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Preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile

A technology of pyridine and dimethylcarbamoyl chloride, applied in the field of medicine and chemical industry, can solve the problems of suboptimal solution, large amount of acid dehydrating agent, strong corrosiveness of instruments and equipment, etc., and achieves reduced dosage, mild reaction conditions and high product purity. Effect

Inactive Publication Date: 2014-11-19
王庆本 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] In this route, the yield of carbamyl is less than 40%, and a large amount of concentrated sulfuric acid and hydrogen peroxide are used to further dehydrate into the step of cyano group. The consumption of acidic dehydrating agent is relatively large, which is highly corrosive to instruments and equipment. , this method is also not optimal

Method used

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  • Preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile
  • Preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile
  • Preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile

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Embodiment 1

[0037] Embodiment 1: the preparation of formula (4) compound 2-cyanoisonicotinic acid methyl ester

[0038] Formula (5) compound methyl isonicotinic acid-N-oxide 1.53g (10mmol), dimethylcarbamoyl chloride (0.11ml, 11mmol), zinc cyanide (1.40g, 12mmol), cuprous iodide 0.19g (1mmol) was dissolved in 50ml of acetonitrile, and the mixture was reacted at 80°C for 5 hours, and the reaction was detected by TLC (n-hexane / ethyl acetate=1:1). After the reaction was completed, it was cooled to room temperature, and 20ml of water was added to stir the reaction for 5-30 Minutes, discard the organic layer, the aqueous layer was extracted three times with ethyl acetate, 50ml each time, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, the crude product was extracted with n-hexane / ethyl acetate=4: 1 column chromatography, 1.53 g of light yellow solid was obtained, yield 94%, HPLC purity (no...

Embodiment 2

[0039] Embodiment 2: the preparation of formula (4) compound 2-cyanoisonicotinic acid methyl ester

[0040] Formula (5) compound methyl isonicotinic acid-N-oxide 1.53g (10mmol), dimethylcarbamoyl chloride (0.11ml, 11mmol), sodium cyanide (0.98g, 20mmol), cuprous iodide 0.19g (1mmol) was dissolved in 50ml of acetonitrile, and the mixture was reacted at 90°C for 7 hours, and the reaction was detected by TLC (n-hexane / ethyl acetate=1:1). After the reaction was completed, it was cooled to room temperature, and 20ml of water was added to stir the reaction for 5-30 Minutes, discard the organic layer, the aqueous layer was extracted three times with ethyl acetate, 50ml each time, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, the crude product was extracted with n-hexane / ethyl acetate=4: 1 column chromatography, 1.16 g of a light yellow solid was obtained, with a yield of 71.6%....

Embodiment 3

[0041] Embodiment 3: the preparation of formula (4) compound 2-cyanoisonicotinic acid methyl ester

[0042]Formula (5) compound methyl isonicotinic acid-N-oxide 1.53g (10mmol), dimethylcarbamoyl chloride (0.11ml, 11mmol), potassium cyanide (1.3g, 20mmol), cuprous iodide 0.19g (1mmol) was dissolved in 50ml of acetonitrile, and the mixture was reacted at 90°C for 8 hours, and the reaction was detected by TLC (n-hexane / ethyl acetate=1:1). After the reaction was completed, it was cooled to room temperature, and 20ml of water was added to stir the reaction for 5-30 Minutes, discard the organic layer, the aqueous layer was extracted three times with ethyl acetate, 50ml each time, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, the crude product was extracted with n-hexane / ethyl acetate=4: 1 column chromatography, 1.15 g of a light yellow solid was obtained, with a yield of 70.8%...

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Abstract

The invention relates to a preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile. The method includes following steps: preparing a compound methyl 2-cyanoisonicotinate represented as the formula (4) with a compound methylisonicotinic-N-oxide (5) being a starting raw material in the presence of a copper catalyst (CuX), a metal cyanide and dimethylcarbamyl chloride; performing hydrazinolysis to the methyl 2-cyanoisonicotinate to obtain a compound 2-cyanoisoniazide represented as the formula (3); and finally performing condensation with a compound 4-cyanopyridine represented as the formula (2) to obtain a compound topiroxostat represented as the formula (1). The method only comprises three steps and is simple in operation and post-treatment. By means of the copper catalyst, a usage amount of the metal cyanide is greatly reduced so that reaction conditions are milder. The method is high in purity of the prepared product and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation method of 4-[5-(pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile, i.e. topicastat, belonging to Pharmaceutical and chemical industry. Background technique [0002] Gout is a common disease caused by abnormal production of uric acid due to purine metabolism disorder. It has been listed by the United Nations as one of the 20 most stubborn diseases in the 21st century, and it is the second most metabolic disease after diabetes. "Hyperuricemia and Gout Treatment Chinese Expert Consensus" pointed out that the prevalence of hyperuricemia (HUA) showed an overall trend of increasing year by year, with males higher than females, and there were certain regional differences. The southern and coastal areas were economically developed. The prevalence rate in this region is higher than that in other regions in China during the same period. More importantly, the patients with HUA are showing a trend of getti...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 不公告发明人
Owner 王庆本
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