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【结 构 式】

【药物名称】RTI-3021-012, CDB-2914

【化学名称】17alpha-Acetoxy-11beta-[4-(dimethylamino)phenyl]-19-norpregna-4,9-diene-3,20-dione

【CA登记号】126784-99-4

【 分 子 式 】C30H37NO4

【 分 子 量 】475.63369

【开发单位】Research Triangle Institute (Originator)

【药理作用】Contraceptives, Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Selective Progesterone Receptor Modulators (SPRM)

合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

The reaction of cyanohydrineketal (I) with dimethyl(chloromethyl)silyl chloride (A), TEA and DMAP in THF gives the silylated cyanohydrine (II), which is treated with Li and 4,4'-di-tert-butylbiphenyl (DBB) in THF followed by acidification with HCl yields 17alpha-hydroxy-19-norpregna-4,9-diene-3,20-dione (III). The reaction of (III) with ethylene-glycol and TsOH afford the bis ethylenedioxy derivative (IV), which is epoxidized with H2O2 and trifluoroacetone in dichloromethane affording the monoepoxide (V). The Grignard condensation of (V) with 4-(dimethylamino)phenylmagnesium bromide in THF provides the 11-beta-(dimethylamino) derivative (VII), which is dehydrated and deprotected with sulfuric acid in refluxing ethanol to furnish 11-beta-[4-(dimethylamino)phenyl]-17alpha-hydroxy-19-norpregna-4,9-diene-3,20-dione (VIII). Finally, this compound is acetylated with AcOH and trifluoroacetic anhydride in dichloromethane.

参考文献 中间体
【1】 Wronski, R.; et al.; A brain derived peptide preparation reduces the translation dependent loss of a cytoskeletal protein in primary cultured chicken neurons. J Neural Transm 2000, 59, 263.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 40865 chloro(chloromethyl)dimethylsilane 1719-57-9 C3H8Cl2Si 详情 详情
(I) 40864 　 C21H27NO3 详情 详情
(II) 40866 　 C24H34ClNO3Si 详情 详情
(III) 40867 (13S,17R)-17-acetyl-17-hydroxy-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one 14340-01-3 C20H26O3 详情 详情
(IV) 40868 　 C24H34O5 详情 详情
(V) 40869 　 C24H34O6 详情 详情
(VI) 10863 Bromo[4-(dimethylamino)phenyl]magnesium 7353-91-5 C8H10BrMgN 详情 详情
(VII) 40870 　 C32H45NO6 详情 详情
(VIII) 40871 (13S,17R)-17-acetyl-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one C28H35NO3 详情 详情

合成路线2

　

参考文献 中间体
【1】 Dancsi L, Visky G, Tuba Z, et al.2007.Industrial process for the synthesis of 17α-acetoxy-11β-[4-(N,N-dimethylamino) Phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process. WO 2007144674 A1.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 67466 1-((8R,13R,14R)-17-hydroxy-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxolan]-17-yl)ethanone 　 C22H30O4 详情 详情
(I) 30502 3,3-Ethylenedioxyestra-5(10),9(11)-dien-17-one 5571-36-8 C20H26O3 详情 详情
(II) 67463 (8R,13R,14R,17S)-17-ethynyl-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxolan]-17-ol 　 C22H28O3 详情 详情
(III) 67464 (8R,13R,14R)-13-methyl-17-(2-(phenylsulfinyl)vinylidene)-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxolane] 　 C28H32O3S 详情 详情
(IV) 67465 (8R,13R,14R)-17-(1-methoxyvinyl)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxolan]-17-ol 　 C23H32O4 详情 详情
(VI) 40868 　 C24H34O5 详情 详情
(VII) 40869 　 C24H34O6 详情 详情
(VIII) 40870 　 C32H45NO6 详情 详情
(IX) 40871 (13S,17R)-17-acetyl-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one C28H35NO3 详情 详情

合成路线3

　

参考文献 中间体
【1】 BoDI Jozsef.2009.Industrial method for the synthesis of 17-acetoxy-11β-[4-(dimethylamino)-phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione and the key intermediates of the process. WO 2009001148 A2.
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) 30502 3,3-Ethylenedioxyestra-5(10),9(11)-dien-17-one 5571-36-8 C20H26O3 详情 详情
(II) 67467 1-(7-methyl-3,4,6,7,8,8a,9,10-octahydro-1H-spiro[4a,10a-epoxyphenanthrene-2,2'-[1,3]dioxolan]-7-yl)ethanone 　 C19H26O4 详情 详情
(III) 67468 (2S)-2-hydroxy-2-((7R,8aR)-7-methyl-3,4,6,7,8,8a,9,10-octahydro-1H-spiro[4a,10a-epoxyphenanthrene-2,2'-[1,3]dioxolan]-7-yl)propanenitrile 　 C20H27NO4 详情 详情
(IV) 67469 (2S)-2-((7R,8aR)-7-methyl-3,4,6,7,8,8a,9,10-octahydro-1H-spiro[4a,10a-epoxyphenanthrene-2,2'-[1,3]dioxolan]-7-yl)-2-((trimethylsilyl)oxy)propanenitrile 　 C23H35NO4Si 详情 详情
(V) 67470 (2S)-2-((7'S,8a'R,10a'S)-5'-(4-(dimethylamino)phenyl)-10a'-hydroxy-7'-methyl-3',4',5',6',7',8',8a',9',10',10a'-decahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthren]-7'-yl)-2-((trimethylsilyl)oxy)propanenitrile 　 C31H46N2O4Si 详情 详情
(VI) 67471 (2S)-2-((7'S,8a'R,10a'S)-5'-(4-(dimethylamino)phenyl)-10a'-hydroxy-7'-methyl-3',4',5',6',7',8',8a',9',10',10a'-decahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthren]-7'-yl)-2-((trimethylsilyl)oxy)propanenitrile 　 C34H55NO5Si2 详情 详情
(VII) 67472 (7S)-7-((2S,3R)-2,3-dihydroxy-4-methoxybutan-2-yl)-5-(4-(dimethylamino)phenyl)-7-methyl-3,4,6,7,8,8a,9,10-octahydrophenanthren-2(5H)-one 　 C28H39NO4 详情 详情
(VIII) 67473 (7S)-5-(4-(dimethylamino)phenyl)-7-((S)-2-hydroxy-4-methoxy-3-oxobutan-2-yl)-7-methyl-3,4,6,7,8,8a,9,10-octahydrophenanthren-2(5H)-one 　 C28H37NO4 详情 详情

合成路线4

　

参考文献 中间体
【1】 Kim H, Pemmaraju N, Simmons Anne-Marie.2004.Process for the preparation of 17α-acetoxy-11β-[4-(N,N-dimethylamino) phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process. WO 2004078709 A2.
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) 40867 (13S,17R)-17-acetyl-17-hydroxy-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one 14340-01-3 C20H26O3 详情 详情
(II) 67474 (13R,17S)-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate 　 C22H28O4 详情 详情
(III) 67466 1-((8R,13R,14R)-17-hydroxy-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxolan]-17-yl)ethanone 　 C22H30O4 详情 详情
(IV) 67475 1-((5S,10S,13R,17S)-17-hydroxy-13- methyl-1,2,4,6,7,8,12,13,14,15,16,17- dodecahydrospiro[5,10-epoxycyclopenta[a] phenanthrene-3,2'-[1,3]dioxolan]-17-yl)ethanone 　 C22H30O5 详情 详情
(V) 67476 1-((5S,13R,17S)-11-(4-(dimethylamino) phenyl)-5,17-dihydroxy-13-methyl- 1,2,4,5,6,7,8,11,12,13,14,15,16,17- tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'- [1,3]dioxolan]-17-yl)ethanone 　 C30H41NO5 详情 详情

合成路线5

　

参考文献 中间体
【1】 Kim Hyun K, San Antonio, Caemie Kirk, et al.1996.Method for preparing 17α-acetoxy-11β-(4-N,N-dimethylamino Phenyl)-19-norpregna-4,9-diene-3,20-dione, Intermediates useful in the method, and method for the preparation of such intermediates. US 9603660.
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) 40864 　 C21H27NO3 详情 详情
(II) 40866 　 C24H34ClNO3Si 详情 详情
(III) 40867 (13S,17R)-17-acetyl-17-hydroxy-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one 14340-01-3 C20H26O3 详情 详情
(IV) 40868 　 C24H34O5 详情 详情
(V) 40869 　 C24H34O6 详情 详情
(VI) 40870 　 C32H45NO6 详情 详情
(VII) 40871 (13S,17R)-17-acetyl-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one C28H35NO3 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)