CN101628892A - Preparation method of pyridoxamine dihydrochloride - Google Patents
Preparation method of pyridoxamine dihydrochloride Download PDFInfo
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- CN101628892A CN101628892A CN200910183778A CN200910183778A CN101628892A CN 101628892 A CN101628892 A CN 101628892A CN 200910183778 A CN200910183778 A CN 200910183778A CN 200910183778 A CN200910183778 A CN 200910183778A CN 101628892 A CN101628892 A CN 101628892A
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Abstract
The invention relates to a preparation method of pyridoxamine dihydrochloride, belonging to the technical field of the preparation of water soluble vitamins. The preparation method comprises the following steps: preparing pyridoxal oxime: taking pyridoxine hydrochloride as initial raw material and water as a reaction medium, adding activated manganese dioxide and concentrated sulfuric acid to generate pyridoxal by the reaction, and then reacting with anhydrous sodium acetate and hydroxylamine hydrochloride to obtain pyridoxal oxime; preparing pyridoxamine dihydrochloride: firstly enabling pyridoxal oxime to react with acetic acid and zinc to obtain acetic acid solution containing pyridoxamine, then decompressing the solution and reclaiming the acetic acid to obtain slurry concentrate, decompressing and reclaiming the acetic acid again to obtain pyridoxamine water solution, regulating the pH value to be alkaline so as to separate pyridoxamine out, adding water and hydrochloric acid after vacuum filteration, decoloring and filtering to obtain filtrate, decompressing and concentrating the filtrate until white solids are separated out, adding solvent and stirring, and finally crystallizing at the lower temperature, filtering and drying to obtain the pyridoxamine dihydrochloride. The invention has the advantages that the prepared pyridoxamine dihydrochloride has high total mol yield and purity, and the preparation method is reduced.
Description
Technical field
The invention belongs to the preparing technical field of water-soluble vitamins, be specifically related to a kind of preparation method of pyridoxamine dihydrochloride.
Background technology
The pyridoxamine dihydrochloride vitamins B that is otherwise known as
6Dihydrochloride is one of water-soluble vitamin B group.The chemistry of pyridoxamine dihydrochloride is by name: 2-methyl-3-hydroxyl-4-aminomethyl-5-4-hydroxymethylpiperidine dihydrochloride; Molecular formula is: C
8H
12N
2O
22Hcl; Molecular weight is: 241.11; English name is: Pyridoxamide Dihydrochloride.The structural formula of pyridoxamine dihydrochloride is as follows:
Pyridoxylamine is a vitamins B
6One of three kinds of natural forms, smaller to the human body side effect, for a long time, various forms of vitamins Bs
6Be used as supplements (also claiming food supply) and medical treatment always.When the various chronic disease of treatment, using dosage is the 100mg/d vitamins B of (d represents every day)
6, can not have a negative impact, and also unprecedented up to now because of using vitamins B
6And cause the report of untoward reaction.
Aminoguanidine also is a vitamins B
6One of three kinds of natural forms, but aminoguanidine can generate Schiff base (schiff base) with the pyridoxal phosphate reaction in vivo, thereby can cause vitamins B
6Disappearance in vivo uses Pyridoxylamine then can not cause vitamins B
6Disappearance in vivo.Studies show that, Pyridoxylamine and aminoguanidine are used in combination eliminate the side effect of aminoguanidine human body.
Vitamins B
6Being crucial biochemical substances in the human body, is the coenzyme of various transaminases, can participate in multiple metabolism in the body and helps to improve the immunizing power of human body, also can prevent the generation of various carninomatosis.Vitamins B
6To preventing various cardiovascular diseasess that active effect is arranged, Allan. doctor Fu Ersemu of Univ Minnesota-Twin Cities USA is being to draw such conclusion after 46～64 years old the elderly carries out tracking investigation to 759 ages: vitamins B in the blood
6Vitamins B in the likelihood ratio blood that the people that content is high suffers from a heart complaint
6The people few 2/3rds that content is low.
Along with people's standard of living significantly improves, good health and a long life become the human important goal of being pursued.In the weathering process of human body, various senile disease will be followed gradually and arrive, for example ephrosis, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases and senile dementia or the like, these geriatric disease cause the elderly's health and have a strong impact on, and its sickness rate is the trend that improves gradually at present.
Pyridoxylamine is as the medicine of treatment geriatric disease, be in clinical experimental stage at present, it is reported (A.Recentadvances in nephrology:highlights from the 35th annual meeting of the Americansociety of nephrology[J] .Drugs today.2002,38 (12): 797-805), using dosage can reduce patient's urinary albumin content for 500mg/d Pyridoxylamine treatment diabetes and nephrotic.If obtain clinical definite checking, Pyridoxylamine has more as a kind of naturally occurring VITAMIN and has broad application prospects so.
The preparation method of Pyridoxylamine mainly contains microorganism preparation method and chemical synthesis, the former microorganism preparation method is representative with patent WO2007142222A1, and this technology still is in the exploratory stage owing to required bacterial classification, and because of technical sophistication, product yield＜50% is so be difficult to be put to suitability for industrialized production.The latter's chemical synthesis is an example with U.S. Pat 2007161678A1, it is as starting raw material with pyridoxine hydrochloride, obtain Pyridoxylamine through four-step reaction, this method is many because of reactions steps, and use a large amount of organic solvents, especially therefore product yield＜45% and purity only＞95% are difficult to satisfy industrial production requirement equally.Relatively be fit to industrial preparation method such as document (" synthesizing of pyridoxamine dihydrochloride " at present, the Gansu chemical industry, 2003 (4)), its method is such: be starting raw material with the pyridoxine hydrochloride, by generating the intermediate pyrrole oxime of trembling with oxammonium hydrochloride reaction after activated manganese dioxide and the vitriol oil oxidation, the pyrrole oxime of trembling reduces under acetic acid/zinc system and obtains Pyridoxylamine, through purifying, obtains the product pyridoxamine dihydrochloride behind the acidizing crystal.But problems such as also there is the cost height in this method, and solvent-oil ratio is big.
Based on above-mentioned prior art, the applicant is through secular effort, and the method described in pyridoxamine dihydrochloride synthetic has been made significant improvement, introduces technical scheme below.
Summary of the invention
Task of the present invention is to provide that a kind of preparation cost is cheap, yield is high and use the preparation method who satisfies Pyridoxylamine two hydrochloric acid that suitability for industrialized production requires.
Task of the present invention is finished like this, and a kind of preparation method of pyridoxamine dihydrochloride may further comprise the steps:
A) the preparation pyrrole oxime of trembling: with the pyridoxine hydrochloride is starting raw material, and water is reaction media, adds the activated manganese dioxide and the vitriol oil and carries out generating pyridoxal after the oxidizing reaction, again with sodium acetate, anhydrous and oxammonium hydrochloride reaction, obtains the pyrrole oxime of trembling;
B) preparation pyridoxamine dihydrochloride: oxime and acetic acid and the zinc reaction of earlier pyrrole being trembled, obtain containing the acetum of Pyridoxylamine, the acetum reclaim under reduced pressure acetic acid that will contain Pyridoxylamine again, obtain the enriched material of pulpous state, in the enriched material of pulpous state, add entry and continue reclaim under reduced pressure acetic acid, obtain the Pyridoxylamine aqueous solution, in the Pyridoxylamine aqueous solution, add ammoniacal liquor or feed ammonia and regulate pH to alkalescence, Pyridoxylamine is separated out from the Pyridoxylamine aqueous solution with the form of free alkali, behind suction filtration, add entry and hydrochloric acid, with the Pyridoxylamine stirring and dissolving, and then through decolouring and filtration, filtrate decompression is concentrated into white solid and separates out, and adds stirring solvent, after cold analysis, filtration and drying obtain pyridoxamine dihydrochloride.
In a specific embodiment of the present invention, step B) the tremble temperature of reaction of oxime and acetic acid and zinc reaction of the pyrrole described in is 40-70 ℃.
The decompression pressure of the reclaim under reduced pressure acetic acid in another specific embodiment of the present invention, step B) is 0.08-0.1MPa.
In another specific embodiment of the present invention, step B) in the enriched material of pulpous state, adds entry for adding pure water described in.
In another specific embodiment of the present invention, step B) the Pyridoxylamine pH value of aqueous solution described in is 5.5-6.5.
In also specific embodiment of the present invention, step B) described in the Pyridoxylamine aqueous solution, add ammoniacal liquor or feed ammonia regulate pH to the scope of the pH of alkalescence be 8.5-10.5.
Adding ammoniacal liquor or feed the temperature of reaction of ammonia when regulating pH to alkalescence in the Pyridoxylamine aqueous solution more of the present invention and in specific embodiment, step B) is 25-45 ℃, and the reaction times is 15-30min.
In of the present invention and then specific embodiment, the described mass percent concentration that adds ammoniacal liquor is 18-25%.
Of the present invention again more and in specific embodiment, step B) solvent described in is an organic solvent.
In again of the present invention and then specific embodiment, described organic solvent is any one or its combination in methyl alcohol, ethanol and the Virahol, and described ethanol is dehydrated alcohol.
Total molar yield of preparation pyridoxamine dihydrochloride reaches more than 80% in the technical scheme provided by the present invention, and purity can reach more than 99%, and can save organic raw material and solvent and be minimized preparation cost, thereby can be suitable for suitability for industrialized production.
Embodiment
Embodiment 1:
A) the preparation pyrrole oxime of trembling:
In the four-hole reaction flask of the 2000ml that whipping appts and thermometer are housed, add earlier 100g (0.486mol) pyridoxine hydrochloride and 750g pure water, at room temperature stir, make the pyridoxine hydrochloride dissolving, then add activated manganese dioxide 75g (0.863mol) and add vitriol oil 90g (0.918mol) in the dropping mode, control reaction temperature 40-45 ℃, the dropping time of the vitriol oil is 45min, after dripping end, temperature of charge remains on 45-48 ℃ of reaction, by the TLC monitoring reaction, after treating that pyridoxine hydrochloride as starting raw material reacts completely, obtain the active substance pyridoxal, add sodium acetate, anhydrous 150g (1.83mol) and oxammonium hydrochloride 59.4g (0.855mol) reaction again, temperature of reaction is 55-60 ℃, reacts 30min under whipped state, after cold analysis, filter and drying, obtain the pyrrole oxime 81.4g that trembles, molar yield is 92%, and chemical purity is 99.5%.The reaction formula of this step is as follows:
The pyridoxine hydrochloride pyrrole oxime of trembling
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g, zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 70 ℃, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, remove by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, with pressure is the 0.08MPa concentrating under reduced pressure, reclaims acetic acid, the pulpous state enriched material after obtaining concentrating, add the 150ml pure water in the pulpous state enriched material after concentrating, continuation is 0.08MPa reclaim under reduced pressure acetic acid with pressure, obtains the pH value and be the Pyridoxylamine aqueous solution of 5.5 80ml, and the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and the adding mass percent concentration is 18% ammoniacal liquor in the Pyridoxylamine aqueous solution, regulate pH to 8.5,25 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, material is suction filtration after stirring 30min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add dehydrated alcohol 200ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 23.8g, molar yield 90%, chemical purity 99.4%.The reaction formula in this step is as follows:
The pyrrole oxime pyridoxamine dihydrochloride of trembling
Embodiment 2:
A) the preparation pyrrole oxime of trembling:
In the four-hole reaction flask of the 1000ml that whipping appts and thermometer are housed, add earlier 50g (0.243mol) pyridoxine hydrochloride and 400g pure water, at room temperature stir, make the pyridoxine hydrochloride dissolving, then add activated manganese dioxide 37.5g (0.43mol) and add vitriol oil 45g (0.46mol) in the dropping mode, control reaction temperature 40-45 ℃, the dropping time of the vitriol oil is 45min, after dripping end, temperature of charge remains on 45-48 ℃ of reaction, by the TLC monitoring reaction, after treating that pyridoxine hydrochloride as starting raw material reacts completely, obtain the active substance pyridoxal, add sodium acetate, anhydrous 75g (0.915mol) and oxammonium hydrochloride 29.7g (.428mol) reaction again, temperature of reaction is 55-60 ℃, reacts 30min under whipped state, after cold analysis, filter and drying, obtain the pyrrole oxime 40.8g that trembles, molar yield is 92%, and chemical purity is 99.5%.This step reaction formula is with embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g, zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 60 ℃, lower the temperature with cooling fluid, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, removing by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, is the 0.1MPa concentrating under reduced pressure with pressure, reclaim acetic acid, pulpous state enriched material after obtaining concentrating adds the 150ml pure water in the pulpous state enriched material after concentrating, continuing with pressure is 0.08MPa reclaim under reduced pressure acetic acid, obtain the pH value and be the Pyridoxylamine aqueous solution of 6.0 80ml, the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and to add mass percent concentration in the Pyridoxylamine aqueous solution be 18% ammoniacal liquor, regulate pH to 9.5,35 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, and material is suction filtration after stirring 30min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add dehydrated alcohol 200ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 23.6g, molar yield 89%, chemical purity 99.2%.This step reaction formula such as embodiment 1.
Embodiment 3:
A) the preparation pyrrole oxime of trembling:
In the four-hole reaction flask of the 2000ml that whipping appts and thermometer are housed, add earlier 120g (0.583mol) pyridoxine hydrochloride and 900g pure water, at room temperature stir, make the pyridoxine hydrochloride dissolving, then add activated manganese dioxide 90g (1.03mol) and add vitriol oil 108g (1.1mol) in the dropping mode, control reaction temperature 40-45 ℃, the dropping time of the vitriol oil is 45min, after dripping end, temperature of charge remains on 45-48 ℃ of reaction, by the TLC monitoring reaction, after treating that pyridoxine hydrochloride as starting raw material reacts completely, obtain the active substance pyridoxal, add sodium acetate, anhydrous 180g (2.2mol) and oxammonium hydrochloride 71.3g (1.03mol) reaction again, temperature of reaction is 55-60 ℃, reacts 30min under whipped state, after cold analysis, filter and drying, obtain the pyrrole oxime 98.0g that trembles, molar yield is 92%, and chemical purity is 99.5%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g, zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 55 ℃, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, remove by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, with pressure is the 0.1MPa concentrating under reduced pressure, reclaims acetic acid, the pulpous state enriched material after obtaining concentrating, add the 150ml pure water in the pulpous state enriched material after concentrating, continuation is 0.1MPa reclaim under reduced pressure acetic acid with pressure, obtains the pH value and be the Pyridoxylamine aqueous solution of 6.0 80ml, and the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and the adding mass percent concentration is 20% ammoniacal liquor in the Pyridoxylamine aqueous solution, regulate pH to 10.5,40 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, material is suction filtration after stirring 30min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add dehydrated alcohol 200ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 24.0g, molar yield 90.5%, chemical purity 99.3%.This step reaction formula such as embodiment 1.
Embodiment 4:
A) the preparation pyrrole oxime of trembling:
Preparation process such as embodiment 2, the pyrrole oxime 40.8g that trembles, molar yield 92%, chemical purity 99.5%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g, zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 50 ℃, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, remove by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, with pressure is the 0.09MPa concentrating under reduced pressure, reclaim acetic acid, the pulpous state enriched material after obtaining concentrating adds the 150ml pure water in the pulpous state enriched material after concentrating, continuation is 0.08MPa reclaim under reduced pressure acetic acid with pressure, obtain the pH value and be the Pyridoxylamine aqueous solution of 5.5 80ml, the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and to add mass percent concentration in the Pyridoxylamine aqueous solution be 20% ammoniacal liquor, regulate pH to 10.0, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, and material is suction filtration after stirring 20min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add dehydrated alcohol 200ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 23.5g, molar yield 88%, chemical purity 99.0%.This step reaction formula such as embodiment 1.
Embodiment 5:
A) the preparation pyrrole oxime of trembling:
Preparation process such as embodiment 2, the pyrrole oxime 40.8g that trembles, molar yield 92%, chemical purity 99.5%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g, zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 65 ℃, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, remove by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, with pressure is the 0.1MPa concentrating under reduced pressure, reclaims acetic acid, the pulpous state enriched material after obtaining concentrating, add the 150ml pure water in the pulpous state enriched material after concentrating, continuation is 0.08MPa reclaim under reduced pressure acetic acid with pressure, obtains the pH value and be the Pyridoxylamine aqueous solution of 6.5 80ml, and the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and in the Pyridoxylamine aqueous solution, feed ammonia, regulate pH to 9.5,45 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, material is suction filtration after stirring 20min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add dehydrated alcohol 200ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 24.3g, molar yield 91.6%, chemical purity 99.1%.This step reaction formula such as embodiment 1.
Embodiment 6:
A) the preparation pyrrole oxime of trembling:
Preparation process such as embodiment 2, the pyrrole oxime 40.8g that trembles, molar yield 92%, chemical purity 99.5%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g, zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 70 ℃, lower the temperature with cooling fluid, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, removing by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, is the 0.1MPa concentrating under reduced pressure with pressure, reclaim acetic acid, pulpous state enriched material after obtaining concentrating adds the 150ml pure water in the pulpous state enriched material after concentrating, continuing with pressure is 0.08MPa reclaim under reduced pressure acetic acid, obtain the pH value and be the Pyridoxylamine aqueous solution of 6.5 80ml, the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and to add mass percent concentration in the Pyridoxylamine aqueous solution be 20% ammoniacal liquor, regulate pH to 9.5,40 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, and material is suction filtration after stirring 15min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add methyl alcohol 200ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 23.7g, molar yield 89.3%, chemical purity 99.5%.This step reaction formula such as embodiment 1.
Embodiment 7:
A) the preparation pyrrole oxime of trembling:
Preparation process such as embodiment 2, the pyrrole oxime 40.8g that trembles, molar yield 92%, chemical purity 99.5%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g, zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 65 ℃, lower the temperature with cooling fluid, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, removing by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, is the 0.1MPa concentrating under reduced pressure with pressure, reclaim acetic acid, pulpous state enriched material after obtaining concentrating adds the 150ml pure water in the pulpous state enriched material after concentrating, continuing with pressure is 0.08MPa reclaim under reduced pressure acetic acid, obtain the pH value and be the Pyridoxylamine aqueous solution of 6.0 80ml, the Pyridoxylamine aqueous temperature is reduced to 30 ℃, and to add mass percent concentration in the Pyridoxylamine aqueous solution be 25% ammoniacal liquor, regulate pH to 9.5,42 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, and material is suction filtration after stirring 15min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add dehydrated alcohol 200ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 23.7g, molar yield 89.3%, chemical purity 99.4%.This step reaction formula such as embodiment 1.
Embodiment 8:
A) the preparation pyrrole oxime of trembling:
Preparation process such as embodiment 2, the pyrrole oxime 40.9g that trembles, molar yield 92%, chemical purity 99.5%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g, zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 70 ℃, lower the temperature with cooling fluid, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, removing by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, is the 0.1MPa concentrating under reduced pressure with pressure, reclaim acetic acid, pulpous state enriched material after obtaining concentrating adds the 150ml pure water in the pulpous state enriched material after concentrating, continuing with pressure is 0.08MPa reclaim under reduced pressure acetic acid, obtain the pH value and be the Pyridoxylamine aqueous solution of 5.5 80ml, the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and in the Pyridoxylamine aqueous solution, feed ammonia, regulate pH to 9.0,45 ℃ of temperature of reaction, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, and material is suction filtration after stirring 30min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add dehydrated alcohol 100ml and methyl alcohol 100ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 23.9g, molar yield 90%, chemical purity 99.2%.This step reaction formula such as embodiment 1.
Embodiment 9:
A) the preparation pyrrole oxime of trembling:
Preparation process such as embodiment 3, the pyrrole oxime 98.2g that trembles, molar yield 92%, chemical purity 99.4%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g (5mol) of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g (0.581mol), zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 70 ℃, lower the temperature with cooling fluid, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, removing by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, is the 0.1MPa concentrating under reduced pressure with pressure, reclaim acetic acid, pulpous state enriched material after obtaining concentrating adds the 150ml pure water in the pulpous state enriched material after concentrating, continuing with pressure is 0.08MPa reclaim under reduced pressure acetic acid, obtain the pH value and be the Pyridoxylamine aqueous solution of 5.5 80ml, the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and to add mass percent concentration in the Pyridoxylamine aqueous solution be 18% ammoniacal liquor, regulate pH to 10.0,25 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, and material is suction filtration after stirring 30min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add Virahol 200ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 23.6g, molar yield 89%, chemical purity 99.2%.This step reaction formula such as embodiment 1.
Embodiment 10:
A) the preparation pyrrole oxime of trembling:
Preparation process such as embodiment 3, the pyrrole oxime 98.2g that trembles, molar yield 92%, chemical purity 99.4%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g (5mol) of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g (0.581mol), zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 70 ℃, lower the temperature with cooling fluid, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, removing by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, is the 0.1MPa concentrating under reduced pressure with pressure, reclaim acetic acid, pulpous state enriched material after obtaining concentrating adds the 150ml pure water in the pulpous state enriched material after concentrating, continuing with pressure is 0.08MPa reclaim under reduced pressure acetic acid, obtain the pH value and be the Pyridoxylamine aqueous solution of 5.5 80ml, the Pyridoxylamine aqueous temperature is reduced to 30 ℃, and to add mass percent concentration in the Pyridoxylamine aqueous solution be 18% ammoniacal liquor, regulate pH to 10.0,25 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, and material is suction filtration after stirring 30min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add dehydrated alcohol 100ml and Virahol 100ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 24.2g, molar yield 91.2%, chemical purity 99.0%.This step reaction formula such as embodiment 1.
Embodiment 11:
A) the preparation pyrrole oxime of trembling:
Preparation process such as embodiment 3, the pyrrole oxime 98.2g that trembles, molar yield 92%, chemical purity 99.4%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g (5mol) of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g (0.581mol), zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 70 ℃, lower the temperature with cooling fluid, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, removing by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, is the 0.1MPa concentrating under reduced pressure with pressure, reclaim acetic acid, pulpous state enriched material after obtaining concentrating adds the 150ml pure water in the pulpous state enriched material after concentrating, continuing with pressure is 0.08MPa reclaim under reduced pressure acetic acid, obtain the pH value and be the Pyridoxylamine aqueous solution of 5.5 80ml, the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and to add mass percent concentration in the Pyridoxylamine aqueous solution be 18% ammoniacal liquor, regulate pH to 10.0,30 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, and material is suction filtration after stirring 30min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add methyl alcohol 100ml and Virahol 100ml and stir, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 24.0g, molar yield 90.5%, chemical purity 99.2%.This step reaction formula such as embodiment 1.
Embodiment 12:
A) the preparation pyrrole oxime of trembling:
Preparation process such as embodiment 3, the pyrrole oxime 98.0g that trembles, molar yield 92%, chemical purity 99.4%.This step reaction formula such as embodiment 1;
B) preparation pyridoxamine dihydrochloride:
Tremble oxime 20g (0.11mol) and acetic acid 300g of pyrrole drops in the four-hole reaction flask of the 500ml that agitator is housed equally, be heated with stirring to temperature of charge and reach 40 ℃, make the pyrrole oxime dissolving back of trembling add zinc powder 38g, zinc powder is divided into three addings, add for the first time the 15g zinc powder, exothermic phenomenon is arranged, stirring also, control reaction temperature is no more than 70 ℃, lower the temperature with cooling fluid, when material is cooled to 40 ℃, add zinc powder 13g once more, stir, when being cooled to 40 ℃, the last zinc powder 10g that adds, material does not have tangible intensification phenomenon, material is warming up to 65 ℃ and insulation 2h, after insulation reaction finishes, cooling, removing by filter residual zinc powder, obtain containing the acetum of Pyridoxylamine, is the 0.1MPa concentrating under reduced pressure with pressure, reclaim acetic acid, pulpous state enriched material after obtaining concentrating adds the 150ml pure water in the pulpous state enriched material after concentrating, continuing with pressure is 0.08MPa reclaim under reduced pressure acetic acid, obtain the pH value and be the Pyridoxylamine aqueous solution of 5.5 80ml, the Pyridoxylamine aqueous temperature is reduced to 25 ℃, and to add mass percent concentration in the Pyridoxylamine aqueous solution be 18% ammoniacal liquor, regulate pH to 9.5,30 ℃ of material reaction temperature, the form that this moment, a large amount of Pyridoxylamines were the Pyridoxylamine free alkali with free alkali is separated out from the Pyridoxylamine aqueous solution, and material is suction filtration after stirring 30min, gets Pyridoxylamine free alkali solid.Solid is placed the 500ml reaction flask, add water 150ml and hydrochloric acid (12mol/L) 20ml stirring and dissolving, add the 3g gac, the filtering gac is crossed in 70 ℃ of decolourings, filtrate decompression (0.1MPa) is concentrated into white solid and separates out, add dehydrated alcohol 100ml, methyl alcohol 50ml, Virahol 50ml stirring, after cold analysis, filtration and the drying, obtain pyridoxamine dihydrochloride 23.8g, molar yield 89.7%, chemical purity 99.3%.This step reaction formula such as embodiment 1.
Claims (10)
1, a kind of preparation method of pyridoxamine dihydrochloride is characterized in that may further comprise the steps:
A) the preparation pyrrole oxime of trembling: with the pyridoxine hydrochloride is starting raw material, and water is reaction media, adds the activated manganese dioxide and the vitriol oil and carries out generating pyridoxal after the oxidizing reaction, again with sodium acetate, anhydrous and oxammonium hydrochloride reaction, obtains the pyrrole oxime of trembling;
B) preparation pyridoxamine dihydrochloride: oxime and acetic acid and the zinc reaction of earlier pyrrole being trembled, obtain containing the acetum of Pyridoxylamine, the acetum reclaim under reduced pressure acetic acid that will contain Pyridoxylamine again, obtain the enriched material of pulpous state, in the enriched material of pulpous state, add entry and continue reclaim under reduced pressure acetic acid, obtain the Pyridoxylamine aqueous solution, in the Pyridoxylamine aqueous solution, add ammoniacal liquor or feed ammonia and regulate pH to alkalescence, Pyridoxylamine is separated out from the Pyridoxylamine aqueous solution with the form of free alkali, behind suction filtration, add entry and hydrochloric acid, with the Pyridoxylamine stirring and dissolving, and then through decolouring and filtration, filtrate decompression is concentrated into white solid and separates out, and adds stirring solvent, after cold analysis, filtration and drying obtain pyridoxamine dihydrochloride.
2, the preparation method of pyridoxamine dihydrochloride according to claim 1 is characterized in that step B) described in the tremble temperature of reaction of oxime and acetic acid and zinc reaction of pyrrole be 40-70 ℃.
3, the preparation method of pyridoxamine dihydrochloride according to claim 1 is characterized in that step B) described in the decompression pressure of reclaim under reduced pressure acetic acid be 0.08-0.1MPa.
4, the preparation method of pyridoxamine dihydrochloride according to claim 1 is characterized in that step B) described in the enriched material of pulpous state, add entry for adding pure water.
5, the preparation method of pyridoxamine dihydrochloride according to claim 1 is characterized in that step B) described in the Pyridoxylamine pH value of aqueous solution be 5.5-6.5.
6, the preparation method of pyridoxamine dihydrochloride according to claim 1 is characterized in that step B) described in the Pyridoxylamine aqueous solution, add ammoniacal liquor or feed ammonia regulate pH to the scope of the pH of alkalescence be 8.5-10.5.
7, the preparation method of pyridoxamine dihydrochloride according to claim 1 is characterized in that step B) described in to add ammoniacal liquor or feed the temperature of reaction of ammonia when regulating pH to alkalescence in the Pyridoxylamine aqueous solution be 25-45 ℃, the reaction times is 15-30min.
8,, it is characterized in that the described mass percent concentration that adds ammoniacal liquor is 18-25% according to the preparation method of claim 1 or 7 described pyridoxamine dihydrochlorides.
9, the preparation method of pyridoxamine dihydrochloride according to claim 1 is characterized in that step B) described in solvent be organic solvent.
10, the preparation method of pyridoxamine dihydrochloride according to claim 9 is characterized in that described organic solvent is any one or its combination in methyl alcohol, ethanol and the Virahol, and described ethanol is dehydrated alcohol.
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| CN102617455A (en) * | 2011-12-26 | 2012-08-01 | 浙江工业大学 | Preparation method of pyridoxal or pyridoxal hydrochloride |
| CN102617455B (en) * | 2011-12-26 | 2014-06-04 | 浙江工业大学 | Preparation method of pyridoxal or pyridoxal hydrochloride |
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