2,3,4-Trifluorobenzoic acid → 3,4-Difluoro-2-[[2-fluoro-4-(trimethylsilylethynyl)phenyl]amino]benzoic acid

HRID 1792996Notes

Reaction equation

HRID 1792996 reaction equation
[F:1][C:2]1[CH:8]=[C:7]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:16]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:25][C:24]1[C:16]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([C:9]#[C:10][Si:11]([CH3:13])([CH3:12])[CH3:14])=[CH:8][C:2]=2[F:1])=[C:17]([CH:21]=[CH:22][C:23]=1[F:26])[C:18]([OH:20])=[O:19]

Participants

5

Reactant 3

HCID 3029322,3,4-Trifluorobenzoic acidHCID 2733832Lithium HexamethyldisilazideHCID 220256802-Fluoro-4-((trimethylsilyl)ethynyl)aniline

Product 1

HCID 220256313,4-Difluoro-2-[[2-fluoro-4-(trimethylsilylethynyl)phenyl]amino]benzoic acidYield 59%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A mixture of the product of Step A, 2-fluoro-4-[(trimethylsilyl)ethynyl]aniline (3.85 g, 18.6 mmol) and 2,3,4-trifluorobenzoic acid (3.27 g, 18.6 mmol) was dissolved in dry THF (25 mL). The flask was fitted with a pressure-equalising dropping funnel and the entire apparatus evacuated and flushed with N2. The solution was then cooled to −78° C. (acetone/dry ice) and a solution of 1.06 M LiHMDS (52.64 mL, 55.8 mmol) was added dropwise from the dropping funnel. Following this addition, the reaction mixture was allowed to warm to room temperature and stirred for a further 15 hours. The reaction solvent was removed under reduced pressure and the resulting residue partitioned between 1 M HCl (100 mL) and EtOAc (2×100 mL). The combined EtOAc fractions were then washed with water (100 mL) and saturated NaCl (100 mL), dried (Na2SO4), and the EtOAc removed under reduced pressure to afford a crude product which was purified by chromatography on flash silica (10% EtOAc/hexanes as eluant), giving the desired product as a pale yellow solid (3.99 g, 59%); m.p. (EtOAc/hexanes) 164–167° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.70 (br s, 1 H), 9.31 (br s, 1 H), 7.82 (ddd, J=9.1, 6.1, 2.0 Hz, 1 H), 7.34 (dd, J=12.0, 1.9 Hz, 1 H), 7.18 (ddd, J=8.3, 1.9, 0.8 Hz, 1 H), 7.16 (td, J=9.5, 7.3 Hz, 1 H), 6.93 (ddd, J=8.9, 8.3, 5.4 Hz, 1 H), 0.22 (s, 9 H). Anal. Calcd for C18H16F3NO2Si: C, 59.5; H, 4.4; N, 3.9. Found: C, 59.7; H, 4.7; N, 3.9.

Workup

  1. customThe flask was fitted with
  2. customthe entire apparatus evacuated
  3. customflushed with N2
  4. additionthis addition
  5. temperatureto warm to room temperature
  6. customThe reaction solvent was removed under reduced pressure
  7. customthe resulting residue partitioned between 1 M HCl (100 mL) and EtOAc (2×100 mL)
  8. washThe combined EtOAc fractions were then washed with water (100 mL) and saturated NaCl (100 mL)
  9. dry with materialdried (Na2SO4)
  10. customthe EtOAc removed under reduced pressure
  11. customto afford a crude product which
  12. customwas purified by chromatography on flash silica (10% EtOAc/hexanes as eluant)

Sources & evidence

ORD record
ord-1af78b468b504952ac05aa866c280e95
Source dataset
uspto-grants-2006_07
Patent number
US07078438B2

Reaction notes

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