2-arylaminopyrimidine derivatives containing hydroxamic acid fragments and their preparation and application
An arylaminopyrimidine and hydroxamic acid technology, which is applied in the field of 2-arylaminopyrimidine derivatives, can solve the problems of poor proliferation inhibition selectivity, adverse drug reactions and the like, and achieves good inhibition effect.
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Embodiment 1
[0035] Example 1 N 1 -2-fluoro-5-((4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-yl)amino)phenyl)-N 4 -Hydroxymaleamide hydrochloride (compound 1)
[0036]
[0037] Reagents and reaction conditions: 1) dichloromethane, room temperature, 3-5 hours; 2) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotri Azole, dichloromethane:N,N-dimethylformamide=2:1, 45°C, 5 hours; 3) 1M hydrochloric acid ether solution, 30 minutes.
[0038] Step 1: (Z)-4-((2-fluoro-5-((4-(N-methyl-3-indolyl)-2-pyrimidine)amino)phenyl)amino)-4-oxo - Preparation of 2-butenoic acid Raw material 1: 2-(4-fluoro-3-aminophenyl)-4-(N-methylindole)-2-aminopyrimidine According to J.Med.Chem.2014,57 , prepared by the method of 8249-8267.
[0039] Dissolve 2-(4-fluoro-3-aminophenyl)-4-(N-methylindole)-2-aminopyrimidine (1mmol) and maleic anhydride (1.2mmol) in 15mL dichloroethane , react for 3-5 hours. After the reaction, spin dry under reduced pressure. Recrystallization from acetone gives ...
Embodiment 2
[0048] Example 2 N 1 -5-((4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-yl)amino)phenyl)-N 4 -Hydroxymaleamide hydrochloride
[0049] Its structural formula is:
[0050]
[0051]Yellow solid; m.p.:181.0-181.4℃; 1 HNMR(500MHz,DMSO-d6)δ11.73(s,1H),10.98(s,1H),10.36(s,1H),8.85(s,1H),8.30(d,J=6.6Hz,2H), 8.07(s,1H),7.61(d,J=8.3Hz,1H),7.51(d,J=8.0Hz,1H),7.48–7.45(m,2H),7.39–7.23(m,3H),7.17 (t, J=7.4Hz, 1H), 6.38(d, J=12.1Hz, 1H), 6.24(d, J=12.1Hz, 1H), 3.93(s, 3H).
[0052] 13 CNMR (125MHz, DMSO-d6) δ169.1, 167.0, 158.1, 157.6, 157.3, 156.4, 137.1, 136.6, 135.3, 135.2, 131.9, 130.0, 126.5, 123.3, 122.7, 121.2, 116.0, 115.42, 100.1, 115 33.2. HRMS(ESI)calcd.for C 23 h 21 N 6 o 3 [M+H] + =429.1670, found 429.1670.
Embodiment 3
[0053] Example 3 N 1 -(2-(Dimethylamino)-5-((4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-yl)amino)phenyl)-N 4 -Hydroxymaleamide hydrochloride
[0054] Its structural formula is:
[0055]
[0056] Yellow solid; m.p.:217.9–218.3℃; 1 H NMR (500MHz, DMSO-d6) δ10.31 (s, 3H), 7.65 (d, J = 7.8Hz, 1H), 7.47–7.39 (m, 6H), 7.24–7.18 (m, 3H), 6.99 ( s,1H),6.78(d,J=12.1Hz,1H),6.28(d,J=12.1Hz,1H),3.81(s,3H),3.80(s,1H),2.08–2.01(m,6H ),1.91(s,1H).HRMS(ESI)calcd.for C 25 h 26 N 7 o 3 [M+H] + = 472.2092, found 472.2095.
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