一种合成拉坦前列素的新方法

doi:10.6023/cjoc201403059

有机化学 ›› 2014, Vol. 34 ›› Issue (9): 1786-1792.DOI: 10.6023/cjoc201403059 上一篇下一篇

研究论文

一种合成拉坦前列素的新方法

修志明^a, 王立成^b, 黄梦媛^a, 张鹏^a, 郭佑铭^a, 张闻起^a, 王丽萍^a

a 吉林大学生命科学学院, 长春 130012;
b 吉林大学化学学院, 长春 130012

收稿日期:2014-03-27 修回日期:2014-04-23 发布日期:2014-05-23
通讯作者: 王丽萍 E-mail:wanglp@jlu.edu.cn
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

Xiu Zhiming^a, Wang Licheng^b, Huang Mengyuan^a, Zhang Peng^a, Guo Youming^a, Zhang Wenqi^a, Wang Liping^a

a School of Life Science, Jilin University, Changchun 130012;
b School of Chemistry, Jilin University, Changchun 130012

Received:2014-03-27 Revised:2014-04-23 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).

文章分享

摘要/Abstract

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.

关键词: 苯甲酰基科里内酯, 拉坦前列素, 合成, 纯化

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

引用此文

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.

Xiu Zhiming, Wang Licheng, Huang Mengyuan, Zhang Peng, Guo Youming, Zhang Wenqi, Wang Liping. A Novel Method for the Synthesis of Latanoprost[J]. Chin. J. Org. Chem., 2014, 34(9): 1786-1792.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

参考文献

[1] Straus, D.S.; Christopher, K.Med.Res.Rev.2001, 21, 185.
[2] Allaj, V.; Guo, C.; Nie, D.Cell Biosci.2013, 8, 1.
[3] Selliah, R.D.; Hellberg, M.R.; Sharif, N.A.; McLaughlin, M.A.Bioorg.Med.Chem.Lett.2004, 14, 4525.
[4] Han, Z.B.; Chang, Y.P.; Luan, G.Y.; Li, J.; Wang, E.B.Chem.J.Chin.Univ.2002, 23(9), 1660 (in Chinese).(韩正波, 常雅萍, 栾国有, 李娟, 王恩波, 高等学校化学学报, 2002, 23(9), 1660.)
[5] Liu, Z.-Y.; Han, W.-P.Acta Chim.Sinica 1981, 39(4), 424 (in Chinese).(刘志煌, 韩卫平, 化学学报, 1981, 39(4), 424.)
[6] Das, S.; Chandrasekhar, S.; Yadav, J.S.; Gre, R.Chem.Rev.2007, 107, 3286.
[7] Levkoeva, E.I.; Yakhontov, L.N.Russ.Chem.Rev.1977, 46, 565.
[8] Collins, P.W.; Djuric, S.W.Chem.Rev.1999, 93, 1533.
[9] Ying, Y.; Lucitt, M.B.; Stubbe, J.; Yan, C.; Friis, U.G.; Hansen, P.B.; Jensen, B.L.; Smyth, E.M.; FitzGerald, G.A.Proc.Natl.Acad.Sci.U.S.A.2009, 106, 7985.
[10] Perrino, E.; Uliva, C.; Lanzi, C.; Soldato, P.D.; Masini, E.; Sparatore, A.Bioorg.Med.Chem.Lett.2009, 19, 1639.
[11] DeLong, M.A.; Amburgey, J.; Taylor, C.; Wos, J.A.; Soper, D.L.; Wang, Y.L.; Hicks, R.Bioorg.Med.Chem.Lett.2000, 10, 1519.
[12] Feng, Z.X.; Hellberg, M.R.; Sharif, N.A.; McLaughlin, M.A.Bioorg.Med.Chem.2009, 17, 576.
[13] Allaire, C.; Dietrich, A.; Allmeier, H.; Grundmane, I.; Mazur, P.G.; Neshev, P.; Kahle, G.Eur.J.Ophthalmol.2012, 22, 19.
[14] Steigerwalt, R.D.; Vingolo, E.M.; Plateroti, P.; Nebbioso, M.Eur.Rev.Med.Pharmacol.Sci.2012, 16, 1723.
[15] Pacella, F.; Turchetti, P.; Santamaria, V.; Impallara, D.; Smaldone, G.; Brillante, C.; Librando, A.; Damiano, A.; Pecori, G.J.; Pacella, E.Clin.Ophthalmol.2012, 6, 811.
[16] Obadalova, I.; Pilarcik, T.; Slavikova, M.; Hajicek, J.Chirality 2005, 17, 109.
[17] Sharif, N.A.Prostaglandins, Leukotrienes Essent.Fatty Acids 2008, 78, 199.
[18] Klimko, P.; Hellberg, M.; McLaughlin, M.; Sharif, N.Bioorg.Med.Chem.2004, 12, 3451.
[19] Liljebris, C.; Selen, G.; Resul, B.; Stjernschantz, J.; Hacksell, U.J.Med.Chem.1996, 38, 289.
[20] Liu, Z.-Y.; Wu, X.-R.Chin.J.Org.Chem.1981, 1, 104 (in Chinese).(刘志煌, 吴向荣, 有机化学, 1981, 1, 104.)
[21] Martynow, J.G.; wik, J.J.; Szelejewski, W.; Achmatowicz, O.; Kutner, A.; Wisniewski, K.; Winiarski, J.; Zegrocka, S.O.; biewski, P.G.Eur.J.Org.Chem.2007, 689.
[22] Resul, B.; Stjernschantz, J.; No, K.; Liljebris, C.; SelBn, G.; Astin, M.; Karlsson, M.; Bib, L.Z.J.Med.Chem.1993, 36, 243.

一种合成拉坦前列素的新方法

A Novel Method for the Synthesis of Latanoprost

PDF

可视化

被引次数

摘要/Abstract

引用此文

分享此文

参考文献

相关文章 15

编辑推荐

相关统计

本文评价

[1]	冯康博, 陈炯, 古双喜, 王海峰, 陈芬儿. 全连续流反应技术在药物合成中的新进展(2019~2022)[J]. 有机化学, 2024, 44(2): 378-397.
[2]	李鹏辉, 谢青洋, 万福贤, 张元红, 姜林. 含环丙基的新型取代嘧啶-5-甲酰胺的合成及杀菌活性研究[J]. 有机化学, 2024, 44(2): 650-656.
[3]	邹发凯, 王能中, 姚辉, 王慧, 刘明国, 黄年玉. 1β-/3R-芳基硫代糖的区域与立体选择性合成[J]. 有机化学, 2024, 44(2): 593-604.
[4]	李路瑶, 贺忠文, 张振国, 贾振华, 罗德平. 三芳基碳正离子在有机合成中的应用[J]. 有机化学, 2024, 44(2): 421-437.
[5]	梅青刚, 李清寒. 可见光促进C(3)(杂)芳硫基吲哚化合物的合成研究进展[J]. 有机化学, 2024, 44(2): 398-408.
[6]	于士航, 刘嘉威, 安碧玉, 边庆花, 王敏, 钟江春. 黑腹尼虎天牛接触性信息素的不对称合成[J]. 有机化学, 2024, 44(1): 301-308.
[7]	杨维清, 葛宴兵, 陈元元, 刘萍, 付海燕, 马梦林. 1,8-萘酰亚胺衍生物的设计、合成及其对半胱氨酸的识别研究[J]. 有机化学, 2024, 44(1): 180-194.
[8]	赵茜帆, 陈永正, 张世明. 碳基非金属催化剂在有机合成领域的应用及机理研究[J]. 有机化学, 2024, 44(1): 137-147.
[9]	陈珊, 陈志林, 胡琼, 蒙艳双, 黄悦, 陶萍芳, 卢丽如, 黄国保. 含双硫脲基团分子钳在非极性溶剂中识别中性分子[J]. 有机化学, 2024, 44(1): 277-281.
[10]	王化坤, 任晓龙, 宣宜宁. 卤盐催化的α,β-环氧羧酸酯与异氰酸酯[3＋2]环加成反应研究[J]. 有机化学, 2024, 44(1): 251-258.
[11]	金玉坤, 任保轶, 梁福顺. 可见光介导的三氟甲基的选择性C－F键断裂及其在偕二氟类化合物合成中的应用[J]. 有机化学, 2024, 44(1): 85-110.
[12]	马翠云, 罗海澜, 张福华, 郭丹, 陈树兴, 王飞. 3-Pyrrolyl BODIPY的绿色生物合成、光物理性质及应用研究[J]. 有机化学, 2024, 44(1): 216-223.
[13]	王博珍, 张婕, 粘春惠, 金茗茗, 孔苗苗, 李物兰, 何文斐, 吴建章. 含有3,4-二氯苯基的酰胺类化合物的合成及抗肿瘤活性研究[J]. 有机化学, 2024, 44(1): 232-241.
[14]	李阳, 袁锦鼎, 赵頔. 低共熔溶剂1,3-二甲基脲/L-(+)-酒石酸中(E)-2-苯乙烯基喹啉-3-羧酸类衍生物的绿色合成[J]. 有机化学, 2023, 43(9): 3268-3276.
[15]	岁丹丹, 岑南楠, 龚若蕖, 陈阳, 陈文博. 无支持电解质条件下连续流电化学合成三氟甲基化氧化吲哚[J]. 有机化学, 2023, 43(9): 3239-3245.