雷帕霉素与2-[ ( 四氢-2H- 吡喃-2- 基) 氧基] 乙基三氟甲磺酸酯在有机碱作用下缩合得到40-O-[ ( 四氢-2H- 吡喃-2- 氧基) 乙基] 雷帕霉素，然后直接在酸性条件下脱除缩醛保护基，最后经制备液相分离纯化得到依维莫司，总收率约66％。该路线选择性较好，反应条件温和，具有工业应用价值。
Abstract
Everolimus was synthesized from rapamycin via condensation with 2-[(tetrahydro-2H-pyran- 2-yl)oxy]ethyl trifluoromethanesulfonate in the presence of organic base to give 40-O-[[(tetrahydro-2H-pyran-2- yl)oxy]ethyl]rapamycin, which was subjected to deprotection under acidic conditions directly. The crude product was isolated and purified by prep-HPLC, and the overall yield was about 66％. This route had better selectivity, mild reaction condition, and industrial application.
关键词
依维莫司 /
雷帕霉素 /
大环内酯类化合物 /
抗肿瘤药 /
合成
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Key words
everolimus /
rapamycin /
macrolides compound /
antitumor agent /
synthesis
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参考文献
[1] Lane HA, Lebwohl D. Future directions in the treatment of hormone-sensitive advanced breast cancer: the RAD001 (Everolimus) letrozole clinical program [J]. Semin Oncol, 2006, 33(7): 18-25.
[2] Yuan RR, Kay A, Berg WJ, et al. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy [J]. J Hematol Oncol, 2009, (2): 45-56.
[3] Cottens S, Sedrani R. O-alkylated rapamycin derivatives and their use, particularly as immunosuppersstants: WO, 1994009010 [P]. 1994-04-28.
[4] Luten J, Keltjens R, Benes M, et al. Process for making everolimus: WO, 2012103959 [P]. 2012-08-09.
[5] 苟少华, 诸海滨. 依维莫斯的制备: 中国, 102127092A [P].2011-07-20.
[6] Shaw CC, Sellstedt JH, Noureldin R, et al. Regiose1ective synthesis of rapamycin derivatives: WO, 2001023395 [P]. 2001-10-25.
[7] 蔡泽贵. 一种依维莫司的合成方法: 中国, 102268015A[P]. 2011-12-07.
[8] Firouzabadi H, Iranpoor N, Karimi B, et al. Highly efficient transdithioacetalization of acetals catalyzed by silica chloride [J]. Synlett, 2000, (2): 263-265.
[9] Ravindranath N, Ramesh C, Das B. Simple, facile and highly selective tetrahydropyranylation of alcohols using silica chloride [J]. Synlett, 2001, (11): 1777-1778.
[10] Thomas GP. Complete assignments of the 1H and 13C resonances of 40-epi-(N1-tetrazolyl)-rapamycin and revised 13C assignments for rapamycin [J]. Magn Reson Chem, 2005, 43(2): 174-175.
[11] Steven VL, Miles NT, Matthew LM, et al. Total synthesis of rapamycin [J]. Chem Eur J, 2009, 15(12): 2874-2914.
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脚注
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