clinically preferred therapeutic drug for arterial hypertension and congestive heart failure. [0003] Perindopril is a peptidomimetic compound with five different chiral centers, and only the isomers whose five chiral carbons are in S configuration have good druggability, and perindopril is stable Poor property, difficult to prepare ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 周佳李方林孙坤杰
Owner SHENZHEN SUNGENING BIO-MEDICAL CO LTD
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