CN111233894B - Cefditoren pivoxil delta3Process for the preparation of isomers - Google Patents
Cefditoren pivoxil delta3Process for the preparation of isomers Download PDFInfo
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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
- C07D501/04—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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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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
- C07D501/60—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 3 and 4
Abstract
The invention relates to cefditoren pivoxil delta3A preparation method of isomer, belonging to the technical field of drug intermediate synthesis. In order to solve the problems of low isomerization and difficult separation of the existing synthetic product, provides cefditoren pivoxil delta3The preparation method of the isomer comprises the steps of adding 7-ATCA, BSA and organic base I into a water-insoluble organic solvent I for isomerization reaction, adding water after the reaction is finished, standing for liquid separation, collecting a water phase, adding acid into the collected water phase to adjust the pH value to 2.0-3.0 to obtain 7-ATCA delta3Isomers: in the presence of organic base II, 7-ATCA delta3The isomer and AE active ester are subjected to condensation reaction to obtain corresponding cefditoren delta3Isomer salts: combining cefditoren delta3The isomer salt reacts with iodomethyl pivalate to obtain cefditoren pivoxil delta3The isomer has high isomerization rate, can improve the yield and purity of the product and is easy to separate and operate.
Description
Technical Field
The invention relates to cefditoren pivoxil delta3A preparation method of isomer, belonging to the technical field of drug intermediate synthesis.
Background
Cefditoren pivoxil has the chemical name 2, 2-dimethylpropionyloxymethyl (6R,7R) -7- [ (Z) -2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido ] -3- [ (Z) -2- (4-methyl-1, 3-thiazol-5-yl) vinyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate and the chemical structure is shown below:
cefditoren pivoxil is an ester type oral third-generation cephalosporin antibiotic developed by the company gming treaty fruit, first marketed in japan in 1994, marketed in china in 4 months in 2001 under the trade name of mexican, and is mainly used clinically for 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, gram-negative bacteria such as Escherichia coli, Catarabundan, Klebsiella, Proteus, Haemophilus influenzae, etc., 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, remarkable curative effect, safety, stability, good oral absorption and the like.
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 firstly determines 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 presence of impurities not only affects the purity of the drug, but also brings non-therapeutic 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 to develop efficient synthesis process of raw drug materials, but also to study the types and sources of impurities in drugs and how to control the generation of process impurities. Generally, research personnel firstly directionally synthesize process impurities, secondly optimize the process to develop an efficient impurity synthesis route, and obtain an impurity reference substance for the development of the quality research work of the bulk drugs.
In the case of cefditoren pivoxil, impurities are also present during the synthesis, wherein δ is in the case of cefditoren pivoxil3Isomers as cefditoren pivoxilOne of important impurities in quality control, at present, few documents report the synthesis method of the impurities, and only some related reports use cefditoren pivoxil as a raw material to perform isomerization reaction under the condition of concentrated ammonia water, and finally, the product is obtained by column purification. The method needs to be carried out under the high-temperature alkaline condition for a long time, is easy to cause the ring opening degradation of the cefditoren pivoxil into other impurities, has extremely low isomerization conversion rate, is difficult to operate by adopting column-passing purification, has low yield, and adopts the cefditoren pivoxil and the delta thereof as raw materials3The isomers have very similar polarity, are difficult to separate, have high extraction difficulty and are difficult to select a mobile phase.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides cefditoren pivoxil delta3The preparation method of the isomer solves the problem of how to improve the isomerization rate, and has the characteristics of easy separation and high yield of the product.
The aim of the invention is realized by the following technical scheme that cefditoren pivoxil delta3A process for the preparation of isomers, characterized in that it comprises the following steps:
A. adding 7-ATCA of the cephalosporin nucleus formula II compound, BSA (N, O-bistrimethylsilyl acetamide) and organic base I into a water-insoluble organic solvent I for isomerization reaction, adding water into the reaction solution after the reaction is finished, standing for liquid separation, collecting a water phase, adding acid into the collected water phase to adjust the pH value to 2.0-3.0 to obtain 7-ATCA delta compound of the formula III3Isomers:
B. in the presence of organic base II, compound 7-ATCA delta of formula III3The isomer and AE active ester are subjected to condensation reaction to obtain a corresponding compound of formula IV, namely cefditoren delta3Isomer salts:
q in the compound shown in the formula IV corresponds to a corresponding organic base II;
C. subjecting a compound of formula IV to cefditoren delta3The isomer salt reacts with iodomethyl pivalate to obtain the corresponding product, namely cefditoren pivoxil delta, of the compound shown in the formula I3Isomers:
the cefditoren pivoxil delta is synthesized by firstly carrying out isomerization reaction on mother nucleus 7-ATCA and then further carrying out condensation reaction and esterification reaction3The isomer can better improve the yield and purity of the product, and has mild reaction process, easy operation, simplified post-treatment process and no need of column separation. More specifically, in the isomerization reaction of the parent nucleus 7-ATCA, the reaction temperature is mild, the reaction time is short, the possibility of other degradation ring-opening impurities can be effectively reduced, BSA is added, amino groups and carboxyl groups in the parent nucleus 7-ATCA can be effectively protected in the isomerization reaction process, an isomerization product is efficiently formed under the action of organic base I, the reaction time is short, after the reaction is finished, water is added to enable an intermediate product formed in the reaction to enter a water phase, the BSA in the intermediate product can be effectively removed through acidification treatment, the corresponding isomerization product is guaranteed to be formed, and 7-ATCA delta is crystallized by adjusting the pH value to obtain 7-ATCA delta3The isomer has the advantages of high yield and purity. Meanwhile, after the parent nucleus 7-ATCA is isomerized, the subsequent reaction can be easier to be carried out and the product can be separated, particularly after the esterification reaction in the third step is finished, the product can be separated by crystallization in a solvent, and the method has the effects of high yield and purity. The extraction by a column is not needed, so that the defects of poor selection of mobile phase and difficult operation caused by the extraction by the column are effectively overcome. Realizes simple operation, can be produced in large scale, provides theoretical basis for safe use of medicines, provides effective data support for quality standard of cefditoren pivoxil, and provides clinical safety for medicinesThe full use provides effective guarantee.
In the above cefditoren pivoxil delta3In the preparation method of the isomer, preferably, the organic base in the step A is one or more selected from pyridine, triethylamine, diethylamine, piperidine and diisopropylamine. The isomerization reaction can be effectively realized, the protection function of BSA on amino and carboxyl can be effectively ensured, the reaction can be carried out under a mild condition, the ring opening of a parent nucleus can be avoided, and the effect of high yield can be better realized.
In the above cefditoren pivoxil delta3In the preparation method of the isomers, the mole ratio of the cephalosporin nucleus type II compound 7-ATCA, BSA and organic base I in the step A is 1: 2.0-3.0: 1.1 to 2.0. The utilization rate of raw materials can be better improved, the molar equivalent of BSA is in the range of 2.0-3.0, the protection of amino and carboxyl in a mother nucleus can be effectively realized, and the better guarantee is provided for better yield of an isomerization product.
In the above cefditoren pivoxil delta3In the preparation method of the isomer, the use of the water-insoluble organic solvent I in the step A can effectively carry out the reaction, is beneficial to simplifying the operation of subsequent treatment, is more beneficial to separating out a corresponding intermediate product, and has higher yield and purity effect. Preferably, the water-insoluble organic solvent in step A is one or more selected from dichloromethane, ethyl acetate and chloroform. The reaction is better carried out, the separation of products and the reduction of the content of impurities are facilitated, and the raw materials are easy to recycle.
The amount of the water-insoluble organic solvent used in step A may be generally used in the conventional amount for the reaction, but it is preferable to use a solvent in which the ratio of mother nucleus 7-ATCA: the mass ratio of the water-insoluble organic solvent I is 1: adding 10-15 of solvent. In addition, the hydrochloric acid used for acidification in the step A is preferably adjusted by dilute hydrochloric acid, and the dilute hydrochloric acid solution with the mass percent of 1-15% is used.
In the above cefditoren pivoxil delta3In the method for producing isomers, step (b) is preferableThe temperature of the isomerization reaction in the step A is 25-35 ℃. By adopting the raw materials of the invention to carry out isomerization reaction, the reaction can be carried out mildly at a lower temperature, the ring opening of mother nucleus can be better avoided, the generation of impurities is reduced, and the purity and yield effect of intermediate products are improved.
In the above cefditoren pivoxil delta3In the method for producing isomers, the reaction in step C is preferably carried out in N, N-dimethylformamide. The reaction is allowed to proceed more mildly, and for N, N-dimethylformamide the amount of solvent is generally used in the art of synthetic reactions, and of course, it is preferred to use the cefditoren δ 3 isomer salt: the mass ratio of the N, N-dimethylformamide is 1: 15 to 25.
In the above cefditoren pivoxil delta3Preferably, in the preparation method of the isomer, after the reaction in the step C, adding a mixed solvent of a water-insoluble organic solvent II and water into the reaction solution, stirring the mixture fully at a temperature of 25-35 ℃, standing the mixture for liquid separation, collecting an organic layer, concentrating the collected organic layer, evaporating the solvent, adding a water-insoluble organic solvent III, stirring the mixture fully for crystallization, and filtering the mixture to obtain the corresponding compound of the formula i, namely the cefditoren pivoxil delta3Isomers. The invention can effectively ensure the cephalosporin nucleus delta with high yield and purity after the isomerization treatment in the step A3The intermediate of the isomer is obtained, so that after the reaction is finished, high-requirement column separation is not needed, the problem of similar polarity is not needed to be considered, only stirring crystallization separation is directly carried out in a solvent, the operation is greatly simplified, and the yield and the purity of the obtained product can be ensured. As a further optimization, the water-insoluble organic solvent II is one or more selected from ethyl acetate and dichloromethane; the water-insoluble organic solvent III is a poor solvent, has low solubility on the product and is beneficial to crystallization, and is preferably selected from one or more of isopropyl ether and cyclohexane.
In the above cefditoren pivoxil delta3In the process for producing isomers, the condensation reaction in step B is preferably carried out in an organic solventIn the mixed solvent of the solvent and the water, the mixed solvent of the water-soluble organic solvent and the water is preferably adopted, so that the reaction is performed in a homogeneous system, the reaction is more favorably performed, and the yield and the purity effect of an intermediate product are improved. Preferably, the water-soluble organic solvent in the step B is selected from tetrahydrofuran and/or acetone, the organic base II is triethylamine, and after the condensation reaction is finished, the method further comprises the steps of adding a water-insoluble organic solvent IV into the reaction liquid, stirring, standing for liquid separation, collecting an aqueous phase, concentrating the obtained aqueous phase to remove the solvent, and obtaining the corresponding concentrate of the compound of the formula IV, namely the cefditoren delta3Isomer triethylamine salt:
has the advantages of high yield of intermediate products and easy control and operation of the process. The organic solvent such as tetrahydrofuran or acetone is preferably used in the form of cephalosporin nucleus delta3Isomers: the mass ratio of the organic solvent is 1: 15 to 20. Tetrahydrofuran or acetone adopted as an organic solvent can be dissolved in water, so that the reaction is carried out in a mixed solvent of the organic solvent and the water, namely the reaction is carried out in a homogeneous solvent system, the reaction is favorably carried out, and the product yield is improved;
the amount of the water-insoluble organic solvent IV used in the post-treatment after completion of the condensation reaction is preferably such that the amount of the cephalosporin nucleus delta3Isomers: the mass ratio of the water-insoluble organic solvent IV is 1: 5 to 15.
In the above cefditoren pivoxil delta3In the preparation method of the isomer, preferably, the organic base II in the step B is one or more selected from pyridine, triethylamine, diethylamine, piperidine and diisopropylamine. Can effectively carry out the condensation reaction and has the advantage of mild reaction. Further preferably, the 7-ATCA delta3Isomers: the molar ratio of the organic base II is 1: 1.1 to 2.0. Preferably, the water-insoluble organic solvent in step B is one or two selected from dichloromethane and ethyl acetate.
Head of bookSporotipnate delta3The reaction equation of the preparation method of the isomers can be represented by the following process:
the organic base II in step B in the above reaction equation is exemplified by triethylamine, i.e. Q in the corresponding compound of formula IV is TEA (triethylamine).
In summary, compared with the prior art, the invention has the following advantages:
1. the cefditoren pivoxil delta is synthesized by firstly carrying out isomerization reaction on mother nucleus 7-ATCA and then further carrying out condensation reaction and esterification reaction3The isomer can better improve the yield and purity of the product, and has mild reaction process, easy operation, simplified post-treatment process and no need of column separation. And BSA is added, so that amino and carboxyl groups in the parent nucleus 7-ATCA can be effectively protected in the isomerization reaction process, an isomerization product can be efficiently formed under the action of organic base I, the reaction time is short, and the advantages of high yield and purity are achieved. The purity of the final product is more than 95.0 percent, and the total molar yield is basically more than 70.0 percent.
2. By adopting the method, the cephalosporin nucleus is subjected to isomerization treatment and then subsequent condensation and esterification reaction are carried out, so that the product after the esterification reaction can be separated directly by crystallization in a solvent without column extraction, the defects of poor mobile phase selection and difficult operation caused by column extraction are effectively overcome, and the method has the effects of high yield and purity.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Cefditoren pivoxil delta of the invention3The specific operation of the isomer synthesis method is as follows:
in a clean reaction bottle, the size of the reaction bottle can be determined according to the feeding materialsSelecting the amount of the cephalosporin mother nucleus 7-ATCA shown in the formula II in a reaction bottle, dissolving the cephalosporin mother nucleus 7-ATCA in a water-insoluble organic solvent I, adding BSA (N, O-bis tri silicyl acetamide) to effectively protect amino and carboxyl groups in the cephalosporin mother nucleus 7-ATCA in the reaction process, improving the reaction effectiveness, reducing the products of other side reactions, controlling the temperature at 25-35 ℃, adding an organic base I to perform an isomerization reaction, stirring for 0.5-1 hour, controlling the temperature at 25-35 ℃ after the isomerization reaction is finished, adding a proper amount of water into the reaction solution, stirring for 5-15 minutes, standing and separating the liquid; and after full layering, removing an organic layer from the liquid, controlling the temperature to be 25-35 ℃, adding acid into the water layer feed liquid, adjusting the pH value to be 2.0-3.0, cooling to 5-15 ℃, and stirring for crystallization for 1-2 hours. Filtering, drying to obtain the corresponding compound 7-ATCA delta of the formula III3The isomer has a purity of more than 95.0 percent and a molar yield of more than 90.0 percent.
Preferably, the cephalosporin nucleus of formula II compound 7-ATCA: BSA: the molar ratio of the organic base I is 1: 2.0-3.0: 1.1-2.0, the organic base is preferably triethylamine, diisopropylamine, piperidine, pyridine or diethylamine, and the non-water-soluble organic solvent is one or more selected from dichloromethane, ethyl acetate and chloroform; the reaction is better carried out, and the raw materials can be better utilized and the waste of the raw materials is reduced by using the dosage proportion of the molar equivalent. The diluted acid is preferably subjected to acid regulation treatment by using diluted hydrochloric acid, wherein the diluted hydrochloric acid is generally 5.0-10% in mass percentage, and the diluted hydrochloric acid can be regulated by using diluted sulfuric acid, wherein the acid addition mainly comprises the step of regulating the pH value of a reaction solution system to 2.0-3.0.
Then, carrying out the next operation, specifically: adding the mixed solution of the water-soluble organic solvent and water into a clean reaction bottle, cooling to 5-15 ℃, wherein the volume ratio of the water-soluble organic solvent to the water is preferably 1.5-3.0: 1, the water-soluble organic solvent preferably adopts tetrahydrofuran and/or acetone, and then adding the corresponding amount of 7-ATCA delta3The isomer and AE active ester are fully dissolved by stirring, wherein the 7-ATCA delta3The molar ratio of isomer to AE active ester was 1: 1.1 to 2.0 parts by weight,then, controlling the temperature to be 5-15 ℃, adding organic base II into the feed liquid for condensation reaction for 2-3 hours, wherein triethylamine, diisopropylamine, piperidine, pyridine or diethylamine are preferably adopted as the organic base II, after the condensation reaction is finished, adding water-insoluble organic solvent IV into the reaction liquid, preferably selecting the water-insoluble organic solvent IV from dichloromethane or ethyl acetate and other poor solvents with poor solubility on corresponding intermediate products, stirring for 5-15 minutes, standing for liquid separation, removing an organic layer by liquid separation, collecting water layer feed liquid into a reaction bottle, and concentrating the collected water layer feed liquid under reduced pressure until the water layer feed liquid is dry to obtain the cefditoren delta compound of the formula IV3The isomer salt has a purity of 90.0% or more and a molar yield of 92.0% or more. The corresponding compound of formula IV cefditoren delta3The selection of the isomer salt corresponding to the organic base II can obtain the corresponding salt, if the organic base II adopts triethylamine, the corresponding salt is cefditoren delta3Isomer triethylamine salt; if the organic base II adopts diisopropylamine, the corresponding is cefditoren delta3Isomer diisopropylamine salt. Herein cefditoren delta3The isomer salt can directly enter the next reaction or can be taken out and put into a reaction bottle for reaction.
Here, cefditoren delta is introduced directly into the above-mentioned reaction flask with concentrate3Dissolving the isomer salt in organic solvent, preferably N, N-Dimethylformamide (DMF), cooling to-30-20 deg.C, adding iodomethyl pivalate to the reaction solution to make 7-ATCA delta3Isomers: the molar ratio of iodomethyl pivalate is 1: 1.1-2.0, controlling the temperature to be-30-20 ℃, and stirring for reaction for 3-4 hours; after the reaction is finished, adding a mixed solution of a water-insoluble organic solvent II and water into the reaction solution, preferably enabling the volume ratio of the water-insoluble organic solvent II to the water to be 1.0-2.0: 1, wherein the water-insoluble organic solvent II has better solubility for corresponding products, preferably enabling the water-insoluble organic solvent II to adopt a solvent which can dissolve the products, such as ethyl acetate or dichloromethane and the like, stirring for 5-15 minutes, and standing for liquid separation; removing water layer, collecting organic layer, putting the collected organic layer into a reaction bottle, concentrating under reduced pressure to a certain volume,generally, one third to two thirds of the volume of the feed liquid is distilled off, then, the temperature is controlled to be 15-25 ℃, a non-water-soluble organic solvent III which adopts a poor solvent such as isopropyl ether or cyclohexane and the like which is poor in solubility to the product is added, the product is favorably and fully separated out in the crystallization process, but not limited to the crystallization process, the dosage of the non-water-soluble organic solvent III is generally 1.5-3.0 times of the volume of the residual feed liquid after partial volume is distilled off, crystallization is carried out for 1-2 hours, and filtration and drying are carried out to obtain the cefditoren pivoxil delta3The isomer has a purity of 95.0% or more and a molar yield of 85.0% or more.
Example 1
Dissolving 7-ATCA 32.3g (0.1mol, 1eq) of cephalosporin mother nucleus shown as formula II in 323g of dichloromethane, adding 50.9g (0.25mol, 2.5eq) BSA (N, O-bis tri silicyl acetamide), stirring uniformly, adding 11.1g (0.11mol, 1.1eq) organic base triethylamine at 25-35 ℃, controlling the temperature to carry out isomerization reaction at 25-30 ℃, stirring for 0.5-1 hour, controlling the temperature of the reaction liquid to be 25-35 ℃ after the isomerization reaction is finished, adding 100mL of water into the reaction liquid, stirring for 5-15 minutes, standing for fully layering, separating and discarding an organic layer, collecting the aqueous layer feed liquid in a reaction bottle, controlling the temperature to be 25-35 ℃, adding a dilute hydrochloric acid solution with the mass percent into the aqueous layer, regulating the pH value to 2.0-3.0, regulating the basic stability, slowly cooling to 5-15 ℃ and stirring for 2-1 hour, after crystallization, filtering, washing a filter cake with 20mL of deionized water to obtain a wet product, putting the wet product into an oven for drying, and drying to obtain an intermediate product 7-ATCA delta329.1g of the isomer, the purity was 95.0% or more, and the molar yield was 90.0%.
Putting the mixed solution of 243g of organic solvent tetrahydrofuran and 100g of deionized water into a clean reaction bottle, cooling to 5-15 ℃, and adding the obtained 7-ATCA delta316.2g (0.05mol, 1eq) of isomer and 21.0g (0.06mol, 1.2eq) of AE active ester are fully stirred and dissolved, the temperature is controlled to be 5-15 ℃, 5.6g (0.06mol, 1.1eq) of triethylamine is added into the feed liquid, the temperature is controlled to be 5-15 ℃ after the addition is finished, condensation reaction is carried out for 2-3 hours, and the reaction is carried outAfter the reaction is finished, adding 100g of ethyl acetate solvent into the reaction solution, stirring for 5-15 minutes, standing for full liquid separation, removing an organic layer by liquid separation, collecting a water layer material liquid, and concentrating the water layer material liquid under reduced pressure until the solvent is removed, thus obtaining a concentrate cefditoren delta3Isomer triethylamine salt, purity 92.1%, molar yield 92.0%.
The concentrate obtained above was cefditoren delta3Dissolving isomer triethylamine salt in 250g of DMF solvent, cooling to-30-20 ℃, adding 14.5g (0.06mol, 1.2eq) iodomethyl pivalate into the feed liquid, continuing to control the temperature to-30-20 ℃ after the addition is finished, stirring and reacting for 3-4 hours, adding a mixed solution of 150g of ethyl acetate and 100g of water into the reaction liquid after the reaction is finished, stirring for 5-15 minutes, standing for liquid separation, removing a water layer, concentrating the collected organic layer under reduced pressure to a certain volume, generally evaporating to remove about two thirds of the volume of the reaction liquid, controlling the temperature to 15-25 ℃, adding 100mL of isopropyl ether serving as a poor solvent, stirring and crystallizing for 1-2 hours, filtering after crystallization, and drying to obtain the product of the cefditoren pivoxil delta326.4g of isomer, 95.8% purity, 85.0% molar yield.
Example 2
Dissolving 32.3g (0.1mol, 1eq) of cephalosporin mother nucleus shown as a formula II in 485g of dichloromethane in a clean reaction bottle, adding 61g (0.3mol, 3.0eq) of BSA (N, O-bis (trimethylsilyl) acetamide), stirring uniformly, adding 15.2g (0.15mol, 1.5eq) of organic base triethylamine at 25-30 ℃, controlling the temperature to carry out isomerization reaction at 25-30 ℃, stirring for 1.0 hour, controlling the temperature of the reaction liquid to be 25-30 ℃, adding 150mL of water into the reaction liquid, stirring for 15 minutes, layering fully, separating, discarding an organic layer, collecting the feed liquid of the water layer in the reaction bottle, controlling the temperature to be 25-35 ℃, adding a dilute hydrochloric acid solution with the mass percent of 10% into the collected water layer, regulating the pH value to 2.0-2.5, regulating to be basically stable, slowly cooling to 5-10 ℃, stirring for crystallization for 2.0 hour, after crystallization, filtering, washing a filter cake with 25mL of deionized water to obtain a wet product, putting the wet product into an oven for drying, and drying to obtain an intermediate product 7-ATCAδ329.9g of isomer, 98.5% purity, 92.3% molar yield.
In another reaction bottle, putting a mixed solution of 300g of organic solvent acetone and 150g of deionized water into a clean reaction bottle, cooling to 5-10 ℃, and adding the obtained 7-ATCA delta316.2g (0.05mol, 1eq) of isomer and 26.3g (0.075mol, 1.5eq) of AE active ester are fully stirred and dissolved, the temperature is controlled to be 5-10 ℃, then 7.6g (0.075mol, 1.5eq) of triethylamine is added into the feed liquid, the temperature is controlled to be 5-10 ℃ after the addition is completed, condensation reaction is carried out for 2.5 hours, after the reaction is finished, 150g of ethyl acetate solvent is added into the reaction liquid, stirring is carried out for 15 minutes, after the standing and liquid separation are fully carried out, an organic layer is separated and discarded, the feed liquid of a water layer is collected, the water layer is concentrated under reduced pressure until the solvent is removed, and the concentrated cefditoren delta is obtained3Isomer triethylamine salt, purity 94.8%, molar yield 93.2%.
The concentrate obtained above was cefditoren delta3Dissolving isomer triethylamine salt in 250g of DMF solvent, cooling to-25-20 ℃, adding 18.2g (0.075mol, 1.5eq) iodomethyl pivalate into the feed liquid, continuing to control the temperature to-25-20 ℃ after the addition is finished, stirring for reaction for 4 hours, adding a mixed solution of 150g of dichloromethane and 100g of water into the reaction liquid after the reaction is finished, stirring for 15 minutes, standing for liquid separation, removing a water layer, concentrating the collected organic layer under reduced pressure to a certain volume, generally evaporating about two thirds of the volume of the reaction liquid, controlling the temperature to 15-20 ℃, adding 100mL of poor solvent cyclohexane, stirring for crystallization for 2 hours, filtering after the crystallization is finished, and drying to obtain a product of cefditoren pivoxil delta327.1g of isomer, 98.6% purity, 87.2% molar yield.
Example 3
Dissolving 32.3g (0.1mol, 1eq) of cephalosporin mother nucleus 7-ATCA (alpha-hydroxy-N-acetyl-N) -presented by formula II in 400g of ethyl acetate in a clean reaction bottle, then adding 40.7g (0.2mol, 2.0eq) of BSA (N, O-bis (trimethylsilyl) acetamide), stirring uniformly, adding 20.2g (0.2mol, 2.0eq) of diisopropylamine at 25-30 ℃, controlling the temperature to carry out isomerization reaction at 25-30 ℃, stirring for 1.0 hour, and after the isomerization reaction is finished, reacting the reaction solutionAdding 150mL of water into the reaction liquid at the temperature of 25-30 ℃, stirring for 15 minutes, standing for layering fully, removing an organic layer from the liquid, collecting a water layer feed liquid in a reaction bottle, controlling the temperature of 25-35 ℃, adding 10 mass percent of dilute hydrochloric acid solution into the collected water layer feed liquid, adjusting the pH value to 2.5-3.0, after basic stability is achieved, slowly cooling to 5-10 ℃, fully stirring for crystallization for 2.0 hours, filtering after crystallization is finished, washing a filter cake with 25mL of deionized water to obtain a wet product, drying in an oven to obtain an intermediate product 7-ATCA delta, and drying to obtain the intermediate product 7-ATCA delta329.7g of isomer, 98.7% purity, 91.8% molar yield.
In another reaction bottle, adding a mixed solution of 240g of organic solvent tetrahydrofuran and 100g of deionized water into a clean reaction bottle, cooling to 5-10 ℃, and adding the obtained 7-ATCA delta316.2g (0.05mol, 1eq) of isomer and 35.1g (0.1mol, 2.0eq) of AE active ester, stirring and dissolving fully, controlling the temperature to be 5-10 ℃, adding 10.1g (0.1mol, 2.0eq) of diisopropylamine into the feed liquid, controlling the temperature to be 5-10 ℃ after adding, carrying out condensation reaction for 2.0 hours, adding 150g of ethyl acetate solvent into the reaction liquid after the reaction is finished, stirring for 15 minutes, standing and separating fully, separating to discard an organic layer, collecting the feed liquid of the water layer, concentrating the feed liquid of the water layer under reduced pressure until the solvent is removed, and obtaining the concentrated cefditoren delta3Isomer diisopropylamine salt, purity 95.6%, molar yield 92.6%.
The concentrate obtained above was cefditoren delta3Dissolving isomer diisopropylamine salt in 300g DMF solvent, cooling to-25-20 ℃, adding 24.2g (0.1mol, 2.0eq) iodomethyl pivalate into the feed liquid, continuing to control the temperature to-25-20 ℃ after the addition is finished, stirring for reaction for 3.5 hours, adding a mixed solution of 150g ethyl acetate and 100g water into the reaction liquid after the reaction is finished, stirring for 15 minutes, standing for liquid separation, discarding a water layer, concentrating the collected organic layer under reduced pressure to a certain volume, generally evaporating about two thirds of the volume of the reaction liquid, controlling the temperature to 15-20 ℃, adding 70mL of poor solvent cyclohexane, stirring for crystallization for 2 hours, filtering after the crystallization is finished, and drying to obtain a product of cefditoren pivoxil delta327.2g of isomer, 98.2% purity, 87.8% molar yield.
Example 4
Dissolving 7-ATCA 32.3g (0.1mol, 1eq) of cephalosporin mother nucleus shown as formula II in 350g of ethyl acetate in a clean reaction bottle, adding 57.0g (0.28mol, 2.8eq) of BSA (N, O-bis tri-silyl acetamide), stirring uniformly, adding 15.8g (0.2mol, 2.0eq) of pyridine at 28-32 ℃, controlling the temperature to carry out isomerization reaction at 28-32 ℃, stirring for 1.0 hour, controlling the temperature of the reaction liquid to be 28-32 ℃ after the isomerization reaction is finished, adding 100mL of water into the reaction liquid, stirring for 15 minutes, standing for 15 minutes, separating and removing an organic layer, collecting the liquid material of the liquid layer in the reaction bottle, controlling the temperature to be 28-32 ℃, adding a 15% by mass percent dilute hydrochloric acid solution into the collected water layer, regulating the pH value to 2.0-2.5, regulating the pH value to be basically stable, slowly cooling to be 5-8 ℃, stirring and crystallizing for 2.0-0 hour, after crystallization, filtering, washing a filter cake with 25mL of deionized water to obtain a wet product, putting the wet product into an oven for drying, and drying to obtain an intermediate product 7-ATCA delta329.8g of isomer, 98.4% purity, 92.1% molar yield.
In another reaction bottle, adding a mixed solution of 280g of organic solvent tetrahydrofuran and 120g of deionized water into a clean reaction bottle, cooling to 5-10 ℃, and adding the obtained 7-ATCA delta316.2g (0.05mol, 1eq) of isomer and 24.5g (0.07mol, 1.4eq) of AE active ester, stirring and dissolving fully, controlling the temperature to be 5-8 ℃, adding 5.9g (0.075mol, 1.5eq) of pyridine into the feed liquid, controlling the temperature to be 5-8 ℃ after adding, carrying out condensation reaction for 1.5 hours, adding 150g of cyclohexane solvent into the reaction liquid after the reaction is finished, stirring for 15 minutes, standing and separating fully, separating liquid, discarding an organic layer, collecting the feed liquid of a water layer, concentrating the water layer under reduced pressure until the solvent is removed, and obtaining a concentrate of cefditoren delta3Isomeric pyridinium salt, purity 95.3%, molar yield 92.4%.
The concentrate obtained above was cefditoren delta3Dissolving isomer pyridinium salt in 300g DMF solvent, cooling to-25-20 deg.C, adding 24.2g (0.1mol, 2.0 g) into the solutioneq) iodomethyl pivalate, controlling the temperature to-25-20 ℃ after adding, stirring for reaction for 3.5 hours, adding a mixed solution of 150g of ethyl acetate and 100g of water into the reaction solution after the reaction is finished, stirring for 15 minutes, standing for liquid separation, discarding a water layer, concentrating the collected organic layer under reduced pressure to a certain volume, generally evaporating to remove about two thirds of the volume of the reaction solution, controlling the temperature to 15-20 ℃, adding 130mL of a poor solvent isopropyl ether, stirring for crystallization for 2 hours, filtering after crystallization is finished, and drying to obtain a product of cefditoren pivoxil delta327.3g of isomer, 98.4% purity, 88.1% molar yield.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (9)
1. Cefditoren pivoxil delta3A process for the preparation of isomers, characterized in that it comprises the following steps:
A. adding a cephalosporin nucleus compound 7-ATCA, BSA and an organic base I into a water-insoluble organic solvent I for isomerization reaction, adding water into the reaction solution after the reaction is finished, standing for liquid separation, collecting a water phase, adding an acid into the collected water phase to adjust the pH value to 2.0-3.0 to obtain a compound 7-ATCA delta of a formula III3Isomers:
B. in the presence of organic base II, compound 7-ATCA delta of formula III3The isomer and AE active ester are subjected to condensation reaction to obtainTo the corresponding compound of formula IV cefditoren delta3Isomer salts:
q in the compound shown in the formula IV corresponds to a corresponding organic base II;
C. subjecting a compound of formula IV to cefditoren delta3The isomer salt and iodomethyl pivalate react in N, N-dimethylformamide solvent at-30 to-20 deg.c to obtain cefditoren pivoxil delta as the corresponding compound3Isomers:
2. cefditoren pivoxil δ according to claim 13The preparation method of the isomer is characterized in that the organic base I in the step A is one or more selected from pyridine, triethylamine, diethylamine, piperidine and diisopropylamine.
3. Cefditoren pivoxil δ according to claim 13A process for the preparation of isomers, characterized in that in step a the cephalosporin nucleus compound 7-ATCA of formula ii: BSA: the molar ratio of the organic base I is 1: 2.0-3.0: 1.1 to 2.0.
4. Cefditoren pivoxil δ according to claim 13The preparation method of the isomer is characterized in that the water-insoluble organic solvent in the step A is one or more selected from dichloromethane, ethyl acetate and trichloromethane.
5. Cefditoren pivoxil δ according to claim 13The preparation method of the isomer is characterized in that the temperature of the isomerization reaction in the step A is 25-35 ℃.
6. Cefditoren pivoxil δ according to claim 13And C, after the reaction in the step C is finished, adding a mixed solvent of a water-insoluble organic solvent II and water into the reaction solution, fully stirring at the temperature of 25-35 ℃, standing for liquid separation, collecting an organic layer, concentrating the collected organic layer, evaporating the solvent, adding a water-insoluble organic solvent III, fully stirring for crystallization, and filtering to obtain the corresponding compound cefditoren pivoxil delta of the formula I3Isomers.
7. Cefditoren pivoxil δ according to claim 63The preparation method of the isomer is characterized in that the water-insoluble organic solvent II is one or more selected from ethyl acetate and dichloromethane; the water-insoluble organic solvent III is one or more selected from isopropyl ether and cyclohexane.
8. Cefditoren pivoxil δ according to any one of claims 1 to 53The preparation method of the isomer is characterized in that the condensation reaction in the step B is carried out in a mixed solvent of an organic solvent and water, and the organic base II adopts triethylamine; the organic solvent is selected from tetrahydrofuran and/or acetone, and after the condensation reaction is finished, the method also comprises the steps of adding a water-insoluble organic solvent IV into the reaction liquid, stirring, standing, separating liquid, collecting an aqueous phase, concentrating the obtained aqueous phase to remove the solvent, and obtaining the corresponding concentrate, namely the compound cefditoren delta of the formula IV-13Isomer triethylamine salt:
9. cefditoren pivoxil δ according to any one of claims 1 to 53The preparation method of the isomer is characterized in that the organic base II in the step B is one or more selected from pyridine, triethylamine, diethylamine, piperidine and diisopropylamine.
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| US20060173175A1 (en) * | 2003-07-04 | 2006-08-03 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of cefditoren |
| 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 |
| CN110372727A (en) * | 2019-06-20 | 2019-10-25 | 重庆医药高等专科学校 | Cefoperon acid δ3Isomers and Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers |
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| US20060173175A1 (en) * | 2003-07-04 | 2006-08-03 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of cefditoren |
| 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 |
| CN110372727A (en) * | 2019-06-20 | 2019-10-25 | 重庆医药高等专科学校 | Cefoperon acid δ3Isomers and Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers |
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| 头孢妥仑匹酯有关物质的合成及其结构确证;朱希，等;《中国抗生素杂志》;20190131;第44卷(第1期);83-87 * |
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