CN103772432A - Production method of benfotiamine - Google Patents
Production method of benfotiamine Download PDFInfo
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- CN103772432A CN103772432A CN201410002154.4A CN201410002154A CN103772432A CN 103772432 A CN103772432 A CN 103772432A CN 201410002154 A CN201410002154 A CN 201410002154A CN 103772432 A CN103772432 A CN 103772432A
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- benfotiamine
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Abstract
The invention relates to a production method of benfotiamine. The production method comprises the following steps: by taking polyphosphoric acid as a phosphoric acid esterification reagent, reacting with vitamin B1, performing hydrolysis at high temperature after the end of reaction, extracting phosphoric acid of a system by using a mixed solution of trioctylamine and an organic solvent after the end of hydrolysis, and then directly adding the organic solvent to precipitate a phosphate monoester crude product of vitamin B1. The obtained crude product is not purified, water is directly used for pulping, the pH value is adjusted by using liquid alkali, the reaction is performed with benzoyl chloride, and solids are filtered. The pH value of filtrate is adjusted to 3.5-4.0, the solids are precipitated, and separation and drying are performed to obtain the white solids, namely benfotiamine. The yield of benfotiamine produced by using the process is high, the product purity is high, the operation is simple, and the production method is environment-friendly and suitable for industrial production.
Description
Technical field
The present invention relates to chemical field, improve for a kind of production technique of VITMAIN B1 derivative, 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 that it absorbs in enteron aisle and target organ.Absorption enters after cell, and the benfotiamine of dephosphorylation is reduced in cell, closes thiazole ring, discharges active VITMAIN B1 and enters cell and the recycle system.
Benfotiamine is synthetic in Japan the sixties in 20th century, starts to be applied to gradually the neuropathy that treatment alcoholism causes, sciatica and other neuropathic pain after 1962.Since the nineties in 20th century, Europe scholar is launching a series of research and is in recent years making remarkable progress benfotiamine aspect Prevention diabetes and complication thereof, research finds, benfotiamine is mainly used in maintaining normal glucose metabolism and nerve, digestive system function.Can play the effect of prevention to the side effect of diabetes and complication, and can effectively treat and prevent diabetes retinopathy, and also there is no up till now the complication that medicine can prevent diabetes.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, all adopting tetra-sodium is Phosphation reagent, under the condition of 100 ℃, complete reaction, after having reacted, reaction solution is placed in to acidic aqueous solution, at room temperature places and within about 1 week, obtain VITMAIN B1 phosphate monoester product.The method need at high temperature be reacted, and phosphoric acid need to be heated to 270 ℃ and form after tetra-sodiums as VITMAIN B1 is reacted.This process need high temperature, expends mass energy.And high temperature is had higher requirement to whole production unit.After having reacted, need room temperature to place about one week, increased greatly the production cycle, reduced production efficiency.And need to re-start processing to producing product, concentrated recrystallization etc., have increased processing step, have produced a large amount of acidic industrial effluents, contaminate environment.
In CA2012928, mention the separation method of phosphoric acid ester, VITMAIN B1 phosphoric acid ester-ortho-phosphoric acid solution, after the excessive phosphoric acid of the methyl methyl isobutyrate solution extraction of trioctylamine, separates and obtains VITMAIN B1 phosphate monoester and VITMAIN B1 pyrophosphate through ion exchange column.The method is due to the extraction agent with expensive and carry out separated product through ion exchange column and also limited output, is unfavorable for the production of mass-producing.
In CN101654464, obtain tetra-sodium as phosphorylation agent with Vanadium Pentoxide in FLAKES and ortho-phosphoric acid reaction, then react with VITMAIN B1, after Phosphation completes, hydrolysis.Neutralize and obtain the phosphate monoester aqueous solution of VITMAIN B1 with an alkali metal salt, then obtain the phosphate monoester of VITMAIN B1 through condensing crystal.The method neutralizes with an alkali metal salt, and in system, with a large amount of solid phosphate of rear generation, extremely difficulty separates.In isolated solid phosphate, be mingled with product, brought 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 generates VITMAIN B1 phosphate monoester product and directly separates out very difficultly, 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 obtaining 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, after having reacted, be hydrolyzed, 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 water making beating, adjusts PH after alkalescence with liquid caustic soda, finally reacts with Benzoyl chloride, filters, and filtrate adjusts pH value to 3.5～4.0 to separate out solid, separates and dry to obtain white solid, is benfotiamine.
The concrete steps of such scheme are:
1) when polyphosphoric acid reacts with VITMAIN B1, temperature of reaction is 80-130 ℃, 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 adds water after complete and 80-120 ℃ of hydrolysis, hydrolysis time is 2-10 hour, and 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, removal top layer phosphoric acid, makes 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 when liberating vitamin B1 phosphate monoester crude product organic solvent 2, its add-on be VITMAIN B1 raw material weight 5-7 doubly;
5) the crude product direct water making beating of not purifying, at 0-5 ℃, adjust pH value to 8.0-14.0 with liquid caustic soda, 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 oven dry obtain white solid, are benfotiamine; The 1-2 that wherein consumption of Benzoyl chloride is VITMAIN B1 doubly.
In preferred scheme, the temperature of reaction of described polyphosphoric acid and VITMAIN B1 is 100-120 ℃, 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 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 of separating 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 reduce production costs by above-mentioned measure, and effective protection of the environment.
The benfotiamine that scheme provided by the invention is produced is simple to operate, in original technique, uses Vanadium Pentoxide in FLAKES etc., has strong absorptive, severe corrosive, and to original transportation, the keeping of material, very burden is all brought in the aspect such as feed intake of production.In the present invention, use polyphosphoric acid, directly solved 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 processing simultaneously, has reduced solvent consumption, has reduced the pollution to environment, has reduced 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 fully object of the present invention, technical characterictic and effect.Following embodiment is for the present invention rather than restriction the present invention, and those skilled in the art can the extremely wide region of practical foregoing description.
Embodiment 1:
In reactor, add after 4000kg polyphosphoric acid, be warming up to 100～120 ℃, the VITMAIN B1 of 1000kg is added in reactor in batches, after adding, in this temperature range, be incubated 8 hours, add the shrend of 3000kg to go out after this reaction, be warming up to 80-90 ℃ of hydrolysis 10 hours; Be down to room temperature, to the mixed solution phosphoric acid extraction that adds trioctylamine/methyl tertiary butyl ether=1/1 of 5000kg in still; In water, add 5000kg methyl alcohol to separate out solid, centrifugation obtains 1200kg VITMAIN B1 phosphate monoester crude product; 1200kg VITMAIN B1 phosphate monoester crude product is mixed after making beating in 6000kg water, be cooled to 0～5 ℃, in this temperature range, drip pH value to 12.0～14.0 of liquid caustic soda regulation system; After PH has adjusted, guarantee to drip in 10～25 ℃ of reactor temperatures the Benzoyl chloride of 1200kg, be added dropwise to complete rear insulation to having reacted; Filter, filtrate adjusts pH value to 3.5～4.0 to separate out solid, separates and dry to obtain white solid 1200kg, is benfotiamine.Yield: 77.38%, purity: 98.70%.
Embodiment 2:
In reactor, add after 5000kg polyphosphoric acid, be warming up to 80～100 ℃, the VITMAIN B1 of 1000kg is added in reactor in batches, after adding, in this temperature range, be incubated 6 hours, add the shrend of 5000kg to go out after this reaction, be warming up to back hydrolysis 5 hours; Be down to room temperature, to the mixed solution extracting twice that adds trioctylamine/methyl tertiary butyl ether=1/1 of 4000kg in still; In water, add 6000kg ethanol to separate out solid, centrifugation obtains 1200kg VITMAIN B1 phosphate monoester crude product; 1200kg VITMAIN B1 phosphate monoester crude product is mixed after making beating in 6000kg water, be cooled to 0～5 ℃, in this temperature range, drip pH value to 10.0～12.0 of liquid caustic soda regulation system; After PH has adjusted, guarantee to drip in 10～25 ℃ of reactor temperatures the Benzoyl chloride of 1200kg, be added dropwise to complete rear insulation to having reacted; Filter, cross filter solid, filtrate adjusts pH value to 3.5～4.0 to separate out solid, separates and dry to obtain white solid 1250kg, is benfotiamine.Yield: 80.61%, purity: 98.50%.
Embodiment 3:
In reactor, add after 3000kg polyphosphoric acid, be warming up to 90～110 ℃, the VITMAIN B1 of 1000kg is added in reactor in batches, after adding, in this temperature range, be incubated 5 hours, add the shrend of 5000kg to go out after this reaction, be warming up to 90-100 ℃ of hydrolysis 5 hours; Be down to room temperature, to the mixed solution extracting twice that adds trioctylamine/methyl tertiary butyl ether=1/1 of 5000kg in still; In water, add 7000kg acetone to separate out solid, centrifugation obtains 1230kg VITMAIN B1 phosphate monoester crude product; 1200kg VITMAIN B1 phosphate monoester crude product is mixed after making beating in 6000kg water, be cooled to 0～5 ℃, in this temperature range, drip pH value to 11.0～13.0 of liquid caustic soda regulation system; After PH has adjusted, guarantee to drip in 10～25 ℃ of reactor temperatures the Benzoyl chloride of 1200kg, be added dropwise to complete rear insulation to having reacted; Filter, filtrate adjusts pH value to 3.5～4.0 to separate out solid, separates and dry to obtain white solid 1240kg, is benfotiamine.Yield: 79.96%, purity: 98.50%.
Embodiment 4
In reactor, add after 4000kg polyphosphoric acid, be warming up to 100～120 ℃, the VITMAIN B1 of 1000kg is added in reactor in batches, after adding, in this temperature range, be incubated 4 hours, add the shrend of 8000kg to go out after this reaction, be warming up to 90-110 ℃ of hydrolysis 7 hours; Be down to room temperature, to the mixed solution phosphoric acid extraction that adds trioctylamine/methyl tertiary butyl ether=1/1 of 4000kg in still; In water, add 6000kg methyl alcohol to separate out solid, centrifugation obtains 1200kg VITMAIN B1 phosphate monoester crude product; 1200kg VITMAIN B1 phosphate monoester crude product is mixed after making beating in 6000kg water, be cooled to 0～5 ℃, in this temperature range, drip pH value to 9.0～11.0 of liquid caustic soda regulation system; After PH has adjusted, guarantee to drip in 10～25 ℃ of reactor temperatures the Benzoyl chloride of 1200kg, be added dropwise to complete rear insulation to having reacted; Filter, filtrate adjusts pH value to 3.5～4.0 to separate out solid, separates and dry to obtain white solid 1260kg, is benfotiamine.Yield: 81.24%, purity: 98.70%.
Embodiment 5
In reactor, add after 5000kg polyphosphoric acid, be warming up to 110～130 ℃, the VITMAIN B1 of 1000kg is added in reactor in batches, after adding, in this temperature range, be incubated 3 hours, add the shrend of 10000kg to go out after this reaction, be warming up to 110-120 ℃ of back hydrolysis 3 hours; Be down to room temperature, to the mixed solution phosphoric acid extraction that adds trioctylamine/methyl tertiary butyl ether=1/1 of 3000kg in still; In water, add 6000kg ethanol to separate out solid, centrifugation obtains 1200kg VITMAIN B1 phosphate monoester crude product; 1200kg VITMAIN B1 phosphate monoester crude product is mixed after making beating in 6000kg water, be cooled to 0～5 ℃, in this temperature range, drip pH value to 8.0～10.0 of liquid caustic soda regulation system; After PH has adjusted, guarantee to drip in 10～25 ℃ of reactor temperatures the Benzoyl chloride of 1200kg, be added dropwise to complete rear insulation to having reacted; Filter, filtrate adjusts pH value to 3.5～4.0 to separate out solid, separates and dry to obtain white solid 1230kg, is benfotiamine.Yield: 79.31%, purity: 98.60%.
Claims (8)
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, after having reacted, be hydrolyzed, 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 water making beating, adjusts PH after alkalescence with liquid caustic soda, finally reacts with Benzoyl chloride, filters, and filtrate adjusts pH value to 3.5～4.0 to separate out solid, separates and dry to obtain white solid, is benfotiamine.
2. the production method of benfotiamine according to claim 1, is characterized in that: concrete step is:
1) when polyphosphoric acid reacts with VITMAIN B1, temperature of reaction is 80-130 ℃, 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 adds water after complete and 80-120 ℃ of hydrolysis, hydrolysis time is 2-10 hour, and 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, removal top layer phosphoric acid, makes 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 when liberating vitamin B1 phosphate monoester crude product organic solvent 2, its add-on be VITMAIN B1 raw material weight 5-7 doubly;
5) the crude product direct water making beating of not purifying, at 0-5 ℃, adjust pH value to 8.0-14.0 with liquid caustic soda, 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 oven dry obtain white solid, are benfotiamine; The 1-2 that wherein consumption of Benzoyl chloride is VITMAIN B1 doubly.
3. the production method of benfotiamine according to claim 1 and 2, is characterized in that: the temperature of reaction of described polyphosphoric acid and VITMAIN B1 is 100-120 ℃, and the reaction times is 5-6 hour.
4. the production method of benfotiamine according to claim 1 and 2, is characterized in that: the time of described hydrolysis reaction is 4-6 hour.
5. the production method of benfotiamine according to claim 2, 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, and the weight ratio of trioctylamine and organic solvent 1 is 1:2-5.
6. the production method of benfotiamine according to claim 2, is characterized in that: the weight ratio of described trioctylamine and organic solvent 1 is 1:3-4.
7. the production method of benfotiamine according to claim 2, is characterized in that: described organic solvent 2 is one or several the mixture in methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), dioxane.
8. the production method of benfotiamine according to claim 2, is characterized in that: step 1)-3) in solvent recyclable recycling after treatment; The mother liquor of the VITMAIN B1 phosphate monoester crude product of separating in step 4) can reclaim organic solvent and recycle.
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| CN109111478A (en) * | 2017-06-26 | 2019-01-01 | 上海日馨生物科技有限公司 | Benfotiamine derivative, preparation method and its pharmaceutical composition |
| WO2020108480A1 (en) * | 2018-11-28 | 2020-06-04 | 上海日馨生物科技有限公司 | Thiamine compounds, preparation method, and pharmaceutical composition thereof |
| WO2020108478A1 (en) * | 2018-11-28 | 2020-06-04 | 上海日馨生物科技有限公司 | Thiamine compound, preparation method and pharmaceutical composition thereof |
| CN111233927A (en) * | 2018-11-28 | 2020-06-05 | 上海日馨生物科技有限公司 | Thiamine compound, preparation method and pharmaceutical composition thereof |
| CN112479960A (en) * | 2020-12-12 | 2021-03-12 | 弘健制药(上海)有限公司 | Vitamin D3Purification method of (2) |
| 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 |
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| CN109111478A (en) * | 2017-06-26 | 2019-01-01 | 上海日馨生物科技有限公司 | Benfotiamine derivative, preparation method and its pharmaceutical composition |
| JP2022511468A (en) * | 2018-11-28 | 2022-01-31 | 上海日馨医▲薬▼科技股▲分▼有限公司 | Thiamine compound, production 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 |
| CN111233927A (en) * | 2018-11-28 | 2020-06-05 | 上海日馨生物科技有限公司 | Thiamine compound, preparation method and pharmaceutical composition thereof |
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| JP7534814B2 (en) | 2018-11-28 | 2024-08-15 | 上海日馨医▲薬▼科技股▲分▼有限公司 | Thiamine compounds, production methods and pharmaceutical compositions thereof |
| JP7307979B2 (en) | 2018-11-28 | 2023-07-13 | 上海日馨医▲薬▼科技股▲分▼有限公司 | Thiamin compound, manufacturing method and pharmaceutical composition thereof |
| CN111233925A (en) * | 2018-11-28 | 2020-06-05 | 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 |
| WO2020108480A1 (en) * | 2018-11-28 | 2020-06-04 | 上海日馨生物科技有限公司 | Thiamine compounds, preparation method, and pharmaceutical composition thereof |
| US11591354B2 (en) | 2018-11-28 | 2023-02-28 | Shanghai Raising Pharmaceutical Co., Ltd. | 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 |
| US11820787B2 (en) | 2019-08-23 | 2023-11-21 | Shanghai Raising Pharmaceutical Co., Ltd. | Benfotiamine derivatives in the treatment of alzheimer's disease |
| 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) |
| CN112479960A (en) * | 2020-12-12 | 2021-03-12 | 弘健制药(上海)有限公司 | Vitamin D3Purification method of (2) |
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