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【结 构 式】

【分子编号】17013

【品名】1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene

【CA登记号】369-34-6

【 分 子 式 】C6H3F2NO2

【 分 子 量 】159.0921664

【元素组成】C 45.3% H 1.9% F 23.88% N 8.8% O 20.11%
与该中间体有关的原料药合成路线共 17 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1

该中间体在本合成路线中的序号：(XII)

a) Condensation of the phenolic compound (I) with 7-benzyloxy-6-methoxyquinolinyl triflate (II) in refluxing 2,6-lutidine affords the quinolinyl ether (III), which is O-debenzylated by transfer hydrogenation with 1,4-cyclohexadiene and Pd/C in EtOH at 65 °C, producing the 7-hydroxyquinoline derivative (IV). Finally, the hydroxyquinoline (IV) is alkylated with N-(3-chloropropyl)morpholine hydrochloride (V) by means of K2CO3 in DMF at 90 °C .
b) Direct coupling of the phenol derivative (I) with 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (VI) in the presence of Pd(OAc)2, 2-(di-tert-butylphosphino)-1,1’-binaphthyl (DTBPB) and K3PO4 in anisole at 110 °C or NMP/toluene at 95 °C .
c) Acylation of the quinolinyloxyaniline intermediate (VII) with 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride (VIII) by means of K2CO3 in THF/H2O .

参考文献 中间体
合成目标
【1】 Bannen, L.C., Chan, D.S.-M., Chen, J. (Exelixis, Inc.). c-Met modulators and methods of use. EP 1673085, EP 2210607, EP 2213661, JP 2007506777, JP 2010235631, JP 2010235632, WO 2005030140.
【2】 Deschamps, N.M., Martin, M.T., Monteith, M.J., Zhou, X. (GlaxoSmithKline Inc.). Preparation of a quinolinyloxydiphenylcyclopropanedicarboxamide. US 2010081805, WO 010036831.
【3】 Wilson, J., Zuberi, S., Naganathan, S., Goldman, E., Kanter, J. (Exelixis, Inc.). Methods of preparing quinoline derivatives. WO 2010056960.
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) 69100 N-(3-fluoro-4-hydroxyphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 　 C17H14F2N2O3 详情 详情
(VIII) 69107 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride 　 C11H9ClFNO2 详情 详情
(IX) 69108 cyclopropane-1,1-dicarboxylic acid 　 C5H6O4 详情 详情
(X) 37690 4-fluorophenylamine; 4-fluoroaniline 371-40-4 C6H6FN 详情 详情
(XI) 69109 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid 　 C11H10FNO3 详情 详情
(XII) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(XIII) 67754 1-benzyloxy-2-fluoro-4-nitrobenzene;1-(benzyloxy)-2-fluoro-4-nitrobenzene 　 C13H10FNO3 详情 详情
(XIV) 67755 4-benzyloxy-3-fluoroaniline 　 C13H12FNO 详情 详情
(XV) 69110 N-(4-(benzyloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 　 C24H20F2N2O3 详情 详情
(XVI) 69111 4-amino-2-fluorophenol;2-Fluoro-4-aminophenol 399-96-2 C6H6FNO 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

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

参考文献 中间体
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】 Lizondo, J.; Rabasseda, X.; Castañer, J.; Linezolid. Drugs Fut 1996, 21, 11, 1116.
【3】 Barbachyn, M.R.; Brickner, S.J.; Hutchinson, D.K. (Pharmacia Corp.); Substd. oxazine and thiazine oxazolidinone antimicrobials. EP 0717738; JP 1997502436; WO 9507271 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(II) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(III) 17014 4-(2-fluoro-4-nitrophenyl)morpholine C10H11FN2O3 详情 详情
(IV) 17015 3-fluoro-4-morpholinophenylamine; 3-fluoro-4-morpholinoaniline; 3-fluoro-4-(4-morpholinyl)phenylamine; 3-Fluoro-4-(4-morpholinyl)benzeneamine 93246-53-8 C10H13FN2O 详情 详情
(V) 17016 benzyl N-(3-fluoro-4-morpholinophenyl)carbamate C18H19FN2O3 详情 详情
(VI) 17017 (2S)oxiranylmethyl butyrate C7H12O3 详情 详情
(VII) 17018 (5R)-3-(3-fluoro-4-morpholinophenyl)-5-(hydroxymethyl)-1,3-oxazolan-2-one 168828-82-8 C14H17FN2O4 详情 详情
(VIII) 17019 [(5R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolan-5-yl]methyl methanesulfonate 174649-09-3 C15H19FN2O6S 详情 详情
(IX) 17020 (5R)-5-(azidomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolan-2-one C14H16FN5O3 详情 详情
(X) 17021 (5S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolan-2-one C14H18FN3O3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

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4

该中间体在本合成路线中的序号：(I)

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5

该中间体在本合成路线中的序号：(I)

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6

该中间体在本合成路线中的序号：(I)

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7

该中间体在本合成路线中的序号：(II)

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8

该中间体在本合成路线中的序号：(I)

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9

该中间体在本合成路线中的序号：(III)

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10

该中间体在本合成路线中的序号：(III)

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11

该中间体在本合成路线中的序号：(V)

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12

该中间体在本合成路线中的序号：(V)

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13

该中间体在本合成路线中的序号：(I)

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14

该中间体在本合成路线中的序号：(IV)

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15

该中间体在本合成路线中的序号：(I)

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16

该中间体在本合成路线中的序号：(I)

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17

该中间体在本合成路线中的序号：(I)

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