CN103772432B - A kind of production method of benfotiamine - Google Patents
A kind of production method of benfotiamine Download PDFInfo
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- CN103772432B CN103772432B CN201410002154.4A CN201410002154A CN103772432B CN 103772432 B CN103772432 B CN 103772432B CN 201410002154 A CN201410002154 A CN 201410002154A CN 103772432 B CN103772432 B CN 103772432B
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Abstract
A production method for benfotiamine, take polyphosphoric acid as Phosphation reagent, reacts with VITMAIN B1, be hydrolyzed under having reacted rear high temperature, after being hydrolyzed, after the phosphoric acid by the mixing solutions extraction system of trioctylamine and organic solvent, directly add the phosphate monoester crude product of organic solvent liberating vitamin B1.The crude product obtained, without purification, directly with water making beating, after adjusting pH value, reacts with Benzoyl chloride, filtering solids with liquid caustic soda.Filtrate adjusts pH value to 3.5 ~ 4.0 to separate out solid, is separated and dries to obtain white solid, is benfotiamine.The benfotiamine productive rate obtained by this explained hereafter is high, and product purity is high, simple to operate, environmentally friendly, is applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to chemical field, for a kind of production technique of VITMAIN B1 derivative is improved, be specially a kind of production method of benfotiamine.
Background technology
Benfotiamine is the fat-soluble derivant of VITMAIN B1, slightly water-soluble.The difference of benfotiamine and VITMAIN B1 is that benfotiamine structurally has an open thiazole ring, is formed with the VITMAIN B1 of physiologically active in vivo by ring closure.After taking, in gi tract, there is dephosphorylation effect, form a lipophilic molecules, be easy to diffuse into cytolemma, therefore more easily absorb than VITMAIN B1.Compared with VITMAIN B1 itself, it is more that this lipotropy makes it absorb in enteron aisle and target organ.After absorption enters cell, the benfotiamine of dephosphorylation is reduced in cell, closes thiazole ring, and the VITMAIN B1 of release activity enters cell and the recycle system.
Benfotiamine synthesizes the sixties in 20th century in Japan, starts to be applied to the neuropathy for the treatment of alcoholism and causing gradually after 1962, sciatica and other neuropathic pain.Since the nineties in 20th century, Europe scholar expands a series of research to benfotiamine and is in recent years making remarkable progress in Prevention diabetes and complication thereof, research finds, benfotiamine is mainly used in maintaining normal sugar metabolism and nerve, digestive system function.The effect of prevention can be played the side effect of diabetes and complication, and can effectively treat and prevent diabetes retinopathy, and also not have medicine can the complication of prevent diabetes up till now.Current research also shows, benfotiamine also has remarkable effect to treatment senile dementia.
The synthetic method (US3064000A, GB1092664A, GB896089A) of the benfotiamine of bibliographical information all relates to the process of VITMAIN B1 Phosphation, in reported method, tetra-sodium is all adopted to be Phosphation reagent, reaction is completed under the condition of 100 DEG C, after having reacted, reaction solution is placed in acidic aqueous solution, at room temperature places and within about 1 week, obtain VITMAIN B1 phosphate monoester product.The method needs at high temperature to react, and is VITMAIN B1 reaction after needing phosphoric acid to be heated to 270 DEG C of formation tetra-sodiums.This process need high temperature, the at substantial energy.And high temperature is had higher requirement to whole production unit.Need room temperature to place after having reacted about one week, significantly increase the production cycle, reduce production efficiency.And need to re-start process to production product, concentrated recrystallization etc., add processing step, create a large amount of acidic industrial effluent, contaminate environment.
The separation method of phosphoric acid ester is refer in CA2012928, VITMAIN B1 phosphoric acid ester-ortho-phosphoric acid solution, after the methyl tert-butyl acid methyl ester solution of trioctylamine extracts excessive phosphoric acid, is separated through ion exchange column and obtains VITMAIN B1 phosphate monoester and VITMAIN B1 pyrophosphate.The method also limit output owing to using expensive extraction agent and carrying out separated product through ion exchange column, is unfavorable for the production of mass-producing.
Be obtained by reacting tetra-sodium as phosphorylation agent with Vanadium Pentoxide in FLAKES and ortho-phosphoric acid in CN101654464, then react with VITMAIN B1, after Phosphation completes, hydrolysis.Obtain the phosphate monoester aqueous solution of VITMAIN B1 with an alkali metal salt neutralization, then obtain the phosphate monoester of VITMAIN B1 through condensing crystal.The method an alkali metal salt neutralizes, solid phosphates a large amount of with rear generation in system, extremely difficult separation.Be mingled with product in isolated solid phosphate, bring larger loss.
In CN102911208, phosphorus oxychloride is as Phosphation reagent, and because phosphorus oxychloride activity is too high, hydrolysis operation inconvenience, exists potential safety hazard, and after Phosphation completes, hydrolysis generation VITMAIN B1 phosphate monoester product is directly separated out very difficult, is unfavorable for operation.
Summary of the invention
The object of this invention is to provide a kind of production method of benfotiamine, the benfotiamine productive rate obtained by this explained hereafter is high, and product purity is high, simple to operate, environmentally friendly, is applicable to suitability for industrialized production.
In order to solve the problems of the technologies described above, the invention provides a kind of production method of benfotiamine, its synthetic route is:
；
The steps include:
Take polyphosphoric acid as Phosphation reagent, react with VITMAIN B1, be hydrolyzed after having reacted, then use the phosphoric acid in extraction agent extraction system, then by adding organic solvent liberating vitamin B1 phosphate monoester crude product; Crude product is without purification, and directly with water making beating, after adjusting PH to alkalescence with liquid caustic soda, last and Benzoyl chloride reacts, and filters, and filtrate adjusts pH value to 3.5 ~ 4.0 to separate out solid, is separated and dries to obtain white solid, is benfotiamine.
The concrete steps of such scheme are:
1) when polyphosphoric acid and VITMAIN B1 are reacted, temperature of reaction is 80-130 DEG C, and the reaction times is 3-8 hour, and the weight ratio of VITMAIN B1 and polyphosphoric acid is 1:3-5;
2) above-mentioned reaction complete after to add water and 80-120 DEG C of hydrolysis, hydrolysis time is 2-10 hour, the weight ratio of amount of water and raw material VITMAIN B1 is 3-10;
3) after being hydrolyzed, be down to room temperature, with the mixing solutions of trioctylamine and organic solvent 1 as the phosphoric acid in extraction agent extraction system, remove top layer phosphoric acid, to make in solution phosphoric acid concentration below 0.1%; The weight ratio of described extraction agent and raw material VITMAIN B1 is 3-5:1;
4) add organic solvent 2 during liberating vitamin B1 phosphate monoester crude product, its add-on is 5-7 times of VITMAIN B1 raw material weight;
5) crude product direct water of not purifying is pulled an oar, adjust pH value to 8.0-14.0 with liquid caustic soda at 0-5 DEG C after, react with Benzoyl chloride, reaction times is 2-3 hour, after having reacted, filters, obtain filtrate, filtrate adjusts pH value to separate out solid to 3.5-4.0 with concentrated hydrochloric acid, and separate solid is also dried and obtained white solid, is benfotiamine; Wherein the consumption of Benzoyl chloride is 1-2 times of VITMAIN B1.
In preferred scheme, the temperature of reaction of described polyphosphoric acid and VITMAIN B1 is 100-120 DEG C, and the reaction times is 5-6 hour.
In preferred scheme, the time of described hydrolysis reaction is 4-6 hour, and the preferred 3-7 of the weight ratio of amount of water and raw material VITMAIN B1.
Described organic solvent 1 is one or several the mixture in ethyl acetate, methyl tertiary butyl ether, methylene dichloride, chloroform, toluene, sherwood oil, and the weight ratio of trioctylamine and organic solvent 1 is 1:2-5, and preferred weight ratio is 1:3-4.
Described organic solvent 2 is one or several the mixture in methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), dioxane.
Step 1)-3) in solvent recyclable recycling after treatment, the mother liquor of the VITMAIN B1 phosphate monoester crude product separated in step 4) can reclaim organic solvent and apply mechanically, in step 5), filtering separation solid out also can be made chemical fertilizer and externally sells, and reduces solid waste; Can production cost be reduced by above-mentioned measure, and can available protecting environment.
The benfotiamine that scheme provided by the invention is produced is simple to operate, uses Vanadium Pentoxide in FLAKES etc., has strong absorptive, severe corrosive in original technique, and to original transport, the keeping of material, very burden is all brought in the aspect such as to feed intake of production.Be employed herein polyphosphoric acid, directly solve above trouble, production operation is simplified.According to post-processing operation of the present invention, filtering separation solid out also can be made chemical fertilizer and externally sell, and reduces the discharge of solid waste, adopts solvent recuperation process simultaneously, decreases solvent consumption, reduce the pollution to environment, reduce production cost.
Embodiment
Below in conjunction with embodiment, technical scheme of the present invention and the technique effect that produces thereof are described further, to understand object of the present invention, technical characteristic and effect fully.Following embodiment is used for the present invention instead of restriction the present invention, those skilled in the art can practical foregoing description to most wide region.
Embodiment 1:
Add 4000kg polyphosphoric acid in reactor after, be warming up to 100 ~ 120 DEG C, the VITMAIN B1 of 1000kg is added in reactor in batches, this temperature range inside holding 8 hours after adding, the shrend adding 3000kg is gone out after this reaction, is warming up to 80-90 DEG C of hydrolysis 10 hours; Be down to room temperature, in still, add the mixed solution phosphoric acid extraction of trioctylamine/methyl tertiary butyl ether=1/1 of 5000kg; Add 5000kg methyl alcohol in aqueous phase and separate out solid, centrifugation obtains 1200kg VITMAIN B1 phosphate monoester crude product; By 1200kg VITMAIN B1 phosphate monoester crude product after 6000kg water mixing making beating, be cooled to 0 ~ 5 DEG C, in this temperature range, drip pH value to 12.0 ~ 14.0 of liquid caustic soda regulation system; After PH has adjusted, ensureing the Benzoyl chloride dripping 1200kg in reactor temperature 10 ~ 25 DEG C, being added dropwise to complete rear insulation to having reacted; Filter, filtrate adjusts pH value to 3.5 ~ 4.0 to separate out solid, is separated and dries to obtain white solid 1200kg, is benfotiamine.Yield: 77.38%, purity: 98.70%.
Embodiment 2:
Add 5000kg polyphosphoric acid in reactor after, be warming up to 80 ~ 100 DEG C, the VITMAIN B1 of 1000kg is added in reactor in batches, this temperature range inside holding 6 hours after adding, the shrend adding 5000kg is gone out after this reaction, is warming up to back hydrolysis 5 hours; Be down to room temperature, in still, add the mixed solution extracting twice of trioctylamine/methyl tertiary butyl ether=1/1 of 4000kg; Add 6000kg ethanol in aqueous phase and separate out solid, centrifugation obtains 1200kg VITMAIN B1 phosphate monoester crude product; By 1200kg VITMAIN B1 phosphate monoester crude product after 6000kg water mixing making beating, be cooled to 0 ~ 5 DEG C, in this temperature range, drip pH value to 10.0 ~ 12.0 of liquid caustic soda regulation system; After PH has adjusted, ensureing the Benzoyl chloride dripping 1200kg in reactor temperature 10 ~ 25 DEG C, being added dropwise to complete rear insulation to having reacted; Filter, filtering solids, filtrate adjusts pH value to 3.5 ~ 4.0 to separate out solid, is separated and dries to obtain white solid 1250kg, is benfotiamine.Yield: 80.61%, purity: 98.50%.
Embodiment 3:
Add 3000kg polyphosphoric acid in reactor after, be warming up to 90 ~ 110 DEG C, the VITMAIN B1 of 1000kg is added in reactor in batches, this temperature range inside holding 5 hours after adding, the shrend adding 5000kg is gone out after this reaction, is warming up to 90-100 DEG C of hydrolysis 5 hours; Be down to room temperature, in still, add the mixed solution extracting twice of trioctylamine/methyl tertiary butyl ether=1/1 of 5000kg; Add 7000kg acetone in aqueous phase and separate out solid, centrifugation obtains 1230kg VITMAIN B1 phosphate monoester crude product; By 1200kg VITMAIN B1 phosphate monoester crude product after 6000kg water mixing making beating, be cooled to 0 ~ 5 DEG C, in this temperature range, drip pH value to 11.0 ~ 13.0 of liquid caustic soda regulation system; After PH has adjusted, ensureing the Benzoyl chloride dripping 1200kg in reactor temperature 10 ~ 25 DEG C, being added dropwise to complete rear insulation to having reacted; Filter, filtrate adjusts pH value to 3.5 ~ 4.0 to separate out solid, is separated and dries to obtain white solid 1240kg, is benfotiamine.Yield: 79.96%, purity: 98.50%.
Embodiment 4
Add 4000kg polyphosphoric acid in reactor after, be warming up to 100 ~ 120 DEG C, the VITMAIN B1 of 1000kg is added in reactor in batches, this temperature range inside holding 4 hours after adding, the shrend adding 8000kg is gone out after this reaction, is warming up to 90-110 DEG C of hydrolysis 7 hours; Be down to room temperature, in still, add the mixed solution phosphoric acid extraction of trioctylamine/methyl tertiary butyl ether=1/1 of 4000kg; Add 6000kg methyl alcohol in aqueous phase and separate out solid, centrifugation obtains 1200kg VITMAIN B1 phosphate monoester crude product; By 1200kg VITMAIN B1 phosphate monoester crude product after 6000kg water mixing making beating, be cooled to 0 ~ 5 DEG C, in this temperature range, drip pH value to 9.0 ~ 11.0 of liquid caustic soda regulation system; After PH has adjusted, ensureing the Benzoyl chloride dripping 1200kg in reactor temperature 10 ~ 25 DEG C, being added dropwise to complete rear insulation to having reacted; Filter, filtrate adjusts pH value to 3.5 ~ 4.0 to separate out solid, is separated and dries to obtain white solid 1260kg, is benfotiamine.Yield: 81.24%, purity: 98.70%.
Embodiment 5
Add 5000kg polyphosphoric acid in reactor after, be warming up to 110 ~ 130 DEG C, the VITMAIN B1 of 1000kg is added in reactor in batches, this temperature range inside holding 3 hours after adding, the shrend adding 10000kg is gone out after this reaction, is warming up to 110-120 DEG C of back hydrolysis 3 hours; Be down to room temperature, in still, add the mixed solution phosphoric acid extraction of trioctylamine/methyl tertiary butyl ether=1/1 of 3000kg; Add 6000kg ethanol in aqueous phase and separate out solid, centrifugation obtains 1200kg VITMAIN B1 phosphate monoester crude product; By 1200kg VITMAIN B1 phosphate monoester crude product after 6000kg water mixing making beating, be cooled to 0 ~ 5 DEG C, in this temperature range, drip pH value to 8.0 ~ 10.0 of liquid caustic soda regulation system; After PH has adjusted, ensureing the Benzoyl chloride dripping 1200kg in reactor temperature 10 ~ 25 DEG C, being added dropwise to complete rear insulation to having reacted; Filter, filtrate adjusts pH value to 3.5 ~ 4.0 to separate out solid, is separated and dries to obtain white solid 1230kg, is benfotiamine.Yield: 79.31%, purity: 98.60%.
Claims (7)
1. a production method for benfotiamine, is characterized in that: its synthetic route is:
；
The steps include:
Take polyphosphoric acid as Phosphation reagent, react with VITMAIN B1, be hydrolyzed after having reacted, then use the phosphoric acid in extraction agent extraction system, then by adding organic solvent liberating vitamin B1 phosphate monoester crude product; Crude product is without purification, and directly with water making beating, after adjusting PH to alkalescence with liquid caustic soda, last and Benzoyl chloride reacts, and filters, and filtrate adjusts pH value to 3.5 ~ 4.0 to separate out solid, is separated and dries to obtain white solid, is benfotiamine;
Concrete step is:
1) when polyphosphoric acid and VITMAIN B1 are reacted, temperature of reaction is 80-130 DEG C, and the reaction times is 3-8 hour, and the weight ratio of VITMAIN B1 and polyphosphoric acid is 1:3-5;
2) above-mentioned reaction complete after to add water and 80-120 DEG C of hydrolysis, hydrolysis time is 2-10 hour, the weight ratio of amount of water and raw material VITMAIN B1 is 3-10;
3) after being hydrolyzed, be down to room temperature, with the mixing solutions of trioctylamine and organic solvent 1 as the phosphoric acid in extraction agent extraction system, remove top layer phosphoric acid, to make in solution phosphoric acid concentration below 0.1%; The weight ratio of described extraction agent and raw material VITMAIN B1 is 3-5:1;
4) add organic solvent 2 during liberating vitamin B1 phosphate monoester crude product, its add-on is 5-7 times of VITMAIN B1 raw material weight;
5) crude product direct water of not purifying is pulled an oar, adjust pH value to 8.0-14.0 with liquid caustic soda at 0-5 DEG C after, react with Benzoyl chloride, reaction times is 2-3 hour, after having reacted, filters, obtain filtrate, filtrate adjusts pH value to separate out solid to 3.5-4.0 with concentrated hydrochloric acid, and separate solid is also dried and obtained white solid, is benfotiamine; Wherein the consumption of Benzoyl chloride is 1-2 times of VITMAIN B1.
2. the production method of benfotiamine according to claim 1, is characterized in that: the temperature of reaction of described polyphosphoric acid and VITMAIN B1 is 100-120 DEG C, and the reaction times is 5-6 hour.
3. the production method of benfotiamine according to claim 1, is characterized in that: the time of described hydrolysis reaction is 4-6 hour.
4. the production method of benfotiamine according to claim 1, it is characterized in that: described organic solvent 1 is one or several the mixture in ethyl acetate, methyl tertiary butyl ether, methylene dichloride, chloroform, toluene, sherwood oil, the weight ratio of trioctylamine and organic solvent 1 is 1:2-5.
5. the production method of benfotiamine according to claim 1, is characterized in that: the weight ratio of described trioctylamine and organic solvent 1 is 1:3-4.
6. the production method of benfotiamine according to claim 1, is characterized in that: described organic solvent 2 is one or several the mixture in methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), dioxane.
7. the production method of benfotiamine according to claim 1, is characterized in that: step 1)-3) in solvent recyclable recycling after treatment; The mother liquor of the VITMAIN B1 phosphate monoester crude product separated in step 4) can reclaim organic solvent and recycle.
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| CN112898342A (en) * | 2017-06-26 | 2021-06-04 | 上海日馨生物科技有限公司 | Benfotiamine derivative, preparation method and pharmaceutical composition thereof |
| CN111233925B (en) * | 2018-11-28 | 2021-03-26 | 上海日馨生物科技有限公司 | Thiamine compound, preparation method and pharmaceutical composition thereof |
| CN111233927B (en) * | 2018-11-28 | 2021-03-26 | 上海日馨生物科技有限公司 | Thiamine compound, preparation method and pharmaceutical composition thereof |
| CN111233926B (en) * | 2018-11-28 | 2021-04-16 | 上海日馨生物科技有限公司 | Thiamine compound, preparation method and pharmaceutical composition thereof |
| US10947258B1 (en) | 2019-08-23 | 2021-03-16 | Shanghai Rixin Biotechnology Co., Ltd. | Benfotiamine derivatives, method for preparing the same and pharmaceutical composition comprising the same |
| CN112479960B (en) * | 2020-12-12 | 2023-02-21 | 弘健制药(上海)有限公司 | Vitamin D 3 Purification method of (2) |
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| CA682778A (en) * | 1964-03-24 | Ito Akira | S-benzoylthiamine o-monophosphate and a process for preparing the same | |
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