4-(Bromomethyl)-1,2-difluorobenzene → n-(3,4-Difluoro-benzyl)-n-(6-methoxy-benzo[b]thiophen-2-yl)-pyridin-3-yl-sulfonamide

HRID 2405864Notes

Reaction equation

HRID 2405864 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([NH:11][S:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[S:8][C:7]=2[CH:21]=1.CC(C)([O-])C.[K+].[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32]Br>C1COCC1.CCOC(C)=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32][N:11]([C:9]1[S:8][C:7]2[CH:21]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:10]=1)[S:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13]

Participants

6

Reactant 3

HCID 5814364-(Bromomethyl)-1,2-difluorobenzeneHCID 23665647Potassium tert-butoxideHCID 57920429n-(6-Methoxy-benzo[b]thiophen-2-yl)-pyridin-3-yl-sulfonamide

Product 1

HCID 57920574n-(3,4-Difluoro-benzyl)-n-(6-methoxy-benzo[b]thiophen-2-yl)-pyridin-3-yl-sulfonamideYield 66%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of compound 141-F (0.488 g; 1.52 mmol) in THF (15 mL) was added 1M potassium tert-butoxide (2.28 mL; 2.28 mmol) and the reaction mixture was stirred at ambient temperature for 30 min. 3,4-Difluorobenzyl bromide (0.409 g; 1.97 mmol), dissolved in THF (1.0 mL), was added drop-wise, and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with EtOAc, washed with 2N HCl, water, brine, dried over Na2SO4, filtered, the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford an oily semi-solid, which was further purified by reverse-phase semi-prep HPLC (Gemini, C-18 column; 100×30 mm I.D.; 5μ) eluting with a 55% to 75% MeCN—H2O gradient to afford compound 141-G as a white solid (0.447 g, 66%). 1H-NMR (DMSO-d6): δ 3.76 (s, 3H), 4.89 (s, 2H), 6.93-6.96 (m, 1H), 7.11 (s, 1H), 7.19-7.20 (m, 1H), 7.34-7.43 (m, 3H), 7.60-7.62 (d, 1H), 7.70-7.73 (m, 1H), 8.21-8.24 (m, 1H), 8.93-8.96 (m, 2H); MS: m/z 447.0 (MH+).

Workup

  1. additionwas added drop-wise
  2. stirringthe reaction was stirred at ambient temperature for 18 h
  3. washwashed with 2N HCl, water, brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. customthe solvent evaporated under reduced pressure
  7. customThe crude residue was purified by flash column chromatography (SiO2)
  8. washeluting with a heptane-EtOAc gradient
  9. customto afford an oily semi-solid, which
  10. customwas further purified by reverse-phase semi-prep HPLC (Gemini, C-18 column; 100×30 mm I.D.; 5μ)
  11. washeluting with a 55% to 75% MeCN—H2O gradient

Sources & evidence

ORD record
ord-5e80b90ed1534c37a44f9d2d74148c8b
Source dataset
uspto-grants-2014_08
Patent number
US08809327B2

Reaction notes

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