Pyridopyrimidone CDK2/4/6 inhibitors
A C1-C4, C3-C8 technology, applied in the field of pyridopyrimidinone CDK2/4/6 inhibitors, can solve problems such as the approval of drugs without CDK2
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[0921] Preparation of synthetic intermediates
[0922] Intermediate 1: (±)-4-{[( 1R* , 2R* )-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylthio)pyrimidine-5-carbaldehyde.
[0923]
[0924] A solution of 1-methyl-6-oxabicyclo[3.1.0]hexane (CAS# 16240-42-9, 330 g, 3.36 mol) in ammonium hydroxide (28 wt % in water, 1.5 L) was dissolved in Stir at 85°C for 24 hours. The solution was concentrated to a brown gum, which was dissolved in water (2.0 L) and THF (200 mL), and the solution was cooled to 0 °C. Sodium hydroxide (287 g, 7.16 mol) and benzyl chloroformate (587 g, 3.44 mol) were added dropwise. The resulting mixture was stirred at room temperature for 18 hours, then extracted with DCM (1000 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride (500 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 10-33% EtOAc / petroleum ether) to afford a yellow solid (550 g, NMR pur...
Embodiment 1
[1040] Example 1: 8-cyclopentyl-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3- d ] pyrimidine - 7 (8 H )-ketone
[1041]
[1042] 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde at -70°C [VanderWel et al. J. Med. Chem. 2005, 48 , 2371] (2.0 g, 8.4 mmol) in anhydrous THF (50 mL) was added EtOAc (2.23 g, 25.3 mmol). The mixture was stirred at this temperature for 15 min, then LHMDS (1.0 M in THF, 29.5 mmol, 29.5 mL) was added dropwise. The reaction was stirred at -70°C for 30 minutes, then at 20°C for 16 hours. The solution was cooled in an ice bath, quenched with water, and extracted with EtOAc (50 mL×3). The combined organic layers were washed with NH 4 It was washed with aqueous Cl solution (30 mL) and saturated aqueous NaCl solution (30 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (elution with petroleum ether / EtOAc 10 / 1 to 3 / 1) to afford 8-cyclopentyl-2-(methylthio)pyrido[2,3- ...
Embodiment 2
[1045] Embodiment 2: 8-[(1 R ,2 R )-2-Hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl] Amino}pyrido[2,3- d ]pyrimidine-7(8 H )-ketone
[1046]
[1047] Add solid 4-{[(1 R ,2 R)-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylthio)pyrimidine-5-carbaldehyde (Intermediate 2, 34.2g, 128mmol), THF (400mL) and EtOAc (33.4mL , 333 mmol). The solution was purged with nitrogen and cooled to -5°C (internal) in a MeOH-ice bath. Via cannula, LHMDS (1.0 M solution in THF, 4 x 100 mL freshly opened bottle, 400 mmol) was added slowly enough to maintain the internal temperature at -5 °C. A pale yellow precipitate started to form after adding about 300 mL of LHMDS solution. Stirring was continued while the mixture was gradually warmed to room temperature overnight. The resulting red solution was cooled to about 3°C (int) in an ice-water bath, then EtOH (224 mL, 3840 mmol) was added via cannula slowly enough to maintain the internal temperature at about 3°C ...
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