Potassium Phosphate, Tribasic → HCID 178517791, compound

HRID 1403091Notes

Reaction equation

HRID 1403091 reaction equation
Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[N:8][C:7]2=[O:16].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19](B(O)O)[CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[N:8][C:7]3=[O:16])[CH:18]=1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 2734663Quinoline-3-boronic acidHCID 178517792HCID 178517792, compound

Product 1

HCID 178517791HCID 178517791, compoundYield 62.6%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 2631-ButanolSolvent

Conditions

Temperature
100 °C

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. temperatureAfter cooling
  2. customthe reaction solution was partitioned between ethyl acetate and water
  3. washThe organic layer was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. distillationThe solvent was distilled off
  6. customthe residue was then purified by neutral silica gel column chromatography (chloroform/methanol)

Sources & evidence

ORD record
ord-26cfba9ca77e442fb0baf69c973535aa
Source dataset
uspto-grants-2014_12
Patent number
US08912181B2

Reaction notes

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