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Synthesis method of anti-insomnia drug Suvorexan intermediate

A synthesis method, methyl technology, applied in the field of synthesis of anti-insomnia drug intermediates, can solve the problems of high cost, expensive raw materials, difficult monitoring, etc., and achieve the effects of easy industrial production, low raw material prices, and low synthesis cost

Active Publication Date: 2017-11-28
安徽联创生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problems of these routes are mainly: the production cost of iodide is relatively high, and the price of raw materials is expensive; there are many reaction impurities, especially the product at the triazole-1 position is similar to the product properties, and it must be formed through salt formation, crystallization, acidification, recrystallization Multiple operations are very cumbersome and difficult to monitor; since the docking of this intermediate and another fragment is the final product, in order to ensure that the API single and total impurities of the product are qualified, the content must be more than 99.5%. The cost of such a standard is very high, so there are certain difficulties in the application and industrial production of this route

Method used

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  • Synthesis method of anti-insomnia drug Suvorexan intermediate
  • Synthesis method of anti-insomnia drug Suvorexan intermediate
  • Synthesis method of anti-insomnia drug Suvorexan intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] This example relates to a method for synthesizing Suvoraxan intermediate 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, which consists of the following steps:

[0026] step one

[0027]

[0028] Add 4-methyl-2-carboxyphenylhydrazine hydrochloride (101.3 g, 0.5 mol) into a 3 L three-necked flask, then add 1 L of 1 mol / L hydrochloric acid solution, stir vigorously until the raw materials are dissolved, and then add dropwise Dialdehyde aqueous solution (mass volume ratio concentration 40%, 36.3g, 0.25mol), control the temperature below 20°C, after the dropwise addition, continue to stir for 2-3 hours, monitor the reaction of raw materials, filter the precipitated solid, 60°C Vacuum drying gave intermediate 2, namely glyoxal di(4′-methyl-2′-carboxy)phenylhydrazone (77.96g, 0.22mol, yield 88%), which can be directly used in the next reaction;

[0029] step two

[0030]

[0031] Add intermediate 2, glyoxal acetal bis(4′-methyl-2′-carboxy)phenylhydrazone (35.4g, 0.1mo...

Embodiment 2

[0033] This example relates to a method for synthesizing Suvoraxan intermediate 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, which consists of the following steps:

[0034] step one

[0035]

[0036] Add 4-methyl-2-carboxyphenylhydrazine hydrochloride (101.3 g, 0.5 mol) into a 3 L three-necked flask, then add 1 L of 3 mol / L hydrochloric acid solution, stir vigorously until the raw materials are dissolved, and then add ethyl alcohol dropwise Dialdehyde aqueous solution (mass volume ratio concentration 40%, 46.6g, 0.30mol), control the temperature below 20°C, after the dropwise addition, continue to stir for 2-3 hours, monitor the reaction of raw materials, filter the precipitated solid, 60°C Vacuum drying gave intermediate 2, namely glyoxal di(4′-methyl-2′-carboxy)phenylhydrazone (81.5g, 0.23mol, yield 77%), which can be directly used in the next reaction;

[0037] step two

[0038]

[0039] Add intermediate 2, glyoxal acetal bis(4′-methyl-2′-carboxy)phenylhydrazone ...

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Abstract

The invention relates to a synthetic method for an intermediate of suvorexant as an anti-insomnia medicament. The synthetic method is characterized in that 4-methyl-2-hydrazinobenzoic acid hydrochloride is taken as a starting raw material, and reacts with glyoxal to generate dihydrazone; then dihydrazone is subjected to cyclization under the action of copper trifluoromethanesulfonate to obtain a key intermediate 5-methyl-2-(2H-1,2,3-triazole-2-yl) benzoic acid of the suvorexant as the anti-insomnia medicament. The synthetic method disclosed by the invention has the advantages of low price of raw materials, short reaction step, simpleness and convenience in operation, no isomers difficult to separate, high content of products and easiness for industrial production; meanwhile, a ring-closing by-product 4-methyl-2-carboxy anilide is separated in a form of forming hydrochloride, and is a raw materials for synthesizing the starting raw material 4-methyl-2-hydrazinobenzoic acid, so that organic materials can be recycled, and further the total synthetic cost is lower; in addition, by recovering treatment, solvent can be used indiscriminately, economy, environment friendliness and important application value are realized.

Description

technical field [0001] The invention relates to a method for synthesizing an intermediate of an anti-insomnia drug, in particular to a method for synthesizing an intermediate of an anti-insomnia drug Suvorexan. Background technique [0002] Suvorexant is an anti-insomnia drug newly developed by Merck Pharmaceuticals in the United States. It was approved by the US Food and Drug Administration (FDA) in August 2014, with the trade name Belsomra. Suvorexant is an orexin (orexin) receptor antagonist that affects signaling in the orexin pathway. Orexin is a small molecule neuropeptide, which is related to the regulation of sleep-wake cycle. Among the insomnia drugs approved by the FDA, this is the only orexin receptor antagonist. The FDA determined that Suvorexant was effective based on three clinical trials that included more than 500 subjects. Studies have shown that those who take the drug fall asleep faster and spend less time waking up during the night than those who take ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/06
CPCC07D249/06
Inventor 葛德培吴其华刘涛
Owner 安徽联创生物医药股份有限公司
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