Ethyl bromoacetate → Ethyl 3-cyano-3-(3,4-dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanoate

To a solution of diisopropylamine (25.9 ml, 1 mol. equiv.) in tetrahydrofuran (200 ml) at −78° C. under nitrogen was added n-butyllithium (73.9 ml of a 2.5M solution, 1 mol. equiv.). The solution was allowed to warm to room temperature over two hours. A solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butanenitrile (PREPARATION 17) (58 g, 158 mmol) in tetrahydrofuran (200 ml) was then added and the solution was stirred for one hour. A solution of ethyl-2-bromoacetate (20.5 ml, 1 mol. equiv.) in tetrahydrofuran (50 ml) was then added and the reaction was heated to reflux for two hours. Water (10 ml) was then added and the solution was concentrated under reduced pressure. Water (300 ml) and brine (300 ml) were added and the mixture was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with water (2×300 ml), dried over anhydrous magnesium sulphate, filtered and the solvent was removed under reduced pressure. Chromatography using silica gel, eluting with diethyl ether:hexane using gradient elution (4:1 to 1:1 by volume), gave the title compound.

1. temperaturethe reaction was heated
2. temperatureto reflux for two hours
3. concentrationthe solution was concentrated under reduced pressure
4. additionWater (300 ml) and brine (300 ml) were added
5. extractionthe mixture was extracted with ethyl acetate (2×300 ml)
6. washThe combined organic layers were washed with water (2×300 ml)
7. dry with materialdried over anhydrous magnesium sulphate
8. filtrationfiltered
9. customthe solvent was removed under reduced pressure
10. washeluting with diethyl ether
11. washhexane using gradient elution (4:1 to 1:1 by volume)

ORD record

ord-277369898091446b9794bf5ba7c7a66e

Source dataset

uspto-grants-2001_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06242438B1