|
【结 构 式】 
|
【药物名称】Turosteride((-)-enantiomer), FCE-26073 【化学名称】17beta-[N-Isopropyl-N-(isopropylcarbamoyl)carbamoyl]-4-methyl-4-aza-5alpha-androstan-3-one 【CA登记号】137099-09-3 【 分 子 式 】C27H45N3O3 【 分 子 量 】459.678 |
【开发单位】Pfizer (Originator) 【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, Antiandrogens, Steroid 5alpha-Reductase Inhibitors |
合成路线1
1) By the reaction of 4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxylic acid (I) with diisopropylcarbodiimide (II) in methylene chloride at room temperature.
| 【1】 Primka, R.L.; Rasmusson, H.G.; Utne, T.; Jobson, R.B.; Reynolds, G.F.; Berman, C.; Brooks, J.R.; Azasteroids as inhibitors of rat prostatic 5alpha-reductase. J Med Chem 1984, 27, 12, 1690-701. |
| 【2】 Panzeri, A.; Di Salle, E.; Nesi, M. (Pharmacia Corp.); 17beta-Substd.-4-aza-5alpha-androstan-3-one derivs. and process for their preparation. EP 0468012; JP 1992505462; US 5155107; WO 9112261 . |
| 【3】 Di Sale, E.; Panzeri, A.; Turosteride. Drugs Fut 1993, 18, 5, 436. |
合成路线2
2) By the reaction of 3-oxoandrost-4-ene-17beta-carboxylic acid (III) with diisopropylcarbodiimide (II) in refluxing ethyl acetate and subsequent A-ring opening of compound (IV) by treatment with the Lamieux-von Rudloff reagent (permanganate-periodate) in isopropanol. The cyclization of the secoacid (V) so obtained, with methylamine in dioxane under pressure, followed by the hydrogenation under pressure, on 10% Pd/C in ethanol, affords turosteride. This method is used for the large scale production of turosteride.
| 【1】 Panzeri, A.; Di Salle, E.; Nesi, M. (Pharmacia Corp.); 17beta-Substd.-4-aza-5alpha-androstan-3-one derivs. and process for their preparation. EP 0468012; JP 1992505462; US 5155107; WO 9112261 . |
| 【2】 Di Sale, E.; Panzeri, A.; Turosteride. Drugs Fut 1993, 18, 5, 436. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 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 |
| (IV) | 14893 | N-[[(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]phenanthren-17-yl]carbonyl]-N,N'-diisopropylurea | C27H42N2O3 | 详情 | 详情 | |
| (V) | 14894 | 3-[(3S,3aS,5aS,6R,9aS,9bS)-3-([isopropyl[(isopropylamino)carbonyl]amino]carbonyl)-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl]propionic acid | C26H42N2O5 | 详情 | 详情 | |
| (VI) | 14895 | N-[[(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]quinolin-7-yl]carbonyl]-N,N'-diisopropylurea | C27H43N3O3 | 详情 | 详情 |
合成路线3
The synthesis of [14C]-turosteride has been reported: The reaction of 20-[14C]-3-hydroxy-5-pregnen-20-one (I) with iodine and pyridine gives the pyridinium derivative (II), which is treated with sodium methoxide and methanol yielding 3-hydroxy-5-androstene-17beta-carboxylic acid methyl ester (III). The oxidation of (III) with cyclohexanone and aluminum isopropoxide affords 3-oxo-5-androstene-17beta-carboxylic acid methyl ester (IV), which is oxidized with potassium permanganate and sodium periodate to the propionic acid derivative (V). The cyclization of (V) with methylamine in diglyme at 180 C affords 4-methyl-3-oxo-4-aza-5-androstene-17beta-carboxylic acid methyl ester (VI), which is hydrogenated with H2 over PtO2 in acetic acid to the corresponding saturated compound (VII). The saponification of (VII) with KOH in refluxing methanol/water gives the 4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxylic acid (VIII), which is finally condensed with diisopropylcarbodiimide (IX) in refluxing dichloromethane.
| 【1】 Panzeri, A.; Dostert, P.; Angiuli, P.; Fontana, E.; Pignatti, A.; Synthesis of carbon-14 labelled 1-[4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carbonyl]-1,3-diisopropylurea (turosteride), a new 5alpha-reductase inhibitor. J Label Compd Radiopharm 1996, 38, 7, 667. |
| 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) | 14896 | 1-[(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; Pregnenolone | 145-13-1 | C21H32O2 | 详情 | 详情 |
| (I) | 63920 | 1-[(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 | C21H32O2 | 详情 | 详情 | |
| (II) | 14897 | 1-[2-[(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 | C26H36NO2 | 详情 | 详情 | |
| (II) | 63921 | 1-{2-[(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 | C26H36NO2 | 详情 | 详情 | |
| (III) | 14898 | methyl (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 | C21H32O3 | 详情 | 详情 | |
| (III) | 63922 | methyl (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 | 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 | |
| (IV) | 63923 | 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) | 14900 | 3-[(3S,3aS,5aS,6R,9aS,9bS)-3-(methoxycarbonyl)-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl]propionic acid | C20H30O5 | 详情 | 详情 | |
| (V) | 63924 | 3-[(3S,3aS,5aS,6R,9aS,9bS)-3-(methoxycarbonyl)-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl]propanoic acid | C20H30O5 | 详情 | 详情 | |
| (VI) | 14901 | methyl (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-carboxylate | C21H31NO3 | 详情 | 详情 | |
| (VI) | 63925 | methyl (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-carboxylate | C21H31NO3 | 详情 | 详情 | |
| (VII) | 14902 | methyl (4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxylate | C21H33NO3 | 详情 | 详情 | |
| (VII) | 63926 | methyl (4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxylate | C21H33NO3 | 详情 | 详情 | |
| (VIII) | 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 | |
| (VIII) | 63927 | (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 | |
| (IX) | 14891 | N,N'-diisopropylcarbodiimide | 693-13-0 | C7H14N2 | 详情 | 详情 |