Sodium Carbonate → tert-butyl(1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclopropyl)carbamate

HRID 1509326Notes

Reaction equation

HRID 1509326 reaction equation
Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:13]=1.[C:20]([O:24][C:25](=[O:45])[NH:26][C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[C:20]([O:24][C:25](=[O:45])[NH:26][C:27]1([C:30]2[CH:31]=[CH:32][C:33]([C:2]3[C:3]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:4][C:5]4[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=4[N:13]=3)=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 69087646tert-Butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamateHCID 866836706-bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

Product 1

HCID 131734408tert-butyl(1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclopropyl)carbamateYield 101.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
80 °C

Procedure

In a 15 mL reaction tube was added 6-bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.125 mmol) and tert-butyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (54 mg, 0.150 mmol) in 1,4-dioxane (1 ml), followed by a solution of sodium carbonate (40 mg, 0.3 mmol) in water (0.25 ml) to give a white suspension. This was degassed by bubbling nitrogen for 10 minutes, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (9 mg, 0.013 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with brine (4 ml) and extracted into ethyl acetate (3×4 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a white solid (60 mg, quantitative yield). 1H-NMR (500 MHz, CDCl3) δ 7.14-7.26 (6H, m), 7.08-7.14 (2H, m), 6.93 (2H, d), 4.99-5.27 (1H, br m), 4.80 (2H, s), 3.31 (3H, s), 1.35 (9H, br s), 1.25 (2H, br s), 1.03 (2H, br s). LCMS (Method D): RT=1.44 min, M+H+=472.20.

Workup

  1. customIn a 15 mL reaction tube
  2. customto give a white suspension
  3. customThis was degassed
  4. customby bubbling nitrogen for 10 minutes
  5. temperatureto cool to room temperature
  6. extractionextracted into ethyl acetate (3×4 ml)
  7. dry with materialThe combined organic phases were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated to dryness under reduced pressure
  10. customThe residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80)

Sources & evidence

ORD record
ord-0dce8557f5ce4199baf44ff2cfdf25bc
Source dataset
uspto-grants-2015_12
Patent number
US09221838B2

Reaction notes

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