Phosphorus oxychloride → HCID 86701148, compound

HRID 1403092Notes

Reaction equation

HRID 1403092 reaction equation
P(Cl)(Cl)([Cl:3])=O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[NH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[N:22][C:21]3=O)[CH:7]=1>>[Cl:3][C:21]1[C:20]2[C:25](=[C:16]([C:8]3[CH:7]=[N:6][C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:17]=[CH:18][CH:19]=2)[N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[N:22]=1

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 178517791HCID 178517791, compound

Product 1

HCID 86701148HCID 86701148, compound

Procedure

A suspension of compound (114a) (0.57 g), 3-quinolineboronic acid (0.45 g), Pd2dba3 (0.031 g), X-Phos (0.064 g), and potassium phosphate (1.4 g) in butanol was stirred at 100° C. for 15 hours in a nitrogen atmosphere. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was then purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-(quinolin-3-yl)-2-(trifluoromethyl)quinazolin-4(1H)-one (0.49 g) as a white solid. Phosphorus oxychloride (5 ml) was added to the obtained 8-(quinolin-3-yl)-2-(trifluoromethyl)quinazolin-4(1H)-one (0.49 g), and the mixture was heated to reflux for 13 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The reaction solution was neutralized with an aqueous sodium bicarbonate solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 4-chloro-8-(quinolin-3-yl)-2-(trifluoromethyl)quinazoline (0.43 g) as a white solid. Compound (114) was obtained as a yellow solid (yield based on 4 steps: 25%) according to Example 1(5) using the obtained 4-chloro-8-(quinolin-3-yl)-2-(trifluoromethyl)quinazoline instead of compound (1d) and 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.

Workup

  1. temperaturethe mixture was heated
  2. temperatureto reflux for 13 hours
  3. distillationThe solvent was distilled off under reduced pressure, and ethyl acetate
  4. additionwas added to the residue
  5. temperaturewith cooling in an ice bath
  6. custompartitioned into organic and aqueous layers
  7. washThe organic layer was washed with brine
  8. washThe organic layer thus washed
  9. dry with materialwas dried over anhydrous sodium sulfate
  10. distillationThen, the solvent was distilled off
  11. customthe residue was purified by neutral silica gel column chromatography (chloroform/methanol)

Sources & evidence

ORD record
ord-28e26c4056e345ec9b2d92df8e6f8e35
Source dataset
uspto-grants-2014_12
Patent number
US08912181B2

Reaction notes

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