Compounds and uses thereof as egfr kinase inhibitors
A compound and inhibitor technology, applied in the field of medicine, can solve problems such as no clinical reports of brigatinib
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Embodiment 1
[0217] The synthesis of embodiment 1 compound C1
[0218]
[0219] The experimental process is as follows:
[0220]
[0221] (1) Synthesis of C1-2
[0222] Dissolve compound C1-1 (31.4g, 0.2mol) in 600ml of THF (dry), cool down to 0°C, add NaH (80g, 2mol, 60% in oil) in batches, react for 1h, and then control the temperature for -10 ℃, drop D 2 O (200g, 10mol), react at 0°C for 1h, then add BrCF dropwise under temperature control -10°C 2 PO(OEt) 2 (106.8g, 0.4mol), reacted at about 5°C for 0.5h, TLC showed that the reaction was complete, diluted with water, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, column layer 40g of product was obtained by analysis. 1 H NMR (400MHz, CDCl3) δ7.96 (dd, J = 9.1, 5.6Hz, 1H), 7.05 (m, 2H), deuteration rate 99.2%.
[0223] (2) Synthesis of C1-4
[0224] Compound C1-2 (700mg, 3.37mmol) and compound C1-3 (928mg, 4...
Embodiment 2
[0236] The synthesis of embodiment 2 compound C2:
[0237]
[0238] The experimental process is as follows:
[0239]
[0240] (1) Synthesis of C2-3
[0241] Compound C2-1 (400mg, 1.92mmol) and compound C1-2 (457mg, 2.30mmol) were dissolved in acetonitrile (10ml), potassium carbonate (530mg, 3.84mmol) was added, and stirred overnight at 80°C. The solvent DMF was evaporated under reduced pressure, the residue was diluted with water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and purified by column chromatography to obtain 443 mg of compound C2-3.
[0242] 1 H NMR (400MHz, CDCl 3 )δ8.10-8.07 (d, 1H, J = 8.95Hz), 6.61-6.58 (dd, 1H, J = 9.37Hz, 2.68Hz), 6.54-6.53 (d, 1H, J = 2.49Hz), 4.33- 4.32(d, 2H, J=6.12Hz), 3.38-3.35(d, 2H, J=11.50Hz), 2.75-2.69(q, 1H), 1.51-1.49(d, 1H, J=9.20Hz), 1.36 (s,9H).
[0243] (2) Synthesis of compound C2-4
[0244...
Embodiment 3
[0248] The synthesis of embodiment 3 compound C3:
[0249]
[0250] The experimental process is as follows:
[0251]
[0252] (1) Synthesis of C3-2
[0253] Take compound C2-3 (1.43g) dissolved in dichloromethane (20mL), add trifluoroacetic acid (20mL), stir at room temperature for 2 hours; after the reaction, concentrate the reaction solution under reduced pressure, add water to the residue, add carbonic acid Potassium, adjust the pH to 9-10, extract 3 times with dichloromethane, wash the organic phase with brine, dry and concentrate to obtain 1.03 g of compound C3-2;
[0254] 1 HNMR (400MHz, CDCl 3 )δ8.09-8.07(d,1H,J=9.36),6.60-6.57(dd,1H),6.52-6.51(d,1H,J=2.6),3.95-3.94(d,2H,J=5.96) , 3.66-3.60 (m, 4H), 2.86-2.81 (m, 1H), 1.62-1.59 (d, 1H, J=9.08).
[0255] (2) Synthesis of C3-3
[0256] Add compound C3-2 (1.03g), 37% formaldehyde aqueous solution (1.17g), acetic acid (0.86g) into tetrahydrofuran (20mL), stir at room temperature for 1h, and add sodium triacetoxy...
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