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【结 构 式】 
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【分子编号】12518 【品名】ethyl (Z)-2-butyryl-3-(2-methoxyanilino)-2-propenoate 【CA登记号】 |
【 分 子 式 】C16H21NO4 【 分 子 量 】291.34708 【元素组成】C 65.96% H 7.27% N 4.81% O 21.97% |
合成路线1
该中间体在本合成路线中的序号：(III)The synthesis of SK&F 96067 can be achieved in five stages: Reaction of ethyl butyrylacetate with triethyl orthoformate and acetic anhydride gives ethyl 2-butyryl-3-ethoxyacrylate (II) as a mixture of (E)- and (Z)-isomers. Treatment of (II) with o-anisidine provides the acyclic quinolone precursor (III), which on thermal cyclization in diphenyl ether gives the quinolone (IV). Conversion to the 4-chloroquinoline (V) is achieved by treatment with phosphorus oxychloride. Reaction of the chloroquinoline (V) with o-toluidine gives SK&F 96067 (VI).
| 【1】 Ife, R.J.; Brown, T.H.; Leach, C.A. (SmithKline Beecham plc); 4-Amino-3-substituted quinolines as inhibitors of gastric acid secretion. AU 8778741; EP 0259174; JP 1989500664; US 4806549; US 4806550; WO 8801621 . |
| 【2】 Brown, T.H.; Reavill, D.R.; Wiggall, K.J.; Ife, R.J.; Keeling, D.J.; Leach, C.A.; Meeson, M.L.; Parsons, M.E.; Theobald, C.J.; Reversible inhibitors of the gastric (H+/K+)-ATPase. 3. 3-Substituted-4-phenylaminoquinolines. J Med Chem 1992, 35, 18, 3413. |
| 【3】 Ife, R.J.; SK&F-96067. Drugs Fut 1992, 17, 9, 796. |
| 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) | 12516 | ethyl 3-oxohexanoate; ethyl butyrylacetate | 3249-68-1 | C8H14O3 | 详情 | 详情 |
| (II) | 12517 | ethyl (E)-2-butyryl-3-ethoxy-2-propenoate | C11H18O4 | 详情 | 详情 | |
| (III) | 12518 | ethyl (Z)-2-butyryl-3-(2-methoxyanilino)-2-propenoate | C16H21NO4 | 详情 | 详情 | |
| (IV) | 12519 | 3-Butyryl-8-methoxy-4(1H)-quinolinone | C14H15NO3 | 详情 | 详情 | |
| (V) | 12520 | 1-(4-Chloro-8-methoxy-3-quinolinyl)-1-butanone | C14H14ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)This compound has been obtained by several related ways: 1) The reaction of ethyl butyrylacetate (I) with triethyl orthoformate and Ac2O gives acrylate (II), which by reaction with o-toluidine (III) yields the aminoacrylate (IV). The cyclization of (IV) by heating at 255 C in diphenyl ether affords the quinolone (V), which is treated with refluxing POCl3 to give 1-(4-chloro-8-methoxyquinolin-3-yl)-1-butanone (VI). The demethylation of (VI) with AlCl3 or BBr3 yields the 8-hydroxyquinoline (VII), which is condensed with o-toluidine (VIII) in refluxing dioxane affording 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX). Finally, this compound is condensed with 2-bromomethanol (X) by means of potassium tert-butoxide or with ethylene carbonate (XI) by means of K2CO3. 2) The condensation of chloroquinoline (VI) with o-toluidine (VIII) in refluxing dioxane gives 1-[8-methoxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (XII), which is demethylated with AlCl3 or BBr3 as before yielding the previously reported 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX).
| 【1】 Atkins, R.J.; et al.; Synthetic routes to quinoline derivatives: Novel syntheses of 3-butyryl-8-methoxy-4-[(2-methylphenyl)amini]quinoline and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quin. Org Process Res Dev 1997, 1, 3, 185. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 | |
| (I) | 12516 | ethyl 3-oxohexanoate; ethyl butyrylacetate | 3249-68-1 | C8H14O3 | 详情 | 详情 |
| (II) | 12517 | ethyl (E)-2-butyryl-3-ethoxy-2-propenoate | C11H18O4 | 详情 | 详情 | |
| (III) | 25193 | 2-methoxyphenylamine; 2-methoxyaniline | 517-28-2 | C7H9NO | 详情 | 详情 |
| (IV) | 12518 | ethyl (Z)-2-butyryl-3-(2-methoxyanilino)-2-propenoate | C16H21NO4 | 详情 | 详情 | |
| (V) | 12519 | 3-Butyryl-8-methoxy-4(1H)-quinolinone | C14H15NO3 | 详情 | 详情 | |
| (VI) | 12520 | 1-(4-Chloro-8-methoxy-3-quinolinyl)-1-butanone | C14H14ClNO2 | 详情 | 详情 | |
| (VII) | 32800 | 1-(4-chloro-8-hydroxy-3-quinolinyl)-1-butanone | C13H12ClNO2 | 详情 | 详情 | |
| (VIII) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (IX) | 32801 | 1-[8-hydroxy-4-(2-toluidino)-3-quinolinyl]-1-butanone | C20H20N2O2 | 详情 | 详情 | |
| (X) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (XI) | 32802 | 1,3-dioxolan-2-one | 96-49-1 | C3H4O3 | 详情 | 详情 |
| (XII) | 32799 | 1-[8-methoxy-4-(2-toluidino)-3-quinolinyl]-1-butanone | C21H22N2O2 | 详情 | 详情 |