Method for preparing heteroaryl cyanide through cyanation reaction on palbociclib intermediate

[0028] According to the following chemical reaction equation, the cyanation of 6-bromo-8-cyclopentyl-5-methyl-2-methylthiopyrido[2,3-d]pyrimidin-7-one prepared 6-cyano- 8-Cyclopentyl-5-methyl-2-methylthiopyrido[2,3-d]pyrimidin-7-one:

[0029]

[0030] Under the protection of inert gas, 6-bromo-8-cyclopentyl-5-methyl-2-methylsulfanylpyrido[2,3-d]pyrimidin-7-one (4,500mg, 1.41 mmol), potassium hexacyanoferrite trihydrate (298 mg, 0.71 mmol), bis[2-(diphenylphosphino)phenyl]ether palladium chloride (303 mg, 0.42 mmol), potassium acetate (69.3 mg, 0.71 mmol), N,N-dimethylformamide (5 mL) and water (0.5 mL), the reaction flask was sealed with a rubber stopper and heated and stirred at 100° C. for 7 hours. After the reaction solution was cooled, ethyl acetate was added, and then washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The light yellow solid obtained after the crude product was subjected to column ch

[0033] According to the following chemical reaction equation, 6-cyano-8-cyclopentyl was prepared by cyanation of 6-bromo-8-cyclopentyl-2-methylthiopyrido[2,3-d]pyrimidin-7-one -2-Methylthiopyrido[2,3-d]pyrimidin-7-one:

[0034]

[0035] Under the protection of inert gas, 6-bromo-8-cyclopentyl-2-methylthiopyrido[2,3-d]pyrimidin-7-one (4a, 680.5 mg, 2 mmol) was added to a 25 mL reaction flask, Potassium hexacyanoferrite trihydrate (422.4 mg, 1 mmol), bis[2-(diphenylphosphino)phenyl]ether palladium chloride (429.5 mg, 0.6 mmol), potassium acetate (98.1 mg, 1 mmol) ), N,N-dimethylformamide (7 mL) and water (0.7 mL), the reaction flask was sealed with a rubber stopper and heated and stirred at 100° C. for 7 hours. After the reaction solution was cooled, ethyl acetate was added, and then washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The light yellow solid obtained after the crude product was subjected to co

[0038] According to the following chemical reaction equation, 4-(6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2 -ylamino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester cyanation to prepare 4-(6-(6-cyano-8-cyclopentyl-5-methyl-7-oxo) -7,8-Dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester:

[0039]

[0040] Under the protection of inert gas, 4-(6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3] was added to a 25 mL reaction flask. -d] pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester (4b, 584.5 mg, 1 mmol), potassium hexacyanoferrite trihydrate (211.2 mg, 0.5 mmol) ), bis[2-(diphenylphosphino)phenyl]ether palladium chloride (214.8 mg, 0.3 mmol), potassium acetate (49.1 mg, 0.5 mmol), N,N-dimethylformamide (4 mL) and water (0.4 mL), the reaction vial was sealed with a rubber stopper and heated and stirred at 100°C for 7 hours. After the reaction solut