Triphenyl phosphite → HCID 178517777, compound

HRID 473182Notes

Reaction equation

HRID 473182 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]([O:24][C:25]([F:28])([F:27])[F:26])=[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.[NH2:52]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:52]=[C:17]([OH:18])[C:16]2[C:15](=[C:23]([O:24][C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][CH:20]=2)[N:14]=1

Participants

6

Reactant 4

HCID 7540Triphenyl phosphiteHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 117461722-amino-3-(trifluoromethoxy)benzoic AcidHCID 666095532,2-Difluoro-2-(5-fluoropyridin-2-yl)acetic acid

Product 1

HCID 178517777HCID 178517777, compoundYield 77.2%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
150 °C

Procedure

To 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid from Example 33 step A (863 mg, 4.52 mmol) and 2-amino-3-(trifluoromethoxy)benzoic acid (1 g, 4.52 mmol) in pyridine (15 mL) was added triphenyl phosphite (1.3 mL, 4.97 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 (763 mg, 4.97 mmol) was added and the mixture heated in a microwave synthesizer at 190° C. for 4 min. The crude mixture was concentrated under reduced pressure. THF (30 mL) was added followed by sodium ethoxide (21% in EtOH, 5 mL) and the mixture stirred at 60° C. for 0.5 h. The cooled mixture was concentrated under reduced pressure, dissolved in water and the pH adjusted to <4 by addition of 4 N HCl. The precipitate was collected by filtration, washed with water, and allowed to dry to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethoxy)quinazolin-4-ol (1.31 g, 77%) as a crude tan solid which was used in the next step without further purification.

Workup

  1. temperatureThe mixture was cooled to rt
  2. temperaturethe mixture heated in a microwave synthesizer at 190° C. for 4 min
  3. concentrationThe crude mixture was concentrated under reduced pressure
  4. additionTHF (30 mL) was added
  5. concentrationThe cooled mixture was concentrated under reduced pressure
  6. dissolutiondissolved in water
  7. additionthe pH adjusted to <4 by addition of 4 N HCl
  8. filtrationThe precipitate was collected by filtration
  9. washwashed with water
  10. customto dry

Sources & evidence

ORD record
ord-50c95cc9623f4c5da9dd7948f0c04252
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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