Triphenyl phosphite → 2-[difluoro-(5-fluoro-2-pyridinyl)methyl]-8-nitro-1H-quinazolin-4-one

HRID 473214Notes

Reaction equation

HRID 473214 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]([N+:24]([O-:26])=[O: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.[NH2:50]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:50]=[C:17]([OH:18])[C:16]2[C:15](=[C:23]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:21][CH:20]=2)[N:14]=1

Participants

6

Reactant 4

HCID 7540Triphenyl phosphiteHCID 2196332-Amino-3-nitrobenzoic acidHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 666095532,2-Difluoro-2-(5-fluoropyridin-2-yl)acetic acid

Product 1

HCID 1785265332-[difluoro-(5-fluoro-2-pyridinyl)methyl]-8-nitro-1H-quinazolin-4-oneYield 31%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
150 °C

Procedure

To a mixture of 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid from Example 33 step A (1.05 g, 5.49 mmol) and 2-amino-3-nitrobenzoic acid (1 g, 5.49 mmol) in pyridine (15 mL) was added triphenyl phosphite (1.59 mL, 6.03 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 (945 mg, 6.03 mmol) was added. The mixture was heated in a microwave synthesizer at 190° C. for 4 min, and then concentrated under reduced pressure. THF (20 mL) and sodium ethoxide (21% in EtOH, 10 mL) were added and the mixture was heated at 50° C. for 0.5 h with stirring. The mixture was concentrated under reduced pressure and then partitioned between EtOAc and 4 N HCl. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then purified by silica gel chromatography eluting with 10-100% EtOAc/hexanes. The residue was triturated with Et2O and the solid was collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-nitroquinazolin-4-ol (566 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.77 (t, J=7.91 Hz, 1H) 7.97-8.11 (m, 2H) 8.30-8.48 (m, 2H) 8.68 (s, 1H) 13.61 (br s, 1H).

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. additionTHF (20 mL) and sodium ethoxide (21% in EtOH, 10 mL) were added
  5. temperaturethe mixture was heated at 50° C. for 0.5 h
  6. concentrationThe mixture was concentrated under reduced pressure
  7. custompartitioned between EtOAc and 4 N HCl
  8. dry with materialThe organic layer was dried over sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. custompurified by silica gel chromatography
  11. washeluting with 10-100% EtOAc/hexanes
  12. customThe residue was triturated with Et2O
  13. filtrationthe solid was collected by filtration

Sources & evidence

ORD record
ord-13e333df52eb4586b65c181d232c5406
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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