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【结 构 式】 
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【分子编号】29694 【品名】3-Oxo-6alpha,7alpha,15alpha,16alpha-tetrahydro-17alpha-dicyclopropa-[6,7:15,16]pregn-4-ene-21,17-carbolactone 【CA登记号】 |
【 分 子 式 】C24H30O3 【 分 子 量 】366.5004 【元素组成】C 78.65% H 8.25% O 13.1% |
合成路线1
该中间体在本合成路线中的序号：(VII)The reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3 dimethoxypropane (II) by means of Li in THF gives the corresponding 3,3-dimethoxypropyl derivative (III), which by cyclization with acetic acid is converted to the lactol (IV). Oxidation of (IV) with cyclohexanone and aluminum isopropoxide in refluxing toluene yields 15beta,16beta-methylene-4-androstene[17(beta-1')-spiro)-5']perhydrofuran-2',3-dione (V), which is dehydrogenated with chloranil in refluxing tert-butanol to the 4,6-androstadiene (VI). Cyclopropanation of (VI) with trimethylsolfoxoniurn iodide (A) and NaH in DMSO affords the 6beta,7beta:15beta,16beta-dimethylene compound (VII), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone in refluxing dioxane.
| 【1】 Petzoldt, K.; Wiechert, R.; Laurent, H.; A new synthesis for aldosterone-antagonistic spirorenone. Angew Chem 1983, 95, 5, 413-414. |
| 【2】 Wiechert, R.; et al. (Schering AG); 6beta,7beta;15,16-Dimethylene-1,4-androstadien-3-ones, their preparation and use as medicinal agents. DE 2922500; EP 0019690; JP 55162799 . |
| 【3】 Serradell, M.N.; Robinson, C.P.; Castaner, J.; Spirorenone. Drugs Fut 1985, 10, 6, 478. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 | |
| 21890 | 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile | 84-58-2 | C8Cl2N2O2 | 详情 | 详情 | |
| 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 | |
| (A) | 29693 | Trimethylsulfoxonium iodide | 1774-47-6 | C3H9IOS | 详情 | 详情 |
| (I) | 29688 | (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) | 29689 | 3-bromo-1,1-dimethoxypropane; 3-bromo-1-methoxypropyl methyl ether | 36255-44-4 | C5H11BrO2 | 详情 | 详情 |
| (III) | 29690 | (4aR,4bS,6aS,7S,7aS,8aS,8bR,8cR)-7-(3,3-dimethoxypropyl)-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2,7-diol | C25H40O4 | 详情 | 详情 | |
| (IV) | 29691 | 3-Hydroxycyclopropa[1',2':15-beta,16-beta]pregn-5-ene-21,17-carbolactone | C23H34O3 | 详情 | 详情 | |
| (V) | 29692 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone | C23H30O3 | 详情 | 详情 | |
| (VI) | 11776 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone | C23H28O3 | 详情 | 详情 | |
| (VII) | 29694 | 3-Oxo-6alpha,7alpha,15alpha,16alpha-tetrahydro-17alpha-dicyclopropa-[6,7:15,16]pregn-4-ene-21,17-carbolactone | C24H30O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Starting compound (I) is hydroxylated microbiologically by means of Botryodiplodia malorum to 3,7-dihydroxy-15beta,16beta-methylene-5-androsten-17-one (VIII), which is selectively acylated with pivalic anhydride to the monoacyl derivative (IX). Epoxidation of (IX) with tert-butyl hydroperoxide in hot toluene yields the epoxide (X), which by reaction with triphenylphosphine and CCl4 is converted to the chloroepoxide (Xl). The reactive elimination of Cl with Zn-acetic acid followed by hydrolysis with KOH yields 3,5-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (XII), which is submitted to cyclopropanation with methyrene iodide and Zn/Cu in glyme yielding 3,5-dihydroxy-6beta,7beta:15beta,16beta-dimethyleneandrostan-17-one (XIII). The reaction of (XIII) with propargyl alcohol (XIV) by means of potassium ethoxide in THF affords the 17-(3-hydroxy-1-propyn-1-yl) derivative (XV), which is reduced with H2 over Pd/CaCO3 in THF to the corresponding 3-hydroxypropyl derivative (XVI). Finally, this compound is oxidized and cyclized by means of pyridinium dichromate to (VII) ), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanohenzoquinone in refluxing dioxane.
| 【1】 Laurent, H.; Hormeister, H.; Nickisch, K.; Butler, D.; Nickolson, R.; Wischert, R.; Petzoldt, K.; Synthesis of spirorenone. A novel highly active aldosterone antagonist. Angew Chem 1982, 94, 718. |
| 【2】 Serradell, M.N.; Robinson, C.P.; Castaner, J.; Spirorenone. Drugs Fut 1985, 10, 6, 478. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 21890 | 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile | 84-58-2 | C8Cl2N2O2 | 详情 | 详情 | |
| (I) | 29688 | (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 | |
| (VII) | 29694 | 3-Oxo-6alpha,7alpha,15alpha,16alpha-tetrahydro-17alpha-dicyclopropa-[6,7:15,16]pregn-4-ene-21,17-carbolactone | C24H30O3 | 详情 | 详情 | |
| (VIII) | 29695 | (4aR,4bS,6aS,7aS,8aS,8bS,8cR)-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 | |
| (IX) | 29696 | (4aR,4bS,6aS,7aS,8aS,8bS,8cR)-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 | |
| (X) | 29697 | (5aR,5bS,7aS,8aS,9aS,9bS,9cR,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 | |
| (XI) | 29698 | (5aR,5bS,7aS,8aS,9aS,9bS,9cR,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 | |
| (XII) | 20015 | (4aR,4bS,6aS,7aS,8aS,8bR,8cR)-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 | |
| (XIII) | 29699 | (1aR,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 | C25H35ClO4 | 详情 | 详情 | |
| (XIV) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (XV) | 29700 | (1aR,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 | |
| (XVI) | 29701 | (1aR,5aR,5bS,7aS,8S,8aS,9aS,9bR,9cR,9dR)-8-hydroxy-8-(3-hydroxypropyl)-5a,7a-dimethyl-1,1a,4,5,5a,5b,6,7,7a,8,8a,9,9a,9b,9c,9d-hexadecahydro-3H-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthren-3-one | C24H34O3 | 详情 | 详情 |