Preparation methods of antihypertensive Fosinopril sodium and key intermediate thereof

A technology for intermediates and compounds, applied in the field of preparation of trans-4-phenyl-L-proline (Formula V), which can solve the problems of low yield, high cost, difficulty in industrial production, and high ee value of products

Active Publication Date: 2017-11-21
CHANGZHOU PHARMA FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the synthetic route 1, the intermediate L6 has two chiral centers, but a single-configuration L6 can be obtained through isopropyl ether recrystallization and cinchonidine resolution. The resolution method is simple to operate, and the obtained The ee value of the product is high; in the synthetic route 2, after separation is involved and the yield is low, the cost is high and it is difficult to realize industrial production

Method used

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  • Preparation methods of antihypertensive Fosinopril sodium and key intermediate thereof
  • Preparation methods of antihypertensive Fosinopril sodium and key intermediate thereof
  • Preparation methods of antihypertensive Fosinopril sodium and key intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0028] 1) Preparation of compound VII:

[0029]

[0030] Add methanesulfonic acid (3.24 g), triphenylphosphine (9.21 g) and toluene (70 ml) into the reaction flask, start stirring, the solution is a suspension, control the temperature of the suspension to 20°C, add azodicarboxylic acid Diisopropyl ester (7.95 g), keep the system temperature below 35°C. Add compound VIII (7.0 g) into the reaction flask, then add triethylamine (1.14 g), and stir for 10 min. Heating, heating up to 65°C, TLC spot plate tracking. After reacting for 3 hours, water (100 ml) and ethyl acetate (100 ml) were added to the reaction liquid, extracted twice, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 11.2 g of oil. Add the oil (11.2 g) and aqueous solution (25 ml) of sodium hydroxide (1.68 g) into a 250 ml reaction flask, stir vigorously at 5°C for 2 h, and adjust the pH to 6-7 with 6N hydrochloric a...

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Abstract

The invention relates to preparation methods of an antihypertensive Fosinopril sodium and a key intermediate thereof trans-4-phenyl-L-proline suitable for industrial production. Synthesis of the key intermediate trans-4-phenyl-L-proline has high chiral selectivity, and the method is simple and easy to operate.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of the antihypertensive drug fosinopril sodium (formula I) and its key intermediate trans-4-phenyl-L-proline (formula V). [0002] Background technique [0003] Angiotensin-converting enzyme inhibitors (ACEI) are a class of highly effective and safe cardiovascular system drugs with outstanding clinical efficacy and good tolerance in the treatment of hypertension and heart failure. Since the first angiotensin-converting enzyme inhibitor (ACEI) drug Captopril (Captopril) came out in 1977, the first generation of ACEI drugs have appeared one after another, and the representative drug is Captopril; the second generation ACEI drugs, the representative drug is Enalapril; Fosinopril is the first representative drug among the third generation ACEI drugs. [0004] Fosinopril is the only ACEI containing a phosphinate group. It has strong lipophilicity, slow onset of action,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16C07F9/572
CPCC07B2200/07C07D207/16C07F9/572
Inventor 刘全涛金晓峰巫美金
Owner CHANGZHOU PHARMA FACTORY
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