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Preparation method of isomer of trandolapril intermediate

A technology for trandolapril and intermediates, applied in the field of isomer preparation, can solve problems such as difficulty in obtaining, preparation and separation of compounds, and influence on the establishment of the quality system of trandolapril, achieving easy realization and mild reaction conditions Effect

Active Publication Date: 2013-10-23
山东瑞银生物工程有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The synthesis reported in this document is the isomer (R, S, R)-octahydroindole-2-carboxylic acid shown in formula B and the (R, S, S)-octahydroindole shown in formula A The ratio of isomers of indole-2-carboxylic acid is 4:96, which causes great difficulties for the preparation and separation of compound B, and it is difficult to obtain (R, S, R)-octahydroindole shown in formula B -2-carboxylic acid, therefore other isomers based on (R, S, R)-octahydroindole-2-carboxylic acid also have greater difficulty such as the compound shown in formula C, thus giving the Trandorpro The establishment of the quality system has a great impact

Method used

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  • Preparation method of isomer of trandolapril intermediate
  • Preparation method of isomer of trandolapril intermediate
  • Preparation method of isomer of trandolapril intermediate

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Embodiment 1

[0029] Example 1. Preparation of Isomer Mixture 3

[0030] 10 g of Compound A was added dropwise to pH=5.8 with concentrated ammonia water, and freeze-dried until no ice appeared on the round bottom flask. The obtained solid, 7.29g (2S, 3S)-tartaric acid, 1.2mL n-butyraldehyde, and 146mL n-butyric acid were successively added into a three-necked flask, and the temperature was raised to 80°C. After 18h, the reaction was stopped and cooled in an ice-water bath. After filtering, the filter cake was washed with cold ether and dried to obtain tartaric acid complex. The complex was poured into a 1000mL reaction flask, and 350mL of methanol was added; concentrated ammonia water was added dropwise in an ice-water bath to adjust the pH to 9, and stirring was continued for 30mins. Suction filtration, and the filtrate was spin-dried to obtain a khaki solid. Add 60mL of methanol, heat to dissolve, and dropwise add methyl tert-butyl ether to the system until no solids are produced, filte...

Embodiment 2

[0031] Embodiment 2. Preparation of Compound C

[0032] Add 3.8mL of benzyl alcohol into a 25mL reaction flask, cool down to -10°C, add 0.845g of the isomer mixture 3 obtained in the previous step to the reaction flask, add 1.6mL of thionyl chloride dropwise into the reaction flask, and add dropwise During the process, gas is produced. After the dropwise addition, it was raised to room temperature and reacted for 16h. Add 5 mL of anhydrous diethyl ether to the system and stir for 2 h. After filtration, the filtrate was rotary evaporated until no liquid dripped out, then diethyl ether was added and stirred until 0.49 g of a white solid was precipitated. The preparation was separated to obtain product C, 0.19 g of (R, S, R)-benzyl octahydroindole-2-carboxylate hydrochloride.

[0033] (R, S, R)-benzyl octahydroindole-2-carboxylate hydrochloride:

[0034] MS (m / z): 260 (Base+H + ), 282 (Base+Na + ).

[0035] 1 H NMR (400MHz, Acetone-d 6 ): δ=7.28-7.45(m, 5H), 5.18(q, J=7....

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Abstract

The invention discloses a preparation method of an isomer of a trandolapril intermediate, and in particular discloses a preparation method of the isomer of the trandolapril intermediate which is shown in a formula C and is acquired by using (R,S,S)-octahydroindole-2-carboxylic acid (shown in a formula A) as an initial raw material with the content of more than 90 percent, performing configuration turning and upper benzyl protection to obtain isomer mixtures C and D of the corresponding trandolapril intermediate and performing separation again. According to the technical scheme, the formula A is subjected to configuration turning, and the content of a compound of the formula B is obviously increased, so that the isomers of the subsequent other intermediates are greatly prepared, and the compound is used for preparing medicines for resisting cardiovascular disease and controlling the quality of the medicines.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to (R, S, S)-octahydroindole-2-carboxylic acid (shown in formula A) with a content higher than 90% as a starting material, which is reversed in configuration, up The benzyl group is protected to obtain the corresponding isomer mixtures C and D of the trandapril intermediate, and then separated to obtain the preparation method of the isomer of the trandapril intermediate shown in formula C. Background technique [0002] Trandolapril (Trandolapril) (as shown in formula E) is developed by Roussel Uclaf Company of Germany, a kind of long-acting angiotensin-converting enzyme inhibitor (ACE1) produced by Sanofi-Aventis Company of France, listed in France in 1993 , for the treatment of hypertension, congestive heart failure and myocardial infarction. [0003] [0004] Trandolapril contains 5 chiral centers, so the isomer control of intermediates in its preparation process and the ...

Claims

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Application Information

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IPC IPC(8): C07D209/42
CPCY02P20/55
Inventor 李鸿峰梅三林王朝东潘新刘勇
Owner 山东瑞银生物工程有限公司
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