|
【结 构 式】 
|
【分子编号】18027 【品名】3-Oxopregna-4,6-diene-21,17-carbolactone 【CA登记号】976-71-6 |
【 分 子 式 】C22H28O3 【 分 子 量 】340.46252 【元素组成】C 77.61% H 8.29% O 14.1% |
合成路线1
该中间体在本合成路线中的序号：(I)Eplerenone was prepared by several related ways. Microbiological hydroxylation of canrenone (I) provided the 11-a hydroxy derivative (II). This was converted to enamino compound (IV) by double addition of cyanide, followed by cyclization, on treatment with acetone cyanohydrin (III) in the presence of triethylamine and lithium chloride in DMF or, alternatively, by treatment with sodium cyanide and sulfuric acid. Hydrolysis of enamine (IV) with HCl in a methanol-water solution gave diketone (V), and further reaction with sodium methoxide in refluxing methanol gave hydroxyester (VI). After mesylation of the 11-a hydroxyl group with with mesyl chloride and triethylamine in cold dichloromethane, elimination of the resulting sulfonate (VII) to give olefin (VIII) was achieved on treatment with potassium formate in a mixture of formic acid and acetic anhydride at 100 C. Other conditions used for the elimination were potassium acetate in trifluoroacetic acid-trifluoroacetic anhydride, isopropenyl acetate and p-TsOH, or thermoelimination in DMSO at 80 C. Alternatively, hydroxyester (VI) was reacted with sulfuryl chloride at -70 C, and then treated with imidazole at room temperature to afford olefin (VIII). Finally, epoxidation was performed by reaction with hydrogen peroxide in the presence of trichloroacetamide or trichloroacetonitrile and PO4HK2 to give eplerenone.
| 【1】 Ng, J.S.; Wang, P.T.; Baez, J.A.; Liu, C.; Anderson, D.K.; Lawson, J.P.; Erb, D.; Wieczorek, J.; Mucciariello, G.; Vanzanella, F.; Kunda, S.A.; Letendre, L.J.; Pozzo, M.J.; Sing, Y.-L.L. (Pharmacia Corp.); Process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. WO 9721720 . |
| 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) | 18027 | 3-Oxopregna-4,6-diene-21,17-carbolactone | 976-71-6 | C22H28O3 | 详情 | 详情 |
| (II) | 18028 | 11-Alpha-hydroxy-3-oxo-17-alpha-pregna-4,6-diene-21,17-carbolactone | C22H28O4 | 详情 | 详情 | |
| (III) | 18029 | Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile | 75-86-5 | C4H7NO | 详情 | 详情 |
| (IV) | 18030 | 4'-Amino-5-beta-cyano-11-alpha-hydroxy-7-alpha,4-metheno-3-oxo-17-alpha-pregnane-21,17-carbolactone | C24H30N2O4 | 详情 | 详情 | |
| (V) | 18031 | 5-beta-Cyano-11-alpha-hydroxy-4,7-alpha-methano-3,4'-dioxo-17-alpha-pregnane-21,17-carbolactone | C24H29NO5 | 详情 | 详情 | |
| (VI) | 18032 | 7-Alpha-(methoxycarbonyl)-11-alpha-hydroxy-3-oxoproegn-4-ene-21,17-carbolatone | C24H32O6 | 详情 | 详情 | |
| (VII) | 18033 | 7-Alpha-(methoxycarbonyl)-11-alpha-(methylsulfonyloxy)-3-oxopregn-4-ene-21,17-carbolactone | C25H34O8S | 详情 | 详情 | |
| (VIII) | 18034 | 7-Alpha-(methoxycarbonyl)-3-oxopregna-4,9(11)-diene-21,17-carbolactone | C24H30O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)In a related way, canrenone (I) was converted to mexrenone (XI) by an analogous sequence including cyanide addition to give enamine (IX), hydrolysis to diketone (X), and ring opening with NaOMe. The microbiological oxidation of mexrenone (XI) yielded either the 9-a (XII) or the 11-b (XIII) hydroxylated compounds, which were dehydrated to the olefin (VIII), whose epoxidation, as before, afforded eplerenone.
| 【1】 Ng, J.S.; Wang, P.T.; Baez, J.A.; Liu, C.; Anderson, D.K.; Lawson, J.P.; Erb, D.; Wieczorek, J.; Mucciariello, G.; Vanzanella, F.; Kunda, S.A.; Letendre, L.J.; Pozzo, M.J.; Sing, Y.-L.L. (Pharmacia Corp.); Process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. WO 9721720 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18029 | Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile | 75-86-5 | C4H7NO | 详情 | 详情 | |
| (I) | 18027 | 3-Oxopregna-4,6-diene-21,17-carbolactone | 976-71-6 | C22H28O3 | 详情 | 详情 |
| (VIII) | 18034 | 7-Alpha-(methoxycarbonyl)-3-oxopregna-4,9(11)-diene-21,17-carbolactone | C24H30O5 | 详情 | 详情 | |
| (IX) | 18035 | 4'-Amino-5-beta-cyano-7-alpha,4-metheno-3-oxo-17-alpha-pregnane-21,17-carbolactone | C24H30N2O3 | 详情 | 详情 | |
| (X) | 18036 | 5-beta-Cyano-4,7-alpha-methano-3,4'-dioxo-17-alpha-pregnane-21,17-carbolactone | C24H29NO4 | 详情 | 详情 | |
| (XI) | 18037 | 7-Alpha-(methoxycarbonyl)-3-oxopregn-4-ene-21,17-carbolactone | C24H32O5 | 详情 | 详情 | |
| (XII) | 18038 | 7-Alpha-(methoxycarbonyl)-9-alpha-hydroxy-3-oxopregn-4-ene-21,17-carbolactone | C24H32O6 | 详情 | 详情 | |
| (XIII) | 18039 | 7-Alpha-(methoxycarbonyl)-11-beta-hydroxy-3-oxopregn-4-ene-21,17-carbolactone | C24H32O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Elimination of the thioacetyl group of spironolactone (VII) by treatment with NaOMe yielded canrenone (VIII). The title compound was then obtained by 1,6-conjugate addition of thiol (VI) to the dienone (VIII) in the presence of metallic sodium at 60 C.
| 【1】 Leblanc, G.; Noël, P.; Poirier, D.; Labrie, F.; Breton, E.; Luu-The, V.; Tremblay, M.R.; Spironolactone-related inhibitors of type II 17beta-hydroxysteroid dehydrogenase: Chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities. Bioorg Med Chem 1999, 7, 6, 1013. |