CN105001112B - Water soluble chlorotetracycline succinic acid monoester salt, and preparation method thereof - Google Patents
Water soluble chlorotetracycline succinic acid monoester salt, and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical synthesis, and more specifically relates to a water soluble chlorotetracycline succinic acid monoester salt, and a preparation method thereof. The preparation method is used for modifying chlorotetracycline. The chlorotetracycline succinic acid monoester salt possesses a structure represented by formula I, wherein M is used for representing Na, K, meglumine, arginine, or lysine. According to the preparation method, grafting modification of chlorotetracycline with succinic anhydride is carried out so as to obtain the chlorotetracycline succinic acid monoester salt with water solubility better than that of chlorotetracycline, and broad-spectrum antibacterial property of the water soluble chlorotetracycline succinic acid monoester salt is the same as that of chlorotetracycline in animal bodies.
Description
Technical field
The invention belongs to chemosynthesis technical field is and in particular to water solublity chlortetracycline succinic monoester salt and its preparation side
Method.
Background technology
Chlortetracycline (chlortetracycline, ctc), is tetracycline antibiotics, in chemical constitution with tetracycline only
C-7 position instead of h with cl, so chlortetracycline is also called 7- duomycin, structural formula is as follows:
Chlortetracycline hydrochloride is golden yellow or yellow crystallization, odorless, bitter in the mouth, and slightly soluble in water and ethanol solution, third
Almost insoluble in ketone, ether or chloroform, but can be dissolved in alkaline hydrated oxide and carbonate solution.Chlortetracycline hydrochloride
Specific rotatory power between -235 to -250, between ph value 2.3-3.3.The has a broad antifungal spectrum of chlortetracycline, to gram positive bacteria, feminine gender
Bacterium, rickettsia, spirillum, chlamydia, mycoplasma, some protozoons etc. all can produce inhibitory action.
Chlortetracycline belongs to tetracycline medication, the main protein synthesis suppressing sensitive microbial, the mechanism of action be with micro-
Biological 30s small subunit a position combines, and interference aminoacyl trna is combined with 30s small subunit further, so that aminoacyl trna can not be entered
Enter on mrna by position it is suppressed that during protein synthesis peptide chain extended；Chlortetracycline can also stop synthetic protein peptide chain
Release.Chlortetracycline effect ribosomal to 70s is more sensitive, can Selective depression sensitive microbial, thus have good
Good security performance.At present, the chlortetracycline types of formulation having used both at home and abroad has: feed grade chlortetracycline
(chlortetracycline feed grade), chlortetracycline hydrochloride (chlortetracycline hydrochloride), gold
Mycin eye ointment (chlortetracycline eye ointment or chlortetracycline hydrochloride
Ophthalmic ointment), chlorotetracycline ointment (chlortetracycline ointment), chlortetracycline hydrochloride tablet
(chlortetracycline hydrochloride tablets), chlortetracycline hydrochloride capsule (capsulate
Chlortetracycline hydrochloride), hydrochloride for injection chlortetracycline (chlortetracycline
Hydrochloride pro injection) etc..
Either chlortetracycline or chlortetracycline hydrochloride dissolubility in water are limited.Easily decompose in water, poor chemical stability, molten
When solving poor performance, having bad abnormal smells from the patient or taste, use, zest or pain etc. are produced to body.Make its preparation type and clinic
Application is subject to certain restrictions, and also have impact on chlortetracycline medicine simultaneously and plays due effect.Therefore, improve the water-soluble of chlortetracycline
Property and improve its stability, find and create new strong antibacterial ability chlortetracycline derivant, become current chlortetracycline structure of modification
With one of the focus modifying Journal of Sex Research.
Tetracyclines derivant has multiple ionizableization functional groups, wherein c1- keto-acid, c3- enol form/keto-acid, c10-,
C11-, c12- phenolic/keto-acid and c4- dimethylamino etc., have corresponding soda acid ionization parameter, affect the fat moisture of chlortetracycline
Distribution coefficient；Tetracycline has three acid dissociation constants (pka=3.3,7.68 and 9.69) and can form cation；Acid, weak acid
Property and alkalescence condition under can be existed with amphion and anionic form.The structural formula of Tetracyclines derivant is as follows:
Therefore, these are structural modification and the transformation of tetracycline antibiotics, and the discovery of prodrug provides and fills
The feasibility in theory foundation divided.The modifying for chemical structure of medicine is based on the original basic chemical structure of medicine, only to wherein certain
A little functional groups are chemically modified, and may change original physicochemical property by modifying, and to overcome disadvantages mentioned above, improve medicine
Activity and heighten the effect of a treatment, therefore, drug modification has extremely important effect in clinical practice.Succinic acid is as domestic at present
The Main Means of outer drug modification, it can be reacted with multi-medicament.
Content of the invention
The technical problem to be solved in the present invention is chlortetracycline to be modified and transforms.
The invention provides chlortetracycline succinic monoester salt, there is the structure as shown in formula:
Wherein, m is na, k, meglumine, arginine or lysine.
Present invention also offers the preparation method of chlortetracycline succinic monoester salt, comprise the following steps:
A. chlortetracycline hydrochloride is dissolved in organic solution, adds sodium carbonate stirring, under the conditions of 30～80 DEG C, agitating solution becomes
Homogeneously；Described organic solution is the mixed solution of organic solvent and water, and the mass ratio shared by organic solvent is mixed solution
40%-90%；
B. succinic anhydrides and catalyst are mixed, be then added to that step a obtains homogeneous in, return stirring 0.5～5 is little
When, hydrochloric acid is acidified to ph=6, and cooling obtains chlortetracycline monomester succinate solid；
C. backflow dissolving chlortetracycline monomester succinate in organic solvent, adds corresponding alkali stirring, cooling, that is, generates target
Product；Described corresponding alkali be pharmaceutically acceptable become saline and alkaline, including sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Arginine, lysine or meglumine.
Specifically, organic solvent described in step a refer to ethanol, acetone, ethylene glycol, acetonitrile, propylene glycol, glycerol, four
Any one in hydrogen furan or 1,4- dioxane.
Specifically, chlortetracycline hydrochloride described in step a and sodium carbonate mol ratio are 1 1～1.5.
Specifically, succinic anhydrides described in step b and catalyst molar ratio are 1 0.1～1.5.
Specifically, catalyst described in step b is dicyclohexylcarbodiimide dcc, 4- dimethylamino pyridine dmap, three second
Any one or more mixture in amine, pyridine；Catalyst mol ratio between any two is 0～1.0 1.0～0, and catalyst
Total amount be not 0.
Specifically, in step b, the mole of succinic anhydrides is 1.2～5.0 times of chlortetracycline hydrochloride mole.
Specifically, organic solvent described in step c is ethanol, isopropanol, acetonitrile, n, n- dimethylformamide, n, n-
The mixture of any one or two kinds of in dimethyl acetylamide, 1,4- dioxane, oxolane, acetone；Body between solvent
Long-pending ratio is 0～1.0 1.0～0, but the cumulative volume of solvent is not 0.
Specifically, chlortetracycline monomester succinate described in step c and corresponding alkali mol ratio 1 1.0～2.0.
Present invention also offers purposes in preparing animal feed for the described chlortetracycline succinic monoester salt.
Present invention also offers purposes in preparing animal feed for the preparation method of described chlortetracycline succinic monoester salt.
Beneficial effects of the present invention: the present invention passes through, by chlortetracycline and succinic anhydrides grafting and modifying, to have synthesized a kind of water-soluble
Property better than chlortetracycline chlortetracycline succinic monoester salt, it has the broad-spectrum antiseptic that chlortetracycline hydrochloride is had in animal body
Property, the bacteriostasis for part gram positive bacteria, gram negative bacteria are better than chlortetracycline hydrochloride, chlortetracycline succinic acid simultaneously
Monoester salt has enhancing human body immunity power, promotes growth of animal effect, can be used for preparing immunostimulant and feed additive, tool
There is preferable application prospect.
Specific embodiment
Embodiment 1, the preparation of chlortetracycline succinic acid monoester sodium salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 40% ethanol water, adds sodium carbonate (1.2mol) solid and stir
Mix, under the conditions of 80 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (5.0mol) and dicyclohexylcarbodiimide
(1.2mol), return stirring 3 hours, hydrochloric acid is acidified to ph=6, and cooling obtains chlortetracycline monomester succinate solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, is dissolved in ethanol, backflow, and sodium hydroxide is added batch-wise
(1.0mol), stir, cooling, that is, generate target product chlortetracycline succinic acid monoester sodium salt.Product is pale yellow powder, and yield is
77.8%.Measure through hplc, product purity is 98.6%；Measure through fab-ms (fast atom bombardment MS), molecular weight of product
For 600.9, it is 600.94 consistent with the molecular weight calculated value of target product.
Embodiment 2, the preparation of chlortetracycline succinic acid monoester sodium salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 90% aqueous acetone solution, adds sodium carbonate (1.5mol) solid and stir
Mix, under the conditions of 60 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (1.2mol) and 4- dimethylamino pyridine (1.8mol),
Return stirring 0.5 hour, hydrochloric acid is acidified to ph=6, and cooling obtains chlortetracycline monomester succinate solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, is dissolved in isopropanol, backflow, and sodium hydroxide is added batch-wise
(2.0mol), stir, cooling, that is, generate target product chlortetracycline succinic acid monoester sodium salt.Product is pale yellow powder, and yield is
81.3%.Measure through hplc, product purity is 98.58%；Measure through fab-ms, molecular weight of product is 600.1, with target product
Molecular weight calculated value be 600.94 consistent.
Embodiment 3, the preparation of chlortetracycline monomester succinate potassium salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 70% glycol water, adds sodium carbonate (1.0mol) solid and stir
Mix, under the conditions of 30 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (3.0mol) and triethylamine (4.5mol), return stirring
5 hours, hydrochloric acid was acidified to ph=6, and cooling obtains chlortetracycline monomester succinate solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, is dissolved in n, in n- dimethylformamide, backflow, and hydrogen is added batch-wise
Potassium oxide (1.5mol), stirring, cooling, that is, generate target product chlortetracycline monomester succinate potassium salt.Product is pale yellow powder,
Yield is 85.9%.Measure through hplc, product purity is 99.1%；Measure through fab-ms, molecular weight of product is 617.2, with mesh
The molecular weight calculated value of mark product is consistent for 617.05.
Embodiment 4, the preparation of chlortetracycline succinic acid monoester sodium salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 80% acetonitrile solution, adds sodium carbonate (1.5mol) solid and stir
Mix, under the conditions of 80 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (3.0mol) and pyridine (0.5mol), return stirring
2.5 hours, hydrochloric acid was acidified to ph=6, and cooling obtains chlortetracycline monomester succinate solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, is dissolved in Isosorbide-5-Nitrae-dioxane, backflow, and sodium carbonate is added batch-wise
(1.5mol), stir, cooling, that is, generate target product chlortetracycline succinic acid monoester sodium salt.Product is pale yellow powder, and yield is
76%.Measure through hplc, product purity is 99.6%；Measure through fab-ms, molecular weight of product is 600.2, with target product
Molecular weight calculated value is consistent for 600.94.
Embodiment 5, the preparation of chlortetracycline monomester succinate potassium salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 70% aqueous solution of propylene glycol, adds sodium carbonate (1.0mol) solid and stir
Mix, under the conditions of 60 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (4.0mol) and triethylamine/pyridine (triethylamine, pyridine
Each 0.5mol), return stirring 3.5 hours, hydrochloric acid is acidified to ph=6, and cooling obtains chlortetracycline monomester succinate solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, is dissolved in oxolane, backflow, and potassium carbonate is added batch-wise
(1.5mol), stir, cooling, that is, generate target product chlortetracycline monomester succinate potassium salt.Product is pale yellow powder, and yield is
80.9%.Measure through hplc, product purity is 99.0%；Measure through fab-ms, molecular weight of product is 617.1, with target product
Molecular weight calculated value be 617.05 consistent.
Embodiment 6, the preparation of chlortetracycline mono succinate ester arginine salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 50% glycerin solution, adds sodium carbonate (1.2mol) solid and stir
Mix, under the conditions of 50 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (2.0mol) and dcc/dmap mixture (wherein
Dcc0.2mol, dmap 0.3mol), return stirring 4 hours, hydrochloric acid is acidified to ph=6, and cooling obtains chlortetracycline monomester succinate
Solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, (volume ratio of ethanol and acetonitrile is 1.0 to be dissolved in ethanol/acetonitrile
1.0) in mixed solvent, backflow, arginine (1.5mol) is added batch-wise, stirring, cooling, that is, generate target product chlortetracycline succinum
Acid monoester arginine salt.Product is pale yellow powder, and yield is 82.2%.Measure through hplc, product purity is 99.01%；Warp
Fab-ms measures, and molecular weight of product is 753.09, consistent for 753.15 with the molecular weight calculated value of target product.
Embodiment 7, the preparation of chlortetracycline monomester succinate lysinate
Chlortetracycline hydrochloride (1.0mol) is dissolved in 70% tetrahydrofuran aqueous solution, adds sodium carbonate (1.5mol) solid
Stirring, under the conditions of 70 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (3.5mol) and dcc/ triethylamine mixture (wherein
Dcc 0.3mol, triethylamine 0.2mol), return stirring 3.5 hours, hydrochloric acid is acidified to ph=6, and cooling obtains chlortetracycline succinic acid
Monoesters solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, is dissolved in Isosorbide-5-Nitrae-dioxane/oxolane (Isosorbide-5-Nitrae-dioxy six
The volume ratio of ring/oxolane is 0.5 1.0) in mixed solvent, backflow, lysine (1.5mol) is added batch-wise, stirring, cold
But, that is, generate target product chlortetracycline monomester succinate lysinate.Product is pale yellow powder, and yield is 86.1%.Warp
Hplc measures, and product purity is 99.34%；Measure through fab-ms, molecular weight of product is 725.11, the molecular weight with target product
Calculated value is consistent for 725.15.
Embodiment 8, the preparation of chlortetracycline monomester succinate meglumine salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 90% Isosorbide-5-Nitrae-dioxane aqueous solution, adds sodium carbonate (1.0mol)
Solid stirs, and under the conditions of 50 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (2.0mol) and the mixing of dcc/dmap/ pyridine
Thing (each 0.1mol), return stirring 5 hours, hydrochloric acid is acidified to ph=6, and cooling obtains chlortetracycline monomester succinate solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, (volume ratio of acetonitrile/acetone is 1.0 to be dissolved in acetonitrile/acetone
0.5) in mixed solvent, backflow, meglumine (2.0mol) is added batch-wise, stirring, cooling, that is, generate target product chlortetracycline succinum
Acid monoester meglumine salt.Product is pale yellow powder, and yield is 89.9%.Measure through hplc, product purity is 99.7%；Warp
Fab-ms measures, and molecular weight of product is 775.20, consistent for 775.18 with the molecular weight calculated value of target product.
Embodiment 9, the preparation of chlortetracycline mono succinate ester arginine salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 70% ethanol water, adds sodium carbonate (1.5mol) solid and stir
Mix, under the conditions of 60 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (4.0mol) and dmap/ triethylamine/pyridine mixtures
(wherein dmap 0.6mol, triethylamine 0.1mol, pyridine 0.9mol), return stirring 1 hour, hydrochloric acid is acidified to ph=6, cooling
Obtain chlortetracycline monomester succinate solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, is dissolved in n, n- dimethylformamide/n, n- dimethyl acetylamide
In (n, n- dimethylformamide/n, the volume ratio of n- dimethyl acetylamide is 1.0 1.0) mixed solvent, backflow, it is added batch-wise
Arginine (1.2mol), stirring, cooling, that is, generate target product chlortetracycline mono succinate ester arginine salt.Product is faint yellow
Powder, yield is 90.2%.Measure through hplc, product purity is 99.0%；Measure through fab-ms, molecular weight of product is 753.1,
Consistent for 753.15 with the molecular weight calculated value of target product.
Embodiment 10, the preparation of chlortetracycline monomester succinate meglumine salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 90% acetonitrile solution, adds sodium carbonate (1.5mol) solid and stir
Mix, under the conditions of 80 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (3.0mol) and dcc/dmap/ pyridine mixtures (its
Middle dcc 0.1mol, dmap 0.2mol, pyridine 0.3mol), return stirring 2 hours, hydrochloric acid is acidified to ph=6, and cooling obtains gold
Mycin monomester succinate solid.
The chlortetracycline monomester succinate (1mol) that will be obtained, is dissolved in acetonitrile/Isosorbide-5-Nitrae-dioxane (acetonitrile/Isosorbide-5-Nitrae-dioxy six
The volume ratio of ring is 1.0 1.0) in mixed solvent, backflow, meglumine (1.5mol) is added batch-wise, stirring, cooling, that is, generate mesh
Mark product chlortetracycline monomester succinate meglumine salt.Product is pale yellow powder, and yield is 87%.Measure through hplc, product is pure
Spend for 99.5%；Measure through fab-ms, molecular weight of product is 775.07, the molecular weight calculated value with target product is
775.18 it is consistent.
Embodiment 11, the preparation of chlortetracycline monomester succinate meglumine salt
Chlortetracycline hydrochloride (1.0mol) is dissolved in 90% tetrahydrofuran aqueous solution, adds sodium carbonate (1.5mol) solid
Stirring, under the conditions of 80 DEG C, agitating solution becomes homogeneous；It is dividedly in some parts succinic anhydrides (3.0mol) and dcc/dmap/ triethylamine mixture
(wherein dcc 0.3mol, dmap 0.2mol, triethylamine 0.1mol), return stirring 2 hours, hydrochloric acid is acidified to ph=6, cooling
Obtain chlortetracycline monomester succinate solid.
Will be obtained chlortetracycline monomester succinate (1mol), be dissolved in oxolane/Isosorbide-5-Nitrae-dioxane (oxolane/1,
The volume ratio of 4- dioxane is 0.5 1.0) in mixed solvent, backflow, meglumine (1.5mol) is added batch-wise, stirring, cooling,
Generate target product chlortetracycline monomester succinate meglumine salt.Product is pale yellow powder, and yield is 85.4%.Survey through hplc
Fixed, product purity is 99.01%；Measure through fab-ms, molecular weight of product is 775.22, the theoretical meter with the molecular weight of target product
Calculation is worth consistent for 775.18.
Embodiment 12, different chlortetracycline succinic monoester salt dissolubility compare
The chlortetracycline succinic monoester salt object that the present invention provides is hence it is evident that improve traditional chlortetracycline and chlortetracycline hydrochloride
Water solublity, according to specifying under dissolubility item in 2010 editions Chinese Pharmacopoeias to carry out solubility test to testing sample.To survey in right amount
Examination thing is fully ground into fine powder, weighs 0.1g powder respectively in a certain amount of 25 DEG C of distilled water.Every strength shaking 30 in 5 minutes
Second, observe the dissolving situation in 30 minutes.During less than visually visible particles of solute, as it is completely dissolved.Record dissolving
The volume of the corresponding distilled water of 0.1g powder.Result is compared with the corresponding explanation of dissolubility vocabulary of terms in pharmacopeia, draws
Respective substance solubility test result.The results are shown in Table 1.As it can be seen from table 1 different chlortetracycline succinic monoester salt are all soluble in
Water, in water, dissolubility is greatly improved.
The dissolving situation of the different compound of table 1
| Determinand | Distilled water volume (ml) | Dissolubility |
| Chlortetracycline | 185.00 | Atomic molten |
| Chlortetracycline hydrochloride | 9.60 | Slightly soluble |
| Chlortetracycline succinic acid monoester sodium salt | 0.32 | Readily soluble |
| Chlortetracycline monomester succinate potassium salt | 0.28 | Readily soluble |
| Chlortetracycline monomester succinate meglumine salt | 0.66 | Readily soluble |
| Chlortetracycline mono succinate ester arginine salt | 0.72 | Readily soluble |
| Chlortetracycline monomester succinate lysinate | 0.83 | Readily soluble |
Embodiment 13, different chlortetracycline succinic monoester salt bacteriostasis compare
By standard E. coli, Diplococcus pneumoniae, Salmonella, haemophiluss, golden staphylococci, streptococcus, mycoplasma
It is inoculated in nutrient broth enrichment liquid with bordetella bacilli, 37 DEG C of incubated overnight.Sterilized agar culture medium is heated to completely
Melt, be poured in culture dish, every ware 15ml (lower floor), treat its solidification.Additionally, the pda culture medium of thawing is cooled to 50 DEG C of left sides
The right side is mixed into the above-mentioned several bacterium solution of test organismss, culture medium 5ml being mixed with bacterium is added to be solidified to (upper strata) in the culture medium of solidification.
Oxford cup is directly vertically put in media surface with sterile working, gently pressurizes so as to contact tight with culture medium, in cup
Middle addition medicinal liquid 100 μ l to be checked.Put 37 DEG C to cultivate 36 hours, observed result, reading directly measured by inhibition zone size chi.
The results are shown in Table 2.Result shows that different chlortetracycline succinic monoester salt have the wide spectrum that chlortetracycline hydrochloride had and resist
Bacterium property, the bacteriostasis for part gram positive bacteria, gram negative bacteria are better than chlortetracycline hydrochloride.
The different chlortetracycline succinic monoester salt of table 2 to antibacterial inhibition zone size (mm), 36 hours
Embodiment 14, the impact to immunity of organism for the chlortetracycline succinic monoester salt
Select 30 ages in days health ablactational baby pig 180, male and female half and half, according to body weight is close, male and female ratio identical principle,
It is randomly assigned, into 6 treatment groups, often to process 5 repetitions, often repeat 6 piglets (3 male 3 is female).Between each repeating groups original body mass it
Between no significant difference, 6.54 ± 0.21 kilograms of average out to.The feedstuff without antibiotic for the feeding, 3 days time, may to exclude early stage
The impact to test pig for the vertical medicine producing.Start to add Experimental agents nursing, in feedstuff, chemical feeding quantity is 75ppm later, from
By searching for food, free water, 21 days experimental periods.In the 21st day morning 8:00 of test, randomly select 5 pigs from every process aseptic quiet
Arteries and veins gathers blood sample 8ml, and slant setting, to separating out after serum, is centrifuged 10mins through 3000r/min, collects serum in -20 low temperature colds
Hide to analysis.The content of serum immune globulin (igg, igm, iga) all according to kit specification, is surveyed using euzymelinked immunosorbent assay (ELISA)
Fixed, carried out with microplate reader；Ifn- γ and il-12 level are all recorded by elisa detectable cassette method.
Measurement result is shown in Table 3.Iga, igm, igg are the common indexs of immunology detection.Immunoglobulin g
(immunoglobulin g, igg) is the most and topmost ig of body content, accounts for total immune globulin 70%～80% certainly,
Belong to secondary immune response antibody, i.e. the important antibody of body subinfection again.It has antibody to live virus, antibacterial and parasite etc.
Property, it is also uniquely new born animal adaptive immune antibody can be made by natural passive immunity by the ig of Placenta Hominiss.Immunoglobulin
A (immunoglobulin a, iga) is divided into serotype iga and secreting type iga (siga) two z kind.The former accounts for the total ig's of serum
10%～15%, the latter is primarily present in juice, such as: saliva, tear, breast milk, nasal secretions, bronchial secretion liquid and
Gastro-intestinal secretion liquid.Siga by respiratory tract, digestive tract, urogenital tract lymphoid tissue synthesize, siga concentration change and this
The pathological changes such as the local infection at a little positions, inflammation or tumor are closely related.Immunoglobulin m (immunoglobulin m, igm) is
Ig in primary immune response reaction, whether in ontogeny or after body is subject to antigenic stimulus, igm is earliest
The antibody occurring.Igm is the maximum ig of molecular mass, accounts for the 5%～l0% of the total ig of serum.Igm has strong coagulation antigen
Ability.Ifn- γ: lymphocytic type interferon.Ifn is a kind of broad-spectrum disease resistance toxic agent, not direct killing or suppression virus,
And mainly make cell produce antiviral protein by cell surface receptor effect, and thus suppressing the duplication of hepatitis B virus, its class
Type is divided three classes, α-(leukocyte) type, β-(fibroblast) type, γ-(lymphocyte) type；Interferon has impact cell life
Long, and the multiple biological activities such as differentiation, regulation immunologic function.Il-12: interleukin 12.It is neutral that il-2 can improve body
Granulocyte phagocytic function, has the effect of enhancing body non-specific immunity.
From table 3 it can be seen that compared with chlortetracycline hydrochloride group, the chlortetracycline succinic monoester salt group (chlortetracycline of the present invention
Succinic acid monoester sodium salt, chlortetracycline monomester succinate potassium salt, chlortetracycline monomester succinate lysinate, chlortetracycline monomester succinate
Arginine salt and chlortetracycline monomester succinate meglumine salt) all can different levels ground improve biological internal iga, igm, igg,
Ifn- γ and il-12 level, enhancing human body immunity power, wherein again with chlortetracycline monomester succinate lysinate, chlortetracycline succinum
The effect of acid monoester arginine salt is preferred.
The impact to the general immune indexes of body for the table 3 chlortetracycline succinic monoester salt
The impact to animal piglet body growth index of embodiment 15, chlortetracycline succinic monoester salt
Select 30 ages in days health ablactational baby pig 120, male and female half and half, according to body weight is close, male and female ratio identical principle,
It is randomly assigned into 6 treatment groups.No significant difference between original body mass between each repeating groups, 6.38 ± 0.17 kilograms of average out to.Open
Begin to add Experimental agents nursing, in feedstuff, chemical feeding quantity is 75ppm, free choice feeding, free water, 27 days experimental periods.Test measures
Initial weight, daily gain, daily ingestion amount, total feed consumption amount, final weight, calculate feedstuff-meat ratio.Record and the results are shown in Table 4.From feedstuff-meat ratio
Data display: the feedstuff-meat ratio of chlortetracycline succinic monoester salt is below chlortetracycline hydrochloride group, illustrates the chlortetracycline succinum of new synthesis
Acid monoester salt is respectively provided with the function of improving efficiency of feed utilization；Wherein comparatively chlortetracycline monomester succinate lysinate, gold are mould
The efficiency of feed utilization of plain mono succinate ester arginine salt and chlortetracycline monomester succinate meglumine salt improves more notable.
The impact to animal piglet body growth index for the table 4 chlortetracycline succinic monoester salt
Finally illustrate, above example only in order to technical scheme to be described and unrestricted, although by ginseng
According to the preferred embodiments of the present invention, invention has been described, it should be appreciated by those of ordinary skill in the art that can
So that in the form and details it is made with various changes, the present invention being limited without departing from appended claims
Spirit and scope.
Claims (10)
1. chlortetracycline succinic monoester salt, has a structure as shown in formula:
Wherein, m is na, k, meglumine, arginine or lysine.
2. chlortetracycline succinic monoester salt preparation method it is characterised in that: comprise the following steps:
A. chlortetracycline hydrochloride is dissolved in organic solution, adds sodium carbonate stirring, under the conditions of 30～80 DEG C, agitating solution becomes homogeneous；
Described organic solution is the mixed solution of organic solvent and water, the mass ratio shared by organic solvent be mixed solution 40～
90%；
B. succinic anhydrides and catalyst are mixed, be then added to that step a obtains homogeneous in, return stirring 0.5～5 hour,
Hydrochloric acid is acidified to ph=6, and cooling obtains chlortetracycline monomester succinate solid；
C. backflow dissolving chlortetracycline monomester succinate in organic solvent, adds corresponding alkali stirring, cooling, that is, generate target and produce
Thing；Described corresponding alkali is that pharmaceutically acceptable becomes saline and alkaline, is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, smart ammonia
Acid, lysine or meglumine.
3. method as claimed in claim 2 it is characterised in that: organic solvent described in step a refers to ethanol, acetone, second two
Any one in alcohol, acetonitrile, propylene glycol, glycerol, oxolane or 1,4- dioxane.
4. method as claimed in claim 2 or claim 3 it is characterised in that: chlortetracycline hydrochloride described in step a and sodium carbonate mol ratio
For 1:1～1.5.
5. method as claimed in claim 2 it is characterised in that: succinic anhydrides described in step b and catalyst molar ratio are 1:
0.1～1.5.
6. method as claimed in claim 2 it is characterised in that: catalyst described in step b be dicyclohexylcarbodiimide
Any one or more mixture in dcc, 4- dimethylamino pyridine dmap, triethylamine, pyridine；Catalyst between any two mole
Than for 0～1.0:1.0～0, but the total amount of catalyst is not 0.
7. method as claimed in claim 2 it is characterised in that: in step b, the mole of succinic anhydrides is rubbed for chlortetracycline hydrochloride
1.2～5.0 times of that amount.
8. method as claimed in claim 2 it is characterised in that: organic solvent described in step c be ethanol, isopropanol, second
Nitrile, n, n- dimethylformamide, n, any one in n- dimethyl acetylamide, 1,4- dioxane, oxolane, acetone or two
The mixture planted；Volume ratio between solvent is 0～1.0:1.0～0, but the cumulative volume of solvent is not 0.
9. method as claimed in claim 2 it is characterised in that: chlortetracycline monomester succinate described in step c is rubbed with corresponding alkali
You are than 1:1.0～2.0.
10. the chlortetracycline succinic monoester salt described in claim 1 or the method described in any one of claim 2～9 are in preparation
Purposes in animal feed.
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| US3047617A (en) * | 1959-05-18 | 1962-07-31 | Pfizer & Co C | Alkanoic acid esters of 5-hydroxytetracycline and process for preparation |
| JPH05117287A (en) * | 1991-10-24 | 1993-05-14 | Mercian Corp | Anthracycline derivative |
| ATE455092T1 (en) * | 2001-04-24 | 2010-01-15 | Paratek Pharm Innc | SUBSTITUTED TETRACYCLINE COMPOUNDS FOR THE TREATMENT OF MALARIA |
| CN1811454A (en) * | 2006-01-19 | 2006-08-02 | 镇江出入境检验检疫局检验检疫综合技术中心 | Cyclomycin family antibiotic enzyme-linked immunoassay reagent kit |
| WO2010126607A2 (en) * | 2009-04-30 | 2010-11-04 | President And Fellows Of Harvard College | Synthesis of tetracyclines and intermediates thereto |
| CN102898326B (en) * | 2012-10-31 | 2014-03-19 | 金河生物科技股份有限公司 | Preparation method of chlortetracycline hydrochloride |
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