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

HRID 1880342Notes

Reaction equation

HRID 1880342 reaction equation
Cl.[CH3:2][C:3]([NH:6][NH2:7])([CH3:5])[CH3:4].O=[C:9](C)[CH:10]=O.[CH:13](=[O:16])[CH:14]=O.[C:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].N1CCC[CH2:32]1>CO.CC(OC)(C)C.O>[C:3]([N:6]1[CH:10]=[C:9]2[O:30][C:27]3([CH2:28][CH2:29][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:25][CH2:26]3)[CH2:32][C:13](=[O:16])[C:14]2=[N:7]1)([CH3:5])([CH3:4])[CH3:2]

Participants

9

Reactant 5

HCID 880MethylglyoxalHCID 7860GlyoxalHCID 31268PyrrolidineHCID 81889tert-Butylhydrazine monohydrochlorideHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate

Product 1

HCID 66843844tert-Butyl 2'-tert-butyl-7'-oxo-6',7'-dihydro-1H,2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazole]-1-carboxylateYield 171.9%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
23 °C

Procedure

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.

Workup

  1. additionTo a 200 L reactor was charged
  2. additionwas added
  3. customheld for a minimum of 4 hours
  4. customReaction solution
  5. extractionwas extracted 2×'s MTBE (54 L)
  6. washThe combined organic layers were washed 2×'
  7. concentrationconcentrated (220 mmHg, 30° C.) to a minimum stirring volume
  8. additionTo the concentrate was added
  9. customreaction to 95° C.
  10. distillationto distill off in order
  11. waitAfter 1.5 hours
  12. temperaturemixture cooled to ambient temperature (over 1 hour)
  13. extractionwas extracted 2×'s MTBE (54 L)
  14. washThe combined organic layers were washed 2×'
  15. temperatureThe combined aqueous layers was cooled to 5° C.
  16. extractionextracted 2×'s MTBE (54 L)
  17. washThe combined organic layers were washed with water (36 L)
  18. concentrationconcentrated (200 mmHg, 30° C.) to a minimal stirring volume
  19. additionTo the concentrate was added
  20. customReaction
  21. temperaturewas heated to 68° C. for 24 hours
  22. temperaturecooled to 50° C.
  23. distillationto distill to a minimum stirring volume
  24. customRemoved vacuum
  25. additionadded ethyl acetate (45 L)
  26. distillationdistilled (atmospheric pressure) to a low stirring volume
  27. waitReturned solution to a gentle reflux, then added n-heptane (82 L), over 30 minutes
  28. temperaturewhile cooling to ambient temperature over 3 hours
  29. filtrationFiltered the solids through a Nutsche
  30. filtrationFilter
  31. washwashed with 1:1.1 MTBE/n-heptane (50 L)
  32. customdried under vacuum at 50° C. for 12 h

Sources & evidence

ORD record
ord-432fa2680a5d427eb45bb725f13720d3
Source dataset
uspto-grants-2012_11
Patent number
US08318762B2

Reaction notes

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