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Preparation method of tetramethyl-pyrazine

A technology of tetramethylpyrazine and ammonium formate, which is applied in the direction of organic chemistry, can solve problems such as safety risks, and achieve the effects of complete reaction, high yield and mild reaction conditions

Active Publication Date: 2015-02-11
WUHAN WUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Although the yields of the three catalytic hydrogenation reactions are relatively high, they all use high temperature and high pressure reaction conditions. Considering the pressure-resistant reaction equipment and safety, there are certain safety risks

Method used

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  • Preparation method of tetramethyl-pyrazine
  • Preparation method of tetramethyl-pyrazine
  • Preparation method of tetramethyl-pyrazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 10.0 g of dimethylglyoxime and 10.0 g of palladium carbon into 120 ml of methanol, then stir and heat up to 60°C. Add 67.4g of ammonium formate in batches, and after the addition of ammonium formate is completed, reflux and stir at 60-65°C for 2 hours. After the reaction, remove the palladium carbon by cloth filtration (recovery), add hydrochloric acid, remove the solvent methanol under reduced pressure, add 120mL water, NaOH to adjust the pH to 8-9, extract three times with 60ml ethyl acetate, combine the organic phases, and add anhydrous sulfuric acid Dry over sodium, filter, and concentrate under reduced pressure to obtain 5.3 g of tetramethylpyrazine, with a yield of 79.2%.

Embodiment 2

[0030] Add 10.0 g of diacetyl monoxime and 5.0 g of palladium carbon into 120 ml of water, then stir and heat up to 90°C. Add 50.5 g of ammonium formate in batches, and after the addition of ammonium formate is completed, reflux and stir at 95-100°C for 2 hours. After the reaction finishes, remove the palladium carbon, and the filtrate is washed with dichloromethane (CH 2 Cl 2 ) was extracted three times, the organic phases were combined, dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5.6 g of tetramethylpyrazine with a yield of 83.7%.

Embodiment 3

[0032] Add 10.0 g of dimethylglyoxime and 1.0 g of palladium carbon to 134 ml of water, then stir and raise the temperature to 80-90°C. Add 67.4g of ammonium formate (HCOONH4) in batches, after the ammonium formate is added, continue to reflux and stir for 4 hours. After the reaction was complete, use a Buchner funnel to filter under reduced pressure to remove palladium carbon, and the filtrate was extracted three times with dichloromethane (CH2Cl2), the organic phases were combined, dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tetramethylpyrazine 5.7 g, the yield is 84.6%.

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Abstract

The invention relates to a synthesis method of medical intermediate tetramethyl-pyrazine. The method takes butanedione monoxime as raw material, water as a solvent and palladium carbon as a catalyst, and comprises the steps of feeding ammonium formate in a reflux state, continuously carrying out reflux mixing for 4 hours after the ammonium formate is fed, filtering to remove the catalyst, cooling, extracting dichloromethane, and concentrating under the reduced pressure to obtain the tetramethyl-pyrazine. The method for preparing the tetramethyl-pyrazine is mild in reaction conditions and simple and convenient in aftertreatment, has the conversion rate of more than 95% and the yield of more than 80%, and is lower in cost and beneficial to industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a pharmaceutical intermediate tetramethylpyrazine. Background technique [0002] Tetramethylpyrazine, the chemical formula is: C 8 h 14 N 2 , Colorless needle crystal, molecular weight 136.20 Melting point: 82~84°C, boiling point: 190°C. Its structural formula is: [0003] [0004] The substance has an aromatic odor, is hygroscopic and readily sublimes. Soluble in hot water, petroleum ether, chloroform, slightly soluble in ether, insoluble in cold water. [0005] Tetramethylpyrazine can be used as flavoring agent, fragrance, food flavoring agent, intermediate of medicine and pesticide. In recent years, it has been discovered that tetramethylpyrazine is one of the active ingredients of Ligusticum chuanxiong Hort, a traditional Chinese medicine, which is mainly used to treat ischemic cardiovascular and cerebrovascular diseases clinically. Especia...

Claims

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Application Information

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IPC IPC(8): C07D241/12
CPCC07D241/12
Inventor 皮金红董建强丁友友赵涛涛郭东坡魏金维张琦谢国范
Owner WUHAN WUYAO PHARMA
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