Hydrochloric Acid → HCID 59395039, compound

HRID 383328Notes

Reaction equation

HRID 383328 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 1N 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-fac0fb94b6c744daa0e48de521bd2103
Source dataset
uspto-grants-2013_02
Patent number
US08367660B2

Reaction notes

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