Diphosgene → tert-Butyl 4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)-2-methylpropyl)pyridin-2-ylcarbamate

HRID 872415Notes

Reaction equation

HRID 872415 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-])(O)=[O:19].[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]([CH3:60])([CH3:59])[CH2:44][C:45]2[CH:50]=[CH:49][N:48]=[C:47]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH:46]=2)=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([O:42][C:43]([CH3:60])([CH3:59])[CH2:44][C:45]3[CH:50]=[CH:49][N:48]=[C:47]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:57])[CH3:56])[CH:46]=3)=[CH:34][CH:33]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

9

Reactant 5

HCID 10426DiphosgeneHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 29741323-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amineHCID 67359542tert-Butyl 4-(2-(4-aminonaphthalen-1-yloxy)-2-methylpropyl)pyridin-2-ylcarbamate

Product 1

HCID 58416777tert-Butyl 4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)-2-methylpropyl)pyridin-2-ylcarbamateYield 14%

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) (250 mg, 1.090 mmol) in DCM (25 mL) was added a saturated solution of aq NaHCO3 (17 mL), and the mixture was stirred vigorously. The mixture was cooled to 0° C. and then trichloromethylchloroformate (395 μl, 3.27 mmol) was added in one portion. The resulting mixture was stirred at 0° C. for 90 min. The layers were then separated, the organic extract was dried and the solvents removed under reduced pressure to afford a brown-orange oil, which was dried under high vacuum, at 30° C. for 30 min. The resulting oil was then taken up in THF (4.0 mL), and was added to tert-butyl 4-(2-(4-aminonaphthalen-1-yloxy)-2-methylpropyl)pyridin-2-ylcarbamate (28) (92 mg, 0.23 mmol). DIPEA (118 μl, 0.677 mmol) was then added, and the reaction mixture was stirred at RT over 17 hr. Water (15 mL) and EtOAc (15 mL) were added to the purple mixture and the layers separated. The aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were washed with brine (20 mL), dried and the solvents removed under reduced pressure. The crude material was purified by column chromatography (40 g) eluting with 0 to 50% EtOAc in iso-hexane, to give tert-butyl 4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)-2-methylpropyl)pyridin-2-ylcarbamate (29) (24 mg, 14%) as a purple foam: m/z 663 (M+H)+ (ES+).

Workup

  1. stirringThe resulting mixture was stirred at 0° C. for 90 min
  2. customThe layers were then separated
  3. extractionthe organic extract
  4. customwas dried
  5. customthe solvents removed under reduced pressure
  6. customto afford a brown-orange oil, which
  7. customwas dried under high vacuum, at 30° C. for 30 min
  8. stirringthe reaction mixture was stirred at RT over 17 hr
  9. customthe layers separated
  10. extractionThe aqueous layer was extracted with EtOAc (10 mL)
  11. washThe combined organic extracts were washed with brine (20 mL)
  12. customdried
  13. customthe solvents removed under reduced pressure
  14. customThe crude material was purified by column chromatography (40 g)
  15. washeluting with 0 to 50% EtOAc in iso-hexane

Sources & evidence

ORD record
ord-f50a8bba4e024a39a1f7044a2ea353fd
Source dataset
uspto-grants-2015_03
Patent number
US08975285B2

Reaction notes

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