Synthesis method of ramipril key intermediate

Abstract

The invention discloses a synthesis method of a ramipril key intermediate. The ramipril key intermediate is 2-azabicyalo [3.3.0] octane-3-carboxylic acid hydrochloride. The 2-azabicyalo [3.3.0] octane-3-carboxylic acid hydrochloride is obtained through sequential dehydration cyclization, formaldehyde condensation, hydrolysis, removal, Michael addition, cyclization and palladium-carbon catalytic hydrogenation reduction of N-benzoyl-glycine as a raw material. According to the synthesis method of the ramipril key intermediate, the required raw material and reagent are cheap and available, the yield is relatively high, the operation is simple, the cost is low and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical and chemical intermediates, in particular to a method for synthesizing 2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride, a key intermediate of ramipril. [0002] technical background [0003] Angiotensin-converting enzyme (ACE) inhibitors act on the renin-angiotensin system, inhibit the activity of angiotensin-converting enzyme, reduce the production of angiotensin II, and achieve the purpose of lowering blood pressure and anti-heart failure. At present, such drugs mainly include captopril, enalapril, ramipril, perindopril, etc. These drugs significantly lower blood pressure and have a large market demand. [0004] Ramipril (Ramipril) is a drug of choice for the treatment of mild and essential hypertension and moderate and malignant congestive heart failure developed by the German Hearst company. The medicine has the characteristics of fast onset of action, strong action, little tox...

AI Technical Summary

Problems solved by technology

This method is loaded down with trivial details, and productive rate is lower (Urbach.H.J.; Henning.R.; Winfried.H.[P].DE3431541A1.1986-03-06.); (2) take cyclopentanone as starting material, after Claisen ketoester condensation reaction to synthesize α-methylene cyclic ketone, and then Michael addition with the active methylene compound 2-acetamidomalonate dimethyl ester, followed by decarboxylation and ring closure reactions under acidic conditions, and finally Hydrogenation to get 2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride, total yield 33%

Although the total yield of this route is higher, the raw materials are more expensive, the atom economy is lower, and it is difficult to adapt to industrial production (Tang Aihua. [Master's Dissertation]. Shandong University, 2007.); (3) use Vilsmeier reagent to cyclopentane Chloroformylation of ketone followed by Erlenmeyer reaction with benzoylglycine followed by alcoholysis, hydrogenation, hydrolysis, cyclization and hydrogenation to give 2-azabicyclo[3.3.0]octane-3-carboxylic acid Hydrochloride, the total yield is 22.2%

The method has many reaction steps, and uses toxic and harmful reagents, which is not conducive to environmental protection (US2011 / 0257408A1); (4) using ethyl cyanoacetate as a starting material, it is first hydrolyzed into amide compounds, and then mixed with paraformaldehyde Condensation reaction to obtain unsaturated carbonyl compound, then Michael addition reaction with N-cyclopentenylmorpholine, and finally Hoffmann degradation, cyclization and hydrogenation to obtain 2-azabicyclo[3.3.0]octane-3 - Carboxylic acid hydrochloride, the total yield is 25.8%

Although the method has fewer reaction steps and a higher yield, it uses more expensive and harmful reagents, resulting in higher production costs and unfavorable environmental protection (CN101514181A)

The problems in the above synthetic methods are: low yield, difficult separation, unfriendly environment

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