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【结 构 式】 
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【药物名称】Alclometasone dipropionate, Sch-22219, Aclosone, Legederm, Aclovate, Almeta, Vaderm, Modrasone, Delonal 【化学名称】(7alpha,11beta,16alpha)-7-Chloro-11-hydroxy-16-methyl-17,21-bis(1-oxopropoxy)pregna-1,4-diene-3,20-dione 【CA登记号】66734-13-2, 67452-97-5 (free base) 【 分 子 式 】C28H37ClO7 【 分 子 量 】521.05589 |
【开发单位】Essex (Originator), Kirby-Warrick (Originator), Schering-Plough (Originator), Dominion Pharma (Not Determined), GlaxoSmithKline (Not Determined), Shionogi (Licensee), Elan (Distributor) 【药理作用】DERMATOLOGIC DRUGS, Antiinflammatory Drugs, Corticosteroids |
合成路线1
The dehydrogenation of 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione-21-acetate (I) with dichlorodicyanobenzoquinone (II) in dioxane HCl gives 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-21-acetate (III), which is hydrolyzed with aqueous NaHCO3 to the corresponding free triol (IV). The reaction of (IV) with triethyl orthopropionate (A) by means of p-toluenesulfonic acid in DMSO yields 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17,21-ethylorthopropionate (V), which is hydrolyzed partially with acetic acid to 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17-propionate (VI). The acylation of (VI) with propionic anhydride affords 16alpha-methyl-11beta,17alpha,21-trihydroxypregna-1,4,6-triene-3,20-dione-17,21-dipropionate (VII), which is finally treated with dry HCl in dioxane.
| 【1】 Green, M.J.; et al. (Schering Corp.); 7alpha-Halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor. US 4124707 . |
| 【2】 Green, M.J.; et al. (Schering Corp.); Process for the preparation of 7{60 -halogeno-3-oxo-4-dehydro steroids and novel 7{60 -halogeno derivatives produced thereby. CA 1099254; US 4076708 . |
| 【3】 Van Wagenen, B.C.; Barmore, R.M. (NPS Pharmaceuticals, Inc.); Chiral reductions of imines leading to the syntheses of optically active amines. WO 9711934 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 | |
| (A) | 10395 | 1,1,1-Triethoxypropane; 1,1-Diethoxypropyl ethyl ether; Triethyl orthopropionate | 115-80-0 | C9H20O3 | 详情 | 详情 |
| (I) | 32645 | 2-[(8S,9S,10R,11S,13S,14S,16R,17R)-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H32O6 | 详情 | 详情 | |
| (II) | 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 |
| (III) | 32646 | 2-[(8S,9S,10R,11S,13S,14S,16R,17R)-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | 13796-64-0 | C24H30O6 | 详情 | 详情 |
| (IV) | 32647 | (8S,9S,10R,11S,13S,14S,16R,17R)-17-glycoloyl-11,17-dihydroxy-10,13,16-trimethyl-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-one | 13954-10-4 | C22H28O5 | 详情 | 详情 |
| (V) | 32648 | 2'-Ethoxy-2'-ethyl-11beta-hydroxy-16alpha-methylspiro[androsta-1,4,6-triene-17(R),4'-[1,3]dioxane]-3,5'-dione | 67212-72-0 | C27H36O6 | 详情 | 详情 |
| (VI) | 32649 | (8S,9S,10R,11S,13S,14S,16R,17R)-17-glycoloyl-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl propionate | C25H32O6 | 详情 | 详情 | |
| (VII) | 32650 | (8S,9S,10R,11S,13S,14S,16R,17R)-11-hydroxy-10,13,16-trimethyl-3-oxo-17-[2-(propionyloxy)acetyl]-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl propionate | 67212-74-2 | C28H36O7 | 详情 | 详情 |
合成路线2
The dehydrogenation of 16alpha-methyl-17alpha,21-dihydroxypregna-1,4-diene-3,11,20-trione-21-acetate (VIII) with (II) in dioxane-HCl gives 16alpha-methyl-17alpha,21-dihydroxypregna-1,4,6-triene-3,11,20-trione-21-acetate (IX), which is hydrolyzed with aqueous NaHCO3 to the corresponding free diol (X). The reaction of (X) with triethyl orthopropionate (A) as before yields 16alpha-methyl-17alpha,21-dihydroxypregna-1,4,6-triene-3,11,20-trione-17,21-ethylorthopropionate (XI), which is hydrolyzed partially with acetic acid to 16alpha-methyl-17alpha,21-dihydroxypregna-1,4,6-triene-3,11,20-trione-17-propionate (XII). The acylation of (XII) with propionic anhydride yields the corresponding dipropionate (XIII), which is treated with dry HCl in dioxane to afford 16alpha-methyl-17alpha,21-dihydroxy-7alpha-chloropregna-1,4-diene-3,11,20-trione 17,21-dipropionate (XIV). Finally, this compound is reduced with NaSH4 in methanol - THF.
| 【1】 Green, M.J.; et al. (Schering Corp.); 7alpha-Halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor. US 4124707 . |
| 【2】 Green, M.J.; et al. (Schering Corp.); Process for the preparation of 7{60 -halogeno-3-oxo-4-dehydro steroids and novel 7{60 -halogeno derivatives produced thereby. CA 1099254; US 4076708 . |
| 【3】 Van Wagenen, B.C.; Barmore, R.M. (NPS Pharmaceuticals, Inc.); Chiral reductions of imines leading to the syntheses of optically active amines. WO 9711934 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 | |
| (A) | 10395 | 1,1,1-Triethoxypropane; 1,1-Diethoxypropyl ethyl ether; Triethyl orthopropionate | 115-80-0 | C9H20O3 | 详情 | 详情 |
| (II) | 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 |
| (VIII) | 32651 | 2-[(8S,9S,10R,13S,14S,16R,17R)-17-hydroxy-10,13,16-trimethyl-3,11-dioxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H30O6 | 详情 | 详情 | |
| (IX) | 32652 | 2-[(8S,9S,10R,13S,14S,16R,17R)-17-hydroxy-10,13,16-trimethyl-3,11-dioxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H28O6 | 详情 | 详情 | |
| (X) | 32653 | (8S,9S,10R,13S,14S,16R,17R)-17-glycoloyl-17-hydroxy-10,13,16-trimethyl-9,10,12,13,14,15,16,17-octahydro-3H-cyclopenta[a]phenanthrene-3,11(8H)-dione | C22H26O5 | 详情 | 详情 | |
| (XI) | 32654 | 2'-Ethoxy-2'-ethyl-16alpha-methylspiro[androsta-1,4,6-triene-17(R),4'-[1,3]dioxane]-3,5',11-trione | C27H34O6 | 详情 | 详情 | |
| (XII) | 32655 | (8S,9S,10R,13S,14S,16R,17R)-17-glycoloyl-10,13,16-trimethyl-3,11-dioxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl propionate | C25H30O6 | 详情 | 详情 | |
| (XIII) | 32656 | 2-oxo-2-[(8S,9S,10R,13S,14S,16R,17R)-10,13,16-trimethyl-3,11-dioxo-17-(propionyloxy)-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl]ethyl propionate | C28H34O7 | 详情 | 详情 | |
| (XIV) | 32657 | (7R,8S,9S,10R,13S,14S,16R,17R)-7-chloro-10,13,16-trimethyl-3,11-dioxo-17-[2-(propionyloxy)acetyl]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate | C28H35ClO7 | 详情 | 详情 |