CN103304563A - Method for efficiently synthesizing vinpocetine from vincamine - Google Patents
Method for efficiently synthesizing vinpocetine from vincamine Download PDFInfo
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- CN103304563A CN103304563A CN2013102383846A CN201310238384A CN103304563A CN 103304563 A CN103304563 A CN 103304563A CN 2013102383846 A CN2013102383846 A CN 2013102383846A CN 201310238384 A CN201310238384 A CN 201310238384A CN 103304563 A CN103304563 A CN 103304563A
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Abstract
The invention relates to a method for efficiently synthesizing vinpocetine from vincamine. The method is used for preparing the vinpocetine by three steps of reactions including vincamine hydrolysis, dehydration-acylating chlorination and esterification. In the method, a catalyst adopted in the vincamine hydrolysis reaction is strong base KOH or NaOH, a catalyst for the vincamine acid dehydration-acylating chlorination reaction is phosphorus oxychloride, and a catalyst for the esterification reaction between the acyl chloride compound and ethanol is sodium ethoxide or triethylamine. According to the method provided by the invention, Lewis acid phosphorus oxychloride is used as a catalysis-dehydration agent, the dehydration and acylating chlorination are finished by one-step coupling, and then the vinpocetine is prepared through the esterification reaction between the acyl chloride compound and ethanol; additional dehydration treatment is not required in the reaction, the efficiency of the dehydration and esterification reaction is high, and the product yield is over 90%; and the method is simple and convenient to operate and has better prospects in industrial application and development.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, it relates to a kind of method by the synthetic vinpocetin of vincamine high-level efficiency.
Background technology
Vinpocetin (Fig. 1) is a kind of alkaloid---derivative of vincamine that separates that extracts from the apocynaceae plant periwinkle.This compound is by the research and development of Hungarian Gedeon Richter pharmaceutical companies and in listing in 1978 the earliest, has become clinically one of disease that treatment ishemic stroke and other cause by cerebrovascular disease and first-line drug of prevention at present.It has the little blood vessel of expansion brain, improves brain to the utilization ratio of blood oxygen, improves the effect of cerebral circulation.Can also suppress platelet aggregation in addition, reduce human blood viscosity, strengthen erythrocyte deformabiliy, improve blood fluidity and microcirculation, promote the cerebral tissue ingestion of glucose, increase the brain oxygen-consumption, improve the brain metabolism.Clinical in cerebral embolism, cerebral blood supply insufficiency and apoplexy sequela etc.To cerebral arteriosclerosis, vestibular vascular disorder, retinal hemorrhage and early metaphase hypertension etc. also have certain curative effect.
The vinpocetin of using clinically at present is mainly derived from the semi-synthetic of vincamine.Reactions steps by the synthetic vinpocetin of vincamine is less, generally need through hydrolysis, dehydration and three principal reaction steps of transesterify, all literature methods mainly concentrate on hydrolysis, dehydration and transesterification steps combination, dewatering agent, esterifying catalyst are selected, and the aspect such as reaction condition optimization.But in the existing method, be suitable for the less of large-scale production, mainly contain following several about its semi-synthetic route:
1) method one (first hydrolysis, rear dehydration-esterification process): the method is take vincamine as raw material, and dehydrated alcohol is solvent, obtains the Changchun amino acid under the catalysis of the highly basic such as KOH or NaOH.Then, with dense H
2SO
4For dewatering agent and catalyst for esterification reaction obtain the product vinpocetin with Changchun amino acid and ethanol synthesis.The advantage of the method is that the raw material that uses is the chemical that is easy to get, and each operation steps is conventional, easily grasps.But there is obvious shortcoming in the method: 1) dense H
2SO
4Have oxidisability, if concentration is little, dehydration and absorption moisture content weak effect if concentration is high, are easy to make Changchun propylhomoserin oxidation; 2) this esterification is balanced reaction, must take the measure of dewatering in the reaction, otherwise, react not thorough.So this method total yield is low, production cost is high, is not suitable for production application;
2) method two (dehydration-esterification one kettle way): the method is from the amino acid of Changchun, take the second eyeball as solvent, 2-fluoro-1,3,5-trinitrobenzene (FTNB) and DMAP (DMAP) are catalyzer, finish with the dehydration of Changchun amino acid with one step of esterification of ethanol, thus the preparation vinpocetin.The method prepares the step of Changchun propylhomoserin with method one, and the reaction yield that is prepared vinpocetin by the Changchun propylhomoserin is higher.But its used FTNB/ DMAP catalyzer is rare, and cost is high; And it is very large to make solvent toxicity with acetonitrile, is unsuitable for large-scale production;
3) method three (Lewis acids dehydration, ester-interchange method): the method is utilized the transesterify of two Lewis acid coupling and catalyzings and dehydration reaction take vincamine as starting raw material.The first step is ZnCl
2Catalysis vincamine and ethanol carry out transesterify, generate the ethyl vincamine; Second step is that the ethyl vincamine is at AlCl
3Dewater under the catalysis, thereby generate vinpocetin.The method yield is higher, and raw material is easy to get.But the method has been used two Louis acid catalysis reactions, and ZnCl
2, AlCl
3Be difficult to aborning process; complex operation; therefore be unsuitable for large-scale production; this seminar has developed the novel method of the synthetic vinpocetin of a kind of vincamine; the method is take the Lewis acid phosphorus oxychloride as catalysis-dewatering agent; to dewater and finish with one step of chloride, then Changchun amino acid and the ethanol by chloride carries out esterification, thereby has synthesized vinpocetin.The method need not to add except water treatment, and dehydration and esterification efficient are high, and efficiency of pcr product improves (90% 〉=) greatly, and easy and simple to handle, is suitable for the industrial-scale production needs.
Summary of the invention
The present invention relates to a kind of novel method by the synthetic vinpocetin of vincamine high-level efficiency.The method synthetic route is Fig. 2;
Concrete preparation process is as follows:
1. the Changchun amino acid is synthetic
In there-necked flask, add 35 g potassium hydroxide and 800～1100 ml dehydrated alcohols, 60～80 ℃ of lower stirrings are all dissolved potassium hydroxide, then 71 g vincamines are added in the there-necked flask heated and stirred reaction 4～6 hours, the reaction of thin-layer silicon offset plate, after question response is finished, change the hot water in the water-bath into cold water, stirring slowly splashes into glacial acetic acid after making the reaction solution cooling, with pH test paper monitoring pH value, until pH is 5～6.Leave standstill for some time, filter out crystal, wash once with appropriate amount of deionized water (300～400 ml) bubble, pure water drip washing, oven dry namely gets Changchun amino acid 68.8g;
Control of reaction end point:
［ TLC ］ gel GF 254 plate, developping agent are chloroform: methyl alcohol=10:1, develop the color the point of raw material should disappear (Rf=0.7) under fluorescence 254 nm
Product quality control:
［ proterties ］ white crystal
［ fusing point ］ 262～266 ℃
［ TLC ］ silica gel G F
254Plate, developping agent are that chloroform: methyl alcohol=2:1(adds 2 glacial acetic acids), iodine smokes colour developing, should be single point (Rf=0.3)
2. vinpocetin is synthetic
Take by weighing 110 g Changchun amino acids and pack in the there-necked flask, measure ethylene dichloride 1500～2000 ml, phosphorus oxychloride 200～500 ml add in the bottle, connect prolong and drying tube, adjust the temperature to 60～70 ℃, heated and stirred reaction 6～7 hours, silica gel thin-layer is followed the tracks of reaction.After reaction is finished, the concentrating under reduced pressure solvent is to a small amount of, concentrated solution changes three mouthfuls of reaction flasks over to, open magnetic agitation, slowly splash into dehydrated alcohol 300～500 ml and carry out esterification, drip off rear restir 30～40 minutes, the triethylamine solution with the dehydrated alcohol preparation with 40～60%, or the ethanolic soln of 50～60% sodium ethylates, constant voltage splashes in the there-necked flask, and pH detects until 8, continues stirring 30～40 minutes after mixing up pH value, the solid-liquid mixed solution is concentrated into dried, wash droplet 2～3 times (approximately 1500 ml) with 3～5% sodium carbonate solution, overanxious, solid dissolves with two ethane of 500～600 ml, adding 200～300 ml pure water are washed and are dripped twice, separatory, ethylene dichloride is evaporated to dried, washes out with ethanol, crystallisation by cooling filters to get the vinpocetin coarse-grain.Water extracts with ethylene dichloride again, and concentrating under reduced pressure ethylene dichloride, resistates are put the refrigerator freezing crystallization after washing out with ethanol, filters, and crystal that will be close with above-mentioned color merges;
3. vinpocetin is refining
Above-mentioned vinpocetin coarse-grain dissolves with a small amount of ethylene dichloride, and the G4 sand core funnel filters, and filtrate is concentrated into crystal and begins to separate out, and adds stirrer and stirs cooling crystallization, filters, and liquid is condensing crystal repeatedly.Re-crystallization step is with a recrystallization for the second time, and last, crystal is used hot ethanol stirring and dissolving 30～40 minutes, filters, and uses the ethanol drip washing of one times of crystal volume again, and 60～80 ℃ of dryings namely get very pure vinpocetin product;
Control of reaction end point:
［ TLC ］ gel GF 254 plate, developping agent are that chloroform: methyl alcohol=2:1(adds 2 glacial acetic acids), iodine smokes colour developing, raw material point should disappear (Rf=0.3);
Product quality control:
［ proterties ］ white crystalline powder
［ specific optical rotation ］+39.0～+ 43.5 ° (pyridine, 10 mg/ml)
［ TLC ］ silica gel G F
254Plate, developping agent are chloroform: methyl alcohol=10:1, develop the color under fluorescence 254 nm, should be single point (Rf=0.6).
The present invention compares with existing vinpocetin preparation method and has the following advantages and outstanding effect:
(1) present method is take the Lewis acid phosphorus oxychloride as dewatering agent with the acylating agent of Changchun propylhomoserin, and dehydration and acidylate efficient are high, almost quantitative reaction; One step was finished dehydration and acylation process simultaneously, had simplified reactions steps;
(2) product after the used dewatering agent phosphorus oxychloride of present method is decomposed is phosphoric acid and hydrochloric acid, and they are easy to process, can not retain in the product, and after neutralization, environmentally safe;
(3) the inventive method efficiency of pcr product is high, and is easy and simple to handle, and quality product meets the European Pharmacopoeia requirement.Present method is suitable for suitability for industrialized production.
Description of drawings
The structure of Fig. 1 vinpocetin.
The route schematic diagram of the synthetic vinpocetin of Fig. 2 vincamine.
Embodiment
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
Embodiment 1
In there-necked flask, add 35 g potassium hydroxide and 800 ml dehydrated alcohols, 60 ℃ of lower stirrings are all dissolved potassium hydroxide, then 71 g vincamines are added in the there-necked flask heated and stirred reaction 4.5 hours, the reaction of thin-layer silicon offset plate, after question response is finished, change the hot water in the water-bath into cold water, stirring slowly splashes into glacial acetic acid after making the reaction solution cooling, with pH test paper monitoring pH value, until pH is 6.Leave standstill for some time, filter out crystal, an amount of 300 ml deionization bubbles are washed once, and Changchun amino acid 68g is dried to get in pure water drip washing.
Embodiment 2
Take by weighing 110 g Changchun amino acids and pack in the there-necked flask, measure ethylene dichloride 1600 ml, phosphorus oxychloride 300 ml add in the bottle, connect prolong and drying tube, adjust the temperature to 70 ℃, heated and stirred reaction 7 hours, and silica gel thin-layer is followed the tracks of reaction.The concentrating under reduced pressure solvent was to a small amount of after reaction was finished, and concentrated solution changes there-necked flask over to, opened magnetic agitation, slowly splashed into dehydrated alcohol 400 ml, dripped off rear restir 30 minutes.Be about 60% with dehydrated alcohol dilution triethylamine, constant pressure funnel slowly splashes into there-necked flask, and pH test paper monitoring pH value is until the pH value is 8.Continue to stir 30 minutes after mixing up pH value.The solid-liquid mixed solution is poured concentrated bottle into, is concentrated into driedly, washes 2 times (approximately 1500 ml) with 3% yellow soda ash water liquid and crosses the crystal ethylene dichloride and dissolve (500 ml) pure water and wash twice, each 200 ml wash rear concentrated ethylene dichloride to doing, and ethanol washes out, the vinpocetin primary crystal is filtered to get in crystallization.Buck extracts with ethylene dichloride, puts the refrigerator freezing crystallization after concentrated dried ethylene dichloride washes out with ethanol, and the crystal close with color merges.Vinpocetin recrystallization a: recrystallization: the vinpocetin primary crystal filters with ethylene dichloride dissolving G4 sand core funnel, and concentrated ethylene dichloride to crystal is separated out, and takes off, and adds stirrer and stirs cooling crystallization, filters, and liquid is condensing crystal repeatedly.Secondary recrystallization: step is with a recrystallization, and last crystal is invaded bubble with ethanol and stirred filtration in 30 minutes, the drip washing of one times of crystal volume ethanol.Dry pure vinpocetin.
Embodiment 3
Claim sodium hydroxide 14 g to add there-necked flask, add 800 milliliters of dehydrated alcohols, stir, heating 60 degree.After sodium hydroxide all dissolves, claim vincamine 36 g to add the there-necked flask heated and stirred 5 hours, thin layer plate is followed the tracks of reaction.Be cooled to room temperature after reaction is finished, slowly add glacial acetic acid, with pH test paper monitoring pH value, until pH is 6.Leave standstill for some time, filter out crystal, an amount of pure water bubble is washed once, and Changchun amino acid 35.3g is dried to get in pure water drip washing.
Embodiment 4
Take by weighing Changchun amino acid 222 g and add there-necked flask, with graduated cylinder amount ethylene dichloride 3500 ml, phosphorus oxychloride 550 ml add in the lump, connect prolong and drying tube again, and water-bath transfers to 70 ℃ of temperature, heated and stirred reaction 7 hours, and the reaction of some plate monitors extent of reaction.Turn off the water-bath heating after reaction is finished, pour concentrated bottle into, to a small amount of, concentrated solution is poured there-necked flask into the Rotary Evaporators concentrated solvent, opens magnetic agitation, slowly splashes into dehydrated alcohol 800 ml, drips off rear restir 30 minutes.With ethanol-alcohol sodium solution (concentration is 60%), constant pressure funnel slowly splashes into there-necked flask, and pH test paper monitoring pH value is until the pH value is 8.Continue to stir 30 minutes after mixing up the pH value.The solid-liquid mixed solution is poured concentrated bottle into, is concentrated into driedly, washes 2 times (approximately 3000 ml) with 5% yellow soda ash water liquid and crosses the crystal ethylene dichloride and dissolve (800 ml) pure water and wash twice, each 400 ml wash rear concentrated ethylene dichloride to doing, and ethanol washes out, the vinpocetin coarse-grain is filtered to get in crystallization.Buck extracts with ethylene dichloride, puts the refrigerator freezing crystallization after concentrated dried ethylene dichloride washes out with ethanol, and the crystal close with color merges.Vinpocetin recrystallization a: recrystallization: the vinpocetin primary crystal filters with ethylene dichloride dissolving G4 sand core funnel, and concentrated ethylene dichloride to crystal is separated out, and takes off, and adds stirrer and stirs cooling crystallization, filters, and liquid is condensing crystal repeatedly.Secondary recrystallization: step is with a recrystallization, and last crystal is invaded bubble with ethanol and stirred filtration in 30 minutes, the drip washing of one times of crystal volume ethanol.Be drying to obtain pure vinpocetin.
Claims (3)
1. method by the synthetic vinpocetin of vincamine high-level efficiency, the method comprises following characteristics: (1) building-up reactions comprises that vincamine hydrolysis preparation Changchun amino acid, Changchun amino acid dehydration-chloride prepare the acid of chloride apovincamine, and three steps of the acid of chloride apovincamine and ethyl esterification reaction preparation vinpocetin; (2) the first step hydrolysis reaction catalyst system therefor is inorganic strong alkali KOH or NaOH etc.; The catalytic reagent of second step Changchun amino acid dehydration-acylation reaction is phosphorus oxychloride; The acid of chloride apovincamine is sodium ethylate or triethylamine organic alkali with the catalyzer of ethyl esterification.
2. requiring the committed step of described method according to right 1 is the dehydration-acyl chloride reaction of Changchun amino acid, and this reacts used dehydration-acylating agent is phosphorus oxychloride, and working concentration is 20～100%(weight ratio of reaction system).
3. method as described in requiring such as right 1 is as follows by operation steps, agents useful for same, each reactant ratio and the reaction conditions of the semi-synthetic vinpocetin of vincamine:
(1) the Changchun amino acid is synthetic: add 35 g potassium hydroxide and 800～1100 ml dehydrated alcohols in there-necked flask, 60～80 ℃ of lower stirrings are all dissolved potassium hydroxide, then 71 g vincamines are added in the there-necked flask, heated and stirred reaction 4～6 hours, the reaction of thin-layer silicon offset plate, after question response is finished, change the hot water in the water-bath into cold water, after stirring makes the reaction solution cooling, slowly splash into glacial acetic acid, with pH test paper monitoring pH value, until pH is 5～6, leave standstill for some time, filter out crystal, an amount of 300～400 ml deionization bubbles are washed once, and Changchun amino acid 68.8g is dried to get in pure water drip washing;
(2) vinpocetin is synthetic: take by weighing 110 g Changchun amino acids and pack in the there-necked flask, measure ethylene dichloride 1500～2000 ml, phosphorus oxychloride 200～500 ml add in the bottle, connect prolong and drying tube, adjust the temperature to 60～70 ℃, heated and stirred reaction 6～7 hours, silica gel thin-layer is followed the tracks of reaction, after reaction is finished, the concentrating under reduced pressure solvent is to a small amount of, concentrated solution changes three mouthfuls of reaction flasks over to, open magnetic agitation, slowly splash into dehydrated alcohol 300～500 ml and carry out esterification, drip off rear restir 30 minutes, the triethylamine with the dehydrated alcohol preparation with 40～60%, or the ethanolic soln of 50～60% sodium ethylates, constant pressure funnel splashes in the there-necked flask, pH detects until 8, continue to stir 30～40 minutes after mixing up the pH value, the solid-liquid mixed solution is concentrated into dried, washes droplet 2～3 times (approximately 1500 ml) with 3～5% sodium carbonate solution overanxious, solid dissolves with two ethane of 500～600 ml, adding 200～300 ml pure water are washed and are dripped twice, separatory, and ethylene dichloride is evaporated to dried, wash out with ethanol, crystallisation by cooling filters to get the vinpocetin coarse-grain, and water extracts with ethylene dichloride again, the concentrating under reduced pressure ethylene dichloride, resistates is put the refrigerator freezing crystallization after washing out with ethanol, filters, and crystal that will be close with above-mentioned color merges;
(3) vinpocetin is refining: above-mentioned vinpocetin coarse-grain dissolves with a small amount of ethylene dichloride, and the G4 sand core funnel filters, and filtrate is concentrated into crystal and begins to separate out, add stirrer and stir cooling crystallization, filter, liquid is condensing crystal repeatedly, and re-crystallization step is with a recrystallization for the second time, at last, crystal is used hot ethanol stirring and dissolving 30～40 minutes, filters, and uses the ethanol drip washing of one times of crystal volume again, drying namely gets purer vinpocetin product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833751A (en) * | 2014-03-01 | 2014-06-04 | 张家港威胜生物医药有限公司 | Synthetic process of related impurity A of vinpocetine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058966A (en) * | 1991-08-30 | 1992-02-26 | 东北制药总厂 | The novel method of vincamine amino acid ester preparation |
| CN102040606A (en) * | 2011-01-26 | 2011-05-04 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of vinpocetine |
| CN102936247A (en) * | 2012-12-04 | 2013-02-20 | 孙新鹏 | Preparation technology of high-purity vinpocetine |
-
2013
- 2013-06-17 CN CN2013102383846A patent/CN103304563A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058966A (en) * | 1991-08-30 | 1992-02-26 | 东北制药总厂 | The novel method of vincamine amino acid ester preparation |
| CN102040606A (en) * | 2011-01-26 | 2011-05-04 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of vinpocetine |
| CN102936247A (en) * | 2012-12-04 | 2013-02-20 | 孙新鹏 | Preparation technology of high-purity vinpocetine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833751A (en) * | 2014-03-01 | 2014-06-04 | 张家港威胜生物医药有限公司 | Synthetic process of related impurity A of vinpocetine |
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Application publication date: 20130918 |