Ramipril intermediate synthesis method

Abstract

The invention discloses a ramipril key intermediate synthesis method. The ramipril key intermediate is shown in the formula I. The method comprises that a compound shown in the formula VI and an amide compound shown in the formula V undergo a condensation reaction to produce a compound shown in the formula IV, the compound shown in the formula IV and an enamine compound shown in the formula III undergo an addition reaction to produce a compound shown in the formula II, the compound shown in the formula II and benzyl alcohol undergo a hydrolytic cyclization reaction and an esterification reaction in the acid solution, and the product is reduced by a reducer to form the ramipril key intermediate shown in the formula I. The ramipril key intermediate synthesis method has the advantages of simple processes, mild reaction conditions, no heavy metal pollution, use of a chlorinated reagent, simple post-treatment, safe and reliable operation and less three wastes.

Description

(1) Technical field [0001] The invention relates to the field of synthesis of pharmaceutical and chemical intermediates, in particular to the synthesis of ramipril key intermediate racemic-2-azabicyclo[3.3.0]octane-3-carboxylate by using amide and pyruvic acid or its esters as raw materials The synthetic method of benzyl acid hydrochloride. (2) Background technology [0002] Ramipril (Ramipril) is a long-acting, potent angiotensin-converting enzyme inhibitor (ACEI), developed by the German Hearst company (EP0079022) for the treatment of mild and primary hypertension. Drug of choice for blood pressure and renal hypertension and moderate and malignant congestive heart failure. It was launched in France for the first time in 1989. The drug is fast and strong, has a long duration of action, and has little side effects. It has been sold in more than 20 countries. It was launched in China in 1999 and has been widely used in large and medium-sized cities across the country. [0...

AI Technical Summary

Problems solved by technology

[0005] In 1986, Schering proposed a route to synthesize key intermediates (US4587258A, 1986) using cyclopentanone and ethyl bromopyruvate as starting materials. , and the reaction conditions for the removal of benzyl groups by hydrogenation reduction are harsh and need to be carried out under the condition of more than 100bar, which requires high pressure resistance of the equipment and the yield is not high

[0006] Subsequently, Hoechst company has reported the imine structure that replaces benzylamine and cyclopentanone condensation with 2-chlorocyclopentene formaldehyde, replaces the route (US5550255A , 1996), but the process uses a large amount of phosphorus oxychloride, environmental problems are prominent and hydrogenation conditions are harsh

[0007] In 2011, Kerry Company proposed a new synthetic process route using cyclopentanone to synthesize 2-chlorocyclopentene formaldehyde and hippuric acid as starting materials, but used a valuable chiral catalyst (a ligand for rhodium), and concentrated sulfuric acid Make carbonization more serious (US2011257408A1, 2011)

[0008] Summarize the common problems of the currently reported synthetic routes: complex steps, low yield, low atom utilization, harsh reaction conditions, unfriendly to the environment, heavy metal catalysis, etc.

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