Hydrochloric Acid → 3-(4-Methyltetrahydro-2H-pyran-4-yl)-1-(p-tolyl)-1H-pyrazol-5-amine

HRID 571088Notes

Reaction equation

HRID 571088 reaction equation
[C:1](#[N:3])[CH3:2].CC([O-])(CC)C.[K+].C1(C)C=CC=CC=1.[CH3:18][C:19]1([C:25](OC)=O)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl.[C:30]1([CH3:38])[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1.Cl>C1COCC1.CCO>[CH3:18][C:19]1([C:25]2[CH:2]=[C:1]([NH2:3])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:38])=[CH:31][CH:32]=3)[N:37]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 1140TolueneHCID 6342AcetonitrileHCID 125044-Methylphenylhydrazine monohydrochlorideHCID 11019135Methyl 4-methyloxane-4-carboxylateHCID 23683543Potassium t-amylate

Product 1

HCID 682299493-(4-Methyltetrahydro-2H-pyran-4-yl)-1-(p-tolyl)-1H-pyrazol-5-amine

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of acetonitrile (300 μL, 5.7 mmol) in THF (20 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 10.1 mL, 17.2 mmol) followed by the dropwise addition of methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (1.36 g, 8.62 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of ˜10 mL and was then diluted with EtOH (20 mL) and p-tolylhydrazine hydrochloride (911 mg, 5.74 mmol) was added. The reaction was acidified to pH 1 by the addition of conc hydrochloric acid and the resulting heterogeneous mixture was heated to 70° C. for 5 hr, was then cooled to RT and concentrated in vacuo to a volume of ˜20 mL. The mixture was diluted with water (30 mL) and adjusted to pH 12 by the addition of 2M aq NaOH and was then extracted with ethyl acetate (2×20 mL). The combined 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, 0-50%, gradient elution) to afford the title compound, Intermediate 21, as a yellow solid (550 mg, 32%); Rt 1.48 min (Method 2); m/z 272 (M+H)+, (ES+).

Workup

  1. concentrationThe resulting mixture was concentrated in vacuo to a volume of ˜10 mL
  2. additionwas added
  3. temperaturethe resulting heterogeneous mixture was heated to 70° C. for 5 hr
  4. temperaturewas then cooled to RT
  5. concentrationconcentrated in vacuo to a volume of ˜20 mL
  6. additionThe mixture was diluted with water (30 mL)
  7. additionadjusted to pH 12 by the addition of 2M aq NaOH
  8. extractionwas then extracted with ethyl acetate (2×20 mL)
  9. washThe combined 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, 0-50%, gradient elution)

Sources & evidence

ORD record
ord-e2a0e7c61a184f08a0814ca253efdb1e
Source dataset
uspto-grants-2015_05
Patent number
US09024041B2

Reaction notes

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