The Synthesis Of Adapalene And Ramipril Intermediate

This paper is made up of the synthesis of the retinoid drugs adapalene and the explore of synthetic route and optimization of anti-hypertension drug Ramipril intermediate.The first part is on the synthesis of adapalene, whose chemical name is 6 -[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid. It is the product of the Galderma Laboratories company for treatment of acne and comedo. The synthesis method of adapalene, as literature referred to was that from 1-adamantanol and 4-bromophenol by Friedel-Crafts reaction and then methylation with dimethyl sulfate to give 2 -(1-adamantanyl)-4-bromoanisole,which subjected to a novel double metal catalyzed coupling reaction with methyl 6-bromo-2-naphthoate and then saponification with an overall yield of 37 %. But there were two times to use column chromatography to purify products, which was unfavorable for industrialization. In this paper, we optimized the synthetic route, abolished column chromatography purification. Compared with literature, there were many merits in our method, such as simple art, easy operation and high total yields about 74%. The structures of the products were characterized by ~1HNMR, IR and MS.The other part is on the synthesis of the Ramipril intermediate, (S, S, S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid. The method from the literature was that the cyclopentenopyrrolidine reacted with the chloroalanine derivative, then through hydrolyzation, cyclation and hydrogenation to give the product. Owing to the chloroalanine derivative was very expensive, so that, we designed a new way to synthesis the intermediate, with choosing the correspondingly cheap materials to substitute chloroalanine derivative. Firstly, cyclopentanone diethyl oxalate and formaldehyde were used to prepare a-methylene cyclopentanone which catalyzed by alkali. Secondly, a-methylene cyclopentanone reacted with the acetamidyl dimethyl malonate to produce the key foregoing intermediate, which can change into 2-azabicyclo-[3.3.0]octane-3-carboxylic acid through hydrolyzation acidification, cleavage of carboxyl, cyclation and hydrogenation. Because we didn't have so much time, all of our work was mainly to produce the key foregoing intermediate, and the work about hydrolyzation which catalyzed by Pd/C was undergoing.