Diphosgene → 1-(4-(2-(2-Aminopyridin-4-yl)propan-2-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea

HRID 2069048Notes

Reaction equation

HRID 2069048 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][C:43]([C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[CH:47]=2)([CH3:45])[CH3:44])=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.CCOC(C)=O.O>[NH2:52][C:48]1[CH:47]=[C:46]([C: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)([CH3:45])[CH3:44])[CH:51]=[CH:50][N:49]=1

Participants

10

Reactant 5

HCID 10426DiphosgeneHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 29741323-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amineHCID 672351724-(2-(4-Aminonaphthalen-1-yloxy)propan-2-yl)pyridin-2-amine

Product 1

HCID 585325331-(4-(2-(2-Aminopyridin-4-yl)propan-2-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureaYield 51%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (5) (447 mg, 1.75 mmol) in DCM (40 mL) was added saturated aq NaHCO3 solution (27 mL). The mixture was stirred vigorously and was cooled to 0° C. and then trichloromethylchloroformate (0.63 mL, 5.25 mmol) was added in one portion. The resulting mixture was stirred at 0° C. for 1.5 hr. The biphasic mixture was separated and the organic layer was dried (MgSO4) and evaporated in vacuo. The oily residue which was taken up in THF (15 mL) and was added to a solution of 4-(2-(4-aminonaphthalen-1-yloxy)propan-2-yl)pyridin-2-amine (42) (253 mg, 0.86 mmol) in THF (2.0 mL). Neat DIPEA (451 μL, 2.59 mmol) was added and the reaction mixture was stirred at RT for 2 hr. Water (30 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (3×15 mL) and the combined organic layers were washed with brine (40 mL), dried (MgSO4), and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 0-10% MeOH in DCM, gradient elution) to afford the title compound (Interm. H) (249 mg, 51%) as a purple amorphous solid: m/z 549 (M+H)+ (ES+).

Workup

  1. stirringThe resulting mixture was stirred at 0° C. for 1.5 hr
  2. customThe biphasic mixture was separated
  3. dry with materialthe organic layer was dried (MgSO4)
  4. customevaporated in vacuo
  5. stirringthe reaction mixture was stirred at RT for 2 hr
  6. customthe layers were separated
  7. extractionThe aqueous layer was extracted with EtOAc (3×15 mL)
  8. washthe combined organic layers were washed with brine (40 mL)
  9. dry with materialdried (MgSO4)
  10. customevaporated in vacuo
  11. customThe residue was purified by flash column chromatography (SiO2, 40 g, 0-10% MeOH in DCM, gradient elution)

Sources & evidence

ORD record
ord-50987054e31d4940882e0452a75594db
Source dataset
uspto-grants-2012_10
Patent number
US08299073B2

Reaction notes

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