Preparation method of enalapril maleate

A technology of enalapril maleate and maleic acid, applied in the field of preparation of enalapril maleate, can solve problems such as unfavorable industrialized production, increased production cost, long reaction time, etc., and achieves the advantages of avoiding toxic reagents. The effect of using, small amount of three wastes, and short reaction steps

Inactive Publication Date: 2021-01-15
CISEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This synthetic method yield is higher, but the required temperature of this reaction process is higher, and the reaction time is longer (generally more than 50 hours), also can produce a large amount of acid gases, and the possibility that phosgene is emitted, will be on the one hand A large amount of three wastes are produced, and on the other hand, the production cost is increased, which brings great safety hazards to production, and this process is not conducive to industrial production.

Method used

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  • Preparation method of enalapril maleate
  • Preparation method of enalapril maleate
  • Preparation method of enalapril maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) Weigh 50g of L-alanine and 34g of sodium hydroxide into the reaction flask, add them into 300ml of purified water, start stirring, cool down to 0°C, and weigh 160g (Boc) 2 O, be dissolved in the THF of 300ml, control reaction temperature 0 ℃, (Boc) 2 The THF solution of O was added dropwise to the reaction system, and then the temperature was raised to 20° C. for 16 h. After the reaction, extract twice with petroleum ether 2*250ml, discard the organic phase, adjust the pH of the aqueous phase to about 2 with 10% hydrochloric acid, then extract four times with ethyl acetate 4*300ml, combine the organic phases, dry Dry over sodium sulfate, filter and concentrate to obtain intermediate 1.

[0035] (2) Measure 2L of dichloromethane, add it to a 5L three-necked flask, add 102g of intermediate 1 into the reaction system, protect it with nitrogen, cool down to -5°C, add 90g of phosphorus trichloride dropwise, and continue the reaction for 2 hours after the addition is com...

Embodiment 2

[0041] (1) Weigh 50g of L-alanine and 80g of potassium carbonate into the reaction flask, add them to 300ml of purified water, start stirring, cool down to 5°C, and weigh 180g (Boc) 2 O, be dissolved in the THF of 300ml, control reaction temperature 5 ℃, (Boc) 2 The THF solution of O was added dropwise into the reaction system, and then the temperature was raised to 30° C. for 24 h. After the reaction, extract twice with petroleum ether 2*250ml, discard the organic phase, adjust the pH of the aqueous phase to about 2 with 10% hydrochloric acid, then extract four times with ethyl acetate 4*300ml, combine the organic phases, dry Dry over sodium sulfate, filter and concentrate to obtain intermediate 1.

[0042] (2) Measure 2L of dichloromethane and add it to a 5L three-necked flask, add 102g of intermediate 1 into the reaction system, protect it under nitrogen, cool down to 5°C, add 90g of thionyl chloride dropwise, and continue the reaction for 2h after the addition. After the...

Embodiment 3

[0048] (1) Weigh 50g of L-alanine and 80g of potassium carbonate into the reaction flask, add them into 300ml of purified water, start stirring, cool down to 3°C, and weigh 180g (Boc) 2 O, be dissolved in the THF of 300ml, control reaction temperature 3 ℃, (Boc) 2 The THF solution of O was added dropwise into the reaction system, and then the temperature was raised to 25° C. for 24 h. After the reaction, extract twice with petroleum ether 2*250ml, discard the organic phase, adjust the pH of the aqueous phase to about 2 with 10% hydrochloric acid, then extract four times with ethyl acetate 4*300ml, combine the organic phases, dry Dry over sodium sulfate, filter and concentrate to obtain intermediate 1.

[0049] (2) Measure 2L of dichloromethane and add it to a 5L three-necked flask, add 102g of intermediate 1 into the reaction system, protect it under nitrogen, cool down to 5°C, add 100g of phosphorus oxychloride dropwise, and continue the reaction for 2 hours after the additi...

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Abstract

The invention discloses a preparation method of enalapril maleate. The preparation method comprises the following steps of adding L-alanine, alkali and water into a container, cooling, adding a (Boc)2O solution, performing heating, stirring and reacting to obtain an intermediate 1; adding the intermediate 1 into a solvent, cooling, adding a chlorination reagent under the protection of nitrogen, and performing stirring for reaction to obtain an intermediate 2; adding L-proline and alkali into water for reaction, then adding the intermediate 2, and carrying out heat preservation reaction to obtain an intermediate 3; adding 2-oxo-4-phenyl ethyl butyrate, the intermediate 3, a molecular sieve and a reducing agent into a solvent, and reacting under set pressure to obtain an enalapril crude product; and dissolving the enalapril crude product, adding maleic acid, and stirring for reaction to obtain enalapril maleate. The method has the advantages of safe and easily available starting materials, low price, relatively short reaction steps, avoidance of the use of toxic reagents, relatively small generation amount of three wastes, relatively simple operation, high product purity, high yield, and suitableness for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method of enalapril maleate. Background technique [0002] Enalapril maleate is a second-generation angiotensin-converting enzyme inhibitor (ACEI), developed by Merck. Enalapril maleate is the first ACEI without sulfhydryl groups. It is clinically used to treat hypertension and congestive heart failure, reduce mortality and improve hemodynamics and symptoms. Due to its definite antihypertensive effect and small side effects , and long-term use does not produce tolerance, so it has been widely used as a first-line antihypertensive drug. [0003] The basic information of the compound is as follows: [0004] Chemical name: N-[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl-L-proline maleate [0005] English name: Enalapril maleate CAS number: 76095-16-4 [0006] Chemical structure: [0007] [0008] According to bibliographical reports, the synthes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K1/02
CPCC07K5/06026
Inventor 许应玉李中井鞠金军尹彦庆
Owner CISEN PHARMA
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