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Synthesis method of deuterated albendazole

A technology of albendazole and a synthetic method, applied in the field of pharmaceutical preparation, can solve problems such as no literature reports, and achieve the effects of reducing production cost, improving atom economy, good reproducibility and stability

Pending Publication Date: 2022-04-22
天津阿尔塔科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] At present, the synthesis methods of albendazole with natural abundance are many and relatively mature, and the literatures such as US2013303782A1 and CN105585333 have reported their synthesis methods, but there is no literature for the synthesis of stable isotope-labeled albendazole Report, in view of this, the present invention has designed a comparatively reasonable preparation route, and has optimized the whole synthesis process, with cheap albendazole original drug as starting material, by hydrolysis, acylation two-step reaction comparatively simple Deuterium-labeled albendazole was synthesized with a total yield of 74.8%, and the utilization rate of deuterium-labeled reagents was high. This route and process can fully meet the needs of large-scale preparation of albendazole internal standard products

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  • Synthesis method of deuterated albendazole
  • Synthesis method of deuterated albendazole
  • Synthesis method of deuterated albendazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the preparation of compound 1:

[0047] Add albendazole (8.0g, 30.2mmol), sodium hydroxide (1.8g, 45.0mmol), methanol (250ml) and water (50ml) in 500 milliliters of round bottom flasks, then reaction system heating reflux 16 hours, Bendazole raw material disappeared. Cooled to room temperature, concentrated under reduced pressure to remove most of the methanol, a large amount of solid precipitated, filtered, washed with water and dichloromethane in turn, the solid was dried to obtain compound 1, 5.5g, yield 88%, MS (m / z): 208.1[ M+H] + .

Embodiment 2-1

[0049] In a 50ml round bottom bottle, compound 1 (207mg, 1.0mmol), sodium bicarbonate (256mg, 3.0mmol) and acetone 6ml were added. With stirring, methyl deuterochloroformate (100 mg, 1.1 mmol) was slowly added. After the addition, the reaction mixture was stirred at room temperature, followed by TLC and LC-MS, and the reaction was complete within 2.5 hours. Filter, wash with water, dichloromethane and methanol successively, and dry the solid to obtain Intermediate 2, 220 mg, yield 83.0%, MS (m / z): 269.0 [M+H] + .

Embodiment 2-2

[0051] In a 100 ml round bottom bottle, compound 1 (2.1 g, 10.1 mmol), sodium bicarbonate (2.5 g, 30.0 mmol) and acetone 50 ml were added. Methyl deuterochloroformate (1.1 g, 11.2 mmol) was slowly added dropwise over 5 minutes. The reaction mixture was stirred at room temperature, followed by TLC and LC-MS, and the reaction was complete within 2.5 hours. Then heated to reflux for 16 hours, LC-MS followed the reaction, intermediate 2 disappeared, waited for the reaction to cool to room temperature, filtered, washed with water, dichloromethane and methanol successively, and the solid was dried to deuterated albendazole, 2.3g. Yield 85%, chemical purity 99.0%, isotopic abundance 99.5%, MS(m / z): 269.0[M+H] + .

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Abstract

The invention relates to a method for synthesizing deuterated albendazole, which comprises the following steps of: hydrolyzing albendazole which is industrially produced on a large scale and is used as a raw material under an alkaline condition to remove a methyl formate group on an amino group at the 2-position of the albendazole, and then connecting the deuterated methyl formate group to the amino group at the 2-position of the albendazole. According to the deuterated albendazole synthesis method, albendazole is taken as a raw material, deuterated albendazole is synthesized through two-step reaction, the raw material is low in price and easy to obtain, the synthesis route is simple, conditions are easy to control, the yield is high, and the obtained product is high in purity.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, in particular to a method for synthesizing deuterated albendazole. Background technique [0002] Albendazole (albendazole), the chemical name is 5-propylthiobenzimidazole-2-methyl carbamate, is a broad-spectrum, high-efficiency, low-toxic anthelmintic drug listed by Smith Kline Company of the United States in 1977. It has significant efficacy against Fasciola hepatica, tapeworm, lung and gastrointestinal nematodes. It is the most effective one among benzimidazoles, and it is the drug of choice for the prevention and treatment of parasitic diseases in livestock and poultry. In recent years, it has been found that this product also has a strong effect on bovine cysticercosis. After treatment, the cysticercosis decreases and the lesions disappear. In addition, this product can also be used to prevent parasitic infection, so it can have good effects on promoting sheep growth and increa...

Claims

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Application Information

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IPC IPC(8): C07D235/32C07B59/00
CPCC07D235/32C07B59/002C07B2200/05
Inventor 张磊龙正宇韩世磊
Owner 天津阿尔塔科技有限公司
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