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【结 构 式】 
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【药物名称】CB-7630;Abiraterone acetate 【化学名称】Acetic acid 17-(3-pyridyl)androsta-5,16-dien-3β-yl ester 【CA登记号】154229-18-2 【 分 子 式 】C26H33NO2 【 分 子 量 】391.5457 |
【开发单位】Couger Biotechnology Inc. (US); licensed from BTG plc. (UK) 【药理作用】CYP17 inhibitor;Oncolytic |
合成路线1
Abiraterone acetate has been synthesized by two related routes.
a) Reaction of dehydroepiandrosterone acetate (Ia) with trifluoromethanesulfonic anhydride and triethylamine in dichloromethane gives the enol triflate (II), which is finally coupled with diethyl(3-pyridyl)borane (III) by means of PdCl2(PPh3)4 in tetrahydrofuran .
b) In an improved procedure, dehydroepiandrosterone (Ib) is converted to the corresponding hydrazone (IV) by treatment with hydrazine hydrate and a catalytic amount of hydrazine sulfate in EtOH. Subsequent reaction of hydrazone (IV) with iodine and 1,1,3,3-tetramethylguanidine (TMG) in THF/Et2O gives the vinyl iodide (V), which undergoes palladium–catalyzed cross coupling with diethyl(3-pyridyl)borane (III) to yield abiraterone (VI). Finally, alcohol (VI) is acetylated using acetic anhydride in pyridine .
| 【1】 Potter, G.A., Barrie, S.E., Jarman, M., Rowlands, M.G. Novel steroidal inhibitors of human cytochrome P45017α (17α-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. J Med Chem 1995, 38(13): 2463-71. |
| 【2】 Barrie, S.E., Jarman, M., Potter, G.A. (BTG plc.). 17-Substituted steroids useful in cancer treatment. EP 0633893, GB 2265624, US 5604213, WO 1993020097. |
| 【3】 Hunt, N.J. (BTG International Ltd). Methanesulfonate salts of abiraterone-3-esters and recovery of salts of abiraterone-3-esters from solution in methyl tert-butyl ether. CA 2576922, EP 1789432, JP 2008510780, US 2007249837, WO 2006021776. |
| 【4】 Bury, P.S. (BTG International Ltd.). Process for the preparation of 17-Ovinyl-triflates as intermediates. EP 1781683, JP 2008510781, US 2007282109, WO 2006021777. |
| 【5】 Potter, G.A. and Hardcastle, I.R. (BTG International Ltd). Synthesis of 17-(3-pyridyl) steroids. CA 2170286, EP 0721461, GB 2282377, JP 1997502994, WO 1995009178. |
| 【6】 Potter, G.A., Hardcastle, I.R., Jarman, M. A convenient, large-scale synthesis of abiraterone acetate [3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene], a potential new drug for the treatment of prostate cancer. Org Prep Proced Int 1997, 29: 123. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 20083 | Prasterone acetate;3b-Hydroxy-5-androstene-17-one acetate；Dehydroisoandrosterone acetate;Dehydroepiandrosterone 3-acetate;Dehydroepiandrosterone acetate;(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | 853-23-6 | C21H30O3 | 详情 | 详情 |
| (Ib) | 11713 | Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | 53-43-0 | C19H28O2 | 详情 | 详情 |
| (II) | 20085 | (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-[[(trifluoromethyl)sulfonyl]oxy]-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C22H29F3O5S | 详情 | 详情 | |
| (III) | 20086 | 3-(diethylboryl)pyridine | C9H14BN | 详情 | 详情 | |
| (IV) | 69461 | (3S,8S,9R,10S,13R,E)-17-hydrazono-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol | C19H30N2O | 详情 | 详情 | |
| (V) | 69460 | (3R,8S,9R,10S,13R)-17-iodo-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol | 32138-69-5 | C19H27IO | 详情 | 详情 |
| (VI) | 69462 | (3R,8S,9R,10S,13R)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol | C24H31NO | 详情 | 详情 |