Derivative having imidazopyrazines, preparation method and application thereof of derivative on medicine
A kind of imidazo, pyrazine technology, applied in the field with imidazopyrazine derivatives, can solve the problems such as no oral dose
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Embodiment 1
[0046] Example 1: 7-acryloyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-amide (B-01) preparation
[0047]
[0048] Step 1: Synthesis of Compound B-01-A
[0049] Add compound SM (2.84g, 10mmol) and 80 ml of chloroform in a 250mL three-necked flask, add NBS (1.96g, 11mmol) and catalytic amount of AIBN to it, cool to room temperature after reflux reaction for 6 hours, and transfer to a separatory funnel Sat. NaHCO with 20 mL 3 Washed, dried over anhydrous magnesium sulfate and spin-dried. The crude product was subjected to flash column chromatography (0-10% ethyl acetate in n-hexane as mobile phase) to obtain light yellow solid B-01-A (2.91 g, yield 79%).
[0050] 1 H NMR (300MHz, CDCl 3 )δ7.55(d, 2H), 7.48(d, 2H), 7.34(m, 1H), 7.10(d, 2H), 7.01(d, 2H), 5.88(s, 1H), 4.23(q, 2H ), 1.33(t, 3H).
[0051] Step 2: Preparation of Compound B-01-B
[0052] Compound B-01-A (2.80 g, 8.04 mmol) was dissolved in 50 mL of absolute ethanol, 2-aminopiperazine (...
Embodiment 2
[0065]Example 2: 7-acryloyl-2-[4-(2-pyridine)phenoxyphenyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-amide preparation
[0066]
[0067] Step 1: Preparation of compound BD-02-A
[0068] 4-Acetylphenol (13.6g, 100mmol) was dissolved in DMF (100mL), NaH (60% in mineral oil, 4.4g, 110mmol) was added at 0°C, stirred at 0°C for 30 minutes, and then 2-fluoropyridine ( 9.7 g, 100 mmol) in DMF (50 mL), slowly warmed to room temperature, and stirred for 2 hours. Water (200 mL) was added to the reaction system, extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed twice with saturated brine (500 mL each time), dried over anhydrous sodium sulfate for 2 hours, filtered to remove the desiccant, and the filtrate was evaporated to dryness with a rotary evaporator. The crude product was purified by flash column chromatography (0-25% ethyl acetate in n-hexane as mobile phase) to obtain B-02-A (15.5 g, 72%), a pale yellow oily liquid.
[0069] LCMS (ESI)...
Embodiment 3
[0089] Example 3: 7-acryloyl-2-[4-(4-fluoro)-phenoxyphenyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-amide Preparation of (B-03)
[0090]
[0091] Step 1: Preparation of compound B-03-A
[0092] Add 4-fluorophenylboronic acid (7.7g, 55mmol), 4-acetylphenol (6.8g, 50mmol), copper acetate (11g, 55mmol), 4A molecular sieve (10g), triethylamine (25.25g, 250mmol) into two in methyl chloride (250 mL), stirred at room temperature overnight, filtered, and the filtrate was evaporated to dryness under reduced pressure with a rotary evaporator, and the residue was purified by flash column chromatography (0-5% ethyl acetate n-hexane solution as mobile phase) to obtain B-03-A (3.22g, 28%), pale yellow oily liquid.
[0093] Step 2: Preparation of Compound B-03-B
[0094] The method is the same as step 2 of Example 2, using B-03-A (3g, 13.04mmol) to obtain B-03-B (3g, 76%), light yellow solid powder.
[0095] Step 3: Preparation of compound B-03-C
[0096] The method was the ...
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