CN110183468B - Preparation method of cefditoren pivoxil dimer - Google Patents
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- CN110183468B CN110183468B CN201910536297.6A CN201910536297A CN110183468B CN 110183468 B CN110183468 B CN 110183468B CN 201910536297 A CN201910536297 A CN 201910536297A CN 110183468 B CN110183468 B CN 110183468B
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- 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
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- 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
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Abstract
The invention discloses a preparation method of cefditoren pivoxil dimer, which is characterized by comprising the following steps: adding an organic solvent and cefditoren sodium into a reaction vessel, stirring for dissolving, cooling to-20- -50 ℃, adding iodomethyl pivalate in batches, reacting for a certain time after adding the iodomethyl pivalate every time, and adding the iodomethyl pivalate again; inorganic base or organic base is added in the reaction process to control the pH value to be 7.5-8.5, and the product is obtained through the subsequent separation and purification processes after the reaction is finished. The preparation method provided by the invention has the advantages of simple steps, simple raw materials and low cost, and is suitable for large-scale preparation. The content of cefditoren pivoxil dimer prepared by the preparation method provided by the invention can reach more than 92.0%, a theoretical basis is provided for safe use of medicines, effective data support is provided for the quality standard of cefditoren pivoxil, and effective guarantee is provided for clinical safe use of medicines.
Description
Technical Field
The invention relates to a preparation method of cefditoren pivoxil dimer, belonging to the field of impurity analysis in drug synthesis.
Background
Cefditoren Pivoxil (Cefditoren Pivoxil) with the chemical name (6R,7R) -2, 2-dimethylpropanoyloxymethyl-7- [ (Z) -2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido ] -3- [ (Z) -2- (4-methyl-1, 3-thiazol-5-yl) ethenyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate.
Cefditoren pivoxil is an ester type oral third-generation cephalosporin antibiotic developed by Mingmingzhiguo corporation, first marketed in Japan in 1994, marketed in China in 4 months in 2001 under the trade name of Meiaic (Meiact), and is mainly used for clinically treating infections caused by gram-positive bacteria and gram-negative bacteria. The product has wide antibacterial effect, and especially has antibacterial effect against gram-positive bacteria such as Staphylococcus and Streptococcus (including Streptococcus pneumoniae), gram-negative bacteria such as Escherichia coli, Carbambust sweat coccus, Klebsiella, Proteus, Haemophilus influenzae, and anaerobic bacteria such as Peptostreptococcus and Bacteroides. The medicine has the action mechanism of inhibiting the synthesis of bacterial cell walls, and has the characteristics of wide antibacterial spectrum, obvious curative effect, safety, stability, good oral absorption, high blood concentration, wide in-vivo distribution and the like.
More methods for synthesizing cefditoren pivoxil are reported at present, such as WO2005016936 and EP 0175610. However, most processes mainly use the synthesis method reported in US2006/0173175, and the route is shown as follows:
the method comprises the steps of reacting cefditoren mother nucleus 7-ATCA with AE active ester to obtain cefditoren acid, salifying under the alkaline condition of sodium isooctanoate to obtain cefditoren sodium, and finally reacting the cefditoren sodium with iodomethyl pivalate to obtain the target product cefditoren pivoxil.
In the process of research and development of new drugs, the quality of the drugs is an important standard for measuring the quality of the drugs, and the quality of the drugs is determined by the curative effect and the toxic and side effects of the drugs, namely the effectiveness and the safety of the drugs. The content of the effective components of the medicine is an important mark for reflecting the purity of the medicine, and impurities in the medicine directly influence the curative effect of the medicine and can cause toxic and side effects. The impurities of the medicine are other chemical substances except the introduced or generated medicine in the processes of production, storage and transportation, and the existence of the impurities not only affects the purity of the medicine, but also brings non-therapeutic active toxic and side effects and must be controlled. For safe and effective use of drugs, the quality standards of drugs have strict requirements on the purity of active ingredients of drugs and the limits of impurities, and generally, more than 0.1% of drug impurities should be identified and quantified by a selective method.
For drug developers, the main work is not only how to obtain high-quality drug Substances (APIs) and develop efficient synthesis processes, but also how to study the types and sources of impurities in the drug substances and how to control the generation of process impurities. Usually, researchers can firstly orient impurities generated in a synthesis process, and secondly develop an efficient impurity synthesis route so as to obtain a large amount of impurity reference substances and ensure the development of quality detection work (such as impurity HPLC positioning, impurity content measurement and the like) of each batch of raw material medicines.
The main impurities present in cefditoren pivoxil are:
cefditoren pivoxil dimer is used as an important impurity to be researched in quality control of cefditoren pivoxil, and the impurity reference substance is mainly obtained by separating and extracting from a cefditoren pivoxil crude product at present, but the method has complicated steps and low yield.
CN201810889116 discloses a preparation method of cefditoren pivoxil dimer, which provides a qualified reference substance and can play a positive role in controlling the quality of cefditoren pivoxil.
Disclosure of Invention
In view of the above technical problems, the present invention aims to provide another method for preparing cefditoren pivoxil dimer, which does not require additional formaldehyde solution and has high product yield.
In order to achieve the purpose, the technical scheme of the invention is as follows: a preparation method of cefditoren pivoxil dimer is characterized by comprising the following steps: adding an organic solvent and cefditoren sodium into a reaction vessel, stirring for dissolving, cooling to-20 to-50 ℃, adding iodomethyl pivalate in batches, reacting for a certain time after adding iodomethyl pivalate each time, and adding iodomethyl pivalate again; inorganic base or organic base is added in the reaction process to control the pH value to be 7.5-8.5, and the product is obtained through the subsequent separation and purification processes after the reaction is finished.
The iodomethyl pivalate is added in batches and is controlled to be carried out at a lower temperature, so that the generation of byproducts is reduced, the product yield is high, and the purity is good. Besides the organic solvent, no other reaction reagent is required to be added in the reaction process.
In the scheme, the separation and purification process comprises the following steps: adding the reaction solution into ethyl acetate and pure water, stirring, standing for layering, removing a lower water layer, washing an organic layer with sodium bicarbonate or sodium hydroxide solution and water in sequence, concentrating the organic layer to dryness, adding the concentrate into n-hexane, stirring, filtering, and drying a filter cake to obtain the product. Through the separation step, impurities can be effectively removed, and the finally obtained product has high purity.
In the scheme, the organic solvent is one of N, N-dimethylformamide, tetrahydrofuran, acetonitrile and 1, 4-dioxane.
In the scheme, the method comprises the following steps: the molar ratio of the cefditoren sodium to the iodomethyl pivalate is 1: 4-6; the addition is carried out in at least three portions. The reaction is facilitated to be carried out, and meanwhile, the reaction is added in batches, so that the byproducts are reduced.
Preferably: the iodomethyl pivalate is added in three times, and the amount of the first two times is larger than that of the last time. Adding iodomethyl pivalate each time, reacting for 20-30min, and adding iodomethyl pivalate again.
In the scheme, the method comprises the following steps: the organic base is one of triethylamine, tributylamine, diethylamine, diisopropylethylamine and pyridine, and the inorganic base is sodium bicarbonate.
In the scheme, the method comprises the following steps: the mass concentration of the sodium bicarbonate or sodium hydroxide solution used for washing is 0.1-1%.
Has the advantages that: the preparation method provided by the invention has the advantages of simple steps, simple raw materials and low cost, and is suitable for large-scale preparation. The content of cefditoren pivoxil dimer prepared by the preparation method provided by the invention can reach more than 92.0%, a theoretical basis is provided for safe use of medicines, effective data support is provided for the quality standard of cefditoren pivoxil, and effective guarantee is provided for clinical safe use of medicines.
Drawings
Figure 1 is a mass spectrum of cefditoren pivoxil dimer.
FIG. 2 is a diagram of cefditoren pivoxil dimer1H-NMR chart.
FIG. 3 is a drawing of cefditoren pivoxil dimer13C-NMR chart.
Detailed Description
The invention is further illustrated by the following examples in conjunction with the accompanying drawings:
example 1
Preparation of cefditoren pivoxil dimer
125ml of N, N-Dimethylformamide (DMF) and 22.2g (0.04mol) of cefditoren sodium are added into a reaction vessel, stirred and dissolved, and cooled to below-80 ℃.
Adding 0.06mol of iodomethyl pivalate, and controlling the temperature to be below 50 ℃ below zero for reaction for 20 min.
Then 0.06mol of iodomethyl pivalate is added, and the temperature is controlled to be below 50 ℃ below zero for reaction for 20 min.
Finally, 0.04mol of iodomethyl pivalate is added, and the temperature is controlled to be below 50 ℃ below zero for reaction till the reaction is complete.
During the reaction, triethylamine is added to control the pH value to be 7.5-8.5, after the reaction is finished, 350ml of ethyl acetate and 270ml of pure water are added into the reaction liquid, the mixture is stirred and kept stand for layering, the lower water layer is discarded, the organic layer is stirred and washed by 0.1% sodium bicarbonate solution and water in sequence, the layering and the water layer are discarded, then the organic layer is concentrated to be dry, the concentrate is added into 500ml of normal hexane, and the product is obtained through stirring, filtering and drying. The purity of the product is 96.8 percent by HPLC detection.
Example 2
Preparation of cefditoren pivoxil dimer
Acetonitrile 150ml and cefditoren sodium 22.2g (0.04mol) are added into a reaction vessel, stirred and dissolved, and cooled to below minus 80 ℃.
Adding 0.06mol of iodomethyl pivalate, and controlling the temperature to be below 40 ℃ below zero for reaction for 30 min.
Then 0.06mol of iodomethyl pivalate is added, and the temperature is controlled to be below 40 ℃ below zero for reaction for 30 min.
Finally, 0.06mol of iodomethyl pivalate is added, and the temperature is controlled to be below 40 ℃ below zero for reaction till the reaction is complete.
Pyridine is added in the reaction process to control the pH value to be 7.5-8.5, after the reaction is finished, 350ml of ethyl acetate and 270ml of pure water are added into the reaction liquid, the mixture is stirred and kept stand for layering, the lower water layer is removed, the organic layer is stirred and washed by 0.5% sodium hydroxide solution and water in sequence, the mixture is kept stand for layering, the water layer is removed, the organic layer is concentrated to be dry, the concentrate is added into 500ml of normal hexane, and the product is obtained after stirring, filtering and drying. The purity of the product is 93.2 percent by HPLC detection.
Example 3
Preparation of cefditoren pivoxil dimer
Adding 120ml of tetrahydrofuran and 22.2g (0.04mol) of cefditoren sodium into a reaction vessel, stirring and dissolving, and cooling to below-80 ℃.
Adding 0.10mol of iodomethyl pivalate, and controlling the temperature to be below 35 ℃ below zero for reaction for 28 min.
Then 0.10mol of iodomethyl pivalate is added, and the temperature is controlled to be below 35 ℃ below zero for reaction for 28 min.
Finally, 0.04mol of iodomethyl pivalate is added, and the temperature is controlled to be below 35 ℃ below zero for reaction till the reaction is complete.
During the reaction, tributylamine is added to control the pH value to be 7.5-8.5, after the reaction is finished, 350ml of ethyl acetate and 270ml of pure water are added into the reaction liquid, the mixture is stirred and kept stand for layering, the lower water layer is discarded, the organic layer is stirred and washed by 1% sodium bicarbonate solution and water in sequence, the mixture is kept stand for layering and discarded, then the organic layer is concentrated to be dry, the concentrate is added into 500ml of normal hexane, and the product is obtained through stirring, filtering and drying. The purity of the product was 92.5% by HPLC.
Example 4
Preparation of cefditoren pivoxil dimer
130ml of 1, 4-dioxane and 22.2g (0.04mol) of cefditoren sodium are added into a reaction vessel, stirred and dissolved, and cooled to below minus 80 ℃.
Adding 0.06mol of iodomethyl pivalate, and controlling the temperature below-20 ℃ for reaction for 20-30 min.
Then 0.06mol of iodomethyl pivalate is added, and the temperature is controlled to be below 20 ℃ below zero for reaction for 20 to 30 min.
Finally, 0.04mol of iodomethyl pivalate is added, and the temperature is controlled to be below 20 ℃ below zero for reaction till the reaction is complete.
And (2) adding diethylamine in the reaction process to control the pH value to be 7.5-8.5, after the reaction is finished, adding 350ml of ethyl acetate and 270ml of pure water into the reaction solution, stirring, standing for layering, removing a lower water layer, washing an organic layer with 0.1% sodium bicarbonate solution and water in sequence, removing the water layer, then concentrating the organic layer to be dry, adding the concentrate into 500ml of n-hexane, stirring, filtering and drying to obtain the product. The purity of the product was 92.5% by HPLC.
Example 5
Preparation of cefditoren pivoxil dimer
125ml of N, N-dimethylformamide and 22.2g (0.04mol) of cefditoren sodium are added into a reaction vessel, stirred and dissolved, and cooled to below minus 80 ℃.
Adding 0.06mol of iodomethyl pivalate, and controlling the temperature below 50 ℃ below zero to react for 20-30 min.
Then 0.06mol of iodomethyl pivalate is added, and the temperature is controlled to be below 50 ℃ below zero for reaction for 20 to 30 min.
Finally, 0.04mol of iodomethyl pivalate is added, and the temperature is controlled to be below 50 ℃ below zero for reaction till the reaction is complete.
During the reaction, diisopropylethylamine is added to control the pH value to be 7.5-8.5, after the reaction is finished, 350ml of ethyl acetate and 270ml of pure water are added into the reaction liquid, the mixture is stirred and kept stand for layering, the lower water layer is discarded, the organic layer is stirred and washed by 0.1% sodium bicarbonate solution and water in sequence, the mixture is kept stand for layering, the water layer is discarded, the organic layer is concentrated to be dry, the concentrate is added into 500ml of normal hexane, and the product is obtained after stirring, filtering and drying. The purity of the product is 95.2 percent by HPLC.
Example 6
Preparation of cefditoren pivoxil dimer
125ml of N, N-dimethylformamide and 22.2g (0.04mol) of cefditoren sodium are added into a reaction vessel, stirred and dissolved, and cooled to below minus 80 ℃.
Adding 0.06mol of iodomethyl pivalate, and controlling the temperature below minus 40 ℃ to react for 20-30 min.
Then 0.06mol of iodomethyl pivalate is added, and the temperature is controlled to be below 40 ℃ below zero for reaction for 20 to 30 min.
Finally, 0.04mol of iodomethyl pivalate is added, and the temperature is controlled to be below 40 ℃ below zero for reaction till the reaction is complete.
And (2) adding sodium bicarbonate during the reaction process, controlling the pH value to be 7.5-8.5, after the reaction is finished, adding 350ml of ethyl acetate and 270ml of pure water into the reaction solution, stirring, standing for layering, removing a lower water layer, stirring and washing an organic layer by using 0.1% sodium bicarbonate solution and water in sequence, standing for layering, removing a water layer, concentrating the organic layer to be dry, adding 500ml of n-hexane into the concentrate, stirring, filtering and drying to obtain the product. The purity of the product is 94.3% by HPLC.
Structural confirmation of cefditoren pivoxil dimer
1. Mass spectrometric analysis
As can be seen from the figure, the molecular ion peak of the product is M/z1253.2(M + 1). Formula C of this product51H56N12O14S6Is consistent with molecular weight 1252.47.
2. Nuclear magnetic resonance hydrogen spectrum (1H-NMR) and spectral analysis
(2) The measurement conditions were as follows: by CD3OD is solvent and TMS is internal standard.
Of samples1The H-NMR spectrum is shown in FIG. 2.
The test results are listed in the following table.
The chemical name of the product is 2.2Vertical and horizontal-[2,2Vertical and horizontal-methylenebis (azanediyl) bis (thiazol-4, 2-diyl) bis { N- [ (6R,7R) -2-pivaloyloxymethoxycarbonyl-8-oxo-3- [ (Z) -2- (thiazol-5-yl) vinyl]-5-thia-1-azabicyclo [4.2.0]Oct-2-en-7-yl]-2- [ (Z) -methoxyimine]Acetamide }, molecular formula C51H56N12O14S6Molecular weight of 1252.47, structural formula:
the product is a methylene-bis-nitrogen alkane compound with a symmetrical structure, and each proton signal peak shows double the number of protons.
1.13 is-COOCH2OCOC(CH 3)3I.e., the 21-H signal peak;
2.41 is 27-CH3The corresponding hydrogen signal peak;
due to the carbocyclic ring being CH2Is magnetic unequal hydrogen nucleus, and 3.29 and 3.63 are judged to be same hydrocarbon, namely 4-CH2-a corresponding hydrogen signal peak;
3.98 is NOCH 3I.e., the 16-H signal peak;
4.90 is-NH-CH 2-a proton peak in NH-i.e. a 28-H signal peak;
5.31 and 5.95 are the 6-H and 7-H signal peaks, respectively;
5.73 and 5.80 are-COOCH 2OCOC(CH3)3I.e., the 18-H signal peak;
coupling constants (J) of 6.39 and 6.71 were equal and both were doublet peaks, judging 6.39 and 6.71 as 22-H and 23-H signal peaks, respectively;
both 6.94 and 8.80 were low field singlet and were judged as hydrogen on the thiazole ring, i.e. the 13-H and 26-H signal peaks, respectively.
3. Nuclear magnetic resonance carbon spectrum (13C-NMR)
(1) The test apparatus comprises: AC-600 NMR spectrometer from BRUKR, Switzerland.
(2) The measurement conditions were as follows: by CD3OD is a solvent.
Of samples13The C-NMR spectrum is shown in FIG. 3.
The test results are listed in the following table.
Method for preparing cefditoren pivoxil dimer molecule13C-NMR shows 24 groups of carbon signal peaks, wherein 3 are same carbon CH3The chemical shift of carbon in the same environment except for the carbon in methylene diazane is the same due to the concordance in the structure, and the resolution is as follows:
15.29 is ═ NOCH3I.e. 16-CH3A signal peak;
27.17 is-COOCH2OCOC(CH3)3I.e. 21-CH3A signal peak;
27.67 is 27-CH3A signal peak;
28.84 is the 28-CH 2-signal peak;
39.70 is-COOCH2OCOC(CH3)3I.e., the 20-C signal peak;
58.98 is 4-CH on hydrogenated thiazine ring2A signal peak;
60.51 is-COOCH2OCOC(CH3)3I.e. 18-CH2A signal peak;
63.01 and 81.02 are the 6-CH and 7-CH signal peaks on the β -lactam ring, respectively;
91.91 is the 11-C signal peak;
111.59 and 122.81 are C ═ C, i.e., 2-C and 3-C signal peaks;
126.19 and 127.98 are-CH ═ CH-i.e. 22-CH and 23-CH signal peaks;
128.53, 143.72 and 150.20 are the 24-C, 25-C and 26-CH signal peaks on the methylthiazole ring, respectively;
153.50, 154.39, and 161.72 are the 12-C, 13-CH, and 14-C signal peaks, respectively, on the aminothiazole ring;
165.45 is the 10-C signal peak;
165.71 is the 8-C signal peak on the β -lactam ring;
169.96 is-COOCH2OCOC(CH3)3I.e., the 17-C signal peak;
178.10 is-COOCH2OCOC(CH3)3I.e., the 19-C signal peak. The product has various carbon atoms in the molecule and the connection relationship between the carbon atoms and cefditoren pivoxilThe corresponding structures of the ester dimers are identical.
The present invention is not limited to the above-described embodiments, and those skilled in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (7)
1. A preparation method of cefditoren pivoxil dimer is characterized by comprising the following steps: adding an organic solvent and cefditoren sodium into a reaction vessel, stirring for dissolving, cooling to-20 to-50 ℃, adding iodomethyl pivalate in batches, reacting for a certain time after adding iodomethyl pivalate each time, and adding iodomethyl pivalate again; inorganic base or organic base is added in the reaction process to control the pH value to be 7.5-8.5;
and after the reaction is finished, adding the reaction solution into ethyl acetate and pure water, stirring, standing for layering, removing a lower water layer, washing an organic layer with sodium bicarbonate or sodium hydroxide solution and water in sequence, concentrating the organic layer to be dry, adding the concentrate into n-hexane, stirring, filtering, and drying a filter cake to obtain the product.
2. The process for preparing cefditoren pivoxil dimer according to claim 1, wherein: the organic solvent is one of N, N-dimethylformamide, tetrahydrofuran, acetonitrile and 1, 4-dioxane.
3. The process for preparing cefditoren pivoxil dimer according to claim 2, wherein: the molar ratio of the cefditoren sodium to the iodomethyl pivalate is 1: 4-6; the addition is carried out in at least three portions.
4. The process for preparing cefditoren pivoxil dimer according to claim 3, wherein: the iodomethyl pivalate is added in three times, and the amount of the first two times is larger than that of the last time.
5. The process for preparing cefditoren pivoxil dimer according to claim 4, wherein: adding iodomethyl pivalate each time, reacting for 20-30min, and adding iodomethyl pivalate again.
6. The process for preparing cefditoren pivoxil dimer according to claim 5, wherein: the organic base is one of triethylamine, tributylamine, diethylamine, diisopropylethylamine and pyridine, and the inorganic base is sodium bicarbonate.
7. The process according to claim 6, wherein the cefditoren pivoxil dimer is prepared by: the mass concentration of the sodium bicarbonate or sodium hydroxide solution used for washing is 0.1-1%.
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| WO2006024900A1 (en) * | 2004-08-31 | 2006-03-09 | Ranbaxy Laboratories Limited | Highly pure cefditoren pivoxil |
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| CN108727418A (en) * | 2018-08-06 | 2018-11-02 | 鲁南制药集团股份有限公司 | A kind of preparation method of Cefditoren pivoxil Cephalosporins dimer |
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| WO2005003141A2 (en) * | 2003-07-04 | 2005-01-13 | Orchid Chemicals & Pharmaceuticals Ltd | An improved process for the preparation of cefditoren |
| WO2006024900A1 (en) * | 2004-08-31 | 2006-03-09 | Ranbaxy Laboratories Limited | Highly pure cefditoren pivoxil |
| CN105175432A (en) * | 2015-09-09 | 2015-12-23 | 山东罗欣药业集团股份有限公司 | Preparation method of cefditore |
| CN106543206A (en) * | 2016-09-22 | 2017-03-29 | 济南康和医药科技有限公司 | A kind of preparation method of cephalo-type dimer compound |
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