2-Acetylbutyrolactone → 9-(Benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

HRID 1866769Notes

Reaction equation

HRID 1866769 reaction equation
[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]

Participants

6

Reactant 4

HCID 106012-Acetylbutyrolactone2×HCID 14923Ammonium HydroxideHCID 24813Phosphorus oxychlorideHCID 903342-Amino-3-benzyloxypyridine

Product 1

HCID 183536429-(Benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneYield 62.3%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

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.

Workup

  1. waitthe stirring was continued for 30 minutes at 90° C
  2. waitto stand overnight at 90° C
  3. additionThe whole was poured
  4. custominto crushed ice
  5. extractionThe product was extracted with trichloromethane
  6. customThe extract was dried
  7. filtrationfiltered
  8. customevaporated
  9. customThe residue was purified by column chromatography over silica gel using
  10. additiona mixture of trichloromethane and methanol (98:2 by volume) as eluent
  11. customThe pure fractions were collected
  12. customthe eluent was evaporated
  13. stirringThe residue was stirred in 2-propanol
  14. filtrationThe product was filtered off
  15. washwashed with a mixture of 2-propanol and 1,1′-oxybisethane
  16. customdried at 50° C.

Sources & evidence

ORD record
ord-73790518b05843da9bf60a663555ea9c
Source dataset
uspto-grants-2009_12
Patent number
US07629469B2

Reaction notes

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