CN102617527A - Method for preparing potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate - Google Patents
Method for preparing potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate Download PDFInfo
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Abstract
The invention discloses a method for preparing potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate, which comprises that firstly, andrographolide serves as a raw material, the andrographolide reacts with succinic anhydride to produce dehydroandroan drographolide disuccinate in a specific non-pyridine solvent under the heating reflux in the presence of a catalyst, and the usage amount ratio (W/W) of the andrographolide and the catalyst is (1:10)-(1:1); and secondly, the purified dehydroandroan drographolide disuccinate reacts with potassium hydroxide, sodium hydroxide, alkalinity sylvite or alkalinity sodium salt to produce the potassium dehydroandrographolide succinate or the potassium sodium dehydroandroan drographolide succinate in methanol, ethanol or hydrosolvent. The method is practical, convenient to operate, low in cost and nontoxic. The potassium dehydroandrographolide succinate or the potassium sodium dehydroandroan drographolide succinate is prepared easily under the normal atmosphere through usage of the solvent, the product quality is guaranteed, and the method is suitable for industrial production particularly.
Description
Technical field
The invention belongs to medical technical field.The preparation method who relates to a kind of potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate, being specifically related to the rographolide is initial feed, the method for suitability for industrialized production potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate.Production applicable to potassium dehydroandrographolide succinate, potassium sodium dehydroandroan drographolide succinate and deoxydidehydrorographolide disuccinic acid half ester industrial chemicals or medicinal raw material.
Technical background
Herba Andrographis is herb or the leaf of acanthaceous plant Herba Andrographis (Andrographis paniculata (Burm.F.) Nees).Have another name called Chun Lianqiuliu, Herba Andrographitis, olive nuclear lotus, Radix Gentianae, golden vanilla, golden tack, India's grass, eel grass etc.Clearing heat and detoxicating, anti-inflammatory, swelling and pain relieving effect are arranged.Cure mainly bacillary dysentery, urinary tract infections, acute tonsillitis, enteritis, pharyngolaryngitis, pneumonia and influenza etc., external application can be treated sore furuncle poison, trauma infection contamination etc.Main product is in provinces such as Guangdong, Fujian, and also introduce a fine variety on ground such as Central China, North China, northwest.This kind has been recorded in one one of 2010 editions pharmacopeia of the People's Republic of China.
Rographolide (Andrographolide) then be by Herba Andrographis through the Chinese medicinal plant monomer that extraction makes, have clearing heat and detoxicating, Azelaic Acid function. be the main effective constituent of Chinese patent medicine creat formulations commonly used such as treatment upper respiratory tract infection, acute bacillary dysentery, viral cold.Early 1970s, behind the domestic cauline leaf or herb extraction that begins Herba Andrographis, common oral preparation such as andrographis tablet have been processed.Though ordinary preparation has certain restraining effect to bacterium, virus, because of the water insoluble power deficiency of its main effective constituent.
Because rographolide is the effective constituent of from Herba Andrographis, extracting, monomer purity is high, and quality product and pharmacological action have more advantage than Herba Andrographis.The SFDA approved is produced oral dosage forms such as rographolide tablet, capsule, soft capsule, dripping pill at present.Its shortcoming is that rographolide is the diterpenes diterpenoids lactones compound, is insoluble in water, usually only can oral administration.To the demand of virus infection acute disease clinically, with introducing different hydrophilic radicals in its structure, strengthen its water-soluble injection that is prepared into, improve curative effect.In China, begin the rographolide soluble derivative is studied from the seventies, developed a series of injections, wherein main product is potassium dehydroandrographolide succinate and potassium sodium dehydroandroan drographolide succinate.
Potassium dehydroandrographolide succinate is a rographolide through esterification, dehydration, salify and the POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE of processing; Potassium sodium dehydroandroan drographolide succinate then is the deoxydidehydrorographolide succinic acid half-ester natrium potassium salt that is got by the reaction of potassium dehydroandrographolide succinate and sodium hydroxide or carbonic acid (hydrogen) sodium; Be widely used in virus diseases such as the high heat of treatment, respiratory tract infection, children's rotavirus enteritis, mumps clinically, be one of indispensable pure Chinese medicinal preparation of emergency department of institute of traditional Chinese medicine (chamber), broken traditional saying that Chinese medicine can only be used for treating chronic disease.These two products have all recorded in Pharmacopoeia of People's Republic of China (two ones) at present.In recent years, along with the widespread use of this medicine, its untoward reaction happens occasionally.Monitoring center circulated a notice of in recent years according to the national drug untoward reaction, about the main adverse reaction of potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate injection is anaphylaxis and thrombopenia.The main reason that the concrete analysis untoward reaction produces has (1) difference between individuals (allergic constitution) to cause; The oxidation of hydrolysis, open loop, isomerizing and the unsaturated link(age) of lactone takes place in (2) rographolide poor stability easily.(3) purity of initial feed (rographolide) is not high; Major impurity is macromolecule plant albumen, rographolide hydrolysis, oxidation products and pigment etc., and bibliographical information is with activated carbon decolorizing, carry out can the LD50 of mouse single intravenously administrable being brought up to 910mg/kg from 757mg/kg after the ultrafiltration with the ultra-filtration membrane of molecular interception amount 5000; (4) rographolide causes unstable product quality because of the production technique instability in the process of esterification, dehydration.In sum, though this characteristic of traditional Chinese medicine has determined that kind untoward reactions more or less such as potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate are inevitable, it also is a undisputable fact that the purity of improving the quality of products can increase substantially the product clinical safety.
The technology of existing preparation deoxydidehydrorographolide disuccinic acid half ester mainly is as solvent with pyridine; By rographolide and succinyl oxide, sodium sulphite anhydrous 99.3 and anhydrous pyridine under vacuum tightness 520～620mmHg condition in the boiling water bath back flow reaction prepare (research of POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE and injection liquid thereof. the herbal medicine communication; 1978, (8): 1).Test shows: difficult control in this reaction conditions (back flow reaction in vacuum tightness 520～620mmHg boiling water bath) actual mechanical process; Particularly under vacuum condition, be unfavorable for suitability for industrialized production; And the easy glueization of product when temperature is too high during back flow reaction; Be unfavorable for aftertreatment, product color is darker, and quality product is also unstable.
Also have as solvent with pyridine; Under nitrogen protection, under normal pressure, under 70-80 ℃ temperature, react earlier by rographolide and succinyl oxide, sodium sulphite anhydrous 99.3, and then under the boiling temperature of pyridine (greater than 115 ℃) reflux several hours (synthesis technique of deoxydidehydrorographolide disuccinic acid half ester improves. Anhui medicine Anhui Medical and Pharmaceutical Journal 2006Mar; 10 (3); The preparation method of potassium sodium dehydroandroan drographolide succinate, potassium sodium dehydroandroan drographolide succinate preparation and preparation method .CN1927854A).This method not only need consume a large amount of pyridines, produces environmental pollution, and the unstable product quality that obtains thus, color are also darker, and yield (about 41.7%) on the low side, are not suitable for suitability for industrialized production, also are difficult to guarantee quality product.
Summary of the invention
In order to overcome the deficiency of prior art,, the objective of the invention is to be to provide the preparation method of a kind of potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate to the problem of above-mentioned existence; Easy to implement the method, easy and simple to handle, cost is low; Nontoxicity; Utilize this solvent under normal pressure, to be very easy to preparation potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate, guaranteed quality product, be particularly suitable for suitability for industrialized production.
In order to realize above-mentioned purpose, the present invention adopts following technical measures:
Its technical conceive is: this specific solvent be exactly ETHYLE ACETATE or acetonitrile or butanone or or two or more solvent with the mixture of any ratio.Acetonitrile (acetonitrile) has another name called the methyl nitrile, colourless liquid, and highly volatile has the special odor that is similar to ether, can not resemble pyridine and can produce extremely unpleasant stench.Acetonitrile is a kind of good organic solvent, can dissolve multiple organic and inorganic and gaseous matter.Its specific density (water=1) is 0.79, and boiling point is 81.1 ℃.Its toxicity is lower than the pyridine [LD of acetonitrile
50: 2730mg/kg (rat oral), 1250mg/kg (rabbit is through skin); The LD of pyridine
50: 1580mg/kg (rat oral), 1121mg/kg (rabbit is through skin)].And can infinitely dissolve each other with water and alcohol.Typical nitrile reaction can take place in acetonitrile, and is used to prepare many typical nitrogenous compounds, is an important organic intermediate.Acetonitrile can be used for synthesise vitamins A, KE, and the solvent of carbon amine drug and midbody thereof also is used to make VITMAIN B1 and amino acid whose active media solvent and as the denaturing agent of alcohol, market value is lower than pyridine.
Butanone (methyl ethyl ketone) has another name called methylethylketone, and colourless liquid has a kind of sweet taste of intensive butterscotch, is similar to acetone, also can not resemble pyridine and can produce extremely unpleasant stench.Butanone also is a kind of good organic solvent and organic synthesis raw material.Its specific density (water=1) is 0.8054, and boiling point is 79.6 ℃.Its toxicity is starkly lower than the pyridine [LD of butanone
50: 3400mg/kg (rat oral), 6480mg/kg (rabbit is through skin); The LD of pyridine
50: 1580mg/kg (rat oral), 1121mg/kg (rabbit is through skin)].Butanone is dissolved in about 4 times water, can be dissolved in the organic solvents such as ethanol, ether.Can form constant boiling mixture (containing butanone 88.7%), 73.4 ℃ of boiling points with water.Butanone is the midbody of preparation spices, inhibitor and some catalyzer mainly as the various kinds of resin solvent of coatings industry, and market value is well below pyridine.
ETHYLE ACETATE also is a kind of colourless transparent liquid, has fruit fragrant.Can be miscible with chloroform, ethanol, acetone and ether, its specific density (water=1) is 0.902, boiling point is 77 ℃.Its toxicity also is starkly lower than the pyridine [LD of ETHYLE ACETATE
50: 11.3ml/kg (rat oral), 4940mg/kg (rabbit per os).ETHYLE ACETATE is a kind of broad-spectrum fine chemical product; Have excellent solvability, quick-drying; Of many uses; Be a kind of very important Organic Chemicals and fabulous industrial solvent, be widely used in the production process of cellulose acetate, ethyl cellulose, chlorinated rubber, ethenoid resin, acetate fiber resin, viton, coating and paint etc.Market value is also well below pyridine.
Embodiment of the present invention be earlier with rographolide and succinyl oxide with selected solvent heating for dissolving; Add appropriate amount of catalysts then; Also can add an amount of oxidation inhibitor in case of necessity or feed nitrogen (protection), heat then under the condition of solvent refluxing and react to prevent the generation of side reaction.Because selected solvent not only can control reaction temperature keep constant in reaction process, but also can utilize boiling reflux to replace whipping process, thereby also guarantee the repeatability and the operability of production process, also guarantee the stable of quality product.
The more important thing is that the present invention has greatly reduced the consumption of use high toxicity pyridine in the prior art, even also avoided the use of high toxicity pyridine, help the protection and the health of operators of environment like this, also reduced production cost simultaneously.Be particularly suitable for large-scale industrial production.
The preparation method of a kind of potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate comprises preparation deoxydidehydrorographolide disuccinic acid half ester and preparation potassium sodium dehydroandroan drographolide succinate or two steps of potassium dehydroandrographolide succinate.
The first step, be initial feed with the rographolide; In specific non-pyridine solvent, under reflux and to have with the amount ratio of rographolide be to become deoxydidehydrorographolide disuccinic acid half ester in the presence of 1: 10～1: 1 the catalyzer (uncle's ammoniac compounds) with the succinyl oxide prepared in reaction for (W/W).
Second step, in methyl alcohol, ethanol or water solvent, the deoxydidehydrorographolide disuccinic acid half ester behind the purifying and Pottasium Hydroxide or sodium hydroxide or alkaline potassium salt or alkaline sodium salt prepared in reaction are become potassium sodium dehydroandroan drographolide succinate or potassium dehydroandrographolide succinate.
Described specific non-pyridine solvent be meant boiling point with 75～85 ℃ and under said reaction conditions not with raw materials used and inert solvent product generation chemical reaction, inert solvent is wherein a kind of of THF, ETHYLE ACETATE, butanone, acetonitrile or propionitrile; Best solvent is ETHYLE ACETATE, butanone or acetonitrile.
Described specific non-pyridine solvent is meant the mixture that two or three solvent of ETHYLE ACETATE, butanone or acetonitrile is formed with any ratio;
Described temperature of reaction is solvent for use temperature 75-100 ℃ when refluxing; Be not less than 75 ℃ in principle, but be no more than 100 ℃.
Described catalyzer is uncle's ammoniac compounds or the alkaline hexa-member heterocycle compounds that contains a nitrogen heteroatom;
The consumption of described rographolide and the amount ratio of succinyl oxide (W/W) are 1: 2～2: 1.
Described rographolide and solvent for use weightmeasurement ratio (W/V) 1: 10～2: 1.
Described uncle's ammoniac compounds is N, the N-diisopropylethylamine.
The described alkaline hexa-member heterocycle compounds that contains a nitrogen heteroatom is pyridine and verivate such as N, the N-Dimethylamino pyridine.
The amount ratio of described catalyst consumption and rographolide is 1: 10～1: 1 for (W/W).
The preparation method of a kind of potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate, embodiment preferred comprises the steps:
(1) with mixture heating up 50-60 ℃ of dissolving of rographolide and succinyl oxide adding acetonitrile or butanone or acetonitrile and butanone, wherein, rographolide is 1: 10～2: 1 with the weightmeasurement ratio (W/V) that adds solvent, is preferably 1: 5～1: 1; The consumption of rographolide and the weight ratio of succinyl oxide (W/W) are 1: 2～2: 1, are preferably 1: 2～1: 1; Add sodium sulphite anhydrous 99.3 and N then; The N-diisopropylethylamine is that catalyzer or pyridine are that the verivate of catalyzer or pyridine is a catalyzer; Wherein the consumption of sodium sulphite anhydrous 99.3 is 1～10% of a rographolide consumption, and the amount ratio of catalyst consumption and rographolide is 1: 10～1: 1 for (W/W).Last reflux is reacted.After back flow reaction is carried out 2 hours, with HPLC detection reaction terminal point.The condition of HPLC is following:
With reference to Chinese Pharmacopoeia two ones of versions (appendix V D) in 2010; Use octadecylsilane chemically bonded silica to be weighting agent; Be moving phase with methyl alcohol-0.05% (volume ratio) potassium dihydrogen phosphate (using phosphoric acid to transfer pH value is 2.5) (7: 3); The detection wavelength is 251nm, and number of theoretical plate calculates by deoxydidehydrorographolide succinic acid half-ester peak and is not less than 3000.Get reacted solution 0.1g, add the solution that 0.1mg/ml is dissolved and be diluted to moving phase, shake up, get 20 μ l and inject liquid chromatograph, adjusting detection sensitivity to color atlas is 2-4 a times of full range, and the record color atlas promptly gets.
When the chromatographic peak completely dissolve of rographolide, be reaction end.Stop reacting by heating then, in reaction soln, add water that reaction soln 10-20 doubly measures volume and stir and be cured, filter, promptly get deoxydidehydrorographolide succinic acid half-ester solid crude product.
With the deoxydidehydrorographolide succinic acid half-ester solid crude product of gained add water that 10-20 doubly measures repeatedly the assay result of washing by soaking to chromatographic peak that can't check catalyzer with HPLC and deoxydidehydrorographolide succinic acid half-ester greater than after 98%; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67Kpa), promptly get deoxydidehydrorographolide succinic acid half-ester elaboration (detection method is referring to two ones the 619th page of Chinese Pharmacopoeia version in 2010).
(2) get deoxydidehydrorographolide succinic acid half-ester elaboration; After adding the ethanol or dissolve with methanol that 1-2 doubly measures; Add the wet chemical reaction with the equimolar Pottasium Hydroxide of deoxydidehydrorographolide succinic acid half-ester or potassium bicarbonate aqueous solution or 1/2 mole again, the ethanol or the acetone that add 10 times of amounts of used volume of water again carry out crystallization, filter; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67Kpa), promptly get potassium dehydroandrographolide succinate (POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE).
The preparation of potassium sodium dehydroandroan drographolide succinate can use potassium dehydroandrographolide succinate to prepare as initial feed, also can use the deoxydidehydrorographolide succinic acid half-ester to prepare as initial feed.
Be that the method for preparing of initial feed is following with the potassium dehydroandrographolide succinate:
Get potassium dehydroandrographolide succinate; After adding the ethanol or dissolve with methanol of 50% (v/v) that 1-2 doubly measures; Add the yellow soda ash solid reaction with molar sodium hydroxide such as potassium dehydroandrographolide succinate or sodium hydrogencarbonate or 1/2 mole again, the ethanol or the acetone of adding and 10 times of amounts of used volume of water carry out crystallization when react after, filtration; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get potassium sodium dehydroandroan drographolide succinate (deoxydidehydrorographolide succinic acid half-ester k-na salt).
With the deoxydidehydrorographolide succinic acid half-ester is that the method for preparing of initial feed is following:
Get deoxydidehydrorographolide succinic acid half-ester elaboration; After adding the ethanol or dissolve with methanol that 1-2 doubly measures; Add salt of wormwood and aqueous sodium carbonate reaction again with the equimolar Pottasium Hydroxide of deoxydidehydrorographolide succinic acid half-ester and aqueous sodium hydroxide solution or saleratus and sodium bicarbonate aqueous solution or 1/2 mole; The ethanol or the acetone that add 10 times of amounts of used volume of water again carry out crystallization; Filter, be dried to constant weight, promptly get potassium sodium dehydroandroan drographolide succinate (deoxydidehydrorographolide succinic acid half-ester k-na salt) in 50 ℃ of decompressions (below the 2.67KPa).
The preparation of potassium sodium dehydroandroan drographolide succinate can also prepare with following method:
Get deoxydidehydrorographolide succinic acid half-ester elaboration; After adding the ethanol or dissolve with methanol that 1-2 doubly measures; Add salt of wormwood and aqueous sodium carbonate reaction again with the equimolar Pottasium Hydroxide of deoxydidehydrorographolide succinic acid half-ester and aqueous sodium hydroxide solution or saleratus and sodium bicarbonate aqueous solution or 1/2 mole; Gained solution is directly reduced pressure (2.67KPa below) drying or lyophilize or spraying drying promptly gets potassium sodium dehydroandroan drographolide succinate (deoxydidehydrorographolide succinic acid half-ester k-na salt).
Perhaps get potassium dehydroandrographolide succinate; After adding the ethanol or dissolve with methanol of 50% (v/v) that 1-2 doubly measures; Add yellow soda ash solid reaction again with molar sodium hydroxide such as potassium dehydroandrographolide succinate or sodium hydrogencarbonate or 1/2 mole; After having reacted, (below the 2.67KPa) drying or lyophilize or spraying drying that gained solution is directly reduced pressure promptly gets potassium sodium dehydroandroan drographolide succinate (deoxydidehydrorographolide succinic acid half-ester k-na salt).
According to potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate that the present invention produces, its content can reach more than 98%, and total recovery can reach more than 80%.
The present invention compared with prior art has following advantage and effect:
(1), and utilize the boiling temperature of solvent to react owing under normal pressure, react, thereby the reaction conditions volume controlled, thereby the stable of quality product also guaranteed.Also avoided the generation of side reaction under the high temperature.
(2) owing to used non-pyridines solvent, not only avoided the unpleasant malodorous generation of pyridine in the production process as reaction solvent.But also help the protection and the health of operators of environment, and reduced toxicity, also reduced production cost, be particularly suitable for large-scale industrial production.
Embodiment
Following embodiment only is used for that the present invention will be described, never is that the present invention is limited.
Embodiment 1:
A kind of preparation method of potassium dehydroandrographolide succinate the steps include:
In the 100L reaction kettle, add 10kg succinyl oxide and 5kg rographolide; Add the 50L butanone; Heating (50-60 ℃) adds 0.5kg sodium sulphite anhydrous 99.3 and N after stirring and making dissolving again, and N-diisopropylethylamine 2kg is a catalyzer; The heating in water bath back flow reaction is after 5 hours, with HPLC detection reaction terminal point then.When the chromatographic peak completely dissolve of rographolide in the high-efficient liquid phase chromatogram and deoxydidehydrorographolide succinic acid half-ester chromatographic peak no longer increase; Stop reacting by heating; Reaction soln under agitation joined in the 1000L water be cured; 2 hours after-filtration promptly get deoxydidehydrorographolide succinic acid half-ester solid crude product.
The water that the deoxydidehydrorographolide succinic acid half-ester solid crude product of gained is added 200L filters after stirring and soaking 2 hours, adds 200L water again and stirs and soak after 2 hours, filters.So repeatedly washing by soaking to the assay result who detects the deoxydidehydrorographolide succinic acid half-ester with HPLC greater than after 98%; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get deoxydidehydrorographolide succinic acid half-ester elaboration (detection method is referring to two ones the 619th page of Chinese Pharmacopoeia version in 2010).
Get above-mentioned deoxydidehydrorographolide succinic acid half-ester elaboration 5.3kg; After adding the 5.3L dissolve with ethanol; Add the solution of processing by 0.56kg Pottasium Hydroxide and 1L water again and carry out stirring reaction, add 20L ethanol after 10 minutes again and carry out crystallization, filter; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get 4.5kg potassium dehydroandrographolide succinate (POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE).
Get above-mentioned potassium dehydroandrographolide succinate 0.57kg; After adding ethanol 2L heating (50 or 52 or 56 or the 58 or 60 ℃) dissolving of 50% (v/v); Add again after the 0.084kg sodium hydrogencarbonate reacts 1 hour, add 10L ethanol again and carry out crystallization, filter; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get 0.5kg potassium sodium dehydroandroan drographolide succinate (deoxydidehydrorographolide succinic acid half-ester k-na salt).
Embodiment 2:
A kind of preparation method of potassium sodium dehydroandroan drographolide succinate the steps include:
In the 50L reaction kettle, add 5kg succinyl oxide and 5kg rographolide; Add the 25L acetonitrile; After heating (50 or 53 or 55 or 57 or 60 ℃) is stirred and is made dissolving; Adding 0.05kg sodium sulphite anhydrous 99.3 and 2.5kg pyridine again is catalyzer, and the heating in water bath back flow reaction is after 4 hours, with HPLC detection reaction terminal point then.After the chromatographic peak completely dissolve of rographolide in the high-efficient liquid phase chromatogram, stop reacting by heating, reaction soln is under agitation joined in the 500L water be cured, 2 hours after-filtration promptly get deoxydidehydrorographolide succinic acid half-ester solid crude product.
The water that the deoxydidehydrorographolide succinic acid half-ester solid crude product of gained is added 200L filters after stirring and soaking 2 hours, adds 200L water again and stirs and soak after 2 hours, filters.So repeatedly washing by soaking to the assay result who detects the deoxydidehydrorographolide succinic acid half-ester with HPLC greater than after 98%; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get deoxydidehydrorographolide succinic acid half-ester elaboration (detection method is referring to two ones the 619th page of Chinese Pharmacopoeia version in 2010).
Get above-mentioned deoxydidehydrorographolide succinic acid half-ester elaboration 5.3kg; After adding the 10L dissolve with methanol; Add the solution of processing by 0.69kg salt of wormwood and 5L water again and react, add 50L acetone after 10 minutes again and carry out crystallization, filter; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get 4.8kg potassium dehydroandrographolide succinate (POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE).
Get above-mentioned potassium dehydroandrographolide succinate 0.57kg; After adding ethanol 2L heating (50-60 ℃) dissolving of 50% (v/v); Add again after solution that 0.053kg yellow soda ash and 5L water processes reacts 30 minutes; Gained solution is carried out spraying drying, promptly get 0.55kg potassium sodium dehydroandroan drographolide succinate (deoxydidehydrorographolide succinic acid half-ester k-na salt).
Embodiment 3:
A kind of preparation method of potassium dehydroandrographolide succinate the steps include:
In the 50L reaction kettle, add 2.5kg succinyl oxide and 5kg rographolide; Add 10L butanone and 10L acetonitrile; After heated and stirred makes dissolving, add 0.1kg sodium sulphite anhydrous 99.3 and N again, N-Dimethylamino pyridine 0.5kg is a catalyzer; Heating in water bath back flow reaction after 4 hours, under the situation of logical nitrogen protection then with HPLC detection reaction terminal point.After the chromatographic peak completely dissolve of rographolide in the high-efficient liquid phase chromatogram, stop reacting by heating, reaction soln is under agitation joined in the 300L water be cured, 2 hours after-filtration promptly get deoxydidehydrorographolide succinic acid half-ester solid crude product.
The water that the deoxydidehydrorographolide succinic acid half-ester solid crude product of gained is added 200L filters after stirring and soaking 2 hours, adds 200L water again and stirs and soak after 2 hours, filters.So repeatedly washing by soaking to detect with HPLC related substance less than 1% and the assay result of deoxydidehydrorographolide succinic acid half-ester greater than after 98%; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get deoxydidehydrorographolide succinic acid half-ester elaboration (detection method is referring to two ones the 619th page of Chinese Pharmacopoeia version in 2010).
Get above-mentioned deoxydidehydrorographolide succinic acid half-ester elaboration 5.3kg; After adding the 10L dissolve with ethanol; Add the solution of processing by 0.69kg salt of wormwood and 0.84Kg sodium hydrogencarbonate and 3L water again and react, add 30L ethanol after 10 minutes again and carried out crystallization 2 hours, filter; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get 5.1kg potassium sodium dehydroandroan drographolide succinate (deoxydidehydrorographolide succinic acid half-ester k-na salt).
Embodiment 4:
A kind of preparation method of potassium sodium dehydroandroan drographolide succinate the steps include:
In the 50L reaction kettle, add 4kg Succinic anhydried and 5kg rographolide and 0.5kg sodium sulphite anhydrous 99.3; Add butanone 2.5L and N after stirring again; N-diisopropylethylamine 5kg; Continue stirring heating (50 or 51 or 53 or 55 or 59 or 60 ℃) and make dissolving, the heating in water bath back flow reaction is after 4 hours, with HPLC detection reaction terminal point then.After the chromatographic peak completely dissolve of rographolide in the high-efficient liquid phase chromatogram, stop reacting by heating, reaction soln is under agitation joined in the 150L water be cured, 2 hours after-filtration promptly get deoxydidehydrorographolide succinic acid half-ester solid crude product.
Add 200L water again and stir immersion after 2 hours, filter.So repeatedly washing by soaking to the assay result who detects the deoxydidehydrorographolide succinic acid half-ester with HPLC greater than after 98%; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get deoxydidehydrorographolide succinic acid half-ester elaboration (detection method is referring to two ones the 619th page of Chinese Pharmacopoeia version in 2010).
Get above-mentioned deoxydidehydrorographolide succinic acid half-ester elaboration 5.3kg; After adding the 5.3L dissolve with ethanol; Add the solution of processing by 0.84kg sodium hydrogencarbonate and 1kg saleratus and 2.5L water again and carry out stirring reaction after 30 minutes; Gained solution is reduced pressure (2.67KPa below) be dried to constant weight, promptly get 6.1kg potassium sodium dehydroandroan drographolide succinate (deoxydidehydrorographolide succinic acid half-ester k-na salt).
Embodiment 5:
A kind of preparation method of potassium dehydroandrographolide succinate the steps include:
In the 50L reaction kettle, add 5kg succinyl oxide and 5kg rographolide; Add 5L butanone, 10L acetonitrile and 15L ETHYLE ACETATE; After heated and stirred makes dissolving, add 0.25kg sodium sulphite anhydrous 99.3 and N again, N-Dimethylamino pyridine 1kg is a catalyzer; The heating in water bath back flow reaction is after 6 hours, with HPLC detection reaction terminal point then.After the chromatographic peak completely dissolve of rographolide in the high-efficient liquid phase chromatogram, stop reacting by heating, reaction soln is under agitation joined in the 300L water be cured, 2 hours after-filtration promptly get deoxydidehydrorographolide succinic acid half-ester solid crude product.
The water that the deoxydidehydrorographolide succinic acid half-ester solid crude product of gained is added 200L filters after stirring and soaking 2 hours, adds 200L water again and stirs and soak after 2 hours, filters.So repeatedly washing by soaking to detect with HPLC related substance less than 1% and the assay result of deoxydidehydrorographolide succinic acid half-ester greater than after 98%; Be dried to constant weight in 50 ℃ of decompressions (below the 2.67KPa), promptly get deoxydidehydrorographolide succinic acid half-ester elaboration (detection method is referring to two ones the 619th page of Chinese Pharmacopoeia version in 2010).
Get above-mentioned deoxydidehydrorographolide succinic acid half-ester elaboration 5.3kg; After adding the 5L dissolve with ethanol; Adding the solution of being processed by 0.69kg salt of wormwood and 0.84Kg sodium hydrogencarbonate and 20L water again reacts; Carry out lyophilize at-40 ℃, promptly get 6kg potassium sodium dehydroandroan drographolide succinate (deoxydidehydrorographolide succinic acid half-ester k-na salt).
Claims (4)
1. the preparation method of potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate the steps include:
A, be raw material, in specific non-pyridine solvent, under reflux and to have with the amount ratio of rographolide be that W/W becomes deoxydidehydrorographolide disuccinic acid half ester with the succinyl oxide prepared in reaction in the presence of the catalyzer of 1:10～1:1 with the rographolide;
B, in methyl alcohol, ethanol or water solvent, the deoxydidehydrorographolide disuccinic acid half ester behind the purifying and Pottasium Hydroxide or sodium hydroxide or alkaline potassium salt or alkaline sodium salt prepared in reaction are become potassium sodium dehydroandroan drographolide succinate or potassium dehydroandrographolide succinate;
Described specific non-pyridine solvent be meant boiling point with 75～85 ℃ and under said reaction conditions not with raw materials used and inert solvent product generation chemical reaction, inert solvent is wherein a kind of of THF, ETHYLE ACETATE, butanone, acetonitrile or propionitrile;
Described specific non-pyridine solvent is meant the mixture that two or three solvent in ETHYLE ACETATE, butanone or the acetonitrile is formed with any ratio;
Described temperature of reaction is solvent for use temperature 75-100 ℃ when refluxing;
Described catalyzer is uncle's ammoniac compounds or the alkaline hexa-member heterocycle compounds that contains a nitrogen heteroatom;
The amount ratio W/W of the consumption of described rographolide and succinyl oxide is 1:2～2:1;
Described rographolide and solvent for use weightmeasurement ratio W/V1:10～2:1.
2. the preparation method of a kind of potassium dehydroandrographolide succinate according to claim 1 or potassium sodium dehydroandroan drographolide succinate is characterized in that: described uncle's ammoniac compounds is N, the N-diisopropylethylamine.
3. the preparation method of a kind of potassium dehydroandrographolide succinate according to claim 1 or potassium sodium dehydroandroan drographolide succinate is characterized in that: the described alkaline hexa-member heterocycle compounds that contains a nitrogen heteroatom is pyridine or N, the N-Dimethylamino pyridine.
4. the preparation method of a kind of potassium dehydroandrographolide succinate according to claim 1 or potassium sodium dehydroandroan drographolide succinate is characterized in that: the amount ratio of described catalyst consumption and rographolide is that W/W is 1:10～1:1.
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