CN110590811B - Preparation method of cefuroxime axetil-3-ene isomer - Google Patents
Preparation method of cefuroxime axetil-3-ene isomer Download PDFInfo
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- CN110590811B CN110590811B CN201910921254.XA CN201910921254A CN110590811B CN 110590811 B CN110590811 B CN 110590811B CN 201910921254 A CN201910921254 A CN 201910921254A CN 110590811 B CN110590811 B CN 110590811B
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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
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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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
Abstract
The invention relates to a preparation method of cefuroxime axetil-3-alkene isomer, belonging to the medicine quality research, quality control and safety research of pharmaceutical enterprises and disclosing the step (1): in an aprotic solvent and a protic solution, the cefuroxime axetil generates 3-alkene isomeric cefuroxime axetil and a mixture of cefuroxime axetil under the action of base catalysis; step (2): and (2) purifying the mixture of cefuroxime axetil and 3-alkene isomeric cefuroxime axetil obtained in the step (1) by a reversed phase C18 column preparative liquid chromatography under the conditions of water/methanol (40/60), flow rate of 40ml/min and ultraviolet detection wavelength of 23nm, extracting, drying and concentrating to obtain the cefuroxime axetil-3-alkene isomer. The invention has simple reaction operation, mild condition and high product purity, and the obtained cefuroxime axetil-3-ene isomer can be used as a standard substance to be applied to the quality control of cefuroxime axetil bulk drugs and preparations.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method of cefuroxime axetil-3-ene isomer.
Technical Field
Cefuroxime is a cephalosporin antibiotic developed by Kuran Smith company, is firstly marketed in the United states in 1988 and expires in 1996, and is taken as the second generation oral cephalosporin, so that the medicine has strong lipid solubility and good oral absorption; cefuroxime axetil is an esterified cefuroxime, which is hydrolyzed in vivo to release cefuroxime and exert its antibacterial activity; the latter has wide antibacterial spectrum, strong antibacterial effect and stability to lactamase. Cefuroxime axetil has very low antibacterial activity, and after being absorbed orally for 3-4 min, it is hydrolyzed fast by non-specific esterase in intestinal mucosa and portal circulation to release cefuroxime and exert its antibacterial action, so that the antibacterial spectrum and antibacterial activity of cefuroxime axetil are the same as those of cefuroxime. The traditional Chinese medicine composition is mainly used for treating mild and moderate respiratory tract infection, urogenital system infection, skin and soft tissue infection, gonorrhea and the like caused by sensitive bacteria clinically.
The 3-ene isomeric cefuroxime axetil is produced due to the ectopic carbon-carbon double bond in the six-membered ring structure of beta-lactam, and the 3-ene isomeric cefuroxime axetil (or referred to as cefuroxime axetil-3-ene isomer) is far from efficacious in comparison with cefuroxime axetil. Therefore, the control of 3-alkene isomeric cefuroxime axetil is necessary in the production process of bulk drugs and preparations. In the quality study of cefuroxime axetil, the 3-alkene isomer thereof was used as a drug impurity for control study.
Disclosure of Invention
The invention aims to provide a method for preparing 3-alkene isomeric cefuroxime axetil (or referred to as cefuroxime axetil-3-alkene isomer) with simple operation and mild conditions.
For cephalosporin antibiotic preparations, the carbon-carbon double bond on the beta-lactam ring can mostly generate 0.1 to 0.5 percent of 3-alkene isomer in the long-term sample retention process. 0.5% of the 3-ene isomer is a concept of high impurity level in quality control, but if it is used for preparing a dry product in which the 3-ene isomer is pure, 0.5% of the 3-ene isomer is a concept of low content level, and if it is purified and enriched from the 0.5% level, it takes a lot of manpower and material resources, which is apparently not a good solution.
According to the invention, researches show that the cefuroxime axetil solid powder has low content of generated 3-alkene isomer, only about 2-5% under high-temperature damage, and the time consumption is long, and needs 5-10 days. The cefuroxime axetil is dissolved and dispersed in an organic solvent, and can generate 40-65% of 3-alkene isomer in a short time by adding base catalysis, and other impurities are few, so that the subsequent separation and purification operation is convenient.
According to the invention, researches show that the concentration of cefuroxime axetil in the organic solvent also has an influence on the effect of generating the 3-alkene isomer through base catalytic destruction, and when the concentration is more than 0.3g/ml, the content of the 3-alkene isomer is sharply reduced and is only about 15%. At a concentration of 0.1g/ml, the content of 3-ene isomers produced by base catalysis is the highest, about 65%.
According to the invention, researches show that aprotic solvents such as ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, dichloromethane and acetone and protic solvents such as methanol, ethanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol and glycerol can be used for dissolving cefuroxime axetil to generate 3-alkene isomers with high purity level. In a dichloromethane system, the content of 3-alkene isomeric cefuroxime axetil generated by base catalytic destruction in the organic solvent is at most about 65 percent. The most impurities of 3-alkene isomeric cefuroxime axetil are generated by the base catalytic destruction of a methanol system, and the separation and purification efficiency is influenced.
According to the invention, the base catalysis time needs to be proper through research. The time is too short, the cefuroxime axetil raw material is not damaged enough, and the generated 3-alkene isomer is less. For a long time, cefuroxime axetil and 3-alkene isomer are destroyed to generate many other impurities, which makes separation and purification difficult. When a certain amount of 3-ene isomer is produced, the increase of the base catalysis time is not continued, but the produced 3-ene isomer is destroyed because of the increase of the base catalysis time.
According to the invention, researches show that the catalytic effect of the organic base is better than that of inorganic base, the effect of piperidine and morpholine in the organic base is the best, and the purity of the 3-alkene isomer of the furoyl ester can reach 60-65%.
The invention adopts reversed phase C18 column to separate and purify cefuroxime axetil and the 3-alkene isomer mixture thereof, the chromatographic condition is that water/methanol is 40/60, the flow rate is 40ml/min, and the wavelength of the ultraviolet detector is 230 nm. The organic phase ratio is more than 60 percent, the peak of the furoyl-3-ene isomer and the main peak of the furoyl ester are overlapped, the organic phase ratio is less than 50 percent, the separation degree of the furoyl-3-ene isomer peak and the main peak of the furoyl ester is good, but the peaks are flat, the number of tower plates is low, the collected fraction is large, and the concentration of the 3-ene isomer is low. The polarity difference between the main peak of the furoyl ester and the furoyl ester-3-alkene isomer peak is not large, and the peak positions are very close in liquid chromatogram, so acetonitrile can not be used as an organic phase, and the main peak and the isomer peak can not be effectively separated because the elution capacity of the acetonitrile is too strong. And other impurities with insufficient ultraviolet absorption can be conveniently observed by adopting the wavelength of 230 nm. If the chromatographic separation condition adopts a buffer salt system such as acetate, phosphate and the like, the 3-alkene isomeric cefuroxime axetil can react with the organic phase methanol to generate cefuroxime methyl ester due to the ion catalytic effect, so that the purity of the finished product is greatly reduced, and secondary purification preparation is required.
The preparation of the 3-alkene isomeric cefuroxime axetil comprises the following two steps:
step (1): weighing 10g of cefuroxime axetil, adding 100ml of dichloromethane, stirring for dissolving, then adding 1ml of 3-ethylamine, stirring for reacting for 6 hours at room temperature to obtain 55% purity 3-alkene isomeric cefuroxime axetil, and mixing;
step (2): separating and purifying the 3-alkene isomer mixture obtained in the step (1) by a reversed phase C18 column, wherein the chromatographic conditions of purification are that water/methanol is 40/60, the flow rate is 40ml/min, and the ultraviolet detection wavelength is 230 nm. Collecting the target fraction, enriching and collecting, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, and rotary evaporating to obtain 3-alkene isomeric cefuroxime axetil with the purity of 98%.
The method for preparing 3-alkene isomeric cefuroxime axetil in the step (1) is characterized in that the aprotic solvent used for preparing the cefuroxime axetil solution in the step (1) is ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, dichloromethane or acetone, and the protic solvent is one of methanol, ethanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol and glycerol; the dosage of the alkali is 0.1 to 1 time, the reaction time is 4 to 12 hours, and the purity of the 3-alkene isomeric cefuroxime axetil is 40 to 65 percent
The purification preparation conditions in the step (2) are reversed phase C18 column, mobile phase is water/methanol 40/60, and ultraviolet detection wavelength is 230 nm. And in the enrichment fraction treatment, the extraction solvent is ethyl acetate, dichloromethane, chloroform and carbon tetrachloride.
The invention has the advantages that: the preparation method of 3-alkene isomeric cefuroxime axetil, which has the advantages of simple operation, mild conditions and low cost, is provided, the obtained 3-alkene isomeric cefuroxime axetil has high purity, and can be used as an impurity reference substance to be applied to the quality control research of cefuroxime axetil raw material medicines and preparations. Compared with the purchased reference substance, the method has great cost advantage. Compared with other literature reports, the ultraviolet irradiation damage method of the invention can produce the cefuroxime axetil with the highest purity of 3-alkene isomer, thereby greatly saving the cost for producing the pure product of the cefuroxime axetil with the 3-alkene isomer.
Detailed Description
EXAMPLE 1 preparation of cefuroxime axetil-3-ene isomer
10g of cefuroxime axetil was weighed, 100ml of an aprotic solvent in methylene chloride was added and dissolved with stirring, and 1ml of 3-ethylamine was added and stirred at room temperature for 4 hours. The isomeric 3-ene cefuroxime axetil was detected by HPLC to be about 50%. Then the product is separated and purified by a preparation liquid phase C18 column. The preparation liquid phase separation and purification conditions are as follows: water/methanol 40/60, flow rate 40ml/min, uv detection wavelength 230 nm. After gathering and enriching the prepared liquid phase of each target fraction, extracting with dichloromethane, drying with anhydrous sodium sulfate, and then carrying out reduced pressure rotary evaporation at 40 ℃ to obtain 4.2g of gray yellow foamy solid, wherein the purity is 96.5% by liquid chromatography detection.
EXAMPLE 2 preparation of cefuroxime axetil-3-ene isomer
10g of cefuroxime axetil was weighed, dissolved in 100ml of tetrahydrofuran which is an aprotic solvent under stirring, and then 10ml of 3-ethylamine was added thereto under stirring at room temperature for 6 hours. By HPLC detection, 3-ene isomeric cefuroxime axetil was about 49%. Then the product is separated and purified by a preparation liquid phase C18 column. The preparation liquid phase separation and purification conditions are as follows: water/methanol 40/60, flow rate 40ml/min, uv detection wavelength 230 nm. After gathering and enriching the prepared liquid phase per-needle target fraction, extracting with chloroform, drying with anhydrous sodium sulfate, and then performing reduced pressure rotary evaporation at 40 ℃ to obtain 4g of gray yellow foamy solid, wherein the purity is 96.9% by liquid chromatography detection.
EXAMPLE 3 preparation of cefuroxime axetil-3-ene isomer
10g of cefuroxime axetil was weighed, 100ml of dioxane as an aprotic solvent was added and dissolved by stirring, and 5ml of piperidine was added and stirred at room temperature for 4 hours. The isomeric 3-ene cefuroxime axetil was found to be about 59% by HPLC. Then the product is separated and purified by a preparation liquid phase C18 column. The preparation liquid phase separation and purification conditions are as follows: water/methanol 40/60, flow rate 40ml/min, uv detection wavelength 230 nm. After gathering and enriching the prepared liquid phase per needle target fraction, extracting with carbon tetrachloride, drying with anhydrous sodium sulfate, and then performing rotary evaporation at 40 ℃ under reduced pressure to obtain 5g of gray yellow foamy solid, wherein the purity is 98.5% by liquid chromatography detection.
EXAMPLE 4 preparation of cefuroxime axetil-3-ene isomer
10g of cefuroxime axetil was weighed, dissolved in 100ml of methylene chloride as an aprotic solvent with stirring, and then 5ml of morpholine was added thereto with stirring at room temperature for 7 hours. The isomeric 3-ene cefuroxime axetil was found to be about 65% by HPLC. Then the product is separated and purified by a preparation liquid phase C18 column. The preparation liquid phase separation and purification conditions are as follows: water/methanol 40/60, flow rate 40ml/min, uv detection wavelength 230 nm. Gathering and enriching the prepared liquid phase per-needle target fraction, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and performing reduced pressure rotary evaporation at 40 ℃ to obtain 5.9g of gray yellow foamy solid, wherein the purity is 97.9% through liquid chromatography detection.
EXAMPLE 5 preparation of cefuroxime axetil-3-ene isomer
10g of cefuroxime axetil was weighed, dissolved in 100ml of acetone as an aprotic solvent under stirring, and then 10ml of pyridine was added thereto, and stirred at room temperature for 5 hours. The isomeric 3-ene cefuroxime axetil was found to be about 43% by HPLC. Then the product is separated and purified by a preparation liquid phase C18 column. The preparation liquid phase separation and purification conditions are as follows: water/methanol 40/60, flow rate 40ml/min, uv detection wavelength 230 nm. After gathering and enriching the prepared liquid phase of each target fraction, extracting with dichloromethane, drying with anhydrous sodium sulfate, and then carrying out reduced pressure rotary evaporation at 40 ℃ to obtain 3.5g of gray yellow foamy solid, wherein the purity is 95.5% by liquid chromatography detection.
EXAMPLE 6 preparation of cefuroxime axetil-3-ene isomer
10g of cefuroxime axetil was weighed, 100ml of methanol as a protic solvent was added and dissolved by stirring, and 10g of potassium carbonate was added and stirred at room temperature for 12 hours. The isomeric 3-ene cefuroxime axetil was found to be about 40% by HPLC. Then the product is separated and purified by a preparation liquid phase C18 column. The preparation liquid phase separation and purification conditions are as follows: water/methanol 40/60, flow rate 40ml/min, uv detection wavelength 230 nm. After gathering and enriching the prepared liquid phase of each target fraction, extracting with dichloromethane, drying with anhydrous sodium sulfate, and then carrying out reduced pressure rotary evaporation at 40 ℃ to obtain 3.1g of gray yellow foamy solid, wherein the purity is 94.9% by liquid chromatography detection.
EXAMPLE 7 preparation of cefuroxime axetil-3-ene isomer
10g of cefuroxime axetil was weighed, added to 100ml of glycerol as a protic solvent, and stirred to dissolve, then 10g of cesium carbonate was added thereto, and stirred at room temperature for 12 hours. The 3-ene isomeric cefuroxime axetil was detected by HPLC to be about 40%. Then the product is separated and purified by a preparation liquid phase C18 column. The preparation liquid phase separation and purification conditions are as follows: 40/60, flow rate 40ml/min, ultraviolet detection wavelength 230 nm. After gathering and enriching the prepared liquid phase of each target fraction, extracting with dichloromethane, drying with anhydrous sodium sulfate, and then carrying out reduced pressure rotary evaporation at 40 ℃ to obtain 3.0g of gray yellow foamy solid, wherein the purity is 95.5% by liquid chromatography detection.
EXAMPLE 8 preparation of cefuroxime axetil-3-ene isomer
10g of cefuroxime axetil was weighed, 100ml of acetonitrile as an aprotic solvent was added and dissolved by stirring, and 2ml of diethylamine was added and stirred at room temperature for 7 hours. By HPLC detection, 3-ene isomeric cefuroxime axetil was about 49%. Then the product is separated and purified by a preparation liquid phase C18 column. The preparation liquid phase separation and purification conditions are as follows: water/methanol 40/60, flow rate 40ml/min, uv detection wavelength 230 nm. After gathering and enriching the prepared liquid phase of each target fraction, extracting with dichloromethane, drying with anhydrous sodium sulfate, and then carrying out reduced pressure rotary evaporation at 40 ℃ to obtain 4g of gray yellow foamy solid, wherein the purity is 97.5% by liquid chromatography detection.
Claims (3)
1. A method for preparing cefuroxime axetil-3-ene isomers, which comprises:
step (1): dissolving cefuroxime axetil in one of an aprotic solvent or a protic solvent to prepare a cefuroxime axetil solution with the concentration of 0.1g/ml, then adding 0.1-1 time of alkali, and stirring and reacting at room temperature for 4-12 hours to obtain a cefuroxime axetil mixture containing 40-65% of 3-alkene isomeric cefuroxime axetil;
step (2): purifying the mixture of cefuroxime axetil and the 3-alkene isomer thereof obtained in the step (1) by reversed phase C18 preparative liquid chromatography under the conditions of water/methanol =40/60, flow rate of 40ml/min and ultraviolet detection wavelength of 230nm, collecting corresponding fractions, extracting, drying and rotary evaporating to obtain a dry cefuroxime axetil-3-alkene isomer;
the aprotic solvent is ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, dichloromethane or acetone;
protic solvents such as methanol, ethanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol, glycerol;
the alkali is sodium carbonate, potassium carbonate, cesium carbonate, 3-ethylamine, diethylamine, pyridine, piperidine or morpholine.
2. The process of claim 1, wherein the reaction time in step (1) is 4-12 hours.
3. The method according to claim 1, wherein the solvent used in the extraction in step (2) is ethyl acetate, dichloromethane, chloroform or carbon tetrachloride.
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| IT1265061B1 (en) * | 1993-08-06 | 1996-10-28 | Dompe Spa | VALIDES OF 7ALPHA-AMINO-1, 1-DIOXO-CEFEM |
| IN181290B (en) * | 1997-06-23 | 1998-05-02 | C O J K Ind Ltd | |
| US7064198B2 (en) * | 2001-07-25 | 2006-06-20 | Lupin Limited | Method for preparation of cefuroxime axetil |
| EP2912040A4 (en) * | 2012-10-29 | 2016-06-01 | Shionogi & Co | Processes for production of intermediates for 2-alkyl cephem compounds |
| CN103450224A (en) * | 2013-08-29 | 2013-12-18 | 东北制药集团股份有限公司 | Preparation method of delta3 isomer of cefoselis |
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