Studies On The Synthesis Of The Analog Of Ritonavir And The Scalable Approach To Synthesis Of Amprenavir And The Intermediate Of Nelfinavir

As one of the thorny diseases in the medical field, AIDS spreads quickly and threatens the mankind's life seriously. However currently the anti-AIDS pharmaceutical mainly depends on import in our country, especially proteinase inhibitor. The expenditure of treatment is so expensive that the research of anti-AIDS pharmaceutical in our country is an urgent task.On the basis of the literatures and the previous research work in our laboratory, this thesis carries on studies of the synthetic craft of Nelfinavir, Amprenavir and analog of Ritonavir. The main results are as follows:Synthesis of the analog of RitonavirThe synthesis was started from L-phenylalanine. via addition of acetonitrile and 2-methylpridine and 4- methylpridine, the product (I a) and (I b) were obtained and then reduced to formed chiral product (II a) and (II b). After reaction with Thiazole derivative (IE) and (IV), the final product (V) was obtained in an overall yield 11.8% over 9 steps, and the product (VI) and (VII) were also obtained in an overall yield 11.2% and 16.6% respectively.Synthesis of the intermediate of AmprenavirThe synthesis was started with L-phenylalanine. Amino expoxide was synthesized as the key intermediate. After successive reaction with isobutylamine, 4-nitrobenzene-sulfonyl chloride and Pd/C, the final product (VIII) was obtained in an overall yield 31.4% over 9 steps.Synthesis of the intermediate of NelfinavirL-serine was used as the raw material. The lactone ring was formed by the Mitsunibo reaction after the protection with benzyloxycarbonyl chloride. The ring was opened by the substitute of the phenylthiol substitution then the ester was formed with methanol. After Claisen condensation, chlorination and hydrolysis, the final product (IX) was obtained in an overall yield 14.1% over 7 steps.