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

HRID 429938Notes

Reaction equation

HRID 429938 reaction equation
P(Cl)(Cl)([Cl:3])=O.[C:6]1([CH2:12][O:13][C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([CH:24]1[CH2:28][CH2:27][O:26][C:25]1=O)(=O)[CH3:22].[OH-].[NH4+]>CC1C=CC=CC=1>[Cl:3][CH2:27][CH2:28][C:24]1[C:25](=[O:26])[N:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:15]2=[N:20][C:21]=1[CH3:22]

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
50 °C

Procedure

To a stirred mixture of 84 parts of phosphoryl chloride and 540 parts of methylbenzene were added 20 parts of 3-(phenylmethoxy)-2-pyridinamine. The mixture was stirred at 50° C. and 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone were added. The reaction mixture was stirred for 5 hours at 90° C. Another portion of 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone was added and 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 parts (62.3%) of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 141.1° C. (intermediate 1) b) A mixture of 3.3 parts of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2.0 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry, yielding 2.4 parts (99%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as an oily residue. (intermediate 2)

Workup

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

Sources & evidence

ORD record
ord-60849242095a4e01abed225e775f22a0
Source dataset
uspto-grants-2001_11
Patent number
US06320048B1

Reaction notes

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