Anti-aids Drug Fosamprenavir And Anti-hepatitis B Drug Ad Ester Synthesis

The first part of this paper relates to a research into a route of synthesizing a new anti-AIDS agent-Fosamprenavir. Fosamprenavir is an inactive phosphate ester that is a highly water soluble prodrug of amprenavir. It allows more convenient dosing as compared to amprenavir and it has been selected for further development. The Vertex Pharmaceutical prepared Fosamprenavir and licensed it to GlaxoSmithKline for development. It was marked in America in 2003.Herein we describe the synthesis of Fosamprenavir: we start from the L-phenylalanine and eventually finish the total synthesis work (including the synthesis of two side chains) in a eighteen-step sequence of reactions including oxidation, nucleophilic substitution, dehydration and cyclization, condensation, etc. In the synthesis of L-phenylalaninol, we make progress in the important conductions and replace the NaBEH4/H2SO4 for NaBH4/I2, making the reaction become safer and more convenient to conduct. In the preparation of Benzyl-phenylalaninal, we use the Swern oxidation instead of the SO3.Pyridine/DMSO and improve the yield from 70% to over 90%. We also improve the operation of the oxidation in the manufacture of para-nitrobenzene sulfonyl chloride, simplify the steps and make the yield arise from 19% to 31%. Furthermore, we disclose the mechanism of the synthesis of chlorohydrin and find that the isomerical product causes the yield become very low. Next we get the suitable solvent to separate the isomerical product. In the experiment of preparing the compound 6, we make the reaction between Boc-phenylalaninal and sulfur ylide directly to produce the oxide under the space effect of the substituent. At the same time, we also do some research in the space effect function on the chiral induction. And we apply the above product to HKR reaction in order to find the effect of the chiral induction function on the HKR reaction.The second part of this paper is on the synthesis of a new antiviral agent AD ester. Adefovir dipivoxil is the prodrug of Adefovir, after being taken into the human body, it can be rapidly hydrolyzed to Adefovir and exhibit its antiviral functions. Thisproduct is researched by Gilead Sciences Co., and it was marked in America in 2002. Herein we start from adenine doing by a series of six reactions for example: condensation, nuleophilic substitution, hydrolysis, esterification, etc. The substitution reaction of the adenine was performed at the 9-substituted mainly, but sometimes it also produce some 3-substitued ones. We make progress in the synthesis of diethyl-PMEA, and replace t-BuONa for NaH, which makes the reaction's yield and safety arise greatly and improve the yield from 29% to 39%. In the preparation of AD ester, we improve the yield by adjusting the reaction's temperature, make the byproduct fewer and also simplify the product's purification. As for the manufacture of two intermediates, we put forward the practical synthetic route, which is suitable to large-scale preparation.