Triethylamine → (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate

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Reaction Steps

To a stirred, ice-cold solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (233 g, 1.2 mol) in THF (1.2 L) was added carbonyldiimidazole (230 g, 1.42 mol) under stirring. The mixture was stirred for 1 h in the ice-water bath. A suspension of triethylamine (207 mL, 1.41 mol) and N,O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900 mL) was added. The reaction mixture was allowed to warm to rt and stirred overnight. Tlc showed the reaction was complete. Solvent was evaporated, and the residue was dissolved in CH2Cl2 (1.2 L), washed successively with 0.5 N aq HCl, satd aq Na2CO3 and brine, dried over Na2SO4 and evaporated to give (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 g, 90.6%), which was used in the next step directly without further purification. Chiral HPLC indicated that the product had an enantiomeric excess of 96%˜98%. 1H NMR (400 MHz, CDCl3): 4.05-4.19 (m, 2H), 3.71 (s, 3H), 3.16 (s, 3H), 2.75-2.85 (m, 2H), 2.65 (t, 1H), 1.90 (d, 1H), 1.60-1.78 (m, 2H), 1.44 (s, 9H).

Provenance & Evidence