Triphenyl phosphite → HCID 178517772, compound

HRID 473184Notes

Reaction equation

HRID 473184 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]([Br: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>[Br: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[CH: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 2702592-Amino-3-bromobenzoic acidHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 666095532,2-Difluoro-2-(5-fluoropyridin-2-yl)acetic acid

Product 1

HCID 178517772HCID 178517772, compoundYield 52%

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 (440 mg, 2.31 mmol) and 2-amino-3-bromobenzoic acid (0.5 g, 2.31 mmol) in pyridine (8 mL) was added triphenyl phosphite (0.667 mL, 2.54 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 (396 mg, 2.54 mmol) was added and the mixture was heated in a microwave synthesizer at 180° C. for 3 min. The mixture was concentrated under reduced pressure. THF (10 mL) was added followed by sodium ethoxide (21% in EtOH, 3.2 mL) and the mixture was stirred at 50° C. for 2 h. An additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added and the mixture stirred at 50° C. for 4 h. The mixture was allowed to cool and was partitioned between EtOAc and 1 N HCl. The organic layer was washed (3×) with 1 N HCl, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with DCM and collected by filtration to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (444 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.52 (t, J=7.91 Hz, 1H) 7.99-8.12 (m, 2H) 8.13-8.23 (m, 2H) 8.69 (d, J=2.45 Hz, 1H) 13.39 (br s, 1H).

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 mixture was concentrated under reduced pressure
  4. additionTHF (10 mL) was added
  5. additionAn additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added
  6. stirringthe mixture stirred at 50° C. for 4 h
  7. temperatureto cool
  8. customwas partitioned between EtOAc and 1 N HCl
  9. washThe organic layer was washed (3×) with 1 N HCl
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was triturated with DCM
  13. filtrationcollected by filtration

Sources & evidence

ORD record
ord-de3c477548f2447b885141edcfed8036
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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