1-Hydroxybenzotriazole → Dapitant

Participants

Reaction Steps

0,025 g of 1-hydroxybenzotriazole, 0.38 g of (S)-2-(2-methoxyphenyl)-propionic acid and 0.32 cm3 of diisopropylethylamine are added to a suspension of 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 60 cm3 of dry methylene chloride, this solution is then cooled to +5° C. and a suspension of 0.43 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in 10 cm3 of dry methylene chloride is added rapidly. The reaction mixture is stirred at +5° C. for 2 hours and at room temperature for 2 hours, washed with 20 cm3 of water, subsequently washed with 20 cm3 of an aqueous saturated solution of sodium chloride (twice), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.8 cm, height 20 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting fractions of 25 cm3. Fractions 9 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised in a mixture of acetonitrile and diisopropyl ether. 0.17 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[2-(2-methoxyphenyl)-(S)-propionyl]-perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 244° C.

Provenance & Evidence