Preparation method of N-carboxyalkyl dipeptide type angiotensin converting enzyme inhibitor

A technology of carboxyalkyl dipeptide type and angiotensin, which is applied in chemical instruments and methods, dipeptide, cardiovascular system diseases, etc., can solve the problem of overdose, and achieve the effect of simple and efficient process

Inactive Publication Date: 2003-07-16
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The defect is that an excessive amount of highly toxic gas phosgene is used in the preparation of NCA

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of (S)-N-((1-ethoxycarbonyl)-3-phenylpropyl)-L-alanine-N-carboxylic acid anhydride:

[0025] Dissolve 45 g (0.15 mol) of bis(trichloromethyl) carbonate and 27.9 g (0.1 mol) of (S)-N-((1-ethoxycarbonyl)-3-phenylpropyl)-L-alanine Add 180ml of anhydrous tetrahydrofuran, stir at 50°C until the reaction is complete, and then distill off tetrahydrofuran under reduced pressure. 90 ml of n-hexane was added to the residue, followed by stirring and crystallization. Filter and dry in vacuo to get (S)-N-((1-ethoxycarbonyl)-3-phenylpropyl)-L-alanine-N-carboxylic acid anhydride: melting point 68~72°C, [α] 25 D +11.0°-+13.0° (c=1, CH 3 CN).

Embodiment 2

[0027] Preparation of (S)-N-((1-ethoxycarbonyl)-butyl)-L-alanine-N-carboxylic acid anhydride:

[0028] Add (S)-N-((1-ethoxycarbonyl)-butyl)-L-alanine 4g (18.4mmol) and dichloromethane 20ml into a 100ml reaction flask, add bis(trichlorohydrin) carbonate at 20°C Methyl) ester 5.5g (18.4mol) and dichloromethane 20ml solution, stirred at reflux for 30h, concentrated to dryness. Add 20ml of dichloromethane, and then concentrate to dryness. The above operation was repeated twice to obtain an oily substance, which gradually solidified to obtain (S)-N-[(1-7,oxycarbonyl)-butyl)-L-alanine-N-carboxylic acid anhydride.

Embodiment 3

[0029] The preparation of embodiment 3 enalapril maleate:

[0030] Dissolve 17.3g (0.15mol) of L-proline, 6g (0.15mol) of sodium hydroxide and 15.9g (0.15mol) of sodium carbonate in 300ml of water, add (S)-N-((1-ethoxycarbonyl) - A solution of 30.5g (0.1mol) of -3-phenylpropyl)-L-alanine-N-carboxylic acid anhydride in 600ml of tetrahydrofuran, stirred at 5°C for 1h. The pH of the reaction solution was adjusted to 4.25 with 6 mol / L hydrochloric acid, and tetrahydrofuran was distilled off under reduced pressure. The resulting aqueous solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil.

[0031] The above oil was dissolved in 100ml of acetonitrile at 60°C, a solution of 11.6g (0.1mol) of maleic acid in 180ml of acetonitrile at 60°C was added, and crystallized by cooling. Filter and recrystallize with water to obtain enalapril maleate, melting point 142-143°C, [α] 25 D -4...

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Abstract

A process for preparing N-carboxyalkyl dipeptide type angiotensin converting enzyme (ACE) depressant (such as enalapril maleate, ramipril, etc) includes such steps as preparing N-carboxylic acid anhydride from bis (trichloromethyl) carbonate, and coupling with relative alpha-amino acid.

Description

technical field [0001] The invention relates to a preparation method of an angiotensin-converting enzyme (ACE) inhibitor of N-carboxyalkyl dipeptide structure type. Background technique [0002] N-carboxyalkyl dipeptide structure type Angiotensin-converting enzyme (ACE) inhibitors are a class of safe and effective drugs for the treatment of hypertension and congestive heart failure, including enalapril maleate and lisinopril, which are best-selling in the world Drugs play an important role in cardiovascular drugs. Its structural general formula is as follows: where: R 1 =C 3 h 7 -; R 2 =CH 3 -; CF 3 CONH(CH 2 ) 3 CH 2 -; NH 2 (CH 2 ) 3 CH 2 -R 3 = H, C 2 h 5 [0003] Existing many patent literatures have reported the preparation method of this type of medicine at present, as: reports such as Jerry WSkiles (Organic Preparations and Procedures International, 1988,20 (2): 109-115) by first preparing N-carboxylic anhydride (N-CarboxyAnhydride, NCA), the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P9/04A61P9/12C07K5/06
Inventor 时惠麟张庆文钟静芬单晓燕陈国梁周明华
Owner SHANGHAI INST OF PHARMA IND CO LTD
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