CN108727410A - A kind of preparation method of methylol Cefditoren pivoxil Cephalosporins - Google Patents
A kind of preparation method of methylol Cefditoren pivoxil Cephalosporins Download PDFInfo
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- CN108727410A CN108727410A CN201810889335.1A CN201810889335A CN108727410A CN 108727410 A CN108727410 A CN 108727410A CN 201810889335 A CN201810889335 A CN 201810889335A CN 108727410 A CN108727410 A CN 108727410A
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- cefditoren pivoxil
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Classifications
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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
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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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
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
Abstract
The present invention provides a kind of preparation methods of methylol Cefditoren pivoxil Cephalosporins.The method includes the steps：Cefditoren pivoxil Cephalosporins is reacted with formaldehyde generates methylol Cefditoren pivoxil Cephalosporins.Preparation method of the present invention is easy to operate, reaction condition is mild, product yield is high, purity is high, pollution is few, and the methylol Cefditoren pivoxil Cephalosporins of high-purity prepared by the present invention can be used as impurity reference substance, the quality control for the Cefditoren pivoxil Cephalosporins in production process.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of methylol Cefditoren pivoxil Cephalosporins.
Background technology
Cefditoren pivoxil Cephalosporins (Cefditoren Pivoxil), entitled (6R, 7R) -2,2- dimethyl propylenes acyl-oxygen first of chemistry
Base -7- [(Z) -2- (2- amino -4- thiazolyls) -2- methoxyl group imido acetamido] -3- [(Z) -2- (4- methyl-1s, 3- thiophenes
Azoles -5- bases) vinyl] -8- oxos -5- thia -1- azabicyclics [4.2.0] oct-2-ene -2- formic acid esters is Japanese Mingzhi's system
The ester type of fruit Co., Ltd. exploitation takes orally third generation cephem antibiotics, lists within 1994, exists in April, 2001 in Japan for the first time
Discussion on Chinese Listed, trade name Meiact (Meiact) are clinically mainly used for treatment by gram-positive bacteria and Gram-negative
Infection caused by bacterium.This product has extensive antibacterial action, especially to staphylococcus, streptococcus (including streptococcus pneumonia)
Equal gram positive bacterias, the leather such as Escherichia coli, catarrh Blanc sweat coccus, Kleb, Proteus, haemophilus influenzae
The antibacterial ability of the anaerobic bacterias such as blue negative bacterium and Peptostreptococcus, Bacteroides is more superior than existing cephalosporanic olefinic.The medicine
Mechanism of action is to inhibit bacteria cell wall synthesis, has antibacterial spectrum width, significant in efficacy, safety and stability, oral absorption is good, blood medicine is dense
Degree is high, is distributed the features such as wide in vivo, and chemical constitution is as follows：
The method for the synthesis Cefditoren pivoxil Cephalosporins reported at present is more, such as WO2005016936 and EP0175610.But it is big
Most techniques mainly use the synthetic method reported in US2006/0173175, route as follows：
Cefoperon acid is obtained by the reaction as starting material using cefoperon parent nucleus 7-ATCA and AE active ester in the route, then
Cefoperon acid sodium is made at salt under the alkaline condition of sodium iso-octoate, last cefoperon acid sodium is reacted with iodometyl pivalate
Obtain target product Cefditoren pivoxil Cephalosporins.But it since final step reaction temperature is higher, the dosage of iodometyl pivalate is larger, leads
It causes to generate such as methylol Cefditoren pivoxil Cephalosporins, α-pivaloyl group Cefditoren pivoxil Cephalosporins and Cefditoren pivoxil Cephalosporins dimer impurity
(its structure is as follows), and related impurities content is higher, directly reduces the drug effect and quality of product, and obtained cephalo is appropriate
Logical sequence pivoxil product also is difficult to meet the standard of pharmacopeia.
In new drug research and development process, the quality of drug is to weigh a major criterion of drug quality, the matter of drug
The effect of amount is decided by drug itself first and toxic side effect, the i.e. validity of drug and safety.The active ingredient of drug
The effect of content is the important symbol of reflection pharmaceutical purity, and impurity present in drug directly influences drug may simultaneously cause
The generation of toxic side effect.The impurity of drug is other chemicals other than the drug of the introduction or generation in production, storage and transport process
Matter, the presence of impurity not only influence the purity of drug, can also bring the active toxic side effect of non-treatment, it is necessary to be controlled.For
Drug, the quality standard of drug is safely and effectively used to have more strictly the purity of effective ingredient and the limit of impurity
Regulation, it is however generally that, impurity of the drug more than 0.1% should be identified and quantitative by process for selective.
For medicament research and development personnel, groundwork is not only only that how to obtain the bulk pharmaceutical chemicals (API) of high quality, open
Send out synthesis technology efficient, it is often more important that dopant species, source and the production for how controlling process contaminants in research bulk pharmaceutical chemicals
It is raw.Usual researcher first can generated impurity in controlled syntheses technique, be secondly then exploitation efficient impurity synthesis road
Line, to obtain a large amount of impurity reference substance, ensure every batch of bulk pharmaceutical chemicals quality detection work development (e.g., impurity HPLC positioning,
Dirt content test etc.).
But the impurity reference substance currently used for Cefditoren pivoxil Cephalosporins quality control is mainly by thick from Cefditoren pivoxil Cephalosporins
Separation and Extraction obtains in product, and this method complex steps, low yield, purity is low, the similar impurity of certain structures is difficult to divide completely
It leaves and, to influence the accuracy of detection.With the propulsion that country works to drug agreement, impurity compound is determined
The preparation method of methylol Cefditoren pivoxil Cephalosporins provides qualified reference substance, can be risen to the quality control of Cefditoren pivoxil Cephalosporins
To positive effect.Therefore, it studies and the preparation method for providing a kind of efficient methylol Cefditoren pivoxil Cephalosporins newly has
Highly important meaning.
Invention content
It is low, pure for current Cefditoren pivoxil Cephalosporins related impurities methylol Cefditoren pivoxil Cephalosporins separation and Extraction difficulty, yield
Low problem is spent, the present invention provides a kind of preparation method of the methylol Cefditoren pivoxil Cephalosporins of simple and effective, prepared by this method
Methylol Cefditoren pivoxil Cephalosporins have higher purity, can be produced for Cefditoren pivoxil Cephalosporins directly as impurity reference substance
Quality Control Links in journey.
The particular technique content of the present invention is as follows：
The preparation method of one kind methylol Cefditoren pivoxil Cephalosporins as shown in formula (I), includes the following steps：
A：Cefditoren pivoxil Cephalosporins is added in organic solvent, reaction solution cools down after its dissolving, and formalin is added, stirs
Temperature control to reaction is mixed to terminate；
B：Reaction solution is added in extract liquor, liquid separation, water phase is extracted with organic solvent, merges organic phase, and organic phase is used
Purified water, saturated salt solution wash respectively, anhydrous sodium sulfate drying, filtering, and filtrate decompression is concentrated to dryness to obtain crude product；
C：Crude product is added in solvent, filters to obtain filter cake after temperature control stirring solidification crystallization, filter cake obtains after recrystallization
Methylol Cefditoren pivoxil Cephalosporins finished product.
Preferred embodiment, the organic solvent described in step A are tetrahydrofuran, acetone, acetonitrile, Isosorbide-5-Nitrae-dioxane, N, N-
Dimethylformamide, one kind or combinations thereof in n,N-dimethylacetamide, wherein particularly preferred acetonitrile.
The mass volume ratio of preferred embodiment, Cefditoren pivoxil Cephalosporins and solvent described in step A is 1: 3~12, g/mL.
It is preferred that select scheme, the mass ratio that feeds intake of the Cefditoren pivoxil Cephalosporins and formalin described in step A is 1: 0.35~
0.8, wherein particularly preferred 0.5, the mass fraction of formaldehyde is 37%~40% in formalin used.
Preferred embodiment, the temperature of mixed liquor is -15~10 DEG C after the material dissolution cooling described in step A, wherein especially
It is preferred that 0~5 DEG C；Reaction temperature is -15~10 DEG C, wherein particularly preferred 0~5 DEG C.
Preferred embodiment, the reaction time described in step A are 1~4h.
Preferred embodiment, extract liquor described in step B are dichloromethane/purified water, chloroform/purified water or ethyl acetate/
Purified water, the volume ratio of organic solvent and purified water is 1~4: 1 wherein in extract liquor；Extraction water phase solvent for use is dichloromethane
Alkane, chloroform or ethyl acetate.
Preferred embodiment, the solvent used in solidification crystallization described in step C is n-hexane, normal heptane, ether, in isopropyl ether
One kind or combinations thereof, wherein particularly preferred n-hexane.
Preferred embodiment, the solidification recrystallization temperature described in step C is -10~5 DEG C, wherein particularly preferred 0~5 DEG C.
Preferred embodiment, the solvent used in recrystallization described in step C are methylene chloride/methanol, dichloromethane/ethyl alcohol body
System, wherein particularly preferred methylene chloride/methanol system, the wherein volume ratio of dichloromethane and alcohols are 1: 6~10.
A kind of methylol Cefditoren pivoxil Cephalosporins preparing gained by any the method for the present invention.
Compared with prior art, what the present invention obtained has the technical effect that：
1. providing the method for preparing methylol Cefditoren pivoxil Cephalosporins of a simple and effective, entire synthetic method route
Short, operating procedure is simple, and reaction yield is high, and product purity is high；
2. providing a kind of Cefditoren pivoxil Cephalosporins related impurities of high-purity, impurity reference substance is can be used as, for producing
The quality control of Cefditoren pivoxil Cephalosporins in the process.
Specific implementation mode
It is further illustrated the present invention below by embodiment, it should which correct understanding is：The embodiment of the present invention is only
Be for illustrating the present invention, rather than limiting the invention, so, the present invention method under the premise of to the present invention it is simple
Improvement belongs to the scope of protection of present invention.
The present invention measures the purity of methylol Cefditoren pivoxil Cephalosporins, chromatographic condition using HPLC：[chromatographic column：Agilent
ZORBAX SB-C18(4.6mm × 250mm, 5.0 μm)；Mobile phase A：Ammonium formate solution (ammonium formate 1.58g is taken, water 900mL is added,
PH to 4.5 is adjusted with formic acid solution, is diluted with water to 1000mL)-acetonitrile-methanol (45: 25: 25)；Mobile phase B：Ammonium formate is molten
Liquid (take ammonium formate 1.58g, add water 900mL, with formic acid solution adjust pH to 4.5, be diluted with water to 1000mL)-acetonitrile-methanol
(45: 55: 55), gradient elution (0 → 5min.A 100%；5→40min：A 100% → 0；40→50min：A0 → 100%)；
Column temperature：40℃；Detection wavelength：254nm；Flow velocity：1.0mL.min-1；Sample size：20μL].
Embodiment 1
Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol) is added in acetonitrile (125mL), after stirring evenly, by the solution
It is cooled to 0~5 DEG C, formalin (12.41g, mass fraction are 37%~40%) is added, is stirred to react at a temperature of 0~5 DEG C
After 2.5h, the mixed liquor of purified water (200mL) and ethyl acetate (200mL) is added, stirs liquid separation after 10min, water layer acetic acid
Ethyl ester (40mL × 2) extracts, and merges organic layer, and purified water (100mL × 2) washs organic layer, saturated salt solution (100mL × 3)
Organic layer is washed, anhydrous sodium sulfate drying is filtered, and filtrate decompression is concentrated to dryness to obtain crude product, n-hexane is added in crude product
(200mL), 0~5 DEG C of solidification crystallization of temperature control filter after stirring 4h, and gained filter cake is through methylene chloride/methanol (volume ratio 1: 8) body
It is methylol Cefditoren pivoxil Cephalosporins finished product after system's recrystallization, yield 85.1% detects, wherein t through HPLCR=13.326min
It is methylol Cefditoren pivoxil Cephalosporins, purity 97.36%.
Embodiment 2
Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol) is added in acetonitrile (125mL), after stirring evenly, by the solution
It is cooled to 0~5 DEG C, formalin (8.69g, mass fraction are 37%~40%) is added, is stirred to react at a temperature of 0~5 DEG C
After 2.5h, the mixed liquor of purified water (200mL) and ethyl acetate (200mL) is added, stirs liquid separation after 10min, water layer acetic acid
Ethyl ester (40mL × 2) extracts, and merges organic layer, and purified water (100mL × 2) washs organic layer, saturated salt solution (100mL × 3)
Organic layer is washed, anhydrous sodium sulfate drying is filtered, and filtrate decompression is concentrated to dryness to obtain crude product, n-hexane is added in crude product
(200mL), 0~5 DEG C of solidification crystallization of temperature control filter after stirring 4h, and gained filter cake is through methylene chloride/methanol (volume ratio 1: 8) body
It is methylol Cefditoren pivoxil Cephalosporins finished product after system's recrystallization, yield 79.7% detects, wherein t through HPLCR=13.330min
It is methylol Cefditoren pivoxil Cephalosporins, purity 96.13%.
Embodiment 3
Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol) is added in acetonitrile (125mL), after stirring evenly, by the solution
It is cooled to 0~5 DEG C, formalin (19.86g, mass fraction are 37%~40%) is added, is stirred to react at a temperature of 0~5 DEG C
After 2.5h, the mixed liquor of purified water (200mL) and ethyl acetate (200mL) is added, stirs liquid separation after 10min, water layer acetic acid
Ethyl ester (40mL × 2) extracts, and merges organic layer, and purified water (100mLL × 2) washs organic layer, saturated salt solution (100mL × 3)
Organic layer is washed, anhydrous sodium sulfate drying is filtered, and filtrate decompression is concentrated to dryness to obtain crude product, n-hexane is added in crude product
(200mL), 0~5 DEG C of solidification crystallization of temperature control filter after stirring 4h, and gained filter cake is through methylene chloride/methanol (volume ratio 1: 8) body
It is methylol Cefditoren pivoxil Cephalosporins finished product after system's recrystallization, yield 80.2% detects, wherein t through HPLCR=13.321min
It is methylol Cefditoren pivoxil Cephalosporins, purity 95.89%.
Embodiment 4
Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol) is added in acetonitrile (75mL), after stirring evenly, by the solution
It is cooled to -5~0 DEG C, formalin (12.41g, mass fraction are 37%~40%) is added, is stirred at a temperature of -5~0 DEG C anti-
After answering 4.0h, the mixed liquor of purified water (100mL) and ethyl acetate (150mL) is added, stirs liquid separation after 10min, water layer second
Acetoacetic ester (30mL × 2) extracts, and merges organic layer, and purified water (75mL × 2) washs organic layer, saturated salt solution (75mL × 3)
Organic layer is washed, anhydrous sodium sulfate drying is filtered, and filtrate decompression is concentrated to dryness to obtain crude product, n-hexane is added in crude product
(200mL), temperature control -5~0 DEG C DEG C solidification crystallization stirring 4h after filters, gained filter cake through methylene chloride/methanol (volume ratio 1:
6) it is methylol Cefditoren pivoxil Cephalosporins finished product after system recrystallization, yield 80.26% detects, wherein t through HPLCR=
13.331min is methylol Cefditoren pivoxil Cephalosporins, purity 96.19%.
Embodiment 5
Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol) is added in acetone (300mL), after stirring evenly, by the solution
It is cooled to 0~5 DEG C, formalin (12.41g, mass fraction are 37%~40%) is added, is stirred to react at a temperature of 0~5 DEG C
After 3.5h, the mixed liquor of purified water (200mL) and dichloromethane (250mL) is added, stirs liquid separation after 10min, water layer dichloro
Methane (50mL × 2) extracts, and merges organic layer, and purified water (150mL × 2) washs organic layer, saturated salt solution (150mL × 3)
Organic layer is washed, anhydrous sodium sulfate drying is filtered, and filtrate decompression is concentrated to dryness to obtain crude product, normal heptane is added in crude product
(200mL), 0~5 DEG C of solidification crystallization of temperature control filter after stirring 3h, and gained filter cake is through methylene chloride/methanol (volume ratio 1: 8) body
It is methylol Cefditoren pivoxil Cephalosporins finished product after system's recrystallization, yield 80.55% detects, wherein t through HPLCR=13.322min
It is methylol Cefditoren pivoxil Cephalosporins, purity 96.56%.
Embodiment 6
Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol) is added in n,N-Dimethylformamide (150mL), stirring is equal
After even, which is cooled to 0~5 DEG C, formalin (12.41g, mass fraction are 37%~40%) is added, at 0~5 DEG C
At a temperature of be stirred to react 2h after, be added the mixed liquor of purified water (250mL) and chloroform (250mL), liquid separation after stirring 10min, water
Layer is extracted with chloroform (75mL × 2), merges organic layer, and purified water (100mL × 2) washs organic layer, saturated salt solution (100mL
× 3) organic layer is washed, anhydrous sodium sulfate drying is filtered, and filtrate decompression is concentrated to dryness to obtain crude product, isopropyl ether is added in crude product
(200mL), 0~5 DEG C of solidification crystallization of temperature control filter after stirring 3h, and gained filter cake is through dichloromethane/ethyl alcohol (volume ratio 1: 10)
It is methylol Cefditoren pivoxil Cephalosporins finished product after system recrystallization, yield 80.16% detects, wherein t through HPLCR=
13.319min is methylol Cefditoren pivoxil Cephalosporins, purity 96.53%.
Embodiment 7
Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol) is added in Isosorbide-5-Nitrae-dioxane (350mL), after stirring evenly,
The solution is cooled to 5~10 DEG C, formalin (7.45g, mass fraction are 37%~40%) is added, in 5~10 DEG C of temperature
Under be stirred to react 1h after, be added the mixed liquor of purified water (200mL) and dichloromethane (200mL), liquid separation after stirring 10min, water
Layer is extracted with dichloromethane (50mL × 2), merges organic layer, and purified water (100mL × 2) washs organic layer, saturated salt solution
(100mL × 3) wash organic layer, and anhydrous sodium sulfate drying is filtered, and filtrate decompression is concentrated to dryness to obtain crude product, second is added in crude product
Ether (150mL) filters after 5~10 DEG C of temperature control solidification crystallizations stirring 4h, gained filter cake through dichloromethane/ethyl alcohol (volume ratio 1:
5) it is methylol Cefditoren pivoxil Cephalosporins finished product after system recrystallization, yield 67.06% detects, wherein t through HPLCR=
13.329min is methylol Cefditoren pivoxil Cephalosporins, purity 91.93%.
Embodiment 8
Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol) is added in tetrahydrofuran (200mL), after stirring evenly, by this
Solution is cooled to 5~10 DEG C, the formalin (22.35g, mass fraction are 37%~40%) of addition, at a temperature of 5~10 DEG C
After being stirred to react 2.5h, the mixed liquor of purified water (200mL) and ethyl acetate (250mL) is added, stirs liquid separation after 10min, water
Layer is extracted with ethyl acetate (50mL × 2), merges organic layer, and purified water (100mL × 2) washs organic layer, saturated salt solution
(100mL × 3) wash organic layer, and anhydrous sodium sulfate drying is filtered, and filtrate decompression is concentrated to dryness to obtain crude product, is added just in crude product
Heptane (200mL) filters after 0~5 DEG C of temperature control solidification crystallization stirring 4h, gained filter cake through methylene chloride/methanol (volume ratio 1:
8) it is methylol Cefditoren pivoxil Cephalosporins finished product after system recrystallization, yield 64.15% detects, wherein t through HPLCR=
13.320min is methylol Cefditoren pivoxil Cephalosporins, purity 90.85%.
Claims (10)
1. a kind of preparation method of the methylol Cefditoren pivoxil Cephalosporins as shown in formula (I), which is characterized in that specific preparation method is such as
Shown in figure below,
2. the preparation method of methylol Cefditoren pivoxil Cephalosporins as described in claim 1, which is characterized in that include the following steps：
A：Cefditoren pivoxil Cephalosporins is added in organic solvent, reaction solution cools down after its dissolving, and formalin, stirring control is added
Temperature to reaction terminates；
B：Reaction solution is added in extract liquor, liquid separation, water phase is extracted with organic solvent, merges organic phase, organic phase purifying
Water, saturated salt solution wash respectively, anhydrous sodium sulfate drying, filtering, and filtrate decompression is concentrated to dryness to obtain crude product；
C：Crude product is added in solvent, filters to obtain filter cake after temperature control stirring solidification crystallization, filter cake obtains hydroxyl first after recrystallization
Base Cefditoren pivoxil Cephalosporins finished product.
3. the preparation method of methylol Cefditoren pivoxil Cephalosporins as claimed in claim 2, which is characterized in that described in step A
Organic solvent is tetrahydrofuran, acetone, acetonitrile, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide, n,N-dimethylacetamide,
One kind in dimethyl sulfoxide (DMSO) or combinations thereof.
4. the preparation method of methylol Cefditoren pivoxil Cephalosporins as claimed in claim 2, which is characterized in that described in step A
The mass volume ratio of Cefditoren pivoxil Cephalosporins and solvent is 1: 3~12, g/mL.
5. the preparation method of methylol Cefditoren pivoxil Cephalosporins as claimed in claim 2, which is characterized in that described in step A
Cefditoren pivoxil Cephalosporins and the mass ratio that feeds intake of formalin are 1: 0.35~0.8, the quality point of formaldehyde in formalin used
Number is 37%-40%.
6. the preparation method of methylol Cefditoren pivoxil Cephalosporins as claimed in claim 2, which is characterized in that described in step A
The temperature of mixed liquor is -15~10 DEG C after material dissolution cooling；The temperature being stirred to react is -15~10 DEG C；Reaction time be 1~
4h。
7. the preparation method of methylol Cefditoren pivoxil Cephalosporins as claimed in claim 2, which is characterized in that described in step B
Extract liquor is dichloromethane/purified water, chloroform/purified water or ethyl acetate/purified water；Extraction water phase solvent for use is dichloromethane
Alkane, chloroform or ethyl acetate.
8. the preparation method of methylol Cefditoren pivoxil Cephalosporins as claimed in claim 2, which is characterized in that described in step C
It is n-hexane, normal heptane, ether, one kind or combinations thereof in isopropyl ether to cure the solvent used in crystallization；Cure recrystallization temperature be-
10~5 DEG C.
9. the preparation method of methylol Cefditoren pivoxil Cephalosporins as claimed in claim 2, which is characterized in that described in step C
Recrystallization solvent used is methylene chloride/methanol, the volume ratio of dichloromethane/ethanol system, wherein dichloromethane and alcohols
It is 1: 6~10.
10. preparing the methylol valeryl Cefditoren pivoxil Cephalosporins of gained by any one of claim 1-10.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111548358A (en) * | 2020-06-18 | 2020-08-18 | 山西千岫制药有限公司 | Synthesis and preparation method of cefepime side chain intermediate |
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| CN111548358A (en) * | 2020-06-18 | 2020-08-18 | 山西千岫制药有限公司 | Synthesis and preparation method of cefepime side chain intermediate |
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