Sodium Hydroxide → N-(3-cyclopropyl-1-((5-hydroxy-6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Temperature

0 °C

To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (101 mg, 0.318 mmol) was added NMP (5 mL, distilled over oven dried MgSO4). A heat gun was used to dissolve the starting material. The reaction was cooled to 0° C. and 2,4,6-trichlorobenzoyl chloride (50.8 μL, 0.318 mmol) was added dropwise. The cold bath was removed once the addition was complete. The reaction mixture was stirred for one hour. 1-((5-(tert-Butyldimethylsilyloxy)-6-methylpyridin-2-yl)methyl)-3-cyclopropyl-1H-indazol-4-amine (100 mg, 0.245 mmol) was then added in one portion to the reaction mixture and the reaction was heated to 88° C. and stirred for 5 hours. NMP was removed by vacuum distillation until the reaction mixture became a thick oil. NaOH (3 equivalents relative to lithium salt starting material) in H2O (5 mL) was added to the thick oil. The mixture was stirred at 80° C. for 30 minutes. The mixture was cooled to ambient temperature and the pH of the dark solution was adjusted to about pH 12-13 with saturated NH4Cl aqueous solution. The mixture was cooled to 0° C. and H2O (10 mL) was added. Stirring was continued for 30 minutes, during which time a solid started to crash out. The mixture was filtered and the solid was washed with a saturated NaHCO3 solution and H2O. The solid was dissolved in DCM and dried (Na2SO4). The solution was filtered, concentrated and triturated with MTBE give the final product (49%). MS (ES+APCI) m/z=581.4 (M+H).

1. dissolutionto dissolve the starting material
2. customThe cold bath was removed once the addition
3. temperaturethe reaction was heated to 88° C.
4. stirringstirred for 5 hours
5. customNMP was removed by vacuum distillation until the reaction mixture
6. stirringThe mixture was stirred at 80° C. for 30 minutes
7. temperatureThe mixture was cooled to ambient temperature
8. temperatureThe mixture was cooled to 0° C.
9. stirringStirring
10. waitwas continued for 30 minutes, during which time
11. filtrationThe mixture was filtered
12. washthe solid was washed with a saturated NaHCO3 solution and H2O
13. dissolutionThe solid was dissolved in DCM
14. dry with materialdried (Na2SO4)
15. filtrationThe solution was filtered
16. concentrationconcentrated
17. customtriturated with MTBE

ORD record

ord-049b152309c44266b2990858b3a19a26

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08841455B2