Sodium amide → tert-Butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A 500-mL flask equipped with an N2 inlet/temperature probe, overhead stirrer and an addition funnel was charged with sodium amide (13.3 g, 327.3 mmol) and tetrahydrofuran (110 g) then warmed to 35° C. Through the addition funnel was slowly charged the tetrahydrofuran/toluene solution of Example 8 (35.57 g, 130.9 mmol). The addition funnel was rinsed with tetrahydrofuran (12 g). The reaction temperature was adjusted to 50° C. and the reaction was stirred for 3 hours before an HPLC sample was taken that showed the reaction was complete. In a separate flask equipped with an overhead stirred and a thermocouple was charged water (142 g), acetic acid (31.5 g) and toluene (54 g). The resulting mixture was then chilled to 0° C. The heterogeneous reaction mixture was quenched by addition to the acetic acid/toluene mixture while maintaining the temperature below 25° C. The reaction flask was rinsed with toluene (14 g) and water (14 g), which were added to the quench flask. The pH of the quench mixture was 6.04. The pH of the mixture was adjusted to 7.5 using 50% NaOH solution (11 g). The aqueous layer was extracted with 1:1 toluene/tetrahydrofuran (50 g). The organic layers were combined, filtered through a fritted glass filter and concentrated to a total volume of about 75 mL. The residue was diluted with toluene (125 g) and concentrated to a total volume of about 100 mL. Solid had formed during the distillations. The mixture was cooled to 0° C. and stirred for 1 hour. The mixture was filtered and the solid was washed with three portions of cold toluene and dried under vacuum to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 3H) 1.37-1.51 (m, 2H) 1.44 (s, 9H) 1.88-1.98 (m, 2H) 3.19-3.32 (m, 2H) 3.51-3.68 (m, 2H) 5.56-5.76 (m, 2H).

Provenance & Evidence