4-Methylpyridine → tert-Butyl 4-(2-oxo-3-(pyridin-4-yl)propyl)piperidine-1-carboxylate

Temperature

-78 °C

To a solution of diisopropylamide (6.15 mL, 43.91 mmol) in dry tetrahydrofuran (40 mL) at 0° C. was added 2.5 M butyl lithium solution in hexane (16.22 mL, 40.53 mmol) dropwise over 10 minutes. After the addition, the lithium diisopropylamide solution was stirred at 0° C. for 20 minutes, then cooled to −78° C. 4-Picoline (3.98 mL, 40.53 mmol) was added to the above lithium diisopropylamide solution under N2 dropwise over 10 minutes. The resulting solution was stirred at −78° C. under N2 for 1.5 hours, then transfered into a suspension of anhydrous cerium chloride (10.0 g, 40.53 mmol) in tetrahydrofuran (40 mL) at −78° C. under N2. The mixture was stirred at −78° C. under N2 for 2 hours, then a solution of ethyl 1-[(1,1-dimethylethoxy)carbonyl]-4-piperidineacetate (from step 1 of this Example) (10.98 g, 40.53 mmol) in tetrahydrofuran (40 mL) was added slowly for 1 hour. The mixture was stirred under N2 from −78° C. to room temperature overnight. The reaction was quenched with water, diluted with ethyl acetate, and washed with a pH 7 buffer. The organic layer was washed with water and brine. After filtration, the solvent was removed under reduced pressure to give a crude product mixture. The desired product 1,1-dimethylethyl 4-[2-oxo-3-(4-pyridinyl)propyl]-1-piperidinecarboxylate (3.19 g, 25%) was isolated by chromatography (silica gel, 50:50–75:25–100:0 ethyl acetate/hexane).

1. additionAfter the addition
2. stirringThe mixture was stirred at −78° C. under N2 for 2 hours
3. customwas added slowly for 1 hour
4. stirringThe mixture was stirred under N2 from −78° C. to room temperature overnight
5. customThe reaction was quenched with water
6. additiondiluted with ethyl acetate
7. washwashed with a pH 7 buffer
8. washThe organic layer was washed with water and brine
9. filtrationAfter filtration
10. customthe solvent was removed under reduced pressure
11. customto give a crude product mixture

ORD record

ord-dd243d6c48544f418374a07fd5e7de6b

Source dataset

uspto-grants-2006_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07153959B2