Phosphorus oxychloride → 4-Chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline

HRID 473134Notes

Reaction equation

HRID 473134 reaction equation
[F:1][C:2]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:21])([F:1])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:12]=1

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 178517775HCID 178517775, compound

Product 1

HCID 866626934-Chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolineYield 82%

Conditions

Temperature
95 °C

Procedure

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol from Example 2 Step D (1.82 g, 6.25 mmol) was added phosphorousoxychloride (20 mL) and the mixture was heated at 95° C. for 3 h. The mixture was concentrated under reduced pressure and then toluene (20 mL) was added and evaporated. The residue was dissolved in EtOAc and washed with saturated NaHCO3 (1×) and brine (1×), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with 10-80% EtOAc/hexanes to afford 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (1.59 g, 82%). 1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J=2.6 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.17-8.29 (m, 2H), 8.06-8.15 (m, 1H), 7.96-8.06 (m, 2H); LC-MS (ESI) m/z 310 (M+H)+.

Workup

  1. concentrationThe mixture was concentrated under reduced pressure
  2. additiontoluene (20 mL) was added
  3. customevaporated
  4. dissolutionThe residue was dissolved in EtOAc
  5. washwashed with saturated NaHCO3 (1×) and brine (1×)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customThe residue was purified by silica gel chromatography
  9. washeluting with 10-80% EtOAc/hexanes

Sources & evidence

ORD record
ord-e0c6332672224f09814095aa5a0fe2a5
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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