Potassium tert-butoxide → (3S,4R)-3-benzyl-7-bromo-chroman-4-ol

HRID 277450Notes

Reaction equation

HRID 277450 reaction equation
[CH2:1]([C@@H:8]([CH2:19][OH:20])[C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1F)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH2:1]([C@@H:8]1[C@@H:9]([OH:10])[C:11]2[C:16](=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 23665647Potassium tert-butoxideHCID 57112909(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol

Product 1

HCID 11278601(3S,4R)-3-benzyl-7-bromo-chroman-4-ol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (prepared from 33.5 kg (54.8 moles) of [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one, 1-methyl-2-pyrrolidinone solvate without isolation) in 185 L of tetrahydrofuran was added 12.9 kg (115 mol) of potassium tert-butoxide. The reaction mixture was heated at reflux for 4 hours at which point the reaction was found to be complete by thin layer chromatography (hexanes/ethyl acetate, 3:1). The reaction mixture was cooled to ambient temperature, quenched with 170 L of water, diluted with 83 L of ethyl acetate, and acidified to pH 5.3 (aqueous layer) with 7.5 L of concentrated hydrochloric acid. The organic layer was concentrated under vacuum to approximately 38 L of a slurry, diluted with 76 L of isopropyl ether, warmed to dissolve the solids, slowly cooled to 0° C., and granulated at 0° C. for 12 hours. (3S,4R)-3-Benzyl-7-bromo-chroman-4-ol, 5.1 kg of white solid, was isolated by filtration. The mother liquor was washed with 4 L of saturated aqueous sodium chloride, concentrated to a final volume of 57 L, and granulated at 0° C. for 12 hours affording a 4.3 kg second crop of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux for 4 hours at which
  3. customquenched with 170 L of water
  4. additiondiluted with 83 L of ethyl acetate
  5. concentrationThe organic layer was concentrated under vacuum to approximately 38 L of a slurry
  6. additiondiluted with 76 L of isopropyl ether
  7. temperaturewarmed
  8. dissolutionto dissolve the solids
  9. temperatureslowly cooled to 0° C.

Sources & evidence

ORD record
ord-79e5269be585437eb98b9570df660fe7
Source dataset
uspto-grants-2002_03
Patent number
US06355825B1

Reaction notes

Loading…