Phosgene → Carprazidil

HRID 464776Notes

Reaction equation

HRID 464776 reaction equation
[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([N:14]2[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]2)[N:3]=1.[C:20](Cl)(Cl)=[O:21].[OH-].[Na+].S(=O)(=O)(O)[O-].[K+]>C(Cl)Cl.C1(C)C=CC=CC=1.C(N(CC)CC)C>[N:14]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[N:7]3[O:8][C:20](=[O:21])[N:1]=[C:2]3[N:3]=2)[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]1

Participants

8

Reactant 4

HCID 6371PhosgeneHCID 14798Sodium HydroxideHCID 516920Potassium bisulfateHCID 178501990HCID 178501990, compound

Product 1

HCID 68875Carprazidil

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Procedure

35 ml of triethylamine are added to a suspension of 13.3 g (0.05 mol) of methyl 2-amino-6-[(3,6-dihydro-1(2H)-pyridyl)]-4-pyrimidinecarbamate-3-oxide in 600 ml of methylene chloride. After cooling to -20°, 32.5 ml (0.06 mol) of a 20% solution of phosgene in toluene are added dropwise within 2 minutes. After 10 minutes, the mixture is treated with 100 ml of 1N sodium hydroxide. The organic phase is separated and extracted with 1N sodium hydroxide. The aqueous extracts are acidified with 25% hydrochloric acid and the milky suspension is extracted with methylene chloride/methanol (95:5). The organic extracts are dried over sodium sulfate and evaporated under reduced pressure. 90 ml of acetonitrile are added to the residue. 5.6 g of dicyclohexylamine are added at 45° to the suspension obtained and the mixture is stirred at this temperature for a further 4 hours. The crystalline precipitate is filtered off under suction, washed with acetonitrile, carefully sucked dry and added to 180 ml of water. The suspension obtained is acidified to pH 3 with a solution of potassium bisulfate and stirred for a further 0.75 hour. After cooling to 0°, the precipitate is filtered off under suction, washed with water and dried at 60° under reduced pressure. After recrystallization from a mixture of methylene chloride/methanol/ether, there is obtained methyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo-[2,3-a]pyrimidine-7-carbamate of melting point 216°-218°.

Workup

  1. temperatureAfter cooling to -20°
  2. customThe organic phase is separated
  3. extractionextracted with 1N sodium hydroxide
  4. extractionthe milky suspension is extracted with methylene chloride/methanol (95:5)
  5. dry with materialThe organic extracts are dried over sodium sulfate
  6. customevaporated under reduced pressure
  7. addition90 ml of acetonitrile are added to the residue
  8. addition5.6 g of dicyclohexylamine are added at 45° to the suspension
  9. customobtained
  10. filtrationThe crystalline precipitate is filtered off under suction
  11. washwashed with acetonitrile
  12. customcarefully sucked dry
  13. additionadded to 180 ml of water
  14. customThe suspension obtained
  15. stirringstirred for a further 0.75 hour
  16. temperatureAfter cooling to 0°
  17. filtrationthe precipitate is filtered off under suction
  18. washwashed with water
  19. customdried at 60° under reduced pressure
  20. customAfter recrystallization
  21. additionfrom a mixture of methylene chloride/methanol/ether

Sources & evidence

ORD record
ord-baa78eb387dc40d2b2924be4d9290b2e
Source dataset
uspto-grants-1985_10
Patent number
US04549019

Reaction notes

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