1-Hydroxybenzotriazole → Dapitant

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.

1. temperaturethis solution is then cooled to +5° C.
2. additionis added rapidly
3. washwashed with 20 cm3 of water
4. washsubsequently washed with 20 cm3 of an aqueous saturated solution of sodium chloride (twice),
5. dry with materialdried over magnesium sulphate
6. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
7. customThe residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.8 cm, height 20 cm)
8. washby eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume)
9. customcollecting fractions of 25 cm3
10. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
11. customThe residue is crystallised in a mixture of acetonitrile and diisopropyl ether

ORD 기록

ord-ef967c78245b4b9db86d25313f10d712

출처 데이터셋

uspto-grants-1995_10

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US05463077