Chloroacetyl chloride → tert-butyl(1-(4-(2-oxo-7-phenyl-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate

HRID 1509186Notes

Reaction equation

HRID 1509186 reaction equation
[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[C:20]([OH:37])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:49][C:50](Cl)=[O:51].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]4[N:30]([CH:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[C:50](=[O:51])[CH2:49][O:37][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 6577Chloroacetyl chlorideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 178452603HCID 178452603, compound

Product 1

HCID 123545847tert-butyl(1-(4-(2-oxo-7-phenyl-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamateYield 60.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of tert-butyl(1-(4-(6-hydroxy-3-phenyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)phenyl)cyclobutyl)carbamate (240 mg, 0.46 mmol) in dry THF (11 mL) was added N,N-diisopropylethylamine (0.41 mL, 2.32 mmol). 2-chloroacetyl chloride (0.19 mL, 2.32 mmol) was added dropwise at 0 C. The resulting mixture was stirred overnight at room temperature. A saturated solution of NaHCO3 (8 mL) was added and the mixture was stirred under reflux for 2 hours. After allowing to cool to room temperature, the organic phase was separated and the aqueous phase extracted with AcOEt (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 50% EtOAc in cyclohexane) to give the title compound (154 mg, 59%). 1H NMR (500 MHz, CDCl3): 7.45 (1H, s), 7.24-7.22 (5H, m), 7.19-7.17 (2H, m), 7.14-7.12 (2H, m), 4.94 (1H, s), 4.71 (2H, s), 4.60-4.55 (1H, m), 4.07-4.03 (2H, m), 3.45 (2H, t), 2.63-2.54 (2H, m), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (3H, m), 1.40-1.10 (9H, br).

Workup

  1. stirringthe mixture was stirred
  2. temperatureunder reflux for 2 hours
  3. temperatureto cool to room temperature
  4. customthe organic phase was separated
  5. extractionthe aqueous phase extracted with AcOEt (3×10 ml)
  6. dry with materialThe combined organic phases were dried over Na2SO4
  7. concentrationconcentrated to dryness under reduced pressure
  8. customThe resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 50% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-58d417d7ed614d128fc9655ba5c987ee
Source dataset
uspto-grants-2015_12
Patent number
US09221838B2

Reaction notes

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