Preparation and use of protein kinase inhibitors
A kind of use, leukemia technology, applied in the direction of medical preparations containing active ingredients, drug combinations, organic chemistry, etc.
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Embodiment 1
[0217] Example 1: General Reaction Sequence for Compounds of Formula IA
[0218] Compounds of formula IA were synthesized according to Scheme 1 . Exemplary methods are also described below.
[0219] Scheme 1: General reaction sequence for compounds of formula IA
[0220]
Embodiment 2
[0221] Embodiment 2: the synthesis of compound 2
[0222]
[0223] ethyl-4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate. To a stirred solution of 500 mL of compound 1 (40 g, 172 mmol) in DCM was slowly added 70 mL of 23% methylamine in ethanol at 0°C. The resulting mixture was stirred at 0°C for 45 minutes. After compound 1 was completely consumed according to TLC monitoring, 300 mL of water was added to the mixture. The organic layer was separated and washed with brine (2 x 200 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give 36.86 g of the desired product as a white solid. Yield: 94%.
Embodiment 3
[0224] Embodiment 3: the synthesis of compound 3
[0225]
[0226] (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol. at 0°C, in N 2A THF solution (200 mL) of compound 2 (36.86 g, 162.2 mmol) was added to a THF (dry, 800 mL) suspension of LAH (7.38 g, 194.6 mmol) through the dropping funnel. The mixture was stirred at room temperature for 2 hours. TLC indicated complete consumption of compound 2. Water (8 mL), 15% NaOH solution (24 mL) and water (24 mL) were added to the reaction mixture. The organic layer was decanted and the solid was washed with EA (2 x 50 mL). All organic layers were combined and washed with brine (100 mL), MgSO 4 Dry, filter and evaporate under reduced pressure. The resulting yellow solid (27 g) was recrystallized from EA / PE (1 / 1) to give 18.5 g of the desired product in the form of a white solid. Yield: 62%. 1 H NMR, 500MHz (CDCl 3 ), 7.68 (s, 1H), 5.87 (bs, 1H), 4.50 (s, 1H), 3.04 (d, 3H, J=5.0Hz), 2.52 (s, 3H), 1.67 (b, 3H).
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