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【结 构 式】 
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【药物名称】Fluasterone, HE-2500, 8354 【化学名称】16alpha-Fluoroandrost-5-en-17-one 【CA登记号】112859-71-9 【 分 子 式 】C19H27FO 【 分 子 量 】290.42484 |
【开发单位】Temple University (Originator), Aeson Therapeutics (Licensee), Hollis-Eden (Licensee) 【药理作用】Actinic Keratoses, Agents for, Antiarthritic Drugs, Antipsoriatics, DERMATOLOGIC DRUGS, ENDOCRINE DRUGS, Immunologic Neuromuscular Disorders, Treatment of, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, ONCOLYTIC DRUGS, Systemic Lupus Erythematosus, Agents for, Treatment of Diabetic Complications, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Other Autoimmune Disorders |
合成路线1
Beckmann rearrangement of oxime (I) in the presence of p-acetamidobenzenesulfonyl chloride and pyridine afforded acetamide (II). Subsequent fluorination of (II) using perchloryl fluoride produced fluoroenamide (III), which was hydrolyzed with HCl to give fluoroketone (IV). After treatmentof (IV) with o-phenylenephosphorochloridite (V) and pyridine, the intermediate phosphite ester (VI) was converted to iodide (VII) by means of iodine in CH2Cl2. Finally, reductive deiodination of (VI) with Zn in AcOH produced the target compound.
| 【1】 Lewbart, M.L.; Schwartz, A.G. (Research Corporation Technologies, Inc.); Steroids useful as anti-cancer and anti-obesity agents, a therapeutic compsn. containing them and use thereof for the preparation of a therapeutic compsn.. EP 0246650; JP 1987283993 . |
| 【2】 Schwartz, A.G.; Lewbart, M.L.; 17-Hydroxy-steroids. US 4898694 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 19362 | 4-(acetamido)benzenesulfonyl chloride; N-acetylsulfanilyl chloride | 121-60-8 | C8H8ClNO3S | 详情 | 详情 |
| (I) | 30068 | (3S,8R,9S,10R,13S,14S)-17-ethanimidoyl-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C23H33NO3 | 详情 | 详情 | |
| (II) | 30069 | (3S,8R,9S,10R,13S,14S)-17-(acetamido)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C23H33NO3 | 详情 | 详情 | |
| (III) | 30070 | (3S,8R,9S,10R,13S,14S)-17-(acetamido)-16-fluoro-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C23H32FNO3 | 详情 | 详情 | |
| (IV) | 30071 | (3S,8R,9S,10R,13S,14S,16R)-16-fluoro-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H27FO2 | 详情 | 详情 | |
| (V) | 30072 | 2-chloro-1,3,2-benzodioxaphosphole | 1641-40-3 | C6H4ClO2P | 详情 | 详情 |
| (VI) | 30073 | (3S,8R,9S,10R,13S,14S,16R)-3-(1,3,2-benzodioxaphosphol-2-yloxy)-16-fluoro-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C25H30FO4P | 详情 | 详情 | |
| (VII) | 30074 | (3S,8R,9S,10R,13S,14S,16R)-16-fluoro-3-iodo-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H26FIO | 详情 | 详情 |
合成路线2
Dehydroepiandrosterone (VIII) was treated with o-phenylenephosphorochloridite (V) and then with iodine to afford iodide (IX), which was reduced to (X) by means of Zn and AcOH. Bromination of (X) with CuBr2 gave bromoketone (XI), and this was hydrolyzed to hydroxyketone (XII) upon treatment with aqueous NaOH in the presence of pyridine and oxygen. Subsequent treatment of (XII) with diethyl (2-chloro-1,1,2-trifluoroethyl)amine (XIII) afforded the target fluoroketone
| 【1】 Lewbart, M.L.; Schwartz, A.G. (Research Corporation Technologies, Inc.); Steroids useful as anti-cancer and anti-obesity agents, a therapeutic compsn. containing them and use thereof for the preparation of a therapeutic compsn.. EP 0246650; JP 1987283993 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 30072 | 2-chloro-1,3,2-benzodioxaphosphole | 1641-40-3 | C6H4ClO2P | 详情 | 详情 |
| (VIII) | 11713 | Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | 53-43-0 | C19H28O2 | 详情 | 详情 |
| (IX) | 30075 | (3S,8R,9S,10R,13S,14S)-3-iodo-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H27IO | 详情 | 详情 | |
| (X) | 30076 | (8R,9S,10R,13S,14S)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H28O | 详情 | 详情 | |
| (XI) | 30077 | (8R,9S,10R,13S,14S,16R)-16-bromo-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H27BrO | 详情 | 详情 | |
| (XII) | 30078 | (8R,9S,10R,13S,14S,16R)-16-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H28O2 | 详情 | 详情 | |
| (XIII) | 30079 | 2-chloro-N,N-diethyl-1,1,2-trifluoro-1-ethanamine; N-(2-chloro-1,1,2-trifluoroethyl)-N,N-diethylamine | C6H11ClF3N | 详情 | 详情 |
合成路线3
Dehydroepiandrosterone (VIII) was first brominated with CuBr2 to give bromoketone (XIV), which was hydrolyzed to hydroxyketone (XV). After protection of (XV) as the monoacetate (XVI), fluorination at position 16 by means of (2-chloro-1,1,2-trifluoroethyl)amine (XIII) afforded fluoroketone (XVII). Ester hydrolysis in (XVI) then gave intermediate (IV).
| 【1】 Schwartz, A.G.; Lewbart, M.L.; 17-Hydroxy-steroids. US 4898694 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 30071 | (3S,8R,9S,10R,13S,14S,16R)-16-fluoro-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H27FO2 | 详情 | 详情 | |
| (VIII) | 11713 | Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | 53-43-0 | C19H28O2 | 详情 | 详情 |
| (XIII) | 30079 | 2-chloro-N,N-diethyl-1,1,2-trifluoro-1-ethanamine; N-(2-chloro-1,1,2-trifluoroethyl)-N,N-diethylamine | C6H11ClF3N | 详情 | 详情 | |
| (XIV) | 30080 | (3S,8R,9S,10R,13S,14S,16R)-16-bromo-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H27BrO2 | 详情 | 详情 | |
| (XV) | 30081 | (3S,8R,9S,10R,13S,14S,16R)-3,16-dihydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H28O3 | 详情 | 详情 | |
| (XVI) | 30082 | (3S,8R,9S,10R,13S,14S,16R)-16-hydroxy-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C21H30O4 | 详情 | 详情 | |
| (XVII) | 30083 | (3S,8R,9S,10R,13S,14S,16R)-16-fluoro-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C21H29FO3 | 详情 | 详情 |