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【结 构 式】

【药物名称】Linezolid, PNU-100766, U-100766, Zyvoxid, Zyvoxam, Zyvoxa, Zyvox

【化学名称】N-[3-[3-Fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5(S)-ylmethyl]acetamide

【CA登记号】165800-03-3

【 分 子 式 】C16H20FN3O4

【 分 子 量 】337.3539

【开发单位】Pfizer (Originator)

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

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9

合成路线1

　

参考文献 中间体
【1】 Barhachyn MR. 1995. Substituted oxazine and thiazine oxatotidinone antimicrobials. W01995007271[本专利为Pfrizer Inc (US)所有]
【2】 Brickner SJ, Hutchinson DK, Barbachyn MR, et aL 1996. Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant Gram-positive bacterial infections. J Med Chem, 39 (3): 673～679
【3】 Du Y.Guo HY. 2002. Synthesis and antibacterial activity of linezolid analogs. Bioorg Med Chem Lett.12(6): 857～859
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) 17015 3-fluoro-4-morpholinophenylamine; 3-fluoro-4-morpholinoaniline; 3-fluoro-4-(4-morpholinyl)phenylamine; 3-Fluoro-4-(4-morpholinyl)benzeneamine 93246-53-8 C10H13FN2O 详情 详情
(II) 66495 4-(4-bromo-2-fluorophenyl)morpholine 513068-89-8 C10H11BrFNO 详情 详情
(III) 66496 5-(((tetrahydro-2H-pyran-2-yl)peroxy)methyl)oxazolidin-2-one 　 C9H15NO5 详情 详情
(IV) 17018 (5R)-3-(3-fluoro-4-morpholinophenyl)-5-(hydroxymethyl)-1,3-oxazolan-2-one 168828-82-8 C14H17FN2O4 详情 详情

合成路线2

　

参考文献 中间体
【1】 Krishna Reddy P. 2005.A novel process for the preparation of linezolicl and related compounds. 2005099353[本专利为Symed Laboratories Ltd (IN)所有]
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 10926 (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium C8H4KNO2 详情 详情
(V) 66499 (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione 　 C22H20FN3O5 详情 详情
(I) 17015 3-fluoro-4-morpholinophenylamine; 3-fluoro-4-morpholinoaniline; 3-fluoro-4-(4-morpholinyl)phenylamine; 3-Fluoro-4-(4-morpholinyl)benzeneamine 93246-53-8 C10H13FN2O 详情 详情
(II) 66497 (S)-1-chloro-3-((3-fluoro-4-morpholinophenyl)amino)propan-2-ol 　 C13H18ClFN2O2 详情 详情
(III) 66498 (S)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one 　 C14H16ClFN2O3 详情 详情

合成路线3

　

参考文献 中间体
【1】 Mohan Rao D.2006. Novel intermediates for linezolid and related compounds. W0 20066008754[本专利为Symed Laboratories Ltd (IN)所有]
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 66501 (S)-2-(3-((3-fluoro-4-morpholinophenyl)amino)-2-hydroxypropyl)isoindoline-1,3-dione 　 C21H22FN3O4 详情 详情
(V) 66502 (S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione 　 C11H9NO3 详情 详情
(I) 66497 (S)-1-chloro-3-((3-fluoro-4-morpholinophenyl)amino)propan-2-ol 　 C13H18ClFN2O2 详情 详情
(II) 10926 (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium C8H4KNO2 详情 详情
(IV) 17015 3-fluoro-4-morpholinophenylamine; 3-fluoro-4-morpholinoaniline; 3-fluoro-4-(4-morpholinyl)phenylamine; 3-Fluoro-4-(4-morpholinyl)benzeneamine 93246-53-8 C10H13FN2O 详情 详情
(VII) 17021 (5S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolan-2-one C14H18FN3O3 详情 详情

合成路线4

　

参考文献 中间体
【1】 Xu GY, Zhou Y, Xu MC, 2006.A convenient synthesis of antibacterial inezolid from (S)-glyceraldehyde acetonide Chinese Chem Lett, 17 (3): 302～304
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) 17015 3-fluoro-4-morpholinophenylamine; 3-fluoro-4-morpholinoaniline; 3-fluoro-4-(4-morpholinyl)phenylamine; 3-Fluoro-4-(4-morpholinyl)benzeneamine 93246-53-8 C10H13FN2O 详情 详情
(II) 66503 (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 　 C6H10O3 详情 详情
(III) 66504 (S)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-fluoro-4-morpholinoaniline 　 C16H23FN2O3 详情 详情
(IV) 17018 (5R)-3-(3-fluoro-4-morpholinophenyl)-5-(hydroxymethyl)-1,3-oxazolan-2-one 168828-82-8 C14H17FN2O4 详情 详情
(V) 17020 (5R)-5-(azidomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolan-2-one C14H16FN5O3 详情 详情

合成路线5

　

参考文献 中间体
【1】 Yu DS,Wang ZQ,XiongY. et aL 2005. New synthetic method of linezolid．中国药物他学杂志，15(2): 89～90, 93
【2】 Yu DS, Huang L, Liang H, et aL 2005. A new and dficient synthetic metbod and antibacterial activities of oxazolidinone analogs Chinese Chem Lett, 16 (7)t 875～ 878
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 66506 (S)-N-((3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide 　 C12H12BrFN2O3 详情 详情
(I) 66505 (R)-5-(chloromethyl)-3-(3-fluorophenyl)oxazolidin-2-one 149524-44-7 C10H9ClFNO2 详情 详情
(II) 60317 (R)-5-(azidomethyl)-3-(3-fluorophenyl)oxazolidin-2-one C10H9FN4O2 详情 详情
(III) 60319 N-{[3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C12H13FN2O3 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线6

　

参考文献 中间体
【1】 Narina SV, Sudalai A. 2006. Short and practical enantioselective of linezolid and eperezoild via proline-catalyzed asymmetric-aminooxylation.Tetrahedron Lett, 47 (38): 6799～6802
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 66509 (R)-benzyl (2,3-dihydroxypropyl)(3-fluoro-4-morpholinophenyl)carbamate 　 C21H25FN2O5 详情 详情
(I) 66507 benzyl (3-fluoro-4-morpholinophenyl)(3-hydroxypropyl)carbamate 　 C21H25FN2O4 详情 详情
(II) 66508 benzyl (3-fluoro-4-morpholinophenyl)(3-oxopropyl)carbamate 　 C21H23FN2O4 详情 详情
(IV) 17018 (5R)-3-(3-fluoro-4-morpholinophenyl)-5-(hydroxymethyl)-1,3-oxazolan-2-one 168828-82-8 C14H17FN2O4 详情 详情

合成路线7

　

参考文献 中间体
【1】 Perrault WR, Pearlman BA, Godrej DB, et aL 2003. The.synthesis of N-aryl-5(S)-aminomethyl-2-oxazolidinone antibacterials and derivatives in one step from aryl carbamates. Org Proc Res Dev,7(4): 533一546
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 17016 benzyl N-(3-fluoro-4-morpholinophenyl)carbamate C18H19FN2O3 详情 详情
(I) 66510 (S)-2-(chloromethyl)oxirane C3H5ClO 详情 详情
(II) 61915 (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate C7H12ClNO3 详情 详情

合成路线8

　

参考文献 中间体
【1】 Mallesham B, Rajesh BM,Reddy PR, et al. 2003. Highly efficient cui-catalyzed coupling of aryl bromides with oxazolidinones using buchwald's prorocolt: a short route to linezolid and toloxatone. Org Lett,5(7):963～965
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) 17015 3-fluoro-4-morpholinophenylamine; 3-fluoro-4-morpholinoaniline; 3-fluoro-4-(4-morpholinyl)phenylamine; 3-Fluoro-4-(4-morpholinyl)benzeneamine 93246-53-8 C10H13FN2O 详情 详情
(II) 66495 4-(4-bromo-2-fluorophenyl)morpholine 513068-89-8 C10H11BrFNO 详情 详情
(III) 66496 5-(((tetrahydro-2H-pyran-2-yl)peroxy)methyl)oxazolidin-2-one 　 C9H15NO5 详情 详情
(IV) 66511 3-(3-fluoro-4-morpholinophenyl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)oxazolidin-2-one 　 C19H25FN2O5 详情 详情
(V) 66512 3-(3-fluoro-4-morpholinophenyl)-5-(hydroxymethyl)oxazolidin-2-one 　 C14H17FN2O4 详情 详情

合成路线9

The condensation of morpholine (I) with 3,4-difluoronitrobenzene (II) by means of diisopropylethylamine in refluxing acetonitrile gives 3-fluoro-4-(4-morpholinyl)nitrobenzene (III), which is reduced with ammonium formate over Pd/C in THF/methanol to the corresponding aniline (IV). The reaction of (IV) with benzyloxycarbonyl chloride and NaHCO3 in acetone/water yields the carbamate ester (V), which is cyclized with 2(R),3-epoxypropyl butyrate (VI) by means of butyllithium in THF affording 5(R)-(hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]oxazolidin-2-one (VII). The reaction of (VII) with methanesulfonyl chloride and triethylamine in dichloromethane gives the mesylate (VIII), which by reaction with NaN3 in hot DMF is converted into the azide (IX). The reduction of (IX) with H2 over Pd/C in ethyl acetate affords the corresponding amine (X), which is finally acetylated with acetic anhydride and pyridine.

参考文献 中间体
【1】 Brickner, S.J.; Hutchinson, D.K.; Barbachyn, M.R.; et al.; Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant Gram-positive bacterial infections. J Med Chem 1996, 39, 3, 673.
【2】 Lizondo, J.; Rabasseda, X.; Castañer, J.; Linezolid. Drugs Fut 1996, 21, 11, 1116.
【3】 Barbachyn, M.R.; Brickner, S.J.; Hutchinson, D.K. (Pharmacia Corp.); Substd. oxazine and thiazine oxazolidinone antimicrobials. EP 0717738; JP 1997502436; WO 9507271 .
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) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(II) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(III) 17014 4-(2-fluoro-4-nitrophenyl)morpholine C10H11FN2O3 详情 详情
(IV) 17015 3-fluoro-4-morpholinophenylamine; 3-fluoro-4-morpholinoaniline; 3-fluoro-4-(4-morpholinyl)phenylamine; 3-Fluoro-4-(4-morpholinyl)benzeneamine 93246-53-8 C10H13FN2O 详情 详情
(V) 17016 benzyl N-(3-fluoro-4-morpholinophenyl)carbamate C18H19FN2O3 详情 详情
(VI) 17017 (2S)oxiranylmethyl butyrate C7H12O3 详情 详情
(VII) 17018 (5R)-3-(3-fluoro-4-morpholinophenyl)-5-(hydroxymethyl)-1,3-oxazolan-2-one 168828-82-8 C14H17FN2O4 详情 详情
(VIII) 17019 [(5R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolan-5-yl]methyl methanesulfonate 174649-09-3 C15H19FN2O6S 详情 详情
(IX) 17020 (5R)-5-(azidomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolan-2-one C14H16FN5O3 详情 详情
(X) 17021 (5S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolan-2-one C14H18FN3O3 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)