Toluene → 8-Cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline

HRID 473216Notes

Reaction equation

Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[S:22][CH3:23].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.O>[CH:24]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([C:12]([F:20])([F:21])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:8]=[C:7]3[S:22][CH3:23])[CH2:26][CH2:25]1

Participants

Conditions

Temperature: 100 °C

Procedure

To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (200 mg, 0.5 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (37 mg, 0.05 mmol), cyclopropylboronic acid (65 mg, 0.75 mmol) and K3PO4 (371 mg, 1.75 mmol) were added toluene (6 mL) and water (0.5 mL). The reaction vessel was evacuated and flushed with argon (3×), and then the mixture was heated at 100° C. for 4 h. The mixture was concentrated under reduced pressure onto Celite and the residue was purified by silica gel chromatography eluting with 10-50% EtOAc/hexanes to afford impure 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (150 mg, 84%) which was used without further purification.

Workup

customThe reaction vessel was evacuated
customflushed with argon (3×)
concentrationThe mixture was concentrated under reduced pressure onto Celite
customthe residue was purified by silica gel chromatography
washeluting with 10-50% EtOAc/hexanes

Sources & evidence

ORD record: ord-4b691892610748fdaab7fcdc1a140446
Source dataset: uspto-grants-2014_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08633207B2

Reaction notes

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