CN112266360B - Synthesis method of high-purity histamine dihydrochloride - Google Patents
Synthesis method of high-purity histamine dihydrochloride Download PDFInfo
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract
The invention discloses a method for synthesizing high-purity histamine dihydrochloride, belonging to the technical field of organic synthesis. The method comprises the following steps: in a solvent A, performing decarboxylation reaction on L-histidine under the action of a composite decarboxylation catalyst at the temperature of 110-150 ℃, and filtering after the reaction is finished, wherein the composite decarboxylation catalyst is composed of a main catalyst and an auxiliary catalyst, the main catalyst is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, pyridine, 4-methylpyridine, aniline, 4-methylaniline, N-dimethylaniline and N, N-dimethylformamide, and the auxiliary catalyst is selected from one of benzophenone, acetophenone, benzophenone and p-methylacetophenone; distilling the filtrate under reduced pressure, adding water into the residue, and adjusting pH to 5-6 with hydrochloric acid to obtain water solution; extracting the aqueous solution at least once by using an extracting agent to remove impurities; and (4) evaporating water in the aqueous solution, pulping by using the solvent B, filtering and drying to obtain the product.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing high-purity histamine dihydrochloride.
Background
Histamine hydrochloride is a substance with extremely strong physiological activity, and also is an important drug intermediate and a drug additive, and histamine can be used for preparing antitumor drugs, such as drugs for preparing pancreatic cancer, epidermal cancer, bladder cancer and colon cancer, and drugs for melanin cancer and prostate cancer, and can also be used as a combined drug of antitumor drugs, so that the synthesis of histamine and histamine compounds becomes a hot problem for research of organic chemists.
At present, cheap histidine is generally used as a raw material for synthesizing histamine through decarboxylation reaction, for example, 2-cyclohexene-1-ketone is used as a catalyst in the earliest period, decarboxylation is carried out at 160 ℃, the method needs high temperature of 160 ℃, and the final product has many unknown impurities and cannot meet the requirement of medicinal use.
JP05255204 discloses the use of acetophenone as catalyst and diethylene glycol as solvent for the reaction and the application of CN1008594A discloses the use of decarboxylation of 2, 4-dihydroxybenzophenone, and the results of the tests show that the product also contains more unknown impurities and is not suitable for pharmaceutical grade production.
The method specially used in China with application number CN201010576353.8 utilizes p-methylacetophenone as a catalyst and methylcyclohexanol as a solvent to react to prepare histamine, the temperature requirement is 170-175 ℃, dihydrochloride is formed by dropwise adding a methylcyclohexanol solvent containing hydrogen chloride, higher requirements are provided for equipment at higher temperature, certain difficulty and risk exist in production, and energy consumption is increased.
The patent CN104402825A discloses a synthesis method of histamine dihydrochloride, which claims that the decarboxylation temperature can be lowered to 100-110 ℃ by adding cuprous bromide as a catalyst, the types and contents of unknown impurities can be reduced, and the conversion rate of raw materials can be improved.
The patent of CN106432089A discloses another synthesis method of histamine dihydrochloride, which uses histidine as a starting material, and prepares a nitrile methyl imidazole intermediate through strong chlorine refining oxidation under an alkaline condition, and then prepares a product through catalytic hydrogenation and salt formation, but the method either needs a hydrogenation pressure of 10MPa, or needs combination of raney nickel and hydrazine hydrate, which is very dangerous, and limits the adoption of the method in production.
Therefore, the search for histamine dihydrochloride with short reaction period, simple operation, high yield and high purity is still an important subject in the current histamine dihydrochloride synthesis process.
Disclosure of Invention
The invention provides a synthesis method of histamine dihydrochloride, which reduces the decarboxylation temperature, shortens the reaction time, improves the conversion rate of raw materials, reduces the types and content of byproducts, and improves the purity and content of final finished products through the perfect combination of a composite decarboxylation catalyst and a decarboxylation solvent and the combined action of the composite decarboxylation catalyst and the decarboxylation solvent. And hydrochloric acid is directly used for salifying in the salifying process, so that the operation of introducing hydrogen chloride or preparing a hydrogen chloride solution in advance is avoided, and the method is very easy for industrial operation. The scheme is as follows:
the embodiment of the invention provides a synthesis method of histamine dihydrochloride, which is synthesized according to the following reaction formula:
the method comprises the following steps:
(1) in the solvent A, L-histidine is subjected to decarboxylation reaction under the action of a composite decarboxylation catalyst at the temperature of 110-150 ℃, and after the reaction is finished, the L-histidine is filtered (mainly used for removing the solid catalyst). The composite decarboxylation catalyst consists of a main catalyst and an auxiliary catalyst, wherein the dosage of the main catalyst is 5-10% of the weight of histidine, and the dosage of the auxiliary catalyst is 0.1-1.0% of the weight of histidine. Wherein the main catalyst is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, pyridine, 4-methylpyridine, aniline, 4-methylaniline, N-dimethylaniline, N-dimethylformamide and the like, and is preferably sodium carbonate or N, N-dimethylformamide; the auxiliary catalyst is selected from one of benzophenone, acetophenone, benzophenone, p-methylacetophenone and the like, and is preferably p-methylacetophenone. Wherein the mass ratio of the L-histidine to the solvent A is 1: 5-10. In the step, the decarboxylation reaction temperature of the main catalyst is above 250 ℃; the use of the auxiliary catalyst alone requires a very large amount, and the auxiliary catalyst is easy to produce impurities with histidine, so that the yield is not high. The two catalysts have synergistic effect, so that the decarboxylation temperature can be reduced, the dosage of the auxiliary catalyst can be greatly reduced, and the yield of the product is improved.
(2) Distilling the filtrate obtained in the step (1) under reduced pressure (to viscous state, mainly for removing the solvent and the liquid catalyst), adding water (small amount) to the residue after the solvent is distilled off, and adjusting the pH value to 5-6 by using hydrochloric acid to obtain an aqueous solution of histamine dihydrochloride.
(3) Extracting the aqueous solution obtained in the step (2) at least once (usually for a plurality of times) by using an extracting agent to remove impurities; wherein the extractant is a water-insoluble organic solvent.
(4) Evaporating water in the aqueous solution obtained in the step (3), pulping by using a solvent B, filtering (mainly used for removing histamine and a side catalyst ketone coupling product) and drying to obtain a product; among them, the solvent B is usually a low boiling point organic solvent.
Wherein, in the step (1), the solvent A is selected from one or more of dimethyl sulfoxide, xylene, cyclohexanol, ethylene glycol and the like, and dimethyl sulfoxide is preferred.
Wherein, in the step (1), the decarboxylation reaction time is 2-6 hours.
Further, in the step (1), decarboxylation reaction is carried out under the protection of nitrogen, and the reaction solution is filtered when the temperature is reduced to 50-80 ℃.
Preferably, in step (1), the composite decarboxylation catalyst is a combination of sodium carbonate and p-methylacetophenone or a combination of N, N-dimethylformamide and p-methylacetophenone, and the solvent a is dimethyl sulfoxide.
Wherein, in the step (2), the amount of water is 1-5 times of the weight of the residue, and the vacuum degree of the reduced pressure distillation is more than-0.09 MPa.
Specifically, in the step (2), concentrated hydrochloric acid is added in an ice bath to adjust the pH value to 5-6.
Wherein, in the step (3), the extractant is selected from one or more of ethyl acetate, butyl acetate, dichloromethane, trichloromethane, benzene, toluene, petroleum ether and the like, preferably ethyl acetate or toluene, and more preferably ethyl acetate.
Wherein, in the step (4), the solvent B is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, butyl acetate, tetrahydrofuran, acetone and the like. Preferably ethanol or isopropanol, more preferably ethanol.
Specifically, in the step (4), the pulping process is as follows: stirring at 40-50 deg.C for 20-120 min, and standing.
Specifically, the synthesis method of histamine dihydrochloride provided by the invention comprises the following steps:
(1) in a solvent A under the protection of nitrogen, L-histidine is subjected to decarboxylation reaction at the temperature of 110-150 ℃ under the action of a composite decarboxylation catalyst, and after the reaction is carried out for 2-6 hours, the reaction liquid is filtered when the temperature is reduced to 50-80 ℃. Wherein, the composite decarboxylation catalyst consists of a main catalyst and an auxiliary catalyst, the dosage of the main catalyst is 5-10% of the weight of histidine, and the dosage of the auxiliary catalyst is 0.1-1.0% of the weight of histidine. The main catalyst is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, pyridine, 4-methylpyridine, aniline, 4-methylaniline, N-dimethylaniline, N-dimethylformamide and the like, the auxiliary catalyst is selected from one of benzophenone, acetophenone, benzophenone, p-methylacetophenone and the like, and the solvent A is selected from one or more of dimethyl sulfoxide, xylene, cyclohexanol, ethylene glycol and the like.
(2) And (2) carrying out reduced pressure distillation on the filtrate obtained in the step (1), adding water into the residue after the solvent is distilled off, and adding concentrated hydrochloric acid in an ice bath to adjust the pH value to 5-6 to obtain an aqueous solution of histamine dihydrochloride. Wherein the amount of water is 1-5 times of the weight of the residue, and the vacuum degree of reduced pressure distillation is more than-0.09 MPa.
(3) And (3) extracting the aqueous solution obtained in the step (2) at least once by using an extracting agent to remove impurities. Wherein the extractant is selected from one or more of ethyl acetate, butyl acetate, dichloromethane, chloroform, benzene, toluene, petroleum ether and the like.
(4) And (4) evaporating water in the aqueous solution obtained in the step (3), adding a solvent B, stirring for 20-120 minutes at 40-50 ℃, standing, filtering and drying to obtain the product. Wherein, the solvent B is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, butyl acetate, tetrahydrofuran, acetone and the like.
Compared with the prior art, the invention has the following advantages:
(1) the catalyst used in the technology has good matching effect when being matched with a decarboxylation solvent, the decarboxylation temperature can be reduced to be not higher than 150 ℃, the reaction time can be greatly shortened to 2-6 hours, the raw materials can be completely converted, and compared with the prior art, the reaction time needs 20 hours at any moment, and is greatly shortened.
(2) After the reaction is finished, the solvent is distilled and recycled, and can be recycled continuously.
(3) The method directly uses the hydrochloric acid for neutralization and salification, omits the steps of introducing hydrogen chloride gas (generally, firstly preparing the primary salt and then preparing the secondary salt after purification) or preparing the hydrogen chloride solution in advance for salification in the prior art, and has the advantages of very simple operation and easy control.
(4) Compared with the prior art, the product obtained by the method provided by the invention has the yield of over 60 percent (the preferable condition can reach over 84 percent), the purity of over 99 percent and single impurity of less than 0.1 percent, and meets the requirement of medical use.
(5) The required instruments and equipment are simple, the process operation is simple and convenient, the environment is friendly, and the industrial large-scale production is facilitated.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.
Example 1
Adding 50 g of L-histidine, 3 g of sodium carbonate, 0.25 g of p-methylacetophenone and 500 g of dimethyl sulfoxide into a 1000ml three-necked bottle provided with a mechanical stirring device, a thermometer and a reflux device, replacing air with vacuum and nitrogen, introducing nitrogen for protection in the whole process, heating to 140 ℃, reacting for 4 hours, stopping the reaction when the content of histidine is monitored to be less than 0.5%, obtaining golden yellow transparent decarboxylation reaction liquid, cooling the reaction liquid to 50-60 ℃, filtering out insoluble substances, evaporating the obtained filtrate under reduced pressure to remove the solvent to obtain a viscous substance, adding about 150 g of water for dispersion, adding about 60 g of concentrated hydrochloric acid for neutralization until the pH is 5-6 under ice bath cooling, stirring for half an hour at 20-25 ℃, extracting the aqueous solution for three times by using about 500 g of ethyl acetate, and evaporating water from the obtained aqueous layer to obtain a crude product of histamine dihydrochloride. Adding 100 g of absolute ethyl alcohol into the obtained crude product, heating to 40-50 ℃, stirring for half an hour, slowly cooling to room temperature, standing for half an hour, filtering, and leaching a filter cake with 50ml of ethyl alcohol for 3 times. The filter cake was dried under vacuum for 1 hour to give 49.8 g of white histamine dihydrochloride in 84% yield with a purity of 99.6% and a single impurity < 0.1%.
COMPARATIVE EXAMPLE 1 addition of sodium carbonate alone
50 g of L-histidine and 3 g of sodium carbonate are added into a 1000ml three-mouth bottle provided with a mechanical stirring device, a thermometer and a reflux device, and 500 g of dimethyl sulfoxide, replacing air with vacuum and nitrogen, introducing nitrogen for protection in the whole process, heating to 170 ℃ for reaction for 4 hours, monitoring only trace histamine generation, continuously heating to 250 ℃, continuously heating for about 6 hours, gradually deepening the color of reaction liquid to dark red, monitoring until the reaction of raw material histidine is finished, stopping the reaction, cooling the reaction liquid to room temperature, filtering out sodium carbonate, decompressing and steaming a filtrate obtained from the filtrate to remove a solvent to obtain a viscous substance, adding about 150 g of water for dispersion, adding about 60 g of concentrated hydrochloric acid for neutralization until the pH value is 5-6 under the cooling of ice bath, dropwise adding, stirring for half an hour at 20-25 ℃, extracting the aqueous solution for three times by using about 500 g of ethyl acetate, and steaming water from the obtained aqueous layer to obtain a crude product of histamine dihydrochloride. The crude product obtained above is added with 100 g of absolute ethyl alcohol, heated to 40-50 ℃, stirred for half an hour, slowly cooled to room temperature and kept stand for half an hour to obtain 18.9 g of yellow histamine dihydrochloride, the yield is 31.8 percent, and the purity is 94.6 percent.
The results show that when sodium carbonate is used alone for catalyzing decarboxylation, higher reaction temperature (250 ℃) is needed, and due to higher temperature, partial decomposition of raw materials results in low yield and purity of the obtained product and darker color.
Comparative example 2
Adding 50 g of L-histidine, 12 g of p-methylacetophenone and 500 g of dimethyl sulfoxide into a 1000ml three-neck flask provided with a mechanical stirring device, a thermometer and a reflux device, replacing air with vacuum and nitrogen, introducing nitrogen for protection in the whole process, heating to 140 ℃ for reaction for 15 hours, stopping the reaction when the content of histidine is less than 0.5%, obtaining a golden yellow transparent decarboxylation reaction solution, cooling the reaction solution to 50-60 ℃, evaporating the solvent and part of p-methylacetophenone under reduced pressure to obtain a viscous substance, adding about 150 g of water for dispersion, adding about 55 g of concentrated hydrochloric acid for neutralization until the pH is 5-6 under ice bath cooling, after dropwise addition, stirring for half an hour at 20-25 ℃, extracting the aqueous solution for three times by using about 500 g of ethyl acetate, and evaporating water from the obtained water layer to obtain a crude product of histamine dihydrochloride. Adding 100 g of absolute ethyl alcohol into the obtained crude product, heating to 40-50 ℃, stirring for half an hour, slowly cooling to room temperature, standing for half an hour, filtering, and leaching a filter cake with 50ml of ethanol for 3 times. The filter cake was dried under vacuum for 1 hour to give 24.9 g of white histamine dihydrochloride in 42% yield with a purity of 99.1% and a single impurity < 0.1%.
The results show that when p-methylacetophenone is used alone for catalytic decarboxylation, longer reaction time (15 hours) is needed, and the yield of the obtained product is low (about 40%) due to the generation of byproducts caused by the large dosage of the p-methylacetophenone.
Example 2
Adding 50 g of L-histidine, 3 g of sodium carbonate, 0.25 g of p-methylacetophenone and 500 g of dimethyl sulfoxide recovered in example 1 into a 1000ml three-necked flask provided with a mechanical stirring device, a thermometer and a reflux device, replacing air with vacuum and nitrogen, introducing nitrogen for protection in the whole process, heating to 140 ℃ for reaction for 4 hours, stopping the reaction when the content of histidine is monitored to be less than 0.5%, obtaining golden transparent decarboxylation reaction liquid, cooling the reaction liquid to 50-60 ℃, filtering out insoluble substances, removing the solvent from the obtained filtrate by reduced pressure evaporation to obtain a viscous substance, adding about 150 g of water for dispersion, adding about 60 g of concentrated hydrochloric acid for neutralization until the pH is 5-6 under ice-bath cooling, stirring for half an hour at 20-25 ℃ after the dropwise addition is finished, extracting the aqueous solution for three times by using about 500 g of ethyl acetate, and evaporating water from the obtained water layer to obtain a crude product of histamine dihydrochloride. Adding 100 g of absolute ethyl alcohol into the obtained crude product, heating to 40-50 ℃, stirring for half an hour, slowly cooling to room temperature, standing for half an hour, filtering, and leaching a filter cake with 50ml of ethyl alcohol for 3 times. The filter cake was vacuum dried for 1 hour to give 48.6 g of white histamine dihydrochloride in 82% yield with a purity of 99.6% and a single impurity < 0.1%.
Compared with the example 1, other conditions are unchanged, the dimethyl sulfoxide is recovered by using the reaction solvent, the yield is reduced from 84% to 82%, the purity is almost unchanged, the yield is slightly reduced, and the solvent can be repeatedly utilized for multiple times, so that the cost is reduced.
Example 3
Adding 50 g of L-histidine, 3 g of sodium carbonate, 0.25 g of p-methylacetophenone and 500 g of xylene into a 1000ml three-necked bottle provided with a mechanical stirring device, a thermometer and a reflux device, replacing air with vacuum and nitrogen, introducing nitrogen for protection in the whole process, heating to 140 ℃, reacting for 4 hours, stopping the reaction when the content of histidine is monitored to be less than 0.5%, obtaining golden yellow transparent decarboxylation reaction liquid, cooling the reaction liquid to 50-60 ℃, filtering out insoluble substances, evaporating the obtained filtrate under reduced pressure to remove the solvent to obtain a viscous substance, adding about 150 g of water for dispersion, adding about 60 g of concentrated hydrochloric acid for neutralization until the pH is 5-6 under ice bath cooling, stirring for half an hour at 20-25 ℃ after dropwise addition, extracting the aqueous solution for three times by using about 500 g of ethyl acetate, and evaporating water from the obtained water layer to obtain a crude product of histamine dihydrochloride. Adding 100 g of absolute ethyl alcohol into the obtained crude product, heating to 40-50 ℃, stirring for half an hour, slowly cooling to room temperature, standing for half an hour, filtering, and leaching a filter cake with 50ml of ethyl alcohol for 3 times. The filter cake was dried under vacuum for 1 hour to yield 43.3 g of white histamine dihydrochloride in 73% yield at 99.1% purity with less than 0.1% single impurity.
Compared with the example 1, other conditions are not changed, only the reaction solvent is changed from dimethyl sulfoxide to xylene, the yield is reduced by about 10 points, probably because the catalytic effect of the catalyst is different under different solvents, and the fact that the catalyst is matched with a proper solvent for use shows that the catalytic efficiency of the catalyst can be improved better.
Example 4
Adding 50 g of L-histidine, 3 g of N, N-dimethylformamide, 0.25 g of p-methylacetophenone and 500 g of dimethyl sulfoxide into a 1000ml three-neck flask provided with a mechanical stirring device, a thermometer and a reflux device, replacing air with vacuum and nitrogen, introducing nitrogen for protection in the whole process, heating to 140 ℃ for reaction for 4 hours, stopping the reaction when the content of histidine is monitored to be less than 0.5%, obtaining golden transparent decarboxylation reaction liquid, cooling the reaction liquid to 50-60 ℃, filtering out insoluble substances, removing the solvent from the obtained filtrate by reduced pressure evaporation to obtain a viscous substance, adding about 150 g of water for dispersion, adding about 60 g of concentrated hydrochloric acid for neutralization until the pH value is 5-6 under ice-bath cooling, stirring for half an hour at 20-25 ℃ after the dropwise addition is finished, extracting the aqueous solution for three times by using about 500 g of ethyl acetate, and evaporating water from the obtained water layer to obtain a crude product of histamine dihydrochloride. Adding 100 g of absolute ethyl alcohol into the obtained crude product, heating to 40-50 ℃, stirring for half an hour, slowly cooling to room temperature, standing for half an hour, filtering, and leaching a filter cake with 50ml of ethyl alcohol for 3 times. The filter cake was dried under vacuum for 1 hour to give 50.5 g of white histamine dihydrochloride in 85.1% yield at 99.6% purity with less than 0.1% single impurity.
Compared with the example 1, other conditions are not changed, the catalyst is changed from sodium carbonate to N, N-dimethylformamide, and the difference of the yield and the purity of the obtained product is not large, which shows that the catalytic effect of the N, N-dimethylformamide and p-methyl acetophenone combined use is also better.
Example 5
Adding 50 g of L-histidine, 3 g of N, N-dimethylformamide, 0.2 g of benzophenone and 500 g of dimethyl sulfoxide into a 1000ml three-necked bottle provided with a mechanical stirring device, a thermometer and a reflux device, replacing air with vacuum and nitrogen, introducing nitrogen for protection in the whole process, heating to 140 ℃, reacting for 4 hours, stopping the reaction when the content of histidine is monitored to be less than 0.5%, obtaining golden transparent decarboxylation reaction liquid, cooling the reaction liquid to 50-60 ℃, filtering out insoluble substances, evaporating the obtained filtrate under reduced pressure to remove the solvent to obtain a viscous substance, adding 150 g of water for dispersion, adding 60 g of concentrated hydrochloric acid for neutralization until the pH is 5-6 under ice bath cooling, after dropwise addition, stirring at 20-25 ℃, extracting the aqueous solution for three times by using 500 g of ethyl acetate, and removing water from the obtained water evaporation layer to obtain a crude product of histamine dihydrochloride. Adding 100 g of ethanol into the obtained crude product, heating to 40-50 ℃, stirring for half an hour, slowly cooling to room temperature, standing for half an hour, filtering, and leaching a filter cake with 50ml of ethanol for 3 times. The filter cake was dried under vacuum for 1 hour to give white histamine dihydrochloride 40.4 g in 68.2% yield at 99.6% purity with single impurity < 0.1%.
Compared with the example 4, other conditions are not changed, the catalyst is changed from p-methylacetophenone to benzophenone, and the yield of the obtained product is reduced by 20 points, which shows that the catalytic effect of the p-methylacetophenone is better than that of the benzophenone.
Example 6
Adding 50 g of L-histidine, 4 g of N, N-dimethylformamide, 0.5 g of benzophenone and cyclohexanol into a 1000ml three-mouth bottle provided with a mechanical stirring device, a thermometer and a reflux device, replacing air with vacuum and nitrogen, introducing nitrogen for protection in the whole process, heating to 155 ℃, reacting for 5 hours, stopping the reaction when the content of histidine is less than 1%, obtaining golden transparent decarboxylation reaction liquid, cooling the reaction liquid to 50 ℃, filtering out insoluble substances, evaporating the obtained filtrate under reduced pressure to remove a solvent to obtain a viscous substance, adding 200 g of water for dispersion, adding 65 g of concentrated hydrochloric acid for neutralization until the pH value reaches 5-6 under the cooling of an ice bath, stirring for half an hour at 25 ℃, extracting the aqueous solution for three times by using 500 g of toluene, and evaporating water from the obtained water layer to obtain a crude product of histamine dihydrochloride. Adding 100 g of isopropanol into the crude product obtained above, heating to 40-50 ℃, stirring for half an hour, slowly cooling to room temperature, standing for half an hour, filtering, and leaching a filter cake with 50ml of isopropanol for 3 times. The filter cake was dried under vacuum for 1 hour to give 44.7 g of white histamine dihydrochloride in 75.4% yield at 99.3% purity with < 0.1% single impurity.
Example 7
Adding 50 g of L-histidine, 4 g of 4-methylpyridine, 0.5 g of benzophenone and cyclohexanol into a 1000ml three-necked bottle provided with a mechanical stirring device, a thermometer and a reflux device, replacing air with vacuum and nitrogen, introducing nitrogen for protection in the whole process, heating to 155 ℃, reacting for 5 hours, stopping the reaction when the content of histidine is less than 1%, obtaining golden yellow transparent decarboxylation reaction liquid, cooling the reaction liquid to 50 ℃, filtering out insoluble substances, evaporating the obtained filtrate under reduced pressure to remove the solvent to obtain a viscous substance, adding about 200 g of water for dispersion, adding about 65 g of concentrated hydrochloric acid for neutralization until the pH is 5-6 under the cooling of an ice bath, stirring for half an hour at 25 ℃, extracting the aqueous solution for three times by using about 500 g of toluene, and evaporating water from the obtained water layer to obtain a crude product of histamine dihydrochloride. The crude product obtained above is added with 100 g of isopropanol, heated to 40-50 ℃, stirred for half an hour, slowly cooled to room temperature, kept stand for half an hour, filtered, and the filter cake is rinsed 3 times with 50ml of ethyl acetate. The filter cake was dried under vacuum for 1 hour to give 36.2 g of white histamine dihydrochloride in 61% yield with a purity of 99.3% and a single impurity < 0.1%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (8)
1. A method for synthesizing high purity histamine dihydrochloride, comprising the steps of:
(1) in a solvent A, performing decarboxylation reaction on L-histidine at the temperature of 110-150 ℃ under the action of a composite decarboxylation catalyst, and filtering after the reaction is finished, wherein the composite decarboxylation catalyst is a combination of sodium carbonate and p-methylacetophenone or a combination of N, N-dimethylformamide and p-methylacetophenone, the solvent A is dimethyl sulfoxide, the dosage of the sodium carbonate or the N, N-dimethylformamide is 5-10% of the weight of histidine, and the dosage of the p-methylacetophenone is 0.1-1.0% of the weight of histidine;
(2) distilling the filtrate obtained in the step (1) under reduced pressure, adding water into residue after solvent evaporation, and adjusting pH value to 5-6 by using hydrochloric acid to obtain an aqueous solution of histamine dihydrochloride;
(3) extracting the aqueous solution obtained in the step (2) by using an extracting agent for at least one time to remove impurities;
(4) and (4) steaming to remove water in the aqueous solution obtained in the step (3), pulping by using a solvent B, filtering and drying to obtain the product.
2. The method for synthesizing high purity histamine dihydrochloride according to claim 1, wherein the decarboxylation reaction time is 2 to 6 hours in the step (1).
3. The method for synthesizing high purity histamine dihydrochloride according to claim 1, wherein the decarboxylation reaction is performed under the protection of nitrogen in step (1), and the reaction solution is filtered when the temperature is reduced to 50-80 ℃.
4. The method for synthesizing high purity histamine dihydrochloride according to claim 1, wherein in the step (2), the amount of water is 1 to 5 times of the weight of the residue, the degree of vacuum of the reduced pressure distillation is more than-0.09 mpa, and concentrated hydrochloric acid is added under ice bath to adjust the pH to 5 to 6.
5. The method for synthesizing high purity histamine dihydrochloride according to claim 1, wherein in step (3), the extracting agent is selected from one or more of ethyl acetate, butyl acetate, dichloromethane, chloroform, benzene, toluene, and petroleum ether.
6. The method for synthesizing high purity histamine dihydrochloride according to claim 1, wherein in step (4), the solvent B is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, butyl acetate, tetrahydrofuran, and acetone.
7. The method for synthesizing high purity histamine dihydrochloride according to claim 1, wherein in the step (4), the pulping process is: stirring at 40-50 deg.C for 20-120 min, and standing.
8. The method of synthesizing high purity histamine dihydrochloride according to claim 1, wherein said method comprises the steps of:
(1) under the protection of neutralizing nitrogen in a solvent A, performing decarboxylation reaction on L-histidine at the temperature of 110-150 ℃ under the action of a composite decarboxylation catalyst, after reacting for 2-6 hours, cooling a reaction liquid to 50-80 ℃, and filtering, wherein the composite decarboxylation catalyst is a combination of sodium carbonate and p-methylacetophenone or a combination of N, N-dimethylformamide and p-methylacetophenone, the solvent A is dimethyl sulfoxide, the amount of the sodium carbonate or the N, N-dimethylformamide is 5-10% of the weight of histidine, and the amount of the p-methylacetophenone is 0.1-1.0% of the weight of histidine;
(2) carrying out reduced pressure distillation on the filtrate obtained in the step (1), adding water into the residue after solvent evaporation, adding concentrated hydrochloric acid in ice bath to adjust the pH value to 5-6 to obtain a histamine dihydrochloride water solution, wherein the using amount of the water is 1-5 times of the weight of the residue, and the vacuum degree of the reduced pressure distillation is more than-0.09 MPa;
(3) extracting the aqueous solution obtained in the step (2) at least once by using an extracting agent to remove impurities, wherein the extracting agent is selected from one or more of ethyl acetate, butyl acetate, dichloromethane, trichloromethane, benzene, toluene and petroleum ether;
(4) and (3) evaporating water in the aqueous solution obtained in the step (3), adding a solvent B, stirring for 20-120 minutes at 40-50 ℃, standing, filtering and drying to obtain a product, wherein the solvent B is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, butyl acetate, tetrahydrofuran and acetone.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86106151A (en) * | 1985-09-09 | 1987-06-03 | 沃纳·兰伯特公司 | The improved method for preparing tetrafluorobenzoic aid |
| CN1331681A (en) * | 1998-12-23 | 2002-01-16 | 马克西姆药品公司 | Synthesis of histamine dihydrochloride |
| CN103739552A (en) * | 2014-01-24 | 2014-04-23 | 国药一心制药有限公司 | Preparation method of histamine dihydrochloride |
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| CN86106151A (en) * | 1985-09-09 | 1987-06-03 | 沃纳·兰伯特公司 | The improved method for preparing tetrafluorobenzoic aid |
| CN1331681A (en) * | 1998-12-23 | 2002-01-16 | 马克西姆药品公司 | Synthesis of histamine dihydrochloride |
| CN103739552A (en) * | 2014-01-24 | 2014-04-23 | 国药一心制药有限公司 | Preparation method of histamine dihydrochloride |
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| 几种具有重要生理活性的氨基酸衍生物的合成研究;聂娟;《中国优秀硕士论文全文数据库》;20041231;正文第47页处理及纯化方法 * |
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