Toluene → 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[(tetrahydrofuran-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-naphthalen-1-yl)-urea

HRID 1824448Notes

Reaction equation

HRID 1824448 reaction equation
Cl.[NH2:2][C:3]1[N:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[C:19]([O-:22])(O)=O.[Na+].C(Cl)(Cl)=O.[N-:28]=[C:29]=[O:30].[O:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[CH2:36][NH:37][C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1.[CH3:44][CH2:45]OCC.[C:49]1([CH3:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl.C1COCC1>[C:8]([C:6]1[CH:7]=[C:3]([NH:2][C:29]([NH:28][C:55]2[C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:19]([O:22][C:42]3[CH:41]=[CH:40][N:39]=[C:38]([NH:37][CH2:36][CH:32]4[CH2:33][CH2:34][CH2:35][O:31]4)[N:43]=3)=[CH:45][CH:44]=2)=[O:30])[N:4]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:5]=1)([CH3:11])([CH3:10])[CH3:9]

Participants

9

Reactant 6

HCID 1140Toluene2×HCID 6371PhosgeneHCID 105034IsocyanateHCID 516892Sodium BicarbonateHCID 119912003-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-amine hydrochlorideHCID 69146403Tetrahydrofuranylmethylaminopyrimidine ether

Product 1

HCID 102186651-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-{2-[(tetrahydrofuran-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-naphthalen-1-yl)-urea

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

3-Amino-5-tert-butyl-2-(p-tolyl)-2H-pyrazole hydrochloride (59 mg, 0.22 mmol, 1 equiv.) was dissolved in 12 mL methylene chloride and 12 mL saturated aqueous NaHCO3 was added. The biphasic mixture was stirred until all solids had completely dissolved and cooled to 0° C. The organic layer was then treated with phosgene in one portion via syringe while not stirring (0.40 mL of a 20% solution toluene, 0.78 mmol, 3.5 equiv.). The resulting mixture was stirred vigorously at 0° C. for 0.5 h. The organic layer was separated, dried (Na2SO4) and filtered. The methylene chloride was removed in vacuo and the resulting isocyanate in toluene was treated with a solution of the above tetrahydrofuranylmethylaminopyrimidine ether intermediate (75 mg, 0.22 mmol, 1.0 equiv.) in 4 mL anhydrous THF. The mixture was stirred at room temperature for 36 h, then the solvent was removed in vacuo. The product urea was purified by column chromatography on silica gel using 0–10% MeOH in methylene chloride eluent mixtures, affording 112 mg of the title compound [(S)-enantiomer] as a light pink foam. Further purification by preparatory reverse-phase HPLC afforded 44 mg of the title compound as a pure, yellow foam.

Workup

  1. dissolutionhad completely dissolved
  2. stirringThe resulting mixture was stirred vigorously at 0° C. for 0.5 h
  3. customThe organic layer was separated
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customThe methylene chloride was removed in vacuo
  7. stirringThe mixture was stirred at room temperature for 36 h
  8. customthe solvent was removed in vacuo
  9. customThe product urea was purified by column chromatography on silica gel using 0–10% MeOH in methylene chloride eluent mixtures

Sources & evidence

ORD record
ord-06872717da73436684270f24032abc85
Source dataset
uspto-grants-2006_05
Patent number
US07041669B2

Reaction notes

Loading…