CN117417352A - Preparation method of cefpodoxime proxetil impurity E - Google Patents
Preparation method of cefpodoxime proxetil impurity E Download PDFInfo
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- CN117417352A CN117417352A CN202311293441.0A CN202311293441A CN117417352A CN 117417352 A CN117417352 A CN 117417352A CN 202311293441 A CN202311293441 A CN 202311293441A CN 117417352 A CN117417352 A CN 117417352A
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- impurity
- cefpodoxime proxetil
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- proxetil
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- JRBKWVHQXXREQH-KMMUMHRISA-N 1-propan-2-yloxycarbonyloxyethyl (6R,7R)-3-(acetyloxymethyl)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(=O)OC(C)OC(=O)OC(C)C)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 JRBKWVHQXXREQH-KMMUMHRISA-N 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000012535 impurity Substances 0.000 claims abstract description 70
- 239000000126 substance Substances 0.000 claims abstract description 34
- 239000002243 precursor Substances 0.000 claims abstract description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 18
- 239000011230 binding agent Substances 0.000 claims abstract description 18
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims abstract description 17
- 235000019439 ethyl acetate Nutrition 0.000 claims abstract description 10
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 238000006482 condensation reaction Methods 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- 238000005886 esterification reaction Methods 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 10
- WRTVTCFELAEIEQ-YVLHZVERSA-N o-(1,3-benzothiazol-2-yl) (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoethanethioate Chemical group N=1C2=CC=CC=C2SC=1OC(=S)\C(=N/OC)C1=CSC(N)=N1 WRTVTCFELAEIEQ-YVLHZVERSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 1
- LTINZAODLRIQIX-FBXRGJNPSA-N cefpodoxime proxetil Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(=O)OC(C)OC(=O)OC(C)C)C(=O)C(=N/OC)\C1=CSC(N)=N1 LTINZAODLRIQIX-FBXRGJNPSA-N 0.000 abstract description 23
- 229960004797 cefpodoxime proxetil Drugs 0.000 abstract description 23
- 238000003908 quality control method Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 239000013558 reference substance Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 29
- 239000000047 product Substances 0.000 description 15
- 230000014759 maintenance of location Effects 0.000 description 10
- XZVBIIRIWFZJOE-UHFFFAOYSA-N 1-iodoethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OC(C)I XZVBIIRIWFZJOE-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229960005090 cefpodoxime Drugs 0.000 description 3
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 201000002014 Suppurative Otitis Media Diseases 0.000 description 1
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
Classifications
-
- 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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the technical field of drug impurity synthesis, and particularly discloses a cefpodoxime proxetil impurity E and a preparation method and application thereof. The invention condenses 7-amino cephalosporanic acid and acetic ester containing benzothiazolyl under the action of acid binding agent to obtain impurity precursor substance, and esterifies to obtain cefpodoxime proxetil impurity E. The cefpodoxime proxetil impurity E provided by the invention is an important impurity to be researched in the quality control of cefpodoxime proxetil, and is a known impurity of cefpodoxime proxetil recorded in both Chinese pharmacopoeia and European pharmacopoeia. The cefpodoxime proxetil impurity E prepared by the method can be used as an impurity reference substance of cefpodoxime proxetil, plays a positive role in quality control of the cefpodoxime proxetil, is simple in preparation method, short in preparation period, high in purity of the obtained impurity E finished product, and suitable for rapid preparation of the reference substance. The invention solves the problems of limited types of cefpodoxime proxetil impurities, complex preparation method and limited purity of the obtained impurities in the prior art.
Description
Technical Field
The invention relates to the technical field of drug impurity synthesis, and particularly discloses a preparation method of cefpodoxime proxetil impurity E.
Background
Cefpodoxime proxetil, chemical name (6 r,7 r) -3-methoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- [ (Z) -methoxyimino ] acetamido ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid- (RS) -1- (isopropoxycarboxyoxy) ethyl ester. The chemical structure is as follows:
cefpodoxime proxetil is a third-generation oral cephalosporin, is a precursor of cefpodoxime, has no antibacterial activity, is absorbed through intestinal tracts after being orally taken, and is hydrolyzed into cefpodoxime by nonspecific esterase in intestinal tracts to exert antibacterial activity. Cefpodoxime has broad-spectrum and powerful antibacterial effect, has inhibiting and killing effects on most gram-positive bacteria and negative bacteria, has high stability on various beta lactamase, and can be widely applied to the treatment of respiratory tract, urinary tract, gynecological infectious diseases, suppurative otitis media and the like.
The content of various impurities in the raw material medicine determines the safety of the final finished medicine. Impurities may be known, unknown, volatile or nonvolatile compounds, sources of which include starting materials, intermediates, unexpected byproducts and degradation products, and may also result from racemization or contamination between enantiomers, and in all of which case the resulting impurities may result in poor biological activity or toxicity. Thus, the identification, quantification, characterization and control of impurities has become a key component of the drug development process. Impurity research and control rely on scientific and reasonable process design and process control of production operation, and meanwhile, the process design and the specification and optimization of production operation are facilitated. Generally, researchers firstly orient impurities generated in the synthesis process, and secondly develop efficient impurity synthesis routes so as to obtain a large amount of impurity reference substances and ensure the development of quality detection work of each batch of bulk drugs.
Although some documents and data report related impurities of cefpodoxime proxetil, the preparation process is complex, the post-treatment process needs to be repeated for a plurality of times, the cost is high, and the purity of the obtained impurity product is limited. And the research on novel impurities in cefpodoxime proxetil synthesis is continuously improved and developed, and the research on novel cefpodoxime proxetil impurities and a simpler operation method have a perfect effect on the quality of cefpodoxime proxetil.
Disclosure of Invention
Aiming at the problems of limited types of cefpodoxime proxetil impurities and complex preparation method and limited purity of the obtained impurities in the prior art, the invention provides a cefpodoxime proxetil impurity E and a preparation method thereof. The cefpodoxime proxetil impurity E provided by the invention is an important impurity to be researched in the quality control of cefpodoxime proxetil, is a known impurity of cefpodoxime proxetil recorded in both Chinese pharmacopoeia and European pharmacopoeia, and has a structure shown as a formula (1). The preparation method of the impurity E provided by the invention is simple, and the purity of the obtained impurity E is higher, so that the impurity E plays a positive role in quality control of cefpodoxime proxetil.
In order to achieve the above purpose, the present invention provides the following technical solutions.
The first aspect of the invention provides a preparation method of cefpodoxime proxetil impurity E, which comprises the following steps:
step one, dissolving 7-aminocephalosporanic acid in a first organic solvent at the temperature of 0-30 ℃, adding acetic ester containing benzothiazolyl and an acid binding agent, performing condensation reaction, and removing the solvent to obtain an impurity precursor substance;
dissolving the impurity precursor in a second organic solvent, adding carbonic ester at the temperature of-10 ℃ to 20 ℃ for esterification reaction, extracting, collecting an organic phase, removing the organic solvent in the organic phase, and drying to obtain cefpodoxime proxetil impurity E;
the acid binding agent is any one or more of triethylamine, diethylamine or ammonia water.
Compared with the prior art, the invention provides a preparation method of cefpodoxime proxetil impurity E. After many attempts, the inventors finally determine the synthesis method and source of the cefpodoxime proxetil impurity E. According to the invention, 7-aminocephalosporanic acid, benzothiazolyl-containing acetate and an acid binding agent are used as raw materials, an impurity precursor substance is synthesized through condensation reaction, and the obtained impurity precursor substance and carbonic ester are subjected to esterification reaction to obtain the cefpodoxime proxetil impurity E.
In preparing the impurity precursor substances, the inventors found that the impurity precursor substances were produced in a small amount, or even could not be produced. Through creative thinking, the inventor adds an acid binding agent in the condensation reaction of 7-aminocephalosporanic acid and benzothiazolyl-containing acetate, and utilizes the acid binding agent to adjust the acid-base balance of a reaction system, absorb excessive acidic substances in the reaction to form neutral salt, and ensure that the reaction is carried out in a neutral environment, thereby greatly improving the production of the obtained impurity precursor substances.
However, not all alkaline substances can be used as acid-binding agents, and it is necessary to ensure that the acid-binding agent not only can generate neutral salt with acidic raw materials, but also can not react with product impurity E precursor substances, therefore, the inventor performs a great deal of experiments on the selection of the acid-binding agent, and finally determines that the acid-binding agent is any one or more of triethylamine, ethylenediamine or ammonia water according to experimental results. Under the action of an acid binding agent, the reaction system is maintained in a neutral environment, and the yield of the cefpodoxime proxetil impurity E is greatly improved.
The preparation method of the cefpodoxime proxetil impurity E provided by the invention is simple and convenient to operate, the purity of the obtained cefpodoxime proxetil impurity E is higher and can reach more than 91%, the cefpodoxime proxetil impurity E can be used as a reference substance for detecting the impurity, and the preparation method has very important significance for quality control and subsequent preparation research of the cefpodoxime proxetil while improving the safety and effectiveness of the cefpodoxime proxetil product.
The reaction equation of cefpodoxime acid the cefpodoxime proxetil impurity E is as follows:
preferably, in the first step, the first organic solvent is any one or more of water, acetone, methanol or dichloromethane.
Preferably, in the first step, the benzothiazolyl-containing acetate is benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) thioacetate.
Preferably, in the first step, the mass-volume ratio of the 7-aminocephalosporanic acid to the first organic solvent is 1g (10-30) mL.
Preferably, in the first step, the molar ratio of the 7-aminocephalosporanic acid, the benzothiazolyl-containing acetate and the acid binding agent is 1:1-1.2:1.1-1.2.
Preferably, in the second step, the second organic solvent is any one or two of anhydrous methanol or N, N-dimethylformamide.
Preferably, in the second step, the mass-volume ratio of the impurity precursor substance to the second organic solvent is 1g (1-10) mL.
Preferably, in the second step, the molar ratio of the impurity precursor substance to the carbonate is 1:1.1-1.2.
Preferably, in the first step, the time of the condensation reaction is 1h to 3h.
Preferably, in the second step, the time of the esterification reaction is 1h-3h.
Preferably, in the second step, the extracting agent is any one of ethyl acetate or dichloromethane.
In summary, the invention provides a preparation method of cefpodoxime proxetil impurity E, and the purity of the cefpodoxime proxetil impurity E obtained by the preparation method is more than 91%, so that the cefpodoxime proxetil impurity E can be used as an impurity reference substance of the cefpodoxime proxetil and plays a positive role in quality control of the cefpodoxime proxetil. In addition, the preparation method disclosed by the invention does not need complex operation steps, is short in preparation period, high in product purity, high in yield and low in cost, and is suitable for rapidly preparing cefpodoxime proxetil impurity E standard substances.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of cefpodoxime proxetil impurity E obtained in example 1;
FIG. 2 is a high performance liquid chromatogram of cefpodoxime proxetil impurity E obtained in example 1;
fig. 3 is a high performance liquid chromatogram for the detection of impurity E in cefpodoxime proxetil samples.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The embodiment provides cefpodoxime proxetil impurity E, which comprises the following steps:
step one, putting 2.72g (0.010 mol) of 7-aminocephalosporanic acid into 30mL of acetone at 20 ℃, adding 3.67g (0.011 mol) of benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) thioacetate, uniformly mixing, dropwise adding 1.12g (0.012 mol) of triethylamine into the mixture, stirring, carrying out condensation reaction for 3h, and removing solvent after the reaction is finished to obtain an impurity precursor substance;
dissolving the impurity precursor substance in 20mL of methanol, cooling to-10 ℃, adding 2.58g (0.010 mol) of 1-iodoethyl isopropyl carbonate, carrying out esterification reaction for 1h, adding 50mL of ethyl acetate and water into a reaction system after the reaction is finished, extracting, standing, layering, collecting an organic phase, drying, and removing a solvent to obtain the cefpodoxime proxetil impurity E. The purity of the obtained impurity E finished product is 1.71g and is 96.1 percent through detection.
Example 2
The embodiment provides cefpodoxime proxetil impurity E, which comprises the following steps:
step one, adding 2.72g (0.010 mol) of 7-aminocephalosporanic acid into a mixed solvent of 30mL of methanol-dichloromethane with the volume ratio of 1:1 at 20 ℃, adding 3.95g (0.012 mol) of benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) thioacetate, uniformly mixing, dropwise adding 1.00g (0.014 mol) of diethylamine into the mixture, stirring, performing condensation reaction for 3h, and removing the solvent after the reaction is finished to obtain impurity precursor substances;
dissolving the impurity precursor substance in 5mL of N, N-dimethylformamide, cooling to 0 ℃, adding 2.58g (0.010 mol) of 1-iodoethyl isopropyl carbonate, carrying out esterification reaction for 1.5h, adding 50mL of dichloromethane and water respectively into a reaction system after the reaction is finished, extracting for 2-3 times, standing, layering, collecting an organic phase, removing a solvent, and drying to obtain the cefpodoxime proxetil impurity E. 1.12g of the finished product of the impurity E is detected, and the purity is 94.5%.
Example 3
The embodiment provides cefpodoxime proxetil impurity E, which comprises the following steps:
step one, putting 2.72g (0.010 mol) of 7-aminocephalosporanic acid into 50mL of acetone at 20 ℃, adding 3.67g (0.011 mol) of benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) thioacetate, uniformly mixing, dropwise adding 2.81g (0.012 mol) of ammonia water with the mass fraction of 15% into the mixture, stirring, carrying out condensation reaction for 3h, and removing solvent after the reaction is finished to obtain an impurity precursor substance;
dissolving the impurity precursor substance in 20mL of methanol, cooling to-20 ℃, adding 2.58g (0.010 mol) of 1-iodoethyl isopropyl carbonate, carrying out esterification reaction for 1h, adding 50mL of dichloromethane and water into a reaction system after the reaction is finished, extracting for 2-3 times, standing, layering, collecting an organic phase, drying, and removing a solvent to obtain the cefpodoxime proxetil impurity E. The purity of the obtained impurity E finished product is 1.93g and is 91.2 percent through detection.
Example 4
The embodiment provides cefpodoxime proxetil impurity E, which comprises the following steps:
step one, at 20 ℃, 2.72g (0.010 mol) of 7-aminocephalosporanic acid is put into a mixed solution of 28mL of acetone and water with the volume ratio of 50:1, 3.67g (0.011 mol) of benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) thioacetate is added, uniformly mixed, 1.12g (0.012 mol) of triethylamine is dripped into the mixture, stirring is carried out, condensation reaction is carried out for 3h, and after the reaction is finished, the solvent is removed, thus obtaining impurity precursor substances;
dissolving the impurity precursor substance in 10mL of N, N-dimethylformamide, cooling to 15 ℃, adding 2.58g (0.010 mol) of 1-iodoethyl isopropyl carbonate, carrying out esterification reaction for 1h, adding 20mL of ethyl acetate and water into a reaction system after the reaction is finished, extracting for 2-3 times, standing, layering, collecting an organic phase, drying, and removing a solvent to obtain the cefpodoxime proxetil impurity E. The purity of the obtained impurity E finished product is detected to be 93.9 percent by 1.82 g.
Example 5
The embodiment provides cefpodoxime proxetil impurity E, which comprises the following steps:
step one, adding 2.72g (0.010 mol) of 7-aminocephalosporanic acid into 80mL of mixed solution of methanol and water with the volume ratio of 10:1 at 20 ℃, adding 3.67g (0.011 mol) of benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) thioacetate, uniformly mixing, dropwise adding 1.12g (0.012 mol) of triethylamine into the mixture, stirring, performing condensation reaction for 2.5h, and removing solvent after the reaction is finished to obtain an impurity precursor substance;
dissolving the impurity precursor substance in 10mL of N, N-dimethylformamide, controlling the temperature to be 20 ℃, adding 2.58g (0.010 mol) of 1-iodoethyl isopropyl carbonate, carrying out esterification reaction for 1h, adding 30mL of ethyl acetate and water into a reaction system after the reaction is finished, extracting for 2-3 times, standing, layering, collecting an organic phase, drying, and removing a solvent to obtain the cefpodoxime proxetil impurity E. 1.47g of the finished product of the impurity E is detected, and the purity is 91.8 percent.
Comparative example 1
This comparative example provides a process for the preparation of cefpodoxime proxetil impurity E, which differs from example 1 in that: the acid binding agent is replaced by equimolar pyridine, and the specific content comprises the following steps:
step one, adding 2.72g (0.010 mol) of 7-aminocephalosporanic acid into 30mL of acetone at 20 ℃, adding 3.67g (0.011 mol) of benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) thioacetate, uniformly mixing, dropwise adding 0.95g (0.012 mol) of pyridine into the mixture, stirring, carrying out condensation reaction for 3h, and removing solvent after the reaction is finished to obtain an impurity precursor substance;
dissolving the impurity precursor substance in 20mL of methanol, cooling to-10 ℃, adding 2.58g (0.010 mol) of 1-iodoethyl isopropyl carbonate, carrying out esterification reaction for 1h, adding 50mL of ethyl acetate and water into a reaction system after the reaction is finished, extracting, standing, layering, collecting an organic phase, drying, and removing a solvent to obtain the cefpodoxime proxetil impurity E. The purity of the finished product of the impurity E is 78.2 percent by detection, wherein 0.98g of the finished product of the impurity E is obtained.
Comparative example 2
This comparative example provides a process for the preparation of cefpodoxime proxetil impurity E, which differs from example 3 in that: the acid binding agent is replaced by sodium bicarbonate solution with equimolar amount, and the specific content comprises the following steps:
step one, putting 2.72g (0.010 mol) of 7-aminocephalosporanic acid into 30mL of acetone at 20 ℃, adding 3.67g (0.011 mol) of benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) thioacetate, uniformly mixing, dropwise adding 6.72g (0.012 mol) of sodium bicarbonate solution with the mass fraction of 15% into the mixture, stirring, carrying out condensation reaction for 3h, and removing solvent after the reaction is finished to obtain an impurity precursor substance;
dissolving the impurity precursor substance in 20mL of methanol, cooling to-20 ℃, adding 2.58g (0.010 mol) of 1-iodoethyl isopropyl carbonate, carrying out esterification reaction for 1h, adding 50mL of dichloromethane and water into a reaction system after the reaction is finished, extracting for 2-3 times, standing, layering, collecting an organic phase, drying, and removing a solvent to obtain the cefpodoxime proxetil impurity E. The purity of the finished product of the impurity E is 76.9 percent after detection, wherein 0.84g of the finished product of the impurity E is obtained.
Comparative example 3
This comparative example provides a process for the preparation of cefpodoxime proxetil impurity E, which differs from example 1 in that: the specific content of the acid binding agent without being added comprises the following steps:
step one, putting 2.72g (0.010 mol) of 7-aminocephalosporanic acid into 30mL of acetone at 20 ℃, adding 3.67g (0.011 mol) of benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) thioacetate, uniformly mixing, performing condensation reaction for 3h, and removing a solvent after the reaction is finished to obtain an impurity precursor substance;
dissolving the impurity precursor substance in 20mL of methanol, cooling to-10 ℃, adding 2.58g (0.010 mol) of 1-iodoethyl isopropyl carbonate, carrying out esterification reaction for 1h, adding 50mL of ethyl acetate and water into a reaction system after the reaction is finished, extracting, standing, layering, collecting an organic phase, drying, removing a solvent, and detecting to obtain the cefpodoxime proxetil impurity E.
In order to further show the technical effects of the invention, the invention carries out nuclear magnetic resonance analysis, high performance liquid chromatography analysis and component analysis comparison test on the cefpodoxime proxetil impurity E finished product obtained in the example 1, and the results are shown in figures 1-3.
Fig. 1 is a nuclear magnetic hydrogen spectrum of the cefpodoxime proxetil impurity E, and specific nuclear magnetic data are: 1 HNMR(DMSOd 6 ,400MHZ):δ:9.64(1H,m,H 13 ),7.21(2H,s,NH 2 ),6.64(2H,m,H 24 ,H 21 ),5.58(1H,dd,H 7 ),5.19(1H,m,H 9 ),5.05(1H,dd,H 6 ),4.81(2H,m,H 10 ),3.83(3H,s,H 23 ),3.55(2H,m,H 4 ),1.99(3H,d,H 12 ),1.34(3H,m,H 14 ),1.18(6H,d,H 17 )。
fig. 2 is a high performance liquid chromatogram of cefpodoxime proxetil impurity E, and fig. 3 is a high performance liquid chromatogram of cefpodoxime proxetil impurity E in cefpodoxime proxetil finished products. As can be seen from fig. 2, the retention times of cefpodoxime proxetil impurity E are 43.292min and 55.732min, with relative retention times of 0.70 and 0.90. As can be seen from fig. 3, the retention time is 42.403min, the peak with the relative retention time of 0.713 is substantially identical to the retention time 43.292min of the cefpodoxime proxetil impurity E sample in fig. 2, the relative retention time is 0.70, the retention time is 54.895min, the peak with the relative retention time of 0.922 is substantially identical to the retention time 55.732min of the cefpodoxime proxetil impurity E sample in fig. 2, and the relative retention time is 0.90, which indicates that the peaks of 42.403min and 55.732min in the existing cefpodoxime proxetil drug product are identified as the peaks of cefpodoxime proxetil impurity E.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.
Claims (10)
1. A preparation method of cefpodoxime proxetil impurity E, which is characterized by comprising the following steps: the method comprises the following steps:
step one, dissolving 7-aminocephalosporanic acid in a first organic solvent at the temperature of 0-30 ℃, adding acetic ester containing benzothiazolyl and an acid binding agent, performing condensation reaction, and removing the solvent to obtain an impurity precursor substance;
dissolving the impurity precursor in a second organic solvent, adding carbonic ester at the temperature of-10 ℃ to 20 ℃ for esterification reaction, extracting, collecting an organic phase, removing the organic solvent in the organic phase, and drying to obtain cefpodoxime proxetil impurity E;
the acid binding agent is any one or more of triethylamine, diethylamine or ammonia water.
2. The method for preparing cefpodoxime proxetil impurity E according to claim 1, characterized in that: in the first step, the first organic solvent is any one or more of water, acetone, methanol or dichloromethane.
3. The method for preparing cefpodoxime proxetil impurity E according to claim 1, characterized in that: in the first step, the benzothiazolyl-containing acetate is benzothiazol-2-yl (Z) -2-methoxyimino-2- (2-aminothiazole-4-yl) thioacetate.
4. The method for preparing cefpodoxime proxetil impurity E according to claim 1, characterized in that: in the first step, the mass volume ratio of the 7-aminocephalosporanic acid to the first organic solvent is 1g (10-30) mL.
5. The method for preparing cefpodoxime proxetil impurity E according to claim 1, characterized in that: in the first step, the molar ratio of the 7-aminocephalosporanic acid to the benzothiazolyl-containing acetate to the acid binding agent is 1:1-1.2:1.1-1.2.
6. The method for preparing cefpodoxime proxetil impurity E according to claim 1, characterized in that: in the second step, the second organic solvent is any one or two of anhydrous methanol or N, N-dimethylformamide.
7. The method for preparing cefpodoxime proxetil impurity E according to claim 1, characterized in that: in the second step, the mass volume ratio of the impurity precursor substance to the second organic solvent is 1g (1-10) mL.
8. The method for preparing cefpodoxime proxetil impurity E according to claim 1, characterized in that: in the second step, the molar ratio of the impurity precursor substance to the carbonic ester is 1:1.1-1.2.
9. The method for preparing cefpodoxime proxetil impurity E according to claim 1, characterized in that: in the first step, the time of the condensation reaction is 1h-3h; and/or
In the second step, the esterification reaction time is 1h-3h.
10. The method for preparing cefpodoxime proxetil impurity E according to claim 1, characterized in that: in the second step, the extracting agent is any one of ethyl acetate or dichloromethane.
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