Toluene → 1-methyl-1-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-3-(2-methylsulfanyl-ethyl)-urea

HRID 1484719Notes

Reaction equation

HRID 1484719 reaction equation
[CH3:1][NH:2][C:3]1[N:4]([CH3:14])[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[C:15](Cl)(Cl)=[O:16].C1(C)C=CC=CC=1.[CH3:26][S:27][CH2:28][CH2:29][NH2:30]>ClCCCl>[CH3:1][N:2]([C:3]1[N:4]([CH3:14])[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)[C:15]([NH:30][CH2:29][CH2:28][S:27][CH3:26])=[O:16]

Participants

6

Reactant 4

HCID 1140TolueneHCID 6371Phosgene2×HCID 87697(2-(Methylthio)ethyl)amineHCID 67499915methyl-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-amine

Product 1

HCID 675003851-methyl-1-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-3-(2-methylsulfanyl-ethyl)-ureaYield 6%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a solution of methyl-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-amine (150 mg, 0.8 mmol) in ice-cold DCE (2 mL) under N2 was added a solution of phosgene in toluene (20%, 0.43 mL, 0.88 mmol). The ice bath was removed after 30 min, and the mixture was stirred at room temperature for 1 h and at reflux for 2 h. The mixture was cooled to room temperature and then more phosgene (0.86 mL, 1.76 mmol) was added. The mixture was stirred at reflux for 90 min and then cooled in an ice bath. To this was added a solution of 2-methylthioethylamine (80 mg, 0.88 mmol) in DCE (2 mL). The ice bath was removed after 10 min, and the reaction mixture was stirred at reflux for 14 h, cooled, and diluted with DCE (30 mL). The diluted reaction mixture was washed with saturated NaHCO3 (20 mL), dried over MgSO4, adsorbed onto silica gel and purified using silica gel chromatography eluting with a gradient of methanol in dichloromethane to afford 1-methyl-1-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-3-(2-methylsulfanyl-ethyl)-urea as a yellow gum (14 mg, 6%): 1H NMR (400 MHz, CDCl3) δ 8.99 (d, J=1.5 Hz, 1H), 8.57 (dd, J=4.8, 1.5 Hz, 1H), 8.08 (ddd, J=8.1, 2.1, 2.1 Hz, 1H), 7.34 (dd, J=7.9, 4.8 Hz, 1H), 6.52 (s, 1H), 4.88 (br t, J=5.5 Hz, 1H), 3.80 (s, 3H), 3.41 (q, J=6.3 Hz, 2H), 3.24 (s, 3H), 2.61 (t, J=6.3, 2H), 2.06 (s, 3H); ESIMS (m/z) 292.2 [M+2].

Workup

  1. customThe ice bath was removed after 30 min
  2. temperatureat reflux for 2 h
  3. temperatureThe mixture was cooled to room temperature
  4. stirringThe mixture was stirred
  5. temperatureat reflux for 90 min
  6. temperaturecooled in an ice bath
  7. customThe ice bath was removed after 10 min
  8. stirringthe reaction mixture was stirred
  9. temperatureat reflux for 14 h
  10. temperaturecooled
  11. additiondiluted with DCE (30 mL)
  12. customThe diluted reaction mixture
  13. washwas washed with saturated NaHCO3 (20 mL)
  14. dry with materialdried over MgSO4
  15. custompurified
  16. washeluting with a gradient of methanol in dichloromethane

Sources & evidence

ORD record
ord-c4dd7e1c152a452199de9e2019a2f6ab
Source dataset
uspto-grants-2016_08
Patent number
US09422278B2

Reaction notes

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