Water → 5-[3-chloro-4-(propan-2-yloxy)phenyl]-1-methyl-1H-pyrazole-4-carbaldehyde

HRID 526753Notes

Reaction equation

HRID 526753 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[C:19](=O)([O-])[O-].[K+].[K+].IC.O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]([CH3:19])[N:14]=[CH:15][C:16]=2[CH:17]=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]

Participants

6

Reactant 4

HCID 962WaterHCID 6328Methyl iodideHCID 11430Potassium CarbonateHCID 178458270HCID 178458270, compound

Product 1

HCID 1176660865-[3-chloro-4-(propan-2-yloxy)phenyl]-1-methyl-1H-pyrazole-4-carbaldehydeYield 20.4%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent3×

Conditions

Temperature
70 °C

Procedure

To a mixture of 3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazole-4-carbaldehyde (530 mg, 1.76 mmol, 1.00 equiv) and potassium carbonate (828 mg, 5.99 mmol, 3.40 equiv) in acetonitrile (100 mL) was added iodomethane (852 mg, 6.00 mmol, 3.41 equiv) dropwise. The reaction was stirred at 70° C. for 8 h. The resulting mixture was cooled to room temperature then concentrated under vacuum. The residue was dissolved in 20 mL of H2O and then extracted with 3×30 mL ethyl acetate. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, XSelect CSH Prep C18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and MeCN (38.0% MeCN up to 45.0% in 15 min); Detector, UV 254/220 nm to afford 100 mg (18%) of 5-[3-chloro-4-(propan-2-yloxy)phenyl]-1-methyl-1H-pyrazole-4-carbaldehyde as colorless oil. 1H-NMR (300 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.03 (s, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.4 Hz, 2.1 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.85-4.77 (m, 1H), 3.78 (s, 3H), 1.33 (d, J=7.5 Hz, 6H) ppm. LCMS (method C, ESI): RT=0.92 min, m/z=279.0 [M+H]+ and 120 mg (22%) of the other regioisomer, 3-(3-chloro-4-isopropoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde as a colorless oil. 1H-NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.51 (s, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.82 (dd, J=8.4 Hz, 2.1 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.77-4.69 (m, 1H), 3.94 (s, 3H), 1.32 (d, J=7.5 Hz, 6H) ppm.

Workup

  1. temperatureThe resulting mixture was cooled to room temperature
  2. concentrationthen concentrated under vacuum
  3. dissolutionThe residue was dissolved in 20 mL of H2O
  4. extractionextracted with 3×30 mL ethyl acetate
  5. washThe combined organic layers was washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated under vacuum
  8. customThe residue was purified by Prep-HPLC with the following conditions

Sources & evidence

ORD record
ord-a2c4ca48d04b4f3897e5300032a69fcc
Source dataset
uspto-grants-2016_05
Patent number
US09346761B2

Reaction notes

Loading…