|
【结 构 式】 
|
【分子编号】28504 【品名】N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide 【CA登记号】 |
【 分 子 式 】C12H14FN3O3 【 分 子 量 】267.2599832 【元素组成】C 53.93% H 5.28% F 7.11% N 15.72% O 17.96% |
合成路线1
该中间体在本合成路线中的序号：(X)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.
| 【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2
该中间体在本合成路线中的序号：(I)Nitrile (II) was prepared from the known amine (I) by diazotization, followed by cyanation with KCN and CuCN. Addition of H2S to (II) in the presence of Et3N in DMF afforded the thioamide (III), which was condensed with chloromalonaldehyde (IV) to produce thiazole (V). Reaction of the formyl group of (V) with hydroxylamine and sodium formate then yielded the target nitrile.
| 【1】 Genin, M.J.; Grega, K.C.; Ford, C.W.; Barbachyn, M.R.; Walker, E.A.; Gadwood, R.C.; Thomasco, L.M.; Zurenko, G.E.; Synthesis and antibacterial activity of azolylphenyl oxazolidinones having carbon-bound 1,3-thiazolyl rings. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-139. |
| 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) | 28504 | N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C12H14FN3O3 | 详情 | 详情 | |
| (II) | 28555 | N-[[(5S)-3-(4-cyano-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C13H12FN3O3 | 详情 | 详情 | |
| (III) | 28556 | N-([(5S)-3-[4-(aminocarbothioyl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C13H14FN3O3S | 详情 | 详情 | |
| (IV) | 28557 | 2-chloromalonaldehyde | 36437-19-1 | C3H3ClO2 | 详情 | 详情 |
| (V) | 28558 | N-([(5S)-3-[3-fluoro-4-(5-formyl-1,3-thiazol-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C16H14FN3O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Diazotization of the known aniline (I), followed by Sandmeyer reaction with CuCN and KCN afforded nitrile (II). Addition of hydrogen sulfide to (II) in the presence of Et3N in hot DMF led to the thioamide (III). Subsequent alkylation of (III) with methyl triflate gave the intermediate thioimidate (IV), and a further treatment of (IV) with hydrogen sulfide and pyridine provided dithioester (V). Displacement of the methylthio group of (V) by hydrazine yielded thiohydrazide (VI). Finally, cyclization of (VI) to the target thiadiazole was achieved upon refluxing in formic acid.
| 【1】 Ford, C.W.; Gadwood, R.C.; Thomasco, L.M.; Weaver, E.A.Zurenko, G.E.; Synthesis and antibacterial activity of azolylphenyl oxazolidinones having 1,3,4-thiadiazolyl C-rings. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F571. |
| 【2】 Gadwood, R.C.; Thomasco, L.M.; Anderson, D.J. (Pharmacia Corp.); Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agents. EP 0994874; WO 9902525 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27344 | hydrazine | 302-01-2 | H4N2 | 详情 | 详情 | |
| (I) | 28504 | N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C12H14FN3O3 | 详情 | 详情 | |
| (II) | 28555 | N-[[(5S)-3-(4-cyano-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C13H12FN3O3 | 详情 | 详情 | |
| (III) | 28556 | N-([(5S)-3-[4-(aminocarbothioyl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C13H14FN3O3S | 详情 | 详情 | |
| (IV) | 32980 | methyl 4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzenecarbimidothioate | C14H16FN3O3S | 详情 | 详情 | |
| (V) | 32981 | methyl 4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzenecarbodithioate | C14H15FN2O3S2 | 详情 | 详情 | |
| (VI) | 32982 | N-([(5S)-3-[3-fluoro-4-(hydrazinocarbothioyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C13H15FN4O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Diazotization of the known aniline (I), followed by Sandmeyer reaction with CuCN and KCN afforded nitrile (II). Addition of hydrogen sulfide to (II) in the presence of Et3N in hot DMF led to the thioamide (III). Subsequent alkylation of (III) with methyl triflate gave the intermediate thioimidate (IV), and a further treatment of (IV) with hydrogen sulfide and pyridine provided dithioester (V). Displacement of the methylthio group of (V) by hydrazine yielded thiohydrazide (VI). This was cyclized to the required thiadiazole (VII) upon treatment with 3-carbomethoxypropionyl chloride (A) in refluxing THF. Aminolysis of the ester group of (VII) with methanolic ammonia at 100 C in a sealed vessel provided amide (VIII). This was finally dehydrated to the title nitrile using trifluoroacetic anhydride and pyridine.
| 【1】 Ford, C.W.; Gadwood, R.C.; Thomasco, L.M.; Weaver, E.A.Zurenko, G.E.; Synthesis and antibacterial activity of azolylphenyl oxazolidinones having 1,3,4-thiadiazolyl C-rings. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F571. |
| 【2】 Gadwood, R.C.; Thomasco, L.M.; Anderson, D.J. (Pharmacia Corp.); Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agents. EP 0994874; WO 9902525 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27344 | hydrazine | 302-01-2 | H4N2 | 详情 | 详情 | |
| (A) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (I) | 28504 | N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C12H14FN3O3 | 详情 | 详情 | |
| (II) | 28555 | N-[[(5S)-3-(4-cyano-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C13H12FN3O3 | 详情 | 详情 | |
| (III) | 28556 | N-([(5S)-3-[4-(aminocarbothioyl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C13H14FN3O3S | 详情 | 详情 | |
| (IV) | 32980 | methyl 4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzenecarbimidothioate | C14H16FN3O3S | 详情 | 详情 | |
| (V) | 32981 | methyl 4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorobenzenecarbodithioate | C14H15FN2O3S2 | 详情 | 详情 | |
| (VI) | 32982 | N-([(5S)-3-[3-fluoro-4-(hydrazinocarbothioyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C13H15FN4O3S | 详情 | 详情 | |
| (VII) | 32983 | methyl 3-[5-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1,3,4-thiadiazol-2-yl]propanoate | C18H19FN4O5S | 详情 | 详情 | |
| (VIII) | 32984 | 3-[5-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1,3,4-thiadiazol-2-yl]propanamide | C17H18FN5O4S | 详情 | 详情 |