Triethylamine → (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone

Temperature

10 °C

To a suspension of (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (45.56 g, 208.3 mmol) in anhydrous acetonitrile (200 mL) at 10° C. was added triethylamine (50 mL). The suspension was poured into a 2 L 3-neck flask equipped with a thermometer and a magnetic stirrer. To the original flask was added anhydrous acetonitrile followed by sonication and addition of triethylamine (80 mL). The suspensions were combined and cooled to 10° C. and 6-chloro-3-nitropyridin-2-amine (32.97 g, 190 mmol) was added. The bright yellow solution was stirred under nitrogen while the temperature was increased gradually to 80° C. over 1 h. The reaction mixture was cooled to room temperature. The resulting suspension was filtered and the solids were rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride (500 mL) was added to the residue and the mixture was extracted into ethyl acetate (2×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried for 18 h under high vacuum to afford (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone as a yellow foam (63.51 g). 1H NMR (400 MHz, CD3OD) δ 1.47-1.64 (m, 1H) 1.71-2.07 (m, 7H) 2.68 (tt, 1H) 3.01 (q, 2H) 3.33-3.46 (m, 2H) 3.52 (dt, 1H) 3.60-3.70 (m, 1H) 4.41 (br s, 1H) 4.71 (d, 1H) 6.23 (d, 1H) 8.05 (d, 1H); MS (ES+) (M+H) 320.4.

1. additionThe suspension was poured into a 2 L 3-neck flask
2. customequipped with a thermometer and a magnetic stirrer
3. temperaturewas increased gradually to 80° C. over 1 h
4. temperatureThe reaction mixture was cooled to room temperature
5. filtrationThe resulting suspension was filtered
6. washthe solids were rinsed with ethyl acetate
7. concentrationThe filtrate was concentrated under reduced pressure
8. additionA saturated aqueous solution of ammonium chloride (500 mL) was added to the residue
9. extractionthe mixture was extracted into ethyl acetate (2×)
10. washThe combined organics were washed with brine
11. dry with materialdried over magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customdried for 18 h under high vacuum

ORD record

ord-c86cf98590304505a40cfac38462692d

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296745B2