Synthetic method for intermediate of suvorexant as anti-insomnia medicament

A synthesis method and an intermediate technology, which are applied in the field of synthesis of anti-insomnia drug intermediates, can solve the problems of high cost, expensive raw materials, and many reaction impurities, and achieve the effects of easy industrial production, low raw material prices, and short reaction steps

Active Publication Date: 2015-09-02
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 ve

Method used

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  • Synthetic method for intermediate of suvorexant as anti-insomnia medicament
  • Synthetic method for intermediate of suvorexant as anti-insomnia medicament
  • Synthetic method for intermediate of suvorexant as anti-insomnia medicament

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Embodiment 1

[0025] This embodiment relates to a method for synthesizing Suvorexan 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 (101.3g, 0.5mol) to 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 drip Glyoxal aqueous solution (40% by mass-volume ratio, 36.3g, 0.25mol), control the temperature below 20°C, after the dripping is completed, continue to stir for 2-3 hours, monitor the raw material after the reaction is completed, suction and filter the precipitated solid, 60 Vacuum drying at ℃ to obtain intermediate 2, namely glyoxal bis(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] Into a 2L three-necked flask, add Intermediate 2 that is glyoxal bis(4'-methyl-2'-c...

Embodiment 2

[0033] This embodiment relates to a method for synthesizing Suvorexan 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 (101.3g, 0.5mol) to a 3 L three-necked flask, then add 1L of 3 mol / L hydrochloric acid solution, stir vigorously until the raw materials are dissolved, and then drip Glyoxal aqueous solution (40% by mass volume ratio, 46.6g, 0.30mol), control the temperature below 20°C, add dropwise, continue to stir for 2-3 hours, monitor the raw material after the reaction is complete, suction and filter the precipitated solid, 60 Vacuum drying at ℃ to obtain Intermediate 2, namely glyoxal bis(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] Into a 2L three-necked flask was added Intermediate 2, namely glyoxal bis(4'-methyl-2'-carboxy) phenylhy...

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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 synthetic method of an anti-insomnia drug intermediate, in particular to a synthetic method of an anti-insomnia drug Suvorexan intermediate. Background technique [0002] Suvorexant is an anti-insomnia drug newly developed by Merck Pharmaceuticals in the United States. It was approved by the Food and Drug Administration (FDA) in August 2014 for marketing under the brand name Belsomra. Suvorexant is an Orexin (orexin) receptor antagonist that can affect the signal transduction of the Orexin pathway. Orexin is a small molecule neuropeptide related to the regulation of sleep-wake cycle. Among the insomnia drugs approved by the FDA, Orexin receptor antagonists are the only one. Based on 3 clinical trials, the FDA recognized Suvorexant as effective, and the total number of subjects in these trials exceeded 500. Studies have shown that compared with subjects taking a placebo, those taking the drug fall asleep faster and wake up less ...

Claims

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Application Information

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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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