Hydrochloric Acid → (S)-1-[3-(2',4'-difluoro-biphenyl-4-yloxymethyl)-benzoyl]-pyrrolidine-2-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

3-(2′,4′-Difluoro-biphenyl-4-yloxymethyl)-benzoic acid (4.0 g, 11.76 mmol) in 125 mL toluene was treated with thionyl chloride (8.28 mL, 117.6 mmol) and DMF (200 uL) was heated to 80-90° C. for 3 hrs. The reaction mixture was cooled, evaporated and re-evaporated from toluene 4 times to give a yellow oil that crystallized by pumping under high vacuum. This acid chloride was dissolved in 160 mL acetonitrile to which was added a solution of L-proline (2.62 g, 22.8 mmol) in 33 mL H2O and 1N Na2CO3 (22.8 mL, 22.8 mmol). The reaction mixture was stirred at RT for 45 min, diluted with 300 mL H2O and 450 mL ethyl acetate. The mixture was acidified to pH 2 with 1N HCl. The ethyl acetate layer was separated, washed with H2O, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography with a 0-90% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in hexanes to yield 4.67 g (90.8%) of (S)-1-[3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-benzoyl]-pyrrolidine-2-carboxylic acid as a white solid. LC-MS (ES) calculated for C25H21F2NO4, 437.45; found m/z 438.1 [M+H]+.

Provenance & Evidence