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【结 构 式】

【分子编号】18385

【品名】(2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate

【CA登记号】60456-26-0

【 分 子 式 】C7H12O3

【 分 子 量 】144.17048

【元素组成】C 58.32% H 8.39% O 33.29%
与该中间体有关的原料药合成路线共 24 条
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10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24

合成路线1

该中间体在本合成路线中的序号：(VII)

The reaction between 1,2,3-triazole (I) and 3,4-difluoronitrobenzene (II) afforded a mixture of two regioisomeric substituted triazoles (III) and (IV), from which the required 1-substituted isomer (III) was isolated by column chromatography. Reduction of the nitro group of (III) by hydrogenation over Raney-Ni gave aniline (V), which was converted to carbamate (VI) upon treatment with benzyl chloroformate. Subsequent condensation of (VI) with (R)-(-)-glycidyl butyrate (VII) in the presence of lithium bis(trimethylsilyl)amide produced the chiral oxazolidinone (VIII). Mesylation of the alcohol group of (VIII), followed by displacement with NaN3 yielded azide (IX). This was reduced by hydrogenation over Raney-Ni to give amine (X), which was finally acetylated using Ac2O and pyridine.

参考文献 中间体
合成目标
【1】 Emmert, D.E.; Reischer, R.J.; Ford, C.W.; Garmon, S.A.; Zurenko, G.E.; Barbachyn, M.R.; Hutchinson, D.K.; Stelzer, L.S.; Hester, J.B.; Synthesis and antibacterial activity of azolylphenyloxazolidinones having nitrogen-bound five-membered heterocyclic rings. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-137.
【2】 Hutchinson, D.K. (Pharmacia & Upjohn AB); Hetero-aromatic ring substd. phenyloxazolidinone antimicrobials. EP 0807112; JP 1998513446; US 5910504; WO 9623788 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 29404 1H-1,2,3-triazole 288-36-8 C2H3N3 详情 详情
(II) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(III) 29405 1-(2-fluoro-4-nitrophenyl)-1H-1,2,3-triazole C8H5FN4O2 详情 详情
(IV) 29406 2-(2-fluoro-4-nitrophenyl)-2H-1,2,3-triazole C8H5FN4O2 详情 详情
(V) 29407 3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenylamine3-fluoro-4-(1H-1,2,3-triazol-1-yl)aniline C8H7FN4 详情 详情
(VI) 29408 benzyl 3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenylcarbamate C16H13FN4O2 详情 详情
(VII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VIII) 29409 (5R)-3-[3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C12H11FN4O3 详情 详情
(IX) 29410 (5R)-5-(azidomethyl)-3-[3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-oxazolidin-2-one C12H10FN7O2 详情 详情
(X) 29411 (5S)-5-(aminomethyl)-3-[3-fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-oxazolidin-2-one C12H12FN5O2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Condensation of 3,4-difluoronitrobenzene (I) with an excess of piperazine (II) in refluxing acetonitrile yielded the 4-nitrophenylpiperazine (III), which was reduced to aniline (IV) by hydrogenation in the presence of Pd/C. Reaction with benzyl chloroformate provided the bis(carbamate) (V). This was treated with butyllithium at -78 C, and the resulting lithium salt was reacted with (R)-glycidyl butyrate (VI) to give chiral (R)-oxazolidinone (VII). Subsequent reaction with methanesulfonyl chloride, followed by displacement of the resulting mesylate with potassium phthalimide afforded the substituted phthalimide (VIII), which was deblocked with aqueous methylamine to give primary amine (IX). Further acetylation with Ac2O in pyridine yielded amide (IX) from which the N-carbobenzoxy group was removed by hydrogenolysis in the presence of Pd/C, providing the piperazine salt (XI). Alkylation of piperazine (XI) with 3,6-dichloropyridazine (XII) in DMF then gave the chloropyridazine derivative (XIII) and final hydrogenolysis of the halogen atom in the presence of palladium black yielded the title compound.

参考文献 中间体
合成目标
【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】 Tucker, J.A.; Allwine, D.A.; Grega, K.C.; Barbachyn, M.R.; Klock, J.L.; Adamski, J.L.; Brickner, S.J.; Hutchinson, D.K.; Ford, C.W.; Zurenko, G.E.; Conradi, R.A.; Burton, P.S.; Jensen, R.M.; Piperazinyl oxazolidinone antibacterial agents containing a pyridine, diazene, or triazene heteroaromatic ring. J Med Chem 1998, 41, 19, 3727.
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) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 18382 1-(2-fluoro-4-nitrophenyl)piperazine C10H12FN3O2 详情 详情
(IV) 18383 3-fluoro-4-(1-piperazinyl)phenylamine; 3-fluoro-4-(1-piperazinyl)aniline C10H14FN3 详情 详情
(V) 18384 benzyl 4-(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl)-1-piperazinecarboxylate C26H26FN3O4 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 18386 benzyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]-1-piperazinecarboxylate C22H24FN3O5 详情 详情
(VIII) 18387 benzyl 4-(4-[(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinecarboxylate C30H27FN4O6 详情 详情
(IX) 18388 benzyl 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-1-piperazinecarboxylate C22H25FN4O4 详情 详情
(X) 18389 benzyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinecarboxylate C24H27FN4O5 详情 详情
(XI) 18390 N-([(5S)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide C16H21FN4O3 详情 详情
(XIII) 18393 N-[((5S)-3-[4-[4-(6-chloro-3-pyridazinyl)-1-piperazinyl]-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide C20H22ClFN6O3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Condensation of 3,4-difluoronitrobenzene (I) with an excess of piperazine (II) in refluxing acetonitrile yielded the 4-nitrophenylpiperazine (III), which was reduced to aniline (IV) by hydrogenation in the presence of Pd/C. Reaction with benzyl chloroformate provided the bis(carbamate) (V). This was treated with butyllithium at -78 C, and the resulting lithium salt was reacted with (R)-glycidyl butyrate (VI) to give chiral (R)-oxazolidinone (VII). Subsequent reaction with methanesulfonyl chloride, followed by displacement of the resulting mesylate with potassium phthalimide afforded the substituted phthalimide (VIII), which was deblocked with aqueous methylamine to give primary amine (IX). Further acetylation with Ac2O in pyridine yielded amide (IX) from which the N-carbobenzoxy group was removed by hydrogenolysis in the presence of Pd/C, providing the piperazine salt (XI). Then, alkylation of piperazine (XI) with 3-chloro-6-methylpyridazine (XII) in dimethylpropyleneurea (DMPU) at 90 C yielded the title compound.

参考文献 中间体
合成目标
【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】 Tucker, J.A.; Allwine, D.A.; Grega, K.C.; Barbachyn, M.R.; Klock, J.L.; Adamski, J.L.; Brickner, S.J.; Hutchinson, D.K.; Ford, C.W.; Zurenko, G.E.; Conradi, R.A.; Burton, P.S.; Jensen, R.M.; Piperazinyl oxazolidinone antibacterial agents containing a pyridine, diazene, or triazene heteroaromatic ring. J Med Chem 1998, 41, 19, 3727.
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) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 18382 1-(2-fluoro-4-nitrophenyl)piperazine C10H12FN3O2 详情 详情
(IV) 18383 3-fluoro-4-(1-piperazinyl)phenylamine; 3-fluoro-4-(1-piperazinyl)aniline C10H14FN3 详情 详情
(V) 18384 benzyl 4-(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl)-1-piperazinecarboxylate C26H26FN3O4 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 18386 benzyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]-1-piperazinecarboxylate C22H24FN3O5 详情 详情
(VIII) 18387 benzyl 4-(4-[(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinecarboxylate C30H27FN4O6 详情 详情
(IX) 18388 benzyl 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-1-piperazinecarboxylate C22H25FN4O4 详情 详情
(X) 18389 benzyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinecarboxylate C24H27FN4O5 详情 详情
(XI) 18390 N-([(5S)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide C16H21FN4O3 详情 详情
(XII) 13485 2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane C11H19NO 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VII)

Treatment of 3,4-difluoronitrobenzene (I) with hydrazine hydrate yielded the aryl hydrazine (II), which was condensed with dialdehyde (III) to give pyrazole (IV). After reduction of the nitro group of (IV) by catalytic hydrogenation, the resulting amine (V) was protected with benzyl chloroformate to afford carbamate (VI). Subsequent treatment of (VI) with (R)-glycidyl butyrate (VII) and n-butyllithium produced the chiral oxazolidinone (VIII). The alcohol group of (VIII) was converted to mesylate (IX) and then displaced with NaN3 to give azide (X), which was reduced to amine (XI) using PPh3. Acetylation of the primary amine of (XI) with Ac2O, followed by ammonolysis of the ethyl ester furnished diamide (XII). Finally, dehydration of the primary amide of (XII) with SOCl2 provided the target nitrile.

参考文献 中间体
合成目标
【1】 Genin, M.J.; et al.; Substituent effects on the antibacterial activity of novel highly potent nitrogen-bound azolylphenyl oxazolidinones. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-138.
【2】 Genin, M.J.; Hutchinson, D.K.; Allwine, D.A.; Hester, J.B.; Emmert, D.E.; Garmon, S.A.; Ford, C.W.; Zurenko, G.E.; Hamel, J.C.; Schaadt, R.D.; Stapert, D.; Yagi, B.H.; Friis, J.M.; Shobe, E.M.; Adams, W.J.; Nitrogen-carbon-linked (azolylphenyl)oxazolidinones with potent antibacterial activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. J Med Chem 1998, 41, 26, 5144.
【3】 Anderson, D.J.; Allwine, D.A.; Genin, M.J.; et al.; Substituted effects of the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. J Med Chem 2000, 43, 5, 953.
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) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 28506 1-(2-fluoro-4-nitrophenyl)hydrazine C6H6FN3O2 详情 详情
(III) 28507 ethyl 2-formyl-3-oxopropanoate C6H8O4 详情 详情
(IV) 28508 ethyl 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole-4-carboxylate C12H10FN3O4 详情 详情
(V) 28509 ethyl 1-(4-amino-2-fluorophenyl)-1H-pyrazole-4-carboxylate C12H12FN3O2 详情 详情
(VI) 28510 ethyl 1-(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl)-1H-pyrazole-4-carboxylate C20H18FN3O4 详情 详情
(VII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VIII) 28511 ethyl 1-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]-1H-pyrazole-4-carboxylate C16H16FN3O5 详情 详情
(IX) 28512 ethyl 1-[2-fluoro-4-((5R)-5-[[(methylsulfonyl)oxy]methyl]-2-oxo-1,3-oxazolidin-3-yl)phenyl]-1H-pyrazole-4-carboxylate C17H18FN3O7S 详情 详情
(X) 28513 ethyl 1-[4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-1H-pyrazole-4-carboxylate C16H15FN6O4 详情 详情
(XI) 28514 ethyl 1-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-1H-pyrazole-4-carboxylate C16H17FN4O4 详情 详情
(XII) 28515 1-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1H-pyrazole-4-carboxamide C16H16FN5O4 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VI)

The reaction between pyrrole (I) and 3,4-difluoronitrobenzene (II) afforded the N-aryl pyrrole (III). Selective reduction of the nitro group of (III) by hydrogenation over sulfided platinum on carbon gave aniline (IV), which was converted to carbamate (V) upon treatment with benzyl chloroformate. Subsequent condensation of (V) with (R)-(-)-glycidyl butyrate (VI) in the presence of lithium bis(trimethylsilyl)amide produced the chiral oxazolidinone (VII). Mesylation of the alcohol group of (VII), followed by displacement with NaN3 yielded azide (VIII). This was reduced by hydrogenation over Pt/C/S to give amine (IX), which was finally acetylated using Ac2O and pyridine.

参考文献 中间体
合成目标
【1】 Emmert, D.E.; Reischer, R.J.; Ford, C.W.; Garmon, S.A.; Zurenko, G.E.; Barbachyn, M.R.; Hutchinson, D.K.; Stelzer, L.S.; Hester, J.B.; Synthesis and antibacterial activity of azolylphenyloxazolidinones having nitrogen-bound five-membered heterocyclic rings. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-137.
【2】 Hutchinson, D.K. (Pharmacia & Upjohn AB); Hetero-aromatic ring substd. phenyloxazolidinone antimicrobials. EP 0807112; JP 1998513446; US 5910504; WO 9623788 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 21674 1H-pyrrole 109-97-7 C4H5N 详情 详情
(II) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(III) 29412 1-(2-fluoro-4-nitrophenyl)-1H-pyrrole C10H7FN2O2 详情 详情
(IV) 29413 3-fluoro-4-(1H-pyrrol-1-yl)phenylamine3-fluoro-4-(1H-pyrrol-1-yl)aniline C10H9FN2 详情 详情
(V) 29414 benzyl 3-fluoro-4-(1H-pyrrol-1-yl)phenylcarbamate C18H15FN2O2 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 29415 (5R)-3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C14H13FN2O3 详情 详情
(VIII) 29416 (5R)-5-(azidomethyl)-3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl]-1,3-oxazolidin-2-one C14H12FN5O2 详情 详情
(IX) 29417 (5S)-5-(aminomethyl)-3-[3-fluoro-4-(1H-pyrrol-1-yl)phenyl]-1,3-oxazolidin-2-one C14H14FN3O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(V)

Treatment of 3,4-difluoronitrobenzene (I) with benzylamine yielded nitroaniline (II), which was reduced to diamine (III) by hydrogenation over Pt/C. Protection of (III) with benzyl chloroformate produced the bis(carbamate) (IV). Conversion of (IV) to the chiral oxazolidinone (VI) was accomplished by treatment with (R)-glycidyl butyrate (V) and n-butyllithium. The alcohol group of (VI) was converted to mesylate (VII) and then displaced with potassium phthalimide to give (VIII). Further hydrazinolysis of (VIII), followed by acetylation of the resulting amine gave acetamide (IX). Hydrogenation of (IX) in the presence of Pd/C removed both N-benzyl and carbamate groups to give the primary amine (X). Condensation of (X) with 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (XI) in refluxing AcOH furnished the required 3-formylpyrrole (XII). The resulting aldehyde (XII) was then condensed with hydroxylamine and the intermediate oxime was finally converted to the target nitrile employing PPh3 as the dehydrating agent.

参考文献 中间体
合成目标
【1】 Genin, M.J.; et al.; Substituent effects on the antibacterial activity of novel highly potent nitrogen-bound azolylphenyl oxazolidinones. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-138.
【2】 Genin, M.J.; Hutchinson, D.K.; Allwine, D.A.; Hester, J.B.; Emmert, D.E.; Garmon, S.A.; Ford, C.W.; Zurenko, G.E.; Hamel, J.C.; Schaadt, R.D.; Stapert, D.; Yagi, B.H.; Friis, J.M.; Shobe, E.M.; Adams, W.J.; Nitrogen-carbon-linked (azolylphenyl)oxazolidinones with potent antibacterial activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. J Med Chem 1998, 41, 26, 5144.
【3】 Anderson, D.J.; Allwine, D.A.; Genin, M.J.; et al.; Substituted effects of the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. J Med Chem 2000, 43, 5, 953.
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) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 28497 N-benzyl-2-fluoro-4-nitroaniline C13H11FN2O2 详情 详情
(III) 28498 N-(4-amino-2-fluorophenyl)-N-benzylamine C13H13FN2 详情 详情
(IV) 28499 benzyl benzyl(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl)carbamate C29H25FN2O4 详情 详情
(V) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VI) 28500 benzyl benzyl[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]carbamate C25H23FN2O5 详情 详情
(VII) 28501 [(5R)-3-(4-[benzyl[(benzyloxy)carbonyl]amino]-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate C26H25FN2O7S 详情 详情
(VIII) 28502 benzyl benzyl(4-[(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)carbamate C33H26FN3O6 详情 详情
(IX) 28503 benzyl 4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl(benzyl)carbamate C27H26FN3O5 详情 详情
(X) 28504 N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide C12H14FN3O3 详情 详情
(XI) 26664 2,5-dimethoxytetrahydro-3-furancarbaldehyde C7H12O4 详情 详情
(XII) 28505 N-([(5S)-3-[3-fluoro-4-(3-formyl-1H-pyrrol-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide C17H16FN3O4 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VIII)

Benzoxazinone (IV) was prepared by condensation of 2-amino-5-nitrophenol (I) with either chloroacetyl chloride (II) in the presence of NaHCO3 or ethyl bromoacetate (III) in the presence of KF. Subsequent N-alkylation of (IV) with iodomethane provided (V). After reduction of the nitro group of (V) to amine (VI) by hydrogenation over Pd/C, condensation with benzyl chloroformate afforded carbamate (VII). The chiral oxazolidinone (IX) was obtained by reaction of (VII) with (-)-(R)-glycidyl butyrate (VIII) in the presence of butyllithium in THF at low temperature. Conversion of (IX) to mesylate, followed by displacement with NaN3 gave azide (X). Amine (XI) was then obtained by either hydrogenation of (X) over Pd/C or by reduction with trimethyl phosphite. Finally, reaction of (XI) with acetyl chloride and triethylamine provided the title acetamide.

参考文献 中间体
合成目标
【1】 Haebich, D.; Haerter, M.; Bartel, S.; Riedl, B.; Stolle, A.; Raddatz, S.; Kroll, H.P.; Guarnieri, W.; Endermann, R.; Wild, H.; Rosentreter, U.; Ruppelt, M.; Synthesis and antibacterial activity of novel heteroaryl oxazolidinones: II. Benzoxazinone- and benzthiazinone-oxazolidinones. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F566.
【2】 Shridhar, D.R.; et al.; A facile synthesis of 2-alkyl(aryl)-6- and -7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazines. Synthesis 1982, 986.
【3】 Endermann, R.; Habich, D.; Ruppelt, M.; Raddatz, S.; Rosentreter, U.; Riedl, B.; Bartel, S.; Wild, H.; Stolle, A.; Guarnieri, W.; Kroll, H.-P. (Bayer AG); Novel bicyclene-substd. oxazolidinones. DE 19802239; WO 9937641 .
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) 33067 2-amino-5-nitrophenol 121-88-0 C6H6N2O3 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IV) 33068 7-nitro-2H-1,4-benzoxazin-3(4H)-one C8H6N2O4 详情 详情
(V) 33069 4-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one C9H8N2O4 详情 详情
(VI) 33070 7-amino-4-methyl-2H-1,4-benzoxazin-3(4H)-one C9H10N2O2 详情 详情
(VII) 33071 benzyl 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-ylcarbamate C17H16N2O4 详情 详情
(VIII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(IX) 33072 7-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one C13H14N2O5 详情 详情
(X) 33073 7-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one C13H13N5O4 详情 详情
(XI) 33074 7-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one C13H15N3O4 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VII)

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.

参考文献 中间体
合成目标
【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

合成路线9

该中间体在本合成路线中的序号：(VII)

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.

参考文献 中间体
合成目标
【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

合成路线10

该中间体在本合成路线中的序号：(IX)

Intramolecular Diels-Alder reaction of the N-pyrazinylmethyl-N-propargyl carbamate (I), with subsequent extrusion of HCN, gave rise to a mixture of the isomeric pyrrolopyridines (II) and (III). Acidic hydrolysis of the pyrrolo[3,4-b]pyridine carbamate (III) provided the bicyclic amine (IV). This was condensed with 3,4-difluoronitrobenzene (V) to give the aryl amine (VI). Catalytic hydrogenation of the nitro group of (VI) yielded aniline (VII), which was converted to the benzyl carbamate (VIII) upon treatment with benzyl chloroformate. The chiral oxazolidinone (X) was then obtained by condensation of the lithium salt of carbamate (VIII) with (R)-glycidyl butyrate (IX) at -78 C. Conversion of alcohol (X) to mesylate (XI), and subsequent mesylate displacement with NaN3 in hot DMF, furnished azide (XII). Finally, hydrogenation of azide (XII) to the corresponding amine, followed by acylation with Ac2O, led to the target acetamide.

参考文献 中间体
合成目标
【1】 Paget, S.; Weidner-Wells, M.; Hlasta, D.; et al.; Synthesis and antibacterial activity of pyrrolopyridine-substituted oxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1048.
【2】 Hlasta, D.; Paget, S. (Ortho-McNeil Pharmaceutical, Inc.); Antibacterial heterobicyclic substd. phenyl oxazolidinones. EP 1206469; US 6413981; WO 0142242 .
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) 55095 ethyl 2-propynyl(2-pyrazinylmethyl)carbamate C11H13N3O2 详情 详情
(II) 55096 ethyl 1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate C10H12N2O2 详情 详情
(III) 55097 ethyl 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate C10H12N2O2 详情 详情
(IV) 55098 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine C7H8N2 详情 详情
(V) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(VI) 55099 6-(2-fluoro-4-nitrophenyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine C13H10FN3O2 详情 详情
(VII) 55100 4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluoroaniline; 4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenylamine C13H12FN3 详情 详情
(VIII) 55101 benzyl 4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenylcarbamate C21H18FN3O2 详情 详情
(IX) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(X) 55102 (5R)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C17H16FN3O3 详情 详情
(XI) 55103 {(5R)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate C18H18FN3O5S 详情 详情
(XII) 55104 (5R)-5-(azidomethyl)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-1,3-oxazolidin-2-one C17H15FN6O2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(IX)

Intramolecular Diels-Alder reaction of the N-pyrazinylmethyl-N-propargyl carbamate (I), with subsequent extrusion of HCN, gave rise to a mixture of the isomeric pyrrolopyridines (II) and (III). Acidic hydrolysis of the pyrrolo[3,4-c]pyridine carbamate (III) provided the bicyclic amine (IV). This was condensed with 3,4-difluoronitrobenzene (V) to give the aryl amine (VI). Catalytic hydrogenation of the nitro group of (V) yielded aniline (VII), which was converted to the benzyl carbamate (VIII) upon treatment with benzyl chloroformate. The chiral oxazolidinone (X) was then obtained by condensation of the lithium salt of carbamate (VIII) with (R)-glycidyl butyrate (IX) at -78 C. Conversion of alcohol (X) to mesylate (XI), and subsequent mesylate displacement with NaN3 in hot DMF, furnished azide (XII). Finally, hydrogenation of azide (XII) to the corresponding amine, followed by acylation with Ac2O, led to the target acetamide.

参考文献 中间体
合成目标
【1】 Paget, S.; Weidner-Wells, M.; Hlasta, D.; et al.; Synthesis and antibacterial activity of pyrrolopyridine-substituted oxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1048.
【2】 Hlasta, D.; Paget, S. (Ortho-McNeil Pharmaceutical, Inc.); Antibacterial heterobicyclic substd. phenyl oxazolidinones. EP 1206469; US 6413981; WO 0142242 .
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) 55095 ethyl 2-propynyl(2-pyrazinylmethyl)carbamate C11H13N3O2 详情 详情
(II) 55096 ethyl 1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate C10H12N2O2 详情 详情
(III) 55097 ethyl 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate C10H12N2O2 详情 详情
(IV) 55105 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine C7H8N2 详情 详情
(V) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(VI) 55106 2-(2-fluoro-4-nitrophenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine C13H10FN3O2 详情 详情
(VII) 55107 4-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-fluorophenylamine; 4-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-fluoroaniline C13H12FN3 详情 详情
(VIII) 55108 benzyl 4-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-fluorophenylcarbamate C21H18FN3O2 详情 详情
(IX) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(X) 55109 (5R)-3-[4-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-fluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C17H16FN3O3 详情 详情
(XI) 55110 {(5R)-3-[4-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate C18H18FN3O5S 详情 详情
(XII) 55111 (5R)-5-(azidomethyl)-3-[4-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-fluorophenyl]-1,3-oxazolidin-2-one C17H15FN6O2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(V)

Addition of thiocyanogen (generated in situ from KSCN and N-bromosuccinimide) to 3-fluoroaniline (I) gave the thiocyanoaniline (II). Subsequent acylation of aniline (II) with benzyl chloroformate afforded carbamate (III). The intermediate thiol produced by treatment of thiocyanate (III) with sodium sulfide was captured as the trityl sulfide (IV) upon quenching with bromotriphenylmethane. The chiral oxazolidinone (VI) was then obtained by condensation of the lithium salt of carbamate (IV) with (R)-glycidyl butyrate (V). Activation of the primary hydroxyl of (VI) as the corresponding mesylate (VII), followed by displacement with NaN3 in hot DMF gave rise to the alkyl azide (VIII). Removal of the S-trityl protecting group of (VIII) by means of trifluoroacetic acid and triisopropylsilane and further alkylation of the resultant thiol with iodomethane yielded the methyl sulfide (IX). Sulfoxide (X) was then obtained by oxidation of sulfide (IX) with m-chloroperbenzoic acid. Reduction of the azido group of (X) to the required amine (XI) was accomplished by treatment with triphenylphosphine followed by aqueous hydrolysis. Finally, condensation of amine (XI) with ethyl dithioacetate furnished the title thioacetamide.

参考文献 中间体
合成目标
【1】 Gadwood, R.C.; Patel, D.V.; Hackbarth, C.J.; Gordeev, M.F.; Luehr, G.W.; Lopez, S.; Trias, J.; Acyclic C-group oxazolidinones: Antimicrobial activity of novel 4'-Sulfide and 4'-sulfoxide 3'-fluorophenyl oxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1044.
【2】 Patel, D.V.; Gadwood, R.C.; Gordeev, M.F.; Luehr, G.W. (Pharmacia Corp.); Oxazolidinones and their use as antiinfectives. EP 1200416; US 6441005; WO 0109107 .
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) 56095 4-amino-2-fluorobenzenesulfenyl cyanide C7H5FN2S 详情 详情
(III) 56096 benzyl 4-(cyanosulfanyl)-3-fluorophenylcarbamate C15H11FN2O2S 详情 详情
(IV) 56097 benzyl 3-fluoro-4-(tritylsulfanyl)phenylcarbamate C33H26FNO2S 详情 详情
(V) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VI) 56098 (5R)-3-[3-fluoro-4-(tritylsulfanyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C29H24FNO3S 详情 详情
(VII) 56099 {(5R)-3-[3-fluoro-4-(tritylsulfanyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate C30H26FNO5S2 详情 详情
(VIII) 56100 (5R)-5-(azidomethyl)-3-[3-fluoro-4-(tritylsulfanyl)phenyl]-1,3-oxazolidin-2-one C29H23FN4O2S 详情 详情
(IX) 56101 (5R)-5-(azidomethyl)-3-[3-fluoro-4-(methylsulfanyl)phenyl]-1,3-oxazolidin-2-one C11H11FN4O2S 详情 详情
(X) 56102 (5R)-5-(azidomethyl)-3-[3-fluoro-4-(methylsulfinyl)phenyl]-1,3-oxazolidin-2-one C11H11FN4O3S 详情 详情
(XI) 56103 (5S)-5-(aminomethyl)-3-[3-fluoro-4-(methylsulfinyl)phenyl]-1,3-oxazolidin-2-one C11H13FN2O3S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VI)

Jones oxidation of 2-fluoro-4-nitrotoluene (I) afforded carboxylic acid (II). After activation of (II) as the corresponding acid chloride with SOCl2, reaction with lithium tert-butoxide furnished the tert-butyl ester (III). Reduction of the nitro group of (III) by means of iron powder in the presence of ammonium chloride gave amine (IV), which was converted to carbamate (V) upon treatment with benzyl chloroformate. The chiral oxazolidinone (VII) was prepared by condensation of the lithium salt of carbamate (V) with (R)-glycidyl butyrate (VI). After activation of the primary hydroxyl of (VII) as the corresponding mesylate, displacement with NaN3 in hot DMF provided the alkyl azide (VIII). Tert-Butyl ester cleavage in (VIII) by means of trifluoroacetic acid afforded the carboxylic acid (IX). Curtius rearrangement of acid (IX) with diphenylphosphoryl azide in the presence of tert-butanol generated the tert-butyl carbamate (X). Further N-alkylation of carbamate (X) using iodomethane and LiH gave the N-methyl analogue (XI). Then, reduction of the azido group of (XI) to the primary amine (XII) was accomplished by treatment with triphenylphosphine followed by aqueous hydrolysis.

参考文献 中间体
合成目标
【1】 Singh, U.; Gordeev, M.F.; Luehr, G.W.; Gadwood, R.C.; Jain, R.; Hackbarth, C.J.; Trias, J.; Patel, D.V.; Lopez, S.; Acyclic C-group oxazolidinones: Antimicrobial 4'-acylamino, 4'-urea and 4'-thiourea phenyloxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1045.
【2】 Patel, D.V.; Gadwood, R.C.; Gordeev, M.F.; Luehr, G.W. (Pharmacia Corp.); Oxazolidinones and their use as antiinfectives. EP 1200416; US 6441005; WO 0109107 .
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) 55902 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene 1427-07-2 C7H6FNO2 详情 详情
(II) 55903 2-Fluoro-4-nitrobenzoic acid 403-24-7 C7H4FNO4 详情 详情
(III) 55904 tert-butyl 2-fluoro-4-nitrobenzoate C11H12FNO4 详情 详情
(IV) 55905 tert-butyl 4-amino-2-fluorobenzoate C11H14FNO2 详情 详情
(V) 55906 tert-butyl 4-{[(benzyloxy)carbonyl]amino}-2-fluorobenzoate C19H20FNO4 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 55907 tert-butyl 2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzoate C15H18FNO5 详情 详情
(VIII) 55908 tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoate C15H17FN4O4 详情 详情
(IX) 55909 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoic acid C11H9FN4O4 详情 详情
(X) 58661 tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenylcarbamate C15H18FN5O4 详情 详情
(XI) 58662 tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl(methyl)carbamate C16H20FN5O4 详情 详情
(XII) 58663 tert-butyl 4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl(methyl)carbamate C16H22FN3O4 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VI)

Oxidation of 2-fluoro-4-nitrotoluene (I) by means of Jones reagent afforded the benzoic acid (II). After activation of (II) as the corresponding acid chloride with SOCl2, reaction with lithium tert-butoxide furnished the tert-butyl ester (III). Reduction of the nitro group of (III) by means of iron powder gave amine (IV), which was further converted into the carbamate (V) upon treatment with benzyl chloroformate. The chiral oxazolidinone (VII) was prepared by condensation of the lithium salt of carbamate (V) with (R)-glycidyl butyrate (VI) at -78 C. After activation of the primary hydroxyl of (VII) as the corresponding mesylate, displacement with NaN3 in hot DMF provided the alkyl azide (VIII). Tert-Butyl ester cleavage in (VIII) employing trifluoroacetic acid afforded the carboxylic acid (IX), which was cyclized to the thiadiazole (XI) by condensation with thiosemicarbazide (X) in the presence of POCl3. Reduction of the azido group of (XI) to the primary amine (XII) was accomplished by treatment with triphenylphosphine followed by aqueous hydrolysis. Finally, acylation of the aliphatic amino group of (XII) with ethyl dithioacetate gave rise to the title thioacetamide.

参考文献 中间体
合成目标
【1】 Gordeev, M.F.; Trias, J.; Lopez, S.; Hackbarth, C.J.; Fan, P.; Gadwood, R.C.; Luehr, G.W.; Patel, D.V.; Antimicrobial activity of novel 1,3,4-thiadiazole, 1,3,4-oxadiazole, and benzimidazole phenyloxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1046.
【2】 Patel, D.V.; Gadwood, R.C.; Gordeev, M.F.; Luehr, G.W. (Pharmacia Corp.); Oxazolidinones and their use as antiinfectives. EP 1200416; US 6441005; WO 0109107 .
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) 55902 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene 1427-07-2 C7H6FNO2 详情 详情
(II) 55903 2-Fluoro-4-nitrobenzoic acid 403-24-7 C7H4FNO4 详情 详情
(III) 55904 tert-butyl 2-fluoro-4-nitrobenzoate C11H12FNO4 详情 详情
(IV) 55905 tert-butyl 4-amino-2-fluorobenzoate C11H14FNO2 详情 详情
(V) 55906 tert-butyl 4-{[(benzyloxy)carbonyl]amino}-2-fluorobenzoate C19H20FNO4 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 55907 tert-butyl 2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzoate C15H18FNO5 详情 详情
(VIII) 55908 tert-butyl 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoate C15H17FN4O4 详情 详情
(IX) 55909 4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzoic acid C11H9FN4O4 详情 详情
(X) 12954 1-Hydrazinecarbothioamide; Thiosemicarbazide 79-19-6 CH5N3S 详情 详情
(XI) 55910 (5R)-3-[4-(5-amino-1,3,4-thiadiazol-2-yl)-3-fluorophenyl]-5-(azidomethyl)-1,3-oxazolidin-2-one C12H10FN7O2S 详情 详情
(XII) 55911 (5S)-5-(aminomethyl)-3-[4-(5-amino-1,3,4-thiadiazol-2-yl)-3-fluorophenyl]-1,3-oxazolidin-2-one C12H12FN5O2S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VI)

2-Methylindole (I) was nitrated employing NaNO3 in H2SO4 and the resultant 5-nitroindole (II) was further reduced to the corresponding indoline (III) by means of NaBH3CN in the presence of HOAc. Catalytic hydrogenation of the nitro group of (III) over Pd/C furnished diamine (IV), which was converted to the bis-carbamate (V) by treatment with benzyl chloroformate. Oxazolidinone (VII) was then obtained by condensation of carbamate (V) with (R)-glycidyl butyrate (VI) in the presence of BuLi at -78 C. After conversion of alcohol (VII) to the corresponding nosylate (VIII), displacement of its sulfonate group with ammonium hydroxide gave rise to the primary amine (IX). Acetylation of amine (IX), followed by hydrogenolysis of the remaining N-benzyloxycarbonyl group, yielded acetamide (X). The indoline N of (X) was then acylated by acetoxyacetyl chloride (XI) to produce amide (XII). The title compound was then obtained by smooth hydrolysis of the acetoxy group of (XII) with K2CO3, followed by separation of the resultant mixture of diastereoisomers by chiral HPLC.

参考文献 中间体
合成目标
【1】 Genin, M.J.; Barbachyn, M.R.; Grega, K.C.; et al.; The potentiating effect of remote chirality on the antibacterial activity of a series of 2-substituted indolinyl phenyloxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1042.
【2】 Hester, J.B. Jr.; Barbachyn, M.R.; Johnson, P.D.; Genin, M.J. (Pharmacia Corp.); Bicyclic oxazolidinones as antibacterial agent. EP 1181288; US 6387896; WO 0073301 .
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) 28747 2-methyl-1H-indole 95-20-5 C9H9N 详情 详情
(II) 55948 2-methyl-5-nitro-1H-indole; 2-Methyl-5-nitroindole 7570-47-0 C9H8N2O2 详情 详情
(III) 55949 2-methyl-5-nitroindoline C9H10N2O2 详情 详情
(IV) 55950 2-methyl-2,3-dihydro-1H-indol-5-ylamine; 2-methyl-5-indolinamine C9H12N2 详情 详情
(V) 55951 benzyl 5-{[(benzyloxy)carbonyl]amino}-2-methyl-1-indolinecarboxylate C25H24N2O4 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 55952 benzyl 5-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-methyl-1-indolinecarboxylate C21H22N2O5 详情 详情
(VIII) 55953 benzyl 2-methyl-5-[(5R)-5-({[(3-nitrophenyl)sulfonyl]oxy}methyl)-2-oxo-1,3-oxazolidin-3-yl]-1-indolinecarboxylate C27H25N3O9S 详情 详情
(IX) 55954 benzyl 5-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-methyl-1-indolinecarboxylate C21H23N3O4 详情 详情
(X) 55955 N-{[(5S)-3-(2-methyl-2,3-dihydro-1H-indol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C15H19N3O3 详情 详情
(XI) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(XII) 55956 2-(5-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl acetate C19H23N3O6 详情 详情

合成路线16

该中间体在本合成路线中的序号：(III)

Reaction of 3-fluoroaniline (I) with benzyl chloroformate provides carbamate (II). The lithium derivative of (II) is then condensed with (R)-glycidyl butyrate (III) to yield the chiral oxazolidinone (IV). After conversion of alcohol (IV) to the corresponding mesylate (V), displacement with NaN3 in hot DMF gives rise to the alkyl azide (VI). Catalytic hydrogenation of azide (VI) furnishes amine (VII), which is further acylated with acetic anhydride, producing acetamide (VIII). Aromatic iodination of (VIII) by means of iodine monochloride in the presence of trifluoroacetic acid gives (IX). Iodide compound (IX) is then converted into the aryl stannane (X) upon treatment with hexamethyl ditin and palladium catalyst

参考文献 中间体
合成目标
【1】 Im, W.; Lee, T.; Cho, J.; Choi, S.; Rhee, J.; In vitro and in vivo studies of hetero-ring substituted pyridine containing oxazolidinone derivatives, including DA-7867. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1311.
【2】 Lee, J.-G.; Lee, J.-J.; Park, S.-K.; Lee, T.-H.; Leem, W.-B.; Cho, J.-H.; Choi, S.-H.; Kim, D.-G.; Sung, H.-J. (Dong-A Pharmaceutical Co., Ltd.); Novel oxazolidinone derivs. and a process for the preparation thereof. WO 0194342 .
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) 60314 phenylmethyl 3-fluorophenylcarbamate C14H12FNO2 详情 详情
(III) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(IV) 60315 3-(3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one C10H10FNO3 详情 详情
(V) 60316 [3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate C11H12FNO5S 详情 详情
(VI) 60317 (R)-5-(azidomethyl)-3-(3-fluorophenyl)oxazolidin-2-one C10H9FN4O2 详情 详情
(VII) 60318 5-(aminomethyl)-3-(3-fluorophenyl)-1,3-oxazolidin-2-one C10H11FN2O2 详情 详情
(VIII) 60319 N-{[3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C12H13FN2O3 详情 详情
(IX) 38138 N-[[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide C12H12FIN2O3 详情 详情
(X) 60320 N-({3-[3-fluoro-4-(trimethylstannanyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide C15H21FN2O3Sn 详情 详情

合成路线17

该中间体在本合成路线中的序号：

The antibacterial activity of RBx-7644 is due to the 5(S)-acetamidomethyl configuration at the oxazolidinone ring, and thus, asymmetric synthesis of only the 5(S)-enantiomer was desirable: 3,4-Difluoronitrobenzene (I) is condensed with piperazine in acetonitrile to give 4-(2-fluoro-4-nitrophenyl)-piperazine (II) as a light yellow compound. Compound (II) is dissolved in dichloromethane and triethylamine, followed by the addition of Boc-anhydride, to provide compound (III). 4-(tert-Butoxycarbonyl)-1-(2-fluoro-4-nitrophenyl)piperazine (III), upon hydrogenation with H2 over Pd/C in methanol at 50 psi, yields 4-(tert-butoxycarbonyl)-1-(2-fluoro-4-aminophenyl)piperazine (IV) as a dark solid. Compound (IV) reacts with benzylchloroformate in dry THF in the presence of solid sodium bicarbonate to afford the desired compound (V). 4-(tert-Butoxycarbonyl)-1-[2-fluoro-4-(benzyloxycarbonylamino)phenyl]piperazine (V), upon treatment with n-BuLi and (R)-glycidyl butyrate at -78 °C, gives the desired (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone (VI). The hydroxymethyl compound (VI) is treated with methanesulfonyl chloride in dichloromethane in the presence of triethylamine to give (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(methylsulfonyloxymethyl)-2-oxazolidinone (VII). The sulfonyl derivative (VII) is treated with sodium azide in dimethylformamide to provide the azide (VIII) as a white solid. (R)-(-)-3-[3-Fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl]-5-(azidomethyl)-2-oxazolidinone (VIII), upon hydrogenation with H2 over Pd/C at 45 psi, gives (S)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)-piperazin-1-yl]phenyl]-5-(aminomethyl)-2-oxazolidinone (IX). The aminomethyl compound (IX), upon treatment with acetic anhydride in dichloromethane in the presence of triethylamine, affords the acetamide derivative (X). The acetamidomethyl-oxazolidinone derivative (X), upon treatment with trifluoroacetic acid, gives (S)-(-)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-5-(acetamidomethyl)-2-oxazolidinone, which, without isolation, is treated with 5-nitro-2-furaldehyde in the presence of sodium triacetoxy borohydride to provide compound (XI). Compound (XI), upon treatment with ethanolic HCl, affords RBx-7644 as a light yellow crystalline solid.

参考文献 中间体
合成目标
【1】 Rattan, A.; RBx-7644. Drugs Fut 2003, 28, 11, 1070.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
51375 5-Nitro-2-furaldehyde; 5-Nitrofurfural 698-63-5 C5H3NO4 详情 详情
(I) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 18382 1-(2-fluoro-4-nitrophenyl)piperazine C10H12FN3O2 详情 详情
(III) 63060 tert-butyl 4-(2-fluoro-4-nitrophenyl)-1-piperazinecarboxylate C15H20FN3O4 详情 详情
(IV) 63061 tert-butyl 4-(4-amino-2-fluorophenyl)-1-piperazinecarboxylate C15H22FN3O2 详情 详情
(V) 63062 tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)-1-piperazinecarboxylate C23H28FN3O4 详情 详情
(VI) 63063 tert-butyl 4-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-piperazinecarboxylate C19H26FN3O5 详情 详情
(VII) 63064 tert-butyl 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-1,3-oxazolidin-3-yl)phenyl]-1-piperazinecarboxylate C20H28FN3O7S 详情 详情
(X) 63067 tert-butyl 4-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl)-1-piperazinecarboxylate C21H29FN4O5 详情 详情
(XI) 63068 N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]-1-piperazinyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C21H24FN5O6 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IV)

Condensation of benzyl carbazate (I) with 2,5-dimethoxytetrahydrofuran (II) affords the N-benzyloxycarbonyl aminopyrrole (III). The lithiated derivative of (III) is condensed with (R)-glycidyl butyrate (IV) to furnish the chiral oxazolidinone (V). Alcohol (V) is converted to the corresponding mesylate (VI) with methanesulfonyl chloride and triethylamine. Finally, nucleophilic displacement of mesylate (VI) with sodium methoxide affords the target methyl ether.

参考文献 中间体
合成目标
【1】 Massa, S.; Befani, O.; Esposito, M.; Sbardella, g.; Mai, A.; Turini, P.; Giovannini, V.; Mondovi, B.; 3-(1H-Pyrrol-1-yl)-2-oxazolidinones as reversible, highly potent, and selective inhibitors of monoamine oxidase type A. J Med Chem 2002, 45, 6, 1180.
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) 36108 benzyl 1-hydrazinecarboxylate 5331-43-1 C8H10N2O2 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 57806 benzyl 1H-pyrrol-1-ylcarbamate C12H12N2O2 详情 详情
(IV) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(V) 57807 (5R)-5-(hydroxymethyl)-3-(1H-pyrrol-1-yl)-1,3-oxazolidin-2-one C8H10N2O3 详情 详情
(VI) 57808 [(5R)-2-oxo-3-(1H-pyrrol-1-yl)-1,3-oxazolidin-5-yl]methyl methanesulfonate C9H12N2O5S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(VIII)

After protection of 1-benzyl-3-pyrrolidinone (I) as the corresponding ethylene ketal (II) with ethylene glycol and p-toluenesulfonic acid, N-benzyl group hydrogenolysis over Pearlman's catalyst provides the secondary amine (III). Subsequent condensation of amine (III) with 3,4-difluoronitrobenzene (IV) in hot DMF furnishes the N-aryl pyrrolidine (V). Reduction of the nitro group of (V) by transfer hydrogenation with ammonium formate and Pd/C leads to aniline (VI). This is further acylated with benzyl chloroformate producing carbamate (VII). Then, reaction of the lithium anion of carbamate (VII) with (R)-glycidyl butyrate (VIII) gives rise to oxazolidinone (IX). After conversion of alcohol (IX) to mesylate (X), the primary amine (XI) is obtained by Gabriel synthesis with potassium phthalimide, followed by hydrazinolysis. Acylation of amine (XI) with Ac2O produces amide (XII). The ethylene ketal of (XII) is then hydrolyzed with p toluenesulfonic acid in aqueous acetone, providing pyrrolidinone (XIII).

参考文献 中间体
合成目标
【1】 Paget, S.; Boggs, C.; Foleno, B.; Goldschmidt, R.; Hilliard, J.; Wira, E.; Bush, K.; Macielag, M.; Synthesis and antibacterial activity of pyrrolopyrimidine oxazolidinones. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1318.
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) 61976 1-(Phenylmethyl)-3-pyrrolidinone; 1-Benzyl-3-pyrrolidinone; 1-Benzyl-3-pyrrolidinon; N-Benzyl-3-pyrrolidone 775-16-6 C11H13NO 详情 详情
(II) 61977 7-benzyl-1,4-dioxa-7-azaspiro[4.4]nonane C13H17NO2 详情 详情
(III) 61978 1,4-dioxa-7-azaspiro[4.4]nonane C6H11NO2 详情 详情
(IV) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(V) 61979 7-(2-fluoro-4-nitrophenyl)-1,4-dioxa-7-azaspiro[4.4]nonane C12H13FN2O4 详情 详情
(VI) 61980 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylamine; 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluoroaniline C12H15FN2O2 详情 详情
(VII) 61981 benzyl 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylcarbamate C20H21FN2O4 详情 详情
(VIII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(IX) 61982 (5R)-3-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C16H19FN2O5 详情 详情
(X) 61983 {(5R)-3-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate C17H21FN2O7S 详情 详情
(XI) 61984 (5S)-5-(aminomethyl)-3-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenyl]-1,3-oxazolidin-2-one C16H20FN3O4 详情 详情
(XII) 61985 N-({(5S)-3-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide C18H22FN3O5 详情 详情
(XIII) 61986 N-({(5S)-3-[3-fluoro-4-(3-oxo-1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide C16H18FN3O4 详情 详情

合成路线20

该中间体在本合成路线中的序号：(V)

The intermediate benzaldehyde (XII) has been obtained as follows: The reduction of 4-nitrobenzaldehyde (I) with NaBH4 and NiCl2 gives 4-aminobenzyl alcohol (II), which is treated with benzyl chloroformate to yield the carbamate (III). The protection of the OH group of (III) with Tbdms-Cl affords the silyl ether (IV). The cyclization of (IV) with glycidyl butyrate (V) by means of BuLi provides the hydroxymethyl oxazolidinone (VI), which is treated with MsCl and TEA to give the mesylate (VII). The reaction of (VII) with NaN3 yields the azidomethyl compound (VIII), which is condensed with thioacetic acid (IX) to afford the acetamide (X). The cleavage of the Tbdms protecting group of (X) by means of TBAF provides the benzyl alcohol (XI), which is oxidized with PDC to furnish the target benzaldehyde intermediate (XII)

参考文献 中间体
合成目标
【1】 Selvakumar, N.; et al.; Synthesis and antibacterial activity of novel chalcone oxazolidinone hybrids. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1323.
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) 18184 4-Nitrobenzaldehyde 555-16-8 C7H5NO3 详情 详情
(II) 34431 diallyl (2S)-2-isocyanatopentanedioate C12H15NO5 详情 详情
(III) 61803 benzyl 4-(hydroxymethyl)phenylcarbamate C15H15NO3 详情 详情
(IV) 61804 benzyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenylcarbamate C21H29NO3Si 详情 详情
(V) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VI) 61805 (5R)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C17H27NO4Si 详情 详情
(VII) 61806 {(5R)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate C18H29NO6SSi 详情 详情
(VIII) 61807 (5R)-5-(azidomethyl)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-1,3-oxazolidin-2-one C17H26N4O3Si 详情 详情
(IX) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(X) 61808 N-({(5S)-3-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide C19H30N2O4Si 详情 详情
(XI) 61809 N-({(5S)-3-[4-(hydroxymethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide C13H16N2O4 详情 详情
(XII) 61812 N-{[(5S)-3-(4-formylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C13H14N2O4 详情 详情

合成路线21

该中间体在本合成路线中的序号：(X)

Condensation between 1,2-difluoro-4-nitrobenzene (I) and L-prolinol (II) affords the N-aryl prolinol (III). Subsequent conversion of alcohol (III) into bromide (IV) is achieved by treatment with CBr4 and PPh3. Displacement of bromide (IV) with sodium thioacetate, followed by basic hydrolysis of the resultant thioacetate ester (V) leads to thiol (VI). Intramolecular cyclization of (VI) in the presence of NaH generates the pyrrolobenzothiazine system (VII). Catalytic hydrogenation of the nitro group of (VII) gives amine (VIII), which is acylated by benzyl chloroformate to provide carbamate (IX). The lithium anion of carbamate (IX) is condensed with (R)-glycidyl butyrate (X) to furnish oxazolidinone (XI). Then, treatment of alcohol (XI) with methanesulfonyl chloride produces mesylate (XII).

参考文献 中间体
合成目标
【1】 Selvakumar, N.; Reddy, B.Y.; Kumar, G.S.; Khera, M.K.; Srinivas, D.; Kumar, M.S.; Das, J.; Iqbal, J.; Trehan, S.; SAR studies on certain conformationally constrained oxazolidinones. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1324.
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) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 64118 (2S)pyrrolidinylmethanol C5H11NO 详情 详情
(III) 64119 [1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]methanol C11H13FN2O3 详情 详情
(IV) 64120 2-(bromomethyl)-1-(2-fluoro-4-nitrophenyl)pyrrolidine C11H12BrFN2O2 详情 详情
(V) 64121 S-{[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]methyl} ethanethioate C13H15FN2O3S 详情 详情
(VI) 64122 [1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]methylhydrosulfide; [1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]methanethiol C11H13FN2O2S 详情 详情
(VII) 64123 7-nitro-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazine C11H12N2O2S 详情 详情
(VIII) 64124 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-ylamine; 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-amine C11H14N2S 详情 详情
(IX) 64125 phenylmethyl 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-ylcarbamate C19H20N2O2S 详情 详情
(X) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(XI) 64126 3-(2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-yl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one C15H18N2O3S 详情 详情
(XII) 64127 [3-(2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-7-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate C16H20N2O5S2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(III)

3-Fluoroaniline (I) is condensed with benzyl chloroformate to give carbamate (II). Reaction of (II) with (R)-glycidol butyrate (III) in the presence of butyllithium affords oxazolidinone (IV). After conversion of alcohol (IV) to the corresponding mesylate, displacement with NaN3 provides azide (V). Reduction and acylation of (V) by means of thioacetic acid leads to acetamide (VI). Friedel-Crafts acylation of the aromatic ring of (VI) with acetic anhydride in the presence of methanesulfonic acid furnishes acetophenone (VII). Acidic hydrolysis of acetamide (VII) yields amine (VIII). This is then treated with thiophosgene, followed by methanol, to produce the thiocarbamate (IX). Finally, aldol condensation of the acetophenone (IX) with pyridine-2-carbaldehyde (X) gives rise to the target compound.

参考文献 中间体
合成目标
【1】 Selvakumar, N.; et al.; Synthesis and antibacterial activity of novel chalcone oxazolidinone hybrids. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1323.
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) 60314 phenylmethyl 3-fluorophenylcarbamate C14H12FNO2 详情 详情
(III) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(IV) 60315 3-(3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one C10H10FNO3 详情 详情
(V) 60317 (R)-5-(azidomethyl)-3-(3-fluorophenyl)oxazolidin-2-one C10H9FN4O2 详情 详情
(VI) 60319 N-{[3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C12H13FN2O3 详情 详情
(VII) 62789 N-{[(5S)-3-(4-acetyl-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C14H15FN2O4 详情 详情
(VIII) 62790 (5S)-3-(4-acetyl-3-fluorophenyl)-5-(aminomethyl)-1,3-oxazolidin-2-one C12H13FN2O3 详情 详情
(IX) 62791 O-methyl [(5S)-3-(4-acetyl-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methylcarbamothioate C14H15FN2O4S 详情 详情
(X) 25173 2-pyridinecarbaldehyde 1121-60-4 C6H5NO 详情 详情

合成路线23

该中间体在本合成路线中的序号：(VI)

Substitution of 1,2-difluoro-4-nitrobenzene (I) with benzyl alcohol in the presence of KOH in CH2Cl2 gives 1-benzyloxy-2-fluoro-4-nitrobenzene (II), which is reduced to 4-benzyloxy-3-fluoroaniline (III) by means of H2 and Pt/C in EtOAc. Condensation of aniline (III) with benzyl chloroformate (IV) in the presence of NaHCO3 in acetone/H2O affords carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) using BuLi in THF at –60 °C to provide the oxazolidinone derivative (VII) . Debenzylation of compound (VII) with H2 over Pd/C in THF/MeOH produces alcohol (VIII), which is condensed with epoxide (IX) in the presence of Na2CO3 in DMF at 100 °C to obtain the corresponding ether (X). N-Deprotection of intermediate (X) by means of H2 over Pd/C in EtOAc/MeOH gives the piperidine derivative (XI), which is finally condensed with the quinolone boron chelate (XII) —prepared by reaction of the quinolone ester (XIII) with B(OH)3 and AcOH in the presence of ZnCl2 at 110 °C — using DIEA in NMP at 85 °C .

参考文献 中间体
合成目标
【1】 Hermecz, I., Kereszturi, g., Vasvari, L. et al. (Chinoin Zrt). Quinoline carboxylic acid boric acid anhydrides and process for the preparation thereof. CN 88101941, EP 0310647, JP 1989003300, US 4940794, WO 1988007998.
【2】 Hubschwerlen, C., Panchaud, P., Specklin, J.-L. (Actelion Pharmaceuticals, Ltd.). 5-Hydroxymethyl-oxazolidin-2-one derivatives. CN 102014903, EP 2086968, JP 2010509314, JP 2010132677, KR 2010137569, US 2009247578, US 8124623, WO 2008056335.
【3】 Hubschwerlen, C., Locher, H. (Actelion Pharmaceuticals, Ltd.). 5-Hydroxymethyl-oxazolidin-2-one derivatives for treating bacterial intestinal diseases. EP 2296651, JP 2011519914, WO 2009136379.
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) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 67754 1-benzyloxy-2-fluoro-4-nitrobenzene;1-(benzyloxy)-2-fluoro-4-nitrobenzene 　 C13H10FNO3 详情 详情
(III) 67755 4-benzyloxy-3-fluoroaniline 　 C13H12FNO 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 67756 benzyl (4-(benzyloxy)-3-fluorophenyl)carbamate 　 C21H18FNO3 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 67757 (R)-3-(4-(benzyloxy)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one 　 C17H16FNO4 详情 详情
(VIII) 67758 (R)-3-(3-fluoro-4-hydroxyphenyl)-5-(hydroxymethyl)oxazolidin-2-one 　 C10H10FNO4 详情 详情
(IX) 67759 benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate 　 C14H17NO3 详情 详情
(X) 67760 (R)-benzyl 4-((2-fluoro-4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxypiperidine-1-carboxylate 　　 C24H27FN2O7 详情 详情
(XI) 67761 (R)-3-(3-fluoro-4-((4-hydroxypiperidin-4-yl)methoxy)phenyl)-5-(hydroxymethyl)oxazolidin-2-one 　 C16H21FN2O5 详情 详情
(XII) 67762 　 　 C17H14BClFNO7 详情 详情
(XIII) 30340 ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate 86483-54-7 C15H13ClFNO3 详情 详情

合成路线24

该中间体在本合成路线中的序号：(VII)

Condensation of 1,2-difluoro-4-nitrobenzene (I) with thiomorpholine (II) using DIEA in refluxing acetonitrile at 85 °C yields 4-(2-fluoro-4-nitrophenyl)thiomorpholine (III) , which is then reduced by means of either Na2S2O4 in THF , Fe in the presence of NH4Cl in refluxing H2O/EtOH/dioxane , or by catalytic hydrogenation over Raney-Ni in THF/H2O (1) or sulfided Pd/C in MeOH , providing 3-fluoro-4-thiomorpholin-4-ylaniline (IV) . Acylation of amine (IV) with benzyl chloroformate (V), optionally in the presence of DMA , in THF affords carbamate (VI) , which then cyclizes with (R)-(–)-glycidyl butyrate (VII) using BuLi in THF at –78 °C to produce the 5-(hydroxymethyl)-2-oxazolidinone derivative (VIII). Reaction of the primary alcohol (VIII) with MsCl using Et3N in CH2Cl2 or with TsCl in pyridine yields the corresponding mesylate (IXa) or tosylate (IXb) , respectively, which by substitution with NaN3 in DMF at 65-85 °C provides azide (X). Staudinger reduction of azide (X) with PPh3 in THF/H2O then yields the corresponding amine (XIa). Finally, amine (XIa) or its hydrochloride (XIb) are acylated with acetic anhydride (XII) in the presence of pyridine in CH2Cl2 or NaOH in H2O/MeOH/CH2Cl2 .

参考文献 中间体
合成目标
【1】 Barbachyn, M.R., Hutchinson, D.K., Brickner, S.J. et al. Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity. J Med Chem 1996, 39(3): 680-5.
【2】 Brickner, S.J., Barbachyn, M.R., Hutchinson, D.K. (Pfizer, Inc.). Substituted oxazine and thiazine oxazolidinone antimicrobials. US 5880118.
【3】 Barbachyn, M.R., Brickner, S.J., Hutchinson, D.K. (Pfizer, Inc.). Substituted oxazine and thiazine oxazolidinone antimicrobials. EP 0717738, JP 1997502436, US 5688792, WO 1995007271.
【4】 Brickner, S.J., Nuermberger, E., Stover, C.K. (Pfizer, Inc.). Combination therapy for tuberculosis. CN 102143748, EP 2340022, JP 20122502017, KR 2011063518, US 2011190199, WO 2010026526.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IXa) 68063 (R)-(3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate 　 C15H19FN2O5S2 详情 详情
(IXb) 68064 (R)-(3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate 　 C21H23FN2O5S2 详情 详情
(XIa) 68066 (R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one 　 C14H18FN3O2S 详情 详情
(XIb) 68067 (R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one hydrochloride 　 C14H18FN3O2S.HCl 详情 详情
(I) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 36317 thiomorpholine 123-90-0 C4H9NS 详情 详情
(III) 68060 4-(2-fluoro-4-nitrophenyl)thiomorpholine 　 C10H11FN2O2S 详情 详情
(IV) 68061 3-fluoro-4-thiomorpholinoaniline 　 C10H13FN2S 详情 详情
(V) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VI) 68062 benzyl (3-fluoro-4-thiomorpholinophenyl)carbamate 　 C18H19FN2O2S 详情 详情
(VII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VIII) 56305 (5R)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C14H17FN2O3S 详情 详情
(X) 68065 (R)-5-(azidomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one 　 C14H16FN5O2S 详情 详情
(XII) 49701 Acetic anhydride; Acetyl oxide 108-24-7 C4H6O3 详情 详情
Extended Information