Methylglyoxal → tert-Butyl 2'-tert-butyl-7'-oxo-6',7'-dihydro-1H,2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazole]-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

To a 200 L reactor was charged: water (72 L) and (1,1-dimethylethyl)hydrazine monohydrochloride (13.4 kg, 108 moles). Solution was agitated for 15 minutes at 23° C. (until all solids dissolved), then 2-oxo-propanal (14.8 kg, 82.1 moles) was added and held for a minimum of 4 hours. Reaction solution was extracted 2×'s MTBE (54 L). The combined organic layers were washed 2×'s 1N NaOH (32 L), 1× water (32 L), and concentrated (220 mmHg, 30° C.) to a minimum stirring volume. To the concentrate was added: water (72 L), Ethanedial (glyoxaldehyde) (27.3 kg, 188 moles) and heated reaction to 95° C., allowing residue MTBE to distill off in order to reach desired temperature. After 1.5 hours, mixture cooled to ambient temperature (over 1 hour) and was extracted 2×'s MTBE (54 L). The combined organic layers were washed 2×'s 1N NaOH (34 L). The combined aqueous layers was cooled to 5° C., acidified to pH 3 with HCl 33-40 wt/wt % in water (6 L), then extracted 2×'s MTBE (54 L). The combined organic layers were washed with water (36 L) and concentrated (200 mmHg, 30° C.) to a minimal stirring volume. To the concentrate was added: methanol (109 L), N—BOC-4-piperidone (16.7 kg, 84 moles), and pyrrolidine (1.4 L, 16 moles). Reaction was heated to 68° C. for 24 hours, cooled to 50° C., and pulled vacuum to distill to a minimum stirring volume. Removed vacuum and added ethyl acetate (45 L), distilled (atmospheric pressure) to a low stirring volume, then added MTBE (72 L). Returned solution to a gentle reflux, then added n-heptane (82 L), over 30 minutes, while cooling to ambient temperature over 3 hours. Filtered the solids through a Nutsche Filter, washed with 1:1.1 MTBE/n-heptane (50 L), and dried under vacuum at 50° C. for 12 h. Isolated 10.0 kg (27.5 moles, 33% overall) of tert-butyl 2′-tert-butyl-7′-oxo-6′,7′-dihydro-2′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazole]-1-carboxylate as a white crystalline solid.

Provenance & Evidence