Oxalic Acid → 3-Hydroxy-2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate

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Reaction Steps

A solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (12.3 g) in toluene (20 cc) is added to a solution of 2-(3-bromopropyl)-3-hydroxy-1-isoindolinone (18.9 g) in toluene (200 cc), at a temperature close to 20° C. and in the course of 10 minutes, followed by a solution of triethylamine (9.8 cc) in toluene (20 cc). The mixture is agitated at a temperature close to 111° C. for 3 hours. After cooling to a temperature close to 20° C, the precipitate formed is separated by filtration and washed with toluene (3×50 cc). The organic phases are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C. The residue obtained is dissolved in methylene chloride (50 cc) and the solution poured onto silica (1 kg) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (98-2 by volume). The first 4000 cc are eliminated and the next 4000 cc are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in methyl ethyl ketone (70 cc). A solution of oxalic acid (1.6 g) in methyl ethyl ketone (20 cc) is added, and agitation is maintained for about 1 hour. The precipitate formed is separated by filtration, washed with methyl ethyl ketone (20 cc), and then recrystallized from a boiling mixture of isopropanol and isopropyl ether (75-25 by volume,150 cc). 4.8 g of 3-hydroxy-2-[3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are obtained, melting at 93° C.

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