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

Active Publication Date: 2020-07-14
JIANGSU ATOM BIOSCI & PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Another object of the present invention is to provide a 3-bromo-5-(2-ethylimidazo[1,2-a ]pyridine-3-carbonyl)-2-hydroxybenzonitrile synthetic method, the method is easy to operate, mild conditions, higher yield, suitable for suitability for industrialized production

Method used

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  • Synthesis of 3-bromo-5-(2-ethylimidazo[1, 2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile
  • Synthesis of 3-bromo-5-(2-ethylimidazo[1, 2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile
  • Synthesis of 3-bromo-5-(2-ethylimidazo[1, 2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile

Examples

Experimental program
Comparison scheme
Effect test

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] + .

[...

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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Abstract

The invention discloses a synthetic method of 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile, particularly relates to a synthetic method of a compound shown as a formula (III), and particularly relates to a step A or a step B; the preparation method comprises the following steps: A, heating a compound shown as a formula (I) and a compound shown as a formula (II) in an organic solvent for reaction, and heating an obtained reaction product and alkali in the presence of water for continuous reaction to obtain a compound shown as a formula (III); and B, heating the compound shown as the formula (I), a compound shown as a formula (II) and alkali in an organic solvent to react, and heating an obtained reaction product in the presence of water to continuously react toobtain a compound shown as a formula (III).

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthesis method of a compound 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile. Background technique [0002] Gout is a chronic metabolic disease caused by hyperuricemia (Hyper-uricemia) due to purine metabolism disorder and / or uric acid excretion disorder in the human body. It is characterized by severe pain caused by urate deposition in joints and other parts main features. When the serum uric acid level in the body exceeds 6.8mg / dL, urate will deposit monosodium urate crystals in the synovial fluid of human tissues, the cartilage of peripheral joints, the auricle of the ear, and the olecranon sac of the elbow. Gout can be diagnosed when such symptoms are present. URAT1 plays an important role in the process of uric acid reabsorption from cells into the lumen of renal tubules. It is the main uric acid reabsorption protein in the huma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04A61K31/437
Inventor 史东方傅长金顾杰张敏龚维伟李鹏飞
Owner JIANGSU ATOM BIOSCI & PHARMA CO LTD
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