Triethylamine → 8-(4-Amino-2-fluoro-phenyl)-2-morpholin-4-yl-benzo[e][1,3]oxazin-4-one

HRID 874913Notes

Reaction equation

HRID 874913 reaction equation
[N:1]1([C:7]2[O:8][C:9]3[C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:28]=[C:29]([NH2:42])[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.CCN(CC)CC>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:42][C:29]1[CH:30]=[CH:31][C:32]([C:17]2[C:9]3[O:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11](=[O:13])[C:10]=3[CH:14]=[CH:15][CH:16]=2)=[C:27]([F:26])[CH:28]=1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 447552073-Fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)anilineHCID 86665644Trifluoro-methanesulfonic acid 2-morpholin-4yl-4-oxo-4H-benzo[e][1,3]oxazin-8-yl ester2×

Product 1

HCID 498552378-(4-Amino-2-fluoro-phenyl)-2-morpholin-4-yl-benzo[e][1,3]oxazin-4-one

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

To a mixture of trifluoro-methanesulfonic acid 2-morpholin-4-yl-4-oxo-4H-benzo[e][1,3]oxazin-8-yl ester, 3 (60 mg, 0.16 mmol, 1 eq), 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (47 mg, 0.20 mmol, 1.3 eq), Pd(PPh3)4 (7.6 mg, 0.007 mmol, 5 mol %) in dioxane (2 mL) and H2O (1mL) was added Et3N (66 mL, 0.48 mmol, 3 eq) dropwise. The reaction mixture was heated up in a pressure tube at 70° C. for 6 h. Upon cooling, the solution was partitioned between EtOAc (15 mL) and H2O (10 mL). The aqueous layer was further extracted with EtOAc (2×5 mL) and DCM (5 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuuo. The residue was further purified by silica gel column chromatography with EtOAc:MeOH (1:0-13:1) to yield the product, B, as a pale brown solid (47 mg, 87%). 1HNMR (400 MHz, CDCl3+10% MeOD) δH: 7.98 (dd, J=7.5, 1.5 Hz, 1H), 7.62 (dd, 1.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.12 (t, J=8.3 Hz, 1H), 6.59 (dd, J=8.3, 2.3 Hz, 1H), 6.52 (dd, J=12.5, 2.0 Hz, 1H), 3.49-3.90 (m, 10H). MS (ES+) 342.1 (100%, [M+H]+).

Workup

  1. temperatureUpon cooling
  2. customthe solution was partitioned between EtOAc (15 mL) and H2O (10 mL)
  3. extractionThe aqueous layer was further extracted with EtOAc (2×5 mL) and DCM (5 mL)
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. customthe solvent was removed in vacuuo
  6. customThe residue was further purified by silica gel column chromatography with EtOAc:MeOH (1:0-13:1)
  7. customto yield the product, B

Sources & evidence

ORD record
ord-c841b1aae19d4577a8a2338cabc67f85
Source dataset
uspto-grants-2015_03
Patent number
US08981087B2

Reaction notes

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