Hydrochloric Acid → 3-(1-Methylcyclohexyl)-1-p-tolyl-1H-pyrazol-5-amine

HRID 571101Notes

Reaction equation

HRID 571101 reaction equation
[C:1](#[N:3])[CH3:2].CC([O-])(CC)C.[K+].[CH3:11][C:12]1([C:18](OC)=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.Cl>C1COCC1>[CH3:11][C:12]1([C:18]2[CH:2]=[C:1]([NH2:3])[N:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:31])=[CH:24][CH:25]=3)[N:30]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 6342AcetonitrileHCID 125044-Methylphenylhydrazine monohydrochlorideHCID 524785Methyl 1-methylcyclohexanecarboxylateHCID 23683543Potassium t-amylate

Product 1

HCID 674516353-(1-Methylcyclohexyl)-1-p-tolyl-1H-pyrazol-5-amine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a mixture of acetonitrile (500 μL, 10.0 mmol) in THF (30 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in THF (1.7 M, 16.9 mL, 28.7 mmol), followed by methyl 1-methylcyclohexanecarboxylate (2.24 g, 14.4 mmol) and the reaction mixture maintained at RT for 17 hr and then concentrated to ˜20 mL in vacuo. The residue was diluted with EtOH (20 mL), treated with p-tolylhydrazine hydrochloride (1.52 g, 9.57 mmol) and the resulting mixture acidified to pH1 by the addition of conc hydrochloric acid and then heated to 70° C. for 5 hr. The mixture was cooled to RT for 16 hr and concentrated to ˜20 mL in vacuo, diluted with water (30 mL) and was then basified to pH 12 by the addition of 2M aq NaOH. The resulting solution was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-20%, gradient elution) to afford the title compound, Intermediate A33, as a yellow oil, (˜50% purity, containing 3-(1-methylcyclohexyl)-3-oxopropanenitrile) (1.30 g, 25%); Rt 1.97 min (Method 2); m/z 270 (M+H)+ (ES+). The material was used in subsequent reactions without further purification.

Workup

  1. concentrationconcentrated to ˜20 mL in vacuo
  2. additionThe residue was diluted with EtOH (20 mL)
  3. temperatureheated to 70° C. for 5 hr
  4. temperatureThe mixture was cooled to RT for 16 hr
  5. concentrationconcentrated to ˜20 mL in vacuo
  6. additiondiluted with water (30 mL)
  7. additionwas then basified to pH 12 by the addition of 2M aq NaOH
  8. extractionThe resulting solution was extracted with EtOAc (2×20 mL)
  9. washthe combined organic extracts were washed with brine (30 mL)
  10. customdried
  11. customevaporated in vacuo
  12. customThe residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-20%, gradient elution)

Sources & evidence

ORD record
ord-47dec1553c2f49b0a26c2318026ab96e
Source dataset
uspto-grants-2015_05
Patent number
US09024041B2

Reaction notes

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