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【结 构 式】 
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【药物名称】PNU-179954 【化学名称】trans-(-)-N-[3-[3-Fluoro-4-(1-oxidoperhydrothiopyran-4-yl)phenyl]-2-oxooxazolidin-5(S)-ylmethyl]propionamide 【CA登记号】 【 分 子 式 】C18H23FN2O4S 【 分 子 量 】382.45741 |
【开发单位】Pfizer (Originator) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Oxazolidinones |
合成路线1
The known dihydrothiopyran derivative (I) was hydrogenated over PtO2 to produce the cis tetrahydrothiopyran sulfoxide (II) along with the trans isomer and the corresponding sulfide, which were separated by column chromatography. Selective hydrolysis of the acetamide function of (II) by means of hydroxylamine and pyridine in EtOH yielded amine (III). This was finally coupled with propionic anhydride to furnish the corresponding propionamide.
| 【1】 Martin, J.P. Jr.; Barbachyn, M.R.; Poel, T.-J. (Pharmacia Corp.); S-Oxide and S,S-dioxide tetrahydrothiopyran phenyloxazolidinones. EP 1036074; US 6083967; WO 9929688 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 | |
| (I) | 38782 | N-([(5S)-3-[3-fluoro-4-(1-oxo-1,2,3,6-tetrahydro-1lambda(4)-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C17H19FN2O4S | 详情 | 详情 | |
| (II) | 38783 | N-([(5S)-3-[3-fluoro-4-(1-oxohexahydro-1lambda(4)-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C17H21FN2O4S | 详情 | 详情 | |
| (III) | 38784 | (5S)-5-(aminomethyl)-3-[3-fluoro-4-(1-oxohexahydro-1lambda(4)-thiopyran-4-yl)phenyl]-1,3-oxazolidin-2-one | C15H19FN2O3S | 详情 | 详情 |
合成路线2
The reaction of 3-fluoroaniline (I) with isobutyl chloroformate (II) by means of K2CO3 in dichloromethane/water gives the carbamate (III), which is brominated with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) to yield the 4-bromo-3-fluorophenyl carbamate (IV). The condensation of (IV) with tetrahydrothiopyran-4-one (V) by means of EtMgBr and BuLi in THF affords the tertiary alcohol (VI), which is dehydroxylated by means of poly(methylhydrosiloxane) (PMHS), (Me3Si)2O and Ts-OH in toluene to provide the intermediate (VII). The stereoselective oxidation of (VII) to the trans sulfoxide (VIII) is performed by means of Ti(OiPr)4 and tert-butyl hydroperoxide in the presence of diisopropyl D-tartrate. The cyclization of the carbamate (VIII) with (S)-3-chloropropane-1,2-diol (IX) by means of Li t-amylate in DMF gives the oxazolidinone (X), whose free OH group is activated with 3-nitrobenzenesulfonyl chloride and TEA in dichloromethane to yield the sulfonate (XII). The reaction of (XII) with NH4OH in methanol/acetonitrile affords the aminomethyl derivative (XIII), which is finally acylated with propionic anhydride (XIV) to provide the target sulfoxide.
| 【1】 Gage, J.R.; et al.; Stereodivergent synthesis of sulfoxide-containing oxazolidinone antibiotics. Tetrahedron Lett 2000, 41, 22, 4301. |
| 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) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (III) | 49690 | isobutyl 3-fluorophenylcarbamate | C11H14FNO2 | 详情 | 详情 | |
| (IV) | 49691 | isobutyl 4-bromo-3-fluorophenylcarbamate | C11H13BrFNO2 | 详情 | 详情 | |
| (V) | 49692 | Tetrahydrothiopyran-4-one; Tetrahydro-4H-thiopyran-4-one; 4-Oxothiane | 1072-72-6 | C5H8OS | 详情 | 详情 |
| (VI) | 49693 | isobutyl 3-fluoro-4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenylcarbamate | C16H22FNO3S | 详情 | 详情 | |
| (VII) | 49702 | isobutyl 3-fluoro-4-tetrahydro-2H-thiopyran-4-ylphenylcarbamate | C16H22FNO2S | 详情 | 详情 | |
| (VIII) | 49706 | 4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]tetrahydro-2H-thiopyranium-1-olate | C16H22FNO3S | 详情 | 详情 | |
| (IX) | 49696 | (S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol | 60827-45-4 | C3H7ClO2 | 详情 | 详情 |
| (X) | 49707 | 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate | C15H18FNO4S | 详情 | 详情 | |
| (XI) | 49703 | m-nitrobenzenesulfonic acid; 3-nitrobenzenesulfonic acid | 98-47-5 | C6H5NO5S | 详情 | 详情 |
| (XII) | 49704 | 4-[2-fluoro-4-[(5R)-5-([[(3-nitrophenyl)sulfonyl]oxy]methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate | C21H21FN2O8S2 | 详情 | 详情 | |
| (XIII) | 49705 | 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate | C15H19FN2O3S | 详情 | 详情 | |
| (XIV) | 49701 | Acetic anhydride; Acetyl oxide | 108-24-7 | C4H6O3 | 详情 | 详情 |