CN106905396A - The preparation method of fumaric acid Tilmicosin double salt - Google Patents
The preparation method of fumaric acid Tilmicosin double salt Download PDFInfo
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- CN106905396A CN106905396A CN201710091834.1A CN201710091834A CN106905396A CN 106905396 A CN106905396 A CN 106905396A CN 201710091834 A CN201710091834 A CN 201710091834A CN 106905396 A CN106905396 A CN 106905396A
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- fumaric acid
- tilmicosin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention discloses a kind of preparation method of fumaric acid Tilmicosin double salt, comprise the following steps：(1) fumaric acid is dissolved in organic solvent, the agitating heating dissolving under the conditions of anhydrous is obtained the organic solution of fumaric acid；(2) organic solvent will be dissolved in the equimolar Tilmicosin bulk drug of fumaric acid, be dissolved under the conditions of anhydrous, the organic solution of Tilmicosin will be obtained；(3) organic solution of fumaric acid is mixed with the organic solution of Tilmicosin, the heating response under the conditions of anhydrous, reaction temperature is controlled at 60~80 DEG C, after question response is complete, cooling reaction solution, insoluble matter is filtered off, filtrate revolving reclaims organic solvent, the solid product for obtaining i.e. fumaric acid Tilmicosin double salt.Preparation process is simple of the present invention, low production cost, and the fumaric acid Tilmicosin double salt good water solubility for preparing, solubility are high, and preparation stable performance, mouthfeel is suitable.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to a kind of preparation method of fumaric acid Tilmicosin double salt.
Background technology
Tilmicosin is a kind of brutish special antibiotic of macrolide, the eighties in 20th century by Britain Elanco animals
Health products Co., Ltd succeeds in developing Tilmicosin and is typically obtained by tylosin is semi-synthetic, with the similar antibacterial of same tylosin
Spectrum, has inhibitory action, especially to pleura lung to gram-positive bacteria and part Gram-negative bacteria, mould type bacterium, conveyor screw etc.
Scorching Actinobacillus, Pasteurella and brutish mould type thalline have the antibacterial activity more stronger than tylosin, with clinical conventional its
Without cross resistance between its antibiotic.
Tilmicosin has macrocyclic lactone structure, and the hydroxyl on ring is linked with sugar or substitution sugar in the way of glycosidic bond, big ring
Tension force is reduced, thus stable in properties.The main protein by suppressing bacterium synthesizes, and plays bactericidal action.It is sub- with 50S ribose
Unit invertibity is combined, the displacement process of influence ribosomes and protein, hinders peptide chain to increase.This product is presently the most safe
One of antibiotic, is not combined with the 80S ribosomes of mammal, and this is probably the less partly cause of its toxicity.
In addition, pharmacokinetic shows, no matter take orally or hypodermic injection, Tilmicosin is in beast fowl body absorption
Hurry up, medicine long half time in blood, drug entities penetration power is strong, apparent volume of distribution is big, especially the medicine in lung tissue, breast is dense
Degree is high and eliminates slow.
Due to various advantages with more than, Tilmicosin clinical practice is extensive.But because Tilmicosin water solubility is extremely low, give
Clinical practice brings inconvenience.In existing market, Tilmicosin primary formulation has pre-mixing agent, solution etc., although one
Determine to be improved in degree its water-soluble, but some problems still suffered from during its use, such as dissolution in low temperature speed relatively slowly or
Precipitation etc. so that solution muddiness etc..In the prior art in order to solve this problem, using expensive dedicated solvent significantly
Increased its use cost.Although being related to prepare the report of the new techniques such as nano-emulsion, liposome, soluble powder in recent years
Road, but because its preparation technology is complicated, preparation stability difference the shortcomings of, greatly limit its clinically should
With.Veterinary clinic often uses its phosphate, but because existing tilmicosin phosphate preparation palatability is poor, animal predation is influenceed, so as to drop
The low curative effect to disease.
Therefore, develop that a kind of solvable, solubility is high, preparation process is simple, low cost, good in taste, property
Tilmicosin medicament that can be stable very has practical value.
The content of the invention
In view of this, it is an object of the invention to provide a kind of preparation method of fumaric acid Tilmicosin double salt, work is prepared
Skill is simple, low production cost, and the fumaric acid Tilmicosin double salt good water solubility for preparing, and solubility is high, preparation stable performance,
Mouthfeel is suitable.
To reach above-mentioned purpose, the present invention provides following technical scheme：
A kind of preparation method of fumaric acid Tilmicosin double salt, comprises the following steps：
(1) fumaric acid is dissolved in organic solvent, the agitating heating dissolving under the conditions of anhydrous is obtained the organic of fumaric acid
Solution；
(2) organic solvent will be dissolved in the equimolar Tilmicosin bulk drug of fumaric acid, be dissolved under the conditions of anhydrous, system
Obtain the organic solution of Tilmicosin；
(3) organic solution of the organic solution of fumaric acid obtained in step (1) and Tilmicosin obtained in step (2) is mixed
Close, the heating response under the conditions of anhydrous, reaction temperature is controlled at 60~80 DEG C, after question response is complete, cool down reaction solution, filter off
Insoluble matter, filtrate revolving reclaims organic solvent, the solid product for obtaining i.e. fumaric acid Tilmicosin double salt；
The organic solvent is methyl alcohol, ethanol or ethyl acetate.
Used as the preferred technical solution of the present invention, in the step (1), the mode of heating that fumaric acid is dissolved in organic solvent is
Oil bath heating, heating-up temperature is 60~80 DEG C.
As the preferred technical solution of the present invention, in the step (1), the concentration of the organic solution of fumaric acid for 0.05~
1.0mol/L。
Used as the preferred technical solution of the present invention, in the step (2), the concentration of the organic solution of Tilmicosin is 0.1
~2.0mol/L.
As the preferred technical solution of the present invention, in the step (3), the organic solution of fumaric acid is first heated to 60~
80 DEG C, then the organic solution of Tilmicosin slowly instilled into the organic solution of fumaric acid, 60 are maintained under the conditions of anhydrous
Reacted at~80 DEG C, organic vapor is condensed out with condenser pipe is returned in reactor.
Used as the preferred technical solution of the present invention, in the step (3), the organic solution of Tilmicosin slowly instills rich horse
When in the organic solution of acid, rate of addition is controlled in 0.5~5ml/min.
Used as the preferred technical solution of the present invention, in the step (3), mode of heating is oil bath heating.
As the preferred technical solution of the present invention, in the step (3), the progress journey of reaction is monitored with thin-layered chromatography
Degree, Indicator Reaction terminal.
The beneficial effects of the present invention are：
The present invention with powdered Tilmicosin bulk drug as raw material, with fumaric acid with methyl alcohol, ethanol or ethyl acetate be anti-
Medium is answered to be reacted, prepared fumaric acid Tilmicosin double salt good water solubility, solubility is high, preparation stable performance, very well
Solve the problems, such as bulk drug poorly water-soluble, and palatability to medicine has certain improvement, is that clinical practice is established
Good basis；Fumaric acid Tilmicosin double salt prepared by the present invention is water-soluble more preferable compared with tilmicosin phosphate, is facing
Bed application is upper more valuable.
Meanwhile, process route of the invention is simple, and reaction condition is gentle, easily operation, and solvent for use safety can be circulated
Utilize, required low production cost, and product yield high, yield up to more than 65%, with preferable commercial application prospect.
Specific embodiment
In order that the purpose of the present invention, technical scheme and beneficial effect are clearer, below will be to preferred reality of the invention
Example is applied to be described in detail.
Embodiment 1
(1) 0.58g fumaric acid and 50ml methyl alcohol are placed in the there-necked flask of 250ml, under the conditions of anhydrous, at 65 DEG C
Oil bath in agitating heating dissolving 10min, be obtained fumaric acid methanol solution；
(2) equimolar Tilmicosin bulk drug 4.345g is dissolved in 30ml methyl alcohol, is dissolved under the conditions of anhydrous, be obtained
The methanol solution of Tilmicosin；
(3) methanol solution of Tilmicosin is transferred in apparatus,Soxhlet's, beaker, washing lotion is cleaned by several times with 10ml methyl alcohol
It is incorporated in apparatus,Soxhlet's；Apparatus,Soxhlet's is connected in the side port of there-necked flask, there-necked flask middle port connects condenser pipe and (ensures
It is anhydrous), condensation pipe end connects drier (preventing the water entrance in air), oil bath heating to after 65 DEG C, under the conditions of anhydrous,
The methanol solution of Tilmicosin is slowly instilled reaction in the methanol solution of fumaric acid with 1ml/min；The 3rd of there-necked flask
Mouth is used for taking liquid when monitoring extent of reaction, should be clogged when not taking liquid；Extracted reaction solution after about 4h in point on chromatographic sheet
Sample, is control with the Tilmicosin methanol solution of 0.1mol/L, with ethyl acetate：N-hexane：Methyl alcohol=1:1:1 is solvent,
If the phosphor dot of the two is kept completely separate, it is considered as reaction and terminates, stops reaction；Allow reaction system natural cooling, stood below 0 DEG C
Overnight, after taking-up, insoluble matter is filtered off, filtrate rotates at 68 DEG C, reclaims methyl alcohol, obtain solid product, yield 66.8%.
The molecular weight that gained solid product is analyzed through efficient liquid phase-mass spectrum (Lc-Ms) is 985, with rich horse as follows
The molecular weight of sour Tilmicosin double salt is consistent, and can confirm products therefrom for target product fumaric acid Tilmicosin double salt.
Embodiment 2
(1) 0.58g fumaric acid and 50ml ethanol are placed in the there-necked flask of 250ml, under the conditions of anhydrous, at 67 DEG C
Oil bath in agitating heating dissolving 10min, be obtained fumaric acid ethanol solution；
(2) equimolar Tilmicosin bulk drug 4.345g is dissolved in 30ml ethanol, is dissolved under the conditions of anhydrous, be obtained
The ethanol solution of Tilmicosin；
(3) ethanol solution of Tilmicosin is transferred in apparatus,Soxhlet's, beaker, washing lotion is cleaned by several times with 10ml ethanol
It is incorporated in apparatus,Soxhlet's；Apparatus,Soxhlet's is connected in the side port of there-necked flask, there-necked flask middle port connects condenser pipe and (ensures
It is anhydrous), condensation pipe end connects drier (preventing the water entrance in air), oil bath heating to after 67 DEG C, under the conditions of anhydrous,
The ethanol solution of Tilmicosin is slowly instilled reaction in the ethanol solution of fumaric acid with 0.5ml/min；The 3rd of there-necked flask
Individual mouth is used for taking liquid when monitoring extent of reaction, should be clogged when not taking liquid；Extracted reaction solution on chromatographic sheet after about 4h
Point sample, is control with the Tilmicosin ethanol solution of 0.1mol/L, with ethyl acetate：N-hexane：Methyl alcohol=1:1:1 is expansion
Agent, if the phosphor dot of the two is kept completely separate, is considered as reaction and terminates, and stops reaction；Reaction system natural cooling is allowed, below 0 DEG C
Stand overnight, after taking-up, filter off insoluble matter, filtrate rotates at 70 DEG C, reclaims ethanol, obtains solid product, yield 67.6%.
The molecular weight for analyzing gained solid product through efficient liquid phase-mass spectrum (Lc-Ms) is 985.
Embodiment 3
(1) 0.58g fumaric acid is dissolved in 50ml ethyl acetate, under the conditions of anhydrous, stirring adds in 75 DEG C of oil bath
Heat of solution 10min, is obtained the ethyl acetate solution of fumaric acid；
(2) equimolar Tilmicosin bulk drug 4.345g is dissolved in 50ml ethyl acetate, is dissolved under the conditions of anhydrous,
The ethyl acetate solution of Tilmicosin is obtained；
(3) ethyl acetate solution of Tilmicosin is placed in 250ml three-neck flasks, adds stirrer, be fixed on constant temperature
In magnetic stirring apparatus, exhaust gas processing device, loading fumaric acid acetic acid that three-neck flask connects condensing unit, loads anhydrous calcium chloride
The dropping funel of ethyl ester solution；Oil bath heating under the conditions of anhydrous, regulates the liquid droping speed of dropping funel to after 80 DEG C,
The ethyl acetate solution of fumaric acid is slowly instilled reaction in the ethyl acetate solution of Tilmicosin with 0.5ml/min；After about 4h
Extract reaction solution in point sample on chromatographic sheet, be control with the Tilmicosin ethyl acetate solution of 0.1mol/L, with ethyl acetate：
N-hexane：Methyl alcohol=1:1:1 is solvent, if the phosphor dot of the two is kept completely separate, is considered as reaction and terminates, and stops reaction；Allow anti-
System natural cooling is answered, is stood overnight below 0 DEG C, after taking-up, filter off insoluble matter, filtrate rotates at 85 DEG C, reclaims acetic acid
Ethyl ester, obtains solid product, yield 65.5%.
The molecular weight for analyzing gained solid product through efficient liquid phase-mass spectrum (Lc-Ms) is 985.
Be added drop-wise to the organic solution of fumaric acid in the organic solution of Tilmicosin by embodiment 3, and embodiment 1 and embodiment
2 are added drop-wise in the organic solution of fumaric acid the organic solution of Tilmicosin, compared with Example 3, embodiment 1 and embodiment 2
Yield it is higher.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
Cross above preferred embodiment to be described in detail the present invention, it is to be understood by those skilled in the art that can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (8)
1. a kind of preparation method of fumaric acid Tilmicosin double salt, it is characterised in that：Comprise the following steps：
(1) fumaric acid is dissolved in organic solvent, the agitating heating dissolving under the conditions of anhydrous is obtained the organic molten of fumaric acid
Liquid；
(2) organic solvent will be dissolved in the equimolar Tilmicosin bulk drug of fumaric acid, be dissolved under the conditions of anhydrous, and be obtained and replace
The organic solution of meter Kao Xing；
(3) organic solution of fumaric acid obtained in step (1) is mixed with the organic solution of Tilmicosin obtained in step (2),
The heating response under the conditions of anhydrous, reaction temperature is controlled at 60~80 DEG C, after question response is complete, cools down reaction solution, is filtered off not
Molten thing, filtrate revolving reclaims organic solvent, the solid product for obtaining i.e. fumaric acid Tilmicosin double salt；
The organic solvent is methyl alcohol, ethanol or ethyl acetate.
2. the preparation method of fumaric acid Tilmicosin double salt according to claim 1, it is characterised in that：The step (1)
In, the mode of heating that fumaric acid is dissolved in organic solvent is oil bath heating, and heating-up temperature is 60~80 DEG C.
3. the preparation method of fumaric acid Tilmicosin double salt according to claim 1, it is characterised in that：The step (1)
In, the concentration of the organic solution of fumaric acid is 0.05~1.0mol/L.
4. the preparation method of fumaric acid Tilmicosin double salt according to claim 1, it is characterised in that：The step (2)
In, the concentration of the organic solution of Tilmicosin is 0.1~2.0mol/L.
5. the preparation method of fumaric acid Tilmicosin double salt according to claim 1, it is characterised in that：The step (3)
In, the organic solution of fumaric acid is first heated to 60~80 DEG C, then the organic solution of Tilmicosin is slowly instilled into fumaric acid
In organic solution, reacted at being maintained at 60~80 DEG C under the conditions of anhydrous, condensed out organic vapor with condenser pipe
Return in reactor.
6. the preparation method of fumaric acid Tilmicosin double salt according to claim 5, it is characterised in that：The step (3)
In, when the organic solution of Tilmicosin is slowly instilled in the organic solution of fumaric acid, rate of addition is controlled in 0.5~5ml/min.
7. the preparation method of fumaric acid Tilmicosin double salt according to claim 5, it is characterised in that：The step (3)
In, mode of heating is oil bath heating.
8. the preparation method of fumaric acid Tilmicosin double salt according to claim 5, it is characterised in that：The step (3)
In, the progress extent of reaction, Indicator Reaction terminal are monitored with thin-layered chromatography.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1429232A (en) * | 2000-04-27 | 2003-07-09 | 辉瑞产品公司 | Use of azalide antibiotic compositions for treating or preventing bacterial or protozoal infection in mammals |
| CN103275155A (en) * | 2013-06-28 | 2013-09-04 | 宁夏泰瑞制药股份有限公司 | Preparation method of tylosin phosphate or tartrate crystal |
| CN103483406A (en) * | 2013-09-25 | 2014-01-01 | 宁夏泰瑞制药股份有限公司 | Preparation method for tilmicosin phosphate |
-
2017
- 2017-02-21 CN CN201710091834.1A patent/CN106905396A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1429232A (en) * | 2000-04-27 | 2003-07-09 | 辉瑞产品公司 | Use of azalide antibiotic compositions for treating or preventing bacterial or protozoal infection in mammals |
| CN103275155A (en) * | 2013-06-28 | 2013-09-04 | 宁夏泰瑞制药股份有限公司 | Preparation method of tylosin phosphate or tartrate crystal |
| CN103483406A (en) * | 2013-09-25 | 2014-01-01 | 宁夏泰瑞制药股份有限公司 | Preparation method for tilmicosin phosphate |
Non-Patent Citations (2)
| Title |
|---|
| 吴云等主编: "《实用有机化学技术》", 31 January 2008, 湖北科学技术出版社 * |
| 张力等主编: "《动物营养与饲料》", 31 August 2007, 中国农业大学出版社 * |
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