CN108727418B - Preparation method of cefditoren pivoxil dimer - Google Patents

Preparation method of cefditoren pivoxil dimer Download PDF

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CN108727418B
CN108727418B CN201810889116.3A CN201810889116A CN108727418B CN 108727418 B CN108727418 B CN 108727418B CN 201810889116 A CN201810889116 A CN 201810889116A CN 108727418 B CN108727418 B CN 108727418B
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cefditoren pivoxil
dimer
purified water
pivoxil
cefditoren
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张贵民
张乃华
刘红江
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Lunan Pharmaceutical Group Corp
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Abstract

The invention provides a preparation method of cefditoren pivoxil dimer. The method comprises the following steps: cefditoren pivoxil reacts with formaldehyde solution under the action of a catalyst to generate cefditoren pivoxil dimer. The preparation method provided by the invention is simple to operate, mild in reaction conditions, high in product yield and high in purity, and the cefditoren pivoxil dimer prepared by the invention can be used as an impurity reference substance and used for quality control of cefditoren pivoxil in the production process.

Description

Preparation method of cefditoren pivoxil dimer
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of cefditoren pivoxil dimer.
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, having the chemical structure shown below:
Figure BDA0001755372140000011
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 employ the synthetic strategy reported in US2006/0173175, the route of which is shown below:
Figure BDA0001755372140000021
according to the method, cefditoren acid is obtained by reacting cefditoren mother nucleus 7-ATCA and AE active ester as starting materials, then salifying is carried out under the alkaline condition of sodium isooctanoate to obtain cefditoren sodium, and finally the cefditoren sodium and iodomethyl pivalate react to obtain a target product of cefditoren pivoxil.
Figure BDA0001755372140000022
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.
However, the impurity reference substance for controlling the quality of cefditoren pivoxil at present is mainly obtained by separating and extracting from a cefditoren pivoxil crude product, the method has the disadvantages of complicated steps, low yield and low purity, and impurities with similar structures are difficult to completely separate, so that the detection accuracy is influenced. With the advancement of the national research work on drug consistency, the preparation method of the impurity compound cefditoren pivoxil dimer is determined, a qualified reference substance is provided, and the quality control of cefditoren pivoxil can be positively performed. Therefore, it is of great importance to research and provide a new and efficient preparation method of cefditoren pivoxil dimer.
Disclosure of Invention
Aiming at the problems of difficult separation and extraction, low yield and low purity of cefditoren pivoxil dimer which is an important impurity related to cefditoren pivoxil at present, the invention provides a simple, convenient and efficient preparation method of the cefditoren pivoxil dimer, and the cefditoren pivoxil dimer prepared by the method has higher purity and can be directly used as an impurity reference substance for quality control in the production process of cefditoren pivoxil.
The specific technical content of the invention is as follows:
Figure BDA0001755372140000031
a preparation method of cefditoren pivoxil dimer shown in formula (I) comprises the following steps:
adding cefditoren pivoxil, a formaldehyde solution and a catalyst into an organic solvent, heating until the reaction is finished, cooling the reaction liquid to room temperature, adding an extraction liquid, separating liquid, extracting a water phase by using the organic solvent, combining organic phases, washing by using purified water, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dry, and recrystallizing the obtained crude product to obtain the cefditoren pivoxil dimer finished product.
Preferably, the organic solvent is one or a combination of tetrahydrofuran, acetonitrile, 1, 4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide, wherein acetonitrile is particularly preferred.
In a preferable scheme, the mass-volume ratio of the cefditoren pivoxil to the solvent is 1: 3-12 g/mL.
In a preferable scheme, the feeding mass ratio of the cefditoren pivoxil to the formaldehyde solution is 1: 0.08-0.25, wherein the preferable ratio is 1: 0.14, and the mass fraction of formaldehyde in the formaldehyde solution is 37-40%.
Preferably, the catalyst is one or a combination of formic acid, acetic acid, sulfuric acid and phosphoric acid, wherein sulfuric acid is particularly preferred.
In a preferable embodiment, the feeding molar ratio of the cefditoren pivoxil to the catalyst is 1: 0.01-0.05, and particularly preferably 1: 0.03.
In a preferable scheme, the reaction temperature is 50-100 ℃, and particularly preferably 80 ℃.
In a preferable scheme, the reaction time is 1.0-4.0 h.
In a preferred scheme, the extraction liquid is ethyl acetate/purified water, isopropyl acetate/purified water, butyl acetate/purified water; the volume ratio of the organic solvent to the purified water in the extraction liquid is 1.0-4.0: 1.0; the solvent used for extracting the water phase is ethyl acetate, isopropyl acetate and butyl acetate.
Preferably, the solvent used for recrystallization is dichloromethane or chloroform, wherein dichloromethane is particularly preferred.
A cefditoren pivoxil dimer prepared by any of the methods of the invention.
Compared with the prior art, the invention has the following technical effects:
1. the method for preparing cefditoren pivoxil dimer is simple, convenient and efficient, the whole preparation method is short in route, simple in operation steps, high in reaction yield and high in product purity;
2. provides a high-purity cefditoren pivoxil-related impurity which can be used as an impurity reference substance and used for controlling the quality of cefditoren pivoxil in the production process.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
The invention adopts HPLC to determine the purity of cefditoren pivoxil dimer, and the chromatographic conditions are as follows: [ column for chromatography: AgilentZORBAX SB-C18(4.6 mm. times.250 mm, 5.0 μm); mobile phase A: ammonium formate solution (1.58 g ammonium formate, 900mL water, pH adjusted to 4.5 with formic acid solution, water diluted to 1000mL) -acetonitrile-methanol (45: 25); mobile phase B: ammonium formate solution (1.58 g ammonium formate, 900mL water, pH adjusted to 4.5 with formic acid solution, dilution to 1000mL water) -acetonitrile-methanol (45: 55), gradient elution (0 → 5 min: A100%; 5 → 40 min: A100% → 0; 40 → 50 min: A0 → 100%); column temperature: 40 ℃; detection wavelength: 254 nm; flow rate: 1.0 mL/min-1(ii) a Sample introduction amount: 20 μ L]。
Example 1
Adding cefditoren pivoxil (24.83g, 0.04mol), formaldehyde solution (3.48g, mass fraction of 37% -40%) and sulfuric acid (0.12g, 1.2mmol) into acetonitrile (125mL), keeping the temperature at 80 ℃ for reaction for 2.0h, cooling the reaction liquid to room temperature, adding a mixture of purified water (100mL) and ethyl acetate (200mL), stirring for 10min, separating liquid, extracting an aqueous layer with ethyl acetate (40mL multiplied by 2), combining organic layers, washing the organic layer with purified water (100mL multiplied by 2), washing the organic layer with saturated saline (100mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, recrystallizing the obtained solid with dichloromethane to obtain a cefditoren pivoxil dimer finished product, wherein the yield is 87.6%, and detecting by HPLC, wherein t is tR34.013min represents cefditoren pivoxil dimer with a purity of 96.56%.
Example 2
Adding cefditoren pivoxil (24.83g, 0.04mol), formaldehyde solution (1.99g, mass fraction of 37% -40%) and sulfuric acid (0.12g, 1.2mmol) into acetonitrile (125mL), keeping the temperature at 80 ℃ for reaction for 2.5h, cooling the reaction liquid to room temperature, adding a mixture of purified water (100mL) and ethyl acetate (200mL), stirring for 10min, separating liquid, extracting an aqueous layer with ethyl acetate (40mL multiplied by 2), combining organic layers, washing the organic layer with purified water (100mL multiplied by 2), washing the organic layer with saturated saline (100mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and subjecting the obtained solid to filtrationRecrystallizing with dichloromethane to obtain cefditoren pivoxil dimer product with yield of 80.2%, and detecting by HPLC, wherein t isR33.996min represents cefditoren pivoxil dimer with a purity of 95.41%.
Example 3
Adding cefditoren pivoxil (24.83g, 0.04mol), formaldehyde solution (6.21g, mass fraction of 37% -40%) and sulfuric acid (0.12g, 1.2mmol) into acetonitrile (125mL), keeping the temperature at 80 ℃ for reaction for 1.5h, cooling the reaction liquid to room temperature, adding a mixture of purified water (100mL) and ethyl acetate (200mL), stirring for 10min, separating liquid, extracting an aqueous layer with ethyl acetate (40mL multiplied by 2), combining organic layers, washing the organic layer with purified water (100mL multiplied by 2), washing the organic layer with saturated saline (100mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, recrystallizing the obtained solid with dichloromethane to obtain a cefditoren pivoxil dimer finished product, wherein the yield is 80.6%, and detecting by HPLC, wherein t is tR34.011min represents cefditoren pivoxil dimer with a purity of 95.39%.
Example 4
Adding cefditoren pivoxil (24.83g, 0.04mol), formaldehyde solution (3.48g, mass fraction is 37% -40%) and sulfuric acid (0.04g, 0.4mmol) into acetonitrile (125mL), keeping the temperature at 80 ℃ for reaction for 4h, cooling the reaction liquid to room temperature, adding a mixture of purified water (100mL) and ethyl acetate (200mL), stirring for 10min, separating liquid, extracting an aqueous layer of ethyl acetate (40mL multiplied by 2), combining organic layers, washing the organic layer with purified water (100mL multiplied by 2), washing the organic layer with saturated saline (100mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, recrystallizing the obtained solid with dichloromethane to obtain the cefditoren pivoxil dimer finished product with the yield of 79.6%, and detecting, wherein t is tR34.020min represents cefditoren pivoxil dimer with a purity of 95.14%.
Example 5
Adding cefditoren pivoxil (24.83g, 0.04mol), formaldehyde solution (3.48g, mass fraction of 37% -40%) and sulfuric acid (0.20g, 2.0mmol) into acetonitrile (125mL), reacting at 80 ℃ for 1h, cooling the reaction solution to room temperature, adding a mixture of purified water (100mL) and ethyl acetate (200mL), stirring for 10min, and then dividingExtracting the solution, water layer and ethyl acetate (40mL multiplied by 2), combining organic layers, washing the organic layer by purified water (100mL multiplied by 2), washing the organic layer by saturated saline (100mL multiplied by 3), drying by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, recrystallizing the obtained solid by dichloromethane to obtain the cefditoren pivoxil dimer finished product, wherein the yield is 81.9%, and detecting by HPLC, wherein t isR34.016min represents cefditoren pivoxil dimer with a purity of 95.91%.
Example 6
Adding cefditoren pivoxil (24.83g, 0.04mol), formaldehyde solution (3.48g, mass fraction of 37% -40%) and acetic acid (0.072g, 1.2mmol) into tetrahydrofuran (200mL), keeping the temperature at 60 ℃ for reaction for 4.0h, cooling the reaction solution to room temperature, adding a mixture of purified water (150mL) and isopropyl acetate (250mL), stirring for 10min, separating liquid, extracting isopropyl acetate (50mL multiplied by 2) in a water layer, combining organic layers, washing the organic layers by using purified water (150mL multiplied by 2), washing the organic layers by using saturated saline (150mL multiplied by 3), drying anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, recrystallizing the obtained solid by dichloromethane to obtain a cefditoren pivoxil dimer finished product, wherein the yield is 78.2%, and detecting by HPLC, wherein t is tR34.022min represents cefditoren pivoxil dimer with a purity of 95.89%.
Example 7
Adding cefditoren pivoxil (24.83g, 0.04mol), formaldehyde solution (3.48g, mass fraction is 37% -40%) and phosphoric acid (0.12g, 1.2mmol) into 1, 4-dioxane (150mL), keeping the temperature for reaction for 2.5h, cooling the reaction liquid to room temperature, adding a mixture of purified water (150mL) and butyl acetate (200mL), stirring for 10min, separating liquid, extracting water layer butyl acetate (40mL multiplied by 2), combining organic layers, washing the organic layer with purified water (100mL multiplied by 2), washing the organic layer with saturated saline (100mL multiplied by 3), drying anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, recrystallizing the obtained solid with chloroform to obtain a cefditoren pivoxil dimer finished product, wherein the yield is 78.9%, and detecting by HPLC, wherein t is tR33.989min represents cefditoren pivoxil dimer with a purity of 95.56%.
Example 8
Cefditoren pivoxil (24.83g, 0.04 mo)l), adding a formaldehyde solution (1.74g, the mass fraction is 37-40%) and formic acid (0.065g, 1.2mmol, the mass fraction is 85%) into acetonitrile (125mL), keeping the temperature at 50 ℃ for reaction for 4.0h, cooling the reaction solution to room temperature, adding a mixture of purified water (100mL) and butyl acetate (50mL), stirring for 10min, separating, extracting water layer butyl acetate (40mL multiplied by 2), combining organic layers, washing the organic layer with purified water (100mL multiplied by 2), washing the organic layer with saturated saline (100mL multiplied by 3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, recrystallizing the obtained solid with dichloromethane to obtain a cefditoren pivoxil dimer finished product, wherein the yield is 65.8%, and detecting by HPLC, wherein t is tR33.994min represents cefditoren pivoxil dimer with a purity of 92.31%.
Example 9
Adding cefditoren pivoxil (24.83g, 0.04mol), formaldehyde solution (6.95g, mass fraction is 37% -40%) and sulfuric acid (0.24g, 2.4mmol) into N, N-dimethylformamide (350mL), keeping the temperature for reaction at 70 ℃ for 2.0h, cooling the reaction liquid to room temperature, adding a mixture of purified water (100mL) and ethyl acetate (500mL), stirring for 10min, separating liquid, extracting an aqueous layer by ethyl acetate (100mL multiplied by 2), combining organic layers, washing the organic layer by purified water (250mL multiplied by 2), washing the organic layer by saturated saline (250mL multiplied by 3), drying anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, recrystallizing the obtained solid by chloroform to obtain a cefditoren pivoxil dimer finished product, wherein the yield is 66.7%, and detecting by HPLC, wherein t is tR34.010min represents cefditoren pivoxil dimer with a purity of 91.75%.

Claims (6)

1. A preparation method of cefditoren pivoxil dimer shown as a formula (I) is characterized by comprising the following steps:
Figure 595074DEST_PATH_IMAGE001
the method specifically comprises the following steps: adding cefditoren pivoxil, a formaldehyde solution and a catalyst into an organic solvent, heating until the reaction is finished, adding an extraction liquid, separating liquid, extracting a water phase by using the organic solvent, combining organic phases, washing by using purified water, washing by using saturated salt solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until the filtrate is dry, and recrystallizing the obtained crude product to obtain a cefditoren pivoxil dimer finished product;
wherein the organic solvent is one or the combination of tetrahydrofuran, acetonitrile, 1, 4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide;
wherein the reaction temperature is 50-100 ℃; the reaction time is 1.0-4.0 h.
2. A process for preparing cefditoren pivoxil dimer according to claim 1, wherein the mass-to-volume ratio of cefditoren pivoxil to the solvent is 1: 3-12 g/mL.
3. The method for preparing cefditoren pivoxil dimer according to claim 1, wherein the mass ratio of the cefditoren pivoxil to the formaldehyde solution is 1: 0.08-0.25, and the mass fraction of formaldehyde in the used formaldehyde solution is 37-40%.
4. The process for preparing cefditoren pivoxil dimer according to claim 1, wherein the catalyst is one or a combination of formic acid, acetic acid, sulfuric acid, and phosphoric acid; the feeding molar ratio of the cefditoren pivoxil to the catalyst is 1: 0.01 to 0.05.
5. The process for preparing cefditoren pivoxil dimer according to claim 1, wherein the extraction liquid is ethyl acetate/purified water, isopropyl acetate/purified water, butyl acetate/purified water; the solvent used for extracting the water phase is ethyl acetate, isopropyl acetate and butyl acetate.
6. A process for preparing cefditoren pivoxil dimer according to claim 1, wherein the solvent used for recrystallization is dichloromethane or chloroform.
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