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A kind of preparation method of enalapril maleate

A technology of enalapril maleate and enalapril, applied in the field of medicine, can solve the problems of unfavorable environment and personnel protection, unsuitable for industrialized production, cumbersome post-processing, etc., and achieve high yield and product purity, environmental protection Small pollution, improve the effect of labor protection

Active Publication Date: 2021-11-09
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The route design is reasonable, and the starting materials are relatively common, but there are problems: the first step Michael addition yield is lower than 50%, the second step high-pressure hydrogenation solvent uses glacial acetic acid and concentrated sulfuric acid to corrode the autoclave; the third step The one-step condensation solvent uses a large amount of DMF, the post-treatment is cumbersome, the pollution is large, the yield is low, and it is not suitable for industrial production; the second type is the triphosgene method: N-[(S)-1-ethoxycarbonyl-3-phenylpropyl ]-L-alanine and triphosgene generate active intermediate N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanine-N-carboxylic acid anhydride, which directly reacts with L -proline produces enalapril crude product, and then refines it with maleic acid to obtain enalapril maleate fine product
It is not conducive to the protection of the environment and personnel, and there are certain risks in mass industrial production

Method used

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  • A kind of preparation method of enalapril maleate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Dissolve disodium hydrogen phosphate (20.4g, 2.0eq) in 100mL of water, add 160mL of dichloromethane after the system dissolves, N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L- Alanine (20.0g, 1.0eq), stirred at room temperature. Dissolve triphosgene (8.4g, 0.4eq) in 40mL of dichloromethane, add dropwise to the reaction system at room temperature, add 0.5mL of pyridine after the reaction for 1h after the dropwise addition, stir for 1h and let stand for liquid separation, and concentrate the organic phase under reduced pressure to obtain an oily substance. Dissolve in 16mL of dichloromethane, add dropwise into 200mL of n-heptane, stir and crystallize at 0~10°C for 1h, filter under reduced pressure to obtain white solid N-[(S)-1-ethoxycarbonyl-3-phenylpropyl] -L-alanine-N-carboxylic acid anhydride, dried in vacuum at 50°C for 10h. 20.4 g was collected, and the yield was 91.6%.

[0047] Add L-proline (9.8g, 1.3eq), sodium hydroxide (3.4g, 1.3eq), 100mL water, and 70mL tetrahyd...

Embodiment 2

[0050] Dissolve disodium hydrogen phosphate (304.9g, 2.0eq) in 1.5L of water, add 900mL of dichloromethane after the system dissolves, N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L - Alanine (300.0 g, 1.0 eq), stirred at room temperature. Dissolve triphosgene (127.5g, 0.4eq) in 600mL of dichloromethane, add it dropwise to the reaction system at room temperature, add 3mL of pyridine after 1h of reaction after the dropwise addition, stir for 1h and let it stand for liquid separation. The organic phase is concentrated under reduced pressure to obtain an oily substance, which is Dissolve 190mL of dichloromethane, add dropwise into 3L of n-heptane, stir and crystallize at 0-10°C, filter under reduced pressure to obtain a white solid, and vacuum-dry at 50°C for 10h. Receipt: 280.3g, yield 86.3%.

[0051] Add L-proline (131.4g, 1.3eq), sodium hydroxide (45.7g, 1.3eq), 1.3L water, and 0.9L tetrahydrofuran to dissolve at room temperature into a 2L three-necked flask. Cool down to 0-10°C ...

Embodiment 3

[0054] Dissolve disodium hydrogen phosphate (1.52kg, 2.0eq) in 7.5L of water, add 4.5L of dichloromethane after the system dissolves, N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]- L-alanine (1.5kg, 1.0eq), stirred at room temperature. Dissolve triphosgene (0.64kg, 0.4eq) in 3L of dichloromethane, add dropwise to the reaction system at room temperature, add 15mL of pyridine after 1 hour of reaction after the dropwise addition, stir for 1 hour and let it stand for liquid separation. The organic phase is concentrated under reduced pressure to obtain an oily substance, which is Dissolve 0.6L of dichloromethane, add dropwise into 15.0L of n-heptane, stir and crystallize at 0-10°C, filter under reduced pressure to obtain a white solid, and vacuum-dry at 50°C for 10h. Receipt: 1.36kg, yield 82.9%.

[0055]Add L-proline (0.64kg, 1.3eq), sodium hydroxide (0.22kg, 1.3eq), 6.5L water, and 4.5L tetrahydrofuran into a 30L reactor and stir to dissolve at room temperature. Cool down to 0-10°C i...

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Abstract

The invention discloses a preparation method of enalapril maleate, which comprises dissolving disodium hydrogen phosphate in water, adding dichloromethane, N-[(S)-1-ethoxycarbonyl-3-phenylpropyl] ‑L‑alanine, dripping triphosgene solution at room temperature generates key intermediate N‑[(S)‑1‑ethoxycarbonyl‑3‑phenylpropyl]‑L‑alanine‑N‑carboxylic acid anhydride, and then Condensation with L-proline and salification of maleic acid can produce crude enalapril maleate, which can be purified with high purity enalapril maleate after one water purification. The preparation method of the invention fully utilizes the theory of atomic economy, and is easy to operate, low in cost and pollution-free. It is suitable for large-scale industrial production; and after only one refinement, the chromatographic purity can reach more than 99.7%, and the total yield is more than 50%. In addition, the preparation method has mild reaction conditions, less pollution, high yield and product purity, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of enalapril maleate. Background technique [0002] Enalapril maleate is a second-generation angiotensin-converting enzyme inhibitor (ACEI). It is clinically used to treat hypertension and congestive heart failure. Due to its definite antihypertensive effect, few side effects, and long-term medication does not produce tolerance, it has been widely used as a first-line antihypertensive drug. Its structural formula is as follows: [0003] [0004] At present, there are two main methods for the preparation of enalapril maleate reported in the literature: one is obtained by Michael addition of ethyl β-benzoylacrylate and benzyl L-alanine to tosylate intermediate, and then obtained N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanine by high-pressure hydrogenation. Condensation reaction of N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanine with L-proline and sa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/02C07K1/02
CPCC07K5/0222
Inventor 邹贻泉宣景安于帅朱云龙张贤斌于向东陈令武蔡伟刘景龙李浩冬
Owner YANGTZE RIVER PHARM GRP CO LTD
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