CN103360350B - A kind of preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection - Google Patents
A kind of preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection Download PDFInfo
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Abstract
The invention belongs to preparation method's technical field of potassium sodium dehydroandroan drographolide succinate; described applicable suitability for industrialized production, the preparation method of highly purified Andrographolide in Andrographolide for Injection; be under nitrogen protection esterification occurs with rographolide and Succinic anhydried, then it is obtained to add basic solution one step salify.Adopt non-polar solvent-weak acid water compound to remove pyridine after esterification, pyridine removal efficiency is high, effectively can reduce the content of related substance, ensure drug quality; Salt-forming reaction adopts acetone-water system, and both can be conducive to salt-forming reaction and carry out, can increase decolorizing with activated carbon effect again, product purity is high.Present invention process is better than the conventional technique from rographolide or Intermediate Preparation potassium sodium dehydroandroan drographolide succinate adopted, and it also avoid the process preparing potassium sodium dehydroandroan drographolide succinate in routine techniques from potassium dehydroandrographolide succinate, direct one-step synthesis, reactions steps is simple, cost is low, product purity is high, environmental friendliness, is applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to field of medicaments, particularly, the present invention relates to a kind of preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection.
Background technology
Potassium sodium dehydroandroan drographolide succinate is the new derivatives of traditional Chinese medicine Herba Andrographis extract rographolide, chemical name is 14-deshydroxy-11,12-bis-dehydrogenation rographolide-3,19-disuccinic acid half ester k-na salt monohydrate, preparation current mainly liquid drugs injection or the freeze-dried powder of this product, early stage capillary permeability can be suppressed clinically to increase and inflammatory exudation and oedema, can excited Pituitary Adrenalcortical function specifically, promote adrenocortical hormone (ACTH) release, increase the biosynthesizing of ACTH in prepituitary gland; The external effect with multiple viruses such as inactivated adenovirus, influenza virus, Respiroviruses.Mainly being applicable to virus pneumonia and viral upper respiratory tract infection, is one of medicine comparatively commonly used in current tcm emergency.Chemical structure is as follows:
This product is easily molten in water, and slightly soluble is in ethanol insoluble in acetone or ether.
Potassium sodium dehydroandroan drographolide succinate is as listing old kind comparatively early, three kinds of modes are had about its synthesis according to starting raw material difference: (1) is direct is that starting raw material and sodium hydroxide, sodium bicarbonate or sodium carbonate etc. react salify with potassium dehydroandrographolide succinate in prior art, potassium sodium dehydroandroan drographolide succinate [Xu Rongzhen is obtained through aftertreatment, Li Haiying, Yu Na. the synthesis of potassium sodium dehydroandroan drographolide succinate, Heilungkiang scientific and technical information]; (2) be that direct the reaction to sodium bicarbonate or saleratus of raw material generates corresponding natrium potassium salt with dehydroandrographolide succinate; (3) take rographolide as raw material, first react to succinyl oxide and generate half corresponding ester structure, then react with corresponding basic sodium sylvite and generate potassium sodium dehydroandroan drographolide succinate [Bai Jun, Hu Shigao, Liu Yan. the study on the synthesis of potassium sodium dehydroandroan drographolide succinate. drug research, 2007,16 (24): 21].
Chinese patent CN100465171 adopt rographolide react with succinyl oxide in pyridine, the dehydroandrograpolide succinate obtained again in water with KOH, KHCO
3, K
2cO
3after reaction forms andrographolide succinic acid half-ester monopotassium salt, with NaOH, NaHCO
3or Na
2cO
3aqueous solution adjust ph to 7 ~ 8, obtain potassium sodium dehydroandroan drographolide succinate through aftertreatment.
In the synthesis technique of potassium sodium dehydroandroan drographolide succinate, with the pyridine that height is malicious and the smell is awful as solvent and catalyzer.Human drugs registration technology specification international coordination meeting (ICH) specifies, pyridine, as Equations of The Second Kind solvent, need limit use.Pyridine has intense stimulus, can central nervous system be anaesthetized, hepatorenal damage, polyneuropathy can occur, to the harm such as skin is irritant, ICH is classified as without genotoxicity but has the solvent of animal carinogenicity, need to be limited in the formulation, its concentration limit is 200ppm.
Chinese patent CN100465171, adds greatly excessive pyridine in the esterification reaction, and it is removed by the boiling under reflux being heated to pyridine.But when in this process, pyridine is removed to a degree, system can be more and more thicker, and temperature requirement is more and more higher, long-time heating product purity also can reduce; And in order to ensure the needs stirred, in system, needing moieties pyridine to exist, so adopt the method for distillation, pyridine can not be eliminated completely.
In addition, also have ordinary method, in the esterification reaction or when the process of potassium sodium dehydroandroan drographolide succinate finished product, the way that adopting adds water repeatedly washs removes pyridine, to control pyridine residual quantity.But this method generally only can remove free pyridine, because potassium sodium dehydroandroan drographolide succinate is with certain acidity, pyridine is weakly alkaline, easily and the carboxylate radical salify of product, the method of simple pure water, can not wash away the pyridine of salify, often causes the pyridine in potassium sodium dehydroandroan drographolide succinate to remain excessive phenomenon.And repeatedly wash, consuming time longer, complex operation, efficiency is very low.
The application finds, in the intermediate reaction process of raw material, adopt non-polar solvent-weak acid water compound to remove pyridine, namely ensure that salify pyridine is separated from product on the one hand, on the other hand, avoid repeatedly washing, by index of central control, easily pyridine content is controlled to≤0.1% (HPLC area normalization method), increase one or many when pyridine can be avoided to exceed standard in finished product and refine, namely by easy operation by risk control in source, ensure that the quality of finished product.
Crystallization many employings solvent crystal of potassium sodium dehydroandroan drographolide succinate, but system differs.Be that start material is prepared in the technique of potassium sodium dehydroandroan drographolide succinate with potassium dehydroandrographolide succinate, CN101260097 is open is the technique that potassium sodium dehydroandroan drographolide succinate prepared by raw material with potassium dehydroandrographolide succinate, employing be dehydrated alcohol/sodium bicarbonate system salify, then use dehydrated alcohol crystallization, purity 98.5%.CN102367243 adopts 95% ethanol/5% sodium bicarbonate crystallization, then uses the ethyl acetate of 2:1: ethyl alcohol recrystallization, purity 99.45%.A kind of crystal formation of the open potassium sodium dehydroandroan drographolide succinate of CN10238208, it at dehydrated alcohol/sodium bicarbonate system salify, then uses dehydrated alcohol crystallization, purity 99% by potassium dehydroandrographolide succinate.
In sum, in prior art, adopt is removed to pyridine in esterification more and wash and reflux mode, poor effect, easily cause pyridine to remain, affect medicine quality.In salt-forming reaction, many gradation are fed in raw material, and after making andrographolide succinic acid half-ester monopotassium salt (i.e. potassium dehydroandrographolide succinate), then add NaOH, NaHCO
3or Na
2cO
3the aqueous solution adjust ph reaction, potassium sodium dehydroandroan drographolide succinate is obtained through the aftertreatment of dehydrated alcohol crystallization, complex operation, and when dripping alkali lye in ethanol system, easy conglomeration, be unfavorable for stirring, therefore there will be local alkalescence excessive, make potassium sodium dehydroandroan drographolide succinate produce ester and decompose and cycloreversion reaction, make related substance not meet quality standard, thus increasing the irritated risk waiting untoward reaction in patient's use procedure, the yield of andrographolide bulk pharmaceutical also can reduce simultaneously.
Summary of the invention
The object of this invention is to provide the preparation method of a kind of applicable suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection, described reaction method under nitrogen protection esterification occurs with rographolide and succinyl oxide, then it is obtained to add basic solution one step salify.Esterification obtains dehydroandrographolide succinate, and Herba Andrographis succinic acid half-ester k-na salt (i.e. potassium sodium dehydroandroan drographolide succinate) is prepared in salt-forming reaction.This preparation method's reaction conditions is gentle, and easy and simple to handle, raw material and reagent are easy to get.Non-polar solvent-weak acid water compound is adopted to remove pyridine in esterification, acetone-water system crystallization, the rear purified product of making beating is adopted after salt-forming reaction, obtain highly purified andrographolide bulk pharmaceutical, for the preparation of Andrographolide in Andrographolide for Injection freeze-dried powder, other Andrographolide in Andrographolide for Injections relatively, have efficient, the significant advantage of low toxicity.
The present invention is compared to the common process from rographolide or Intermediate Preparation potassium sodium dehydroandroan drographolide succinate, and pyridine removal efficiency is high, effectively can reduce the content of related substance, ensure that drug quality.And avoiding the process preparing potassium sodium dehydroandroan drographolide succinate in routine techniques from potassium dehydroandrographolide succinate, direct one-step synthesis, reactions steps is easy, cost is low, and product purity is high, environmental friendliness, is applicable to suitability for industrialized production.Adopt acetone-water system crystallization, both can be conducive to salt-forming reaction and carry out, and decolorizing with activated carbon effect can have been increased again.Compared with existing technology of preparing, the reagent that the present invention uses, reactant consumption, reaction times have obviously different from prior art, simpler than prior art, rationally safer.
For realizing object of the present invention, the present invention adopts following technical scheme: the preparation method of a kind of applicable suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection, comprises the steps:
A, esterification: under nitrogen protection, be starting material with rographolide and succinyl oxide, take sodium sulphite anhydrous 99.3 as antioxidant, 45 ~ 95 DEG C are warming up to from 10 ~ 30 DEG C, reaction 4 ~ 20h, follows the tracks of reaction to intermediate state and mores than less than 0.1% stopped reaction, cooling, non-polar solvent-weak acid water compound is adopted to remove pyridine, concentrated, decolouring;
B, salt-forming reaction: add acetone-water by system, nitrogen protection borehole cooling, to-10 ~ 5 DEG C, drips basic solution; react to obtain molten clear solution, system is added crystallization in acetone-water, suction filtration under nitrogen protection; filter cake adds acetone making beating, and suction filtration final vacuum is dry, obtains high purity potassium sodium dehydroandroan drographolide succinate.
Wherein, in step a esterification, the mol ratio of rographolide and succinyl oxide is 1:3 ~ 1:5, is preferably 1:3.5 ~ 1:4.8, most preferably is 1:3.8 ~ 1:4.5.
Esterification reaction temperature is 45 ~ 95 DEG C, and reaction 4 ~ 20h, is preferably 70 ~ 90 DEG C, and reaction 10 ~ 14h, most preferably is 80 DEG C, reaction 12h.
Non-polar solvent-weakly acidic aqueous solution cleaning is adopted to remove pyridine after esterification, non-polar solvent is for being selected from trichloromethane, methylene dichloride, ethyl acetate, at least one in Iso Butyl Acetate, weak acid is for being selected from succinic acid, oxalic acid, citric acid, dilute hydrochloric acid, at least one in phosphoric acid, preferred non-polar solvent is for being selected from trichloromethane, methylene dichloride, at least one in ethyl acetate, preferred weak acid is for being selected from succinic acid, oxalic acid, at least one in citric acid, most preferably non-polar solvent is for being selected from methylene dichloride, at least one in ethyl acetate, most preferably weak acid is for being selected from oxalic acid, at least one in citric acid.
Preferred non-polar solvent-weak acid water compound is for adding rographolide 5 ~ 10 times amount (v/w), non-polar solvent: 0.5mol/L ~ 1.0mol/L weak acid water compound (v/v=1:1), most preferably non-polar solvent-weak acid water compound is for adding rographolide 6 ~ 8 times amount (v/w), non-polar solvent: 0.5mol/L ~ 0.6mol/L weak acid water compound (v/v=1:1).
After removing pyridine, system becomes oily thick liquid at 20 ~ 35 DEG C of vacuum concentration, add the acetone-water of 3 ~ 6 times of volumes, activated carbon decolorizing 40 ~ 70min, obtained dehydroandrographolide succinate, preferably add the acetone-water of 4 ~ 5 times of volumes, activated carbon decolorizing 60min.
Step b drips KOH/K simultaneously
2cO
3/ KHCO
3in at least one and NaOH/Na
2cO
3/ NaHCO
3middle at least one carries out salt-forming reaction, preferably, drips the KHCO of 1eq. simultaneously
3with the Na of 0.5eq.
2cO
3solution, time for adding is preferably 30min.
Salt-forming reaction temperature is 10 ~ 30 DEG C, and reaction 50 ~ 90min, is preferably 10 ~ 20 DEG C, reaction 60 ~ 70min.
Adopt the acetone-water of 40 ~ 60 times of volumes to tie up to 10 ~ 40 DEG C of crystallizatioies, the acetone-water being preferably 50 ~ 60 times of volumes ties up to 20 ~ 30 DEG C of crystallizatioies, and the acetone-water most preferably being 55 times of volumes ties up to 25 DEG C of crystallizatioies.
Reaction scheme is as follows:
Accompanying drawing explanation
Accompanying drawing 1 dehydroandrographolide succinate hydrogen is composed
The HPLC collection of illustrative plates (pyridine appearance time is 2.765min, and adopting area normalization method to calculate and remaining is 0.0058%, is less than 0.1%) that in accompanying drawing 2 esterification, pyridine is residual
The HPLC collection of illustrative plates of accompanying drawing 3 potassium sodium dehydroandroan drographolide succinate purity testing
Embodiment
Be described below in detail embodiments of the invention, it should be noted that embodiment described below is exemplary, only for explaining the present invention, and can not limitation of the present invention be interpreted as.
Embodiment 1
Step a esterification:
Under room temperature, toward be equipped with thermometer drying 2L there-necked flask in add 700mL pyridine (KF<0.05%), nitrogen is extended liquid level blowing down 1.5h, sodium sulphite anhydrous 99.3 (30g is added under nitrogen protection, 0.238 mole), succinyl oxide (350g, 3.50 mole), after nitrogen blows 20min, add rographolide (300g, 0.856 mole), nitrogen blows 15min again, then start to be warming up to 70 DEG C of reactions, sampling is started after reaction 12h, sample every 1h, follow the tracks of reaction to intermediate state and more than less than 0.1% stopped reaction (about 15h), be cooled to 40 DEG C, be poured into water crystallization 30min, suction filtration, filter cake adds 8 times amount (v/w) methylene dichloride-0.5mol/L oxalic acid (1:1, v/v) aqueous cleaning, when without solid materials, leave standstill, separatory, organic phase 1-2 times of volume 0.25mol/L aqueous oxalic acid washs, monitoring pyridine LC area fraction is to≤0.1% (HPLC area normalization method).Again methylene dichloride is used mutually the washing three times of 1 ~ 2 times of volume, separatory.By methylene dichloride phase breakdown of emulsion, separatory, and at 20 ~ 35 DEG C of vacuum concentration into about 500mL(1.6mL/g) oily thick liquid, recording dehydroandrographolide succinate content is 70%.In concentrate system, add the acetone of 3 times of volumes: water (3:1, v/v), molten clear after add the gac of 60g, at 20-30 DEG C of decolouring 60min, suction filtration, filter cake 100mL washing with acetone, collects filtrate.
Dehydroandrographolide succinate hydrogen spectrum (nuclear-magnetism condition: solvent C DCl
3, nuclear-magnetism frequency 400MHz): 0.83 (s, 3H), 1.02 (s, 3H), 1.17 ~ 1.28 (m, 1H), 1.35 (d, 1H), 1.47 ~ 1.62 (m, 2H), 1.64 ~ 1.70 (m, 2H), 1.82 (d, 1H), 2.01 ~ 2.07 (m, 1H), 2.33 ~ 2.80 (m, 10H), 4.16 (d, 1H), 4.39 (d, 1H), 4.56 (s, 1H), 4.62 ~ 4.66 (m, 1H), 4.74 (s, 1H), 4.81 (s, 2H), 6.13 (d, 1H), 6.91 (dd, 1H), 7.17 (s, 1H), 8.72 (br, 2H).
Embodiment 2
Step a esterification:
Under room temperature, toward be equipped with thermometer drying 2L there-necked flask in add 600mL pyridine (KF<0.05%), nitrogen is extended liquid level blowing down 1.5h, sodium sulphite anhydrous 99.3 (30g is added under nitrogen protection, 0.238 mole), succinyl oxide (300g, 3.0 moles), after nitrogen blows 20min, add rographolide (300g, 0.856 mole), nitrogen blows 15min again, then start to be warming up to 80 DEG C of reactions, sampling is started after reaction 10h, sample every 1h, follow the tracks of reaction to intermediate state and more than less than 0.1% stopped reaction (about 12h), be cooled to 40 DEG C, be poured into water crystallization 30min, suction filtration, filter cake adds 9 times amount (v/w) methylene dichloride-0.5mol/L oxalic acid and citric acid mixing solutions (1:1, v/v) clean, when without solid materials, leave standstill, separatory, organic phase 1-2 times of volume 0.25mol/L aqueous oxalic acid washs, monitoring pyridine LC area fraction is to≤0.1% (HPLC area normalization method).Again methylene dichloride is washed three times, separatory with 1 ~ 2 times of volume mutually.By methylene dichloride phase breakdown of emulsion, separatory, and at 20 ~ 35 DEG C of vacuum concentration into about 400mL(1.8mL/g) oily thick liquid, recording dehydroandrographolide succinate content is 73%.In concentrate system, add 4 times of volume acetone: water (3:1, v/v), molten clear after add the gac of 60g, at 20-30 DEG C of decolouring 60min, suction filtration, filter cake 100ml washing with acetone, collects filtrate.
Embodiment 3
Step a esterification:
Under room temperature, toward be equipped with thermometer drying 2L there-necked flask in add 600mL pyridine (KF<0.05%), nitrogen is extended liquid level blowing down 1.5h, sodium sulphite anhydrous 99.3 (30g is added under nitrogen protection, 0.238 mole), succinyl oxide (400g, 4.0 moles), after nitrogen blows 20min, add rographolide (300g, 0.856 mole), nitrogen blows 15min again, then start to be warming up to 95 DEG C of reactions, sampling is started after reaction 2h, sample every 1h, follow the tracks of reaction to intermediate state and more than less than 0.1% stopped reaction (about 4h), be cooled to 60 DEG C, be poured into water crystallization 40min, suction filtration, filter cake adds 10 times amount (v/w) ethyl acetate-1.0mol/L oxalic acid (1:1, v/v) aqueous cleaning, when without solid materials, leave standstill, separatory, organic phase 1-2 times of volume 0.5mol/L aqueous oxalic acid washs, monitoring pyridine LC area fraction is to≤0.1% (HPLC area normalization method).Again methylene dichloride is washed three times, separatory with 1 ~ 2 times of volume mutually.By methylene dichloride phase breakdown of emulsion, separatory, and at 20 ~ 35 DEG C of vacuum concentration into about 550mL(1.5mL/g) oily thick liquid, recording dehydroandrographolide succinate content is 49%.In concentrate system, add 3 times of volume acetone: water (3:1, v/v), molten clear after add the gac of 60g, at 20 ~ 30 DEG C of decolouring 40min, suction filtration, filter cake 100mL washing with acetone, collects filtrate.
Embodiment 4
Step a esterification:
Under room temperature, toward be equipped with thermometer drying 2L there-necked flask in add 500mL pyridine (KF<0.05%), nitrogen is extended liquid level blowing down 1.5h, sodium sulphite anhydrous 99.3 (30g is added under nitrogen protection, 0.238 mole), succinyl oxide (326g, 3.257 mole), after nitrogen blows 20min, add rographolide (300g, 0.856 mole), nitrogen blows 15min again, then start to be warming up to 45 DEG C of reactions, sampling is started after reaction 15h, sample every 1h, follow the tracks of reaction to intermediate state and more than less than 0.1% stopped reaction (about 20h), be cooled to 40 DEG C, be poured into water crystallization 50min, suction filtration, filter cake adds 6 times amount (v/w) trichloromethane-0.5mol/L citric acid (1:1, v/v) aqueous cleaning, when without solid materials, leave standstill, separatory, organic phase 2 times of volume 0.2mol/L aqueous citric acid solutions wash, monitoring pyridine LC area fraction is to≤0.1% (HPLC area normalization method).Again methylene dichloride is washed three times, separatory with 1 ~ 2 times of volume mutually.By methylene dichloride phase breakdown of emulsion, separatory, and at 20 ~ 35 DEG C of vacuum concentration into about 450mL(1.6mL/g) oily thick liquid, recording dehydroandrographolide succinate content is 35%.In concentrate system, add 4 times of volume acetone: water (3:1, v/v), molten clear after add the gac of 60g, at 20 ~ 30 DEG C of decolouring 70min, suction filtration, filter cake 100mL washing with acetone, collects filtrate.
Embodiment 5
Step a esterification:
Under room temperature, toward be equipped with thermometer drying 2L there-necked flask in add 500mL pyridine (KF<0.05%), nitrogen is extended liquid level blowing down 1.5h, sodium sulphite anhydrous 99.3 (30g is added under nitrogen protection, 0.238 mole), succinyl oxide (385.5g, 3.852 mole), after nitrogen blows 20min, add rographolide (300g, 0.856 mole), nitrogen blows 15min again, then start to be warming up to 85 DEG C of reactions, sampling is started after reaction 8h, sample every 1h, follow the tracks of reaction to intermediate state and more than less than 0.1% stopped reaction (about 10h), be cooled to 50 DEG C, be poured into water crystallization 30min, suction filtration, filter cake adds 8 times amount (v/w) methylene dichloride-0.6mol/L oxalic acid (1:1, v/v) aqueous cleaning, when without solid materials, leave standstill, separatory, organic phase 2 times of volume 0.3mol/L aqueous oxalic acid wash, monitoring pyridine LC area fraction is to≤0.1% (HPLC area normalization method).Again a methylene dichloride 1-2 times volume is washed three times, separatory.By methylene dichloride phase breakdown of emulsion, separatory, and at 20 ~ 35 DEG C of vacuum concentration into about 450mL(1.6mL/g) oily thick liquid, recording dehydroandrographolide succinate content is 84%.In concentrate system, add 4 times of volume acetone: water (3:1, v/v), molten clear after add the gac of 60g, at 20 ~ 30 DEG C of decolouring 60min, suction filtration, filter cake 100mL washing with acetone, collects filtrate.
Embodiment 6
Step a esterification:
Under room temperature, toward be equipped with thermometer drying 2L there-necked flask in add 500mL pyridine (KF<0.05%), nitrogen is extended liquid level blowing down 1.5h, sodium sulphite anhydrous 99.3 (30g is added under nitrogen protection, 0.238 mole), succinyl oxide (300g, 3.0 moles), after nitrogen blows 20min, add rographolide (300g, 0.856 mole), nitrogen blows 15min again, then start to be warming up to 85 DEG C of reactions, sampling is started after reaction 8h, sample every 1h, follow the tracks of reaction to intermediate state and more than less than 0.1% stopped reaction (about 10h), be cooled to 50 DEG C, be poured into water crystallization 30min, suction filtration, filter cake adds 8 times amount (v/w) methylene dichloride-0.5mol/L citric acid (1:1, v/v) aqueous cleaning, when without solid materials, leave standstill, separatory, organic phase 2 times of volume 0.2mol/L aqueous citric acid solutions wash, monitoring pyridine LC area fraction is to≤0.1% (HPLC area normalization method).Again methylene dichloride is washed three times, separatory with 1 ~ 2 times of volume mutually.By methylene dichloride phase breakdown of emulsion, separatory, and at 20 ~ 35 DEG C of vacuum concentration into about 450mL(1.6mL/g) oily thick liquid, recording dehydroandrographolide succinate content is 78%.In concentrate system, add 4 times of volume acetone: water (3:1, v/v), molten clear after add the gac of 60g, at 20 ~ 30 DEG C of decolouring 60min, suction filtration, filter cake 100mL washing with acetone, collects filtrate.
Embodiment 7
Step a esterification:
Under room temperature, toward be equipped with thermometer drying 2L there-necked flask in add 500mL pyridine (KF<0.05%), nitrogen is extended liquid level blowing down 1.5h, sodium sulphite anhydrous 99.3 (30g is added under nitrogen protection, 0.238 mole), succinyl oxide (700g, 4.277 mole), after nitrogen blows 20min, add rographolide (300g, 0.856 mole), nitrogen blows 15min again, then start to be warming up to 80 DEG C of reactions, sampling is started after reaction 9h, sample every 1h, follow the tracks of reaction to intermediate state and more than less than 0.1% stopped reaction (about 12h), be cooled to 40 DEG C, be poured into water crystallization 30min, suction filtration, filter cake adds 8 times amount (v/w) Iso Butyl Acetate-0.5mol/L succinic acid (1:1, v/v) aqueous cleaning, when without solid materials, leave standstill, separatory, organic phase 2 times of volume 0.2mol/L succinic acid solution washings, monitoring pyridine LC area fraction is to≤0.1% (HPLC area normalization method).Again methylene dichloride is washed three times, separatory with 1 ~ 2 times of volume mutually.By methylene dichloride phase breakdown of emulsion, separatory, and at 20 ~ 35 DEG C of vacuum concentration into about 500mL(1.5mL/g) oily thick liquid, recording dehydroandrographolide succinate content is 83%.In concentrate system, add 3 times of volume acetone: water (3:1, v/v), molten clear after add the gac of 60g, at 20 ~ 30 DEG C of decolouring 60min, suction filtration, filter cake 100mL washing with acetone, collects filtrate.
Embodiment 8
Step a esterification:
Under room temperature, toward be equipped with thermometer drying 500L enamel still in add 125L pyridine (KF<0.05%), nitrogen is extended liquid level blowing down 1.5h, sodium sulphite anhydrous 99.3 (7.5kg is added under nitrogen protection, 59.5 mole), succinyl oxide (81.4kg, 813.3 moles), after nitrogen blows 20min, add rographolide (75kg, 214 moles), nitrogen blows 15min again, then start to be warming up to 80 DEG C of reactions, sampling is started after reaction 10h, sample every 1h, follow the tracks of reaction to intermediate state and more than less than 0.1% stopped reaction (about 12h), be cooled to 40 DEG C, be poured into water crystallization 30min, suction filtration, filter cake adds 8 times amount (v/w) methylene dichloride-0.5mol/L succinic acid (1:1, v/v) aqueous cleaning, when without solid materials, leave standstill, separatory, organic phase 2 times of volume 0.2mol/L succinic acid solution washings, monitoring pyridine LC area fraction is to≤0.1% (HPLC area normalization method).Again a methylene dichloride 1-2 times volume is washed three times, separatory.By methylene dichloride phase breakdown of emulsion, separatory, and at 20 ~ 35 DEG C of vacuum concentration into about 125L(1.5mL/g) oily thick liquid, recording dehydroandrographolide succinate content is 85%.In concentrate system, add 3 times of volume acetone: water (3:1, v/v), molten clear after add the gac of 15kg, at 20 ~ 30 DEG C of decolouring 60min, suction filtration, filter cake 25L washing with acetone, collects filtrate.
Embodiment 9
Step b salt-forming reaction:
System is poured in 3L three-necked flask; add acetone and the water (3:1 of 4 times of volumes respectively; v/v); nitrogen protection borehole cooling is to-5 ~ 5 DEG C; drip the saleratus of purified water-soluble 1eq. and the sodium carbonate solution of 0.5eq. of 0 ~ 10 DEG C, 20min drips, and keeps 20min at this temperature; start to be warming up to 10 ~ 30 DEG C of reaction 60min, now solution is almost clearly molten.System joined in acetone-water (3:1, the v/v) system of 55 times of volumes, at 20 DEG C of crystallizatioies, 20min adds again, and-5 ~ 5 DEG C are stirred 70min.Suction filtration under nitrogen protection, obtains light green solid.Pull an oar filter cake 3.5L acetone under 20 DEG C of nitrogen protections 60min, and suction filtration is done, and filter cake is transferred to drip pan, obtains white crystalline powder after 25 DEG C of vacuum-drying to moisture content are not more than 3.0%.Purity is 98.0%.
Embodiment 10
Step b salt-forming reaction:
System is poured in 3L three-necked flask; add acetone and the water (3:1 of 3 times of volumes respectively; v/v); nitrogen protection borehole cooling is to-5 ~ 5 DEG C; drip the saleratus of purified water-soluble 1eq. and the sodium carbonate solution of 1eq. of 0 ~ 10 DEG C, 20min drips, and keeps 30min at this temperature; start to be warming up to 10 ~ 30 DEG C of reaction 90min, now solution is almost clearly molten.System joined in acetone-water (3:1, the v/v) system of 60 times of volumes, at 10 ~ 30 DEG C of crystallizatioies, 30min adds again, and-5 ~ 5 DEG C are stirred 60min.Suction filtration under nitrogen protection, pull an oar filter cake 5L acetone under 20 DEG C of nitrogen protections 60min, and suction filtration is done, and filter cake is transferred to drip pan, obtains white crystalline powder after 35 DEG C of vacuum-drying to moisture content are not more than 3.0%.Purity is 97.9%.
Embodiment 11
Step b salt-forming reaction:
System is poured in 3L three-necked flask; add acetone and the water (3:1 of 5 times of volumes respectively; v/v); nitrogen protection borehole cooling is to-5 ~ 5 DEG C; drip the saleratus of purified water-soluble 1eq. and the sodium carbonate solution of 0.5eq. of 0 ~ 10 DEG C, 30min drips, and keeps 30min at this temperature; start to be warming up to 10 ~ 20 DEG C of reaction 60min, now solution is almost clearly molten.System joined in acetone-water (3:1, the v/v) system of 55 times of volumes, at 20 DEG C of crystallizatioies, 30min adds again, and-5 ~ 5 DEG C are stirred 60min.Suction filtration under nitrogen protection, pull an oar filter cake 4L acetone under 20 DEG C of nitrogen protections 60min, and suction filtration is done, and filter cake is transferred to drip pan, obtains white crystalline powder after 30 DEG C of vacuum-drying to moisture content are not more than 3.0%.Purity is 99.76%.
Embodiment 12
Step b salt-forming reaction:
System is poured in 3L three-necked flask; add acetone and the water (3:1 of 5 times of volumes respectively; v/v); nitrogen protection borehole cooling is to-5 ~ 5 DEG C; drip the saleratus of purified water-soluble 1eq. and the sodium carbonate solution of 0.5eq. of 0 ~ 10 DEG C, 20min drips, and keeps 30min at this temperature; start to be warming up to 10 ~ 20 DEG C of reaction 80min, now solution is almost clearly molten.System joined in acetone-water (3:1, the v/v) system of 50 times of volumes, at 10 ~ 30 DEG C of crystallizatioies, 30min adds again, and-5 ~ 5 DEG C are stirred 60min.Suction filtration under nitrogen protection, pull an oar filter cake 4L acetone under 20 DEG C of nitrogen protections 40min, and suction filtration is done, and filter cake is transferred to drip pan, obtains white crystalline powder after 30 DEG C of vacuum-drying to moisture content are not more than 3.0%.Purity is 98.9%.
Embodiment 13
Step b salt-forming reaction:
System is poured in 3L three-necked flask; add acetone and the water (3:1 of 4 times of volumes respectively; v/v); nitrogen protection borehole cooling is to-5 ~ 5 DEG C; drip the salt of wormwood of purified water-soluble 1eq. and the sodium hydrogen carbonate solution of 0.5eq. of 0 ~ 10 DEG C, 20min drips, and keeps 30min at this temperature; start to be warming up to 10 ~ 20 DEG C of reaction 70min, now solution is almost clearly molten.System joined in acetone-water (3:1, the v/v) system of 40 times of volumes, at 10 ~ 30 DEG C of crystallizatioies, 30min adds again, and-5 ~ 5 DEG C are stirred 60min.Suction filtration under nitrogen protection, pull an oar filter cake 4L acetone under 20 DEG C of nitrogen protections 60min, and suction filtration is done, and filter cake is transferred to drip pan, obtains white crystalline powder after 30 DEG C of vacuum-drying to moisture content are not more than 3.0%.Purity is 98.6%.
Embodiment 14
Step b salt-forming reaction:
System is poured in 3L three-necked flask; add acetone and the water (3:1 of 4 times of volumes respectively; v/v); nitrogen protection borehole cooling is to-5 ~ 5 DEG C; drip the potassium hydroxide of purified water-soluble 1eq. and the sodium carbonate solution of 0.5eq. of 0 ~ 10 DEG C, 20min drips, and keeps 20min at this temperature; start to be warming up to 10 ~ 20 DEG C of reaction 80min, now solution is almost clearly molten.System joined in acetone-water (3:1, the v/v) system of 60 times of volumes, at 10 ~ 30 DEG C of crystallizatioies, 30min adds again, and-5 ~ 5 DEG C are stirred 60min.Suction filtration under nitrogen protection, pull an oar filter cake 4L acetone under 20 DEG C of nitrogen protections 40min, and suction filtration is done, and filter cake is transferred to drip pan, obtains white crystalline powder after 30 DEG C of vacuum-drying to moisture content are not more than 3.0%.Purity is 98.4%.
Embodiment 15
Step b salt-forming reaction:
System is added respectively acetone and the water (3:1 of 6 times of volumes; v/v); nitrogen protection borehole cooling is to-5 ~ 5 DEG C; drip the saleratus of purified water-soluble 1eq. and the sodium hydroxide solution of 0.5eq. of 0 ~ 10 DEG C; 30min drips; keep 30min at this temperature, start to be warming up to 10 ~ 20 DEG C of reaction 80min, now solution is almost clearly molten.System joined in acetone-water (3:1, the v/v) system of 60 times of volumes, at 10 ~ 30 DEG C of crystallizatioies, 30min adds again, and-5 ~ 5 DEG C are stirred 60min.Suction filtration under nitrogen protection, pull an oar filter cake 50L acetone under 20 DEG C of nitrogen protections 40min, and suction filtration is done, and filter cake is transferred to drip pan, obtains white crystalline powder after 30 DEG C of vacuum-drying to moisture content are not more than 3.0%.Purity is 98.5%.
Claims (11)
1. be suitable for a preparation method for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection, comprise the following steps:
A, esterification: under nitrogen protection, be starting material with rographolide and succinyl oxide, take sodium sulphite anhydrous 99.3 as antioxidant, 45 ~ 95 DEG C are warming up to from 10 ~ 30 DEG C, reaction 4 ~ 20h, follows the tracks of reaction to intermediate state and mores than less than 0.1% stopped reaction, cooling, non-polar solvent-weak acid water compound is adopted to remove pyridine, concentrated, decolouring;
B, salt-forming reaction: add acetone-water by system, nitrogen protection borehole cooling, to-10 ~ 5 DEG C, drips basic solution, reacts to obtain molten clear solution; system is added crystallization in acetone-water, suction filtration under nitrogen protection, filter cake adds acetone making beating; suction filtration final vacuum is dry, obtains high purity potassium sodium dehydroandroan drographolide succinate
Wherein,
Described non-polar solvent is be selected from least one in trichloromethane, methylene dichloride, ethyl acetate, Iso Butyl Acetate, and described weak acid is be selected from least one in succinic acid, oxalic acid, citric acid, dilute hydrochloric acid, phosphoric acid,
Described non-polar solvent-weak acid water compound is for adding rographolide 5 ~ 10 times amount (v/w), non-polar solvent: 0.5mol/L ~ 1.0mol/L weak acid water compound (v/v=1:1);
Become oily thick liquid at 20 ~ 35 DEG C of vacuum concentration in step a, add the acetone-water of 3 ~ 6 times of volumes, activated carbon decolorizing 40 ~ 70min, obtained dehydroandrographolide succinate,
Step a esterification reaction temperature is 80 DEG C, reaction 12h,
Step b drips the KHCO of 1eq. simultaneously
3with the Na of 0.5eq.
2cO
3solution, time for adding is 30min,
Step b salt-forming reaction temperature is 10 ~ 30 DEG C, reaction 50 ~ 90min,
Step b adopts the acetone-water of 40 ~ 60 times of volumes to tie up to 10 ~ 40 DEG C of crystallizatioies.
2. the preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 1, is characterized in that: in step a esterification, the mol ratio of rographolide and succinyl oxide is 1:3 ~ 1:5.
3. the preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 2, is characterized in that: in step a esterification, the mol ratio of rographolide and succinyl oxide is 1:3.5 ~ 1:4.7.
4. the preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 3, is characterized in that: in step a esterification, the mol ratio of rographolide and succinyl oxide is 1:3.8 ~ 1:4.5.
5. the preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 1, it is characterized in that: after step a esterification, adopt non-polar solvent-weak acid water compound cleaning to remove pyridine, non-polar solvent is be selected from least one in trichloromethane, methylene dichloride, ethyl acetate, and weak acid is be selected from least one in succinic acid, oxalic acid, citric acid.
6. the preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 5, it is characterized in that: after step a esterification, adopt non-polar solvent-weak acid water compound cleaning to remove pyridine, non-polar solvent is be selected from least one in methylene dichloride, ethyl acetate, and weak acid is be selected from least one in oxalic acid, citric acid.
7. the preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 1, it is characterized in that: described non-polar solvent-weak acid water compound is for adding rographolide 6 ~ 8 times amount (v/w), non-polar solvent: 0.5mol/L ~ 0.6mol/L weak acid water compound (v/v=1:1).
8. the preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 1, it is characterized in that: in step a, become oily thick liquid at 20 ~ 35 DEG C of vacuum concentration, add the acetone-water of 4 ~ 5 times of volumes, activated carbon decolorizing 60min.
9. the preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 1, is characterized in that: step b salt-forming reaction temperature is 10 ~ 20 DEG C, reaction 60 ~ 70min.
10. the preparation method being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 1, is characterized in that: step b adopts the acetone-water of 50 ~ 60 times of volumes to tie up to 20 ~ 30 DEG C of crystallizatioies.
11. preparation methods being suitable for suitability for industrialized production, highly purified Andrographolide in Andrographolide for Injection according to claim 10, is characterized in that: step b adopts the acetone-water of 55 times of volumes to tie up to 25 DEG C of crystallizatioies.
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| CN103622960B (en) * | 2013-12-11 | 2015-07-08 | 胡少平 | Compound andrographolidume preparation for veterinary use |
| CN103755670B (en) * | 2014-02-20 | 2015-08-12 | 湖北美林药业有限公司 | A kind of Andrographolide compound and pharmaceutical composition thereof |
| CN104945357B (en) * | 2015-06-09 | 2018-01-02 | 湖北荆楚理工科技开发有限公司 | A kind of process for purification of dehydroandrographolide succinate |
| CN108239051A (en) * | 2016-12-23 | 2018-07-03 | 四川文龙药业有限公司 | Dehydroandrograpolide succinate and purifying technique and potassium dehydroandrographolide succinate |
| CN108503611B (en) * | 2018-05-31 | 2022-06-24 | 黑龙江珍宝岛药业股份有限公司鸡西分公司 | Preparation method of potassium sodium dehydroandroan drographolide succinate |
| CN111793049A (en) * | 2019-04-08 | 2020-10-20 | 武汉长联来福制药股份有限公司 | Preparation method of potassium sodium dehydroandroan drographolide succinate and intermediate thereof |
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