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【结 构 式】 
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【分子编号】38747 【品名】2-bromoacetamide 【CA登记号】683-57-8 |
【 分 子 式 】C2H4BrNO 【 分 子 量 】137.9639 【元素组成】C 17.41% H 2.92% Br 57.92% N 10.15% O 11.6% |
合成路线1
该中间体在本合成路线中的序号：(XI)The cyclization of the diazo azetidinone (I) by means of a Rhodium catalyst in dichloromethane gives the -methyl-2-oxocarbapenam derivative (II), which is treated with methanesulfonic anhydride and TEA in dichloromethane yielding the enol triflate (II). The silylation of the OH group of (III) with triethylsilyl triflate and TEA affords the silyl ether (IV), which is condensed with the fluorenone boronic acid (V) by means of KOH and a Pd catalyst giving the adduct (VI) (1). The mesylation of (VI) with MsCl and TEA in dichloromethane, followed by reaction with NaI in acetone yields the iodomethyl compound (VII), which is condensed with 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (VIII) by means of silver triflate in THF/acetonitrile to afford the protected intermediate (IX). Finally, this compound is deprotected first with HCl in THF/water and then by hydrogenation with H2 over Rh/C. The intermediate 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (VIII) has been obtained as follows: The condensation of 1,4-diazabicyclo[2.2.2]octane (X) with 2-bromoacetamide (XI) in acetonitrile gives 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide bromide (XII), which is then treated with silver triflate in acetonitrile/methanol to yield (VIII).
| 【1】 DiNinno, F.; Laub, J.B.; Greenlee, M.L.; Rouen, G.P.; Hammond, G.G.; Sundelof, J.G.; Hammond, M.L.; Huber, J.L.; Dicationic 2-fluorenylcarbapenems: Potent anti-MRS agents with improved solubility and pharmacokinetic properties. Bioorg Med Chem Lett 1999, 9, 22, 3225. |
| 【2】 Greenlee, M.L.; Dininno, F.P.; Hammond, M.L. (Merck & Co., Inc.); 1-beta-Methyl-carbapenem, compsns. containing same and methods of use. US 5451579; WO 9521841 . |
| 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) | 38749 | 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C17H18N4O7 | 详情 | 详情 | |
| (II) | 37720 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (III) | 38750 | 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C18H17F3N2O9S | 详情 | 详情 | |
| (IV) | 38751 | 4-nitrobenzyl (4R,5R,6S)-4-methyl-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C24H31F3N2O9SSi | 详情 | 详情 | |
| (V) | 38752 | 7-(hydroxymethyl)-9-oxo-9H-fluoren-3-ylboronic acid | C14H11BO4 | 详情 | 详情 | |
| (VI) | 38753 | 4-nitrobenzyl (4S,5R,6S)-3-[7-(hydroxymethyl)-9-oxo-9H-fluoren-3-yl]-4-methyl-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C37H40N2O8Si | 详情 | 详情 | |
| (VII) | 38754 | 4-nitrobenzyl (4S,5R,6S)-3-[7-(iodomethyl)-9-oxo-9H-fluoren-3-yl]-4-methyl-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C37H39IN2O7Si | 详情 | 详情 | |
| (VIII) | 30156 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate | C9H16F3N3O4S | 详情 | 详情 | |
| (IX) | 38755 | 1-(2-amino-2-oxoethyl)-4-[[6-((4S,5R,6S)-4-methyl-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl)-9-oxo-9H-fluoren-2-yl]methyl]-1,4-diazoniabicyclo[2.2.2]octane di(trifluoromethanesulfonate | C47H55F6N5O14S2Si | 详情 | 详情 | |
| (X) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |
| (XI) | 38747 | 2-bromoacetamide | 683-57-8 | C2H4BrNO | 详情 | 详情 |
| (XII) | 38748 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide | C8H16BrN3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The mesylation of carbapenem (I) with MsCl and TEA in dichloromethane, followed by reaction with NaI in acetone yields the iodomethyl compound (II), which is condensed with 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (III) by means of silver triflate in THF/acetonitrile to afford the protected intermediate (IV). Finally, this compound is deprotected first with HCl in THF/water and then by hydrogenation with H2 over Rh/C The intermediate 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide triflate (III) has been obtained as follows: The condensation of 1,4-diazabicyclo[2.2.2]octane (V) with 2-bromoacetamide (VI) in acetonitrile gives 2-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)acetamide bromide (VII), which is then treated with silver triflate in acetonitrile/methanol to yield (III).
| 【1】 DiNinno, F.; Laub, J.B.; Greenlee, M.L.; Rouen, G.P.; Hammond, G.G.; Sundelof, J.G.; Hammond, M.L.; Huber, J.L.; Dicationic 2-fluorenylcarbapenems: Potent anti-MRS agents with improved solubility and pharmacokinetic properties. Bioorg Med Chem Lett 1999, 9, 22, 3225. |
| 【2】 Greenlee, M.L.; Dininno, F.P.; Hammond, M.L. (Merck & Co., Inc.); 1-beta-Methyl-carbapenem, compsns. containing same and methods of use. US 5451579; WO 9521841 . |
| 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) | 38629 | 4-nitrobenzyl (5R,6S)-3-[7-(hydroxymethyl)-9-oxo-9H-fluoren-3-yl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C36H38N2O8Si | 详情 | 详情 | |
| (II) | 38745 | 4-nitrobenzyl (5R,6S)-3-[7-(iodomethyl)-9-oxo-9H-fluoren-3-yl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C36H37IN2O7Si | 详情 | 详情 | |
| (III) | 30156 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate | C9H16F3N3O4S | 详情 | 详情 | |
| (IV) | 38746 | 1-(2-amino-2-oxoethyl)-4-[[6-((5R,6S)-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl)-9-oxo-9H-fluoren-2-yl]methyl]-1,4-diazoniabicyclo[2.2.2]octane di(trifluoromethanesulfonate) | C46H53F6N5O14S2Si | 详情 | 详情 | |
| (V) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |
| (VI) | 38747 | 2-bromoacetamide | 683-57-8 | C2H4BrNO | 详情 | 详情 |
| (VII) | 38748 | 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide | C8H16BrN3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)Condensation of 3-fluoroaniline (I) with the cyclic anhydride (II) in AcOH gave amide (III). Subsequent cyclization of (III) in hot H2SO4 produced quinolineacetic acid (IV). After esterification of (IV) with methanol in the presence of SOCl2, the resulting methyl ester (V) was reduced to alcohol (VI) using NaBH4 in refluxing THF. Treatment of alcohol (VI) with SOCl2 afforded chloride (VII), which was condensed with 4-(1-piperazinyl)thieno[3,2-c]pyridine (VIII) yielding adduct (IX), isolated as the dihydro-chloride salt. Finally, alkylation of the quinoline N atom of (IX) with bromoacetamide (A) under phase-transfer conditions furnished the title compound.
| 【1】 McCort, G.; et al.; Synthesis and SAR of 3- and 4-substituted quinolin-2-ones: Discovery of mixed 5-HT1b/5-HT2A receptor antagonists. Bioorg Med Chem 2001, 9, 8, 2129. |
| 【2】 Demarquay, D.; Lavergne, O.; Bailly, C.; et al.; Topoisomerase I-mediated antiproliferative activity of enantiomerically pure fluorinated homocamptothecins. J Med Chem 2000, 43, 11, 2285. |
| 【3】 Mc Cort, G.; Hoornaert, C.; Dellac, G.; Aletru, M. (Sanofi-Synthelabo ); Quinolein-2(1H)-one derivs. as serotonin antagonists. EP 0850235; FR 2738822; FR 2739100; JP 1999514982; US 5958924; WO 9710238 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 38747 | 2-bromoacetamide | 683-57-8 | C2H4BrNO | 详情 | 详情 |
| (I) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 40692 | 2,6-dioxo-3,6-dihydro-2H-pyran-4-yl acetate | C7H6O5 | 详情 | 详情 | |
| (III) | 40693 | (Z)-3-(acetoxy)-5-(3-fluoroanilino)-5-oxo-2-pentenoic acid | C13H12FNO5 | 详情 | 详情 | |
| (IV) | 40694 | 2-(7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl)acetic acid | C11H8FNO3 | 详情 | 详情 | |
| (V) | 40695 | methyl 2-(7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl)acetate | C12H10FNO3 | 详情 | 详情 | |
| (VI) | 40696 | 7-fluoro-4-(2-hydroxyethyl)-2(1H)-quinolinone | C11H10FNO2 | 详情 | 详情 | |
| (VII) | 40697 | 4-(2-chloroethyl)-7-fluoro-2(1H)-quinolinone | C11H9ClFNO | 详情 | 详情 | |
| (VIII) | 40698 | 4-(1-piperazinyl)thieno[3,2-c]pyridine | C11H13N3S | 详情 | 详情 | |
| (IX) | 40699 | 7-fluoro-4-[2-(4-thieno[3,2-c]pyridin-4-yl-1-piperazinyl)ethyl]-2(1H)-quinolinone | C22H21FN4OS | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The alkylation of 3-fluoroaniline (I) with 2-bromoacetamide (II) by means of KOH and Bu4NBr in THF gives 2-(3-fluorophenylamino)acetamide (III), which is condensed with 4-acetoxy-3,6-dihydro-2H-pyran-2,6-dione (IV) in Ac-OH to yield intermediate (V). The cyclization of (V) by means of H2SO4 or Ms-OH at 100?C affords the quinolone (VII), which is esterified with SOCl2 and methanol to provide the corresponding methyl ester (VII). The reduction of (VII) with NaBH4 in refluxing THF furnishes the 2-hydroxyethyl quinolone (VIII), which is treated with SOCl2 in refluxing CHCl3 to give the 2-chloroethyl derivative (IX). Finally, this compound is condensed with the arylpiperazine (X) by means of K2CO3 and KI in hot DMF to afford the desired quinolone.
| 【1】 McCort, G.; et al.; Synthesis and SAR of 3- and 4-substituted quinolin-2-ones: Discovery of mixed 5-HT1b/5-HT2A receptor antagonists. Bioorg Med Chem 2001, 9, 8, 2129. |
| 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) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 38747 | 2-bromoacetamide | 683-57-8 | C2H4BrNO | 详情 | 详情 |
| (III) | 50951 | 2-(3-fluoroanilino)acetamide | C8H9FN2O | 详情 | 详情 | |
| (IV) | 40692 | 2,6-dioxo-3,6-dihydro-2H-pyran-4-yl acetate | C7H6O5 | 详情 | 详情 | |
| (V) | 50952 | (Z)-3-(acetoxy)-5-[(2-amino-2-oxoethyl)-3-fluoroanilino]-5-oxo-2-pentenoic acid | C15H15FN2O6 | 详情 | 详情 | |
| (VI) | 50953 | 2-[1-(2-amino-2-oxoethyl)-7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl]acetic acid | C13H11FN2O4 | 详情 | 详情 | |
| (VII) | 50954 | methyl 2-[1-(2-amino-2-oxoethyl)-7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl]acetate | C14H13FN2O4 | 详情 | 详情 | |
| (VIII) | 50955 | 2-[7-fluoro-4-(2-hydroxyethyl)-2-oxo-1(2H)-quinolinyl]acetamide | C13H13FN2O3 | 详情 | 详情 | |
| (IX) | 50956 | 2-[4-(2-chloroethyl)-7-fluoro-2-oxo-1(2H)-quinolinyl]acetamide | C13H12ClFN2O2 | 详情 | 详情 | |
| (X) | 40698 | 4-(1-piperazinyl)thieno[3,2-c]pyridine | C11H13N3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The title compound is prepared by alkylation of 3,3-diphenylpropylamine (I) with bromoacetamide (II) in the presence of K2CO3 in acetonitrile (1).
| 【1】 Ognyanov, V.I.; Borden, L.; Bell, S.C.; Zhang, J. (NPS Allelix Corp.); Pharmaceutical for treatment of neurological and neuropsychiatric disorders. EP 1014966; JP 2002515037; US 6191165; WO 9745115 . |