Ethyl Acetate → HCID 178424149, compound

Temperature

95 °C

Under inert gas, 40 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium were added to a mixture of 97 mg of 2-methylphenylboronic acid, 350 mg of [5-(4-bromophenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]amine and 571 mg of cesium carbonate in 4.5 ml of dioxane and 1.5 ml of water. After stirring at 95° C. for 30 minutes, the reaction was allowed to cool to room temperature, 50 ml of ethyl acetate were added and the organic phase was washed with 20 ml of water and 20 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. To detach the protecting group, the residue was dissolved in 4 ml of methanol, 0.4 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated by rotary evaporation, and the residue was taken up in 20 ml of dichloromethane and washed with 10 ml of water. The aqueous phase was extracted once again with 10 ml of dichloromethane, and the combined organic phases were dried using a phase separator cartridge (Chromabond® PTS) and concentrated by rotary evaporation. The crude product was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (120 mg) with a molecular weight of 496.6 g/mol (C27H29FN2O4S); MS (ESI): m/e=497 (M+H+).

1. temperatureto cool to room temperature
2. washthe organic phase was washed with 20 ml of water and 20 ml of saturated aqueous sodium chloride solution
3. dry with materialThe organic phase was dried over MgSO4
4. concentrationconcentrated by rotary evaporation
5. customThe crude product was purified by means of normal phase chromatography
6. concentrationconcentrated by rotary evaporation
7. dissolutionthe residue was dissolved in 4 ml of methanol
8. addition0.4 ml of concentrated hydrochloric acid was added
9. stirringthe mixture was stirred at room temperature for 16 hours
10. concentrationThe reaction solution was concentrated by rotary evaporation
11. washwashed with 10 ml of water
12. extractionThe aqueous phase was extracted once again with 10 ml of dichloromethane
13. customthe combined organic phases were dried
14. concentrationconcentrated by rotary evaporation
15. customThe crude product was purified in a purification laboratory by means of preparative HPLC
16. customthe acetonitrile was removed under reduced pressure
17. extractionextracted with dichloromethane
18. dry with materialThe organic phase was dried over MgSO4
19. concentrationconcentrated by rotary evaporation
20. additionthe residue was taken up again in a mixture of acetonitrile and water

ORD record

ord-41c5aa39e4bb447cb302a8639296c911

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08895547B2