Potassium Carbonate → Paliperidone

HRID 2175048Notes

Reaction equation

HRID 2175048 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+].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

6

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 77.4%

Reagents, catalysts & solvents 2

HCID 4875Potassium IodideCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
65 °C

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 for 5 minutes and 20.0 g of potassium carbonate and 0.7 g of potassium iodide were charged. Further, 0.2 g of butylated hydroxytoluene 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 at 30-35° C., 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 (27 g, yield: 135% w/w, efficiency: 76.6%, keto impurity by HPLC: 0.03%, total impurity level by HPLC: 1.0%)

Workup

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

Sources & evidence

ORD record
ord-9f3913359100420f8aac4593e0e3ef11
Source dataset
uspto-grants-2015_06
Patent number
US09062049B2

Reaction notes

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