Synthesis Of SIPI-4529 And Abacavir

This dissertation focuses on the synthetic process of SIPI-4529, a novel antifungal agent discovered by Shanghai Institute of Pharmacuetical Industry and Abacair sulfate, an anti-AIDS drug launched to market by GlaxoSmithKline.3-Amino-10-bromo-8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[l,2-b]pyridinyl-ll-one(I) was served as the starting material for preparation of 10-bromo-3,8-dichloro-11 -imidazol-1-yl-6,11 -dihydro-5H-benzo[5,6]cyclohepta[ 1,2-b]pyridine (SIPI-4529). I was underwent the diazotization, Sandmeyer reaction and reduction with NaBHU to form 10-bromo-3,8-dichloro-6,ll-dihydro-5H-benzo[5,6]cyclohepta [l,2-b]pyridine-ll-ol(III), which was subjected to chloration, followed by condensation with imidazole to form SIPI-4529. The total yield of the five reactions was 35%. SIPI-4529's dextro-isomer or levo-isomer was resolved by (+)-dibenzoyl-D-tartaric acid or (-)-dibenzoyl-L-tartaric acid, respectively. The in vitro antifungal test showed that the levo-isomer had weaker antifungal activity while the raceme was as potent as the dextro-isomer. In order to obtain the more soluble compounds for the in vivo antifungal test, the different salts of SIPI-4529, such as the nitrate, hydro-chloride, methanesulfonate were prepared. Their aqueous solubility test showed that SIPI-4529's nitrate(Va) was over five times more soluble than the base. In addition, the hydrochloride of the dextro-isomer(VIa) was prepared. The in vivo antifungal test of Va and VIa is on process.AIDS has become a serious social burden today. Abacavir sulfate possesses strong anti-HIV activity and has synergistic action in combination with Lamivudine and/or Zidovudine. Thus, it becomes one important component in Cocktail Therapy of AIDS.The synthesis of abacavir sulfate was demonstrated as the following: cyclopentadiene and glyoxylic acid underwent the Diels-Alder reaction, acylation with butyric anhydride, enzymatic hydrolysis, respectively, to form (1R,4S,5R)-(-)-4-endo-hydroxy-2-oxabicyclo[3.3.0]oct-7-en-3-one((-)-VIIIa), which was further reduced with LiAlH4, followed by oxidation with NaIO₄, reduction with NaBH₄ and acetylation to give (lR,2R)-2-acetoxy-cyclopent-3-en-l-methanol acetate(XIV). XIV was converted to abacavir sulfate in three steps: condensation with 2-amino-6-cyclo-propylamino-9H-purine, hydrolysis in NaOH solution and salt formation with sulfuric acid. The structure of abacavir sulfate was confirmed by HPLC, elemental analysis, IR, ¹HNMR, H-Hcosy, ¹³CNMR, DEPT, HMQC and MS.