New Process For The Synthesis Of Angiotensin Converting Enzyme Inhibitor-Quinapril Hydrochloride

Quinapril hydrochloride is a novel kind of Angiotensin Converting Enzyme Inhibitors(ACEI) for treating hypertension with minimal toxicity, good effect. It can be synthesized with many methods. However, those methods have several shortcomings, such as long synthetic process, high cost, serious pollution and difficulty in industrialization. Therefore it is important to develop new synthetic process of Quinapril hydrochloride with low cost, less pollution and feasibility in industrialization.Referring to the literature home and abroad, Quinapril hydrochloride was synthesized according to following route. Firstly, ethyl 3-benzoylacrylate was synthesized using acetophenone and glyoxylic acid as starting materials. Secondly,N-[(1-(S)-ethoxycarbonyl-3-phenylpropyl)]-L-alanine(NEPA) was synthesized through the Michael addition of ethyl 3-benzoylacrylate and L-alanine phenylmethyl ester, then hydrogenization.Thirdly, phenylmethyl 2-[2-[[1-(Emoxywu-bonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate was synthesized through the condensation of NEPA activated by triphosgene with phenylmethyl 1,2,3,4-tetrahypro-3-isoquinolinecarboxylate. Finally, Quinapril hydrochloride was obtained through the debenzylation of the above ester.The better synthetic conditions of ethyl 3-benzoylacrylate were as follows: n(acetophenone): n(glyoxylic acid) :n(ethanol):n(catalyst)=1.00:1.25:5.07:0.02, esterification temperature 85 ℃, esterification time 3 h, dehydration temperature 120℃, dehydration time 9 h. Under these contions, the yield of ethyl 3-benzoylacrylate was 78.2% and the mass fraction was 91.07%.Compared with the method using maleic anhydride and benzene as raw materials, this method has several merits, such as feasibility in industrialization, less pollution, low cost and so on.The better conditions of the Michael addition of ethyl 3-benzoylacrylate and L-alanine phenylmethyl ester were as follows: n(ethyl 3-benzoylacrylate) :n(L-alanine phenylmethyl ester p-toluenesulfonate):n(triethylamine)=1.0:1.0:1.2, reaction time 32 h, reaction temperature 15 ℃.