CN105732547A - Preparation method of dehydrated andrographolide diacid half ester basic salt - Google Patents
Preparation method of dehydrated andrographolide diacid half ester basic salt Download PDFInfo
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Abstract
The invention provides a preparation method of a dehydrated andrographolide diacid half ester basic salt. The method comprises the following steps: by using andrographolide as a raw material, adding a small amount of acidic catalyst into a weakly alkaline reaction solvent system, heating to generate dehydrated andrographolide, and directly adding acid anhydride for esterification without separating the intermediate, thereby preparing the dehydrated andrographolide diacid half ester basic salt. The method can selectively perform dehydration and esterification reaction respectively, thereby avoiding many side reactions, reducing the generation of impurities, and further obtaining the high-purity dehydrated andrographolide diacid half ester basic salt. It is accidentally detected that the dehydration product can be directly esterified without separation. The method ensures the high-yield preparation of the dehydrated andrographolide diacid half ester basic salt. The purity of the dehydrated andrographolide diacid half ester basic salt prepared by the method can reach 99.5% or above, and the yield can reach 90% or above.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly relate to the preparation method that medicine is new, be specifically related to the new preparation method of a kind of dehydrorographolide diacid half esters basic salt.
Background technology
Herba Andrographis is herb or the leaf of acanthaceous plant Herba Andrographis (Andrographispaniculata (Burm.F.) Nees).Have another name called Chun Lianqiuliu, Herba Andrographitis, Lan Helian, Radix Gentianae, gold Rhizoma et radix valerianae, Tremella aurantialba Bandoni et Zang hook, India's grass, Herba vallisneriae Spiralis etc..There are heat-clearing and toxic substances removing, antiinflammatory, reducing swelling and alleviating pain effect.Curing mainly bacillary dysentery, urinary tract infection, acute tonsillitis, enteritis, pharyngolaryngitis, pneumonia and influenza etc., external can treat furuncle toxic swelling, trauma infection contamination etc..Main product is economized in Guangdong, Fujian etc., and the ground such as Central China, North China, northwest is also introduced a fine variety.
Dehydrorographolide diacid half esters and derivant thereof, its representative species andrographolide, English name is PotassiumsodiumDehydroandroandrographolideSuccinate, chemical name is PSDS, there is heat clearing away, anti-inflammation, the pharmacological action such as antiviral, there is the title of Chinese medicine " antibiotic ".Current andrographolide is all prepared through one-tenth salt by intermediate (shown in Formulas I compound).
Current document [1] _ Hu Tugao, Bai Jun, Liu Yan, Anhui Prov. Inst. of Pharmacology. the improvement in synthesis [J] of dehydroandrographolide succinate. Anhui medicine, 2006 (10): 3；[2] _ Yao Hua room, Traditional Chinese Medicine Research Institute, Sichuan Province Herba Andrographis seminar. the research [J] of POTASSIUM DEHYDRO-OGRAPHOLIDE SUCCINATE and injection thereof. Chinese herbal medicine communication, 1978 (8): 1；[3] _ CN1927854A, [4] _ Zhou Huijin company jade, the improvement in synthesis of dehydroandrographolide succinate and critical process control point [J], Heilungkiang scientific and technological information, 2009 (10): 72-73；[5]_CN102863408A,[6]_CN102617527A；The synthesising process research of [7] _ Andrographolide, Hou Qianqian, He'nan Normal University, 2014.The method of preparation I compound reported above is as follows:
Said method is with andrographolide and succinic anhydrides for raw material; using pyridine or other organic base as solvent and catalyst or acid binding agent; and under antioxidant anhydrous sodium sulfite or inert gas shielding; heating or back flow reaction; then a large amount of sour water or moisture is used to separate out intermediate dehydroandrographolide succinate (Formulas I); re-use sodium carbonate well-known to those skilled in the art; potassium carbonate; or sodium bicarbonate; potassium bicarbonate point one-step or two-step becomes natrium potassium salt, and then obtains andrographolide.
Said method preparation I compound is adopted to be primarily present following defect:
Reaction adopts andrographolide and succinic anhydrides one step to complete dehydration and esterification, dehydration and esterification to intersect unordered carrying out.Three alcoholic extract hydroxyl groups existed in molecule, one is primary alconol, and one is 1-propenol-3, and one is secondary alcohol.Especially the alcoholic extract hydroxyl group of allylic, dehydration and esterification are vied each other.No matter adopting which kind of condition, convert which kind of parameter, reaction all unavoidably has the alcoholic extract hydroxyl group of allylic and esterification first occurs, and after occurring esterification to generate ester, under this kind of reaction system, it is difficult to eliminate and form alkene.The impurity produced therefrom, it is difficult to remove, it is impossible to obtain highly purified dehydroandrograpolide succinate, let alone prepare that highly purified to wear (inflammation) amber peaceful.Adopt this method dehydroandrograpolide succinate or its basic salt of preparation.Though the requirement of industrialized production can be met, but HPLC purity is generally less than 99.0%.
Document [8] _ Xin-FengLuo, LingHe, Hai-BinYinetal.EfficientAcylationandOne-PotSynthesisofDe hydroandrographolideSuccinateonaLargeScaleAssistedwithMi crowaveRadiation [J], SyntheticCommunications, 39:3444 3452,2009 to report use andrographolide and succinic anhydrides be raw material, and with pyridine for solvent, sodium sulfite is antioxidant.Use microwave irradiation reacts, and the response time is 2 minutes, though product purity higher (more than 99.0%).But the response time be 1.5 minutes and 2.5 minutes product purity only have about 95%.Show that reaction is very fierce, it is difficult to control, be not suitable for industrialized great production.And microwave irradiation reaction condition is fierce, adding anhydrous sodium sulfite as antioxidant, sodium sulfite easily and the side reaction of substrate generation addition, causes separation purification difficult, affects quality and the yield of finished product.
Document [9] _ CN1810794A；[10]_CN101245056A；[11]_Hai-WeiXu,JianyeZhang,Hong-MinLiuetal.SynthesisofAndrographolideCyclophosphateDerivativesandTheirAntitumorActivities[J],SyntheticCommunications,36:407–414,2006；[12]_XuHai-WeiWangJun-FengLiuHong-Minetal.SynthesisandCrystalStructureofDehydroandrographolideDipolycyclophosphate[J]ChineseJ.Struct.Chem.24(10),1198-1202,2005；[13]_Gui-FuDai,Hai-WeiXu,Jun-FengWangetal.Studiesonthenovela-glucosidaseinhibitoryactivityandstructure–activityrelationshipsforandrographolideanalogues[J].Bioorganic&MedicinalChemistryLetters16(2006)2710–2713；[14]_CN104045612A.Bibliographical information or relate to the preparation of dehydrorographolide, its dehydration conditions adopted or dehydrant, document [9] does not use any catalyst or dehydrant, directly in solvent pyridine heating (this kind of condition dehydration conversion ratio is less than 5%, and reaction needed a couple of days just can reach), document [11], [13] adopting aluminium sesquioxide with [14] is dehydrant, owing to aluminium sesquioxide is amphoteric oxide, reaction substrate and target product have certain degraded destroy, produce impurity mechanism not only complicated and more, it is difficult to remove.Document [14] further mentions the use alkali cpd such as sodium sulfite and paratoluenesulfonic acid sodium salt simultaneously is catalyst, and wherein sodium sulfite is antioxidant, there is no dehydrating effect.Paratoluenesulfonic acid sodium salt is highly basic strong acid salt, and for neutral compound, and paratoluenesulfonic acid sodium salt dissolubility in pyridine is poor, uses the method to carry out dehydration, and effect is suitable with document [9], and conversion ratio is relatively low.Document [10] and [12] adopt anhydride or acyl chlorides (phosphorus oxychloride) to carry out dehydration, are inevitably esterified in course of reaction, or chloro, or become the side reactions such as phosphate ester, it is extremely difficult to obtain the sterling that purity is higher.And document above all be not directed to adopt dehydrorographolide be that substrate is prepared dehydroandrograpolide succinate or its basic salt.
The method preparing dehydrorographolide of current bibliographical information, has all carried out separation purification to dehydrorographolide product.It is primarily due to catalyst choice improper, causes that must carry out purification carries out next step reaction.And separate purification, the loss of dehydrorographolide will be caused again.Reduce the follow-up yield preparing its derivant.
The method of the purification & isolation Formulas I of current bibliographical information, it is nearly all the character utilizing product almost not allow in water, precipitate out from substantial amounts of water, product crystal formation is superfine, specific surface area is big, being no matter with sucking filtration during separation or centrifugal all cannot take out (getting rid of) and do, in industrialized great production process, not only disengaging time is long.Product water content is high.And be highly detrimental to follow-up production operation and ensure product and separated from impurities.
To sum up, make preparation I compound in aforementioned manners, restriction due to theoretical and big production practices, though partial parameters can be optimized, but in commercial process, still cannot obtain purity and the higher product of quality, especially meet recent regulations requirement, total purity more than 99.5%, the single impurity crude drug product less than 0.1%.For this urgently a kind of new technical scheme, to provide more excellent process conditions, improve the quality of product, raise labour productivity, reduce production cost to greatest extent so that it is be more beneficial for large-scale industrial production.
Summary of the invention
For overcoming prior art defect, it is an object of the invention to provide a kind of dehydrorographolide diacid half esters (formula II) preparation method, it is clear and definite that the method has reaction mechanism, mild condition, raw material is low with reagent toxicity, separates purge process simple, product quality is high, is especially suitable for industrialization.
The preparation method that the present invention provides a kind of formula II compound, it is characterised in that with andrographolide for raw material, in faintly alkaline reaction dicyandiamide solution, adds a small amount of acidic catalyst, under inert gas shielding, and reacted prepared dehydrorographolide；Anhydride is added in above-mentioned reaction system, continue reaction, it is cooled to 40-70 DEG C, adding acetone, methanol or ethanol dilution, then temperature control is to 30-70 DEG C, drips purified water crystallization, decrease temperature crystalline is continued after dropwising, filter, obtain formula II, product drying or moist process and be used for preparing dehydrorographolide diacid half esters basic salt；Synthetic route is as follows:
R is selected from H, any one in alkyl, cycloalkyl, aryl.
Preferably, the temperature of described dehydration is 50-120 DEG C；It is furthermore preferred that temperature is 70-120 DEG C；Most preferred, temperature is 80-110 DEG C.
Preferably, the time of described dehydration is 3-12 hour；It is furthermore preferred that the response time is 5-10 hour.
Preferably, the temperature of described esterification is 30-100 DEG C；It is furthermore preferred that reaction temperature is 50-100 DEG C.
Preferably, the time of described esterification is 3-24 hour；It is furthermore preferred that the response time is 5-10 hour.
Preferably, described faintly alkaline reaction dicyandiamide solution is alkalescence organic base solvent system and/or non-protonic solvent system.
It is further preferred that described alkalescence organic base is selected from any one in pyridine, triethylamine, DMAP or DIPEA.
It is further preferred that described non-protonic solvent is selected from ketone or the nitrile of below hydrocarbon or halogenated hydrocarbons, ester, ether, cyclic ethers, four carbon atom；
It is furthermore preferred that hydrocarbon or halogenated hydrocarbons are selected from any one in toluene, 1,2-dichloroethanes, chloroform；Most preferred, described non-protonic solvent is toluene or 1,2 dichloroethanes；
It is furthermore preferred that ester is selected from any one in ethyl acetate, butyl acetate, propyl acetate；
It is furthermore preferred that ether, cyclic ethers are selected from any one in ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, methyltetrahydrofuran, dioxane；Most preferred, described non-protonic solvent is dioxane；
It is furthermore preferred that the ketone below four carbon atom is selected from any one in acetone, butanone, isobutyl ketone；
It is furthermore preferred that nitrile is selected from acetonitrile or propionitrile；Most preferred, described non-protonic solvent is acetonitrile.
Preferably, the solvent load of described faintly alkaline reaction dicyandiamide solution and the ratio of andrographolide are 1.5～20:1 (V/M, mL/g)；Preferably, ratio is 2.0～10:1 (V/M, mL/g).
Preferably, described acidic catalyst is any one in the organic acid of 1≤C≤15 selected from concentrated sulphuric acid, phosphoric acid, polyphosphoric acids, pyrovinic acid, hydrochloric acid, trifluoromethanesulfonic acid, trifluoroacetic acid, montmorillonite, acidic silica gel, carbon atoms；It is further preferred that the organic acid that described carbon atoms is 1≤C≤15 is formic acid, acetic acid, monoxone, oxalic acid, propanoic acid, succinic acid, citric acid, p-methyl benzenesulfonic acid or LOMAR PWA EINECS 246-676-2；
It is furthermore preferred that described acidic catalyst is concentrated sulphuric acid, hydrochloric acid, phosphoric acid, oxalic acid, polyphosphoric acids, p-methyl benzenesulfonic acid, trifluoroacetic acid or acidic silica gel.
Preferably, the consumption of described acidic catalyst and the ratio of andrographolide are 0.02～1.0 (M/M, g/g)；Preferably, ratio is 0.05～0.5 (M/M, g/g).
Preferably, described noble gas is selected from nitrogen, argon.
Preferably, anhydride or the mixed acid anhydride of described anhydride to be carbon atoms be 2≤C≤16；It is further preferred that described anhydride or mixed acid anhydride include acetic anhydride, propionic andydride, butyryl oxide., succinic anhydride, maleic anhydride, glutaric anhydride, adipic anhydride, benzoyl oxide or phthalic anhydride.
Preferably, described andrographolide is 1:2.0～10.0 (n/n) with the molar ratio of anhydride；Preferably, ratio is 1:2.0～7.0 (n/n)
Described add acetone, methanol or the consumption of ethanol are 5～10:1 (V/M, ml/g) with the ratio of andrographolide.
Compared with prior art, the technological merit of the present invention program is embodied in the following aspects:
1, one of the advantages is that of the present invention: prepare in dehydroandrographolide succinate (formula II) process, in faintly alkaline reaction dicyandiamide solution, add a small amount of acidic catalyst elder generation selectivity and carry out dehydration, the alcoholic extract hydroxyl group of allylic is carried out selectivity elimination, reduce by a reaction site, make follow-up esterification carry out relative unification, so that side reaction reduces, and then reduce the generation of impurity.Adopt dehydroandrographolide succinate (formula II) purity prepared by this kind of mentality of designing can reach 99.5% and more than.
2, the two of the key of the present invention are in that: prepare in dehydroandrographolide succinate (formula II) process, can be respectively adopted different reaction temperatures according to the activity of hydroxyls different in molecule and the time carries out dehydration and esterification when carrying out dehydration and esterification.And complete this operation and dehydrorographolide need not be easily separated purification.And current technology scheme adopts dehydration and becomes ester one step to complete, it is difficult to carry out the selectivity design of technological parameter according to the activity of each reaction site in molecule.Thus its process parameters design of the design of the present invention and adjusting range are wide in range, leave design space widely for preparing highly purified dehydroandrographolide succinate (formula II).
3, the three of the key of the present invention are in that: prepare in dehydroandrographolide succinate (formula II) process, in faintly alkaline reaction dicyandiamide solution, add the acid reagent of catalytic amount, can complete dehydration.Make the more current technical scheme of anhydride amount that subsequent reactions uses be greatly decreased, thus can directly reduce the consumption of material, reduce industrial production cost.
4, the four of the key of the present invention are in that: prepare in dehydrorographolide process, the high selectivity of dehydration is ensure that from theory and practical level, and then ensure that product has higher purity, can without dehydrorographolide being easily separated purification, and dehydration adopt dicyandiamide solution may be equally applicable for follow-up esterification.Thus not increasing reactions steps, actual effect is beyond the expection of the present inventor.
5, the five of the key of the present invention are in that: prepare in dehydrorographolide diacid half esters (formula II) process, the separation purification of dehydrorographolide diacid half esters (formula II), preferential use diluent acetone, methanol or Ethanol Treatment, then control temperature, add the mode of water crystallization.Can obtaining granule relatively big, specific surface area is little, it is easy to subsequent filter or centrifugal product.Not only make product easily dry, and residue of mother can be reduced.And then reduce the residual of impurity.Another technology is provided to ensure for preparing high-purity dehydrated andrographolide disuccinic acid half ester (formula II).
Accompanying drawing explanation
The structural formula of Fig. 1 andrographolide；
Fig. 2 is the structural formula of dehydrorographolide diacid half esters, and R is selected from any one in H, alkyl, cycloalkyl, aryl；
Fig. 3 is the route map preparing dehydrorographolide diacid half esters, and wherein R is selected from any one in H, alkyl, cycloalkyl, aryl.
Detailed description of the invention
For making the object, technical solutions and advantages of the present invention clearly understand, below in conjunction with detailed description of the invention and with reference to accompanying drawing, the present invention is described in more detail.It should be understood that these descriptions are illustrative of, and it is not intended to limit the scope of the present invention.
1. embodiment one:
Under the protection of noble gas, in reaction bulb, add andrographolide 25g, pyridine 75ml, when stirring, be slowly added to concentrated sulphuric acid 0.7ml.It is warming up to 105 DEG C, stirring reaction 6 hours.Succinic anhydrides 16.8g, 90 DEG C of stirring reactions of temperature control 5 hours are added after being cooled to 40 DEG C.Reacting complete, be cooled to 50 DEG C, add dehydrated alcohol 125ml, proceed in the reaction bulb of another cleaning after stirring, temperature control 50 DEG C dropping purified water 500ml, period has white solid to precipitate out as seen.Dropwising, be cooled to 10 DEG C of crystallizes stirred below 1 hour, filter, filter cake purified water 30ml × 2 wash twice, and obtain wet product 53.3g, in 65 DEG C of drying under reduced pressure 6 hours, obtain off-white color pressed powder 35.6g, yield: 93.7%.HPLC purity 99.51%.
2. embodiment two:
Under the protection of noble gas, in reaction bulb, add andrographolide 30g, dioxane 240ml, pyridine 60ml, when stirring, be slowly added to strong phosphoric acid 1.8ml.It is warming up to 101 DEG C, back flow reaction 8 hours.Succinic anhydrides 34.2g, 85 DEG C of stirring reactions of temperature control 6 hours are added after being cooled to room temperature.Reacting complete, reduce pressure Distillation recovery dioxane, is distilled to after no liquid flows out and is cooled to 40 DEG C, adds dehydrated alcohol 180ml, proceed in the reaction bulb of another cleaning after stirring, and temperature control 40 DEG C dropping purified water 720ml, period has white solid to precipitate out as seen.Dropwising, be cooled to 10 DEG C of crystallizes stirred below 1 hour, filter, filter cake purified water 40ml × 2 wash twice, and obtain wet product 66.5g, in 65 DEG C of drying under reduced pressure 6 hours, obtain off-white color pressed powder 43.5g, yield: 95.3%.HPLC purity 99.61%.
3. embodiment three:
Under the protection of noble gas, in reaction bulb, add andrographolide 20g, acetonitrile 200ml, triethylamine 40ml, when stirring, be slowly added to polyphosphoric acids 1.0ml.It is warming up to 81 DEG C, back flow reaction 12 hours.Succinic anhydrides 20g, 80 DEG C of stirring reactions of temperature control 7 hours are added after being cooled to room temperature.Reacting complete, reduce pressure Distillation recovery acetonitrile, is distilled to temperature control 45 DEG C after no liquid flows out, adds absolute methanol 100ml, proceed in the reaction bulb of another cleaning after stirring, and temperature control 45 DEG C dropping purified water 500ml, period has white solid to precipitate out as seen.Dropwising, be cooled to 10 DEG C of crystallizes stirred below 1 hour, filter, filter cake purified water 25ml × 2 wash twice, and obtain wet product 39.9g, in 65 DEG C of drying under reduced pressure 5 hours, obtain off-white color pressed powder 28.5g, yield: 94.1%.HPLC purity 99.67%.
4. embodiment four:
Under the protection of noble gas, in reaction bulb, add andrographolide 40g, dioxane 400ml, DIPEA 120ml, acidic silica gel 20g.Open stirring, be warming up to 95 DEG C and react 10 hours.It is cooled to 40 DEG C, filters and remove silica gel.It is subsequently adding succinic anhydrides 32g, 85 DEG C of stirring reactions of temperature control 8.5 hours.Reacting complete, reduce pressure Distillation recovery dioxane, is distilled to after no liquid flows out and adds acetone 240ml, proceeds in the reaction bulb of another cleaning after stirring, and temperature control 50 DEG C dropping purified water 800ml, period has white solid to precipitate out as seen.Dropwising, be cooled to 15 DEG C of crystallizes stirred below 1 hour, filter, filter cake purified water 50ml × 2 wash twice, and obtain wet product 70.5g, in 65 DEG C of drying under reduced pressure 5 hours, obtain off-white color pressed powder 56.4g, yield: 92.8%, HPLC purity 99.43%.
5. embodiment five:
Under the protection of noble gas, in reaction bulb, add andrographolide 35g, DMAP 10g, toluene 525ml, when stirring, be slowly added to concentrated sulphuric acid 2.9ml.It is warming up to 85 DEG C, stirring reaction 12 hours.Maleic anhydride 24.5g, 90 DEG C of stirring reactions of temperature control 5.5 hours are added after being cooled to 40 DEG C.Reacting complete, reduce pressure Distillation recovery toluene, is distilled to after no liquid flows out and is cooled to 50 DEG C, adds absolute methanol 245ml, proceed in the reaction bulb of another cleaning after stirring, and temperature control 50 DEG C dropping purified water 840ml, period has white solid to precipitate out as seen.Dropwising, be cooled to 10 DEG C of crystallizes stirred below 1 hour, filter, filter cake purified water 40ml × 2 wash twice, and obtain wet product 69.1g, in 65 DEG C of drying under reduced pressure 6 hours, obtain off-white color pressed powder 48.6g, yield: 91.7%.HPLC purity 99.55%
6. embodiment six:
Under the protection of noble gas, in reaction bulb, add andrographolide 60g, pyridine 120ml, n-propyl acetate 900ml, when stirring, be slowly added to strong phosphoric acid 5.3ml.It is warming up to 100 DEG C, stirring reaction 8 hours.Acetic anhydride 78g, 85 DEG C of stirring reactions of temperature control 5 hours are added after being cooled to 40 DEG C.Reacting complete, reduce pressure Distillation recovery n-propyl acetate, is distilled to after no liquid flows out and adds dehydrated alcohol 360ml, proceeds in the reaction bulb of another cleaning after stirring, and temperature control 60 DEG C dropping purified water 1320ml, period has white solid to precipitate out as seen.Dropwising, be cooled to 10 DEG C of crystallizes stirred below 1 hour, filter, filter cake purified water 80ml × 2 wash twice, and obtain wet product 133.4g, in 65 DEG C of drying under reduced pressure 6 hours, obtain off-white color pressed powder 64.4g, yield: 90.6%.HPLC purity 99.65%.
7. comparative example one:
Under the protection of noble gas, in reaction bulb, add andrographolide 30g, succinic anhydrides 45g, pyridine 75ml.It is warming up to 80 DEG C, stirring reaction 5 hours.Reacting complete, be cooled to 35 DEG C and add dehydrated alcohol 150ml, proceed in the reaction bulb of another cleaning after stirring, temperature control 35 DEG C dropping purified water 600ml, period has white solid to precipitate out as seen.Dropwising, be cooled to 10 DEG C of crystallizes stirred below 1 hour, filter, filter cake purified water 30ml × 3 are washed three times, obtain wet product 39.8g, in 65 DEG C of drying under reduced pressure 6 hours, obtain off-white color pressed powder 26.2g, yield: 86.3%.HPLC purity 98.68%
8. comparative example two:
(1) preparation of dehydrorographolide: under the protection of noble gas, adds andrographolide 40g, pyridine 100ml in reaction bulb, is slowly added to concentrated sulphuric acid 2.2ml when stirring.It is warming up to 105 DEG C, stirring reaction 6 hours.React complete, absolute methanol 120ml is added after being cooled to 40 DEG C, temperature control 40 DEG C dropping purified water 800ml, dropwises, is cooled to 0 DEG C of stirring and crystallizing 1 hour, filter, filter cake purified water 50ml × 2 washed twice, and obtain wet product 48.6g, in 65 DEG C of drying under reduced pressure 6 hours, obtain dehydrorographolide 32.4g, yield: 85.4%.
(2) preparation of dehydroandrographolide succinate: under the protection of noble gas, adds dehydrorographolide 32g, succinic anhydrides 22.4g, pyridine 96ml in reaction bulb, is warming up to 85 DEG C of stirring reactions 5 hours.Reacting complete, be cooled to 50 DEG C, add dehydrated alcohol 160ml, proceed in the reaction bulb of another cleaning after stirring, temperature control 50 DEG C dropping purified water 640ml, period has white solid to precipitate out as seen.Dropwising, be cooled to 10 DEG C of crystallizes stirred below 1 hour, filter, filter cake purified water 40ml × 2 wash twice, and obtain wet product 69.9g, in 65 DEG C of drying under reduced pressure 6 hours, obtain off-white color pressed powder 46.6g, yield: 90.9%.HPLC purity 99.44%.
Claims (15)
1. the preparation method of a formula II compound, it is characterised in that with andrographolide for raw material, in faintly alkaline reaction dicyandiamide solution, adds a small amount of acidic catalyst, under inert gas shielding, and reacted prepared dehydrorographolide；Anhydride is added in above-mentioned reaction system, continue reaction, be cooled to 40-70 DEG C, add acetone, methanol or ethanol dilution, then temperature control is to 30-70 DEG C, dropping purified water crystallization, continues decrease temperature crystalline, filters after dropwising, obtain formula II, product drying or moist, obtains dehydrorographolide diacid half esters basic salt, and synthetic route is as follows:
R is selected from H, any one in alkyl, cycloalkyl, aryl.
2. preparation method according to claim 1, it is characterised in that the temperature of described dehydration is 50-120 DEG C；It is further preferred that temperature is 70-120 DEG C；It is furthermore preferred that temperature is 80-110 DEG C.
3. preparation method according to claim 1, it is characterised in that the time of described dehydration is 3-12 hour；It is further preferred that the response time is 5-10 hour.
4. preparation method according to claim 1, it is characterised in that the temperature of described esterification is 30-100 DEG C；It is further preferred that reaction temperature is 50-100 DEG C.
5. preparation method according to claim 1, it is characterised in that the time of described esterification is 3-24 hour；It is further preferred that the response time is 5-10 hour.
6. preparation method according to claim 1, it is characterised in that described faintly alkaline reaction dicyandiamide solution is alkalescence organic base solvent system and/or non-protonic solvent system.
7. preparation method according to claim 6, it is characterised in that described alkalescence organic base is selected from any one in pyridine, triethylamine, DMAP or DIPEA.
8. preparation method according to claim 6, it is characterised in that described non-protonic solvent ketone below hydrocarbon or halogenated hydrocarbons, ester, ether, cyclic ethers, four carbon atom or any one in nitrile；Preferably, described hydrocarbon or halogenated hydrocarbons are selected from any one in toluene, 1,2-dichloroethanes, chloroform；It is further preferred that described hydrocarbon or halogenated hydrocarbons are toluene or 1,2 dichloroethanes；Preferably, ester is selected from any one in ethyl acetate, butyl acetate, propyl acetate；Preferably, ether, any one in ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, methyltetrahydrofuran, the dioxane of cyclic ethers；Most preferred, described non-protonic solvent is dioxane；Preferably, the ketone below four carbon atom is selected from any one in acetone, butanone, isobutyl ketone；Preferably, nitrile is selected from acetonitrile or propionitrile；Most preferred, described non-protonic solvent is acetonitrile.
9. preparation method according to claim 1, it is characterised in that the solvent load of described faintly alkaline reaction dicyandiamide solution and the ratio of andrographolide are 1.5～20:1 (V/M, mL/g)；Preferably, ratio is 2.0～10:1 (V/M, mL/g).
10. preparation method according to claim 1, it is characterized in that, described acidic catalyst is any one in the organic acid of 1≤C≤15 selected from concentrated sulphuric acid, phosphoric acid, polyphosphoric acids, pyrovinic acid, hydrochloric acid, trifluoromethanesulfonic acid, trifluoroacetic acid, montmorillonite, acidic silica gel, carbon atoms；It is further preferred that the organic acid that described carbon atoms is 1≤C≤15 is formic acid, acetic acid, monoxone, oxalic acid, propanoic acid, succinic acid, citric acid, p-methyl benzenesulfonic acid or LOMAR PWA EINECS 246-676-2；It is furthermore preferred that described acidic catalyst is concentrated sulphuric acid, hydrochloric acid, phosphoric acid, oxalic acid, polyphosphoric acids, p-methyl benzenesulfonic acid, trifluoroacetic acid or acidic silica gel.
11. preparation method according to claim 1, it is characterised in that the consumption of described acidic catalyst and the ratio of andrographolide are 0.02～1.0 (M/M, g/g)；Preferably, ratio is 0.05～0.5 (M/M, g/g).
12. preparation method according to claim 1, it is characterised in that described noble gas is nitrogen or argon.
13. preparation method according to claim 1, it is characterised in that described anhydride is carbon atoms is anhydride or the mixed acid anhydride of 2≤C≤16；It is further preferred that described anhydride or mixed acid anhydride include acetic anhydride, propionic andydride, butyryl oxide., succinic anhydride, maleic anhydride, glutaric anhydride, adipic anhydride, benzoyl oxide, phthalic anhydride.
14. preparation method according to claim 1, it is characterised in that the molar ratio stating andrographolide and anhydride is 1:2.0～10.0 (n/n)；Preferably, ratio is 1:2.0～7.0 (n/n).
15. preparation method according to claim 1, it is characterised in that described add acetone, methanol or the consumption of ethanol are 5～10:1 (V/M, ml/g) with the ratio of andrographolide.
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| CN106420711A (en) * | 2016-10-11 | 2017-02-22 | 哈尔滨珍宝制药有限公司 | Andrographolide composition, injection preparation of andrographolide composition and preparation method |
| CN109053648A (en) * | 2018-09-10 | 2018-12-21 | 成都通德药业有限公司 | A kind of preparation process of potassium dehydroandrographolide succinate |
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