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【结 构 式】

【分子编号】15324

【品名】methyl (2S,4R)-1-[(4-methylphenyl)sulfonyl]-4-[[(4-methylphenyl)sulfonyl]oxy]tetrahydro-1H-pyrrole-2-carboxylate

【CA登记号】

【 分 子 式 】C20H23NO7S2

【 分 子 量 】453.53716

【元素组成】C 52.97% H 5.11% N 3.09% O 24.69% S 14.14%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

Danofloxacin (XI) is synthesized by the addition of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X), and further converted to its monomethanesulfonate salt as outlined in Scheme 17912701a: The diazabicycloalkane sidechain (VII) is prepared in one of two ways, both routes starting with trans-4-hydroxy-L-proline (I). In the first sequence, the amino acid (I) is selectively monotosylated on nitrogen by stirring an aqueous solution of (I) in the presence of p-toluenesulfonyl chloride (TsCl) with sodium carbonate as base. The monotosylate (II) is then reduced to the diol (III) with diborane generated in situ. The diol (III) is next converted to either the tritosylate (IV) selectively or to a mixture of (IV) and the monochloride (V) by treatment with excess TsCl in pyridine at either 0 C or room temperature, respectively. Either pure (IV) or a mixture of (IV) and (V) can be cyclized equally well to the bicyclic intermediate (VI) by treatment with methylamine in a sealed container. Finally, (VI) can be deprotected to give the desired (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) in excellent overall yield by treatment with 30% anhydrous hydrogen bromide in acetic acid. By an alternative route, (I) is esterified under Fischer conditions and treated with excess p-toluenesulfonyl chloride in the presence of pyridine and triethylamine. The resulting ester (VIII) is then treated with methylamine to obtain the amide (IX), which is reductively cyclized with lithium aluminum hydride to the bicyclic intermediate (VI). Finally, (VI) is deprotected as described above to give (VII). The reaction of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X) to give danofloxacin free base (XI) is effected by the action of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in pyridine. Conversion of (XI) to danofloxacin mesylate using one equivalent of methanesulfonic acid in ethanol completes the synthesis.

1 Fox, D.E.; Braish, T.F.; Synthesis of (S,S)- and (R,R)-2-alkyl-2,5-diazabicyclo[2.2.1]heptanes. J Org Chem 1990, 55, 1684-7.
2 Braish, T.F.; Fox, D.E. (Pfizer Inc.); Process for optically active 2-alkyl-2,5-diazabicyclo(2.2.1)heptanes. US 5013839 .
3 McGuirk, P.R.; Jefson, M.R.; Mann, D.D.; et al.; Synthesis and structure-activity relationships of 7-diazabicycloalkylquinolones, including danofloxacin, a new quinolone antibacterial agent for veterinary medicine. J Med Chem 1992, 35, 4, 611.
4 Jefson, M.R.; Shryock, T.R.; Schaaf, T.K.; McGuirk, P.R.; The synthesis and antibacterial activity of danofloxacin (CP-76,136): A new quinolone for veterinary medicine. 29th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, Houston) 1989, Abst 1187.
5 McGuirk, P.R.; Jefson, M.R.; Danofloxacin Mesylate. Drugs Fut 1992, 17, 2, 93.
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) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(II) 15318 (2S,4R)-4-hydroxy-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrole-2-carboxylic acid C12H15NO5S 详情 详情
(III) 15319 (3R,5S)-5-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-ol C12H17NO4S 详情 详情
(IV) 15320 (3R,5S)-1-[(4-methylphenyl)sulfonyl]-5-([[(4-methylphenyl)sulfonyl]oxy]methyl)pyrrolidinyl 4-methylbenzenesulfonate C26H29NO8S3 详情 详情
(V) 15321 (3R,5S)-5-(chloromethyl)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-yl 4-methylbenzenesulfonate C19H22ClNO5S2 详情 详情
(VI) 15322 (1S,4S)-2-methyl-5-[(4-methylphenyl)sulfonyl]-2,5-diazabicyclo[2.2.1]heptane C13H18N2O2S 详情 详情
(VII) 15323 (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane C6H12N2 详情 详情
(VIII) 15324 methyl (2S,4R)-1-[(4-methylphenyl)sulfonyl]-4-[[(4-methylphenyl)sulfonyl]oxy]tetrahydro-1H-pyrrole-2-carboxylate C20H23NO7S2 详情 详情
(IX) 15325 (3R,5S)-5-[(methylamino)carbonyl]-1-[(4-methylphenyl)sulfonyl]pyrrolidinyl 4-methylbenzenesulfonate C20H24N2O6S2 详情 详情
(X) 15326 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C13H9F2NO3 详情 详情
(XI) 15327 1-Cyclopropyl-6-fluoro-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid; Danofloxacin C19H20FN3O3 详情 详情
Extended Information