Methanesulfonyl chloride → tert-Butyl 4-cyano-3,6-dihydropyridine-1(2H)-carboxylate

Temperature

0 °C

Methanesulfonyl chloride (0.189 mL, 2.43 mmol) was added to a mixture of tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate (500 mg, 2.21 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.579 mL, 3.31 mmol) in chloroform (8.8 mL) at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes, and was then partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, and the dried solution was filtered. The filtrate was concentrated in vacuo, and the residue was dissolved in pyridine (5.5 mL). The reaction mixture was heated to 120° C. for 4 hours, and was then cooled to ambient temperature. The cooled reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed sequentially with water and saturated aqueous sodium chloride solution. The washed solution was dried over anhydrous sodium sulfate, and the dried solution was filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash-column chromatography (using a gradient elution of 0-100%, ethyl acetate/hexanes) to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 6.55 (br s, 1H), 4.05 (m, 2H), 3.55 (t, J=5.6 Hz, 2H), 2.34 (br s, 2H), 1.46 (s, 9H).

1. customwas then partitioned between dichloromethane and water
2. dry with materialThe organic layer was dried over anhydrous sodium sulfate
3. filtrationthe dried solution was filtered
4. concentrationThe filtrate was concentrated in vacuo
5. dissolutionthe residue was dissolved in pyridine (5.5 mL)
6. temperatureThe reaction mixture was heated to 120° C. for 4 hours
7. temperaturewas then cooled to ambient temperature
8. customThe cooled reaction mixture
9. customwas partitioned between ethyl acetate and water
10. washthe organic layer was washed sequentially with water and saturated aqueous sodium chloride solution
11. dry with materialThe washed solution was dried over anhydrous sodium sulfate
12. filtrationthe dried solution was filtered
13. concentrationThe filtrate was concentrated in vacuo
14. customthe residue was purified by flash-column chromatography (
15. washa gradient elution of 0-100%, ethyl acetate/hexanes)

ORD record

ord-111ec17b6a394e53a81c574a8eeccd0d

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09394282B2