Triphenyl phosphite → HCID 178517776, compound

HRID 473180Notes

Reaction equation

HRID 473180 reaction equation
[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3](O)=O.[NH2:14][C:15]1[C:23]([C:24]([F:27])([F:26])[F:25])=[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.[NH2:51]CCC(OCC)=O>N1C=CC=CC=1>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[N:51]=[C:17]([OH:18])[C:16]2[C:15](=[C:23]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:21][CH:20]=2)[N:14]=1

Participants

6

Reactant 4

HCID 7540Triphenyl phosphiteHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 6045692-Amino-3-(trifluoromethyl)benzoic acidHCID 666095532,2-Difluoro-2-(5-fluoropyridin-2-yl)acetic acid

Product 1

HCID 178517776HCID 178517776, compoundYield 43.3%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
150 °C

Procedure

To 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid (172 mg, 0.9 mmol) and 2-amino-3-(trifluoromethyl)benzoic acid (185 mg, 0.9 mmol) in pyridine (3 mL) was added triphenyl phosphite (0.26 mL, 1 mmol) and the mixture was heated in a microwave synthesizer at 150° C. for 10 min. The mixture was cooled to rt and then ethyl 3-aminopropanoate hydrochloride (156 mg, 1 mmol) was added and the mixture was heated in a microwave synthesizer at 180° C. for 3 min. The crude mixture was concentrated under reduced pressure. THF (6 mL) was added followed by sodium ethoxide (21% in EtOH, 1.2 mL) and the mixture was stirred at 50° C. for 1 h. An additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added and the mixture was stirred at 70° C. for 45 min. The cooled mixture was then was partitioned between EtOAc and 4 N HCl and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in hexanes and Et2O and concentrated under reduced pressure. The residue was then triturated with hexanes and collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethyl)quinazolin-4-ol (140 mg, 43%) as a brown solid. LC-MS (ESI) m/z 360 (M+H)+.

Workup

  1. temperatureThe mixture was cooled to rt
  2. temperaturethe mixture was heated in a microwave synthesizer at 180° C. for 3 min
  3. concentrationThe crude mixture was concentrated under reduced pressure
  4. additionTHF (6 mL) was added
  5. additionAn additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added
  6. stirringthe mixture was stirred at 70° C. for 45 min
  7. customThe cooled mixture was then was partitioned between EtOAc and 4 N HCl
  8. dry with materialthe organic phase was dried over sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. dissolutionThe residue was dissolved in hexanes
  11. concentrationEt2O and concentrated under reduced pressure
  12. customThe residue was then triturated with hexanes
  13. filtrationcollected by filtration

Sources & evidence

ORD record
ord-57856b48dc874da284988da694032f05
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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