Cesium carbonate → {3-[4-(3-{2-Dimethylaminomethylene-6-[2-(3-fluoro-phenyl)-ethyl]-2H-benzo[1,4]oxazin-3-yl}-ureido)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester

HRID 570156Notes

Reaction equation

HRID 570156 reaction equation
Cl[C:2]1[C:3](=[CH:21][N:22]([CH3:24])[CH3:23])[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:8][C:6]=2[N:7]=1.[C:25]([O:29][C:30](=[O:45])[NH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42]([NH2:44])=[O:43])[CH2:37][CH2:36]1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:25]([O:29][C:30](=[O:45])[NH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:36][CH2:37][CH:38]([NH:41][C:42]([NH:44][C:2]2[C:3](=[CH:21][N:22]([CH3:24])[CH3:23])[O:4][C:5]3[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)=[CH:8][C:6]=3[N:7]=2)=[O:43])[CH2:39][CH2:40]1)([CH3:28])([CH3:26])[CH3:27]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 66578630{3-Chloro-6-[2-(3-fluoro-phenyl)-ethyl]-benzo[1,4]oxazin-2-ylidenemethyl}-dimethyl-amineHCID 66578855[3-(4-Ureido-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester

Product 1

HCID 66578840{3-[4-(3-{2-Dimethylaminomethylene-6-[2-(3-fluoro-phenyl)-ethyl]-2H-benzo[1,4]oxazin-3-yl}-ureido)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl esterYield 36%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
23 °C

Procedure

To a solution of {3-chloro-6-[2-(3-fluoro-phenyl)-ethyl]-benzo[1,4]oxazin-2-ylidenemethyl}-dimethyl-amine (500 mg, 1.45 mmol, 1 equiv) and [3-(4-ureido-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester (435 mg, 1.45 mmol, 1 equiv) in dioxane (15 mL) was added palladium(II) acetate (3.2 mg, 0.0145 mmol, 0.01 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos, 17 mg, 0.029 mmol, 0.02 equiv) and cesium carbonate (709 mg, 2.18 mmol, 1.5 equiv). The reaction mixture was sparged with argon then the reaction vessel sealed (screw cap) and placed in 100° C. oil bath. After 14 h at 100° C. the reaction was cooled to 23° C., and then partitioned between ethyl acetate and water (100 mL each). The organic layer was separated and washed with saturated brine solution (100 mL) then dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto an 80 g silica gel column as a solution in dichloromethane (5 mL) then eluted with 2 M ammonia in methanol in dichloromethane (0-8% 2 M ammonia in methanol linear gradient over 18 column volumes at a flow rate of 60 mL/min) to give 313 mg (0.515 mmol, 36%) of the title compound as a yellow/brown solid.

Workup

  1. customThe reaction mixture was sparged with argon
  2. customthe reaction vessel sealed
  3. custom(screw cap)
  4. customplaced in 100° C.
  5. custompartitioned between ethyl acetate and water (100 mL each)
  6. customThe organic layer was separated
  7. washwashed with saturated brine solution (100 mL)
  8. dry with materialthen dried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe product was purified
  12. washthen eluted with 2 M ammonia in methanol in dichloromethane (0-8% 2 M ammonia in methanol linear gradient over 18 column volumes at a flow rate of 60 mL/min)

Sources & evidence

ORD record
ord-36df0272358943c2854b524581ebdd81
Source dataset
uspto-grants-2015_05
Patent number
US09023843B2

Reaction notes

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