CN106478669A - A kind of process for purification of high-purity hydrochloric acid Ceftiofur - Google Patents
A kind of process for purification of high-purity hydrochloric acid Ceftiofur Download PDFInfo
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- CN106478669A CN106478669A CN201610768546.0A CN201610768546A CN106478669A CN 106478669 A CN106478669 A CN 106478669A CN 201610768546 A CN201610768546 A CN 201610768546A CN 106478669 A CN106478669 A CN 106478669A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- Cephalosporin Compounds (AREA)
Abstract
The present invention provides a kind of method of refined Ceftiofur Hydrochloride:The Ceftiofur Hydrochloride for needing refined is dissolved in water, in the mixed solution of organic solvent or water and organic solvent, the chlorination hydrogen molecule in solution is sloughed by alkali or ion exchange resin, so that the free acid crystal of Ceftiofur is separated out from solution.Then free for Ceftiofur acid crystal is added in organic solvent, then in solution, concentrated hydrochloric acid is dripped, adjust pH, reaction generates Ceftiofur Hydrochloride, then, by the organic solution of Ceftiofur Hydrochloride, in being slowly added dropwise to purified water, dilution crystallization generates high-purity hydrochloric acid ceftiofur crystalline.The method of the present invention:Process is simple, strong operability, low production cost, can stably prepare regular, the even particle size distribution of brilliant habit, purity>99.7% Ceftiofur Hydrochloride crystal product.
Description
Technical field
The invention belongs to bulk drug for livestock chemical synthesis purification field, and in particular to high-purity (>=99.7%) hydrochloric acid cephalo
The method of thiophene furan recrystallizing and refining purification.
Background technology
Ceftiofur Hydrochloride, (6R, 7R) -7- [2- (thiazolamine -4- base) (methoxyl group imido grpup) acetamido] -3-
[(2- furyl carbonyl) sulfidomethyl] -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid.English name
Claim:Ceftiofur CAS NO:103980-44-5, molecular formula:C19H17N5O7S3.HCL (see Fig. 1).Molecular weight:560.03.Outward
See as off-white color to pale yellow powder.Insoluble in water, almost insoluble in ethanol, slightly soluble in acetone and tetrahydrofuran,
Readily soluble in dimethyl sulfoxide (DMSO) and DMF.
Ceftiofur is semisynthetic third generation animal specific cynnematin.Sodium salt and hydrochloride are usually made for injection
With.Its has a broad antifungal spectrum, antibacterial activity are strong, all have powerful antibacterial activity to gram positive bacteria, gram-negative bacteria and anaerobic bacteria, its
In gram-positive bacteria is compared with first generation cephalosporin close or weaker, husky to gram-negative bacteria such as Escherichia coli, typhoid fever
Door rod bacterium, killing property and pasteurella haemolytica, streptococcus etc. are with powerful antibacterial activity more.It is the U.S. in 80 years 20th century
In generation, succeeds in developing.The medicine 1988 in U.S.'s Initial Public Offering, due to its excellent antibacterial activity and characteristics of pharmacokinetics, successively by
The U.S., Canada, Japan and some national official approvals European are used for beef cattle, milk cow, horse, pig, the controlling of the breathing problem of sheep
Treat.
Ceftiofur Hydrochloride has certain hygroscopicity, additionally, the impurity of some of which building-up process residual also can shadow
Its stability is rung, as the increase of standing time, medicine itself constantly can be degraded, color burn, impurity content constantly increase,
Affect the quality of production of follow-up ceftiofur formulation product.Wherein, 4- ketone group Ceftiofur and -2 decarburization acid amides cephalo of 2- acetyl
The content of thiophene furan affects larger on the purity of medicine and drug effect.In order to reduce Ceftiofur Hydrochloride solid impurity to subsequent production
Impact, needs to develop a kind of Ceftiofur Hydrochloride content height, and what stability was high prepares purification process.Prior art only provides salt
The synthetic method of sour Ceftiofur, there is no Ceftiofur Hydrochloride to be further purified method.With Ceftiofur Hydrochloride placement and
Unreasonable storage, declines Ceftiofur Hydrochloride content, and impurity increases, it is impossible to carry out production and the use of further preparation.
For the actual demand to high-purity hydrochloric acid Ceftiofur, the present invention with Ceftiofur Hydrochloride as raw material, through anti-
Should, dilution crystallization prepares the free acid crystal of Ceftiofur, removes partial impurities, and then reactive crystallization obtains hydrochloric acid cephalo again
Thiophene furan, reduce further the impurity content in Ceftiofur Hydrochloride, and then prepares highly purified Ceftiofur Hydrochloride, this
Bright is particular in that, whole process is divided into two-step crystallization, and crystallization process was controlled in the dilution crystallization stage, and avoids
The crystallization process for directly being caused using reactive crystallization is uncontrollable, so as to cause impurity content to be difficult to reduce.The high-purity of the present invention
Ceftiofur Hydrochloride process for purification, process stabilizing, it is easily controlled, repeatable strong, can stably obtain purity>99.7% product
Product, and habit is regular, and stability is high.
102993216 A (publication date of patent CN:On March 27th, 2013) it is related to one kind side of preparation of Ceftiofur Hydrochloride
Method, mainly bulk drug building-up process, the acid of cephalo furan and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, after reaction, crystallization is prepared into Ceftiofur Hydrochloride.Close
Become after obtaining Ceftiofur, add hydrochloric acid reaction that Ceftiofur Hydrochloride is obtained, without reference to the knot again of Ceftiofur Hydrochloride finished product
Brilliant purification process.
101654458 B (publication date of patent CN:On 2 24th, 2010) with the acid of cephalo furan as raw material, cephalo thiophene will be prepared
Furan free acid condensation reaction and ceftiofur free acid hydrochloric acid reactant salt process " treating different things alike " are carried out.The patent system is for mistake
Journey, free for the Ceftiofur for preparing acid mother liquor is directly generated Ceftiofur Hydrochloride with hydrochloric acid reaction, and centre does not have Ceftiofur
The crystal precipitation process of free acid, although simplify process, but in terms of reducing impurity content, slightly not enough.
Above patent relates generally to building-up process:After the acid of cephalo furan and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester reaction, hydrochloric acid is added to prepare salt
Sour Ceftiofur, but the recrystallization purification of Ceftiofur Hydrochloride finished product is specific to, also not enough, in order to solve hydrochloric acid cephalo
Thiophene furan finished product, long-term placement or underproof solid product itself, the present invention specially propose the recrystallization of Ceftiofur Hydrochloride
Purifying technique.
Content of the invention
Deficiency and Production requirement for current Ceftiofur Hydrochloride, the invention provides one kind prepare high-purity (>
99.7%) method of Ceftiofur Hydrochloride.It is different from the process for purification of above-mentioned Ceftiofur Hydrochloride.
The intermediate of present invention process route-Ceftiofur free acid is as shown in Figure 2.
The purpose of the present invention is realized as follows:The Ceftiofur Hydrochloride for needing refined is dissolved in water, organic solvent
Or in the mixed solution of water and organic solvent, the chlorination hydrogen molecule in solution is sloughed by alkali, then to Ceftiofur free acid
Purified water is added in solution, so that the free acid crystal of Ceftiofur is separated out from solution, after filtration drying, by Ceftiofur free acid
Crystal is added in organic solvent and is dissolved, and then drips concentrated hydrochloric acid in solution, adjusts pH, and reaction generates Ceftiofur Hydrochloride, most
Afterwards by the organic solution of Ceftiofur Hydrochloride, in being slowly added dropwise to purified water, dilution crystallization generates high-purity hydrochloric acid Ceftiofur
Crystal.
The preparation method of high-purity hydrochloric acid Ceftiofur of the present invention employs the following technical solutions realization:
1st, a kind of process for purification of high-purity hydrochloric acid Ceftiofur, it is characterised in that its preparation process is:
A:Ceftiofur Hydrochloride raw material is taken, and adds the mixing that organic solvent and water is added in reactor, under uniform temperature
Liquid, after stirring and dissolving, adds activated carbon decolorizing, filters, obtain Ceftiofur Hydrochloride solution;
B:Ceftiofur Hydrochloride solution after filtering in step A is added in reactor, under uniform temperature, in reactor
Dropping alkali regulation pH value, removing hydrogen chloride, dropping purified water, dilution crystallization, solid is separated out, is filtered, dry, acquisition Ceftiofur
Free acid crystal;
C, in reactor 1 add organic solvent, add step B in ceftiofur free acid crystal, after stirring and dissolving,
To in solution, add concentrated hydrochloric acid to adjust pH value to 0.5-1.5.Under uniform temperature, purity more than 99.7% is added in reactor 2
Ceftiofur Hydrochloride crystal as crystal seed and purified water, by the water of the Ceftiofur Hydrochloride solution in reactor 1 to reactor 2
In, dilution crystallization, centrifugal filtration, washing, dry high-purity hydrochloric acid ceftiofur crystalline.
The organic solvent that step A is used is dimethyl sulfoxide (DMSO), ethanol, methyl alcohol, solvent ratio-water in mixed solution/have
Machine solvent (v:V)=1:1-5.It is preferred that 1:2.
In step A, temperature range is 20-45 DEG C;
In step A, the ratio of solvent and Ceftiofur Hydrochloride is (v:m)5-20:1, preferably 5:1;
In step A, the addition of activated carbon is the 0.5-3% of solution total amount;
In step B, temperature range is 20-75 DEG C, and pH value terminal is 2.5-3.3;
In step B, the species of alkali is ammoniacal liquor, NaOH, pyridine or triethylamine;
In step B, the rate of addition of alkali is 0.2-5ml/min;
In step B, the dripping quantity of purified water is 1-5 times of mother liquor volume, and rate of addition is 1-10ml/min;
In step C, solvent is dimethyl sulfoxide (DMSO) or DMF;
In step C, the ratio (v of solvent and Ceftiofur free acid:M)=2-10:1;
In step C, temperature range is 5-45 DEG C;
In step C, the addition of crystal seed is the 0.5-3% of Ceftiofur Hydrochloride quality;
In step C, it is 0.5-1.5 that pH adjusts terminal;
In step C, the ratio of water and Ceftiofur Hydrochloride overall solution volume is (v:V)=1-10:1, preferably 5:
1.
Beneficial effects of the present invention are:
Using present invention exquisiteness method process is simple, strong operability, low production cost, stably can prepare brilliant practise regular,
Even particle size distribution, purity>99.7% Ceftiofur Hydrochloride crystal product.
Description of the drawings
Fig. 1, Ceftiofur Hydrochloride molecular structure
Fig. 2, Ceftiofur free acid molecular structure
The free acid crystal SEM picture of Fig. 3, Ceftiofur
Fig. 4, Ceftiofur Hydrochloride crystal SEM picture
Specific embodiment
Embodiments of the invention are presented herein below, the explanation present invention that can be detailed, but the invention is not limited in following realities
Apply example.
Embodiment 1
1. 100g Ceftiofur Hydrochloride raw material is weighed, add in reactor, be subsequently adding purified water 250ml, ethanol
250ml, after stirring and dissolving, adds 0.5g Powdered Activated Carbon, after stirring is decolourized 20 minutes, filters, obtain Ceftiofur Hydrochloride molten
Liquid;Add the Ceftiofur Hydrochloride solution after filtration in reactor, adjustment temperature is to 20 DEG C.To in reactor with 5ml/min
Speed drip 2.5% ammoniacal liquor, adjust pH value to 2.8, in reactor, then add 2500ml purified water, dilution crystallization, analysis
Go out solid, filter, dry, obtain ceftiofur free acid crystal 84.5g.
2. 170ml dimethyl sulfoxide (DMSO) is added in reactor 1, and free for dry Ceftiofur acid crystal 84.5g is added instead
Answer in kettle, stirring and dissolving.Then concentrated hydrochloric acid, regulation pH value to 0.5, stirring reaction 30min are dripped in reactor 1.To reaction
1700mL purified water and 0.43g Ceftiofur Hydrochloride (purity 99.7%) crystal seed are added in kettle 2,35 DEG C are adjusted the temperature to, will be anti-
The Ceftiofur Hydrochloride solution in kettle 1 is answered to drop in reactor 2 in the aqueous solution, dilution crystallization, precipitation crystal, centrifugal filtration,
Dry high-purity hydrochloric acid ceftiofur crystalline 89.6g.Detect through HPLC, the Ceftiofur in Ceftiofur Hydrochloride product is
It is -2 decarburization acid amides Ceftiofur of 0.05%, 2- acetyl that 99.71%, 4- ketone group Ceftiofur is 0.08%, MW537de unknown material
0.16%.
Embodiment 2
1. 100g Ceftiofur Hydrochloride raw material is weighed, add in reactor, be subsequently adding purified water 340ml, methyl alcohol
660ml, after stirring and dissolving, adds 1.5g Powdered Activated Carbon, after stirring is decolourized 20 minutes, by Ceftiofur Hydrochloride solution, filters,
Obtain Ceftiofur Hydrochloride solution.Add the Ceftiofur Hydrochloride solution after filtration in reactor, adjustment temperature is to 50 DEG C.
2.5% sodium hydroxide solution is dripped with the speed of 3ml/min in reactor, pH value is adjusted to 2.5, then add in reactor
Enter 3000ml purified water, dilution crystallization, precipitation solid, filtration, dry, acquisition ceftiofur free acid crystal 82.2g.
2. in reactor 1 add 250mlN, N-dimethylformamide, temperature adjustment to 20 DEG C, by dry Ceftiofur free acid
Crystal 82.2g, adds in reactor 1, stirring and dissolving.Then concentrated hydrochloric acid being dripped in reactor 1, adjusting pH value to 1, stirring is anti-
Answer 30min.1250mL purified water and 1.5g Ceftiofur Hydrochloride crystal seed are added in reactor 2,35 DEG C are adjusted the temperature to, will reaction
Ceftiofur Hydrochloride solution in kettle 1 is dropped in reactor 2 in the aqueous solution, dilution crystallization, precipitation crystal, and centrifugal filtration is done
Dry high-purity hydrochloric acid ceftiofur crystalline 87.6g.Detect through HPLC, the Ceftiofur in Ceftiofur Hydrochloride product is
It is -2 decarburization acid amides Ceftiofur of 0.06%, 2- acetyl that 99.79%, 4- ketone group Ceftiofur is 0.05%, MW537 unknown material
0.10%.
Embodiment 3
1. 100g Ceftiofur Hydrochloride raw material is weighed, add in reactor, be subsequently adding purified water 330ml, ethanol
1670ml, after stirring and dissolving, adds 3.0g Powdered Activated Carbon, after stirring is decolourized 20 minutes, by Ceftiofur Hydrochloride solution, mistake
Filter, obtains Ceftiofur Hydrochloride solution.Add the Ceftiofur Hydrochloride solution after filtration in reactor, adjustment temperature to 45
℃.Pyridine is dripped with the speed of 3ml/min in reactor, pH value is adjusted to 3.3, in reactor, then add 6000ml pure
Change water, dilution crystallization, precipitation solid, filtration, dry, acquisition ceftiofur free acid crystal 81.9g.
2. 450ml dimethyl sulfoxide (DMSO) is added in reactor 1, and 35 DEG C of temperature adjustment, by free for dry Ceftiofur acid crystal
81.9g, adds in reactor 1, stirring and dissolving.Then concentrated hydrochloric acid, regulation pH value to 1.5, stirring reaction are dripped in reactor 1
30min.500mL purified water and 3g Ceftiofur Hydrochloride crystal seed are added in reactor 2,35 DEG C are adjusted the temperature to, by reactor 1
Ceftiofur Hydrochloride solution drop in reactor 2 in the aqueous solution, dilution crystallization, separate out crystal, centrifugal filtration, highly dry
Purity Ceftiofur Hydrochloride crystal 83.2g.Detect through HPLC, the Ceftiofur in Ceftiofur Hydrochloride product is 99.82%, 4-
It is -2 decarburization acid amides Ceftiofur 0.08% of 0.07%, 2- acetyl that ketone group Ceftiofur is 0.03%, MW537 unknown material, impurity
Total amount is 0.18%.
Embodiment 4
1. 100g Ceftiofur Hydrochloride raw material is weighed, add in reactor, purified water 100ml is subsequently adding, dimethyl is sub-
Sulfone 400ml, after stirring and dissolving, plus 1.0g Powdered Activated Carbon, after stirring is decolourized 20 minutes, by Ceftiofur Hydrochloride solution, filter,
Obtain Ceftiofur Hydrochloride solution.Add the Ceftiofur Hydrochloride solution after filtration in reactor, adjustment temperature is to 50 DEG C.
2.5% ammoniacal liquor is dripped with the speed of 1.5ml/min in reactor, pH value is adjusted to 2.8, then add in reactor
1000ml purified water, dilution crystallization, solid is separated out, is filtered, dry, obtain ceftiofur free acid crystal 85.8g.
2. in reactor 1, add 200ml dimethyl sulfoxide (DMSO), temperature adjustment to 5 DEG C, by free for dry Ceftiofur acid crystal
85.8g, adds in reactor 1, stirring and dissolving.Then concentrated hydrochloric acid, regulation pH value to 0.5, stirring reaction are dripped in reactant liquor
30min.1000mL purified water and 0.5g Ceftiofur Hydrochloride crystal seed are added in another reactor, 35 DEG C are adjusted the temperature to, will be anti-
The Ceftiofur Hydrochloride solution in kettle 1 is answered to drop in reactor 2 in the aqueous solution, dilution crystallization, precipitation crystal, centrifugal filtration,
Dry high-purity hydrochloric acid ceftiofur crystalline 92.5g.Detect through HPLC, the Ceftiofur in Ceftiofur Hydrochloride product is
It is -2 decarburization acid amides Ceftiofur of 0.02%, 2- acetyl that 99.72%, 4- ketone group Ceftiofur is 0.10%, MW537d unknown material
0.16%, total impurities are 0.28%.
Embodiment 5
1. 100g Ceftiofur Hydrochloride raw material is weighed, add in reactor, be subsequently adding purified water 200ml, ethanol
400ml, after stirring and dissolving, adds 2.0g Powdered Activated Carbon, after stirring is decolourized 20 minutes, by Ceftiofur Hydrochloride solution, filters,
Obtain Ceftiofur Hydrochloride solution.Add the Ceftiofur Hydrochloride solution after filtration in reactor, adjustment temperature is to 75 DEG C.
2.5% ammoniacal liquor is dripped with the speed of 2ml/min in reactor, pH value is adjusted to 2.7, then add 2000ml in reactor
Purified water, dilution crystallization, solid is separated out, is filtered, dry, obtain ceftiofur free acid crystal 87.1g.
2. in reactor 1, add 200ml dimethyl sulfoxide (DMSO), temperature adjustment to 5 DEG C, by free for dry Ceftiofur acid crystal
87.1g, adds in reactor 1, stirring and dissolving.Then concentrated hydrochloric acid, regulation pH value to 1.0, stirring reaction are dripped in reactant liquor
30min.2000mL purified water and 2.5g Ceftiofur Hydrochloride crystal seed are added in reactor 2,45 DEG C are adjusted the temperature to, by reactor
Ceftiofur Hydrochloride solution in 1 is dropped in reactor 2 in the aqueous solution, dilution crystallization, precipitation crystal, and centrifugal filtration dries
Obtain high-purity hydrochloric acid ceftiofur crystalline 93.2g.Detect through HPLC, the Ceftiofur in Ceftiofur Hydrochloride product is
It is -2 decarburization acid amides Ceftiofur of 0.05%, 2- acetyl that 99.75%, 4- ketone group Ceftiofur is 0.09%, MW537 unknown material
0.11%, total impurities are 0.25%.
Claims (5)
1. a kind of process for purification of high-purity hydrochloric acid Ceftiofur, it is characterised in that its preparation process is:
A:Ceftiofur Hydrochloride raw material is taken, and adds the mixed liquor that organic solvent and water is added in reactor, after stirring and dissolving, plus
Enter activated carbon decolorizing, filter, obtain Ceftiofur Hydrochloride solution;
B:Ceftiofur Hydrochloride solution after filtering in step A is added in reactor, in reactor, dropping alkali adjusts pH value
For 2.5-3.3, purified water, dilution crystallization, precipitation solid, filtration, dry, the free acid crystal of acquisition Ceftiofur is then dripped;
C, in reactor 1 add organic solvent, add step B in ceftiofur free acid crystal, after stirring and dissolving, Xiang Rong
Add concentrated hydrochloric acid pH value to be adjusted to 0.5-1.5 in liquid, add the hydrochloric acid cephalo of purified water and purity >=99.7% in reactor 2
Thiophene furan crystal seed, the Ceftiofur Hydrochloride solution addition reactor 2 in reactor 1, dilution crystallization, centrifugal filtration, washing dry
Obtain high-purity hydrochloric acid ceftiofur crystalline;
Organic solvent described in step A is dimethyl sulfoxide (DMSO), ethanol, the one kind in methyl alcohol or combination, organic molten in mixed solution
Agent is water/organic solvent (v with the mixeding liquid volume ratio of water:v)1:1-5, the ratio of the mixed liquor and Ceftiofur Hydrochloride is
(v:m)5-20:1, the addition of the activated carbon is the 0.5-3% of solution total amount;;
Organic solvent described in step C is dimethyl sulfoxide (DMSO) or the one kind in DMF, the solvent and cephalo
Volume mass ratio (the v of ceftiofur free acid:M) it is 2-10:1;The addition organic solvent in reactor 1, adds in step B
Ceftiofur free acid crystal, after stirring and dissolving, adjustment solution temperature ranges are 5-45 DEG C;The Ceftiofur Hydrochloride crystal seed
Addition is the 0.5-3% of Ceftiofur Hydrochloride quality;The water is (v with Ceftiofur Hydrochloride liquor capacity ratio:v)1-10:
1.
2. a kind of process for purification of high-purity hydrochloric acid Ceftiofur as claimed in claim 1, is characterized in that living in step A
Property carbon decoloring temperature be 20-45 DEG C.
3. a kind of process for purification of high-purity hydrochloric acid Ceftiofur as claimed in claim 1 or 2, is characterized in that step A
Middle organic solvent is water/organic solvent (v with the mixeding liquid volume ratio of water:v)1:2;Solvent and Ceftiofur Hydrochloride volume mass
Than for (v:m)5:1.
4. a kind of process for purification of high-purity hydrochloric acid Ceftiofur as claimed in claim 1, it is characterized in that described in step B to
It is 2.5-3.3 that in reactor, dropping alkali adjusts pH value, and reactor keeping temperature scope is 20-75 DEG C;The alkali is ammoniacal liquor, hydrogen-oxygen
Change sodium, pyridine or triethylamine;The rate of addition of the alkali is 0.2-5ml/min;The dripping quantity of the purified water is mother liquor volume
1-5 times, rate of addition be 1-10ml/min.
5. a kind of process for purification of high-purity hydrochloric acid Ceftiofur as claimed in claim 1, is characterized in that in step C, described
Water is (v with Ceftiofur Hydrochloride liquor capacity ratio:V) it is 5:1.
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CN114249750A (en) * | 2021-12-29 | 2022-03-29 | 河南立诺制药有限公司 | Preparation method of ceftiofur hydrochloride |
CN116003439A (en) * | 2023-01-05 | 2023-04-25 | 山东久隆信和药业有限公司 | Refining method of ceftiofur hydrochloride |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114249750A (en) * | 2021-12-29 | 2022-03-29 | 河南立诺制药有限公司 | Preparation method of ceftiofur hydrochloride |
CN116003439A (en) * | 2023-01-05 | 2023-04-25 | 山东久隆信和药业有限公司 | Refining method of ceftiofur hydrochloride |
CN117088896A (en) * | 2023-01-05 | 2023-11-21 | 山东久隆信和药业有限公司 | Refining method of ceftiofur hydrochloride |
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