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【结 构 式】 
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【分子编号】42515 【品名】(1aR,3S,5aR,5bS,7aS,8S,8aS,9aS,9bR,9cR,9dR)-8-(3-hydroxy-1-propynyl)-5a,7a-dimethyloctadecahydro-1bH-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthrene-1b,3,8-triol 【CA登记号】 |
【 分 子 式 】C24H34O4 【 分 子 量 】386.53156 【元素组成】C 74.58% H 8.87% O 16.56% |
合成路线1
该中间体在本合成路线中的序号：(X)Drospirenone can been obtained by different ways: 1) Fermentation of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with Botryodiplodia malorum gives the corresponding 7beta-hydroxy derivative (II), which is regioselectively acylated with pivaloyl anhydride and DMAP in pyridine to yield the 3beta-pivaloyloxy steroid (III). The epoxidation of (III) with tert-butylhydroperoxide catalyzed by VO(acetonylacetonate)2 complex affords the corresponding epoxide (IV), which is treated with PPh3 and CCl4 in dichloromethane to provide the 7alpha-chloro derivative (V). Reaction of (V) with Zn in AcOH/THF gives 5beta-hydroxy-3beta-(pivaloyloxy)-15beta,16beta-methylene-6-androsten-17-one (VI), which is hydrolyzed with KOH and NaClO4 in methanol/THF to provide 3beta,5beta-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (VII). The cyclopropanation of (VII) with diiodomethane and Zn in hot ethylene glycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-dimethyleneandrostan-17-one (VIII), which is condensed with propargyl alcohol (IX) by means of EtOK in THF, yielding 17alpha-(3-hydroxy-1-propynyl)-6beta,7beta:15beta,16beta-dimethyleneandrostan-3beta,5beta,17beta-triol (X). The hydrogenation of (X) with H2 over either Pd/C in THF/methanol/pyridine (1) or Pd/CaCO3 in THF/2-propanol affords the corresponding 17alpha-(3-hydroxypropyl) derivative (XI), which is finally oxidized, lactonized and dehydrated by means of CrO3 in hot pyridine/water. Similar synthetic pathways have been described replacing the pivaloyl-protecting group with either tert-butyldimethylsilyl (TBDMS), dimethyl(3-methylbutyl)silyl or tribenzylsilyl groups: 2) Alternatively, the 17alpha-(3-hydroxypropyl) derivative (XI) can be oxidized with RuCl3 and NaBrO3 in hot acetonitrile/water to give the 3-hydroxyspirolactone (XII), which is finally dehydrated by means of TsOH in THF.
| 【1】 Angew Chem 1982, 94, 718-719. |
| 【2】 Norman, P.; Castaner, R.M.; Castaner, J.; Drospirenone. Drugs Fut 2000, 25, 12, 1247. |
| 【3】 Nickisch, K.; Wiechert, R.; Laurent, H.; Petzoldt, K.; Bittler, D. (Schering AG); Process for preparing 3beta,7beta-dihydroxy-DELTA5-steroids. DE 3042136; EP 0051143; JP 1982122798; US 4416985; US 4614616 . |
| 【4】 Mohr, J.-T.; Nickisch, K. (Schering AG); Process for producing drospirenone (6beta,7beta;15beta,16beta-dimethylene-3-oxo-17alpha-preg-4-en-21,17-carbolactone, DRSP), as well as 7alpha-(3-hydroxy-1-propyl)-6beta,7beta;15beta,16beta-dimethylene-5beta-androstane-3beta,5,17beta-triol (ZK 92836) and . DE 19633685; US 6121465; WO 9806738 . |
| 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) | 42507 | (2S,4aR,4bS,6aS,7aS,8aS,8bR,8cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C20H28O2 | 详情 | 详情 | |
| (II) | 42508 | (2S,4aR,4bS,6aS,7aS,8aS,8bS,8cR,9R)-2,9-dihydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C20H28O3 | 详情 | 详情 | |
| (III) | 42509 | (2S,4aR,4bS,6aS,7aS,8aS,8bS,8cR,9R)-9-hydroxy-4a,6a-dimethyl-7-oxo-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-yl pivalate | C25H36O4 | 详情 | 详情 | |
| (IV) | 42518 | (1aS,3S,5aR,5bS,7aS,8aS,9aS,9bS,9cR,10R,10aR)-10-hydroxy-5a,7a-dimethyl-8-oxohexadecahydro-2H-cyclopropa[4',5']cyclopenta[1',2':1,2]phenanthro[8a,9-b]oxiren-3-yl pivalate | C25H36O5 | 详情 | 详情 | |
| (V) | 42510 | (1aS,3S,5aR,5bS,7aS,8aS,9aS,9bS,9cR,10S,10aS)-10-chloro-5a,7a-dimethyl-8-oxohexadecahydro-2H-cyclopropa[4',5']cyclopenta[1',2':1,2]phenanthro[8a,9-b]oxiren-3-yl pivalate | C25H35ClO4 | 详情 | 详情 | |
| (VI) | 42511 | (2S,4aR,4bS,6aS,7aS,8aS,8bR,8cR,10aR)-10a-hydroxy-4a,6a-dimethyl-7-oxo-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,10a-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-yl pivalate | C25H36O4 | 详情 | 详情 | |
| (VII) | 42512 | (2S,4aR,4bS,6aS,7aS,8aS,8bR,8cR,10aR)-2,10a-dihydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,10a-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C20H28O3 | 详情 | 详情 | |
| (VIII) | 42513 | (1aR,1bR,3S,5aR,5bS,7aS,8aS,9aS,9bR,9cR,9dR)-1b,3-dihydroxy-5a,7a-dimethyloctadecahydro-8H-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthren-8-one | C21H30O3 | 详情 | 详情 | |
| (IX) | 42514 | 2-butyn-1-ol | 764-01-2 | C4H6O | 详情 | 详情 |
| (X) | 42515 | (1aR,3S,5aR,5bS,7aS,8S,8aS,9aS,9bR,9cR,9dR)-8-(3-hydroxy-1-propynyl)-5a,7a-dimethyloctadecahydro-1bH-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthrene-1b,3,8-triol | C24H34O4 | 详情 | 详情 | |
| (XI) | 42516 | (1aR,3S,5aR,5bS,7aS,8S,8aS,9aS,9bR,9cS,9dR)-8-(3-hydroxypropyl)-5a,7a-dimethyloctadecahydro-1bH-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthrene-1b,3,8-triol | C24H38O4 | 详情 | 详情 | |
| (XII) | 42517 | C24H32O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)This compound has been obtained by different ways: 1. The fermentation of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) or 3beta-acetoxy-15beta,16beta-methylene-5-androsten-17-one (II) with Botryodiplodia malorum gives the corresponding 3beta,7beta-dihydroxy derivative (III), which is regioselectively silylated with Tbdms-Cl and imidazole to yield the 3-beta-silylated compound (IV). The epoxidation of (IV) by means of tert-butyl hydroperoxide catalyzed by VO(acetonylacetonate)2 complex affords the corresponding epoxide (V), which is treated with PPh3 and CCl4 in dichloromethane to provide the 7-alpha-chloro derivative (VI). The desilylation of (VI) with HCl in THF/methanol gives the 3beta-hydroxy compound (VII), which is treated with Zn in AcOH/THF to yield 3beta, 5beta-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (VIII) (1). The cyclopropanation of (VIII) with diiodomethane and Zn in hot ethyleneglycol dimethylether gives 3beta,5beta-dihydroxy-6beta,7beta:15beta,16beta-bismethyleneandrostan-17-one (IX), which is condensed with propargyl alcohol (X) by means of K-OEt in THF, yielding 17alpha-(3-hydroxy-1-propynyl)-6beta,7beta:15beta,16beta-bismethyleneandrostan-3,5beta,17beta-triol (XI). The hydrogenation of (XI) with H2 over Pd/C in THF/methanol/pyridine affords the corresponding 17alpha-(3-hydroxypropyl) derivative (XII), which is finally oxidized, lactonized and dehydrated by means of CrO3 in hot pyridine/water. 2. Alternatively, the 17alpha-(3-hydroxypropyl) derivative (XII) can be oxidized with RuCl3 and NaBrO3 in hot acetonitrile/water, giving the hydroxy carbolactone (XIII), which is finally dehydrated by means of Ts-OH in THF. 3. Similar synthetic pathways have been described replacing the Tbdms protecting group with either dimethyl(3-methylbutyl)silyl or tribenzylsilyl groups.
| 【1】 Angew Chem 1982, 94, 718-719. |
| 【2】 Nickisch, K.; Wiechert, R.; Laurent, H.; Petzoldt, K.; Bittler, D. (Schering AG); Process for preparing 3beta,7beta-dihydroxy-DELTA5-steroids. DE 3042136; EP 0051143; JP 1982122798; US 4416985; US 4614616 . |
| 【3】 Mohr, J.-T.; Nickisch, K. (Schering AG); Process for producing drospirenone (6beta,7beta;15beta,16beta-dimethylene-3-oxo-17alpha-preg-4-en-21,17-carbolactone, DRSP), as well as 7alpha-(3-hydroxy-1-propyl)-6beta,7beta;15beta,16beta-dimethylene-5beta-androstane-3beta,5,17beta-triol (ZK 92836) and . DE 19633685; US 6121465; WO 9806738 . |
| 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) | 42507 | (2S,4aR,4bS,6aS,7aS,8aS,8bR,8cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C20H28O2 | 详情 | 详情 | |
| (II) | 42862 | (2S,4aR,6aS,7aS,8aS)-4a,6a-dimethyl-7-oxo-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-yl acetate | C22H30O3 | 详情 | 详情 | |
| (III) | 42508 | (2S,4aR,4bS,6aS,7aS,8aS,8bS,8cR,9R)-2,9-dihydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C20H28O3 | 详情 | 详情 | |
| (IV) | 42863 | (2S,4aR,6aS,7aS,8aS,9R)-2-[[tert-butyl(dimethyl)silyl]oxy]-9-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C26H42O3Si | 详情 | 详情 | |
| (V) | 42864 | (1aS,3S,5aR,7aS,8aS,9aS,10R,10aR)-3-[[tert-butyl(dimethyl)silyl]oxy]-10-hydroxy-5a,7a-dimethyltetradecahydro-2H-cyclopropa[4',5']cyclopenta[1',2':1,2]phenanthro[8a,9-b]oxiren-8(6H)-one | C26H42O4Si | 详情 | 详情 | |
| (VI) | 42510 | (1aS,3S,5aR,5bS,7aS,8aS,9aS,9bS,9cR,10S,10aS)-10-chloro-5a,7a-dimethyl-8-oxohexadecahydro-2H-cyclopropa[4',5']cyclopenta[1',2':1,2]phenanthro[8a,9-b]oxiren-3-yl pivalate | C25H35ClO4 | 详情 | 详情 | |
| (VII) | 42865 | (1aS,3S,5aR,7aS,8aS,9aS,10S,10aS)-10-chloro-3-hydroxy-5a,7a-dimethyltetradecahydro-2H-cyclopropa[4',5']cyclopenta[1',2':1,2]phenanthro[8a,9-b]oxiren-8(6H)-one | C20H27ClO3 | 详情 | 详情 | |
| (VIII) | 42512 | (2S,4aR,4bS,6aS,7aS,8aS,8bR,8cR,10aR)-2,10a-dihydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,10a-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C20H28O3 | 详情 | 详情 | |
| (IX) | 42513 | (1aR,1bR,3S,5aR,5bS,7aS,8aS,9aS,9bR,9cR,9dR)-1b,3-dihydroxy-5a,7a-dimethyloctadecahydro-8H-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthren-8-one | C21H30O3 | 详情 | 详情 | |
| (X) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (XI) | 42515 | (1aR,3S,5aR,5bS,7aS,8S,8aS,9aS,9bR,9cR,9dR)-8-(3-hydroxy-1-propynyl)-5a,7a-dimethyloctadecahydro-1bH-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthrene-1b,3,8-triol | C24H34O4 | 详情 | 详情 | |
| (XII) | 42516 | (1aR,3S,5aR,5bS,7aS,8S,8aS,9aS,9bR,9cS,9dR)-8-(3-hydroxypropyl)-5a,7a-dimethyloctadecahydro-1bH-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthrene-1b,3,8-triol | C24H38O4 | 详情 | 详情 | |
| (XIII) | 42517 | C24H32O4 | 详情 | 详情 |