Hydrogen Bromide → 6-Bromo-7-hydroxy-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-3-(4-trifluoromethyl-phenyl)-chromen-2-one

HRID 1296698Notes

Reaction equation

HRID 1296698 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:28][CH:27]=1.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=1)=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)=[CH:28][CH:27]=1

Participants

5

Reactant 3

HCID 260Hydrogen BromideHCID 516892Sodium BicarbonateHCID 589131386-Bromo-7-methoxy-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-3-(4-trifluoromethyl-phenyl)-chromen-2-one

Product 1

HCID 114332596-Bromo-7-hydroxy-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-3-(4-trifluoromethyl-phenyl)-chromen-2-oneYield 25.5%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

A solution of 6-bromo-7-methoxy-4-(4-(2-pyrrolidin-1-yl-ethoxy)-benzyl)-3-(4-trifluoromethyl-phenyl)-chromen-2-one (0.20 g, 0.3 mmol) and hydrogen bromide in acetic acid (10 mL) was heated to reflux overnight. After cooling, excess acetic acid was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, water, and saturated sodium chloride in succession; dried over magnesium sulfate; filtered; and concnetrated under reduced pressure to afford crude product. Purification using reverse-phase preparatory HPLC (20–80% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) provided fractions that were subsequently neutralized with sodium bicarbonate and extracted using ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (>98% pure, 45.0 mg, 23%). 1H NMR (300 MHz, d6-DMSO) δ 7.78 (m, 2H), 7.69 (s, 1H), 7.55 (m, 2H), 7.08 (m, 2H), 6.88 (s, 1H), 6.83 (m, 2H), 4.04 (t, 2H), 3.94 (s, 2H), 2.92 (t, 2H), 2.67 (bm, 4H), 1.72 (bm, 4H). MS (ESI) m/z 588.3 (M+1)+, 590.3 (M+1+2)+.

Workup

  1. temperatureto reflux overnight
  2. temperatureAfter cooling
  3. customexcess acetic acid was removed under reduced pressure
  4. dissolutionThe resulting residue was dissolved in ethyl acetate
  5. washwashed with saturated sodium bicarbonate, water, and saturated sodium chloride in succession
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. customto afford crude product
  9. customPurification
  10. customreverse-phase preparatory HPLC (20–80% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min)
  11. customprovided fractions that
  12. extractionextracted
  13. dry with materialdried over magnesium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-d970ab7709fb4068b4a9849d0c748548
Source dataset
uspto-grants-2007_07
Patent number
US07247646B2

Reaction notes

Loading…