Acetonitrile → HCID 49833482, compound

HRID 473850Notes

Reaction equation

HRID 473850 reaction equation
[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:30](#[N:32])[CH3:31]>CC(N(C)C)=O.O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:31]4[CH:30]=[N:32][C:8]([NH2:10])=[N:5][CH:4]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1

Participants

6

Reactant 3

HCID 6342AcetonitrileHCID 11430Potassium CarbonateHCID 70815174HCID 70815174, compound

Product 1

HCID 49833482HCID 49833482, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
95 °C

Procedure

To a mixture of 2-amino-5-bromopryimidine (65 mg, 0.37 mmol), {4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-yl}boronic acid (100 mg, 0.31 mmol) and potassium carbonate (215 mg, 1.6 mmol) in DMA (5.0 mL) and water (0.5 mL) was added dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (23 mg, 0.03 mmol). The reaction mixture was stirred at 95° C. for 2.5 hours and then partitioned between dichloromethane (10 mL) and 1M aqueous sodium hydroxide (10 mL). The organic layer was separated and washed with brine (10 mL) then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 2% methanol in dichloromethane as eluent and the combined product containing fractions were concentrated. The residue thus obtained was taken into a minimum of acetonitrile and purified by preparative reverse phase HPLC to afford 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyrimidin-2-amine (24 mg) as an amorphous solid. 1H NMR (400 mHz, DSMO-d6): 8.51 (s, 2H), 7.47 (d, 1H), 7.42 (dd, 1H), 6.98 (d, 1H), 6.75 (s, 2H), 4.39 (s, 2H), 4.12-4.18 (m, 2H), 3.46-3.59 (m, 4H), 2.70 (t, 2H), 1.42-1.61 (m, 3H), 1.04-1.18 (m, 2H), 0.91 (d, 3H); MS (EI) for C20H25N5O2: 368 (MH+).

Workup

  1. custompartitioned between dichloromethane (10 mL) and 1M aqueous sodium hydroxide (10 mL)
  2. customThe organic layer was separated
  3. washwashed with brine (10 mL)
  4. dry with materialthen dried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was chromatographed on silica gel using 2% methanol in dichloromethane as eluent
  8. additionthe combined product containing fractions
  9. concentrationwere concentrated
  10. customThe residue thus obtained
  11. custompurified by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-352b09cd5a81464c8cfd366df608ca7b
Source dataset
uspto-grants-2014_01
Patent number
US08637499B2

Reaction notes

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