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【结 构 式】 
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【分子编号】46376 【品名】ethyl 3-(3-[2-[[(6-bromo-1,3-benzodioxol-5-yl)methyl](2-ethoxy-2-oxoacetyl)amino]phenyl]-3-oxopropyl)benzoate 【CA登记号】 |
【 分 子 式 】C30H28BrNO8 【 分 子 量 】610.45826 【元素组成】C 59.03% H 4.62% Br 13.09% N 2.29% O 20.97% |
合成路线1
该中间体在本合成路线中的序号：(IX)Condensation of o-nitroacetophenone (I) with aldehyde (II) in the presence of piperidine acetate afforded the chalcone (III). Both the double bond and the nitro group of (III) were reduced by catalytic hydrogenation over PtO2 to give (IV). 5-Bromopiperonal (VI) was prepared by treatment of 5-bromo-3,4-dihydroxybenzaldehyde (V) with dibromomethane. Reductive condensation of aldehyde (V) with amine (IV) by means of sodium cyanoborohydride produced the secondary amine (VII), which was condensed with ethyl oxalyl chloride (VIII) to produce amide (IX). Cyclization of (IX) to the corresponding quinolone (X) was achieved by treatment with K2CO3 in EtOH. The ethyl group of the target compound was introduced by Stille coupling of bromide (X) with vinyl tributyltin, followed by catalytic hydrogenation of the resulting ethylene derivative (XI) to give (XII). Finally, saponification of diester (XII) with KOH furnished the title dipotassium salt.
| 【1】 Haesslein, J.-L. (Aventis Pharma SA); Quinoline derivs., process for their preparation, the resultant intermediates, their use as medicaments and the pharmaceutical compsns. containing them. FR 2733233; WO 9633190 . |
| 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) | 46369 | 1-(2-nitrophenyl)-1-ethanone | C8H7NO3 | 详情 | 详情 | |
| (II) | 46370 | ethyl 3-formylbenzoate | C10H10O3 | 详情 | 详情 | |
| (III) | 46371 | ethyl 3-[(E)-3-(2-nitrophenyl)-3-oxo-1-propenyl]benzoate | C18H15NO5 | 详情 | 详情 | |
| (IV) | 46372 | ethyl 3-[3-(2-aminophenyl)-3-oxopropyl]benzoate | C18H19NO3 | 详情 | 详情 | |
| (V) | 46374 | 2-bromo-4,5-dihydroxybenzaldehyde | C7H5BrO3 | 详情 | 详情 | |
| (VI) | 46373 | 6-bromo-1,3-benzodioxole-5-carbaldehyde | C8H5BrO3 | 详情 | 详情 | |
| (VII) | 46375 | ethyl 3-[3-(2-[[(6-bromo-1,3-benzodioxol-5-yl)methyl]amino]phenyl)-3-oxopropyl]benzoate | C26H24BrNO5 | 详情 | 详情 | |
| (VIII) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (IX) | 46376 | ethyl 3-(3-[2-[[(6-bromo-1,3-benzodioxol-5-yl)methyl](2-ethoxy-2-oxoacetyl)amino]phenyl]-3-oxopropyl)benzoate | C30H28BrNO8 | 详情 | 详情 | |
| (X) | 46377 | ethyl 1-[(6-bromo-1,3-benzodioxol-5-yl)methyl]-3-[3-(ethoxycarbonyl)benzyl]-4-oxo-1,4-dihydro-2-quinolinecarboxylate | C30H26BrNO7 | 详情 | 详情 | |
| (XI) | 46378 | ethyl 3-[3-(ethoxycarbonyl)benzyl]-4-oxo-1-[(6-vinyl-1,3-benzodioxol-5-yl)methyl]-1,4-dihydro-2-quinolinecarboxylate | C32H29NO7 | 详情 | 详情 | |
| (XII) | 46379 | ethyl 3-[3-(ethoxycarbonyl)benzyl]-1-[(6-ethyl-1,3-benzodioxol-5-yl)methyl]-4-oxo-1,4-dihydro-2-quinolinecarboxylate | C32H31NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Piperonal (I) is brominated by means of Br2 in AcOH to produce (II). Subsequent Suzuki coupling of aryl bromide (II) with 4-(methylsulfanyl)benzeneboronic acid (III) furnishes adduct (IV). Addition of 3-fluorophenylmagnesium bromide (V) to aldehyde (IV) leads to carbinol (VI). The sulfide group is further oxidized to sulfone (VII) employing oxone in aqueous MeOH. Finally, oxidation of alcohol (VII) with pyridinium chlorochromate provides the target ketone. (1,2)
| 【1】 Ezawa, M.; Khanapure, S.P.; Garvey, D.S.; Young, D.; Earl, R.; Gaston, R.; Fang, F.; Marek, P.; Shumway, M.; Trocha, M.; Tam, S.W.; Janero, D.R.; Letts, L.G.; Design and synthesis of novel benzo-dioxolane cyclooxygenase (COX-2) selective inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 243. |
| 【2】 Earl, R.A.; Garvey, D.S.; Khanapure, S.P.; Gaston, R.D.; Fang, X.; Ezawa, M. (NitroMed Inc.); Substd. aryl cpds. as novel cyclooxygenase-2 selective inhibitors, compsns. and methods of use. US 2002119977; WO 0260378 . |
| 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) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 46376 | ethyl 3-(3-[2-[[(6-bromo-1,3-benzodioxol-5-yl)methyl](2-ethoxy-2-oxoacetyl)amino]phenyl]-3-oxopropyl)benzoate | C30H28BrNO8 | 详情 | 详情 | |
| (III) | 18561 | 4-(methylsulfanyl)phenylboronic acid | 98546-51-1 | C7H9BO2S | 详情 | 详情 |
| (IV) | 64023 | 6-[4-(methylsulfanyl)phenyl]-1,3-benzodioxole-5-carbaldehyde | C15H12O3S | 详情 | 详情 | |
| (V) | 35384 | bromo(3-fluorophenyl)magnesium | C6H4BrFMg | 详情 | 详情 | |
| (VI) | 64024 | (3-fluorophenyl){6-[4-(methylsulfanyl)phenyl]-1,3-benzodioxol-5-yl}methanol | C21H17FO3S | 详情 | 详情 | |
| (VII) | 64025 | (3-fluorophenyl){6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxol-5-yl}methanol | C21H17FO5S | 详情 | 详情 |