Cesium carbonate → tert-Butyl 4-(1-(cyclopropylmethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzylcarbamate

HRID 1509330Notes

Reaction equation

HRID 1509330 reaction equation
Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:5]2[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:9](=[O:15])[CH2:8][O:7][C:6]=2[N:16]=1.CC1(C)C(C)(C)OB([C:31]2[CH:45]=[CH:44][C:34]([CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH:12]1([CH2:11][N:10]2[C:9](=[O:15])[CH2:8][O:7][C:6]3[N:16]=[C:2]([C:31]4[CH:45]=[CH:44][C:34]([CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:33][CH:32]=4)[C:3]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:5]2=3)[CH2:14][CH2:13]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 34154424-(tert-Butoxycarbonylaminomethyl)phenylboronic acid, pinacol esterHCID 866836856-bromo-1-(cyclopropylmethyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

Product 1

HCID 86683684tert-Butyl 4-(1-(cyclopropylmethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)benzylcarbamateYield 74%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
50 °C

Procedure

In a 15 mL reaction tube was added 6-bromo-1-(cyclopropylmethyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (80 mg, 0.223 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (89 mg, 0.267 mmol) and CESIUM CARBONATE (363 mg, 1.114 mmol) in a mixture of 1,4-Dioxane (3341 NI) and water (1114 μl) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of PdC12(dppf)-CH2Cl2Adduct (36.4 mg, 0.045 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50° C. under a nitrogen atmosphere for one hour. LC-MS analysis showed reaction completion. The reaction mixture was allowed to cool to room temperature, diluted with water (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give an off-white solid. The resulting residue was purified via Biotage (15-85% cyclohexane:EtOAc; 10 g column) to give the title compound (80 mg, 74%). 1H NMR (500 MHz, CDCl3): 7.39 (1H, s), 7.32-7.26 (5H, m), 7.20-7.18 (2H, dd), 7.12-7.10 (2H, d), 4.89 (2H, s), 4.80 (1H, br), 4.27 (2H, s), 3.87-3.86 (2H, d), 1.48-1.45 (9H, br), 1.18-1.15 (1H, m), 0.60-0.56 (2H, m), 0.48-0.45 (2H, m).

Workup

  1. customIn a 15 mL reaction tube
  2. customto give a colourless solution
  3. customThis was degassed
  4. customby bubbling nitrogen for 15 minutes
  5. customdegassing for a further 5 minutes
  6. customreaction completion
  7. temperatureto cool to room temperature
  8. extractionextracted into ethyl acetate (3×5 mL)
  9. dry with materialThe combined organic phases were dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated to dryness under reduced pressure
  12. customto give an off-white solid
  13. customThe resulting residue was purified via Biotage (15-85% cyclohexane:EtOAc; 10 g column)

Sources & evidence

ORD record
ord-c62255ce3a574e27a92e27e421d67498
Source dataset
uspto-grants-2015_12
Patent number
US09221838B2

Reaction notes

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