CN103242403B - High-purity dibutyryladenosine cyclophosphate calcium and preparation method thereof - Google Patents
High-purity dibutyryladenosine cyclophosphate calcium and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of High-purity dibutyryladenosine cyclophosphate calcium and preparation method thereof.Calcium Dibutyryladenosine Cyclophosph-ate medicine material purification difficult, the lower 80-95% of currently available products purity, is difficult to meet needs of medical treatment.Therefore, conventional preparation techniques improves by the present invention, have employed spraying dry and column chromatographic isolation and purification technology, and obtain highly purified Calcium Dibutyryladenosine Cyclophosph-ate medicine, purity more than 99%, maximum contaminant content is reduced to less than 0.2%.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, be specially highly purified Calcium Dibutyryladenosine Cyclophosph-ate and preparation method thereof.
Background technology
Calcium Dibutyryladenosine Cyclophosph-ate is a kind of nucleotide derivative; as G-protein conjugated receptor medicine; can simultaneously activated protein kinase A and protein kinase C; protein kinase is a kind of allosteric enzyme; regulate subunit to form by two catalytic subunits and two, catalytic subunit has catalytic proteins (or enzyme) phosphorylation.Therefore Calcium Dibutyryladenosine Cyclophosph-ate can be the most basic in catalysis human body biochemistry metabolism---oxidative phosphorylation reaction and tricarboxylic acid cycle; most protein and enzyme are produced active; the various reaction of human activin; produce a large amount of ATP simultaneously; improve cell and energy metabolism, thus realize its promote neurotization, transform abnormal cells, vasodilation, diastole unstriated muscle, improve the effects such as myocardial ischemia.
Calcium Dibutyryladenosine Cyclophosph-ate is the regeneration product of second messenger's cAMP (cAMP); due to cAMP not easily permeate through cell membranes; and enter intracellular cAMP soon by the phosphodiester enzymic hydrolysis in cell; therefore make the derivative of adenosine phosphate; the two perviousness of butyryl ester to cell of cyclic monophosphate is stronger than cAMP; and can resist the destruction of di(2-ethylhexyl)phosphate enzyme in body, therefore its action time and speed are all lasting and rapid than cAMP.Cell function activator of new generation, the combination of nutrition and treatment.
Calcium Dibutyryladenosine Cyclophosph-ate can treat the various diseases because G-protein functional disorder causes; protein function imbalance can show as function and strengthens or decline, and causes some cardiovascular disorder as stenocardia, myocardial infarction, myocarditis, cardiogenic shock, immune genetic diseases lupus erythematosus and psoriatic etc.
Chinese patent CN100457770C discloses a kind of process for purification of Calcium Dibutyryladenosine Cyclophosph-ate.By adding methyl alcohol and acetone in crude product, carrying out separation and purification, finally obtaining the Calcium Dibutyryladenosine Cyclophosph-ate dry powder of purity >=98%.Than commercially available currently available products, purity has had large increase.
Summary of the invention
The present invention, through special purifying process, is promoted to more than 99% by the purity of target compound Calcium Dibutyryladenosine Cyclophosph-ate; and single impurity level is all less than 0.2%; with commercially available prod, the Calcium Dibutyryladenosine Cyclophosph-ate bulk drug that the biochemical medicine company in Shanghai first is produced is compared, and purity improves significantly.
Calcium Dibutyryladenosine Cyclophosph-ate medicine, feed purification difficulty, currently available products purity is lower, is generally 80-95%, and be difficult to meet needs of medical treatment, and impurity is more, content is higher.
Object of the present invention, is to provide a kind of highly purified Calcium Dibutyryladenosine Cyclophosph-ate.
Another object of the present invention, is the preparation method providing a kind of highly purified Calcium Dibutyryladenosine Cyclophosph-ate, it is characterized in that, take special purifying process, spray drying technology, and column chromatography technology, obtains highly purified target product.
The synthetic method of Calcium Dibutyryladenosine Cyclophosph-ate, take generally cAMP as starting raw material, after n butanoic anhydride acidylate, then becomes calcium salt and obtain.
" up-to-date biochemical drug technology of preparing " (China Medical Science Press first version 246-248 in March calendar year 2001 page) provides detailed synthetic method (see figure 1).
(1) salify.CAMP and triethylamine feed intake in proportion, and after dissolving, concentrating under reduced pressure, adds anhydrous pyridine, jolting dehydration decompressing and extracting, dry cAMP-ethylamine salt.
(2) acidylate, hydrolysis.Above-mentioned cAMP-ethylamine salt, adds anhydrous pyridine and butanoic anhydride, lucifuge reaction 6-7 days; after acylation reaction is complete, add distilled water, low temperature hydrolysis 2-3 hour; concentrating under reduced pressure; successively add qdx ether, 3 times amount distilled water extraction, water intaking layer; concentrating under reduced pressure pulp thing; use ether extraction twice again, extract ether, become syrupy shape with anhydrous alcohol solution.
(3) calcium salt is become.Above-mentioned syrup adds Calcium Chloride Powder Anhydrous, is evaporated to dry, adds dehydrated alcohol and ether, separates out and filters, and washing, drying under reduced pressure, obtains Calcium Dibutyryladenosine Cyclophosph-ate.
Aforesaid method products obtained therefrom, yield 84%.Technological operation is loaded down with trivial details, labour intensity is large, and yield is lower and quality product is poor, assorted more than 4% through detecting maximum list, moisture content about 6%, and there are other impurity such as residual butyric acid, has a strong impact on the security of medication.
In Japanese Patent JP51113896, propose new synthetic method.
Ring phosphinylidyne glycosides directly react with n butanoic anhydride, after product hydrolysis, washs and remove butyric acid, after ion exchange resin column, obtain dibutyryl adenosine cyclophosphate sodium.Owing to adopting direct acidylate method, and be combined the process such as ion exchange resin, shorten process cycle.Specifically see Fig. 2.
But result yield is very low, and contaminant problem does not also well solve.Dibutyryl adenosine cyclophosphate sodium can only be obtained simultaneously, instead of calcium salt.
For Problems existing in existing Calcium Dibutyryladenosine Cyclophosph-ate feed preparation process, we are on the basis that great many of experiments is groped, and propose a kind of new Calcium Dibutyryladenosine Cyclophosph-ate preparation method (see figure 3).
CAMP elder generation and triethylamine salify, then acidylate; Product ether washes away acid anhydrides, and through water extraction, obtains the aqueous solution of dibutyryl adenosine cyclophosphate triethylamine salt; Direct spraying is dry, obtains the dibutyryl adenosine cyclophosphate triethylamine salt pressed powder of off-white color.Again with calcium chloride salify in aqueous ethanolic solution of equivalent, underpressure distillation is concentrated into dry, obtains Calcium Dibutyryladenosine Cyclophosph-ate crude product.Crude product crosses silica gel column chromatography, with methylene dichloride-anhydrous methanol wash-out; Use the monitoring of planar lamina method, discard initial impure fraction, collect the component containing Calcium Dibutyryladenosine Cyclophosph-ate, be evaporated to dry, obtain Calcium Dibutyryladenosine Cyclophosph-ate product.
Calcium Dibutyryladenosine Cyclophosph-ate preparation method provided by the invention, is characterized in that, adopts spray drying technology and column chromatography purification isolation technique.
Present invention employs spray drying technology, ensure rapid drying, avoid the degraded caused for a long time in the presence of water, thus impurity is introduced the finished product.
The several important parameters affecting spraying dry result are inlet temperatures, input speed, atomizing pressure etc.Spray-drying process of the present invention is avoided introducing impurity, does not adopt drying aid.Water selected by solvent.
By inlet temperature, input speed, atomizing pressure three parameters, as investigation factor, to be damaged degree with powder moisture after drying and product purity content checking drying effect and product, to carry out orthogonal test, level of factor and test-results in table 1, table 2.
Table 1 drying process with atomizing level of factor table
Using water content and product purity content as index, design orthogonal test, carry out condition optimizing, result is as follows, in table 2.
Table 2 spray drying technology processing condition orthogonal experiments
| Inlet temperature | Input speed | Pressure | Water content % | Purity content % | |
| 1 | 1 | 1 | 1 | 8 | 92 |
| 2 | 1 | 2 | 2 | 10 | 94 |
| 3 | 1 | 3 | 3 | 11 | 91 |
| 4 | 2 | 1 | 2 | 3 | 96 |
| 5 | 2 | 2 | 1 | 3 | 95 |
| 6 | 2 | 3 | 3 | 6 | 94 |
| 7 | 3 | 1 | 2 | 1 | 84 |
| 8 | 3 | 2 | 3 | 4 | 87 |
| 9 | 3 | 3 | 1 | 3 | 86 |
Table 3 result shows: from extreme difference, and obviously, the impact of temperature is all maximum for water content and product assay, input speed and pressure influence less.Along with the rising of temperature, water content obviously reduces, but temperature is too high, then also larger to the destruction of product.When temperature is at 120 DEG C, product does not suffer obvious destruction, and therefore, thermal creep stress 120 DEG C, input speed selects 3mL/h-5mL/h, and pressure is 19 × 10kPa.
Table 3 analysis of variance table (α=0.05)
Column chromatography purification technology high specificity, bearing capacity is large, and degree of purification is high.
Column chromatography technology of the present invention, filler is selected from silica gel (100-200 order, 200-300 order and 300-400 order), silica gel H, aluminum oxide (100-200 order, 200-300 order and 300-400 order), diatomite (200-300 order) etc., preferred silica gel 200-300 order.
Elutriant is including but not limited to water, methyl alcohol, anhydrous methanol, ethanol, dehydrated alcohol, Virahol, n-propyl alcohol, acetonitrile, methylene dichloride, trichloromethane, acetone, ethyl acetate, methyl acetate, ethyl formate, methyl-formiate, 1,4-dioxane, tetrahydrofuran (THF), methyl tertiary butyl ether, sherwood oil etc., wherein one or more mixtures.Be preferably methanol dichloromethane, dehydrated alcohol-dichloromethane mixture, blending ratio is 10:1-60:1.
Preparation method's products obtained therefrom provided by the invention is white or off-white color pressed powder, and purity > 99%, single foreign matter content is all less than 0.2%.
Calcium Dibutyryladenosine Cyclophosph-ate medicine of the present invention, is characterized in that, have employed spray drying technology and column chromatography purification isolation technique in synthesis preparation process.Compared with currently available products, there is the advantage of following several respects.
(1) adopt spray drying technology, rapid drying middle sample, causes degraded under avoiding water surrounding, and products obtained therefrom purity is high, dopant species and content less, single impurity maximum level is all less than 0.2%.
(2) column chromatography technology bearing capacity is large, and degree of purification is high, and target product purity content reaches more than 99%, is obviously better than commercially available prod.
(3) technique reproducible is high, and product stability is good, simple and easy to do.
The present invention obtains Calcium Dibutyryladenosine Cyclophosph-ate medicine and can be used for being prepared into various formulation, is applied to the disease treatment fields such as stenocardia, myocardial infarction, myocarditis, cardiogenic shock, psoriatic, lupus erythematosus.
accompanying drawing illustrates:
Fig. 1 is the prior synthesizing method figure of Calcium Dibutyryladenosine Cyclophosph-ate;
Fig. 2 is the novel synthesis figure of Calcium Dibutyryladenosine Cyclophosph-ate;
Fig. 3 is the novel synthesis figure of Calcium Dibutyryladenosine Cyclophosph-ate provided by the invention.
embodiment:
Following examples are further explanation to Calcium Dibutyryladenosine Cyclophosph-ate and preparation method thereof and explanation, do not limit the present invention in any way.
Embodiment 1
(1) become quaternary ammonium salt: by cAMP (m): triethylamine (V): pyridine feeds intake by the ratio of components of (V)=1:7.2:5.3, adds triethylamine solution, make it all dissolve under cAMP is freezing, regulate PH, add pyridine jolting dehydration, obtain quaternary amine.
(2) acidylate: above-mentioned salt adds butyryl oxide and pyridine, 25-30 DEG C of lucifuge reacts 7 days, carries out acidylate.Wash away acid anhydrides with appropriate ether, 2-3 times of volume water extracts, and repeats two to three times, obtains the aqueous solution of dibutyryl adenosine cyclophosphate triethylamine salt.
(3) dry: with water as solvent, directly to carry out spraying dry, inlet temperature 120 DEG C, air outlet temperature 70 DEG C.Obtain the dibutyryl adenosine cyclophosphate triethylamine salt pressed powder of off-white color.
(4) calcium salt is become: the calcium chloride adding equivalent carries out salt-forming reaction in aqueous ethanolic solution, and reactant underpressure distillation is concentrated into dry, obtains Calcium Dibutyryladenosine Cyclophosph-ate crude product.
(5) sample preparation: get above-mentioned Calcium Dibutyryladenosine Cyclophosph-ate crude product 10g, add 100 ~ 200ml anhydrous methanol stirring and dissolving, drops into 20g neutral chromatography silica gel, stirring at room temperature 0.5h.In 30 ~ 40 DEG C, under 0.08 ~ 0.9MPa, vacuum rotary steam is to dry.Prepare loading.
(6) loading and wash-out: separately get preferably 150 ~ 200g, 200 ~ 300 order neutral chromatography silica gel wet method dress post.Above-mentioned sample dry method loading; to silicagel column top; wash-out is carried out: methylene dichloride, methylene dichloride-anhydrous methanol (40:1), methylene dichloride-anhydrous methanol (30:1), methylene dichloride-anhydrous methanol (20:1), methylene dichloride-anhydrous methanol (10:1) according to following program; collect the component containing Calcium Dibutyryladenosine Cyclophosph-ate; be evaporated to dry, obtain final product.
With the Calcium Dibutyryladenosine Cyclophosph-ate raw material of commercially available (Shanghai first is biochemical) for contrast, liquid phase method detects, and result is as table 4.Can find out, preparation method's products obtained therefrom of the present invention is in weight loss on drying, and maximum list is assorted is obviously better than commercially available prod with purity aspect.
Table 4 Calcium Dibutyryladenosine Cyclophosph-ate product physico-chemical property
| Proterties | pH | Weight loss on drying | Maximum list is mixed | Liquid phase purity | |
| Comparative group | White powder | 5.8 | 6% | ＞4.0% | 92.0% |
| Test group | White powder | 6.4 | ＜1% | 0.15% | 99.6% |
Claims (1)
1. a preparation method for Calcium Dibutyryladenosine Cyclophosph-ate, comprises into quaternary ammonium salt, acidylate, drying, one-tenth calcium salt, sample preparation, loading and elution step, it is characterized in that:
(1) become quaternary ammonium salt: feed intake by the ratio of components with m:V:V=1:7.2:5.3 by cAMP-triethylamine-pyridine, under cAMP is freezing, add triethylamine solution, make it all dissolve, regulate pH, add pyridine jolting dehydration, obtain quaternary amine;
(2) acidylate: above-mentioned salt adds butyryl oxide and pyridine, 25-30 DEG C of lucifuge reacts 7 days, carries out acidylate; Wash away acid anhydrides with appropriate ether, 2-3 times of volume water extracts, and repeats two to three times, obtains the aqueous solution of dibutyryl adenosine cyclophosphate triethylamine salt;
(3) dry: with water as solvent, directly to carry out spraying dry, inlet temperature 120 DEG C, air outlet temperature 70 DEG C; Obtain the dibutyryl adenosine cyclophosphate triethylamine salt pressed powder of off-white color;
(4) calcium salt is become: the calcium chloride adding equivalent carries out salt-forming reaction in aqueous ethanolic solution, and reactant underpressure distillation is concentrated into dry, obtains Calcium Dibutyryladenosine Cyclophosph-ate crude product;
(5) sample preparation: get above-mentioned Calcium Dibutyryladenosine Cyclophosph-ate crude product 10g, add 100 ~ 200ml anhydrous methanol stirring and dissolving, drops into 20g neutral chromatography silica gel, stirring at room temperature 0.5h; In 30 ~ 40 DEG C, under 0.08 ~ 0.9MPa, vacuum rotary steam is to dry, prepares loading;
(6) loading and wash-out: separately get 150 ~ 200g, 200 ~ 300 order neutral chromatography silica gel wet method dress post; Above-mentioned sample dry method loading; to silicagel column top; wash-out is carried out: methylene dichloride, methylene dichloride-anhydrous methanol 40:1, methylene dichloride-anhydrous methanol 30:1, methylene dichloride-anhydrous methanol 20:1, methylene dichloride-anhydrous methanol 10:1 according to following program; collect the component containing Calcium Dibutyryladenosine Cyclophosph-ate; be evaporated to dry, obtain final product.
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| CN104017040B (en) * | 2014-06-27 | 2016-09-21 | 上海第一生化药业有限公司 | Only son's acyl adenosine cyclophosphate or the preparation method and application of its salt |
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| CN104906124B (en) * | 2015-07-01 | 2018-06-12 | 上海上药第一生化药业有限公司 | Application of the Calcium Dibutyryladenosine Cyclophosph-ate in the drug for preparing treatment spinal cord injury |
| CN106336439B (en) * | 2016-08-24 | 2018-11-06 | 南京工业大学 | A kind of preparation method of Dibutyryladenosine cyclophosphate calcium |
| CN108997430B (en) * | 2018-07-16 | 2020-05-22 | 南京工业大学 | Crystal of calcium dibutyryladenosine cyclophosphate |
| CN112321660B (en) * | 2020-11-06 | 2022-05-24 | 上海上药第一生化药业有限公司 | Preparation method of dibutyryl adenosine cyclophosphate compound and metal salt thereof |
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