Rebamipide, Pramipide, Proamipide, OPC-12759, Mucosta, -Drug Synthesis Database

【结构式】

【药物名称】Rebamipide, Pramipide, Proamipide, OPC-12759, Mucosta

【化学名称】(±)-N-(4-Chlorobenzoyl)-3-(2-oxo-1,2-dihydro-4-quinolyl)alanine
　　　　　　(±)-2-(4-Chlorobenzamido)-3-(1,2-dihydro-2-oxo-4-quinolyl)propionic acid

【CA登记号】111911-87-6, 90098-04-7 (undefined stereoch.)

【分子式】C₁₉H₁₅ClN₂O₄

【分子量】370.7954

【开发单位】Otsuka (Originator)

【药理作用】Antiulcer Drugs, GASTROINTESTINAL DRUGS

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

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.

参考文献中间体

【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

2) The same reaction sequence of (I) and (IVr) yields intermediates (Vs), (VIs) and (VIIs), and finally (S)-OPC-12759.

参考文献中间体

【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
(IVR)	10296	(R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (3R)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; (2R)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine	109838-85-9	C₉H₁₆N₂O₂	详情	详情
(VS)	10297	2-Chloro-4-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl]methyl]quinoline; (3R,6S)-6-[(2-Chloro-4-quinolinyl)methyl]-3-isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether		C₁₉H₂₂ClN₃O₂	详情	详情
(VIS)	10298	methyl (2S)-2-amino-3-(2-chloro-4-quinolinyl)propanoate		C₁₃H₁₃ClN₂O₂	详情	详情
(VIIS)	10299	(2S)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid		C₁₂H₁₂N₂O₃	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3

3) The methylation of 3-(2-oxo-1,2-dihydroquinolin-4-yl)-(R,S)-alanine (IX) with SOCl2 and methanol yields the corresponding methyl ester (X), which is submitted to optical resolution with D-(-)-mandelic acid, affording adducts (XII) and (XIII). The hydrolytic treatment of (XII) and (XIII) with HCl and propylene oxide finally yields isomers (VIIr) and (VIIs), already obtained. Racemic OPC-12759 can also be resolved into its optical isomers by treatment with brucine and fractionated crystallization.

参考文献中间体

【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
(VII-S)	10299	(2S)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid		C₁₂H₁₂N₂O₃	详情	详情
(VIIR)	10306	(2R)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid		C₁₂H₁₂N₂O₃	详情	详情
(IX)	10301	2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid		C₁₂H₁₂N₂O₃	详情	详情
(X)	10302	methyl 2-amino-3-(2-chloro-4-quinolinyl)propanoate		C₁₃H₁₃ClN₂O₂	详情	详情
(XI)	10303	(2R)-2-Hydroxy-2-phenylethanoic acid; R-(-)-Mandelic acid	611-71-2	C₈H₈O₃	详情	详情
(XII)	10304	compound with hydroxy-phenyl-acetic acid; 2-Amino-3-(2-oxo-1,2-dihydro-quinolin-4-yl)-propionic acid methyl ester		C₁₃H₁₄N₂O₃.C₈H₈O₃	详情	详情
(XIII)	10305	2-Amino-3-(2-oxo-1,2-dihydro-quinolin-4-yl)-propionic acid methyl ester; compound with hydroxy-phenyl-acetic acid		C₁₃H₁₄N₂O₃.C₈H₈O₃	详情	详情

合成路线4

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.

参考文献中间体

【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

Extended Information