CN103242403A - 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 invention relates to a high-purity dibutyryladenosine cyclophosphate calcium and a preparation method thereof. Raw materials of dibutyryladenosine cyclophosphate calcium medicine are difficult to purify, so the purity of the existing product is lower, namely 80-95%, and medical need is difficult to meet, so that the traditional preparation technology is improved in the invention, spray drying and column chromatography isolation purification technologies are adopted, high-purity dibutyryladenosine cyclophosphate calcium is obtained, the purity is above 99%, and the maximum impurity content is reduced to below 0.2%.
Description
Technical field
The present invention relates to the synthetic field of medicine, 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; simultaneously activated protein kinase A and protein kinase C; protein kinase is a kind of allosteric enzyme; be made up of two catalytic subunits and two adjusting subunits, catalytic subunit has catalytic proteins (or enzyme) phosphorylation.But so the most basic biochemistry metabolism---oxidative phosphorylation reaction and tricarboxylic acid cycle in the Calcium Dibutyryladenosine Cyclophosph-ate catalysis human body; it is active that most protein and enzyme are produced; the various reactions of human activin; produce a large amount of ATP simultaneously; improve cell and energy metabolism, thereby realize that it promotes neurotization, transforms abnormal cells, vasodilation, diastole unstriated muscle, improves effect such as myocardial ischemia.
Calcium Dibutyryladenosine Cyclophosph-ate is the regeneration product of second messenger's cAMP (cAMP); because cAMP is difficult for permeate through cell membranes; and enter intracellular cAMP soon by the phosphodiester enzymic hydrolysis in the cell; so make the derivative of adenosine phosphate; the two butyryl esters of cyclic monophosphate are stronger than cAMP to the perviousness of cell; and can resist the destruction of di(2-ethylhexyl)phosphate enzyme in the body, so its action time and speed are all lasting and rapid than cAMP.Be cell function activator of new generation, the combination of nutrition and treatment.
Calcium Dibutyryladenosine Cyclophosph-ate can be treated the various diseases that causes because of the imbalance of G protein function; protein function imbalance can show as increased functionality or decline, causes some cardiovascular disorder as stenocardia, myocardial infarction, myocarditis, cardiogenic shock, immune genetic disease lupus erythematosus and psoriatic etc.
Chinese patent CN 100457770C discloses a kind of process for purification of Calcium Dibutyryladenosine Cyclophosph-ate.By in crude product, adding methyl alcohol and acetone, carry out separation and purification, finally obtain 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 the purity of target compound Calcium Dibutyryladenosine Cyclophosph-ate more than 99%; and single impurity level is all less than 0.2%; with the commercially available prod, the Calcium Dibutyryladenosine Cyclophosph-ate bulk drug that the Shanghai first biochemical medicine company is produced is compared, and purity improves significantly.
The Calcium Dibutyryladenosine Cyclophosph-ate medicine, the feed purification difficulty, currently available products purity is lower, is generally 80-95%, is difficult to satisfy needs of medical treatment, and impurity is more, and content is higher.
Purpose of the present invention is to provide a kind of highly purified Calcium Dibutyryladenosine Cyclophosph-ate.
Another purpose of the present invention is to provide a kind of preparation method of highly purified Calcium Dibutyryladenosine Cyclophosph-ate, it is characterized in that take special purifying process, spray drying technology, and column chromatography technology obtain highly purified target product.
The synthetic method of Calcium Dibutyryladenosine Cyclophosph-ate is starting raw material with the cAMP generally, after the n butanoic anhydride acidylate, becomes calcium salt again and makes.
" up-to-date biochemical drug technology of preparing " (the Chinese Medicine science and technology first version 246-248 in March calendar year 2001 of press page or leaf) provides detailed synthetic method (see figure 1).
(1) salify.CAMP and triethylamine feed intake in proportion, and after the dissolving, concentrating under reduced pressure adds anhydrous pyridine, jolting dehydration decompressing and extracting, the dry cAMP-ethylamine salt that gets.
(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 the qdx ether, 3 times of 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) become calcium salt.Above-mentioned syrup adds Calcium Chloride Powder Anhydrous, is evaporated to driedly, adds dehydrated alcohol and ether, separates out filtration, washing, and drying under reduced pressure namely gets Calcium Dibutyryladenosine Cyclophosph-ate.
The aforesaid method products obtained therefrom, yield 84%.Technological operation is loaded down with trivial details, labour intensity is big, and yield is lower and quality product is relatively poor, maximumly singly assortedly surpasses 4% through detecting, and moisture content is about 6%, and has residual other impurity such as butyric acid, has a strong impact on the security of medication.
Among the Japanese Patent JP51113896, new synthetic method has been proposed.
To encircle the direct and n butanoic anhydride reaction of phosphinylidyne glycosides, after the product hydrolysis, butyric acid is removed in washing, after ion exchange resin column, namely gets dibutyryl adenosine cyclophosphate sodium.Owing to adopt direct acidylate method, and be used in combination processing such as ion exchange resin, shortened process cycle.Specifically see Fig. 2.
But yield is very low as a result, and the impurity problem does not well solve yet.Simultaneously can only obtain dibutyryl adenosine cyclophosphate sodium, rather than calcium salt.
At the problem that exists in the existing Calcium Dibutyryladenosine Cyclophosph-ate feedstock production technology, we have proposed a kind of new Calcium Dibutyryladenosine Cyclophosph-ate preparation method's (see figure 3) on the basis that a large amount of experiments are groped.
CAMP elder generation and triethylamine salify, acidylate again; Product ether flush away acid anhydrides, and through water extraction, obtain the aqueous solution of dibutyryl adenosine cyclophosphate triethylamine salt; Direct spraying drying obtains the dibutyryl adenosine cyclophosphate triethylamine salt pressed powder of off-white color.With calcium chloride salify in aqueous ethanolic solution of equivalent, underpressure distillation is concentrated into dried, obtains the Calcium Dibutyryladenosine Cyclophosph-ate crude product again.Crude product is crossed silica gel column chromatography, with methylene dichloride-anhydrous methanol wash-out; Use plane thin-layer method monitoring, discard initial impurity cut, collect the component that contains Calcium Dibutyryladenosine Cyclophosph-ate, be evaporated to driedly, namely get the 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.
The present invention has adopted spray drying technology, guarantees rapid drying, has avoided the degraded that causes for a long time under the situation that has water to exist, thereby impurity is introduced the finished product.
The several important parameters that influence the spraying drying result are inlet temperatures, input speed, atomizing pressure etc.Spray-drying process of the present invention avoids introducing impurity, does not adopt drying aid.Solvent is selected water for use.
With inlet temperature, input speed, three parameters of atomizing pressure be as the investigation factor, with powder moisture after the drying and product purity content checking drying effect and the product degree of being damaged, carries out orthogonal test, and level of factor and test-results see Table 1, table 2.
Table 1 drying process with atomizing level of factor table
As index, the design orthogonal test is carried out condition optimizing with water content and product purity content, and the result is as follows, sees 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 is the result show: from extreme difference, obviously, Temperature Influence all is maximum for water content and product content, and input speed and pressure influence are less.Along with the rising of temperature, water content obviously reduces, but temperature is too high, and is then also bigger to the destruction of product.When temperature at 120 ℃, product does not suffer obvious destruction, therefore, temperature is selected 120 ℃, input speed is selected 3mL/h-5mL/h, pressure is 19 * 10kPa.
Table 3 analysis of variance table (α=0.05)
Column chromatography purification technology high specificity, bearing capacity is big, the degree of purification height.
Column chromatography technology of the present invention, filler are 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 methyl alcohol-methylene dichloride, 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, purity＞99%, and single foreign matter content is all less than 0.2%.
Calcium Dibutyryladenosine Cyclophosph-ate medicine of the present invention is characterized in that, has adopted spray drying technology and column chromatography purification isolation technique in the synthetic preparation process.Compare with currently available products, have the advantage of following several respects.
(1) adopt spray drying technology, the rapid drying middle sample is avoided causing degraded under the water surrounding, products obtained therefrom purity height, and dopant species and content are less, and single impurity maximum level is all less than 0.2%.
(2) the column chromatography technology bearing capacity is big, the degree of purification height, and target product purity content reaches more than 99%, obviously is better than the commercially available prod.
(3) technique reproducible height, product stability is good, and is simple and easy to do.
The present invention obtains the Calcium Dibutyryladenosine Cyclophosph-ate medicine and can be used for being prepared into various formulations, is applied to disease treatment fields such as stenocardia, myocardial infarction, myocarditis, cardiogenic shock, psoriatic, lupus erythematosus.
Description of drawings:
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 and the explanations to Calcium Dibutyryladenosine Cyclophosph-ate and preparation method thereof, 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, with the freezing triethylamine solution that adds down of cAMP, makes its whole dissolvings, regulates PH, adds the pyridine jolting and dewaters, and gets quaternary amine.
(2) acidylate: above-mentioned salt adds butyryl oxide and pyridine, and 25-30 ℃ of lucifuge reacted 7 days, carried out acidylate.With an amount of ether flush away acid anhydrides, 2-3 times of volume water extracts, and repeats two to three times, obtains the aqueous solution of dibutyryl adenosine cyclophosphate triethylamine salt.
(3) drying: with water as solvent, directly carry out spraying drying, 120 ℃ of inlet temperature, 70 ℃ of air outlet temperatures.Obtain the dibutyryl adenosine cyclophosphate triethylamine salt pressed powder of off-white color.
(4) become calcium salt: the calcium chloride that adds equivalent carries out salt-forming reaction in aqueous ethanolic solution, the reactant underpressure distillation is concentrated into dried, obtains the 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, drop into 20g neutral chromatography silica gel, stirring at room 0.5h.In 30 ~ 40 ℃, vacuum rotary steam is to doing under 0.08 ~ 0.9MPa.Sample in the preparation.
(6) go up sample and wash-out: other gets preferred 150 ~ 200g, and 200 ~ 300 order neutral chromatography are adorned post with the silica gel wet method.Sample on the above-mentioned sample dry method; to the silicagel column top; carry out wash-out according to following program: 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); collection contains the component of Calcium Dibutyryladenosine Cyclophosph-ate; be evaporated to dried, namely.
Calcium Dibutyryladenosine Cyclophosph-ate raw material with commercially available (Shanghai first biochemistry) is contrast, and liquid phase method detects, result such as table 4.As can be seen, preparation method's products obtained therefrom of the present invention is in weight loss on drying, and maximum single mixing obviously is better than the commercially available prod with the purity aspect.
Table 4 Calcium Dibutyryladenosine Cyclophosph-ate product physico-chemical property
| ? | Proterties | pH | Weight loss on drying | Maximum single assorted | 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 (5)
1. high purity cAMP calcium is characterized in that among the preparation method, has adopted spray drying technology and column chromatography technology.
2. the described spray drying technology of claim 1 is characterized in that, inlet temperature is 105 ℃-120 ℃, does not adopt drying aid, and solvent is selected water for use.
3. the described column chromatography technology of claim 1, the filler of selecting for use is silica gel, the 200-300 order.
4. the described column chromatography technology of claim 1, 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, wherein one or more mixtures.
5. the described column chromatography technology of claim 4, elutriant is methyl alcohol-methylene dichloride, dehydrated alcohol-dichloromethane mixture, blending ratio is 10:1-60:1.
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| CN104262436A (en) * | 2014-09-19 | 2015-01-07 | 北京赛盟医药科技发展有限公司 | Amorphous calcium bucladesine sterile powder |
| CN104478979A (en) * | 2014-12-24 | 2015-04-01 | 上海第一生化药业有限公司 | Crystal water-free calcium dibutyryladenosine cyclophosphate crystal form, as well as preparation method and application thereof |
| CN104490798A (en) * | 2014-12-24 | 2015-04-08 | 上海第一生化药业有限公司 | Crystal water-free calcium dibutyryladenosine cyclophosphate crystal form freeze-dried powder injection and preparation method thereof |
| CN104906124A (en) * | 2015-07-01 | 2015-09-16 | 上海上药第一生化药业有限公司 | Application of calcium dibutyryladenosine cyclophosphate in preparation of medicine for treating spinal cord injuries |
| CN105566424A (en) * | 2014-10-17 | 2016-05-11 | 上海紫源制药有限公司 | Method for preparing calcium dibutyryladenosine cyclophosphate |
| CN105566423A (en) * | 2014-10-17 | 2016-05-11 | 上海紫源制药有限公司 | Method for purifying calcium dibutyryladenosine cyclophosphate |
| CN106336439A (en) * | 2016-08-24 | 2017-01-18 | 南京工业大学 | Calcium dibutyryladenosine cyclophosphate preparation method |
| CN108997430A (en) * | 2018-07-16 | 2018-12-14 | 南京工业大学 | A kind of crystal of Calcium Dibutyryladenosine Cyclophosph-ate salt |
| CN112321660A (en) * | 2020-11-06 | 2021-02-05 | 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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| CN104262436A (en) * | 2014-09-19 | 2015-01-07 | 北京赛盟医药科技发展有限公司 | Amorphous calcium bucladesine sterile powder |
| CN105566424A (en) * | 2014-10-17 | 2016-05-11 | 上海紫源制药有限公司 | Method for preparing calcium dibutyryladenosine cyclophosphate |
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| US10420787B2 (en) | 2014-12-24 | 2019-09-24 | Sph No.1 Biochemical & Pharmaceutical Co., Ltd. | Crystal-water-free calcium dibutyryladenosine cyclophosphate crystal form and preparation method and application thereof |
| CN104478979A (en) * | 2014-12-24 | 2015-04-01 | 上海第一生化药业有限公司 | Crystal water-free calcium dibutyryladenosine cyclophosphate crystal form, as well as preparation method and application thereof |
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| CN104490798B (en) * | 2014-12-24 | 2018-05-11 | 上海第一生化药业有限公司 | Nodeless mesh water Calcium Dibutyryladenosine Cyclophosph-ate crystal form freeze-dried powder and preparation method thereof |
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| CN106336439A (en) * | 2016-08-24 | 2017-01-18 | 南京工业大学 | Calcium dibutyryladenosine cyclophosphate preparation method |
| CN106336439B (en) * | 2016-08-24 | 2018-11-06 | 南京工业大学 | A kind of preparation method of Dibutyryladenosine cyclophosphate calcium |
| CN108997430A (en) * | 2018-07-16 | 2018-12-14 | 南京工业大学 | A kind of crystal of Calcium Dibutyryladenosine Cyclophosph-ate salt |
| WO2020015763A1 (en) * | 2018-07-16 | 2020-01-23 | 南京工业大学 | Calcium dibutyacyladenosine cyclophosphate salt crystal |
| CN112321660A (en) * | 2020-11-06 | 2021-02-05 | 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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