Synthesis Of Deuterium-labelled Fosamprenavir Calcium

Fosamprenavir (the brand name is Lexiva), developed by Glaxo Wellcome Inc. and Vertex Inc., is an effective therapeutic agents for the treatment of HIV infection. As the phosphate ester pro-drug of the protease inhibitor amprenavir, fosamprenavir has improved solubility and bioavailability over the parent protease inhibitor. It was approved by the FDA and came onto the market in October 2003. Deuterium-labelled fosamprenavir can be used as the internal standards for bioavailability and bioequivalent studies of fosamprenavir. But the synthesis of fosamprenavir-d4 have not been described previously. Fosamprenavir labelled with stable isotopes of hydrogen was required for drug metabolism studies and bioavailability studies.In this thesis, the synthesis of deuterium-labelled fosamprenavir was prepared starting from L-phenylalanine in eighteen steps. Reduction of compound 1 with Pd/C and ammonium formate produced 2. Treatment of compound 2 with acetic anhydride gave 3, which was then reacted with chlorosulfonic acid (HSO3Cl) and gave 4. Compound 4 was treated with 10% NaOH to generate 5. The oxidation of compound 5 with 30% H2O2 in acetic acid yielded 6. This compound 6 was treated with PCl5 to form 7. Compound 9 was prepared by reacting L-phenylalanine with sodium borohydride and iodine. Compound 9 was treated with benzyl bromide and K2CO3 to yield 10. The oxidation of compound 10 with Pyridine-sulfurtrioxide complex produced 11. Treatment of compound 11 with lithium and bromochloromethane, and then quenched with 6M HCl to give 12. Hydrogenolysis of compound 12 under standard conditions (1 atm H2, MeOH, 20% Pd(OH)2/C) gave 13. Protection of the amine of 13 with di-tert-butyl dicarbonate and triethylamine in THF, followed by in situ epoxide ring closure with methanolic potassium hydroxide, gave 14. Treatment of compound 14 with isobutyl amine gave 15. Conversion of compound 15 into 16 using p-[2H4]-nitrobenzenesulfonyl chloride 7 and triethylamine in toluene and subsequent treatment with concentrated hydrochloric acid gave 16. Compound 16 reacted with (S)-3-Hydroxytetrahydrofuran and bis(trichloromethyl)carbonate to produce 17. The reaction of compound 17 and PClO3, followed by the hydrolysis using 6M HCl afforded 18. Compound 18 was treated with 10% Pd/C and H2 to give 19. Compound 19 was treated with calcium acetate monohydrate to produce target compound 20.