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Synthesis method of high-purity histamine dihydrochloride

A technology of histamine dihydrochloride and synthesis method, which is applied in the field of synthesis of high-purity histamine dihydrochloride, can solve the problems of limitation and high risk, achieve the reduction of species and content, simple equipment and simple operation Effect

Active Publication Date: 2021-01-26
WUHAN JASON BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The patent of CN106432089A discloses another synthesis method of histamine dihydrochloride, using histidine as the starting material, under alkaline conditions, the nitrile methylimidazole intermediate is prepared by strong chlorine oxidation, and then through catalytic hydrogenation and salt formation to prepare the product, but this method either requires a hydrogenation pressure of 10MPa, or requires the combination of Raney nickel and hydrazine hydrate, which is very dangerous, which limits the adoption of this method in production

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  • Synthesis method of high-purity histamine dihydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]Add 50 grams of L-histidine, 3 grams of sodium carbonate, 0.25 grams of p-methylacetophenone and 500 grams of dimethyl sulfoxide into a 1000ml three-necked flask equipped with a mechanical stirrer, a thermometer and a reflux device. Replace the air, protect the whole process with nitrogen, heat to 140°C and react for 4 hours, stop the reaction when the histidine content is less than 0.5%, and obtain a golden yellow transparent decarboxylation reaction solution, cool the reaction solution to 50-60°C, filter out insoluble The obtained filtrate was evaporated to remove the solvent under reduced pressure to obtain a viscous substance, add about 150 grams of water to disperse, add about 60 grams of concentrated hydrochloric acid to neutralize to pH 5-6 under ice-bath cooling, after the addition is completed, stir at 20-25 ° C After half an hour, the aqueous solution was extracted three times with about 500 g of ethyl acetate, and the obtained aqueous layer was evaporated to ob...

Embodiment 2

[0047] Add 50 gram L-histidine, 3 gram sodium carbonate, 0.25 gram p-methyl acetophenone and 500 gram embodiment 1 in the 1000ml there-necked flask that mechanical stirring, thermometer, reflux device are housed and reclaim dimethyl sulfoxide , replace the air with vacuum and nitrogen, protect the whole process with nitrogen, heat to 140°C for 4 hours, and stop the reaction when the content of histidine is monitored to be less than 0.5%. ℃, filter out the insoluble matter, evaporate the solvent from the obtained filtrate under reduced pressure to obtain a viscous substance, add about 150 grams of water to disperse, add about 60 grams of concentrated hydrochloric acid to neutralize to pH to 5-6 under ice bath cooling, and dropwise. After stirring at 20-25°C for half an hour, the aqueous solution was extracted three times with about 500 g of ethyl acetate, and the obtained aqueous layer was evaporated to obtain a crude product of histamine dihydrochloride. Add 100 g of absolute ...

Embodiment 3

[0050] Add 50 gram L-histidine, 3 gram sodium carbonate, 0.25 gram p-methyl acetophenone and 500 gram xylene in the 1000ml there-necked bottle that mechanical stirring, thermometer, reflux device are housed, replace air with vacuum and nitrogen, Nitrogen protection throughout the whole process, heating to 140°C for 4 hours, monitoring the histidine content to stop the reaction when it is less than 0.5%, and obtaining a golden yellow transparent decarboxylation reaction solution, cooling the reaction solution to 50-60°C, filtering out insolubles, and obtaining Remove the solvent from the filtrate under reduced pressure to obtain a viscous substance, add about 150 grams of water to disperse, add about 60 grams of concentrated hydrochloric acid to neutralize to pH 5-6 under ice-cooling, after the dropwise addition is completed, stir at 20-25 ° C for half an hour, The aqueous solution was extracted three times with about 500 g of ethyl acetate, and the obtained aqueous layer was ev...

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Abstract

The invention discloses a synthesis method of high-purity histamine dihydrochloride, and belongs to the technical field of organic synthesis. The method comprises the steps: in a solvent A, carrying out a decarboxylation reactionon L-histidine at the temperature of 110-150 DEG C under the effect of a composite decarboxylation catalyst, and carrying out filtering after the reaction is completed, wherein the composite decarboxylation catalyst is composed of a main catalyst and an auxiliary catalyst, the main catalyst is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, pyridine, 4-methylpyridine, aniline, 4-methylaniline, ,N,N-dimethylaniline and N, N-dimethylformamide, and the auxiliary catalyst is one selected from benzophenone, acetophenone, benzophenone and p-methyl acetophenone; carrying out reduced pressure distillation on a filtrate, adding water into residues, and adjusting the pH value to 5-6 by using hydrochloric acid to obtain an aqueous solution; extracting the aqueous solution at least once by using an extracting agent to remove impurities; and evaporating to remove water in the aqueous solution, pulping with a solvent B, filtering and drying to obtain the product.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing high-purity histamine dihydrochloride. Background technique [0002] Histamine hydrochloride is a substance with extremely strong physiological activity, and it is also an important drug intermediate and drug additive. Histamine can be used to prepare anti-tumor drugs, such as drugs against pancreatic cancer, epidermal cancer, and bladder cancer Drugs for colon cancer, melanoma and prostate cancer can also be used as a combination of antineoplastic drugs. Therefore, the synthesis of histamine and histamine compounds has become a hot issue for organic chemists. [0003] At present, the synthesis of histamine usually uses cheap histidine as raw material to prepare histamine through decarboxylation reaction. For example, 2-cyclohexen-1-one was used as catalyst in the earliest stage to decarboxylate at 160°C. This method requires a high temperature...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64
CPCC07D233/64
Inventor 唐启明吴伟伟李健雄冯议汪黎明
Owner WUHAN JASON BIOTECH CO LTD
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