Triphenyl phosphite → HCID 178517779, compound

HRID 473196Notes

Reaction equation

HRID 473196 reaction equation
[F:1][C:2]([F:13])([C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3](O)=O.[NH2:14][C:15]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.Cl.[NH2:48]CCC(OCC)=O>N1C=CC=CC=1>[Cl:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:16]2[C:15]=1[N:14]=[C:3]([C:2]([F:13])([F:1])[C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[N:48]=[C:17]2[OH:18]

Participants

6

Reactant 4

HCID 7540Triphenyl phosphiteHCID 808072-Amino-3-chlorobenzoic acidHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 66608972HCID 66608972, compound

Product 1

HCID 178517779HCID 178517779, compoundYield 35.3%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
150 °C

Procedure

To 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetic acid (700 mg, 3.64 mmol) and 2-amino-3-chlorobenzoic acid (625 mg, 3.64 mmol) in pyridine (10 mL) was added triphenyl phosphite (1.05 mL, 4 mmol) and the mixture heated in a microwave synthesizer at 150° C. for 10 min. The mixture was allowed to cool to rt and then ethyl 3-aminopropanoate hydrochloride (615 mg, 4 mmol) was added. The mixture was heated in a microwave synthesizer at 190° C. for 4 min, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and 4 N HCl, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added THF (10 mL) followed by sodium ethoxide (21% in EtOH, 1 mL) and the mixture was stirred at 65° C. for 0.5 h. An additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added and the mixture was stirred at 60° C. for 30 min. The mixture was allowed to cool to rt, and then partitioned between EtOAc and 4 N HCl. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with hexanes and Et2O, and the solid was collected by filtration to afford 8-chloro-2-(difluoro(5-fluoropyrimidin-2-yl)methyl)quinazolin-4-ol (420 mg, 35%) as a tan solid. LC-MS (ESI) m/z 327 (M+H)+.

Workup

  1. temperatureto cool to rt
  2. temperatureThe mixture was heated in a microwave synthesizer at 190° C. for 4 min
  3. concentrationconcentrated under reduced pressure
  4. customThe residue was partitioned between EtOAc and 4 N HCl
  5. dry with materialthe organic layer was dried over sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. additionTo the residue was added THF (10 mL)
  8. additionAn additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added
  9. stirringthe mixture was stirred at 60° C. for 30 min
  10. temperatureto cool to rt
  11. custompartitioned between EtOAc and 4 N HCl
  12. dry with materialThe organic phase was dried over sodium sulfate
  13. concentrationconcentrated under reduced pressure
  14. customThe residue was triturated with hexanes and Et2O
  15. filtrationthe solid was collected by filtration

Sources & evidence

ORD record
ord-65f7036023d444dfb4b7e334be81942d
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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