Hydrochloric Acid → 4-Methyl-6-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid

HRID 1690783Notes

Reaction equation

HRID 1690783 reaction equation
C([O:3][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])C.[C:20]([O-])([O-])=O.[K+].[K+].IC.Cl>CN(C=O)C.O>[CH3:20][N:10]1[C:9]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:8]=2[O:7][CH:6]([C:4]([OH:3])=[O:5])[CH2:11]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 6328Methyl iodideHCID 11430Potassium CarbonateHCID 11747775ethyl 6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate

Product 1

HCID 581186544-Methyl-6-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acidYield 14.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of 6-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (650 mg, 2.4 mmol) in anhydrous DMF (7 mL) was added K2CO3 (816 mg, 5.9 mmol), followed by iodomethane (294 μL, 4.7 mmol). The reaction was heated in the microwave (300 W, 150° C.) for 1 hour. After cooling, the mixture was poured into water (50 mL), acidified with 2N HCl and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (3×50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 12% MeOH in DCM) gave the title compound (90 mg, 10%) as a solid. m/z=262.1 (M+1), r.t.=3.28 mins. 1H NMR (400 MHz; d6-DMSO) δ 6.93-6.86 (3H, m), 4.85 (1H, s), 3.45-3.36 (2H, m), 2.86 (3H, s).

Workup

  1. temperatureAfter cooling
  2. extractionextracted with EtOAc (3×50 mL)
  3. washThe combined organics were washed with brine (3×50 mL)
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-a2715a1688f14695a506a0e9efa94f48
Source dataset
uspto-grants-2012_04
Patent number
US08153651B2

Reaction notes

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