Ethanol → (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid ethyl ester

HRID 277451Notes

Reaction equation

HRID 277451 reaction equation
I[C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:17]([C@@H:24]1[C@@H:33]([OH:34])[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[O:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+].C(O)C>[Pd].C(OC(C)C)(C)C.C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=1[C:29]1[CH:28]=[C:27]2[C:32]([C@H:33]([OH:34])[C@@H:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][O:26]2)=[CH:31][CH:30]=1)[CH3:8]

Participants

8

Reactant 4

HCID 702EthanolHCID 522689Potassium FluorideHCID 11044276(3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acidHCID 18431635Ethyl 2-iodo-4-(trifluoromethyl)benzoate

Product 1

HCID 15462267(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid ethyl esterYield 93.6%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 7914Diisopropyl EtherSolventHCID 18331056Acetic acid tolueneSolvent

Procedure

A mixture of ethyl 2-iodo-4-trifluoromethyl-benzoate (723 g, 2.1 mol), (3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid (627 g, 2.2 mol), potassium fluoride (366 g, 6.3 mol), 10% palladium on carbon (157 g, 50% water wet), and anhydrous ethanol (6.27 L) was heated at reflux for 3 hours at which point thin layer chromatography (toluene/acetic acid, 5:1) indicated the reaction to be complete. The reaction mixture was diluted with isopropyl ether (8 L), filtered through Celiteeand washed with 10% aqueous sodium bicarbonate (1.5 L). The aqueous layer was separated and extracted with isopropyl ether (3 L). The combined organic layers were washed with water (6 L), dried over magnesium sulfate, and treated with Darco®G-60 (1.0 kg) and silica gel (1 kg, 70-230 mesh) at ambient temperature. This mixture was filtered through a pad of silica gel (70-230 mesh) and concentrated in vacuo to 922 g of dark oil. This oil was diluted with ethyl acetate (1 L) and filtered through a column of silica gel (2 kg) eluting with ethyl acetate giving a light amber solution which was concentrated to afford 897 g (92%) of (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid ethyl ester as a light amber oil: 1H NMR (400 MHz, CDCl3) δ7.89 (d, J=8.1 Hz, 1H), 7.63-7.67 (m, 2H), 7.18-7.38 (m, 6H), 6.91 (dd, J=1.8, 7.8 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.55 (bs, 1H), 4.25 (dd, J=2.7, 11.2 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.00 (ddd, J=1.0, 4.5,11.2 Hz, 1H), 2.75 (dd, J=6.4, 13.9 Hz, 1H), 2.56 (dd, J=9.3, 13.8 Hz, 1H), 2.26 (m, 1H), 1.93 (d, J=4.3 Hz, 1H), 1.09 (t, J=7.2 Hz, 3H); IR 3307 (br), 3216 (br), 1734, 1339, 1298, 1247, 1191, 1175, 1118, 1097, 1050 cm−1.

Workup

  1. temperaturewas heated
  2. customthe reaction
  3. filtrationfiltered through Celiteeand
  4. washwashed with 10% aqueous sodium bicarbonate (1.5 L)
  5. customThe aqueous layer was separated
  6. extractionextracted with isopropyl ether (3 L)
  7. washThe combined organic layers were washed with water (6 L)
  8. dry with materialdried over magnesium sulfate
  9. additiontreated with Darco®G-60 (1.0 kg) and silica gel (1 kg, 70-230 mesh) at ambient temperature
  10. filtrationThis mixture was filtered through a pad of silica gel (70-230 mesh)
  11. concentrationconcentrated in vacuo to 922 g of dark oil
  12. additionThis oil was diluted with ethyl acetate (1 L)
  13. filtrationfiltered through a column of silica gel (2 kg)
  14. washeluting with ethyl acetate giving a light amber solution which
  15. concentrationwas concentrated

Sources & evidence

ORD record
ord-cda89e4df9064d8e82d52e0cb5ac033a
Source dataset
uspto-grants-2002_03
Patent number
US06355825B1

Reaction notes

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