2-MethylpyriMidine-5-boronic Acid Pinacol Ester synthesis

Yield:-

Reaction Conditions:

with (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride;potassium acetate in 1,4-dioxane at 90; for 3 h;Sealed tube;Inert atmosphere;

Steps:

8.3 Step 3: Methyl 1- j2-(tert-butoxy)-2-oxoethylj -5-(2-methylpyrimidin-5-yl)indazole-3- carboxylate (6):
5-Bromo-2-methylpyrimidine (250 mg, 1.44 mmol, 1 equiv.),bis(pinacolato)diboron (0.385 g, 1.52 mmol, 1.05 equiv.), potassium acetate (0.425 g, 4.34 mmol,3 equiv.), and 1,1’-bis(diphenylphosphino)ferrocene-dichloropalladium (1:1) (0.106 g, 0.144mmol, 0.1 equiv.) were combined in a sealed reaction vessel, evacuated and charged with Ar gas. The mixture was then diluted with 1,4-dioxane (5.0 mL, 0.29 M, 20 Vols) and heated to 90 °C for 3 hours at which point the LCMS showed conversion to the desired boronate. To this mixture was added potassium carbonate (0.665 g, 4.81 mmol, 3 equiv.) followed by methyl 5-bromo-1-[2-(tert-butoxy)-2-oxoethyl]indazole-3-carboxylate (0.592 g, 1.60 mmol, 1 equiv.) and water (0.3 mL). The orange mixture was allowed to stir at 100 °C for 2 hours at which point the LCMS showed conversion to a peak with a mass corresponding to the desired product. The mixture was diluted with EtOAc (20 mL) and washed with water. The aqueous layer was extracted once with EtOAc (20 mL). The organic extracts were washed with brine, dried over Na2SO4, filtered andconcentrated to afford an orange solid. This solid was then purified on silica gel chromatography eluting with a 0 - 100 % EtOAc in hexanes gradient over 15 CVs to afford 6 as a colorless solid.

References:

ACHILLION PHARMACEUTICALS, INC.;WILES, Jason, Allan;PHADKE, Avinash, S.;DESHPANDE, Milind;AGARWAL, Atul;CHEN, Dawei;GADHACHANDA, Venkat, Rao;HASHIMOTO, Akihiro;PAIS, Godwin;WANG, Qiuping;WANG, Xiangzhu;BARRISH, Joel, Charles;GREENLEE, William;EASTMAN, Kyle, J. WO2018/160889, 2018, A1 Location in patent:Page/Page column 660; 661; 662

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