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拉坦前列素是治疗青光眼和高眼压症的首选药物.现有合成方法存在路线长、收率低、异构体杂质难以分离等问题.本研究以苯甲酰基科里内酯为原料,氧化后与2-氧代-4-苯丁基膦酸二甲酯通过改良Horner-Wadsworth-Emmons反应形成ω侧链,经还原、脱保护、氢化、四氢吡喃基(THP)保护、还原内酯得到内半缩醛,然后以(4-羧基丁基)三苯基溴化鏻与六甲基二硅基胺基钠(NaHMDS)形成磷叶立德通过Wittig反应形成α侧链,经酯化、脱保护基后,合成了拉坦前列素,并用正相液相色谱法纯化,制得终产物,产物用1H NMR,13C NMR,IR和HRMS进行了结构表征.结果表明,拉坦前列素纯度达99.91%,总收率为19.2%.为拉坦前列素的合成提供一种高收率、高纯度、可大批量合成的新方法.
Latanoprost is the drug of choice for the treatment of glaucoma and ocular hypertension.The existing synthesis methods have the problems of long route, low yield, difficult separation of impurities of isomers, etc. In this study, benzoylcorrylolide was used as raw material, After oxidation, the omega side chain is formed by the reaction of modified Horner-Wadsworth-Emmons with dimethyl 2-oxo-4-phenylbutylphosphonate, which is reduced, deprotected, hydrogenated and protected by tetrahydropyranyl (THP) Lactone to give the hemiacetal, and then (4-carboxybutyl) triphenylphosphonium bromide and sodium hexamethyldisilazane (NaHMDS) to form phosphorus ylide by Wittig reaction to form α side chain, esterified , After deprotection, latanoprost was synthesized and purified by normal-phase liquid chromatography to obtain the final product, which was characterized by 1H NMR, 13C NMR, IR and HRMS.The results showed that latanoprost Purity of 99.91%, the total yield of 19.2% for the synthesis of latanoprost provided a high yield, high purity, high-volume synthesis of new methods.