EGFR protein degradation agent and anti-tumor application thereof
A solvate, selected technology, applied in the field of bifunctional compounds and their preparation
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Embodiment 2
[0370] Preparation of Dacomitinib Derivative B: Using a method similar to that of Dacomitinib Derivative A in Example 1, Dacomitinib Derivative B was prepared according to Scheme 1, and its intermediate synthesis data and structural characterization data are as follows :
[0371]
[0372] (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(piperazin-1-yl)pipe ridin-1-yl) but-2-enamide (SIAIS262021). (yellow solid, 166.3mg, two-step total yield 79%) 1 H NMR (500MHz, MeOD) δ9.26(s, 1H), 8.75(s, 1H), 7.93(dd, J=6.6, 2.6Hz, 1H), 7.67-7.63(m, 1H), 7.40–7.34( m,2H),7.05-7.01(m,1H),6.84(d,J=15.2Hz,1H),4.17(s,3H),4.03(d,J=7.0Hz,2H),3.66(s,1H ),3.29–3.26(m,4H),3.22–3.09(m,2H),3.01–2.80(m,6H),2.16(s,2H),2.01–1.85(m,2H).HRMS(ESI)C 28 h 34 ClFN 7 o 2 + [M+H] + : The calculated value is 554.2441, and the measured value is 554.2433.
Embodiment 3
[0374] Preparation of Poziotinib Derivative A (SIAIS219149B): Poziotinib Derivative A (SIAIS219149B) was prepared according to Scheme 2.
[0375]
[0376] Preparation of 4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (SIAIS219148):
[0377] Under argon atmosphere, 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4(3H)-one (468.4mg, 2mmol) was dissolved in 4mL of thionyl chloride, added A drop of DMF initiates the reaction, stir at 90°C for 4 hours, remove excess thionyl chloride by rotary evaporation at low temperature, and put it directly into the next step; add the product of the previous step (2mmol), 10mL DMF, 3,4-dichloro -2-fluoroaniline (432mg, 2.4mmol), stirred at 80°C for 1h. After the reaction, quench with ice water, filter to obtain the crude product, and proceed directly to the next step; add the product from the previous step (2 mmol), 10 mL methanol, and 2 mL ammonia water to a clean 100 mL egg-shaped flask in sequence, reflux and stir at 70 ° C for...
preparation Embodiment 7
[0397]Preparation of Canertinib Derivative B: Using a method similar to that of Canertinib Derivative A in Example 6 of Intermediate Preparation, the Canertinib Derivative B was prepared according to Scheme 4, its synthesis data and structural characterization data as follows:
[0398]
[0399] N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide (SIAIS249183 ).(Yellow solid, 200mg, two-step total yield 62%) 1 H NMR (500MHz,MeOD)δ9.22(s,1H),8.78(s,1H),7.96–7.91(m,1H),7.67-7.62(m,1H),7.38(d,J=5.5Hz, 1H),6.89-6.83(m,1H),6.55-6.51(m,1H),5.91(dd,J=10.3,1.6Hz,1H),4.52(t,J=5.8Hz,2H),3.79-3.68 (m,10H),3.64–3.56(m,3H),2.54-2.43(m,6H).HRMS(ESI)C 29 h 36 ClFN 7 o 2 + [M+H] + : The calculated value is 568.2598, and the measured value is 568.2591.
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