Dichloromethane → (R)-5,5-Difluoro-4-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine

HRID 1626136Notes

Reaction equation

HRID 1626136 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29](B(O)O)[CH:28]=[N:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCCC1.O>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]([C:29]2[CH:28]=[N:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH:30]=2)[CH:3]=[CH:4][C:5]=1[F:18])[CH3:17]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 467386841-(4-Fluorophenyl)pyrazole-4-boronic acidHCID 58304205(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine

Product 1

HCID 71008888(R)-5,5-Difluoro-4-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamineYield 48%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

In a tube a mixture of (R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A6.1) (60 mg, 186 μmol), 1-(4-fluorophenyl)-1H-pyrazol-4-ylboronic acid (39.0 mg, 186 μmol), and cesium carbonate (242 mg, 743 μmol) in tetrahydrofuran (4 ml) and water (2 ml) was purged with argon for minutes. Thereafter, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (7.58 mg, 9.28 μmol) was added, the tube was sealed and the mixture heated at 80° C. for 16 hours. After evaporation, the residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 40:60 as the eluent. The (R)-5,5-Difluoro-4-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (36 mg, 48% yield) was obtained as a yellow solid. MS (ISP): m/z=405.0 [M+H]+.

Workup

  1. customwas purged with argon for minutes
  2. customthe tube was sealed
  3. customAfter evaporation
  4. customthe residue was purified by chromatography on a silica-NH2 phase

Sources & evidence

ORD record
ord-2560d7a31a644c76a386cf09f03bd26a
Source dataset
uspto-grants-2014_07
Patent number
US08785436B2

Reaction notes

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