Potassium Carbonate → 6-Fluoro-4-[3-(1,1,2,2-tetrafluoro-ethoxy)-benzyl]-2-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine

HRID 990448Notes

Reaction equation

HRID 990448 reaction equation
F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=1)[CH2:10][CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[O:16][CH:11]([C:12]([F:13])([F:14])[F:15])[CH2:10][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[CH:19]=3)[C:3]=2[CH:4]=1

Participants

5

Reactant 2

HCID 11430Potassium CarbonateHCID 235060713-[(2,5-Difluorophenyl)[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

Product 1

HCID 108952136-Fluoro-4-[3-(1,1,2,2-tetrafluoro-ethoxy)-benzyl]-2-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazineYield 48%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
145 °C

Procedure

The 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.45 mmol) product from EX-661B was dissolved in anhydrous dimethylformamide (20 mL), and powdered K2CO3 (180 mg) was added. The mixture was stirred and heated to 145° C. for 15 h. The mixture was diluted with water (60 mL) and extracted into ether (2×40 mL), which was washed with brine and water. The ether solution was dried over anhydrous MgSO4, and the ether was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:15) to give 86.9 mg (48%) of the desired 6-fluoro-3,4-dihydro-4-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2-(tri-fluoromethyl)-2H-1,4-benzoxazine product as a yellow oil, 98% pure by HPLC analysis. 1H NMR (CDCl3) δ7.39 (t, 1H), 7.17 (m, 3H), 6.88 (m, 1H), 6.41 (m, 2H), 5.92 (tt, 1H), 4.54 (m, 1H), 4.45 (s, 2H), 3.44 (m, 2H). 19F NMR (CDCl3) δ−77.7 (d, 3F), −88.6 (m, 2F), −120.28 (m, 1F), −137.2 (dt, 2F). HRMS calcd. for C18H13F8NO2: 428.0899 [M+H]+. found: 428.0910.

Workup

  1. extractionextracted into ether (2×40 mL), which
  2. washwas washed with brine and water
  3. dry with materialThe ether solution was dried over anhydrous MgSO4
  4. customthe ether was removed in vacuo
  5. customThe crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:15)

Sources & evidence

ORD record
ord-2458f8aecbc34f698fb22bbf969efcff
Source dataset
uspto-grants-2002_10
Patent number
US06458803B1

Reaction notes

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