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Preparation method of ramipril

A compound and organic base technology, applied in the field of preparation of ramipril as an ACE inhibitor drug, can solve the problems of difficult separation of isomers, ineffective effects, and increased industrialization costs, etc.

Inactive Publication Date: 2015-04-15
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] At the same time, the ramipril compound contains 5 chiral centers, and it is difficult to separate the isomers. The patent US5061722 needs to be purified by column separation, and the patent US6407262 uses recrystallization, etc., the effect is not obvious and the cost of industrialization is increased.

Method used

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  • Preparation method of ramipril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1 preparation of benzyl ramipril

[0032] Add dichloromethane (250L), N-[1-(s)-ethoxycarbonyl-3-phenylpropyl]-L-alanine (17.5kg), (s,s,s) to the reaction kettle in sequence -2-Azabicyclo[3,3,0]octane-3-carboxylic acid benzyl ester hydrochloride (17.7kg), DCC (15.5kg), HOBt (8.5kg), stirring (210rpm), temperature control 10 ℃; slowly add triethylamine (13L) to the above kettle, and finish adding in about 1 hour, and control the temperature at about 10 ℃; after adding triethylamine, keep warm at about 10 ℃ and stir for 6 hours; ; Slowly add 50L0.5mol / L hydrochloric acid to the filtrate, stir rapidly (300rpm), stir and react for 1h; centrifuge and filter, separate liquid, collect organic phase; use saturated sodium bicarbonate solution to wash 3 times (200L / time); separate liquid, Collect the organic phase and wash it once with deionized water (200L / time); separate the liquid, collect the organic phase, and concentrate under reduced pressure (30°C-40°C, vacuum ...

Embodiment 2

[0033] Embodiment 2 preparation of benzyl ramipril

[0034]Add dichloromethane (250L), N-[1-(s)-ethoxycarbonyl-3-phenylpropyl]-L-alanine (16.5kg), (s,s,s) to the reaction kettle in sequence -2-Azabicyclo[3,3,0]octane-3-carboxylate benzyl sulfate (19.5kg), DCC (16.3kg), HOBt (7.3kg), stirring (240rpm), temperature control 15℃ About; slowly add triethylamine (15L) to the above kettle, and finish adding in about 1.5h, and control the temperature at about 16°C; after adding triethylamine, keep warm at about 10°C and stir for 6h; ; Slowly add 45L0.5mol / L hydrochloric acid to the filtrate, stir rapidly (300rpm), stir and react for 2h; centrifuge and filter, separate liquid, collect organic phase; use saturated sodium bicarbonate solution to wash 3 times (250L / time); separate liquid, Collect the organic phase and wash it once with deionized water (250L / time); separate the liquid, collect the organic phase, and concentrate under reduced pressure (30°C-40°C, vacuum degree-0.08Mpa-0.1M...

Embodiment 3

[0035] Embodiment 3 Ramipril crude product preparation

[0036] Transfer the oil obtained in Example 1 to a hydrogenation reactor, add 95% ethanol (200L), 10% palladium carbon (1.8kg), and seal it; nitrogen replaces the air in the reactor; after the replacement, feed hydrogen (pressure 0.4MPa- 0.45MPa), the temperature is controlled at about 15°C, the stirring is started, and the heat preservation and pressure reaction is carried out; the hydrogen pressure indication number has not decreased, and the hydrogenation is continued for about 3.5h; the reaction is completed, exhausted, and replaced by nitrogen; The filtrate was collected; the filtrate was concentrated under reduced pressure (30°C-40°C, vacuum degree -0.08Mpa-0.1Mpa); after concentration, an oily substance (20.7kg, yield 82.6%) was obtained.

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Abstract

The invention relates to a large-scale industrialized preparation method of ramipril. The preparation method includes following steps; (1) performing a reaction directly from a compound (s,s,s)-2-azobicyclo[3,3,0]octane-3-carboxylic acid derivative and N-[1-(s)-ethoxycarbonyl-3-phenylpropyl]-L-alanine under action of a condensation reagent; and (2) performing catalytic hydrogenation deprotection and a purifying process to obtain the ramipril. In the preparation method, by means of optimization of technology conditions, generation of impurities can be reduced and a DCU residual problem can be solved. The preparation method is more than 60% in total yield and can reach a HPLC detected purity of 99.95%.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of ramipril as an ACE inhibitor drug. Background technique [0002] Ramipril chemical name: (S)-2-[N-(1-ethoxycarbonyl-3-phenyl-propyl)alanyl]-2-azabicyclo[3.3.0] Octane-3-carboxylic acid, the structural formula is as follows: [0003] [0004] Ramipril (Ramipril), as an ACE inhibitor, was first developed by Hoechst in Germany for the treatment of mild and essential hypertension and renal hypertension as well as moderate and malignant congestive heart failure. Its drug effect is fast and strong, the action time is long, and the toxic and side effects are small, and it is a best-selling drug in the market nowadays. Ramipril is a prodrug that is hydrolyzed in the liver after being absorbed from the gastrointestinal tract into an active angiotensin-converting enzyme (ACE) inhibitor—ramiprilat. Taking ramipril can lead to an increase in plasma ...

Claims

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Application Information

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IPC IPC(8): C07K5/065
Inventor 赵志全提文利张健
Owner SHANDONG NEWTIME PHARMA
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