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【结 构 式】 
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【分子编号】14899 【品名】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 【CA登记号】 |
【 分 子 式 】C21H30O3 【 分 子 量 】330.4674 【元素组成】C 76.33% H 9.15% O 14.52% |
合成路线1
该中间体在本合成路线中的序号：(IV)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
该中间体在本合成路线中的序号：(IV)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 |
合成路线3
该中间体在本合成路线中的序号：(I)Methyl 3-oxoandrost-4-en-17beta-carboxylate (I) was converted to methyl 3-bromoandrosta-3,5-diene-17beta-carboxylate (II) by treatment with phosphorus tribromide in glacial acetic acid. Saponification of (II) in methanolic potassium hydroxide afforded 3-bromoandrosta-3,5-diene-17beta-carboxylic acid (III), which was further converted to 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17beta-carboxamide (IV) by treatment with oxalyl chloride and quenching with tert-butylamine. Treatment of (IV) with ethyl magnesium bromide, followed by halogen metal-exchange with sec-butyllithium and gassing with carbon dioxide afforded crude epristeride (V). Alternatively, 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17beta-carboxamide (IV) was prepared in one step by treatment of 17beta-androst-4-en-3-one carboxylic acid (VI) with bromomethylenedimethylammonium bromide, followed by quenching with tert-butylamine. Crude epristeride was purified and converted to the desired polymorph by heating a suspension in ethyl acetate.
| 【1】 Levy, M.A.; Holt, D.A.; Wier, P.J.; Baine, N.H.; Audet, P.R.; Metcalf, B.W.; Benincosa, L.J.; Rappaport, E.B.; Epristeride. Drugs Fut 1994, 19, 7, 646. |
| 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) | 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 | |
| (II) | 14918 | methyl (8S,9S,10R,13S,14S,17S)-3-bromo-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylate | C21H29BrO2 | 详情 | 详情 | |
| (III) | 14919 | (8S,9S,10R,13S,14S,17S)-3-bromo-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid | C20H27BrO2 | 详情 | 详情 | |
| (IV) | 14920 | (8S,9S,10R,13S,14S,17S)-3-bromo-N-(tert-butyl)-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide | C24H36BrNO | 详情 | 详情 | |
| (V) | 14921 | (8S,9S,10R,13S,14S,17S)-17-[(tert-butylamino)carbonyl]-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-carboxylic acid | C25H37NO3 | 详情 | 详情 | |
| (VI) | 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 |
合成路线4
该中间体在本合成路线中的序号：(I),(IV)The synthesis of [14C]-labeled epristeride has been reported: The oxidation and decarboxylation of 3-oxo-4-androstene-17beta-carboxylic acid methyl ester (I) gives the 3-oxo-4-oxasteroid (II), which is methylated with [14C]-labeled methyl magnesium iodide, yielding labeled 3-hydroxy-3-methyl-4-oxa-5-androstene-17beta-carboxylic acid methyl ester (III). The cyclization of (III) by means of NaOH affords labeled 3-oxo-4-androstene-17beta-carboxylic acid methyl ester (IV), which is hydrolyzed with KOH to the corresponding acid (V). The reaction of (V) with trifluoromethanesulfonic anhydride gives the androstadiene triflate (VI), which by reaction first with SOCl2 and then with tert-butylamine is converted to the amide (VII). The carboxylation of (VII) with CO and triphenylphosphine palladium diacetate complex in methanol affords [14C]-labeled 17beta-(N-tert-butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid methyl ester (VIII), which is finally treated with K2CO3 in refluxing methanol/water.
| 【1】 Heys, J.R.; Shu, A.Y.L.; Synthesis of carbon-14 and tritiated steroidal 5alpha-reductase inhibitors. J Label Compd Radiopharm 1994, 34, 7, 587. |
| 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),(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 | |
| (II) | 14924 | methyl (4aR,4bS,6aS,7S,9aS,9bS)-4a,6a-dimethyl-2-oxo-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydroindeno[5,4-f]chromene-7-carboxylate | C20H28O4 | 详情 | 详情 | |
| (III) | 14925 | methyl (4aR,4bS,6aS,7S,9aS,9bS)-2-hydroxy-2,4a,6a-trimethyl-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydroindeno[5,4-f]chromene-7-carboxylate | C21H32O4 | 详情 | 详情 | |
| (III) | 45227 | methyl (4aR,4bS,6aS,7S,9aS,9bS)-2-hydroxy-2,4a,6a-trimethyl-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydroindeno[5,4-f]chromene-7-carboxylate | C21H32O4 | 详情 | 详情 | |
| (IV) | 45228 | 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 |
| (V) | 45229 | (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 | C20H28O3 | 详情 | 详情 | |
| (VI) | 14928 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-[[(trifluoromethyl)sulfonyl]oxy]-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid | C21H27F3O5S | 详情 | 详情 | |
| (VI) | 45230 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-[[(trifluoromethyl)sulfonyl]oxy]-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid | C21H27F3O5S | 详情 | 详情 | |
| (VII) | 14929 | (8S,9S,10R,13S,14S,17S)-17-[(tert-butylamino)carbonyl]-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl trifluoromethanesulfonate | C25H36F3NO4S | 详情 | 详情 | |
| (VII) | 45231 | (8S,9S,10R,13S,14S,17S)-17-[(tert-butylamino)carbonyl]-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl trifluoromethanesulfonate | C25H36F3NO4S | 详情 | 详情 | |
| (VIII) | 14930 | methyl (8S,9S,10R,13S,14S,17S)-17-[(tert-butylamino)carbonyl]-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-carboxylate | C26H39NO3 | 详情 | 详情 | |
| (VIII) | 45232 | methyl (8S,9S,10R,13S,14S,17S)-17-[(tert-butylamino)carbonyl]-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3-carboxylate | C26H39NO3 | 详情 | 详情 |