Targeted ubiquitination TRK degradation compound and preparation method, composition and application thereof
A compound and alkyl technology, applied in the field of compounds targeting ubiquitination to degrade TRK, can solve problems such as drug resistance, drug resistance, and off-target
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[0079] In a second aspect, an embodiment of the present invention provides a method for preparing the compound or a pharmaceutically acceptable salt thereof as described in the first aspect, comprising the following steps:
[0080] S1.
[0081] Compound II is reacted with pinacol biboronate in a first reaction solvent in the presence of a first base under the action of a first catalyst to obtain intermediate III;
[0082] S2.
[0083] The intermediate III and compound IV are reacted in a second reaction solvent in the presence of a second base under the action of a second catalyst to obtain intermediate V;
[0084] S3. When the compound or a pharmaceutically acceptable salt thereof has the structure of formula I-a:
[0085]
[0086] The intermediate V and the compound having the structure of formula VI are reacted in the third reaction solvent in the presence of the third base to obtain the intermediate having the structure of formula VII;
[0087]When the compound o...
Embodiment 1
[0118] Preparation of Example 1 Compound 1
[0119]
[0120]
[0121]
[0122] Synthesis of S1, intermediate a2:
[0123] Compound a1 (5.0 g, 23.58 mmol), pinacol diboronate (7.2 g, 28.3 mmol) and potassium acetate (4.6 g, 47.00 mmol) were dissolved in 1,4-dioxane (50 mL) and stirred Disperse, add Pd(dppf)Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1.7g, 2.36mmol), replaced with nitrogen three times, heated to 100°C, reacted for 4 hours, monitored by TLC, the reaction was complete After that, it was cooled to room temperature, filtered, and the filter cake was discarded. The filtrate was collected, and the filtrate was concentrated to dryness under reduced pressure to obtain a concentrated residue. To the concentrated residue, ethyl acetate was added until it was completely dissolved, washed twice with water, and saturated with sodium chloride. The aqueous solution was washed once, the organic phase was dried over anhydrous sodium sulfate, and ...
Embodiment 2
[0138] Preparation of Example 2 Compound 2
[0139]
[0140] Synthesis of S1, intermediate b6:
[0141] Intermediate a4 (2.1 g, 8.10 mmol) and compound b5 (1.6 g, 9.72 mmol) were dissolved in absolute ethanol (100 mL), piperidine (63 drops) was added at room temperature, and the temperature was raised to 85 °C for 4 hours. TLC The reaction was monitored. After the reaction was completed, it was lowered to room temperature, filtered, and the filter cake was washed with 30 mL of n-heptane, dried by suction, and dried in vacuo to obtain 2.6 g of intermediate b6, which was a yellow solid with a yield of 78.6%.
[0142] Synthesis of S2, intermediate b7:
[0143] Intermediate b6 (2.6 g, 6.37 mmol) was dissolved in methanol (81 mL), 2 mol / L aqueous sodium hydroxide solution (27 mL) was added, the temperature was raised to 65 °C for 7 hours, and the reaction was monitored by TLC. After the reaction was completed, it was lowered to room temperature, Concentrate under reduced press...
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