Chinese Journal of Organic Chemistry >
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).
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
Xiu Zhiming , Wang Licheng , Huang Mengyuan , Zhang Peng , Guo Youming , Zhang Wenqi , Wang Liping . A Novel Method for the Synthesis of Latanoprost[J]. Chinese Journal of Organic Chemistry, 2014 , 34(9) : 1786 -1792 . DOI: 10.6023/cjoc201403059
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