Pyridine → 6-Methyl-N-[1-methyl-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide

Temperature

50 °C

6-Methyl-2-pyridinecarboxylic acid (32 mg, 0.234 mmol) and (1-chloro-2-methyl-1-propen-1-yl)dimethylamine (0.031 mL, 0.234 mmol) were added to dichloromethane (5 mL) and stirred for 10 minutes. This mixture was added to a stirred solution of 1-methyl-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-indazol-4-amine (75 mg, 0.180 mmol) and pyridine (0.029 mL, 0.359 mmol) in dichloromethane (5 mL) under nitrogen and stirred for 7 days. Only starting material remained so using a new bottle, (1-chloro-2-methyl-1-propen-1-yl)dimethylamine (0.031 mL, 0.234 mmol) and 6-methyl-2-pyridinecarboxylic acid (32 mg, 0.234 mmol) were added to dichloromethane (5 mL) under nitrogen and stirred for 10 min. The resultant mixture was added to the reaction mixture, and stirring continued for 30 min. A further portion each of (1-chloro-2-methyl-1-propen-1-yl)dimethylamine (0.031 mL, 0.234 mmol) and 6-methyl-2-pyridinecarboxylic acid (32.0 mg, 0.234 mmol) were then added to dichloromethane (5 mL) under nitrogen and stirred for 10 min. The resultant mixture was added to the reaction mixture, and stirring continued for 30 min, then solvents were removed in vacuo. The crude product (349 mg) was presumed to be 6-methyl-N-(1-methyl-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-indazol-4-yl)-2-pyridinecarboxamide and this was used directly without further purification. To 6-methyl-N-(1-methyl-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-indazol-4-yl)-2-pyridinecarboxamide (349 mg, crude) was added potassium trimethyl silanolate (115 mg, 0.650 mmol) and THF (6 mL) under nitrogen and the mixture was heated at 50° C. overnight. A further portion of potassium trimethyl silanolate (230 mg, 1.3 mmol) was then added and heating and stirring continued. The conversion was monitored by LCMS and when the reaction was deemed complete, the reaction mixture was cooled to room temperature and partitioned between water (30 mL) and DCM (30 mL). The organics were concentrated in vacuo and the residue was purified by column chromatography on silica using Flashmaster II technology (100 g Si cartridge, 40 minute gradient of cyclohexane/ethylacetate 0-100%, 0-20% MeOH) to afford the title compound (37 mg).

1. stirringstirred for 7 days
2. stirringstirred for 10 min
3. stirringstirring
4. waitcontinued for 30 min
5. stirringstirred for 10 min
6. stirringstirring
7. waitcontinued for 30 min
8. customsolvents were removed in vacuo
9. customthis was used directly without further purification
10. temperatureheating
11. stirringstirring
12. temperaturethe reaction mixture was cooled to room temperature
13. custompartitioned between water (30 mL) and DCM (30 mL)
14. concentrationThe organics were concentrated in vacuo
15. customthe residue was purified by column chromatography on silica using Flashmaster II technology (100 g Si cartridge, 40 minute gradient of cyclohexane/ethylacetate 0-100%, 0-20% MeOH)

ORD record

ord-ddc9fce5f2124bc8bc020b9f80ec2dbd

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08765743B2