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【结 构 式】 
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【分子编号】43471 【品名】ethyl 3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)propanoate 【CA登记号】 |
【 分 子 式 】C16H23NO2 【 分 子 量 】261.36416 【元素组成】C 73.53% H 8.87% N 5.36% O 12.24% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)2-Aminobenzonitrile (XV) was acylated with 2-bromoisobutyryl bromide (XVI) to afford the cyano amide (XVII). Halogen-metal exchange with ethylmagnesium bromide followed by intramolecular addition to the cyano group of (XVII) gave rise to the quinoline dione (XVIII). This was reduced to the tetrahydroquinoline (XIX) by means of LiAlH4 and AlCl3. Iodination of (XIX) with benzyltrimethylammonium iodine dichloride furnished (XX), which was coupled with ethyl acrylate (XXI) in the presence of palladium acetate, yielding the unsaturated ester (XXII). After catalytic hydrogenation of the olefin (XXII) to propionyl ester (XXIII), sulfonation and treatment with POCl3, intermediate sulfonyl chloride (XXIV) was obtained.
| 【1】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 19493 | 2-aminobenzonitrile | 1885-29-6 | C7H6N2 | 详情 | 详情 |
| (XVI) | 19367 | 2-bromo-2-methylpropanoyl bromide | 20769-85-1 | C4H6Br2O | 详情 | 详情 |
| (XVII) | 43466 | 2-bromo-N-(2-cyanophenyl)-2-methylpropanamide | C11H11BrN2O | 详情 | 详情 | |
| (XVIII) | 43467 | 3,3-dimethyl-2,4(1H,3H)-quinolinedione | C11H11NO2 | 详情 | 详情 | |
| (XIX) | 43468 | 3,3-dimethyl-1,2,3,4-tetrahydroquinoline | C11H15N | 详情 | 详情 | |
| (XX) | 43469 | 6-iodo-3,3-dimethyl-1,2,3,4-tetrahydroquinoline | C11H14IN | 详情 | 详情 | |
| (XXI) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XXII) | 43470 | ethyl (E)-3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-propenoate | C16H21NO2 | 详情 | 详情 | |
| (XXIII) | 43471 | ethyl 3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)propanoate | C16H23NO2 | 详情 | 详情 | |
| (XXIV) | 43472 | ethyl 3-[8-(chlorosulfonyl)-3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl]propanoate | C16H22ClNO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIII)An alternative procedure for the preparation of tetrahydroquinoline (XXIII) consisted in the acylation of ethyl 4-aminocinnamate (XXV) with the in situ prepared dimethylmalonyl chloride (to give (XXVI)), followed by cyclization to the quinoline dione (XXVII) by means of phosphorus pentoxide and methanesulfonic acid. The hydrogenation of the double bond of (XXVII) and simultaneous reduction of the keto group produced quinolinone (XXVIII). Further reduction of the lactam carbonyl group of (XXVIII) to provide (XXIII) was carried out via conversion to thiolactam (XXIX), which was alkylated with iodomethane to the S-methyl thioimidate (XXX) and then reduced with NaBH3CN.
| 【1】 Hayler, J.; LeGrand, D.; Kane, P.D.; et al.; The design and synthesis of thrombin inhibitors: The introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors. Bioorg Med Chem Lett 2000, 10, 14, 1567. |
| 【2】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 43477 | ethyl 3-(3,3-dimethyl-2-thioxo-1,2,3,4-tetrahydro-6-quinolinyl)propanoate | C16H21NO2S | 详情 | 详情 | |
| (XXIII) | 43471 | ethyl 3-(3,3-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)propanoate | C16H23NO2 | 详情 | 详情 | |
| (XXV) | 43473 | ethyl (E)-3-(4-aminophenyl)-2-propenoate | 5048-82-8 | C11H13NO2 | 详情 | 详情 |
| (XXVI) | 43474 | 3-[4-[(E)-3-ethoxy-3-oxo-1-propenyl]anilino]-2,2-dimethyl-3-oxopropionic acid | C16H19NO5 | 详情 | 详情 | |
| (XXVII) | 43475 | ethyl (E)-3-(3,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-propenoate | C16H17NO4 | 详情 | 详情 | |
| (XXVIII) | 43476 | ethyl 3-(3,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)propanoate | C16H21NO3 | 详情 | 详情 | |
| (XXX) | 43478 | ethyl 3-[3,3-dimethyl-2-(methylsulfanyl)-3,4-dihydro-6-quinolinyl]propanoate | C17H23NO2S | 详情 | 详情 |