Diisopropylamine → tert-Butyl 4-(1-hydroxy-3-methoxy-3-oxo-1-(2-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate

Temperature

0 °C

A solution of diisoproplyamine (6.0 mL, 43 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. A 2.5M solution of n-butyllithium in hexanes (17.0 mL, 43 mmol) was added to the mixture drop-wise. Mixture was held at −78° C. with stirring for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (9.3 g, 36 mmol) in tetrahydrofuran (35 mL) was added to the mixture drop-wise. Mixture was held at −78° C. for 1.5 hours. In a separate flask, 60% sodium hydride in mineral oil (1.57 g, 39 mmol) was washed in hexanes and then suspended in tetrahydrofuran (70 mL). Mixture was cooled to 0° C. A solution of N-(3-formylpyridin-2-yl)pivalamide (6.74 g, 33 mmol) in tetrahydrofuran (20 mL) was added to the mixture drop-wise. Reaction was held at 0° C. with stirring for 2 hours. Mixture was warmed to room temperature and then added to the butyllithium containing solution drop-wise. Reaction mixture was held at −78° C. with stirring for 2 hours. Mixture was allowed to slowly warm to room temperature. Mixture stirred at room temperature for 14 hours. Reaction was quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate (2×100 mL). Organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as white foam in 93% yield. (M+H)+=464.2.

1. customwas held at −78° C.
2. waitMixture was held at −78° C. for 1.5 hours
3. customReaction
4. customwas held at 0° C.
5. stirringwith stirring for 2 hours
6. temperatureMixture was warmed to room temperature
7. customReaction mixture
8. customwas held at −78° C.
9. stirringwith stirring for 2 hours
10. temperatureto slowly warm to room temperature
11. stirringMixture stirred at room temperature for 14 hours
12. customReaction
13. customwas quenched with aqueous ammonium chloride
14. extractionThe mixture was extracted with ethyl acetate (2×100 mL)
15. dry with materialdried (magnesium sulfate)
16. filtrationfiltered
17. concentrationconcentrated in vacuo

ORD record

ord-97e69dc233ba4759ba1fa23bacedf769

Source dataset

uspto-grants-2008_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07384930B2