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【结 构 式】 
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【分子编号】29692 【品名】3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone 【CA登记号】 |
【 分 子 式 】C23H30O3 【 分 子 量 】354.4894 【元素组成】C 77.93% H 8.53% O 13.54% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(XVI)3) Reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3-dimethoxypropane (XIII) and lithium in THF gives the 17alpha-(3,3-dimethoxypropyl) derivative (XIV), which by treatment with 70% acetic acid provides the spiro compound (XV). Oxidation of compound (XV) with cyclohexanone in the presence of (i-PrO)3Al and then treatment with 2N H2SO4 affords 15beta,16beta-methylene-3-oxo-17alpha-pregn-4-ene-21,17-carbolactone (XVI). Treatment of (XVI) with chloranil in t-BuOH yields the pregnadiene carbolactone (XVII), which is finally reacted with trimethylsulfoxonium iodide (XVIII) and NaH in DMSO.
| 【1】 Norman, P.; Castaner, R.M.; Castaner, J.; Drospirenone. Drugs Fut 2000, 25, 12, 1247. |
| 【2】 Losert, W.; Bittler, D.; Vasals-Stenzel, J.; Wiechert, R.; Kerb, U. (Schering AG); Novel spironolactones and process for their preparation. DE 2652761; US 4129564 . |
| 【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 . |
| 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 | |
| (XIII) | 29689 | 3-bromo-1,1-dimethoxypropane; 3-bromo-1-methoxypropyl methyl ether | 36255-44-4 | C5H11BrO2 | 详情 | 详情 |
| (XIV) | 42519 | (2S,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 | |
| (XV) | 42520 | C23H34O3 | 详情 | 详情 | ||
| (XVI) | 29692 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone | C23H30O3 | 详情 | 详情 | |
| (XVII) | 11776 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone | C23H28O3 | 详情 | 详情 | |
| (XVIII) | 29693 | Trimethylsulfoxonium iodide | 1774-47-6 | C3H9IOS | 详情 | 详情 |