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【结 构 式】 
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【分子编号】51550 【品名】3-Bromo-4-fluorobenzaldehyde 【CA登记号】77771-02-9 |
【 分 子 式 】C7H4BrFO 【 分 子 量 】203.0105632 【元素组成】C 41.42% H 1.99% Br 39.36% F 9.36% O 7.88% |
合成路线1
该中间体在本合成路线中的序号：(II)The Hantzsch reaction between 3-oxotetrahydrothiophene-1,1-dioxide (I), 3-bromo-4-fluorobenzaldehyde (II) and 3-amino-2-cyclohexen-1-one (III) in refluxing EtOH yielded the hydroxy tetrahydropyridine derivative (IV). Dehydration of the cyclic hemiaminal function of (IV) was carried out in refluxing toluene to produce the racemic dihydropyridine, which was resolved into the individual enantiomers by chiral HPLC.
| 【1】 Drizin, I.; et al.; Novel sulfonyldihydropyridine potassium channel openers with potential utility in the treatment of overactive bladder (OAB). 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 197. |
| 【2】 Drizin, I.; Holladay, M.W.; Carroll, W.A.; Zhang, H.Q.; Sullivan, J.P. (Abbott Laboratories Inc.); Potassium channel openers. EP 1040097; US 6265417; WO 9931059 . |
| 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) | 51549 | 3-Oxosulfolane | C4H6O3S | 详情 | 详情 | |
| (II) | 51550 | 3-Bromo-4-fluorobenzaldehyde | 77771-02-9 | C7H4BrFO | 详情 | 详情 |
| (III) | 31475 | 3-amino-2-cyclohexen-1-one | 5220-49-5 | C6H9NO | 详情 | 详情 |
| (IV) | 51551 | 9-(3-bromo-4-fluorophenyl)-3a-hydroxy-2,3,3a,5,6,7,9,9a-octahydro-1H-2H-thieno[3,2-b]quinoline-1,1,8(4H)-trione | C17H17BrFNO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with morpholine-4-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.
| 【1】 Pargas, R.E.M.; Tucker, J.A.; Schnute, M.E.; et al.; 1-Amino-4-oxo-1,4-dihydroquinolines with broad-spectrum antiherpetic activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1669. |
| 【2】 Thaisrivongs, S.; Strohbach, J.W.; Turner, S.R.; Vaillancourt, V.A.; Tucker, J.A.; Schnute, M.E. (Pharmacia Corp.); Quinolinecarboxamides as antiviral agents. EP 1140850; US 6248739; WO 0040561 . |
| 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) | 51550 | 3-Bromo-4-fluorobenzaldehyde | 77771-02-9 | C7H4BrFO | 详情 | 详情 |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 53185 | 4-(3-bromo-4-fluorobenzyl)morpholine | n/a | C11H13BrFNO | 详情 | 详情 |
| (IV) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (V) | 53186 | 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone | n/a | C13H16FNO2 | 详情 | 详情 |
| (VI) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VII) | 53187 | ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate | n/a | C16H20FNO4 | 详情 | 详情 |
| (VIII) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (IX) | 53188 | ethyl (Z)-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate | n/a | C19H24FNO5 | 详情 | 详情 |
| (X) | 35977 | 4-morpholinylamine; 4-morpholinamine | 4319-49-7 | C4H10N2O | 详情 | 详情 |
| (XI) | 53191 | ethyl (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-(4-morpholinylamino)-2-propenoate | n/a | C21H28FN3O5 | 详情 | 详情 |
| (XII) | 53192 | ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C21H27N3O5 | 详情 | 详情 |
| (XIII) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 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 reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with piperazine-1-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.
| 【1】 Pargas, R.E.M.; Tucker, J.A.; Schnute, M.E.; et al.; 1-Amino-4-oxo-1,4-dihydroquinolines with broad-spectrum antiherpetic activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1669. |
| 【2】 Thaisrivongs, S.; Strohbach, J.W.; Turner, S.R.; Vaillancourt, V.A.; Tucker, J.A.; Schnute, M.E. (Pharmacia Corp.); Quinolinecarboxamides as antiviral agents. EP 1140850; US 6248739; WO 0040561 . |
| 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) | 51550 | 3-Bromo-4-fluorobenzaldehyde | 77771-02-9 | C7H4BrFO | 详情 | 详情 |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 53185 | 4-(3-bromo-4-fluorobenzyl)morpholine | n/a | C11H13BrFNO | 详情 | 详情 |
| (IV) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (V) | 53186 | 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone | n/a | C13H16FNO2 | 详情 | 详情 |
| (VI) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VII) | 53187 | ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate | n/a | C16H20FNO4 | 详情 | 详情 |
| (VIII) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (IX) | 53188 | ethyl (Z)-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate | n/a | C19H24FNO5 | 详情 | 详情 |
| (X) | 40655 | 4-Methyl-1-piperazinamine; 1-Amino-4-methylpiperazine; 4-Methyl-1-piperazinylamine | 6928-85-4 | C5H13N3 | 详情 | 详情 |
| (XI) | 53189 | ethyl (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-[(4-methyl-1-piperazinyl)amino]-2-propenoate | n/a | C22H31FN4O4 | 详情 | 详情 |
| (XII) | 53190 | ethyl 1-(4-methyl-1-piperazinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C22H30N4O4 | 详情 | 详情 |
| (XIII) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 详情 | 详情 |