CN102206233B - Industrial preparation method for riboflavine sodium phosphate - Google Patents
Industrial preparation method for riboflavine sodium phosphate Download PDFInfo
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Abstract
The invention discloses an industrial preparation method for riboflavin sodium phosphate, which uses riboflavin, phosphorus oxychloride, pyridine and purified water as initial raw materials, and comprises the following steps of: 1) carrying out phosphation reaction on riboflavin to generate riboflavin cyclophosphate; 2) hydrolyzing the riboflavin cyclophosphate to generate riboflavin phosphate; 3) carrying out salifying reaction on the riboflavin phosphate to generate riboflavin sodium phosphate; and 4) refining the riboflavin sodium phosphate. The riboflavin sodium phosphate product prepared by the preparation method provided by the invention has high quality and low impurity content, and can reach the quality requirement on riboflavin sodium phosphate in various current pharmacopoeias at home and abroad. The preparation method has the advantages of mild production conditions, no requirements for very low temperature, extra-high temperature and extra-high pressure, no special requirement on equipment, easiness in mastery of production technique, low production cost of a product, high product purity and easiness in recycling of wastes, and is suitable for industrial mass production.
Description
Technical field
The invention belongs to medical preparing technical field, refer to a kind of industrialized process for preparing of Sodium riboflavin phosphate particularly.
Background technology
Vitamin G (B
2) be the integral part of many enzymes in the human body metabolism, can be synthetic by plant, yeast, fungi and other mikrobe, but animal itself can not be synthesized.Lack vitamin G in the body, mainly show as the pathology of face tissue, like bridou, cheilitis, glossitis, keratitis, males scrotum inflammation etc.Because the vitamin G poorly water-soluble, it receives certain restriction in use range pharmaceutically, is made into to have water miscible phosphoric acid salt and can enlarge its use range, is used for industries such as medicine, foodstuff additive, feed, veterinary drug.Sodium riboflavin phosphate commonly used is clinically processed injection and is used to treat diseases such as aphtha, tetter, vitamin deficiency.In recent years, market constantly increases the demand of Sodium riboflavin phosphate, also the quality of Sodium riboflavin phosphate is had higher requirement simultaneously.Before the present invention, the patent No. is the USP of US5095115, has reported the preparation method of a kind of vitamin G 5 '-SULPHOSUCCINIC ACID ESTER; Vitamin G joined in the mixing liquid that contains gamma-butyrolactone, POCl3 react, then reaction solution is joined in the excessive water, at high temperature the POCl3 of decomposing excessive; Produce hydrochloric acid, hydrolysis vitamin G cyclic phosphate obtains vitamin G 5 '-SULPHOSUCCINIC ACID ESTER under the high temperature; Under higher temperatures, add alkali then and become sodium salt, obtain thick product.Too high among this preparation method owing to the POCl3 activity; In the time of with 4 ', 5 ' hydroxyl Cheng Huan of vitamin G also with 3 ', 5 ' and 3 '; 4 ' Cheng Huan; Its reaction preference extreme difference and to generate other by products more, high quality is not poor for last products obtained therefrom purity, can not reach the specification of quality of domestic and international various pharmacopeia to Sodium riboflavin phosphate.
Summary of the invention
The object of the invention is exactly the industrialized process for preparing that a kind of Sodium riboflavin phosphate will be provided, and it is gentle to utilize this method to prepare the Sodium riboflavin phosphate reaction conditions, and technological operation is simple, and quality product is high.
For realizing above-mentioned purpose, the industrialized process for preparing of Sodium riboflavin phosphate of the present invention is a starting raw material with vitamin G, POCl3, pyridine, purified water, may further comprise the steps:
1) riboflavin phosphate reaction generates intermediate II vitamin G cyclic phosphate;
Vitamin G, POCl3, water are joined in the aprotic solvent, do at pyridine to react under the condition of catalyzer, temperature of reaction is controlled at-5～15 ℃ of scopes, and the reaction times is controlled to be 8～10h, generates intermediate II vitamin G cyclic phosphate; The mol ratio that wherein adds vitamin G, POCl3, pyridine, water is: 1: 1～5: 1～5: 1～3, and described aprotic polar solvent is a kind of in THF, acetonitrile, the dioxane;
The reaction that takes place in this step is following:
2) vitamin G cyclic phosphate hydrolysis generates the intermediate III cytoflavin;
Is hydrolysis in 5～18% the hydrochloric acid with intermediate II vitamin G cyclic phosphate in concentration expressed in percentage by weight; Used hydrochloric acid optimum concn is 10～12%; The hydrochloric acid weight of selecting for use is 1～5 times of intermediate II vitamin G cyclic phosphate; Hydrolysising reacting temperature is 30～80 ℃, and hydrolysis time is 3～30h, generates the intermediate III cytoflavin;
The reaction that this step takes place is following:
3) cytoflavin salt-forming reaction;
The adding weight percent concentration is 10～25% NaOH solution in the intermediate III riboflavin phosphate ester solution, regulates pH value to 5.0～6.0, and vacuum filtration or spinning can obtain Sodium riboflavin phosphate bullion IV;
The reaction that takes place in this step is following:
4) Sodium riboflavin phosphate is refining;
Above-mentioned Sodium riboflavin phosphate bullion IV is dissolved in the purified water that is equivalent to 5～20 times of its weight; Under 40～60 ℃ of conditions, dissolve, behind the insoluble impurity of elimination, filtrating is cooled to below 20 ℃; Add the ethanol that is equivalent to 1～6 times of weight of said filtrating; Promptly separate out solid, dry 8h in 55 ℃ of loft drier promptly gets the elaboration Sodium riboflavin phosphate.
Further, temperature of reaction is controlled at 0～10 ℃ in the step 1).
Further, the mol ratio that adds vitamin G, POCl3, pyridine, water in the step 1) is: 1: 4.5: 4: 2.5.
A step ground again, step 2) the hydrochloric acid weight percent concentration is 10～12% described in, and the hydrochloric acid weight of selecting for use is 2.5 times of vitamin G cyclic phosphate weight, and hydrolysising reacting temperature is controlled to be 40～45 ℃, and hydrolysis time is controlled to be 20h.
Also further, the concentration of the said NaOH solution of step 3) is controlled to be 20%, and regulating the pH value is 5.5.
Each step reaction technique parameter principle of qualification of the industrialized process for preparing of Sodium riboflavin phosphate of the present invention is following:
In the step 1, under coldcondition, add solvent acetonitrile in the reaction kettle, and a certain amount of pyridine and POCl3, temperature of reaction is controlled at-5～15 ℃ of scopes, and the best is 0～10 ℃, causes the control of intermediate compound I difficult quality if the too high side reaction of temperature increases.Add quantitative vitamin G then and stir, react, its product is through suction filtration, and filter cake washs with anhydrous solvent, drains, and promptly gets intermediate II vitamin G cyclic phosphate.Mol ratio with vitamin G, POCl3, pyridine, water during reaction is controlled to be: 1: 1～5: 1～5: 1～3; Preferred mol ratio is: 1: 4.5: 4: 2.5, and the amount of so controlling reactant can better promote the reactivity of vitamin G, improves intermediate II output and quality, reduces foreign matter content.
In the step 2; With the quantitative hydrochloric acid for preparing in advance; Add the hydrolysis of above-mentioned midbody vitamin G cyclic phosphate again, said hydrochloric acid weight percent concentration is controlled to be 5～18%, and optimum acidity is controlled to be 10～12%; Too high two ester bonds that then can hydrolysis vitamin G cyclic phosphate of concentration of hydrochloric acid dissociate out with vitamin G.The hydrochloric acid of selecting for use acid amount be 1～5 times of vitamin G cyclic phosphate, intermediate II is fully dissolved; Hydrolysising reacting temperature is 30～80 ℃, and optimum temps is 40～45 ℃; Hydrolysis time is 3～30h, and the best is 20h, can make a complete hydrolysis in two ester bonds of vitamin G cyclic phosphate.
In the step 3, add NaOH solution in the intermediate III riboflavin phosphate ester solution, the NaOH strength of solution is 10～25%; The best is 20%, regulates pH value to 5.0～6.0, and the best is 5.5; Separate out thick product I V Sodium riboflavin phosphate; Filter cake is used washing with alcohol, drains, and obtains the Sodium riboflavin phosphate bullion.
In the step 4, purified water is heated to 50～60 ℃, adds bullion while stirring and dissolve clearly, selected purified water consumption is 5～20 times of Sodium riboflavin phosphate bullion, and water yield the best is 12 times of thick product, can fully dissolve fully.Under 40～60 ℃ of conditions, the best is to dissolve under 50 ℃ of conditions, behind the insoluble impurity of elimination; Filtrating is cooled to below 20 ℃; Add 1～6 times of amount of filtrating volume of ethanol again, can separate out solid, dry 8h promptly gets the Sodium riboflavin phosphate elaboration in 55 ℃ of loft drier.
Adopt the industrialized process for preparing of Sodium riboflavin phosphate of the present invention; 5 '-riboflavin phosphate sodium content is greater than 85% in the flavin phosphate sodium the finished product of preparation; Total impurities is less than 1%; Quality product is high, and foreign matter content is low, can reach the specification of quality of present domestic and international various pharmacopeia to Sodium riboflavin phosphate.And the industrialized process for preparing of Sodium riboflavin phosphate of the present invention is owing to working condition gentleness, electrodeless low temperature, very high temperature and extra high tension requirement; Equipment there is not particular requirement; The production technology easy master, the products production cost is low, and product purity is high; The waste easy recovery is utilized, and is suitable for industriallization and prepares Sodium riboflavin phosphate salt in a large number.
Embodiment
Below in conjunction with specific embodiment the preparation method of Sodium riboflavin phosphate of the present invention is done further explain.
Embodiment 1
1) riboflavin phosphate reaction, product nucleus flavine cyclic phosphate;
Extract 180kg (being 4390mol) acetonitrile to retort, open the chuck cryosel and be cooled to below 8 ℃.Open pyridine test tank vacuum valve and accurately extract 126kg pyridine (being 1064mol) to the pyridine test tank, behind the vacuum pumping, open the test tank bottom valve, slowly pyridine is joined in the retort, the chuck cryosel continues cooling, and temperature is no more than 8 ℃.Accurately extract 244kg (being 1195mol) POCl3 again in test tank, slowly drop down and be added in the retort, reacting liquid temperature is lower than 5 ℃.First suction 80kg acetonitrile (being 1951mol) in the mixed solution test tank, suction 12kg purified water (being 665mol) again.Close vacuum valve, temperature is reduced to below 5 ℃ in the retort, and beginning is slowly dropped down and added the acetonitrile-water mixed solution, guarantees that temperature is below 10 ℃ in the reaction process.After adding mixed solution, reduce mixing speed.Open a jar charging opening, add 100kg (266mol) vitamin G fast, the sealed can mouth and the valve that links to each other.React 10h down at 5～10 ℃.In plastic filter, complete filter bag, guarantee anhydrously, open bottom valve feed liquid is put in the strainer; Open vacuum filtration, close vacuum after draining, embathe vitamin G cyclic phosphate filter cake twice with about 40～50kg acetonitrile; About each 5min, open vacuum again and drain, for use.
2) vitamin G cyclic phosphate hydrolysis, the product nucleus flavin phosphate;
With the 100kg weight percent is that 18% hydrochloric acid and 80kg purified water are pumped in the hydrolytic decomposition pot, opens stirring, adds above-mentioned midbody vitamin G cyclic phosphate again, is warming up to 50 ℃ of acidolysis 5h.
3) cytoflavin salt-forming reaction;
Open the chuck cryosel and be cooled to below 20 ℃, through high-order liquid caustic soda test tank drop down weight percent be 25% NaOH solution to hydrolytic decomposition pot and salify, pH transfers to 5.5, this process temperature is separated out a large amount of solids below 25 ℃.Be cooled at last below 10 ℃.Filter, draining back use 40～50kg volume(tric)fraction is 90% washing with alcohol twice, drains as far as possible, promptly gets the Sodium riboflavin phosphate bullion.
4) Sodium riboflavin phosphate is refining;
In treatment tank, add the 1200kg purified water, be heated to 55 ℃, stir down, add above-mentioned Sodium riboflavin phosphate bullion; Dissolving, insulation is opened chuck cold water at 50～55 ℃, reduces to below 20 ℃; Drop down that to add the 1500kg volume(tric)fraction be 95% ethanol, promptly separate out solid, leave standstill 2h, whizzer gets rid of filter.Using 40～50kg volume(tric)fraction again is 90% washing with alcohol 2 times, gets rid of filter and does, and at 55 ℃ of dry 8h down, promptly gets elaboration.
Through weighing, gained Sodium riboflavin phosphate elaboration 126kg detects through adopting HPLC (performance liquid chromatography) method, and wherein 5 '-Sodium riboflavin phosphate weight percentage is 85.8%, total impurities content＜1%.The molar yield of present embodiment Sodium riboflavin phosphate elaboration is 86%, and the specific optical rotation of this riboflavin sodium phosphate elaboration is 40.2 °.
Embodiment 2
Get 200kg (being 4878mol) acetonitrile to retort, open the chuck cryosel and be cooled to below 5 ℃.Get in 126kg (being 1615mol) pyridine to the pyridine test tank, behind the vacuum pumping, open the test tank bottom valve, slowly pyridine is joined in the retort, the chuck cryosel continues cooling, and temperature is no more than 10 ℃.Get 260kg (being 1688mol) POCl3 in test tank, slowly drop down and be added in the retort, reacting liquid temperature is lower than 5 ℃.First suction 100g (being 2439mol) acetonitrile in the mixed solution test tank adds 10kg (being 555mol) purified water.Reduce to below 5 ℃ etc. temperature in the retort, beginning is slowly dropped down and is added the acetonitrile-water mixed solution, guarantees that reacting liquid temperature is below 10 ℃ in the process.Add 100kg (being 266mol) vitamin G, react 8h down at 5～10 ℃.Embathe vitamin G cyclic phosphate filter cake at twice with the 100kg acetonitrile behind the suction filtration, about each 5min, open vacuum again, drain, for use.
2) vitamin G cyclic phosphate hydrolysis, the product nucleus flavin phosphate;
With the 100kg weight percentage is that 15% hydrochloric acid and 100kg purified water are pumped in the hydrolytic decomposition pot, opens stirring, adds above-mentioned midbody vitamin G cyclic phosphate again, is warming up to 50 ℃ of acidolysis 3h.
3) cytoflavin salt-forming reaction;
Open the chuck cryosel and be cooled to below 20 ℃, through high-order liquid caustic soda test tank drop down add the weight mark be 25% NaOH liquid caustic soda to hydrolytic decomposition pot and salify, pH transfers to 5.5, this process temperature is separated out a large amount of solids below 25 ℃.Be cooled at last below 10 ℃.Filter, after draining, using volume(tric)fraction is 90% ethanol, 40～50kg washing 2 times, drains, and promptly gets cytoflavin ester sodium bullion.
4) cytoflavin ester sodium is refining;
In treatment tank, add the 1500kg purified water, be heated to 55 ℃, stir down, add above-mentioned bullion, dissolving, insulation is opened chuck cold water at 50～55 ℃, reduces to below 20 ℃, drops down that to add the 1500kg volume(tric)fraction be 95% ethanol, separates out solid, leaves standstill 2h.Whizzer gets rid of filter, and using volume(tric)fraction again is ethanol 40～50kg of 90% washing 2 times, gets rid of filter and does, and dry 8h in 55 ℃ of following loft drier promptly gets the Sodium riboflavin phosphate elaboration.
Through weighing, gained Sodium riboflavin phosphate elaboration 118kg detects through adopting HPLC (performance liquid chromatography) method, and wherein 5 '-Sodium riboflavin phosphate weight percentage is 85.3%, total impurities content＜1%.The molar yield of present embodiment riboflavin sodium phosphate elaboration is 80%, and the specific optical rotation of this riboflavin sodium phosphate elaboration is 38.8 °.
Embodiment 3
Get 200kg (being 2632mol) THF to retort, open the chuck cryosel and be cooled to below 5 ℃.Get in 126kg (being 1615mol) pyridine to the pyridine test tank, behind the vacuum pumping, open the test tank bottom valve, slowly pyridine is joined in the retort, the chuck cryosel continues cooling, and temperature is no more than 10 ℃.Get 260kg (being 1688mol) POCl3 in test tank, slowly drop down and be added in the retort, reacting liquid temperature is lower than 5 ℃.First suction 80kg (being 1111mol) THF in the mixed solution test tank adds 12kg (being 665mol) purified water.Reduce to below 5 ℃ etc. temperature in the retort, beginning is slowly dropped down and is added the acetonitrile-water mixed solution, guarantees that reacting liquid temperature is below 10 ℃ in the process.Add 100kg (being 266mol) vitamin G (B2), react 8h down at 5～10 ℃.Embathe about vitamin G cyclic phosphate filter cake 5min with an amount of THF (about 100kg * 2 time) behind the suction filtration, drain, filter is done for use.
2) vitamin G cyclic phosphate hydrolysis, the product nucleus flavin phosphate;
With the 100kg parts by weight is that 15% hydrochloric acid and 60kg purified water are pumped in the hydrolytic decomposition pot, opens stirring, adds above-mentioned midbody again, is warming up to 50 ℃ of acidolysis 5h.
3) cytoflavin salt-forming reaction;
Open the chuck cryosel and be cooled to below 20 ℃, through high-order liquid caustic soda test tank drop down add the weight mark be 25% NaOH liquid liquid caustic soda to hydrolytic decomposition pot and salify, pH transfers to 5.5, this process temperature is separated out a large amount of solids below 25 ℃.Be cooled at last below 10 ℃.Filter, after draining, using volume(tric)fraction is ethanol 40～50kg washing of 90% 2 times, drains, and promptly gets the Sodium riboflavin phosphate bullion.
4) Sodium riboflavin phosphate is refining;
In treatment tank, add the 1500kg purified water, be heated to 55 ℃, stir down, add above-mentioned Sodium riboflavin phosphate bullion; Dissolving, insulation is opened chuck cold water at 50～55 ℃, reduces to below 20 ℃; Drop down that to add the 1500kg volume(tric)fraction be 95% ethanol, separate out solid, leave standstill 2h.Whizzer gets rid of filter, and using volume(tric)fraction again is 90% ethanol, 40～50kg washing 2 times, gets rid of filter and does, and dry 8h under 55 ℃ promptly gets the Sodium riboflavin phosphate elaboration.
Through weighing, gained Sodium riboflavin phosphate elaboration 109kg detects through adopting HPLC (performance liquid chromatography) method, and wherein 5 '-Sodium riboflavin phosphate weight percentage is 80.1%, total impurities content＜1%.The molar yield of present embodiment riboflavin sodium phosphate elaboration is 80%, and the specific optical rotation of this riboflavin sodium phosphate elaboration is 38.2 °.
Claims (9)
1. the industrialized process for preparing of a Sodium riboflavin phosphate is with B
2, POCl3, pyridine, purified water be starting raw material, may further comprise the steps:
1) riboflavin phosphate reaction, product nucleus flavine cyclic phosphate;
Vitamin G, POCl3, purified water joined in the aprotic polar solvent under pyridine is made the condition of catalyzer react, temperature of reaction is controlled at-5～15 ℃ of scopes, and the reaction times is controlled to be 8～10h, product nucleus flavine cyclic phosphate; Wherein, add vitamin G, POCl3, pyridine, purified water mol ratio be: 1: 1～5: 1～5: 1～3, described aprotic polar solvent is a kind of in THF, acetonitrile, the dioxane;
The reaction that takes place in this step is following:
2) vitamin G cyclic phosphate hydrolysis, the product nucleus flavin phosphate;
Is hydrolysis in 5～18% the hydrochloric acid with the vitamin G cyclic phosphate in weight percent concentration, and the hydrochloric acid weight of selecting for use is 1～5 times of vitamin G cyclic phosphate weight, and hydrolysising reacting temperature is controlled to be 30～80 ℃, and the reaction times is controlled to be 3～30h;
The reaction that takes place in this step is following:
3) cytoflavin salt-forming reaction generates Sodium riboflavin phosphate;
The adding weight percent concentration is 10～25% NaOH solution in the riboflavin phosphate ester solution, regulates pH value to 5.0～6.0, and vacuum filtration or spinning can obtain the finished product Sodium riboflavin phosphate, and the reaction of generation is following:
4) Sodium riboflavin phosphate is refining;
It is in 5～20 times the purified water that above-mentioned thick product Sodium riboflavin phosphate is dissolved in weight, under 40～60 ℃ of conditions, dissolves, and behind the insoluble impurity of elimination, filtrating is cooled to below 20 ℃, adds the ethanol that is equivalent to 1.5 times of amounts of said filtrating, promptly separates out solid; Solid is dry 8h under 55 ℃, promptly gets the Sodium riboflavin phosphate elaboration.
2. the industrialized process for preparing of Sodium riboflavin phosphate according to claim 1, it is characterized in that: temperature of reaction described in the step 1) is controlled at 0～10 ℃ of scope.
3. the industrialized process for preparing of Sodium riboflavin phosphate according to claim 1 and 2 is characterized in that: add B in the step 1)
2, POCl3, pyridine, water mol ratio be: 1: 4.5: 4: 2.5.
4. the industrialized process for preparing of Sodium riboflavin phosphate according to claim 1 and 2; It is characterized in that: step 2) described in the hydrochloric acid weight percent concentration be 10～12%; The hydrochloric acid weight of selecting for use is 2.5 times of said vitamin G cyclic phosphate weight; Hydrolysising reacting temperature is controlled to be 40～45 ℃, and hydrolysis time is controlled to be 20h.
5. the industrialized process for preparing of Sodium riboflavin phosphate according to claim 3; It is characterized in that: step 2) described in the hydrochloric acid weight percent concentration be 10～12%; The hydrochloric acid weight of selecting for use is 2.5 times of said vitamin G cyclic phosphate weight; Hydrolysising reacting temperature is controlled to be 40～45 ℃, and hydrolysis time is controlled to be 20h.
6. the industrialized process for preparing of Sodium riboflavin phosphate according to claim 1 and 2, it is characterized in that: the weight percent concentration of the said NaOH solution of step 3) is controlled to be 20%, and conditioned reaction liquid pH value is 5.5.
7. the industrialized process for preparing of Sodium riboflavin phosphate according to claim 3, it is characterized in that: the weight percent concentration of the said NaOH solution of step 3) is controlled to be 20%, and conditioned reaction liquid pH value is 5.5.
8. the industrialized process for preparing of Sodium riboflavin phosphate according to claim 4, it is characterized in that: the weight percent concentration of the said NaOH solution of step 3) is controlled to be 20%, and conditioned reaction liquid pH value is 5.5.
9. the industrialized process for preparing of Sodium riboflavin phosphate according to claim 5, it is characterized in that: the weight percent concentration of the said NaOH solution of step 3) is controlled to be 20%, and conditioned reaction liquid pH value is 5.5.
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| CN102617643B (en) * | 2012-03-06 | 2013-04-10 | 黄金秀 | Riboflavin sodium phosphate compound |
| CN103396452B (en) * | 2013-08-19 | 2015-09-30 | 周晓东 | A kind of Riboflavin sodium phosphate compound and composition thereof |
| CN106674225B (en) * | 2016-11-09 | 2019-04-02 | 珠海同源药业有限公司 | A kind of Riboflavin sodium phosphate compound and its pharmaceutical composition |
| CN107286194A (en) * | 2017-06-07 | 2017-10-24 | 山西集翔生物工程有限公司 | A kind of riboflavin phosphate process for producing sodium |
| CN111094309A (en) * | 2018-09-21 | 2020-05-01 | 邦泰生物工程(深圳)有限公司 | Preparation method of high-purity riboflavin sodium phosphate |
| CN114702524A (en) * | 2022-04-29 | 2022-07-05 | 湖北广济药业股份有限公司 | Method for preparing high-purity riboflavin sodium phosphate |
| CN116925144B (en) * | 2023-07-28 | 2024-02-09 | 广东嘉亨新材料有限公司 | Halogen-free flame retardant, preparation method thereof and prepared flame-retardant fiber |
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| WO2003010172A1 (en) * | 2001-07-23 | 2003-02-06 | Eisai Co., Ltd. | Process for producing highly pure riboflavin-5’-phosphate sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003010172A1 (en) * | 2001-07-23 | 2003-02-06 | Eisai Co., Ltd. | Process for producing highly pure riboflavin-5’-phosphate sodium |
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| 孙文敬等.核黄素磷酸钠生产工艺的研究.《食品科学》.2008,第29卷(第8期), * |
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