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【结 构 式】 
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【药物名称】PNU-176723 【化学名称】cis-(-)-N-[3-[3-Fluoro-4-(1-oxidoperhydrothiopyran-4-yl)phenyl]-2-oxooxazolidin-5(S)-ylmethyl]acetamide 【CA登记号】 【 分 子 式 】C17H21FN2O4S 【 分 子 量 】368.43032 |
【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 a mixture of cis tetrahydrothiopyran sulfoxide (II) and sulfide (III), which were separated by column chromatography. Oxidation of sulfide (III) using m-chloroperbenzoic acid then yielded a mixture of cis and trans sulfoxides, from which the title trans isomer was isolated by preparative HPLC.
| 【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 |
|---|---|---|---|---|---|---|
| (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) | 38785 | N-[[(5S)-3-(3-fluoro-4-tetrahydro-2H-thiopyran-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C17H21FN2O3S | 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 dehydrated by means of TFA in dichloromethane and oxidized with NaIO4 in methanol/water to provide the unsaturated sulfoxide (VII). The stereoselective reduction of (VII) by means of H2 over Pt/C in DMF gives the cis sulfoxide (VIII). 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 2,5-dichlorobenzenesulfonyl chloride (XI) 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 acetic 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) | 49694 | 4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]-3,6-dihydro-2H-thiopyranium-1-olate | C16H20FNO3S | 详情 | 详情 | |
| (VIII) | 49695 | 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) | 49697 | 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) | 49698 | 2,5-Dichlorobenzenesulfonic acid | 88-42-6 | C6H4Cl2O3S | 详情 | 详情 |
| (XII) | 49699 | 4-[4-[(5R)-5-([[(2,5-dichlorophenyl)sulfonyl]oxy]methyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate | C21H20Cl2FNO6S2 | 详情 | 详情 | |
| (XIII) | 49700 | 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 |