Diisopropylethylamine → 7-[(2-Chloro-4-fluorophenyl)carbonyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I4) (287 mg, 1.5 mmol) and DIPEA (0.314 mL, 1.800 mmol) were dissolved at 0° C. in dichloromethane (DCM) (15 mL). 2-chloro-4-fluorobenzoyl chloride (290 mg, 1.500 mmol, commercially available from e.g. Sigma-Aldrich, Maybridge or Apollo) dissolved in DCM (5 mL) was added dropwise and the solution stirred to room temperature over 4 h. Solvents were removed in vacuo and the residue was partitioned between dichloromethane (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with dichloromethane (3×50 mL) and the combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil (759 mg). The crude product was purified by flash chromatography (Isolera, 25 g, 0-100% 2M ammonia in methanol:dichloromethane (1:9)/dichloromethane) to afford crude product. Concentration of the waste afforded material which was also identified as product. Samples were combined to afford crude product. This was purified by MDAP, product containing fractions concentrated and loaded directly on to an SCX cartridge (Varian, 10 g). The column was washed with methanol and the product eluted with 2M ammonia methanol. The solvents were evaporated in vacuo to afford the desired product in 318 mg.

1. additionwas added dropwise
2. customSolvents were removed in vacuo
3. customthe residue was partitioned between dichloromethane (50 mL) and saturated sodium bicarbonate solution (25 mL)
4. extractionThe aqueous phase was extracted with dichloromethane (3×50 mL)
5. washthe combined extracts were washed with water (50 mL), brine (50 mL)
6. dry with materialdried over anhydrous sodium sulfate
7. concentrationconcentrated in vacuo
8. customto afford a crude oil (759 mg)
9. customThe crude product was purified by flash chromatography (Isolera, 25 g, 0-100% 2M ammonia in methanol:dichloromethane (1:9)/dichloromethane)
10. customto afford crude product
11. customConcentration of the waste afforded material which
12. customto afford crude product
13. customThis was purified by MDAP, product
14. additioncontaining fractions
15. concentrationconcentrated and loaded directly on to an SCX cartridge (Varian, 10 g)
16. washThe column was washed with methanol
17. washthe product eluted with 2M ammonia methanol
18. customThe solvents were evaporated in vacuo

ORD-Eintrag

ord-ff3fc47b58894d9c8b466df7cf02afb2

Quelldatensatz

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08513248B2