Tolcapone, Ro-40-7592, Tasmar
托卡朋Chemical Name: 3,4-Dihydroxy-4'-methyl-5-nitrobenzophenone
CAS No. 134308-13-7
项目整合开发状态: Launched-1998
项目研究机构: Chugai (Originator), Roche (Originator), Bristol-Myers Squibb (Licensee), Valeant (Licensee)
合成路线:The bromination of 5-fluoro-2-methylquinoline (I) with Br2 and Ag2SO4 in H2SO4 or with Br2 and AlCl3 gives 5-bromo-6-fluoro-2-methylquinoline (II),which is reduced with H2 over PtO2 in acetic acid,yielding 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (III).The cyclization of (III) with diethyl ethoxymethylenemalonate (IV) and polyphosphoric acid (PPA) at 150 C affords 8-bromo-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (V),which is finally condensed with 4-hydroxypiperidine (VI) by heating at 160 C in HMPT.
合成路线:The synthesis of Ro 40-7592 is carried out as follows:Addition of 4-bromotoluene (I) to 4-(benzyloxy)-3-methoxybenzaldehyde (II) in the presence of butyllithium in THF at -78 C gives 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol (III).Oxidation of this compound with pyridinium chlorochromate in CH2Cl2 yields the corresponding 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone (IV).Debenzylation of (IV) with 30% aqueous hydrobromic acid in acetic acid affords 4-hydroxy-3-methoxy-4'-methylbenzophenone (V).Regioselective nitration of (V) with 65% aqueous nitric acid in acetic acid gives 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone (VI).Hydrolysis of the methoxy group in (VI) with 30% aqueous hydrobromic acid in boiling acetic acid affords 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone,Ro 40-7592.
📌 参考资料/链接：
参考文献标题:3,5-Disubstituted pyrocatechol derivs
文献作者:Bernauer,K.; Borgulya,J.; Bruderer,H.; Da Prada,M.; Zurcher,G.(F.Hoffmann-La Roche AG)
参考来源:EP 0237929; US 5389653; US 5476875
📄 详细内容
合成路线:The synthesis of Ro 40-7592 is carried out as follows:Addition of 4-bromotoluene (I) to 4-(benzyloxy)-3-methoxybenzaldehyde (II) in the presence of butyllithium in THF at -78 C gives 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol (III).Oxidation of this compound with pyridinium chlorochromate in CH2Cl2 yields the corresponding 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone (IV).Debenzylation of (IV) with 30% aqueous hydrobromic acid in acetic acid affords 4-hydroxy-3-methoxy-4'-methylbenzophenone (V).Regioselective nitration of (V) with 65% aqueous nitric acid in acetic acid gives 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone (VI).Hydrolysis of the methoxy group in (VI) with 30% aqueous hydrobromic acid in boiling acetic acid affords 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone,Ro 40-7592.
参考文献标题:Ro 40-7592
文献作者:Scherschlicht,R.; Schl鋚pi,B.; Borgulya,J.; Dingemanse,J.; Da Prada,M.; Z黵cher,G.
参考来源:Drugs Fut 1991,16(8),719
合成路线:The synthesis of Ro 40-7592 is carried out as follows:Addition of 4-bromotoluene (I) to 4-(benzyloxy)-3-methoxybenzaldehyde (II) in the presence of butyllithium in THF at -78 C gives 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol (III).Oxidation of this compound with pyridinium chlorochromate in CH2Cl2 yields the corresponding 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone (IV).Debenzylation of (IV) with 30% aqueous hydrobromic acid in acetic acid affords 4-hydroxy-3-methoxy-4'-methylbenzophenone (V).Regioselective nitration of (V) with 65% aqueous nitric acid in acetic acid gives 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone (VI).Hydrolysis of the methoxy group in (VI) with 30% aqueous hydrobromic acid in boiling acetic acid affords 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone,Ro 40-7592.
参考文献标题:Catechol-O-methyltransferase-inhibiting pyrocatechol derivatives: Synthesis and structure-activity studies
文献作者:Z黵cher,G.; Da Prada,M.; Borgulya,J.; Bernauer,K.; Bruderer,H.
参考来源:Helv Chim Acta 1989,72952-68
产品链接: CAS No. 134308-13-7››