2,6-Dibromopyridine → (6-Bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone

Temperatur

-70 °C

Add a solution of n-butyllithium (1.9M in n-hexane, 4 ml, 7.6 mmol) to a solution of 2,6-dibromopyridine (1.81 g, 7.64 mmol) in MTBE (20 mL) dropwise under nitrogen, over 20 min., maintaining the temperature between −72 and −67° C. Stir the yellow heterogeneous solution at −70° C. for 20 min. to provide a green homogeneous solution. Add a solution of 1-methyl-4-(pyrrolidin-1-yl-carbonyl)piperidine (1 g, 5.09 mmol) in 10 mL MTBE dropwise over 20 min., maintaining the temperature below −69° C. Stir the yellow mixture at −75° C. for 1 hr. Quench the reaction mixture with a saturated solution of ammonium chloride (5 mL) between 0 and 10° C. Acidify the mixture to pH 2 with fuming HCl (2 mL). Extract the organic layer. Wash the aqueous phase with MTBE (50 mL), make the aqueous layer basic with a solution of 30% NaOH, and extract with ethyl acetate (2×50 mL). Combine the organic layers, dry over MgSO4, and concentrate under reduced pressure at 40° C. to provide the title intermediate as an oil (1.23 g, 85% yield).

1. temperaturemaintaining the temperature between −72 and −67° C
2. customto provide a green homogeneous solution
3. temperaturemaintaining the temperature below −69° C
4. stirringStir the yellow mixture at −75° C. for 1 hr
5. customQuench the reaction mixture with a saturated solution of ammonium chloride (5 mL) between 0 and 10° C
6. extractionExtract the organic layer
7. washWash the aqueous phase with MTBE (50 mL)
8. extractionextract with ethyl acetate (2×50 mL)
9. dry with materialCombine the organic layers, dry over MgSO4
10. concentrationconcentrate under reduced pressure at 40° C.

ORD-Eintrag

ord-e4a2a567d95c41c0ad27abb7aab0d7f8

Quelldatensatz

uspto-grants-2008_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07423050B2