Macrocyclic kinase inhibitor compound, preparation method and application as medicine
A technology of kinase inhibitors and compounds, which is applied in the field of preparation of macrocyclic kinase inhibitor compounds and can solve problems such as easy drug resistance and limited indications
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Embodiment 1
[0143] Synthetic route one
[0144] (1) 3-(2-Chloro-pyrimidin-4-yl)-benzyl alcohol (iiiA)
[0145]
[0146] In the 100mL round bottom flask, add compound iiA (10.0g, 0.065mol) successively, compound iA (10.8g, 0.072mol), tetrakis (triphenylphosphine palladium) (5.2g, 0.0045mol), potassium fluoride dihydrate ( 25.2g, 0.264mol), dioxane (170mL) and water (30mL), the resulting suspension was placed in an oil bath at 110°C and stirred for 4h. The reaction solution was cooled to room temperature and filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a reddish-brown solid. This solid was recrystallized from ethyl acetate to obtain 5.2 g of a light yellow solid (compound iiiA). 1 HNMR (400MHz, DMSO-d 6 ): δ8.67(d, J=5.2Hz, 1H), 8.09(s, 1H), 7.97(dd, J=1.4and6.8Hz, 1H), 7.65(d, J=5.2Hz, 1H), 7.55 -7.47 (m, 2H), 4.79 (d, J=6.0Hz, 2H), 2.36 (t, J=6.0Hz, 1H). MS (m / z): 243 (MNa) + .
[0147] (2) 4-(3-(allyloxymethyl)-phenyl)-2-chloropyrimidine...
Embodiment 2
[0170] Front 1-6 step is the same as embodiment 1
[0171]
[0172] Compound ixA (100 mg, 0.28 mmol), potassium carbonate (387 mg, 2.8 mmol), xvA (151 mg, 0.84 mmol) and acetonitrile (10 mL) were sequentially added into a 50 mL round bottom flask, and the resulting mixture was stirred at 90° C. for 36 h. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated and subjected to silica gel column chromatography [V (petroleum ether): V (acetone) = 5: 1] to obtain 87 mg of a white solid (compound 22). 1 HNMR (400MHz, CDCl 3 ): δ9.59(s, 1H), 8.54(d, J=4.8Hz, 1H), 8.43(s, 1H), 8.27(s, 1H), 8.04(s, 1H), 7.54-7.51(m, 2H), 7.44(d, J=5.2Hz, 1H), 7.20(t, J=7.6Hz, 1H), 7.06(d, J=8.0Hz, 1H), 6.90(d, J=7.2Hz, 1H) , 5.73-5.63(m, 2H), 4.52(s, 2H), 3.92(s, 2H), 3.54(s, 2H), 3.08(s, 2H), 2.27-2.22(m, 4H), 1.93(s , 3H), 1.30 (m, 4H). MS (m / z): 457 (MH) + .
Embodiment 3
[0174] Front 1-6 step is the same as embodiment 1
[0175]
[0176] In the 50mL round bottom flask, add N,N-dicyclohexylcarbodiimide (330mg, 1.6mmol), monomethyl suberate (152mg, 0.80mmol) and dichloromethane (5mL) successively, the mixture of gained is in After stirring at room temperature for 10 min, compound ixA (145 mg, 0.40 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction solution was filtered, the filtrate was concentrated, and silica gel column chromatography [V (petroleum ether): V (acetone) = 2: 1] gave 137 mg of a white solid (compound 15). 1 HNMR (400MHz, DMSO-d 6 ): δ9.83(d, J=10.8Hz, 1H), 8.68-6.68(m, 10H), 5.75-5.57(m, 2H), 4.63(s, 2H), 4.49(d, J=8.0Hz, 2H), 3.98(d, J=5.2Hz, 2H), 3.57(d, J=6.4Hz, 3H), 2.33-2.26(m, 2H), 1.73-1.50(m, 8H).
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