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【结 构 式】

【分子编号】18386

【品名】benzyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]-1-piperazinecarboxylate

【CA登记号】

【 分 子 式 】C22H24FN3O5

【 分 子 量 】429.4481832

【元素组成】C 61.53% H 5.63% F 4.42% N 9.78% O 18.63%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VII)

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.

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2

该中间体在本合成路线中的序号:(VII)

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.

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3

该中间体在本合成路线中的序号:(I)

Deprotection of the benzyloxycarbonyl piperazine (I) by catalytic hydrogenolysis provided the secondary amine (II), which was then acylated by benzyloxyacetyl chloride (III) to afford amide (IV). After activation of the hydroxyl group of (IV) as the sulfonate (VI) by treatment with 3-nitrobenzenesulfonyl chloride (V), its displacement with ammonium hydroxide provided the amine (VII). The O-benzyl group of (VII) was then removed by hydrogenolysis, yielding alcohol (VIII). Finally, acylation of the primary amino group of (VIII) with ethyl dithioacetate (IX) in the presence of KOH and NaF gave rise to the title thioacetamide.

1 Hester, J.B. Jr.; Perricone, S.C.; Nidy, E.G.; Poel, T.-J. (Pharmacia Corp.); Oxazolidinone antibacterial agents having a thiocarbonyl functionality. EP 0984947; JP 2002501530; US 6218413; WO 9854161 .
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) 18386 benzyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]-1-piperazinecarboxylate C22H24FN3O5 详情 详情
(II) 55847 (5R)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one C14H18FN3O3 详情 详情
(III) 10493 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride 19810-31-2 C9H9ClO2 详情 详情
(IV) 55848 (5R)-3-(4-{4-[2-(benzyloxy)acetyl]-1-piperazinyl}-3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one C23H26FN3O5 详情 详情
(V) 41948 3-nitrobenzenesulfonyl chloride 121-51-7 C6H4ClNO4S 详情 详情
(VI) 55849 [(5R)-3-(4-{4-[2-(benzyloxy)acetyl]-1-piperazinyl}-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl 3-nitrobenzenesulfonate C29H29FN4O9S 详情 详情
(VII) 55850 (5S)-5-(aminomethyl)-3-(4-{4-[2-(benzyloxy)acetyl]-1-piperazinyl}-3-fluorophenyl)-1,3-oxazolidin-2-one C23H27FN4O4 详情 详情
(VIII) 17828 (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-glycoloyl-1-piperazinyl)phenyl]-1,3-oxazolidin-2-one C16H21FN4O4 详情 详情
(IX) 55851 Ethyl dithioacetate C4H8S2 详情 详情
Extended Information