Potassium Carbonate → Paliperidone

HRID 2175047Notes

Reaction equation

HRID 2175047 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][C:5]=1[CH3:16].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].[BH4-].[Na+].C(#N)C>[CH3:16][C:5]1[N:6]=[C:7]2[N:8]([CH2:11][CH2:12][CH2:13][CH:14]2[OH:15])[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:29]1[CH2:28][CH2:27][CH:26]([C:23]2[C:22]3[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=3[O:25][N:24]=2)[CH2:31][CH2:30]1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 11334359R-56109 hydrochlorideHCID 155471943-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Product 1

HCID 115237PaliperidoneYield 86%

Reagents, catalysts & solvents 3

HCID 4875Potassium IodideCatalystHCID 4311764Sodium borohydrideCatalystHCID 6342AcetonitrileSolvent

Procedure

300 ml of acetonitrile was charged followed by 20.0 g of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin-4-one and 21.0 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride at room temperature. The reaction mass was stirred at room temperature for 5 minutes and 20.0 g of potassium carbonate and 0.7 g of potassium iodide were charged. Further, 0.2 g of sodium borohydride was charged and the temperature was raised to 65±2° C. The reaction mass was maintained at 65±2° C. for 25 hours. After reaction completion, the reaction mass was slowly cooled to room temperature. The solids were filtered, washed with 50 ml of acetonitrile and then dissolved in 800 ml of methylene chloride at room temperature. The contents were heated to 30-35° C., maintained for 10 minutes, filtered and washed with 20 ml of methylene chloride. The clear filtrate was distilled completely under vacuum below 35° C. and replaced with 50 ml of acetone. Further, 300 ml of acetone was charged, heated to 45° C. and stirred for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour. The product was filtered, washed with 20 ml of acetone and dried under vacuum at 50-55° C. to yield paliperidone (30 g, yield: 150% w/w, efficiency: 85.11%, keto impurity by HPLC: 0.01%, total impurity level by HPLC: 1.0%)

Workup

  1. temperaturethe temperature was raised to 65±2° C
  2. temperatureThe reaction mass was maintained at 65±2° C. for 25 hours
  3. customAfter reaction completion
  4. temperaturethe reaction mass was slowly cooled to room temperature
  5. filtrationThe solids were filtered
  6. washwashed with 50 ml of acetonitrile
  7. dissolutiondissolved in 800 ml of methylene chloride at room temperature
  8. temperatureThe contents were heated to 30-35° C.
  9. temperaturemaintained for 10 minutes
  10. filtrationfiltered
  11. washwashed with 20 ml of methylene chloride
  12. distillationThe clear filtrate was distilled completely under vacuum below 35° C.
  13. additionFurther, 300 ml of acetone was charged
  14. temperatureheated to 45° C.
  15. stirringstirred for 30 minutes
  16. temperatureThe reaction mass was cooled to room temperature
  17. stirringstirred for 1 hour
  18. filtrationThe product was filtered
  19. washwashed with 20 ml of acetone
  20. customdried under vacuum at 50-55° C.

Sources & evidence

ORD record
ord-1484c14c8cf3416fa2ac63717a96caf7
Source dataset
uspto-grants-2015_06
Patent number
US09062049B2

Reaction notes

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