[NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]([CH:19]1[CH2:24][CH2:23]O[C:20]1=[O:21])(=O)[CH3:17].P(Cl)(Cl)([Cl:27])=O.[OH-].[NH4+]>C1(C)C=CC=CC=1>[Cl:27][CH2:23][CH2:24][C:19]1[C:20](=[O:21])[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:2]2=[N:1][C:16]=1[CH3:17]Previously known processes for producing paliperidone have low yields and produce large amounts of HCl gas as a by-product. In U.S. Pat. No. 5,158,952 (its European counterpart is EP0368388), a process is disclosed wherein 2-amino-3-benzyloxypyridine (I′) was reacted with 1.7 mole equivalents 2-acetyl-4-butyrolactone in the presence of 5.5 mole equivalents phosphoryl chloride in toluene. The reaction mixture was stirred for 5 hours at 90° C. Another 1.7 mole equivalents of 2-acetyl-4-butyrolactone were then added and the stirring was continued for 30 minutes at 90° C. The solution was allowed to stand overnight at 90° C. The whole was poured into crushed ice and treated with an ammonium hydroxide solution 25%. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2-propanol. The product was filtered off, washed with a mixture of 2-propanol and 1,1′-oxybisethane and dried at 50° C., yielding 20.5 mole equivalents (Yield: 62.3%) of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 141.1° C. See the scheme shown below.
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