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【结 构 式】

【药物名称】RWJ-306490

【化学名称】N-[3-[3-Fluoro-4-[1-(2-hydroxyacetyl)piperidin-4-yloxy]phenyl]-2-oxooxazolidin-5(S)-ylmethyl]acetamide

【CA登记号】

【 分 子 式 】C19H24FN3O6

【 分 子 量 】409.41803

【开发单位】R.W. Johnson (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Oxazolidinones

合成路线1

4-Hydroxypiperidine (I) was protected as the N-Boc derivative (II), which was then condensed with 1,2-difluoro-4-nitrobenzene (III) in the presence of potassium tert-butoxide, yielding ether (IV). Reduction of the nitro group of (IV) by transfer hydrogenation, followed by treatment of the resulting aniline (V) with benzyl chloroformate, afforded carbamate (VI). After deprotonation of the carbamate group of (VI) with n-butyllithium, reaction with (R)-glycidyl butyrate (VII) generated the chiral oxazolidinone (VIII). Conversion of (VIII) to mesylate (IX) and subsequent displacement with NaN3 provided azide (X). This was reduced to the corresponding amine, which was acetylated with Ac2O to furnish amide (XI). Cleavage of the Boc protecting group of (XI) with trifluoroacetic acid, followed by acylation of the resulting piperidine with benzyloxyacetyl chloride, provided amide (XII). Finally, hydrogenolysis of the O-benzyl group of (XII) by transfer hydrogenation in the presence of ammonium formate and Pd/C yielded the title hydroxyacetamide.

1 Weidner-Wells, M.A.; et al.; Novel piperidinyloxy oxazolidinone antibacterial agents. Diversification of the N-substituent. Bioorg Med Chem 2002, 10, 7, 2345.
3 Boggs, C.M.; et al.; Novel piperidinyloxy-oxazolidinone antimicrobial agents: Effects of position, fluorine substitution, and ring-size on in vitro antimicrobial activity. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 98.
4 Boggs, C.; Nelson, E.; Weidner-Wells, M.; Hlasta, D. (Ortho-McNeil Pharmaceutical, Inc.); Piperidinyloxy and pyrrolidinyloxyphenyl oxazolidinones as antibacterials. WO 0146164 .
2 Hilliard, J.J.; Montenegro, D.A.; Nelson, E.A.; Goldschmidt, R.M.; Boggs, C.M.; Weidner-Wells, M.A.; Wira, E.; Hlasta, D.J.; Melton, J.; Foleno, B.D.; Bush, K.; Piperidinyloxy substituted oxazolidinones as antibacterial agents. Diversification of the N-substituent. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1828.
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) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(II) 18625 tert-butyl 4-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(III) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(IV) 45645 tert-butyl 4-(2-fluoro-4-nitrophenoxy)-1-piperidinecarboxylate C16H21FN2O5 详情 详情
(V) 45646 tert-butyl 4-(4-amino-2-fluorophenoxy)-1-piperidinecarboxylate 654-01-3 C16H23FN2O3 详情 详情
(VI) 45647 tert-butyl 4-(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenoxy)-1-piperidinecarboxylate C24H29FN2O5 详情 详情
(VII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VIII) 45648 tert-butyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy]-1-piperidinecarboxylate C20H27FN2O6 详情 详情
(IX) 45649 tert-butyl 4-[2-fluoro-4-((5R)-5-[[(methylsulfonyl)oxy]methyl]-2-oxo-1,3-oxazolidin-3-yl)phenoxy]-1-piperidinecarboxylate 22888-70-6 C21H29FN2O8S 详情 详情
(X) 45650 tert-butyl 4-[4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy]-1-piperidinecarboxylate C20H26FN5O5 详情 详情
(XI) 45651 tert-butyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy)-1-piperidinecarboxylate C22H30FN3O6 详情 详情
(XII) 45653 benzyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy)-1-piperidinecarboxylate C25H28FN3O6 详情 详情
Extended Information