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【结 构 式】 
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【分子编号】67591 【品名】(2R,4aS,4bR,6aR,9aR,9bS,9cS,12aS)-2-hydroxy-4a,6a,11,11-tetramethyltetradecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7(8H)-one 【CA登记号】 |
【 分 子 式 】C22H34O4 【 分 子 量 】362.50956 【元素组成】C 72.89% H 9.45% O 17.65% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Protection of prasterone (I) with ethylene glycol (II) in the presence of p-TsOH in refluxing benzene gives the corresponding ketal (III), which is further protected as the 3-O-silyl ether (IV) by treatment with TBDMSCl and imidazole in DMF. Allylic oxidation of compound (IV) by means of CrO3 and 3,5-dimethylpyrazole in CH2Cl2 or using RuCl3 and t-BuOOH in cyclohexane/water affords enone (V), which by chemoselective 1,2-reduction with NaBH4 and CeCl3 in THF/MeOH provides (R)-alcohol (VI). Subsequent esterification of alcohol (VI) with Ac2O and DMAP in pyridine produces acetate (VII), which is subjected to double bond hydroboration with BH3·THF in THF and oxidative hydrolysis using H2O2 and NaOH to yield diol (VIII). Protection of diol (VIII) with Ac2O and DMAP in pyridine gives diacetate (IX), which is selectively deprotected at C-3 by treatment with TBAF in THF resulting in the 3-hydroxysteroid (X). Hydrolysis of diacetate (X) using NaOMe in MeOH affords compound (XI), which by deketalization by means of AcOH provides ketone (XII). Protection of the 6,7-diol (XII) with 2,2-dimethoxypropane (XIII) in the presence of CSA then gives acetonide (XIV), which is submitted to a Wittig reaction with CH3PPh3Br in the presence of t-BuOK in refluxing THF to give alkene (XV) .
| 【1】 Burgoyne, D.L., Shen, Y., Langlands, J.M., Rogers, C., Chau, J.H.-L., Piers, E., Salari, H. (Biolipox AB). 6,7-Oxygenated steroids and uses related thereto. EP 1304333; US 6046185; WO 1998002450; JP 2001503732. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 67588 | (3R,6S,7S,8S,9R,10S,13R,14R)-3-hydroxy-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane]-6,7-diyl diacetate | C25H38O7 | 详情 | 详情 | |
| (I) | 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (III) | 67581 | (3R,8S,9R,10S,13R,14R)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-3-ol | C21H32O3 | 详情 | 详情 | |
| (IV) | 67582 | tert-butyl(((3R,8S,9R,10S,13R,14R)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-3-yl)oxy)dimethylsilane | C27H46O3Si | 详情 | 详情 | |
| (V) | 67583 | (3R,8S,9R,10S,13R,14R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethyl-1,3,4,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-7(2H)-one | C27H44O4Si | 详情 | 详情 | |
| (VI) | 67584 | C27H46O4Si | 详情 | 详情 | ||
| (VII) | 67585 | (3R,7S,8S,9R,10S,13R,14R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-7-yl acetate | C29H48O5Si | 详情 | 详情 | |
| (VIII) | 67586 | (3R,6S,7S,8S,9R,10S,13R,14R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane]-6,7-diol | C27H48O5Si | 详情 | 详情 | |
| (IX) | 67587 | (3R,6S,7S,8S,9R,10S,13R,14R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane]-6,7-diyl diacetate | C31H52O7Si | 详情 | 详情 | |
| (XI) | 67589 | (3R,6S,7S,8S,9R,10S,13R,14R)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane]-3,6,7-triol | C21H34O5 | 详情 | 详情 | |
| (XII) | 67590 | (3R,6S,7S,8S,9R,10S,13R,14R)-3,6,7-trihydroxy-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-17(2H)-one | C19H30O4 | 详情 | 详情 | |
| (XIII) | 67580 | 2,2-dimethoxypropane | C4H12O2 | 详情 | 详情 | |
| (XIV) | 67591 | (2R,4aS,4bR,6aR,9aR,9bS,9cS,12aS)-2-hydroxy-4a,6a,11,11-tetramethyltetradecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7(8H)-one | C22H34O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Treatment of compound (XV) with Ac2O and DMAP in pyridine yields acetate (XVI), which by hydrolysis with AcOH produces diol (XVII). Oxidative cleavage of diol (XVII) by means of NaIO4 in H2O/THF provides dialdehyde (XVIII), which is reduced with NaBH4 in MeOH/THF to afford the corresponding diol (XIX). Selectively monoesterification of diol (XIX) with Ac2O in the presence of DMAP in pyridine produces acetate (XX), which is treated with MsCl in pyridine to obtain mesylate (XXI). Treatment of compound (XXI) with NaN3 in DMF at 60 °C results in azide (XXII), which is finally reduced with LiAlH4 in THF and treated with AcOH .
| 【1】 Yee, J.G.K., Raymond, J.R., He, Y., Noren, B., Han, K., Zhou, Y. (Aquinox Pharmaceuticals). Indene derivatives as pharmaceutical agents. CN 102010298; CN 102001916; JP 2011068677; US 7999010; US 2014371252; US 8084503; EP 1615866; EP 2277848; US 2005004086; US 2011172258; US 8673975; US 7601874; JP 2006523624; US 2012270901; WO 2004092100; CA 2521883. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 67593 | (2R,4aS,4bR,6aR,9aR,9bS,9cS,12aS)-4a,6a,11,11-tetramethyl-7-methylenehexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-yl acetate | C25H38O4 | 详情 | 详情 | |
| (XIV) | 67591 | (2R,4aS,4bR,6aR,9aR,9bS,9cS,12aS)-2-hydroxy-4a,6a,11,11-tetramethyltetradecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7(8H)-one | C22H34O4 | 详情 | 详情 | |
| (XV) | 67592 | (2R,4aS,4bR,6aR,9aR,9bS,9cS,12aS)-4a,6a,11,11-tetramethyl-7-methylenehexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-ol | C23H36O3 | 详情 | 详情 | |
| (XVII) | 67594 | (2R,4aS,4bR,6aR,9aR,9bS,9cS,12aS)-4a,6a,11,11-tetramethyl-7-methylenehexadecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-2-yl acetate | C22H34O4 | 详情 | 详情 | |
| (XVIII) | 67595 | (1R,3R,4S)-3-formyl-4-((3aR,4R,5R,7aR)-4-formyl-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate | C22H32O4 | 详情 | 详情 | |
| (XIX) | 67596 | (1R,3R,4S)-3-(hydroxymethyl)-4-((3aR,4R,5R,7aR)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-4-methylcyclohexyl acetate | C22H36O4 | 详情 | 详情 | |
| (XX) | 67597 | ((1R,2S,5R)-5-acetoxy-2-((3aR,4R,5R,7aR)-4-(hydroxymethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate | C24H38O5 | 详情 | 详情 | |
| (XXI) | 67598 | ((1R,2S,5R)-5-acetoxy-2-methyl-2-((3aR,4R,5R,7aR)-7a-methyl-1-methylene-4-(((methylsulfonyl)oxy)methyl)octahydro-1H-inden-5-yl)cyclohexyl)methyl acetate | C25H40O7S | 详情 | 详情 | |
| (XXII) | 67599 | ((1R,2S,5R)-5-acetoxy-2-((3aR,4R,5R,7aR)-4-(azidomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-2-methylcyclohexyl)methyl acetate | C24H37N3O4 | 详情 | 详情 | |
| (XXIII) | 67600 | (1R,3R,4S)-4-((3aR,4R,5R,7aR)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol | C20H35NO2 | 详情 | 详情 |