CN102911208A - Method for synthesizing benfotiamine - Google Patents
Method for synthesizing benfotiamine Download PDFInfo
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- CN102911208A CN102911208A CN2012103586523A CN201210358652A CN102911208A CN 102911208 A CN102911208 A CN 102911208A CN 2012103586523 A CN2012103586523 A CN 2012103586523A CN 201210358652 A CN201210358652 A CN 201210358652A CN 102911208 A CN102911208 A CN 102911208A
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Abstract
The invention relates to a method for synthesizing benfotiamine, in particular to a process for synthesizing benfotiamine which is an anti-diabetic medicament by the phosphorylation of thiamine which severs as the raw material, the opening of the thiazole ring and the reaction of multiple steps. Benfotiamine is subjected to phosphorylation under the control of appropriate temperature and other conditions in a short time by taking phosphorus oxychloride as a phosphorylation reagent to obtain monophosphothiamine, and finally the steps of ring opening and benzoylation are carried out to obtain benfotiamine. The process has the advantages of high conversion rate of raw materials, low-cost, high product purity and greatly reduced production cycle and is suitable for industrial production.
Description
Technical field
The invention belongs to the organic compound preparation process amelioration, be specifically related to the synthetic method of a kind of benfotiamine (Benfotiamine).
Background technology
Benfotiamine (Benfotiamine) is the fat-soluble derivant of VitB1, is a kind of synthetic VITMAIN B1 derivative, and is slightly water-soluble.The sixties in 20th century is synthetic in Japan, begins to be applied to gradually treat neuropathy, sciatica and other neuropathic pains that alcoholism causes after 1962.Since the nineties in 20th century, European scholar is launching a series of researchs to VitB1 especially benfotiamine aspect Prevention diabetes and the complication thereof, and is making remarkable progress in recent years.This medicine uses the treatment various diseases more than ten years in Europe, comprises the nervous lesion relevant with diabetes.Benfotiamine is researched and developed by the Akira of Japanese firm, the chemistry of benfotiamine is by name: S-[2-[[(4-amino-2-methyl-5-pyrimidinyl) methyl] formylamino]-1-[2-(phosphonooxy) ethyl]-1-propenyl] ester, the structural formula of benfotiamine is as follows:
Benfotiamine (Benfotiamine)
Outside benfotiamine and water-soluble (vitamin) B 1 are different, be to have on the structure thiazole ring of an opening, be formed with in vivo the VITMAIN B1 of physiologically active by ring closure.After benfotiamine is oral, the dephosphorylation effect occuring in gi tract, form a lipophilic molecules, is easy to diffuse into cytolemma, thereby than water-soluble (vitamin) B 1 easier absorption.Compare with VITMAIN B1 itself, this lipotropy make its in intestines and target organ in absorb more.After absorption entered cell, the benfotiamine of dephosphorylation was closed thiazole ring by intracellular sulfhydryl compound and/or debenzoylation enzyme catalysis reduction, discharges active vitamin B1 and enters cell and the recycle system.
At present, the scholar is arranged through a large amount of cell experiments and give to point out after the research such as the oral benfotiamine of STZ diabetes rat, benfotiamine is by the activating phosphatase pentose pathway, reduce the generation of meta-bolites fructose-1, 6-diphosphate, glyceraldehyde 3-phosphate etc., thereby the abnormal metabolism approach such as blocking-up DAG-PKG approach, hexosamine approach, polyol pathway and AGEs formation, the retina blood capillary endothelial cells loss that tissue causes because of hyperglycemia.More there are some researches show, after giving the oral VitB1 of STZ diabetes rat and benfotiamine, find that proteinuria generates obviously attenuating.Especially find, benfotiamine can obviously suppress the renal glomerulus ultrafiltration that diabetes cause, further prove VitB1 and benfotiamine and can reduce the apoptosis of vascular endothelial cell and pericyte, nearest research also shows, the blood fat disorder of heavy dose of benfotiamine reversible STZ diabetes rat is saved STZ diabetes myocardial cell's contractility etc.
Diabetes can cause two types of retinopathies---proliferative and non-proliferative retinopathy.Diabetic retinopathy is one of main blinding disease.No matter whether use of exogenous insulin, all occurrence of diabetes retinopathy.The diabetes impairs retina increases mainly due to blood sugar, and little vascular wall thickens, and perviousness increases, and makes the more yielding and seepage of little blood vessel.The seriousness of diabetic retinopathy is relevant with glucose level control situation and trouble diabetes time length with the degree of visual deterioration.Sick time length is particularly important, generally suffers from diabetes and just diabetic retinopathy can occur after at least ten years.At non-proliferative (simple form) retinopathy, the little blood vessel of retina breaks and seepage.In each capillary rupture part of expanding, form a folliculus that has haemproteins to precipitate.The doctor can find these pathologies according to fundoscopy.Fluorescein angiography (a kind of diagnostic method, the doctor treats that in patient's intravenous injection dyestuff dyestuff carries out eye-ground photography when arriving retina with blood) helps to determine lesion degree.Getting up early non-proliferative retinopathy can not cause visual deterioration, if but the hemorrhage hemorrhage macula area that involves of local field of view loss that causes of retina small pieces, eyesight obviously descends.At proliferative retinopathy, retinal damage stimulates neovascularization growth.Neovascularization growth does harm rather than good retina.Compare with the non-proliferative retinopathy, proliferative retinopathy is larger to the hazardness of eyesight, and it can cause severe visual to descend even be as blind as a bat.
There is recently one about growth and the apoptotic impact research of benfotiamine on the bovine retina capillary endothelial cell cultivated in the sugared environment of external height.The research shows that certain density benfotiamine can reduce high sugar to the restraining effect of bovine retina capillary endothelial cell growth, and is the concentration dependency.The OD value difference is different when concentration is 75Lmol/L a statistical significance (P＜0101).The flow cytometry technology shows that the benfotiamine of 75Lmol/L can obviously reduce the apoptosis of bovine retina capillary endothelial cell.So certain density benfotiamine can be described the bovine retina capillary endothelial cell of cultivating in the sugared environment of external height is had significant protective effect, its mechanism may be that benfotiamine can reduce apoptosis.The small capillary vessel infringement of diabetic retina.If the retina disease damage is to late period, new abnormal vascular will be grown at retina, if untimely treatment can cause losing one's sight.Current research shows that benfotiamine also has remarkable effect to the treatment senile dementia.
The synthetic method of the benfotiamine of bibliographical information (US 3064000A, GB 1092664A, GB 896089A) all relates to the process that the VitB1 Phosphation generates Vitamin B1 Phosphate, in the method for reporting, all adopting tetra-sodium is Phosphation reagent, 100 ℃ of lower reactions, after reaction is finished the hydroxyl of VitB1 and disconnected be monophosphate but tetra-sodium need to place acidic aqueous solution with product, and at room temperature place about 1 week, tetra-sodium is decomposed into monophosphate gradually, forms Vitamin B1 Phosphate.The method needs at high temperature reaction, and reacts with VitB1 after phosphoric acid need being heated to 270 ℃ of formation tetra-sodiums, and this process need high temperature expends mass energy.And high temperature is had higher requirement to whole production unit.Need room temperature to place about 1 week after reaction is finished, increased greatly the production cycle, reduced production efficiency, and need to re-start processing to reaction product, concentrated recrystallization etc. have increased processing step, and produced a large amount of acidic industrial effluents, contaminate environment.
It is Phosphation reagent that the present invention adopts phosphorus oxychloride, phosphorus oxychloride is a kind of common industrial raw material, it is cheap, reactive behavior is high, it is comparatively gentle that reaction has condition, and the Vitamin B1 Phosphate purity that generates after the reaction is high, does not need aftertreatment can put into subsequent reactions, greatly shorten the preparation time of Vitamin B1 Phosphate, greatly improved production efficiency.
Summary of the invention
The object of the invention is to provide a kind of with short production cycle, low in the pollution of the environment, simple process, is easy to the synthetic method of suitability for industrialized production benfotiamine.Benfotiamine is a kind of diabetes complicated disease drug that prevents and treat.
The synthetic method of the benfotiamine that the present invention proposes; synthesis technique through number step reaction preparation antidiabetic medicine benfotiamines such as Phosphation, thiazole ring open loops; be Phosphation reagent with phosphorus oxychloride; under the suitable conditions such as temperature control; short period of time is interior with raw material VitB1 Phosphation; obtain Vitamin B1 Phosphate, obtain benfotiamine by steps such as open loop, benzoylations at last.
It is Phosphation reagent that the present invention adopts phosphorus oxychloride, and the Vitamin B1 Phosphate purity that generates after the reaction is high, does not need aftertreatment can carry out open loop and benzoylation reaction.Its reaction scheme is as follows:
Concrete steps are as follows:
In reactor, add solvent, under condition of ice bath, add phosphorus oxychloride, return to stirring at room 0.5-2 hour after adding, the Phosphation reagent that obtains configuring, the mol ratio 0.1:1-1:10 of phosphorus oxychloride and solvent; VitB1 is joined in the Phosphation reagent that configures in batches, carried out phosphating reaction 1-24 hour under-10-150 ℃ temperature, reaction obtains yellow oily liquid after finishing, and is cooled to room temperature and obtains the Vitamin B1 Phosphate crude product; Dissolved phosphorus thiamines crude product, then the pH value of regulator solution adds subsequently Benzoyl chloride and continued to stir 1-12 hour to alkalescence, temperature is controlled at 0-5 ℃, filtration after reaction is finished, filtrate is concentrated after, regulate the pH value to 3.5-4.0, recrystallization obtains white solid, obtains the products benzene Vitamin B1 Phosphate.
Among the present invention, described phosphating reaction temperature is 25-100 ℃, and the reaction times is 1-3 hour.
Among the present invention, described solvent is water, acetone, methyl alcohol, ethanol, acetic acid DMSO, DMA, dioxane or acetonitrile and any solvent that can dissolve each other with water.
Among the present invention, the mol ratio of VitB1 and phosphorus oxychloride is 0.1:1-1:1 in the described phosphating reaction.
Among the present invention, the mol ratio of Phosphation reagent phosphorus oxychloride and solvent is 1:1-1:5 in the described phosphating reaction.
Among the present invention, the pH value of regulator solution to alkalescence adopts sodium hydroxide.
It is Phosphation reagent that the present invention adopts phosphorus oxychloride, phosphorus oxychloride is a kind of common industrial raw material, it is cheap, reactive behavior is high, it is comparatively gentle that reaction has condition, and the Vitamin B1 Phosphate purity that generates after the reaction is high, does not need aftertreatment can put into subsequent reactions, greatly shorten the preparation time of Vitamin B1 Phosphate, improved production efficiency.
Embodiment
The present invention is described in further detail below in conjunction with embodiment, but the present invention is not done any restriction.
Embodiment 1: with phosphorus oxychloride 15.33g(0.1mol) join in the 10.8mL water, place under the ice bath and stirred 0.5 hour, add VitB1 26.53g(0.1mol) in batches, being warming up to subsequently 50 ℃ stirred 2 hours, be cooled to room temperature, obtain Vitamin B1 Phosphate solution, Vitamin B1 Phosphate HPLC content is 91.36%, regulate this pH value of solution to 8-9 with 15% NaOH solution, add 28.11g(0.2mol) Benzoyl chloride, 0-5 ℃ of lower the stirring, and the variation of monitoring reaction liquid pH, stabilizing solution pH value, pH no longer changes when reaction solution, continues stirring reaction after 1 hour, and pH value of solution is adjusted to 3.5-4.0, suction filtration obtains 33.58g benfotiamine white solid.Yield 71.9%.
MP:164-165℃;?H
1?NMR(400MHz
,CDCl
3)?:2.18(s，3H)?，2.56?(s，3H)?，?2.58?(t，
J=6.7，2H)?，4.33?(t，
J=6.7，2H?)?，?4.83?(s，2H)?，7.44?(m，2H)?，?7.57?(dd，
J=7.3?,?
J=1.5,1H)?，?7.60?(m，2H)?，?7.70(s，1H)?，8.67?(s，1H)。
Embodiment 2: with phosphorus oxychloride 15.33g(0.1mol) join in the 7.2mL water, place under the ice bath and stirred 0.5 hour, add VitB1 21.23g(0.08mol) in batches, being warming up to subsequently 60 ℃ stirred 2 hours, be cooled to room temperature, obtain Vitamin B1 Phosphate solution, Vitamin B1 Phosphate HPLC content is 92.37%, regulate this pH value of solution to 8-9 with 15% NaOH solution, add 28.11g(0.2mol) Benzoyl chloride, 0-5 ℃ of lower the stirring, and the variation of monitoring reaction liquid pH, stabilizing solution pH value, pH no longer changes when reaction solution, continues stirring reaction after 1 hour, and pH value of solution is adjusted to 3.5-4.0, suction filtration obtains 27.69g benfotiamine white solid.Yield 74.2%.
MP:164-165℃;H
1?NMR(400MHz
,CDCl
3)?:2.18(s，3H)?，2.56?(s，3H)?，?2.58?(t，
J=6.7，2H)?，4.33?(t，
J=6.7，2H?)?，?4.83?(s，2H)?，7.44?(m，2H)?，?7.57?(dd，
J=7.3?,?
J=1.5,1H)?，?7.60?(m，2H)?，?7.70(s，1H)?，8.67?(s，1H)。
Embodiment 3: with phosphorus oxychloride 15.33g(0.1mol) join in the 3.6mL water, place under the ice bath and stirred 0.5 hour, add VitB1 15.92g(0.06mol) in batches, being warming up to subsequently 70 ℃ stirred 2 hours, be cooled to room temperature, obtain Vitamin B1 Phosphate solution, Vitamin B1 Phosphate HPLC content is 93.23%, regulate this pH value of solution to 8-9 with 15% NaOH solution, add 28.11g(0.2mol) Benzoyl chloride, 0-5 ℃ of lower the stirring, and the variation of monitoring reaction liquid pH, stabilizing solution pH value, pH no longer changes when reaction solution, continues stirring reaction after 1 hour, and pH value of solution is adjusted to 3.5-4.0, suction filtration gets benfotiamine white solid 23.71g.Yield 84.7%.
MP:164-165℃;H
1?NMR(400MHz
,CDCl
3)?:2.18(s，3H)?，2.56?(s，3H)?，?2.58?(t，
J=6.7，2H)?，4.33?(t，
J=6.7，2H?)?，?4.83?(s，2H)?，7.44?(m，2H)?，?7.57?(dd，
J=7.3?,?
J=1.5,1H)?，?7.60?(m，2H)?，?7.70(s，1H)?，8.67?(s，1H)。
Embodiment 4: with phosphorus oxychloride 15.33g(0.1mol) join in the 7.2mL water, place under the ice bath and stirred 0.5 hour, add VitB1 10.62g(0.04mol) in batches, being warming up to subsequently 80 ℃ stirred 2 hours, be cooled to room temperature, obtain Vitamin B1 Phosphate solution, Vitamin B1 Phosphate HPLC content is 95.26%, regulate this pH value of solution to 8-9 with 15% NaOH solution, add 28.11g(0.2mol) Benzoyl chloride, 0-5 ℃ of lower the stirring, and the variation of monitoring reaction liquid pH, stabilizing solution pH value, pH no longer changes when reaction solution, continues stirring reaction after 1 hour, and pH value of solution is adjusted to 3.5-4.0, suction filtration gets benfotiamine white solid 15.22g.Yield 85.2%.
MP:164-165℃;H
1?NMR(400MHz
,CDCl
3)?:2.18(s，3H)?，2.56?(s，3H)?，?2.58?(t，
J=6.7，2H)?，4.33?(t，
J=6.7，2H?)?，?4.83?(s，2H)?，7.44?(m，2H)?，?7.57?(dd，
J=7.3?,?
J=1.5,1H)?，?7.60?(m，2H)?，?7.70(s，1H)?，8.67?(s，1H)。
Claims (6)
1. the synthetic method of a benfotiamine is characterized in that synthetic route is as follows:
Concrete steps are as follows:
In reactor, add solvent, under condition of ice bath, add phosphorus oxychloride, return to stirring at room 0.5-2 hour after adding, the Phosphation reagent that obtains configuring, the mol ratio 0.1:1-1:10 of phosphorus oxychloride and solvent; VitB1 is joined in the Phosphation reagent that configures in batches, carried out phosphating reaction 1-24 hour under-10-150 ℃ temperature, reaction obtains yellow oily liquid after finishing, and is cooled to room temperature and obtains the Vitamin B1 Phosphate crude product; Dissolved phosphorus thiamines crude product, then the pH value of regulator solution adds subsequently Benzoyl chloride and continued to stir 1-12 hour to alkalescence, temperature is controlled at 0-5 ℃, filtration after reaction is finished, filtrate is concentrated after, regulate the pH value to 3.5-4.0, recrystallization obtains white solid, obtains the products benzene Vitamin B1 Phosphate.
2. synthetic method according to claim 1 is characterized in that described phosphating reaction temperature is 25-100 ℃, and the reaction times is 1-3 hour.
3. synthetic method according to claim 1 is characterized in that described solvent is water, acetone, methyl alcohol, ethanol, acetic acid DMSO, DMA, dioxane or acetonitrile and any solvent that can dissolve each other with water.
4. synthetic method according to claim 1 is characterized in that the mol ratio of VitB1 and phosphorus oxychloride is 0.1:1-1:1 in the described phosphating reaction.
5. synthetic method according to claim 1 is characterized in that the mol ratio of Phosphation reagent phosphorus oxychloride and solvent is 1:1-1:5 in the described phosphating reaction.
6. synthetic method according to claim 1 is characterized in that pH value to the alkalescence of regulator solution adopts sodium hydroxide.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772432A (en) * | 2014-01-03 | 2014-05-07 | 湖北瑞锶科技有限公司 | Production method of benfotiamine |
| CN105285504A (en) * | 2015-11-20 | 2016-02-03 | 南京农业大学 | Regulation composition for improving fish body sugar tolerance, preparation method and application thereof |
| 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 |
| 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 |
| CN112611819A (en) * | 2020-12-30 | 2021-04-06 | 南京正济医药研究有限公司 | Method for measuring related substances in benfotiamine raw material and preparation thereof |
| CN112778366A (en) * | 2020-12-29 | 2021-05-11 | 江苏正济药业股份有限公司 | Benfotiamine related substance, preparation method, application and detection method |
| CN112778367A (en) * | 2020-12-29 | 2021-05-11 | 江苏正济药业股份有限公司 | Benfotiamine related substance, preparation method, application and detection method |
| CN112778357A (en) * | 2020-12-29 | 2021-05-11 | 南京友杰医药科技有限公司 | Benfotiamine related substance, preparation method, application and detection method thereof |
-
2012
- 2012-09-25 CN CN2012103586523A patent/CN102911208A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| MOTOJI ASAI, ET AL.: "A Synthetic Method of S-benzoylthiamine O-monophosphate", 《高峰研究所年报》, vol. 13, 31 December 1961 (1961-12-31), pages 45 - 47, XP008179308 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772432A (en) * | 2014-01-03 | 2014-05-07 | 湖北瑞锶科技有限公司 | Production method of benfotiamine |
| CN103772432B (en) * | 2014-01-03 | 2016-01-20 | 湖北瑞锶科技有限公司 | A kind of production method of benfotiamine |
| CN105285504A (en) * | 2015-11-20 | 2016-02-03 | 南京农业大学 | Regulation composition for improving fish body sugar tolerance, preparation method and application thereof |
| CN105285504B (en) * | 2015-11-20 | 2019-02-26 | 南京农业大学 | A kind of regulatory composition and the preparation method and application thereof improving fish body sugared tolerance |
| 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 |
| CN109111478B (en) * | 2017-06-26 | 2021-02-26 | 上海日馨生物科技有限公司 | Benfotiamine derivative, 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 |
| CN112778366A (en) * | 2020-12-29 | 2021-05-11 | 江苏正济药业股份有限公司 | Benfotiamine related substance, preparation method, application and detection method |
| CN112778367A (en) * | 2020-12-29 | 2021-05-11 | 江苏正济药业股份有限公司 | Benfotiamine related substance, preparation method, application and detection method |
| CN112778357A (en) * | 2020-12-29 | 2021-05-11 | 南京友杰医药科技有限公司 | Benfotiamine related substance, preparation method, application and detection method thereof |
| CN112611819A (en) * | 2020-12-30 | 2021-04-06 | 南京正济医药研究有限公司 | Method for measuring related substances in benfotiamine raw material and preparation thereof |
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Application publication date: 20130206 |