一种合成拉坦前列素的新方法
收稿日期: 2014-03-27
修回日期: 2014-04-23
网络出版日期: 2014-05-23
基金资助
吉林省自然科学基金(No. 201015171)、吉林省科技发展计划(No. 201205017)、吉林省医药产业发展专项资金(No. YYZX201150-2)、长春市科技局社 会发展科技支撑计划(No. 12SF23)资助项目.
A Novel Method for the Synthesis of Latanoprost
Received date: 2014-03-27
Revised date: 2014-04-23
Online published: 2014-05-23
Supported by
Project supported by the Natural Science Foundation of Jilin Province (No. 201015171), the Scientific and Technological Planning Poject of Jilin Province (No. 201205017), the Pharmaceutical Industry Development Special Fundation Project of Jilin Province (No. YYZX201150-2), and the Social Development Science and Technology Supported Planning Project of Changchun Technology Bureau (No. 12SF23).
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.
修志明 , 王立成 , 黄梦媛 , 张鹏 , 郭佑铭 , 张闻起 , 王丽萍 . 一种合成拉坦前列素的新方法[J]. 有机化学, 2014 , 34(9) : 1786 -1792 . DOI: 10.6023/cjoc201403059
Latanoprost is a kind of PGF2α analogues, which is now one of the first-choice drugs in the clinic for open angle glaucoma and ocular hypertension. However, the previous synthetic methods have problems of long steps, low yield and difficult separation of isomeric impurities. Herein, we report a novel method for the synthesis of latanoprost in ten steps. Benzoyl Corey lactone as starting material was oxidized to form corresponding aldehyde by Dess-Martin oxidation. The ω side chain was bonded by improving Horner-Wadsworth-Emmons reaction with dimethyl(2-oxo-4-phenylbutyl)phosphonate and lithium chloride, and reduced with (－)-diisopinocampheyl chloroborane at -30 ℃ because of its greater selectivity towards the production of desired S-isomer (95%). The deprotection step wherein the protecting group of benzoyl on the hydroxyl group of the cyclopentane ring was removed, was preferably carried out by potassium carbonate in methanol. The hydrogenation of double bond in ω side chain was carried out by using 5% palladium-carbon as catalyst. The tetrahydropyranyl (THP) group was used for the protection of the diol with p-toluenesulfonic acid as catalyst. Latanoprost lactol was obtained by reducing the lactone with diisobutylaluminum hydride (DIBAL) at -78 ℃. α side chain of latanoprost was bonded by Wittig reaction with 4-carboxybutyl triphenylphosphoium bromide and NaHMDS forming phosphorus ylide. The carboxylic acid was alkylated with isopropyl iodide in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), and then removed the THP protecting groups with pyridinium 4-toluenesulfonate (PPTS). Latanoprost was separated from two isomers of 15(S)-latanoprost and 5,6-trans-latanoprost after purification by normal-phase high performance liquid chromatography. Thus latanoprost was obtained with high purity of 99.91% and high overall yield of 19.2%, and the structure was characterized by 1H NMR, 13C NMR, IR and HRMS. Compared with the previous routes, the current synthesis is shorter, more practical, and more suitable for large-scale preparation.
Key words： benzoyl Corey lactone; latanoprost; synthesis; purification
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