CN100434435C - Method for preparing phosphate eritrocina using eritrocina - Google Patents
Method for preparing phosphate eritrocina using eritrocina Download PDFInfo
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- CN100434435C CN100434435C CNB200610041759XA CN200610041759A CN100434435C CN 100434435 C CN100434435 C CN 100434435C CN B200610041759X A CNB200610041759X A CN B200610041759XA CN 200610041759 A CN200610041759 A CN 200610041759A CN 100434435 C CN100434435 C CN 100434435C
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Abstract
The present invention relates to a preparation method of erythrocin salt, particularly to a method for preparing phosphoric acid erythrocin by using erythrocin. The present invention is characterized in that the erythrocin is dissolved in an organic solvent in which C2-C6 comprises a hydroxyl group and a carbonyl group or water, stirring is carried out, and the temperature of a salt forming reaction is controlled; through the mode of dripping a phosphoric acid, the pH value of the solution is adjusted, a reaction end is controlled and a synthesis reaction is carried out; finally, separation and desiccation are carried out, and the finished product of the phosphoric acid erythrocin is obtained. The present invention has the advantages of advanced process, small danger to human and environment, high yield and low cost.
Description
Technical field
The present invention relates to a kind of preparation method of erythromycin salt, particularly a kind of about method with preparing phosphate eritrocina erythromycin.
Background technology
Phosphoric acid erythromycin is the phosphoric acid salt of erythromycin, is a kind of novel veterinary drug that just uses in recent years.It is consistent with Matachrom, Stellamicina, erythromycin estolate, the effect of erythromycin acetic ester, and drug effect and erythromycin are suitable, is mainly used in the treatment of inflammation in the animal body.Erythromycin and derivative thereof are at clinical application Macrolide Broad spectrum antibiotics very widely, and gram-positive microorganism is had the strong antibiotic effect, are used for the infection that responsive gram-positive cocci causes.Antibacterial mechanisms is by combine the displacement of blocking-up transpeptidation and mRNA with the ribosomal 50S subunit of the bacterium of sensitivity.Suppress the synthetic of bacterioprotein and bring into play antibacterial or germicidal action.Phosphoric acid erythromycin is mainly used in control fowl chronic respiratory tract disease, infective rhinitis, enteritis, diarrhea, staphylococcus, streptococcal infection etc. as veterinary drug.That can also prevent and treat that environmental change causes stress.Phosphoric acid erythromycin is water-soluble, is choice drug to the diseases such as rotted gill disease, erythroderma and enteritis of fish, eel, and common diseases such as soft-shelled turtle, shrimp are had remarkable prevention effect.By clinical study repeatedly, phosphoric acid erythromycin is obtained significant curative effect in the intravital treatment of animals such as pony, fish.The effect of phosphoric acid erythromycin is consistent with erythromycin, but the advantage of its maximum is water-soluble all good than erythromycin, Matachrom, and oral animal absorbs good, again can injection for intravenous.Because erythromycin is 14 membered macrolide class alkaline antibiotics, be alkaline glycosides by erythromycin lactone is sugared with the deoxidation base and red mould sugared condensation forms.There are a plurality of hydroxyls in the structure, the hydroxyl reaction of the ketone group of C-9 position and C-12 and C-6 in the erythromycin under acidic conditions, alkene ether in generating, and then be condensed into keto-lactol.The erythromycin acidifying is carried out under acidic conditions just, so erythromycin can form salt with the various acid with certain acid number (comprising organic acid, mineral acid or acid salt).
The patent that the patent US3276956 of the U.S. discloses a kind of " infection that the erythromycin for treating poultry is caused because of class pleuropneumonia germ ", its technology one adopts 340g 0.46mol erythromycin to be dissolved in the 500ml methyl alcohol, and to produce in the solution, dropwise add 52g 0.52mol and contain 85% phosphate aqueous solution, stir through brute force.Filter reaction mixture, and the spray do this filtration product, obtain the white solid of phosphoric acid erythromycin, fusing point is 145 ℃.But methyl alcohol is as the organic solvent of erythromycin, and its toxicity is big, and volatility is big, and is unfavorable to environment protection, and is big to human body harm; The phosphoric acid of use 85% needs powerful stirring because the concentration height is prone to local overacidification and destroys activeconstituents in the reaction process; The yield of this method is on the low side, the cost height.Technology two adopts 40g (0.054mol) erythromycin is suspended in the 500ml water, and slowly adds the aqueous solution of 10% phosphoric acid of equimolar amount, the powerful stirring, and pH reaches 6.0 up to reaction mixture.The solution that generates obtains amorphous white solid of phosphoric acid erythromycin through freeze-drying, and fusing point is 145 ℃, solubilized 5g this product in the water of every 100ml.It is lower that but this technology obtains the weight yield and the activeconstituents of phosphoric acid erythromycin.European patent RU2190410 discloses a kind of patent of phosphoric acid erythromycin injection, its process using: in the time of 4～7 ℃, and with the aqueous suspension of erythromycin, through the acidifying of ortho-phosphoric acid solution, 5% one-tenth piece, the pH value of solution that obtains reaches 6.4～6.6.At 30～35 ℃, phosphoric acid erythromycin solution through sterile filtration, freeze-drying, is progressively raise the thermal barrier temperature 20 ℃ to 60 ℃ the deeper vacuum drying.But take this technology, easily separate out crystal in the reaction process, yield is low-cost high, and operation is difficult.
Summary of the invention
The purpose of this invention is to provide a kind of method with preparing phosphate eritrocina erythromycin, its technology advanced person, little to human and environment hazardness, the yield height, cost is low.
Technical scheme of the present invention is that the method with preparing phosphate eritrocina erythromycin is characterized in that: erythromycin is dissolved in C
2-C
6Contain in the organic solvent or water of hydroxyl, carbonyl, stir, be controlled to the reactant salt temperature, by dripping the mode regulator solution pH value of phosphoric acid solution, the control reaction end carries out building-up reactions, obtains phosphoric acid erythromycin finished product after separate drying.
Described C
2-C
6The organic solvent that contains hydroxyl, carbonyl is a n-butyl acetate, isobutyl acetate, acetone, ethanol.
Described salt-forming reaction temperature remains on 10～30 ℃.
The preparation of described phosphoric acid solution is to prepare with the phosphoric acid solvent identical with reaction medium, and concentration of phosphoric acid is 15%～60%.
The pH value of described regulator solution, the pH value is chosen in 4.0～5.5 or 7.0～9.0.
Described reaction medium is the C that erythromycin is dissolved in
2-C
6The organic solvent a kind of or water wherein that contains hydroxyl, carbonyl.
Described erythromycin is (weight/volume) 1: 1～25 with the ratio of organic solvent.
Described erythromycin is (weight/volume) 1: 15～25 with the ratio of water.
Characteristics of the present invention are: the present invention compares with the patent US3276956 of the U.S., the yield height of technology of the present invention, and cost is low.And adopt the organic solvent n-butyl acetate, and isobutyl acetate, acetone, ethanol has substituted methyl alcohol, and toxicity is little.Methyl alcohol is second kind solvent, solvent for the restriction use, residual permission limit is 0.3% (seeing 2005 editions appendix P56 of Chinese Pharmacopoeia subordinate list 1), it has stronger toxicity, neural system and blood system to human body have the greatest impact, and it is taken in all and can react by toxigenicity through digestive tube, respiratory tract or skin; And n-butyl acetate, isobutyl acetate, acetone, ethanol are the 3rd kind solvents, and residual permission limit is 0.5% (seeing 2005 editions appendix P56 of Chinese Pharmacopoeia subordinate list 1), and it easily absorbs and enters in the blood, is distributed in whole body very soon.N-butyl acetate, isobutyl acetate, acetone, its steam of ethanol has moderate hormesis to mucous membrane.With respect to organic solvent methyl alcohol, make phosphoric acid erythromycin and adopt the organic solvent n-butyl acetate, isobutyl acetate, acetone, ethanol, little to the pollution of environment, little to the harm of human body.The patent US3276956 water preparation phosphoric acid of the U.S., and the employing of the present invention solvent identical with reaction medium prepared, the existence of water makes the generation of material generation bonding situation in the preparation process when having avoided using non-aqueous solvent.Adopt the solvent identical, also simplified solvent recovery step, reduced solvent and used kind, reduced solvent consumption simultaneously, reduced material cost with reaction medium.Because phosphoric acid erythromycin is water soluble antibiotics, when with an organic solvent preparing phosphoric acid erythromycin, adopts water-soluble little solvent can reduce the meltage of phosphoric acid erythromycin, prevent the generation of bonding phenomenon in the preparation process.
The present invention is when the control reaction end, employing is controlled to the method for reactant salt PH can control reaction end more accurately, and the concrete numerical value of selecting of PH is different, yield is different, it takes to control the method for phosphoric acid consumption than United States Patent (USP), and more accurately yield is higher, prevents that the excessive destruction activeconstituents of phosphoric acid from having avoided reacting the on the low side and higher situation of residual erythrocin of insufficient yield that brings simultaneously.
The present invention compares with European patent RU2190410, and maximum difference is that the present invention is simple to operate, yield is high, cost is low, belongs to bulk drug.European patent RU2190410 belongs to injection, and temperature of reaction is low, easily separates out crystal in the operating process, influences yield, increases post-processing difficulty, and operation is comparatively complicated.The present invention's yield height, cost when adopting organic solvent is low, though there is certain solvent residual, meets 2005 editions regulations of Chinese Pharmacopoeia.When the present invention adopted water as solvent, because temperature control is different, terminal point PH selects difference, so than European patent RU2190410 yield height, quality is good, no solvent was residual, and the temperature of reaction of employing has been avoided the operating process crystalline to separate out having improved yield.
The present invention's erythromycin is that starting raw material prepares phosphoric acid erythromycin, to compare step few with the method for preparing phosphoric acid erythromycin with erythromycin salt, operational path is short, prepared phosphoric acid erythromycin quality is good, but raw materials cost height, present world market erythromycin price is about 580 yuan/kilogram (containing tax), and Matachrom only is about 340 yuan/kilogram (containing tax), and the method material cost for preparing phosphoric acid erythromycin with erythromycin salt is obviously on the low side.Two kinds of preparation methods respectively have superiority.
The selection of phosphoric acid solution concentration can controls reaction speed, and processing ease is carried out, and is difficult for local overacidification; Range of reaction temperature can in time carry out reaction, is difficult for separating out crystal in the reaction process; Terminal point pH scope guarantees the activeconstituents maximum of phosphoric acid erythromycin, and the weight yield of phosphoric acid erythromycin is higher.
Below the present invention will be further described by the present invention and U.S. Pat 3276956 and European patent RU2190410 test contrast.
By U.S. Pat 3276956 embodiment 1, adopt methyl alcohol as reaction medium, the phosphoric acid with 85% carries out acidification reaction, filter this solution after, spray is done, and obtains phosphoric acid erythromycin white powder.
Experimental phenomena: drip in the phosphatase reaction process, local overacidification very easily occurs, be difficult for stirring, very easily destroy activeconstituents, not easy to operate.Experimental data sees Table one.
Table one:
| Phosphoric acid concentration % | Weight yield % | Activeconstituents u/mg | Moisture % | Residue % | Residual solvent % |
| 85 | 74.8 | 770/811 | 5.1 | 2.2 | 0.1 |
By U.S. Pat 3276956 embodiment 2, as reaction medium, the phosphoric acid with 10% carries out acidification reaction with water.Experimental data sees Table two.
Experimental phenomena: sluggish.
Table two:
| Phosphoric acid concentration % | Terminal point pH | Weight yield % | Activeconstituents u/mg | Moisture % | Residue % | Residual solvent % |
| 10 | 6.0 | 70.3 | 769/815 | 5.6 | 0.7 | Do not detect |
Press European patent RU2190410 embodiment, as reaction medium, under 4～7 ℃, carry out acidification reaction, control reaction end pH6.4～6.6 through ortho-phosphoric acid solution with water.Experimental data sees Table three.
Experimental phenomena: easily separate out crystal in the reaction process, operation is difficulty.
Table three:
| Temperature of reaction ℃ | Terminal point pH | Weight yield % | Activeconstituents u/mg | Moisture % | Residue % | Residual solvent % |
| 6 | 6.5 | 68.5 | 774/819 | 5.5 | 0.6 | Do not detect |
※ (one), water of the present invention are compared with the US and European patent respectively as reaction medium:
1, temperature of reaction of the present invention is controlled at 10～30 ℃, compare at 4～7 ℃ with European patent RU2190410 (table three) temperature of reaction, advantage is that crystal is difficult for separating out in the reaction process, easy control of temperature, the weight yield height of reaction product, activeconstituents (tiring) height, when temperature greater than 30 ℃ or all decrease less than 10 ℃ of weight yields and activeconstituents.Experimental data sees Table four.
Experimental phenomena: temperature transforms slowly during less than 10 ℃, and reaction solution is very easily separated out crystal, influences yield.Temperature is during greater than 30 ℃, instability, and the destructible activeconstituents, yield is low.
Table four:
| Temperature of reaction ℃ | 6 | 10 | 18 | 30 | 38 |
| Weight yield % | 83.5 | 90.3 | 93.8 | 90.1 | 80.6 |
| Activeconstituents u/mg | 778/818 | 790/832 | 805/846 | 789/831 | 778/817 |
| Moisture % | 4.9 | 5.1 | 4.9 | 5.0 | 4.8 |
2, the present invention controls salify terminal point pH scope 4.0～5.5 o'clock, reacts completely, and the weight yield of comparing with U.S. Pat 3276956 (table two) terminal point pH6.0 and European patent RU2190410 (table three) is higher, the activeconstituents height.Experimental data sees Table five.
Table five:
| Terminal point pH | 3.5 | 4.0 | 4.8 | 5.5 |
| Weight yield % | 80.4 | 93.8 | 93.5 | 92.5 |
| Activeconstituents u/mg | 781/820 | 792/835 | 804/845 | 795/840 |
| Moisture % | 4.7 | 5.1 | 4.9 | 5.4 |
Terminal point pH scope 7.0～9.0 o'clock is compared the activeconstituents height of gained phosphoric acid erythromycin, weight yield height with U.S. Pat 3276956 (table two) terminal point pH6.0 with European patent RU2190410 (table three) terminal point pH6.5.Compared (table five) at 4～5.5 o'clock with terminal point pH scope, weight yield decreases, but activeconstituents is higher.PH was greater than 9.0 o'clock, and reaction is incomplete, and yield is low, and residual erythrocin is higher.Experimental data sees Table six.
Table six:
| Terminal point pH | 7.0 | 7.8 | 9.0 | 10 |
| Weight yield % | 91.3 | 90.8 | 90.1 | 77.8 |
| Activeconstituents u/mg | 812/852 | 818/857 | 808/850 | 787/823 |
| Moisture % | 4.7 | 4.5 | 4.9 | 4.4 |
3, phosphoric acid concentration: 15～60%, compare with used 85% phosphoric acid solution among U.S. Pat 3276956 (table one) embodiment 1, be difficult for producing local overacidification's phenomenon, and be not easy to destroy erythromycin unit in the reaction solution, reaction process easily stirs, during reaction if adopt 85% phosphoric acid solution, easy gum deposit, produce local overacidification, destroy erythromycin unit in the reaction solution easily, activeconstituents and yield are all reduced.Experimental data sees Table seven.
Table seven:
| Phosphoric acid concentration % | 15 | 35 | 60 |
| Weight yield % | 90.5 | 93.7 | 90.8 |
| Activeconstituents u/mg | 787/826 | 803/844 | 786/823 |
| Moisture % | 4.7 | 4.9 | 4.5 |
As reaction medium, temperature of reaction is at 20 ℃ with water, and phosphoric acid solution concentration is 25%, reaction end pH be controlled at 5.0 or 7.5 o'clock weight yields higher.Experimental data sees Table eight in detail.
Table eight:
※ (two), usefulness organic solvent are as reaction medium and water ratio
With organic solvent as reaction medium and water ratio, under same temperature of reaction, use the phosphoric acid solution of same concentrations, control under the identical terminal point pH condition, the weight yield height, cost is low, has certain solvent residual, but the limit less than allowing in 2005 editions appendix P56 of Chinese Pharmacopoeia subordinate list 1 meets 2005 editions requirements of Chinese Pharmacopoeia fully.The organic solvent that uses among the present invention is compared residual low and toxicity is little with methyl alcohol, and less than the limit that allows in 2005 editions appendix P56 of Chinese Pharmacopoeia subordinate list 1, meets the requirement of Chinese Pharmacopoeia 2005 editions fully.See Table nine.
Table nine:
| Reaction medium | N-butyl acetate | Isobutyl acetate | Acetone | Ethanol | Water |
| Weight yield % | 97.7 | 97.5 | 97.8 | 98.1 | 93.4 |
| Activeconstituents u/mg | 806/847 | 799/841 | 804/845 | 804/842 | 797/842 |
| Moisture % | 4.8 | 5.0 | 4.9 | 4.5 | 5.4 |
| Residual solvent % | 0.03 | 0.04 | 0.02 | 0.01 | Do not detect |
As reaction medium, temperature of reaction is at 15 ℃ with described organic solvent, and phosphoric acid solution concentration is 45%, reaction end pH be controlled at 4.8 or 8.0 o'clock weight yields higher.Experimental data sees Table ten in detail.
Table ten:
Embodiment
Further set forth the synthetic method of using preparing phosphate eritrocina erythromycin below by embodiment.
The equipment that is adopted among the embodiment is commercially available equipment, can both make following product by industry is known.Phosphoric acid among the embodiment-n-butyl acetate solution is meant that wherein the per-cent of phosphoric acid is volume percent with phosphoric acid and 60% formulated phosphoric acid of n-butyl acetate.Phosphoric acid in following examples-isobutyl acetate solution; Phosphoric acid-ethanolic soln; Phosphoric acid-acetone soln; Phosphate aqueous solution also as mentioned above.
Embodiment 1
20g erythromycin is joined in the 500ml n-butyl acetate organic solvent, stir, the phosphoric acid-n-butyl acetate solution that drips 3.2ml 60% is regulated the pH value to reaction end pH4.5,10 ℃ of control reaction temperature, after centrifugal, oven drying, obtain the white powder of phosphoric acid erythromycin.
Embodiment 2
12g erythromycin is joined in the 250ml isobutyl acetate organic solvent, stir, phosphoric acid-isobutyl acetate the solution that drips 10ml 15% is regulated the pH value to reaction end pH4.0,12 ℃ of control reaction temperature, wash reactant at last with water, through separation, drying, obtain the white powder of phosphoric acid erythromycin.
Embodiment 3
80g erythromycin is joined in the 80ml ethanol organic solvent, stir, the phosphoric acid-ethanolic soln that drips 16ml45% is regulated the pH value to reaction end pH8.0, and 15 ℃ of control reaction temperature after spouted drying, obtain the white powder of phosphoric acid erythromycin.
Embodiment 4
100g erythromycin is joined in the mixing solutions of 1500ml n-butyl acetate and 100ml water, stir, regulate pH9.8 with sodium hydroxide solution, upper strata n-butyl acetate phase is got in layering, phosphoric acid-n-butyl acetate the solution that adds 18.5ml 55%, 23 ℃ of control reaction temperature, reaction end PH5.5 is after centrifugal, oven drying obtains the white powder of phosphoric acid erythromycin.
Embodiment 5
60g erythromycin is joined in the 380ml acetone organic solvent, stir, drip phosphoric acid-acetone soln of 26.5ml20%, 19 ℃ of control reaction temperature, reaction end pH7.0, after centrifugal, oven drying obtains the white powder of phosphoric acid erythromycin.
Embodiment 6
80g erythromycin is joined in the 2000ml water, stir, the phosphate aqueous solution that drips 24ml 30% is regulated the pH value to reaction end pH9.0, and 30 ℃ of control reaction temperature after spouted drying, obtain the white powder of phosphoric acid erythromycin.
Embodiment 7
150g erythromycin is joined in the 2250ml water, stir, the phosphate aqueous solution of Dropwise 5 2ml 25% is regulated the pH value to reaction end pH5.0, and 20 ℃ of control reaction temperature after spouted drying, obtain the white powder of phosphoric acid erythromycin.
Embodiment 8
40g erythromycin is joined in the 800ml water, stir, the phosphate aqueous solution that drips 6.5ml 40% is regulated the pH value to reaction end pH7.5, and 28 ℃ of control reaction temperature after spouted drying, obtain the white powder of phosphoric acid erythromycin.
Embodiment 9
25g erythromycin is joined in the 250ml n-butyl acetate, stir, the phosphoric acid of Dropwise 5 ml45%-n-butyl acetate solution is regulated the pH value to reaction end pH4.8 continuously, and 15 ℃ of control reaction temperature after spouted drying, obtain the white powder of phosphoric acid erythromycin.
Claims (6)
1, with the method for preparing phosphate eritrocina erythromycin, it is characterized in that: erythromycin is dissolved in C
2-C
6Contain in the organic solvent or water of hydroxyl, carbonyl, stir, be controlled to the reactant salt temperature, by dripping the mode regulator solution pH value of phosphoric acid solution, the control reaction end carries out building-up reactions, obtains phosphoric acid erythromycin finished product after separate drying; The salt-forming reaction temperature remains on 10～30 ℃; The pH value is chosen in 4.0～5.5 or 7.0～9.0.
2, the method with preparing phosphate eritrocina erythromycin according to claim 1 is characterized in that: described C
2-C
6The organic solvent that contains hydroxyl, carbonyl is a n-butyl acetate, isobutyl acetate, acetone or alcohol.
3, the method with preparing phosphate eritrocina erythromycin according to claim 1, it is characterized in that: the preparation of described phosphoric acid solution is to prepare with the phosphoric acid solvent identical with reaction medium, and concentration of phosphoric acid is 15%～60%.
4, the method with preparing phosphate eritrocina erythromycin according to claim 1, it is characterized in that: described reaction medium is that erythromycin is dissolved in C
2-C
6Contain a kind of or water in the organic solvent of hydroxyl, carbonyl.
5, the method with preparing phosphate eritrocina erythromycin according to claim 1, it is characterized in that: described erythromycin is weight/volume 1: 1～25 with the ratio of organic solvent.
6, the method with preparing phosphate eritrocina erythromycin according to claim 4, it is characterized in that: described erythromycin is weight/volume 1: 15～25 with the ratio of water.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3276956A (en) * | 1963-05-31 | 1966-10-04 | Abbott Lab | Treating infections in poultry caused by pleuropneumoniia-like organisms with erythromycin phosphate |
| RU2190410C1 (en) * | 2001-06-18 | 2002-10-10 | Акционерное Курганское общество медицинских препаратов и изделий "Синтез" | Method of injection form of erythromycin phosphate preparing |
-
2006
- 2006-02-07 CN CNB200610041759XA patent/CN100434435C/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3276956A (en) * | 1963-05-31 | 1966-10-04 | Abbott Lab | Treating infections in poultry caused by pleuropneumoniia-like organisms with erythromycin phosphate |
| RU2190410C1 (en) * | 2001-06-18 | 2002-10-10 | Акционерное Курганское общество медицинских препаратов и изделий "Синтез" | Method of injection form of erythromycin phosphate preparing |
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| CN1807443A (en) | 2006-07-26 |
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Denomination of invention: Method for preparing phosphate eritrocina using eritrocina Effective date of registration: 20150929 Granted publication date: 20081119 Pledgee: Shaanxi Qin Nong rural commercial bank Limited by Share Ltd Pledgor: Xi'an Lijun Pharmaceutical LLC Registration number: 2015990000836 |
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