Hydrochloric Acid → HCID 63083433, compound

Isopropylmagnesium chloride-lithium chloride complex-tetrahydrofuran solution (1.3 M, 20.7 mL, 27.0 mmol) was added dropwise to 5-bromo-2-chloropyridine (5.20 g, 27.0 mmol) in tetrahydrofuran (40 mL) under cooling with ice, and the reaction mixture was stirred for 30 minutes and then mixed with ethyl 2,2,2-trifluoroacetate (11.5 g, 81.0 mmol) under cooling with ice and stirred at room temperature for 10 minutes. After addition of 1M hydrochloric acid, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil. The yellow oil was dissolved in nitromethane (30 mL) and stirred with potassium carbonate (3.73 g, 27.0 mmol) at room temperature for 30 minutes. The reaction mixture was added to 1M hydrochloric acid and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 (v/v)) to give a yellow oil. The yellow oil was dissolved in tetrahydrofuran (20 mL), mixed with 10% palladium-carbon (600 mg) and triethylamine (2.60 mL, 18.7 mmol) and then stirred at room temperature for one day under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate/methanol/triethylamine=9/1/1 (v/v/v)) to give the title compound as a colorless solid (913 mg, yield 31% (4 steps)).

1. temperatureunder cooling with ice
2. temperatureunder cooling with ice
3. stirringstirred at room temperature for 10 minutes
4. extractionthe reaction mixture was extracted with ethyl acetate
5. dry with materialthe organic layer was dried over anhydrous sodium sulfate
6. concentrationconcentrated under reduced pressure
7. customto give a yellow oil
8. extractionextracted with ethyl acetate
9. dry with materialthe organic layer was dried over anhydrous sodium sulfate
10. concentrationconcentrated under reduced pressure
11. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 (v/v))
12. customto give a yellow oil
13. stirringstirred at room temperature for one day under a hydrogen atmosphere
14. filtrationThe reaction mixture was filtered
15. concentrationthe filtrate was concentrated under reduced pressure
16. customThe residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate/methanol/triethylamine=9/1/1 (v/v/v))

ORD record

ord-5d2d5438a0704c938e100d6fa11fced3

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09216999B2