Benzoic acid, 4-fluoro-, ethyl ester → HCID 59346590, compound

HRID 19685Notes

Reaction equation

HRID 19685 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].[Li]CCCC.[F:21][C:22]1[CH:32]=[CH:31][C:25]([C:26](OCC)=[O:27])=[CH:24][CH:23]=1>C1COCC1>[F:1][C:2]1[C:3]([C:26](=[O:27])[C:25]2[CH:31]=[CH:32][C:22]([F:21])=[CH:23][CH:24]=2)=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]

Participants

5

Reactant 3

HCID 67976Benzoic acid, 4-fluoro-, ethyl esterHCID 1121909N-(3,4-difluorophenyl)-2,2-dimethylpropanamideHCID 178418339Butyllithium

Product 1

HCID 59346590HCID 59346590, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a −78° C. solution of 2.5 g (11.724 mmol) N-(3,4-difluorophenyl)-2,2-dimethylpropanamide in 39 ml anhydrous THF was added drop wise over 15 mins 18 mL (28.136 mmol) n-BuLi (1.6M solution in cyclohexanes). After 1 hr at −78° C., 4 mL (26.966 mmol) ethyl 4-fluorobenzoate was added dropwise and the reaction mixture stirred from −78° C. to rt. After 45 mins, the reaction mixture was cooled to 0 C and quenched with saturated ammonium chloride and poured into a 1:1 mixture of ether:water and warmed to room temperature. The organic phase was isolated, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide (6-3). A solution of 3.5 g (10.706 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide in 43 mL 6N HCl and 8.6 mL DME was heated to 100° C. After 24 h at 100° C., the reaction mixture was cooled to room temperature and sodium carbonate was added until reaction mixture was basic. The reactions was diluted with water, extracted three times with ether, and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-20% EtOAc:hexane) afforded (6-amino-2,3-difluorophenyl)(4-fluorophenyl)methanone. 1H NMR (CDCl3, 400 MHz) δ 7.85-7.80 (m, 2H, ArH); 7.17-7.11 (m, 3H, ArH); 6.47 (ddd, J=2.01 Hz, 3.66 Hz, 9.16 Hz, 1H, ArH); 4.84 (br s, 2H, ArNH2). ES MS+1=252.1.

Workup

  1. waitAfter 45 mins
  2. temperaturethe reaction mixture was cooled to 0 C
  3. customquenched with saturated ammonium chloride
  4. additionpoured into a 1:1 mixture of ether
  5. customThe organic phase was isolated
  6. washwashed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-205d238f752642f99319d25cfeae0967
Source dataset
uspto-grants-2010_06
Patent number
US07745452B2

Reaction notes

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