Diisopropylamine → tert-Butyl 4-(1-(3-fluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate

Temperature

-78 °C

Diisopropylamine (24.2 mmol, 3.40 mL) was dissolved in tetrahydrofuran (70 mL). The mixture was cooled to −78° C. 2N Butyllithium in cyclohexane (24.40 mmoles, 12.20 mL) was added drop-wise to the reaction. The mixture was held at −78° C. with stirring on and held for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (20.21 mmoles, 5.20 g) in 15 mL tetrahydrofuran was added to the mixture drop-wise. The mixture was held at −78° C. with stirring on and held for 45 min. In a seperate flask, 60% Sodium hydride in mineral oil (24.25 mmoles, 970.00 mg) was washed with hexanes then suspended in tetrahydrofuran (50.00 mL). The mixture was cooled to 0° C. A solution of N-(2-Fluoro-6-formylphenyl)pivalamide (20.16 mmoles, 4.50 g) in 20 mL tetrahydrofuran was added to the mixture drop-wise. The mixture was held at 0° C. with stirring on and held for 1 hr. Aldehyde mixture was added to the ester mixture drop-wise over 1.25 hours. The mixture was held at −78° C. with stirring on and held for 1 hr. The reaction was quenched with aq. ammonium chloride. Mixture was warmed to room temperature then diluted with water. The mixture was extracted 2 times with ethyl acetate and the aqueous phase was discarded. The material was dried (magnesium sulfate), filtered, and concentrated to dryness. Silica gel chromatography gave the title compound as white foam in 81% yield. MS m/e (M-C4H8O2+H)+=381.2.

1. customto the reaction
2. customwas held at −78° C.
3. customwas held at −78° C.
4. stirringwith stirring on and
5. waitheld for 45 min
6. temperatureThe mixture was cooled to 0° C
7. customwas held at 0° C.
8. stirringwith stirring on and
9. waitheld for 1 hr
10. customwas held at −78° C.
11. stirringwith stirring on and
12. waitheld for 1 hr
13. customThe reaction was quenched with aq. ammonium chloride
14. temperatureMixture was warmed to room temperature
15. additionthen diluted with water
16. extractionThe mixture was extracted 2 times with ethyl acetate
17. dry with materialThe material was dried (magnesium sulfate)
18. filtrationfiltered
19. concentrationconcentrated to dryness

ORD record

ord-7b045dba7149441e8c55a575ca308f6f

Source dataset

uspto-grants-2010_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07834007B2