Hydrochloric Acid → HCID 59395039, compound

HRID 1465063Notes

Reaction equation

HRID 1465063 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=3[O:13][CH:12]([C:25]([OH:27])=[O:26])[CH2:11]2)=[CH:5][CH:4]=1.[Li+].[CH3:29]C([N-]C(C)C)C.IC.Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:19][C:14]=3[O:13][C:12]([CH3:29])([C:25]([OH:27])=[O:26])[CH2:11]2)=[CH:7][CH:8]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 6328Methyl iodideHCID 2724682Lithium diisopropylamideHCID 59394948HCID 59394948, compound

Product 1

HCID 59395039HCID 59395039, compoundYield 99.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-50 °C

Procedure

To a solution of 4[(4-methoxyphenyl)methyl]-6-(trifluoromethoxy)-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid (290 mg, 0.76 mmol) in tetrahydrofuran (7 mL), under N2 atmosphere and cooled to −50° C., was added LDA (1.5 mL of 2 M, 3.03 mmol). The mixture was stirred for 2 h at −50° C. then treated with iodomethane (430 mg, 188 μL, 3.03 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h. 30 mL water was added and the solution acidified to ˜pH 3 with 1 N HCl. The solution was extracted with ethyl acetate (3×10 mL) and the organic layer washed with brine, dried over Na2SO4, filtered and dried down to provide 4-[(4-methoxyphenyl)methyl]-2-methyl-6-(trifluoromethoxy)-3H-1,4-benzoxazine-2-carboxylic acid as an orange oil (300 mg, quantitative yield). LC/MS m/z 398.0 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 13.11 (s, 1H), 7.21 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.51 (d, J=8.7 Hz, 1H), 4.45 (d, J=15.7 Hz, 1H), 4.30 (d, J=15.7 Hz, 1H), 3.73 (s, 3H), 3.67 (d, J=11.8 Hz, 1H), 3.15 (d, J=11.8 Hz, 1H), 1.48 (s, 3H).

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 16 h
  3. extractionThe solution was extracted with ethyl acetate (3×10 mL)
  4. washthe organic layer washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. customdried down

Sources & evidence

ORD record
ord-976ab34d3fed44fab9562d0849be073f
Source dataset
uspto-grants-2015_04
Patent number
US08999976B2

Reaction notes

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