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【结 构 式】 
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【药物名称】RWJ-302377 【化学名称】N-[3-[4-[1-(2-Benzyloxyacetyl)piperidin-4-yloxy]-3-fluorophenyl]-2-oxooxazolidin-5(S)-ylmethyl]acetamide 【CA登记号】 【 分 子 式 】C26H30FN3O6 【 分 子 量 】499.5439 |
【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 gave piperidine (XII). This was finally acylated with benzyloxyacetyl chloride (XIII) to provide the title amide.
| 【2】 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. |
| 【3】 Boggs, C.; Nelson, E.; Weidner-Wells, M.; Hlasta, D. (Ortho-McNeil Pharmaceutical, Inc.); Piperidinyloxy and pyrrolidinyloxyphenyl oxazolidinones as antibacterials. WO 0146164 . |
| 【1】 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) | 45652 | N-([(5S)-3-[3-fluoro-4-(4-piperidinyloxy)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | 2642-63-9 | C17H22FN3O4 | 详情 | 详情 |
| (XIII) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |