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【结 构 式】 
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【分子编号】20085 【品名】(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 【CA登记号】 |
【 分 子 式 】C22H29F3O5S 【 分 子 量 】462.5304696 【元素组成】C 57.13% H 6.32% F 12.32% O 17.3% S 6.93% |
合成路线1
该中间体在本合成路线中的序号：(III)Treatment of dehydroepiandrosterone 3-acetate (I) with triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine provided the desired enol triflate (III) along with some 3,5-diene (II), which were separated by column chromatography. Subsequent coupling of triflate (III) with pyridylborane (IV) using bis(triphenylphosphine)- palladium(II) chloride as the catalyst afforded the (3-pyridyl)androstadiene (V), which after hydrolysis of the acetate ester with NaOH provided the target compound.
| 【1】 Potter, G.A.; et al.; Novel steroidal inhibitors of human cytochrome P450(17alpha) (17alpha-hydroxylase-C17,20-lyase): Potential agents for the treatment of prostatic cancer. J Med Chem 1995, 38, 13, 2463. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 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 |
| (II) | 20084 | (8R,9S,10R,13S,14S)-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthren-17-yl trifluoromethanesulfonate | C20H25F3O3S | 详情 | 详情 | |
| (III) | 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 | |
| (IV) | 20086 | 3-(diethylboryl)pyridine | C9H14BN | 详情 | 详情 | |
| (V) | 20087 | (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridinyl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C26H33NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)3-beta-Acetoxyandrost-5-en-17-one (I) was converted into enol triflate (II) by reaction with trifluoromethanesulfonic anhydride in the presence of a hindered base. The subsequent palladium-catalyzed coupling of (II) with ethyl vinyl ether produced a mixture of regioisomeric enol ethers which, after acid hydrolysis, afforded aldehyde (III) and ketone (IV). The minor aldehyde compound (III) was isolated by liquid chromatography and then converted into oxime (V) using hydroxylamine hydrochloride and NaOAc. Finally, the acetate ester group of (V) was hydrolyzed by means of methanolic KOH.
| 【1】 Hartmann, R.W.; Ehmer, P.B.; Hector, M.; Reichert, W.; Jose, J.; Haidar, S.; Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17alpha-hydroxylase/C17-20-lyase)and 5alpha-reductase types 1 and 2. J Med Chem 2000, 43, 22, 4266. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 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 |
| (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) | 45516 | (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-[(Z)-2-oxoethylidene]-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl acetate | C23H32O3 | 详情 | 详情 | |
| (IV) | 32586 | (3S,8R,9S,10R,13S,14S)-17-acetyl-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | 979-02-2 | C23H32O3 | 详情 | 详情 |
| (V) | 45517 | (3S,8R,9S,10R,13S,14S)-17-[(Z)-2-(hydroxyimino)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl acetate | C23H33NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)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 |