Study On The Syntheses Of Prostaglandin E Analogs

Preparation of prostaglandin E analogs with 1,4-addition reaction of organozinc agent contains three parts:① study of the syntheses of substituted cyclopentenones. ② study of the syntheses of ω-side chain compounds ③ study on preparations of prostaglandin E analogs by 1,4-additon reaction of ω-side chain compounds and substituted cyclopentenones.A synthetic route of ethyl β-(2-furyl)propionate from furfural and ethyl acetate was designed. The experiment approach that is low cost ,high yield and facile operation was built through optimum selection of the reaction conditions. From ethylβ-(2-furyl)propionate, 2-(6-carboxyl-2-cis- hexenyl)-4-hydroxy-2- cyclopentenone was synthesized via several steps. For latter 1,4-conjugate addition reaction, the compound was further changed into 2-(6-trimethylsilyloxycarbonyl-2-cis-hexenyl)-4-trimethylsilyloxy-2-cyclo -pentenone by reaction with chlorotrimethylsilane and hexamethyldisilazane. 2-(6-methoxylcarbonylhexyl)-4-hydroxyl-2-cyclopentenone was prepared starting from 10-undecylenic acid. The synthetic routes of two substituted cyclopentenone were also compared.Based on hexanoyl chloride, the syntheses of 1-bromo-1-octen-3-ol, 1-bromo-3-metnyl-1-octen-3-ol, 1-bromo-3-phenyl-1-octen-3-ol, 1-iodo-1- octen-3-ol, 1-iodo-3-methyl-1-octen-3-ol and 1-iodo-3-ethyl-1-octen-3-ol were completed. In preparation of these halo alkenol , for inducing the addition reaction of the Grignard agent with carbonyl in molecular of halide alkenone and reducing the coupling reaction of the Grignard agent with akenyl halide in the molecular, the experiment indicated that the yield of halide alkenol from Grignard agent and halide alkenone reached a peak at -5～0℃.The analytic results on the yields of these compounds show that its yield is lower as the 3-position's alkyl is bigger. Starting from benzoyl chloride and acetylene, by catalysis of AlCl3, trans-1-chloro-3-phenyl-1- propen-3-one was first prepared in dry dichloromethane at 20～25℃, which the yield is higher 7% than that in CCl4 at 40～45℃. After two-step reactions(halogen interchange and reduction) of trans-1-chloro-3-phenyl-1- propen-3-one, a new compound, trans-1-iodo-3-phenyl-1-propen-3-ol was obtained.That 1,4-addition reactions of Grignard agent made from 1-bromo-3- triphenylmethoxyl-1-octene and organozinc agent made from 1-iodo-3- trimethysiloxy-1-octene with 2-(6-methoxylcarbonylhexyl)-4-(2- tetrahydro -pyranyloxy)-2-cyclopentenone both gave prostaglandin E1 methyl ester state that prostaglandin E compounds can be prepared by 1,4-addition reaction of organozinc agent. Research results on the reaction conditions indicated that under catalysis of CuCN, addition yield of organozinc agent is higher 10% than that of Grignard agent. Simultaneously, 15-methyl PGE1 methyl ester, 15-ethyl PGE1 methyl ester and 15-phenyl-16,17,18,19,20-pentnor- prostaglandin E1 methyl ester were also synthesized by 1,4-addition approach of organozinc agent. This also illustrate that the method is suitable for large area.