Quinazoline compound, preparation method and application thereof
A compound, selected technology, applied in the fields of organic chemistry, drug combination, anti-tumor drugs, etc., can solve the problems of prolonging the overall survival of patients, difficult to take effect, and no observed therapeutic effect.
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Embodiment 1
[0102] Example 1: (S, E)-N-(4-(3-chloro-4-fluoroanilino)-7-(tetrahydrofuran-3-yloxy) Synthesis of quinazolin-6-yl)-4-(cyclopropylamino)-2-butenamide (compound 1)
[0103]
[0104] a. Synthesis of N-(3-chloro-4-fluorophenyl)-6-nitro-7-fluoroquinazolin-4-amine
[0105]
[0106]Take 4-hydroxy-7-fluoro-6-nitroquinazoline (20g) into a 1000ml single-necked bottle, add 390ml of chloroform (W / V=1:19.5), and start to cool down to below 5°C under stirring . The reaction temperature was controlled below 5°C, and 24.5g (2eq) of oxalyl chloride was added dropwise with stirring. After dropping, control the internal temperature below 5°C, and drop DMF in chloroform solution (2.4ml dissolved in 100ml chloroform) under stirring. After dropping, the temperature of the reaction began to rise, and the reaction was stirred in an oil bath at 70° C. (reflux), followed by TLC until the reaction was completed, and the temperature was lowered to 20° C. A mixture of anhydrous magnesium su...
Embodiment 2
[0118] Example 2: (R, E)-N-(4-(3-chloro-4-fluoroanilino)-7-(tetrahydrofuran-3-yloxy) Synthesis of quinazolin-6-yl)-4-(cyclopropylamino)-2-butenamide (compound 2)
[0119]
[0120] In a similar manner to the preparation of compound 1, compound 2 (19% yield) could be obtained as a khaki granular solid using (R)-3-hydroxytetrahydrofuran as a starting material.
[0121] ESI-MS (m / z): [M+H] + 498.2.
Embodiment 3
[0122] Example 3: (E)-N-(4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl)-4-(3, Synthesis of 3-difluorocyclobutylamino)-2-butenamide (Compound 3)
[0123]
[0124] Similar to the preparation of compound 1, using methanol and 3,3-difluorocyclobutylamine as starting materials, compound 3 (13% yield) could be obtained as a yellow solid.
[0125] 1 H-NMR (600MHz, DMSO-d 6 ,δ ppm ): 9.81(s, 1H), 9.65(s, 1H), 8.92(s, 1H), 8.34(s, 1H), 8.13(dd, 1H, J 1 =7.2Hz,J 2 =3.0Hz), 7.80(m, 1H), 7.43(t, 1H), 7.29(s, 1H), 6.85(m, 1H), 6.56(d, 1H, J=15.0Hz), 4.04(s, 3H ), 3.30(d, 2H), 3.15(m, 1H), 2.75(m, 2H), 2.34(m, 2H).
[0126] ESI-MS (m / z): [M+H] + 492.4.
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