|
【结 构 式】 
|
【分子编号】37104 【品名】(8R,9S,10R,13S,14S,17S)-17-hydroxy-2-[(Z)-hydroxymethylidene]-4,10,13,17-tetramethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one 【CA登记号】 |
【 分 子 式 】C22H32O3 【 分 子 量 】344.49428 【元素组成】C 76.7% H 9.36% O 13.93% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of 17beta-hydroxy-17-methylandrost-4-en-3-one (I) with thiophenol (A) and formaldehyde by means of triethylamine in refluxing ethanol gives 17beta-hydroxy-17-methy-4-(phenylthiomethyl)androst-4-en-3-one (II), which is desulfurized by treatment with Raney-Ni in water yielding 17beta-hydroxy-4,17-dimethylandrost-4-en-3-one (III). The reaction of (III) with methyl formate by means of sodium methoxide in methanol affords 17beta-hydroxy-4,17-dimethyl-2-hydroxymethyleneandrost-4-en-3-one (IV), which by cyclization with hydroxylamine in acetic acid-sodium acetate is converted into 4,17-dimethylandrosta-2,4-dieno[2,3-d]isoxazol-17beta-ol (V). The epoxidation of (V) with m-chloroperbenzoic acid in methylene chloride gives 4alpha,5alpha-epoxy-4,17-dimethylandrost-2-eno [2,3-d]isoxazol-17beta-ol (VI), which is finally isomerized by treatment with sodium methoxide in THF.
| 【1】 Christiansen, R.G. (Sanofi-Synthelabo); Steroid cyanoketones and intermediates. US 4160027 . |
| 【2】 Castaner, J.; Hillier, K.; Blancafort, P.; Serradell, M.N.; WIN-32,729. Drugs Fut 1982, 7, 9, 661. |
| 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) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (I) | 34383 | (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13,17-trimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | 58-18-4 | C20H30O2 | 详情 | 详情 |
| (II) | 37102 | (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13,17-trimethyl-4-[(phenylsulfanyl)methyl]-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C27H36O2S | 详情 | 详情 | |
| (III) | 37103 | (8R,9S,10R,13S,14S,17S)-17-hydroxy-4,10,13,17-tetramethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H32O2 | 详情 | 详情 | |
| (IV) | 37104 | (8R,9S,10R,13S,14S,17S)-17-hydroxy-2-[(Z)-hydroxymethylidene]-4,10,13,17-tetramethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one | C22H32O3 | 详情 | 详情 | |
| (V) | 37105 | (1S,3aS,3bR,10aR,10bS,12aS)-1,6,10a,12a-tetramethyl-2,3,3a,3b,4,5,10,10a,10b,11,12,12a-dodecahydro-1H-cyclopenta[7,8]phenanthro[3,2-d]isoxazol-1-ol | C22H31NO2 | 详情 | 详情 | |
| (VI) | 37106 | (1S,3aS,3bS,5aS,6aS,10aR,10bS,12aS)-1,6a,10a,12a-tetramethyl-1,2,3,3a,3b,4,5,6a,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[7,8]oxireno[2',3':10a,1]phenanthro[3,2-d]isoxazol-1-ol | C22H31NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The first method required the chiral building block (S)-(4-fluorophenyl)glycine (VI), which was prepared from 4-fluorophenyl acetic acid (I) by two routes. Condensation of (I) with (S)-4-benzyl-2-oxazolidinone (II), via activation as the corresponding mixed anhydride with pivaloyl chloride, furnished the N-acyl oxazolidinone (III). The potassium enolate of (III) was then reacted with 2,4,6-triisopropylphenylsulfonyl azide, producing stereoselectively azide (IV). Hydrolytic removal of the chiral auxiliary of (IV) gave (S)-azido-(4-fluorophenyl)acetic acid (V), which was then reduced to the desired amino acid (VI) by catalytic hydrogenation over Pd/C. Alternatively, 4-fluorophenyl acetic acid (I) was converted to the corresponding acid chloride (VII) with SOCl2. Bromination of (VII) under Hell-Volhard-Zelinskii conditions, followed by quenching with MeOH, afforded the racemic alpha-bromo ester (VIII). Displacement of the bromide of (VIII) with NaN3 using a phase-transfer catalyst produced the azido ester (IX). Catalytic hydrogenation of the azido group of (IX) gave the racemic amino ester, which was resolved via formation of the diastereomeric salts with (+)-dibenzoyltartaric acid. The desired (S)-amino ester (X) was then hydrolyzed to (VI) under acidic conditions.
| 【1】 Baker, R.; Harrison, T.; Mcleod, A.M.; Owens, A.P.; Seward, E.M.; Swain, C.J.; Teall, M.R. (Merck Sharp & Dohme Ltd.); Substd. morpholine derivs. and their use as therapeutic agents. EP 0737192; EP 1099702; JP 1997507484; JP 2000219629; US 5612337; WO 9518124 . |
| 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) | 18999 | 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid | 405-50-5 | C8H7FO2 | 详情 | 详情 |
| (II) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (III) | 44186 | (4S)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one | C18H16FNO3 | 详情 | 详情 | |
| (IV) | 44188 | (4S)-3-[(2S)-2-azido-2-(4-fluorophenyl)ethanoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H15FN4O3 | 详情 | 详情 | |
| (V) | 44189 | (2S)-2-azido-2-(4-fluorophenyl)ethanoic acid | C8H6FN3O2 | 详情 | 详情 | |
| (VI) | 37104 | (8R,9S,10R,13S,14S,17S)-17-hydroxy-2-[(Z)-hydroxymethylidene]-4,10,13,17-tetramethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one | C22H32O3 | 详情 | 详情 | |
| (VII) | 44191 | methyl 2-bromo-2-(4-fluorophenyl)acetate | C9H8BrFO2 | 详情 | 详情 | |
| (VIII) | 53260 | (1R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}tricyclo[3.2.0.0~2,7~]heptan-6-one | n/a | C13H22O2Si | 详情 | 详情 |
| (IX) | 53261 | bicyclo[3.2.0]hept-2-en-6-one | 13173-09-6 | C7H8O | 详情 | 详情 |
| (X) | 43098 | (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid | 7292-73-1 | C8H8FNO2 | 详情 | 详情 |