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Anti - AIDS drug Fosamprenavir and anti- hepatitis B drug AD Study of the Synthesis

Author: XuPeng
Tutor: YangPing
School: East China Normal University
Course: Organic Chemistry
Keywords: Fight AIDS Study on the Synthesis New drugs Non - enantiomer Adefovir Adenine US-listed Hepatitis B The reaction yield NaBH4
CLC: TQ463
Type: Master's thesis
Year: 2004
Downloads: 172
Quote: 1
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Abstract


The first part of this thesis is the synthesis of anti-AIDS drug Fosamprenavir research. Fosamprenavir is a prodrug of the protease inhibitors amprenavir, is a highly water-soluble low-active phosphate ester, medication, there are good prospects for development. The product jointly developed by GSK and Vertex, in October 2003 in the United States. L-phenylalanine as raw material, through oxidation, nucleophilic addition, dehydration cyclization, condensation and other 18-step reaction (including the synthesis of the two side chains) completed the total synthesis of the target molecule. Important part of the reaction and the operation has been improved: NaBH 4 / I 2 instead of NaBH 4 / H 2 < / sub> SO 4 Restore L-phenylalanine, making it easy to operate and suitable for industrial; Swern oxidation alternative SO 3 . The pyridine / DMSO oxidation, making phenylalaninal yield increased from 70% to over 90%; improved with a one-step preparation of nitrobenzene sulfonyl chloride brief reaction steps, from 19% to 31% ; recrystallized by finding suitable solvents separated diastereomeric isomers and diastereomeric isomers generated by analysis of the reaction mechanism that is the reason for the low yield of this reaction; the to try directly BOC protected amphetamine aldehyde with sulfur ylide reaction and the use of the steric effect induced to generate the required epoxide, but also on the steric chiral induction of the study; tries to study the HKR reaction to the preparation of intermediates obtained, in order to find of chiral inducing effect HKR reaction. The second part of this thesis is the anti-hepatitis B drug AD ester synthesis. Adefovir dipivoxil (adefovir dipivoxil) adenine phosphate compound, adefovir, adefovir prodrug rapidly hydrolyzed after oral administration of adefovir exert antiviral activity. This product is developed by Gilead Sciences, and in 2002 in the United States. From adenine, condensation, nucleophilic substitution, hydrolysis skim, esterification six-step reaction completed the total synthesis of adefovir dipivoxil. Partial response link analysis and improvement: the adenine substitution reaction occurs mainly in the 9 - position, sometimes a small amount of 3 - substituted by-product formation; 9 - [2 - (diethoxy-phosphono methoxy) ethyl] adenine Synthesis Improvement, instead of NaH t-BuONa, so that the yield and the reaction has been greatly improved security, the yield from 29% to 39%; in the preparation of A experiment of the Defu Wei ester, the reaction temperature was controlled to improve the reaction yield, so that the product was purified easy and at the same time also reduce the reaction byproducts. For the two intermediate synthesis method suitable for industrial production.

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