Water → 5-(4-{5-[(4-Fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyrazin-2-amine

HRID 241171Notes

Reaction equation

HRID 241171 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24](B5OC(C)(C)C(C)(C)O5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:42]=[N:41][C:40](Br)=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:40]5[N:41]=[CH:42][C:37]([NH2:36])=[N:38][CH:39]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 5995392-Amino-5-bromopyrazineHCID 668205164-(5-[(4-Fluorophenyl)methyl]-6-methylpyrimidin-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine

Product 1

HCID 573893405-(4-{5-[(4-Fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyrazin-2-amineYield 20%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
95 °C

Procedure

A solution of 4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.10 g, 0.21 mmol), 2-amino-5-bromopyrazine (40 mg, 0.21 mmol) and potassium carbonate (0.12 g, 0.84 mmol) in N,N-dimethylformamide (5 mL), and water (0.5 mL) was degassed by bubbling nitrogen gas for five minutes followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.021 mmol), then stirred at 95° C. for 16 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (30 mL). The organic layer was separated, washed with brine, dried over sodium sulfate then filtered and concentrated. Purification by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyrazin-2-amine (18 mg, 20%). 1H NMR (400 MHz, d6-DMSO): 8.80 (s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.72 (d, 1H), 7.50 (br s, 1H), 7.25-7.14 (m, 4H), 6.93 (d, 1H), 4.90 (s, 2H), 4.32 (m, 2H), 4.00 (m, 4H), 2.22 (s, 3H). MS (EI) for C25H23FNO6: 443 (MH+).

Workup

  1. customby bubbling nitrogen gas for five minutes
  2. temperatureAfter cooling to room temperature the reaction mixture
  3. customwas partitioned between ethyl acetate (50 mL) and brine (30 mL)
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationthen filtered
  8. concentrationconcentrated
  9. customPurification by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile)

Sources & evidence

ORD record
ord-7471236f89dd48e69f27488f159621a4
Source dataset
uspto-grants-2014_02
Patent number
US08648066B2

Reaction notes

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