Diphosgene → 1-(4-(1-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea

HRID 872412Notes

Reaction equation

HRID 872412 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([O-:21])(O)=O.[Na+].ClC(OC(Cl)=O)(Cl)Cl.[NH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([O:42][CH:43]([C:45]2[CH:50]=[CH:49][N:48]=[C:47]([NH2:51])[CH:46]=2)[CH3:44])=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.O>[NH2:51][C:47]1[CH:46]=[C:45]([CH:43]([O:42][C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([NH:31][C:18]([NH:10][C:8]3[N:7]([C:11]4[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:21])=[CH:33][CH:34]=2)[CH3:44])[CH:50]=[CH:49][N:48]=1

Participants

9

Reactant 5

HCID 10426DiphosgeneHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 29741323-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amineHCID 584167804-(1-(4-Aminonaphthalen-1-yloxy)ethyl)pyridin-2-amine

Product 1

HCID 584167491-(4-(1-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureaYield 38%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4) (WO 2000043384) (57 mg, 0.250 mmol) in DCM (6.0 mL) was added a saturated aq NaHCO3 solution (4.0 mL), and the mixture was stirred vigorously. The mixture was cooled to 0° C. and then trichloromethylchloroformate (0.091 ml, 0.750 mmol) was added in one portion. The resulting mixture was stirred at 0° C. for 1.5 hr. The layers were separated, the organic extract was dried and the solvents removed under reduced pressure to afford an oil, which was left drying under high vacuum, at 35° C. for a further 35 min. The resulting oil was taken up into THF (5.0 mL), and then added to 4-(1-(4-aminonaphthalen-1-yloxy)ethyl)pyridin-2-amine (24) (81 mg, 0.290 mmol). DIPEA (179 μl, 1.029 mmol) was added, and the reaction mixture was stirred at RT for 16 hr. Water (15 mL) and EtOAc (10 mL) were added to the reaction mixture and the layers were separated. The aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine (20 mL), dried and the solvents removed under reduced pressure. The resulting residue was dissolved in MeOH (5.0 mL) and AcOH (2.0 mL) and subjected to SCX capture and release. The crude mixture was purified by column chromatography (12 g), eluting with 0 to 10% MeOH in DCM, to give 1-(4-(1-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate F) (63 mg, 38%) as a beige powder: m/z 535 (M+H)+ (ES+).

Workup

  1. stirringThe resulting mixture was stirred at 0° C. for 1.5 hr
  2. customThe layers were separated
  3. extractionthe organic extract
  4. customwas dried
  5. customthe solvents removed under reduced pressure
  6. customto afford an oil, which
  7. waitwas left
  8. customdrying under high vacuum, at 35° C. for a further 35 min
  9. stirringthe reaction mixture was stirred at RT for 16 hr
  10. customthe layers were separated
  11. extractionThe aqueous layer was extracted with EtOAc (15 mL)
  12. washThe combined organic extracts were washed with brine (20 mL)
  13. customdried
  14. customthe solvents removed under reduced pressure
  15. dissolutionThe resulting residue was dissolved in MeOH (5.0 mL)
  16. customThe crude mixture was purified by column chromatography (12 g)
  17. washeluting with 0 to 10% MeOH in DCM

Sources & evidence

ORD record
ord-744a940a20e747558256b5ff36be1d2c
Source dataset
uspto-grants-2015_03
Patent number
US08975285B2

Reaction notes

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