Diisopropylamine → Paliperidone

HRID 467001Notes

Reaction equation

HRID 467001 reaction equation
Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][CH:5]=1.Cl.[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.[CH3:33]C(NC(C)C)C>CO>[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]5=[N:6][C:5]=4[CH3:33])[CH2:29][CH2:30]3)=[N:23][O:24][C:20]=2[CH:19]=1

Participants

5

Reactant 3

HCID 7912DiisopropylamineHCID 11334359R-56109 hydrochlorideHCID 18372420HCID 18372420, compound

Product 1

HCID 115237PaliperidoneYield 21.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 12.5 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, 10.0 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride, 10 parts of N-(1-methylethyl)-2-propanamine and 120 parts of methanol was stirred overnight at 60° C. The reaction mixture was evaporated and the oily residue was taken up in trichloromethane and washed with water. The organic layer was dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel first using a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluents. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. After cooling, the precipitated product was filtered off, washed with a mixture of 2-propanol and 2,2'-oxybispropane and recrystallized from 2-propanol. The product was filtered off and dried, yielding 3.6 parts (21.1%) of 3-[ 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin4-one; mp. 179.8° C. (Compound 1)

Workup

  1. customThe reaction mixture was evaporated
  2. washwashed with water
  3. customThe organic layer was dried
  4. filtrationfiltered
  5. customevaporated
  6. customThe residue was purified twice by column chromatography over silica gel
  7. additiona mixture of trichloromethane and methanol (95:5 by volume)
  8. additiona mixture of trichloromethane and methanol
  9. customThe pure fractions were collected
  10. customthe eluent was evaporated
  11. customThe residue was crystallized from 2-propanone
  12. temperatureAfter cooling
  13. filtrationthe precipitated product was filtered off
  14. washwashed with a mixture of 2-propanol and 2,2'-oxybispropane
  15. customrecrystallized from 2-propanol
  16. filtrationThe product was filtered off
  17. customdried

Sources & evidence

ORD record
ord-38f59ec68ba544cbafdfe3b45a4804d4
Source dataset
uspto-grants-1992_10
Patent number
US05158952

Reaction notes

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