Diethyl Oxalate → 1-(6-Methoxy-3-pyridyl)-5-(1-methylpyrrol-2-yl)pyrazole-3-carboxylic acid

HRID 1437286Notes

Reaction equation

HRID 1437286 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=O)[CH3:18].[C:20](OCC)(=O)[C:21]([O:23]CC)=[O:22].Cl.[NH:31]([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)[NH2:32]>O1CCCC1.C(O)(=O)C.C(O)C.C(N(CC)CC)C>[CH3:40][O:39][C:36]1[N:37]=[CH:38][C:33]([N:31]2[C:17]([C:13]3[N:12]([CH3:11])[CH:16]=[CH:15][CH:14]=3)=[CH:18][C:20]([C:21]([OH:23])=[O:22])=[N:32]2)=[CH:34][CH:35]=1

Participants

9

Reactant 4

HCID 7268Diethyl OxalateHCID 612402-Acetyl-1-methylpyrroleHCID 2733832Lithium HexamethyldisilazideHCID 230902035-Hydrazinyl-2-methoxypyridine hydrochloride

Product 1

HCID 230901161-(6-Methoxy-3-pyridyl)-5-(1-methylpyrrol-2-yl)pyrazole-3-carboxylic acid

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent2×HCID 8471TriethylamineSolvent

Conditions

Temperature
-78 °C

Procedure

Under cooling at −78° C., 1.0 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (10.4 mL) was added to 1-(1-methylpyrrol-2-yl)-1-ethanone (1.19 mL) in tetrahydrofuran (10 mL), followed by stirring for 35 minutes. Diethyl oxalate (2.05 mL) was added to the reaction mixture, and the resultant mixture was gradually returned to room temperature, followed by stirring at room temperature for 2.5 hours. To the reaction mixture, triethylamine (1.64 mL), 5-hydrazino-2-methoxypyridine hydrochloride (2.52 g) obtained from Referential Example 1, and ethanol (50 mL) were added. The mixture was refluxed under heat for 2.5 days. Acetic acid (5 mL) was added thereto, and the reaction mixture was refluxed under heat for 3 days, and then cooled in air. The reaction solvent was removed under reduced pressure. The residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonat, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate-hexane), to thereby give 1-(6-methoxy-3-pyridyl)-5-(1-methylpyrrol-2-yl)pyrazole-3-carboxylic acid ethyl ester as an oily product (2.70 g, 82%). Aqueous 1N sodium hydroxide (21 mL) was added to the thus-obtained ethyl ester (2.70 g) in ethanol (20 mL), followed by stirring at room temperature for 26 hours. The reaction mixture was partitioned by use of aqueous 1N hydrochloric acid and ethyl acetate, and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give the title compound as an amorphous solid (2.57 g, quantitative amount). Without further purification, the compound was subjected to the following reaction.

Workup

  1. customwas gradually returned to room temperature
  2. stirringby stirring at room temperature for 2.5 hours
  3. additionwere added
  4. temperatureThe mixture was refluxed
  5. temperatureunder heat for 2.5 days
  6. temperaturethe reaction mixture was refluxed
  7. temperatureunder heat for 3 days
  8. temperaturecooled in air
  9. customThe reaction solvent was removed under reduced pressure
  10. customThe residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonat
  11. extractionthe aqueous layer was extracted with ethyl acetate
  12. dry with materialdried over sodium sulfate anhydrate
  13. filtrationfollowed by filtration
  14. customThe solvent was removed under reduced pressure
  15. customthe residue was purified through silica gel column chromatography (ethyl acetate-hexane)
  16. additionAqueous 1N sodium hydroxide (21 mL) was added to the thus-obtained ethyl ester (2.70 g) in ethanol (20 mL)
  17. stirringby stirring at room temperature for 26 hours
  18. customThe reaction mixture was partitioned by use of aqueous 1N hydrochloric acid and ethyl acetate
  19. extractionthe aqueous layer was extracted again with ethyl acetate
  20. dry with materialdried over magnesium sulfate anhydrate
  21. filtrationfollowed by filtration
  22. customThe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-97fcef9d964d42b38a8d05d0caf935c0
Source dataset
uspto-grants-2009_11
Patent number
US07622471B2

Reaction notes

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