2,4-Dichloro-5-fluoropyrimidine → 6-((2-Chloro-5-fluoro-4-pyrimidinyl)amino)-2,2-dimethyl-2H-pyrido(3,2-b)-1,4-oxazin-3(4H)-one

HRID 1051977Notes

Reaction equation

HRID 1051977 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1>CO.O.ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9][C:10]=3[N:11]=2)[C:19]([F:23])=[CH:18][N:17]=1

Participants

6

Reactant 2

HCID 2507052,4-Dichloro-5-fluoropyrimidine2×HCID 454804022H-Pyrido(3,2-b)-1,4-oxazin-3(4H)-one, 6-amino-2,2-dimethyl-

Product 1

HCID 575629316-((2-Chloro-5-fluoro-4-pyrimidinyl)amino)-2,2-dimethyl-2H-pyrido(3,2-b)-1,4-oxazin-3(4H)-oneYield 77%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
65 °C

Procedure

6-amino-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (450 kg, 1.00 mol eq) is stirred in a mixture of methanol (1971 kg) and water (1610 kg) under a nitrogen atmosphere with heating to about 65° C. To this is added a solution of 2,4-dichloro-5-fluoro-pyrimidine in dichloromethane (545 kg 2,4-dichloro-5-fluoro-pyrimidine, 1.40 mol eq, about 50% w/w solution) over a period of about 4 hours, during which dichloromethane is distilled off. The mixture is then stirred at about 70° C. until distillation is complete and then at reflux for about 15 hours. This is then cooled to about 45° C. and filtered. The filtered solid is washed twice with methanol (2×675 kg) and then dried under vacuum at about 55° C. Once dry, the solid is slurried in 85% w/w aqueous formic acid (3150 kg) at about 50° C. for about 6 hours and then filtered. This slurry may be repeated. The resulting damp solid is cooled to about 20° C., washed twice with methanol (2×1800 kg) and dried under vacuum at about 80° C. to give the title compound (577 kg, 77%) as a colored solid.

Workup

  1. distillationduring which dichloromethane is distilled off
  2. temperatureat reflux for about 15 hours
  3. temperatureThis is then cooled to about 45° C.
  4. filtrationfiltered
  5. washThe filtered solid is washed twice with methanol (2×675 kg)
  6. customdried under vacuum at about 55° C
  7. customOnce dry
  8. waitthe solid is slurried in 85% w/w aqueous formic acid (3150 kg) at about 50° C. for about 6 hours
  9. filtrationfiltered
  10. temperatureThe resulting damp solid is cooled to about 20° C.
  11. washwashed twice with methanol (2×1800 kg)
  12. customdried under vacuum at about 80° C.

Sources & evidence

ORD record
ord-c4af1a6be7a048419829d96a5f6c060e
Source dataset
uspto-grants-2016_07
Patent number
US09388203B2

Reaction notes

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