【结 构 式】 |
【药物名称】4-MA 【化学名称】N,N-Diethyl-4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxamide 【CA登记号】73671-86-0 【 分 子 式 】C24H40N2O2 【 分 子 量 】388.5986 |
【开发单位】 【药理作用】 |
合成路线1
The reaction of pregnenolone (I) with I2 and pyridine at 90 C gives (3beta-hydroxypregn-5-en-20-one-21-yl)pyridinium iodide (II), which by treatment with sodium methoxide in refluxing methanol is converted into methyl 5-androsten-3beta-ol-17beta-carboxylate (III). The Meerwein-Poundorf oxidation of (III) with cyclohexanone (A) and aluminum isopropoxide in refluxing toluene yields methyl 4-androsten-3-one-17beta-carboxylate (IV), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding free acid (3-oxo-4-etienic acid) (V). The reaction of (V) with oxalyl chloride (B) and diethylamine in refluxing toluene affords 17beta-(N,N-diethylcarbamoyl)-4-androstene-3-one (VI), which is oxidized with O3 or with NaIO4 and KMnO4 giving 17beta-(N,N-diethylcarbamoyl)-5-oxo-3,5-secoandrostan-3-oic acid (VII). The cyclization of (VII) with methylamine ethylene glycol at 180 C in a pressure vessel affords 17beta-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5-androsten-3-one (VIII), which is finally reduced with H2 over Pt in acetic acid. The cyclization of the acid (VII) with NH3 in ethanol at 180 C in a pressure vessel gives 17beta-(N,N-diethylcarbamoyl)-4-aza-5-androsten-3-one (IX), which is reduced with H2 over Pt in acetic acid yielding 17beta-(N,N-diethylcarbamoyl)-4-aza-5alpha-androstan-3-one (X). Finally, this compound is methylated with CH3I by means of NaH in toluene.
【1】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; 4-MA. Drugs Fut 1983, 8, 4, 323. |
【2】 Jobson, R.B.; Johnston, D.B.R.; Rasmusson, G.H.; Reinhold, D.F.; Utne, T. (Merck & Co., Inc.); Preparation of 4-aza-17-substituted-5 alpha -androstan-3-ones useful as 5 alpha -reductase inhibitors. US 4220775 . |
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) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
(B) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
(I) | 36070 | 1-[(3S,8S,9S,10R,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-ethanone | 145-13-1 | C21H32O2 | 详情 | 详情 |
(II) | 36071 | 1-[2-[(3S,8S,9S,10R,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl]pyridinium iodide | C26H36INO2 | 详情 | 详情 | |
(III) | 36072 | Methyl 3[beta]-hydroxyandrost-5-ene- 17[beta]carboxylate; methyl (3S,8S,9S,10R,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylate | 7254-03-7 | C21H32O3 | 详情 | 详情 |
(IV) | 14899 | methyl (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylate | C21H30O3 | 详情 | 详情 | |
(V) | 14892 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid; 4-Androstene-3-oxo-17-beta-carboxylic acid | 7385-78-6 | C20H28O3 | 详情 | 详情 |
(VI) | 36073 | (8S,9S,10R,13S,14S,17S)-N,N-diethyl-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide | C24H37NO2 | 详情 | 详情 | |
(VII) | 36074 | 3-[(3S,3aS,5aS,6R,9aS,9bS)-3-[(diethylamino)carbonyl]-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl]propionic acid | C23H37NO4 | 详情 | 详情 | |
(VIII) | 36075 | (4aR,4bS,6aS,7S,9aS,9bS)-N,N-diethyl-1,4a,6a-trimethyl-2-oxo-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C24H38N2O2 | 详情 | 详情 | |
(IX) | 36076 | (4aR,4bS,6aS,7S,9aS,9bS)-N,N-diethyl-4a,6a-dimethyl-2-oxo-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C23H36N2O2 | 详情 | 详情 | |
(X) | 36077 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N,N-diethyl-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C23H38N2O2 | 详情 | 详情 |
合成路线2
The oxidation of 3-oxo-4-etienic acid (V) with NaIO4 and KMnO4 in tert-butanol - water gives 5-oxo-3,5-secoandrostane-3,17beta-dioic acid (XI), which is cyclized with methylamine in ethanol at 180 C in a pressure vessel yielding 17beta-carboxy-4-methyl-4-aza-5-androsten-3-one (XII). The hydrogenation of (XII) with H2 over Pt in acetic acid affords 17beta-carboxy-4-methyl-4-azaandrostan-3-one (XIII), which is finally treated with oxalyl chloride (B) and diethylamine in toluene-THF. The amidation of (XIII) with oxalyl chloride (B) and NH3 in toluene-THF gives 17beta-carboxamide-4-methyl-4-azaandrostanone (XIV), which is alkylated with ethyl bromide and NaH in toluene. The amidation of (XIII) with ethylamine and oxalyl chloride (B) in toluene-THF gives 17beta-(N-ethylcarbamoyl)-4-methyl-4-azaandrostan-3-one (XV), which is finally alkylated with ethyl bromide and NaH in toluene.
【1】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; 4-MA. Drugs Fut 1983, 8, 4, 323. |
【2】 Jobson, R.B.; Johnston, D.B.R.; Rasmusson, G.H.; Reinhold, D.F.; Utne, T. (Merck & Co., Inc.); Preparation of 4-aza-17-substituted-5 alpha -androstan-3-ones useful as 5 alpha -reductase inhibitors. US 4220775 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(B) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
(V) | 14892 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid; 4-Androstene-3-oxo-17-beta-carboxylic acid | 7385-78-6 | C20H28O3 | 详情 | 详情 |
(XI) | 22451 | (3S,3aS,5aS,6R,9aS,9bS)-6-(2-carboxyethyl)-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalene-3-carboxylic acid | C19H28O5 | 详情 | 详情 | |
(XII) | 36078 | (4aR,4bS,6aS,7S,9aS,9bS)-1,4a,6a-trimethyl-2-oxo-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic acid | C20H29NO3 | 详情 | 详情 | |
(XIII) | 14890 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic acid | C20H31NO3 | 详情 | 详情 | |
(XIV) | 36079 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C20H32N2O2 | 详情 | 详情 | |
(XV) | 36080 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-ethyl-1,4a,6a-trimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C22H36N2O2 | 详情 | 详情 |