2,6-Dichloropyridine → HCID 86609668, compound

Temperature

-78 °C

Dissolve 1-methyl-4-(methylamino)piperidine (10 mL, 68.8 mmol) in tetrahydrofuran (50 mL) and cool to −78° C. Slowly add n-butyllithium (1.6 N in hexane, 43 mL, 68.8 mmol) to the reaction mixture and stir at −78° C. for 30 min. Warm the reaction mixture to room temperature and stir for 30 min. Then cool the reaction mixture to −78° C. and add 2,6-dichloropyridine (11.2 g, 75.7 mmol) in tetrahydrofuran (50 mL). Stir the reaction mixture at −78° C. for 15 min, warm to room temperature, and then heat to 60° C. for 19 hr. Cool the reaction mixture to room temperature and partition between ethyl acetate and water. Separate the organic layer and extract the aqueous layer with dichloromethane (2×50 mL). Combine organic extracts, dry (MgSO4), filter, and concentrate in vacuo. Purify the residue by column chromatography on silica gel using a gradient of 2%-10% (2M NH3 in methanol) in CH2Cl2 to give of the title intermediate (11.91 g, 72%): mass spectrum (ion spray): m/z=240.1 (M+1); 1H NMR: δ (CDCl3, ppm) 7.34 (t, J=7.6, 16.0 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H), 4.41 (m, 1H), 2.94 (m, 2H), 2.86 (s, 3H), 2.32 (s, 3H), 2.15 (m, 2H), 1.84 (m, 2H), 1.68 (m, 2H).

1. temperatureWarm the reaction mixture to room temperature
2. temperatureThen cool the reaction mixture to −78° C.
3. stirringStir the reaction mixture at −78° C. for 15 min
4. temperaturewarm to room temperature
5. temperatureheat to 60° C. for 19 hr
6. temperatureCool the reaction mixture to room temperature
7. custompartition between ethyl acetate and water
8. customSeparate the organic layer
9. extractionextract the aqueous layer with dichloromethane (2×50 mL)
10. dry with materialCombine organic extracts, dry (MgSO4)
11. filtrationfilter
12. concentrationconcentrate in vacuo
13. customPurify the residue by column chromatography on silica gel using a gradient of 2%-10% (2M NH3 in methanol) in CH2Cl2

ORD record

ord-a80899d09a5542ae82531cc9074630bb

Source dataset

uspto-grants-2010_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07803813B2