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【结 构 式】

【分子编号】18382

【品名】1-(2-fluoro-4-nitrophenyl)piperazine

【CA登记号】

【 分 子 式 】C10H12FN3O2

【 分 子 量 】225.2227032

【元素组成】C 53.33% H 5.37% F 8.44% N 18.66% O 14.21%

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:(III)

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:(III)

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:(II)

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.

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
Extended Information