【结 构 式】 |
【分子编号】10288 【品名】4-(Bromomethyl)-2(1H)-quinolinone 【CA登记号】 |
【 分 子 式 】C10H8BrNO 【 分 子 量 】238.08366 【元素组成】C 50.45% H 3.39% Br 33.56% N 5.88% O 6.72% |
合成路线1
该中间体在本合成路线中的序号:(I)The synthesis of (R)- and (S)-isomers of OPC-12759 has been described: These optical isomers can be obtained in three different ways: 1) The reaction of 4-(bromomethyl)quinolin-2(1H)-one (I) with hot phosphorus oxychloride gives a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III), which, without separation, is condensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) by means of butyllithium in hexane, yielding (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr). The hydrolysis of (Vr) with HCl affords 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr), which is treated with HCl and propylene oxide to give 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr). Finally, this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K2CO3 in acetone, affording (R)-OPC-12759.
【1】 Morita, S.; Yamasaki, K.; Shimizu, T.; Uchida, M.; Otsubo, K.; Kanbe, T.; Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide). Chem Pharm Bull 1991, 39, 11, 2906. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IVS) | 10291 | (S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (2S)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine; (3S)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether | 78342-42-4 | C9H16N2O2 | 详情 | 详情 |
(VR) | 10292 | (3R,6S)-3-[(2-Chloro-4-quinolinyl)methyl]-6-isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; 2-Chloro-4-[[(2R,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl]methyl]quinoline | C19H22ClN3O2 | 详情 | 详情 | |
(VIR) | 10293 | methyl (2R)-2-amino-3-(2-chloro-4-quinolinyl)propanoate | C13H13ClN2O2 | 详情 | 详情 | |
(VIIR) | 10294 | (2R)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid | C12H12N2O3 | 详情 | 详情 | |
(I) | 10288 | 4-(Bromomethyl)-2(1H)-quinolinone | C10H8BrNO | 详情 | 详情 | |
(II) | 10289 | 4-(Bromomethyl)-2-chloroquinoline | C10H7BrClN | 详情 | 详情 | |
(III) | 10290 | 2-Chloro-4-(chloromethyl)quinoline | C10H7Cl2N | 详情 | 详情 | |
(VIII) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 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 condensation of 4-(bromomethyl)quinolin-2(1H)-one (I) with diethyl acetamidomalonate (II) by means of sodium ethoxide in refluxing ethanol gives ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4yl)propionate (III), which is submitted to a decarboxylative hydrolysis with refluxing 20% HCl yielding 3-(2-oxo-1,2-dihydroquinolin-4yl)alanine (IV). Finaily this compound is acylated with 4-chlorobenzoyl chloride by means of K2CO3 in acetone water.
【1】 Kanbe, T.; Nakagawa, K.; Morita, S.; Uchida, M.; Komatsu, M.; Tabusa, F.; Studies on 2(1H)-quinolinone derivatives as gastri. Chem Pharm Bull 1985, 33, 9, 3775. |
【2】 Uchida, M.; Komatsu, M.; Nakagawa, K. (Otsuka Pharmaceutical Co., Ltd.); Carbostyril derivs., process for their preparation. DE 3324034; US 4578381 . |
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) | 10288 | 4-(Bromomethyl)-2(1H)-quinolinone | C10H8BrNO | 详情 | 详情 | |
(II) | 16710 | Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate | 1068-90-2 | C9H15NO5 | 详情 | 详情 |
(III) | 23536 | diethyl 2-(acetamido)-2-[(2-oxo-1,2-dihydro-4-quinolinyl)methyl]malonate | C19H22N2O6 | 详情 | 详情 | |
(IV) | 10301 | 2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid | C12H12N2O3 | 详情 | 详情 | |
(V) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |