Compound serving as protein degradation agent and preparation method and application thereof
A compound, alkyl technology, applied to the compound as a protein degrading agent and its preparation and application fields, can solve problems such as not necessarily applicable
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reference example 1
[0154] Reference Example 1: Preparation of Intermediate I-1
[0155]
[0156] 5-Bromo-3,3-dimethyl-1H-indol-2-one (3.50 g, 14.60 mmol) and potassium tert-butoxide (2.46 g, 21.90 mmol) were dissolved in dimethylsulfoxide ( 50mL). After the mixture was stirred and reacted for 30 minutes, 2-chloro-4-fluorobenzonitrile (2.72 g, 17.50 mmol) was added to the above reaction solution, and the reaction solution was stirred at 20° C. for 20 hours. Water (100 mL) and ethyl acetate (50 mL) were added to the reaction system, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-1.
[0157] LC-MS(ESI)[M+H] + 375.1;
[0158] 1 H NMR (400MHz, DMSO-d 6 )δ8.18(d, J=8.4Hz, 1H), 7.96(d, J...
reference example 2
[0159] Reference Example 2: Preparation of Intermediate I-2
[0160]
[0161] At room temperature, intermediate I-1 (1.00g, 2.67mmol), pinacol diboronate (1.02g, 4.01mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (195mg, 0.27mmol) and potassium acetate (785mg, 8.01mmol) were dissolved in dioxane (40mL), and the reaction solution was replaced with nitrogen three times, then heated to 90°C and stirred for two hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-2.
[0162] LC-MS(ESI)[M+H] + 423.3
reference example 3
[0163] Reference Example 3: Preparation of Intermediate I-3
[0164]
[0165] At room temperature, intermediate I-2 (100mg, 0.24mmol), 2-fluoro-4-bromophenol (50mg, 0.26mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (17mg, 0.024mmol) and potassium carbonate (100mg, 0.72mmol) were dissolved in dioxane and water (10mL / 3mL), and the reaction solution was replaced with nitrogen three times, then heated to 80°C and stirred for two hours. The reaction solution was cooled to room temperature, water (15 mL) and ethyl acetate (15 mL) were added to the mixture, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-3.
[0166] LC-MS(ESI)[M+H] + 407.1
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