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A method for preparing ramipril

A molecular formula, optical technology, used in the preparation of intermediates, angiotensin-converting enzyme (ACE) inhibitors, and the synthesis of stereoisomers, can solve the problem of unsuitable industrial production, long efforts, and difficulties in obtaining optical intermediates And other issues

Active Publication Date: 2013-09-04
AARTI HEALTHCARE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] However, it is very difficult to obtain the optical intermediate (Ba) and it will take a long time
In addition, the above method has only low yield and is not suitable for industrial production

Method used

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  • A method for preparing ramipril
  • A method for preparing ramipril
  • A method for preparing ramipril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Preparation of (2S)-acetylamino-3-(2-oxocyclopentyl)-propionic acid (I)

[0048] 2-Acetamido-3-(2-oxocyclopentyl)-propionic acid methyl ester (90 g) was dissolved in water (350 ml) and stirring was continued until the solution was clear. The pH of the above solution was adjusted to 6.8 with freshly prepared sodium carbonate solution. Immobilized Protex 6L (0.75 g) was added to the solution with stirring. At 24-26° C., adjust the pH value of the reaction material to 6.2 to 6.8 with sodium carbonate, and react for 20 hours. The pH value of the above reaction solution was adjusted to 6 with freshly prepared 10% acetic acid solution. The catalyst was isolated by filtration of the reaction mass and the filtrate was extracted with dichloromethane (MDC) (3 x 250ml). After separation of the two phases, the pH of the aqueous layer was adjusted to 3 with activated amber 15 resin (30 g). The resin was activated with concentrated hydrochloric acid. The reaction material was f...

Embodiment 2

[0050] Preparation of (2S)-2,3,3a,4,5,6-hexahydro-cyclopentopyrrole-2-carboxylic acid (IV) hydrochloride

[0051] The product obtained in Example 1 (15 g) was dissolved in water (30 ml), and concentrated hydrochloric acid (12 ml) was added. The mixture was heated to reflux and maintained at reflux temperature for 3 hours. MDC (3×45ml) was added to the reaction solution and extracted thoroughly. The water layer was vacuum distilled below 45°C to obtain the hydrochloride (11 g ) (purity: 99.1%; 97.3%ee).

Embodiment 3

[0053] Preparation of the hydrochloride salt of (2S,3aS,6aS)-octahydrocyclopentapyrrole-2-carboxylic acid (C)

[0054] While stirring, the hydrochloride (10 g) of (2S)-2,3,3a,4,5,6-hexahydro-cyclopentapyrrole-2-carboxylic acid (IV) obtained in Example 2 was added to acetic acid (60ml). The reaction mixture was heated to 40-45°C. Add 5% palladium-carbon catalyst (0.8g), and hydrogenate it at a hydrogen pressure of 5-6Kg / cm2 at a temperature of 55-60°C. After ensuring completion of the reaction, the reaction mass was filtered to remove the catalyst and concentrated. Acetone (20ml) was added and the reaction mixture was stirred at 30-35°C for 30 minutes. The mixture was cooled to 0-5 °C. The reaction mass was filtered and dried. The obtained solid was (2S,3aS,6aS)-octahydrocyclopentapyrrole-2-carboxylic acid hydrochloride (6 g) (purity: 99.2%; 97.5%ee).

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PUM

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Abstract

Enantio-specific synthesis of optically pure (2S)-acetylamino-3-(2-oxo-cyclopentyl)- propionic acid (I) comprising converting enantiomeric mixture of (1 -4C alkyl)-2- acetylamino-3-(2-oxocyclopentyl) propionoate (II) (+ and -) under the influence of an Alkaline serine endopeptidase is disclosed. The invention further describes use of optically pure (2S)-acetylamino-3-(2-oxocyclopentyl)-propionic acid (I) formed by the process of present invention, in the preparation of Ramipril.

Description

technical field [0001] The present invention relates to an improved method for preparing ramipril, intermediates used in the method and uses thereof. In particular, the present invention relates to an improved preparation method of angiotensin-converting enzyme (ACE) inhibitors, and also relates to the synthesis of stereoisomers required for important intermediates in the preparation process of ramipril. Background technique [0002] Ramipril is an ACE inhibitor with the chemical name: [2S,3aS,6aS]-1-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl ]amino]-1-oxopropyl]octahydrocyclopentapyrrole-2-carboxylic acid. As shown in (A): [0003] [0004] Ramipril is effective in both hypertension and congestive heart failure. It reduces the production of angiotensin II, which dilates the arterial muscles and simultaneously relaxes the arteries, allowing the heart to pump blood more easily and increasing blood flow. [0005] Patent US4587258 is the first application to protect ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52C07C231/18C07C231/20C07C233/47
CPCC07C231/18C07C231/20C07D209/52C07C233/47
Inventor 帕瑞莫·德塞纳兰德·萨尔维巴哈尔库马·帕塔瓦勒
Owner AARTI HEALTHCARE LTD
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