|
【结 构 式】 
|
【分子编号】18390 【品名】N-([(5S)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide 【CA登记号】 |
【 分 子 式 】C16H21FN4O3 【 分 子 量 】336.3663032 【元素组成】C 57.13% H 6.29% F 5.65% N 16.66% O 14.27% |
合成路线1
该中间体在本合成路线中的序号：(XI)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：(XI)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)The title compound is prepared by reductive alkylation of the known piperazinyl oxazolidinone derivative (I) with 5-nitro-2-furfural (II) in the presence of NaBH(OAc)3, followed by conversion to the corresponding hydrochloride salt.
| 【1】 Arora, S.K.; Mehta, A.; Rattan, A.; Das, B.; Ray, A.; Rudra, S. (Ranbaxy Laboratories Ltd.); Oxazolidinone derivs. as antimicrobials. EP 1303511; US 2002103186; WO 0206278; WO 0307870; WO 0308389 . |
合成路线4
该中间体在本合成路线中的序号：(I)The title adduct is prepared by condensation between the piperazinyl oxazolidinone derivative (I) and chloroquinoline (II) in hot N-methylpyrrolidinone.
| 【1】 Locher, H.H.; Specklin, J.; Borer, Y.; Brohammer, S.; Schroeder, S.; Sigwalt, C.; Hubschwerlen, C.; Synthesis and antibacterial action of novel quinolone-linked oxazolidinones. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1317. |
| 【2】 Barbachyn, M.R.; Patel, D.V.; Gage, J.R.; Gordeev, M.F. (Pharmacia Corp.); Antimicrobial quinolone derivs. and use of the same to treat bacterial infections. WO 0259116 . |