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.
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.