Synthesis of 3-bromo-5-(2-ethylimidazo[1, 2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile
A kind of technology of acetonitrile and synthesis method, applied in the direction of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve problems such as low yield, harsh reaction conditions, and immature synthetic routes
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Embodiment 1
[0069]
[0070] Step A: Add dichloromethane (30L) to the reactor, then add 2-aminopyridine (5.0kg, 53.1mol), triethylamine (10.7kg, 106mol) and propionic anhydride (8.3kg , 63.8mol). After the addition was complete, the resulting mixture was stirred at reflux for 22-24 hours. After the reaction was completed, 10% sodium hydroxide solution (25 L) was added at 20-25°C. The layers were separated, and the organic layer was washed with water (15 L×2). The combined aqueous layers were extracted with dichloromethane (30 L). The combined organic layers were evaporated under reduced pressure to remove most of the solvent, and then recrystallized from n-heptane / dichloromethane to obtain N-(pyridin-2-yl)propanamide (1) (7.7kg) as a yellow solid. The HPLC purity was 100%, and the yield was 96.6%. 1 H NMR (DMSO-d6, 300MHz) δ10.38(s, 1H), 8.30-8.28(m, 1H), 8.11-8.08(m, 1H), 7.78-7.73(m, 1H), 7.08-7.04(m , 1H), 2.39 (q, J=7.5Hz, 2H), 1.07 (t, J=7.5Hz, 3H). LCMS: 151.2[M+H] + .
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Embodiment 2
[0079]
[0080] Step A-1: To a solution of 4-methoxyacetophenone (600 g, 4.0 mol) in acetonitrile (5.4 L) was added iodine (518 g, 2.04 mol) and 1-chloromethyl-4-fluoro-1,4 - Diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (1.42kg, 4.0mol), after the addition, the resulting mixture was stirred at 12-20°C for 20 hours. After the reaction was completed, water (24 L) was added, stirred for 15 minutes, and filtered. The filter cake was washed successively with 5% sodium thiosulfate solution (1.5 L) and water (3.0 L). Drying gave 3-iodo-4-methoxyacetophenone (8) (894 g) as a yellow solid. The yield was 81.0%.
[0081] The experimental operation of Step A-2 is the same as Step B in Example 1 to obtain 1-(3-bromo-4-methoxyphenyl)ethanone (2).
[0082] Step B-1: Add cuprous cyanide (228g, 2.55mol) to the DMF (2.0L) solution of compound 8 (467g, 1.69mol), after the addition, the resulting mixture was stirred overnight at 110-120°C under nitrogen . Cool to room temperatu...
Embodiment 3
[0090]
[0091] Step A: A mixture containing compound 9 (50.0 g, 285 mmol), sodium ethanethiolate (28.8 g, 342 mmol) and DMF (200 mL) was stirred at 70-80° C. for 1 hour. After cooling to room temperature, water (700 mL) was added, the insoluble matter was removed by filtration, the filtrate was extracted with ethyl acetate (100 mL), and the product was in the aqueous phase. The aqueous phase was adjusted to pH 5-6 with 10% citric acid solution, and extracted with ethyl acetate (200 mL×3). The combined organic phases were washed with water (100mL×2) and saturated brine (100mL) successively, the solvent was evaporated under reduced pressure, and the resulting product was recrystallized from petroleum ether / ethyl acetate to obtain 5-acetyl-2-hydroxybenzyl Nitrile (11) (42.3 g). The yield was 92.1%.
[0092] Step B: NBS (36.8 g, 207 mmol) was added in portions to a solution of compound 11 (30.3 g, 188 mmol) in DMF (150 mL). After the addition was complete, the resulting mix...
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