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Resolution method for racemate of trandolapril intermediate

A technology of trandolapril and intermediates, applied in the field of biocatalysis, can solve complex problems such as racemization, and achieve the effect of short reaction time, mild reaction conditions, and high-efficiency resolution

Inactive Publication Date: 2019-11-15
JIANGSU YONGDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the product obtained by this production method is a racemized structure, and the current methods of deracemization are relatively complicated.

Method used

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  • Resolution method for racemate of trandolapril intermediate
  • Resolution method for racemate of trandolapril intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Utilize the ammonium acetate buffer solution in the beaker to configure the reaction solution with a pH of 8.0, weigh it according to the mass ratio of Trumplidol intermediate and Pichia pastoris lipase as 2:1, add it to the beaker, and then place the beaker In a constant temperature water bath at 25°C, react for 6 hours, add a certain amount of hydrochloric acid to terminate the reaction, transfer all the reaction solution to a volumetric flask, use mobile phase to constant volume, dilute a certain number of times, and then filter through a microporous organic filter membrane , and finally use a high-performance liquid chromatograph to analyze and detect that the conversion rate is 99.8%.

[0023] Example 1

[0024] Utilize the ammonium acetate buffer solution in the beaker to configure the reaction solution with a pH of 8.0, weigh it according to the mass ratio of Trumplidol intermediate and Pichia pastoris lipase as 2:1, add it to the beaker, and then place the beake...

Embodiment 2

[0026] Utilize the ammonium acetate buffer solution in the beaker to configure the reaction solution with a pH of 8.5, weigh it according to the mass ratio of Trumplidol intermediate and Pichia pastoris lipase as 4:1, add it to the beaker, and then place the beaker React for 4 hours in a constant temperature water bath at 30°C, add a certain amount of hydrochloric acid to terminate the reaction, transfer the entire reaction solution to a volumetric flask, dilute to a certain volume with mobile phase, and then filter through a microporous organic filter membrane , and finally use a high-performance liquid chromatograph to analyze and detect and measure the conversion rate to be 97.6%.

Embodiment 3

[0028] Utilize the ammonium acetate buffer solution in the beaker to configure the reaction solution with a pH of 7.7, weigh it according to the mass ratio of the intermediate of Trumplidol and Pichia pastoris lipase as 3:1, add it to the beaker, and then place the beaker React for 3 hours in a constant temperature water bath at 27°C, add a certain amount of hydrochloric acid to terminate the reaction, transfer the entire reaction solution to a volumetric flask, dilute to a certain volume with mobile phase, and then filter through a microporous organic filter membrane , and finally use a high-performance liquid chromatograph to analyze and detect that the conversion rate is 94%.

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Abstract

The invention discloses a resolution method for a racemate of a trandolapril intermediate. The trandolapril intermediate is shown by a structural formula I and subjected to a catalytic reaction undera weak alkaline environment by utilizing pichia pastoris lipase. It is found through research that the pichia pastoris lipase can resolve the racemate of the trandolapril intermediate under a room-temperature condition and an alkaline condition to obtain the intermediate suitable for producing trandolapril, and the resolution method is safe, environmentally friendly and free of toxins and pollution.

Description

technical field [0001] The present invention relates to the field of biocatalysis, and more specifically, relates to a method for splitting racemates of trandapril intermediates. Background technique [0002] Trandolapril, chemical name: (2S,3aS,7aS)-[(2S)-{[(1S)-(ethoxycarbonyl)-phenylpropyl]amino}]-propionyl]- Octahydroindole-2-carboxylic acid was developed by France RousselUclaf Company. It is a long-acting angiotensin-converting enzyme inhibitor, which can treat a variety of cardiovascular diseases, and has the advantages of significant curative effect, long acting time, and small side effects. Further research found that trandolapril can effectively improve peripheral neuropathy in normotensive diabetic patients. (2S,3aS,7aS)-Octahydroindole-2-carboxylic acid is an important intermediate of Trandolapril. [0003] In US4933361A, it is disclosed that a cyclohexanone is used as a raw material, which is obtained after addition of acrylonitrile and cyclization, and after ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P41/00C12P17/10
CPCC12P17/10C12P41/005
Inventor 曹庆华
Owner JIANGSU YONGDA PHARMA
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