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【结 构 式】 
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【药物名称】L-654066, MK-963, MK-0963 【化学名称】23-Methyl-21-nor-4-aza-5alpha-chol-1-ene-3,20-dione 【CA登记号】103497-68-3 【 分 子 式 】C23H35NO2 【 分 子 量 】357.5409 |
【开发单位】Merck & Co. (Originator) 【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, Antiandrogens, Steroid 5alpha-Reductase Inhibitors |
合成路线1
L-654066 has been obtained by three related ways: 1) Reaction of methyl (5alpha)-3-oxo-4-azaandrostene-17beta-carboxylate (I) with potassium hydroxide, followed by treatment with pyridyl disulfide, gives S-(2-pyridyl) (5alpha)-3-oxo-4-azaandrostene-17beta-thiocarboxylate (II). Compound (II) is reacted with isobutylmagnesium chloride (III) in THF to give (5alpha)-23-methyl-4-aza-21-norcholane-3,20-dione (IV), which is finally dehydrogenated using benzeneseleninic anhydride in chlorobenzene. 2) Compound (I) is converted to its dehydro analogue methyl (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylate (V) with benzeneselenic anhydride, followed by reaction with isobutylmagnesium bromide (VI) in THF in the presence of hexamethyldisilazane. 3) Reaction of (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylic acid (VII) with carbonyldiimidazole in THF gives 1-[[(5alpha,17beta)-3-oxo-4-azaandrost-1-en-17-yl]carbonyl]-1H-imidazole (VII), which is treated with isobutylmagnesium chloride (III) in THF in the presence of ferric chloride.
| 【1】 Rasmusson, G.H.; Reynolds, G.F. (Merck & Co., Inc.); 17beta-Substd.-4-aza-5alpha-androstenones and their use as 5alpha-reductase inhibitors. AU 8539167; EP 0155096; EP 0314199; ES 8702430; JP 1985222497; JP 1989093600; US 4760071 . |
| 【2】 Rasmusson, G.H.; Reynolds, G.F. (Merck & Co., Inc.); 17beta-Acyl-4-aza-5alpha-androst-1-en-3-ones as 5alpha-reductase inhibitors. EP 0271219; JP 1988139196 . |
| 【3】 Gormley, G.J.; Stoner, E. (Merck & Co., Inc.); Pharmaceutical combination for the treatment of prostatic hyperplasia, containing a 5alpha-reductase inhibitor and an antiandrogen. JP 1994506227; WO 9216213 . |
| 【4】 Bhattacharya, A.; Dolling, U.H.; Amato, J.S.; Williams, J.M. (Merck & Co., Inc.); Methods of synthesizing benign prostatic hypertropic agents and their intermediates. EP 0367502 . |
| 【5】 Williams, J.M. (Merck & Co., Inc.); Process for making 17-beta alkanoyl 3-oxo-4-aza-5-alpha-androst-1-enes. US 5061803 . |
| 【6】 Rasmusson, G.H.; Reynolds, G.F.; Steinberg, N.G.; Walton, E.; Patel, G.F.; Liang, T.; Cascieri, M.A.; Cheung, A.H.; Brooks, J.R.; Berman, C.; Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding. J Med Chem 1986, 29, 11, 2298. |
| 【7】 Bhattacharya, A.; Williams, J.M.; Amato, J.S.; Dolling, U.-H.; Grabowski, E.J.J.; Acylimidazolides as versatile synthetic intermediates for the preparation of sterically congested amides and ketones: A practical synthesis of Proscar(R). Synth Commun 1990, 30, 17, 2683. |
| 【8】 Prous, J.; Mealy, N.; Castaner, J.; L-654066. Drugs Fut 1993, 18, 8, 701. |
| 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) | 13527 | methyl (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxylate | C20H31NO3 | 详情 | 详情 | |
| (II) | 13528 | S-(2-pyridinyl) (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carbothioate | C24H32N2O2S | 详情 | 详情 | |
| (III) | 13529 | Chloro(isopentyl)magnesium | C5H11ClMg | 详情 | 详情 | |
| (IV) | 13530 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-Dimethyl-7-(3-methylbutanoyl)hexadecahydro-2H-indeno[5,4-f]quinolin-2-one | C23H37NO2 | 详情 | 详情 | |
| (V) | 13009 | methyl (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylate | C20H29NO3 | 详情 | 详情 | |
| (VI) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (VII) | 13533 | (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-Dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic acid | C19H27NO3 | 详情 | 详情 | |
| (VIII) | 13534 | (4aS,4bS,6aS,7S,9aS,9bS,11aR)-7-(1H-Imidazol-1-ylcarbonyl)-4a,6a-dimethyl-1,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-2H-indeno[5,4-f]quinolin-2-one | C22H29N3O2 | 详情 | 详情 |