Heterocyclic amide compound as well as preparation method and application thereof
A technology of compound and heterocycloalkyl, applied in the field of heterocyclic amide compounds and their preparation and application
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Embodiment 1
[0142] Embodiment 1: the preparation of compound 1
[0143] Step 1: Preparation of Compound 1-2
[0144]
[0145] Compound 1-1 (8g, 32.57mmol) was dissolved in methanol solution of ammonia (7M, 70.00mL), and the system was heated to 50°C in a sealed tube and stirred for 20h. The reaction liquid was filtered, and the resulting solid was washed with petroleum ether and dried in vacuo to obtain crude product 1-2, which was directly used in the next reaction without further purification.
[0146] 1 H NMR (400MHz, DMSO-d 6 )δ8.30(br s,1H),8.05(d,J=2.0Hz,1H),7.88(d,J=2.0Hz,1H),7.80(br s,1H),4.02(s,3H).
[0147] Step 2: Preparation of Compound 1-3
[0148]
[0149] 15°C, under the condition of nitrogen protection, compound 1-2 (7.5g, 32.52mmol) was dissolved in dichloromethane (100mL), and a dichloromethane solution of boron tribromide (40.74g, 162.62mmol, 15.67 mL) (1.0M solution in dichloromethane), the addition was completed, and the reaction was stirred for 24h. The r...
Embodiment 2
[0206] Embodiment 2: the preparation of compound 2
[0207] Step 1: Preparation of compound 2-1
[0208]
[0209] Compound 1-6 (1.5g, 4.74mmol) and compound 1-4 (2.03g, 5.21mmol) were dissolved in n-butanol (20mL), and diisopropylethylamine (1.84g, 14.21mmol, 2.5mL ), the reaction was heated to 120°C and stirred for 24h in a sealed tube. The reaction solution was filtered, and the filter cake was dried. The crude product was purified by high performance preparative silica gel plate chromatography (dichloromethane / methanol (v / v)=1 / 0-10 / 1) to obtain compound 2-1.
[0210] MS(ESI)m / z(M+Na) + = 655.1.
[0211] Step 2: Preparation of compound 2-2
[0212]
[0213] At 0°C, compound 2-1 (680mg, 1.07mmol) was dissolved in methanol (10mL) and tetrahydrofuran (5mL), and an aqueous solution (5mL) of sodium dithionite (1.87g, 10.75mmol) was added, followed by ammonia ( 3.36g, 26.87mmol, 3.7mL, 28% aqueous solution), the system was warmed up to 15°C and stirred for 1h. The reacti...
Embodiment 3
[0232] Embodiment 3: the preparation of compound 3
[0233] Step 1: Preparation of compound 3-3
[0234]
[0235] Compound 3-1 (10g, 60.9mmol) was dissolved in pyridine (30mL), added 3-2 (23g, 73.1mmol), and stirred at room temperature for 3h. The system was diluted with ethyl acetate (800mL), the organic phase was washed with saturated brine (400mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by flash silica gel column chromatography (petroleum ether / Ethyl acetate (v / v)=1 / 0~1 / 9), to obtain compound 3-3.
[0236] 1 H NMR (400MHz, Chloroform-d) δ4.82(s, 1H), 4.50(t, J=5.3Hz, 1H), 4.09–3.98(m, 3H), 3.75(dd, J=10.5, 8.7Hz, 1H), 3.32(s,3H), 2.97(s,1H), 1.09–1.02(m,28H).
[0237] Step 2: Preparation of Compound 3-4
[0238]
[0239] Under nitrogen protection, compound 3-3 (11g, 27.1mmol) was dissolved in tetrahydrofuran (150mL), and allyl methyl carbonate (4.72g, 40.65mmol) ...
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