Diisopropylethylamine → Paliperidone

HRID 448539Notes

Reaction equation

HRID 448539 reaction equation
[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][C:20]1[C:25](=[O:26])[N:24]2[CH2:27][CH2:28][CH2:29][CH:30]([OH:31])[C:23]2=[N:22][C:21]=1[CH3:32].C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>CO.ClCCl>[CH3:32][C:21]1[N:22]=[C:23]2[N:24]([CH2:27][CH2:28][CH2:29][CH:30]2[OH:31])[C:25](=[O:26])[C:20]=1[CH2:19][CH2:18][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 8494213-(4-Piperidyl)-6-fluoro-1,2-benzisoxazoleHCID 4311764Sodium borohydrideHCID 155471943-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Product 1

HCID 115237Paliperidone

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
67.5 °C

Procedure

To the solution of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (formula-8) (10.0 grams) in methanol (50 ml), 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-7) (11 grams) and diisopropyl ethyl amine (9 grams) were added. The reaction mixture heated to 65-70° C. and stirred for 24 hrs at the same temperature. The reaction mixture was cooled. Dichloromethane (100 ml) and sodium borohydride (0.086 grams) were added to it and stirred for 60 minutes at the same temperature. The solvent was distilled off under reduced temperature. Methanol was added to the residue and heated to reflux for 30 min. The reaction mixture was cooled to 20° C. and stirred for 1 hour. Filtered the solid precipitated. Washed the solid with chilled methanol and dried the compound.

Workup

  1. temperatureThe reaction mixture was cooled
  2. stirringstirred for 60 minutes at the same temperature
  3. distillationThe solvent was distilled off
  4. additionMethanol was added to the residue
  5. temperatureheated
  6. temperatureto reflux for 30 min
  7. temperatureThe reaction mixture was cooled to 20° C.
  8. stirringstirred for 1 hour
  9. filtrationFiltered the solid
  10. customprecipitated
  11. washWashed the solid with chilled methanol
  12. customdried the compound

Sources & evidence

ORD record
ord-88344ff4cb9e4ce09d684bb0409c3f85
Source dataset
uspto-grants-2013_07
Patent number
US08481729B2

Reaction notes

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