CN109232609B - Method for preparing high-purity cefpodoxime proxetil - Google Patents
Method for preparing high-purity cefpodoxime proxetil Download PDFInfo
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- CN109232609B CN109232609B CN201811135618.3A CN201811135618A CN109232609B CN 109232609 B CN109232609 B CN 109232609B CN 201811135618 A CN201811135618 A CN 201811135618A CN 109232609 B CN109232609 B CN 109232609B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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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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Abstract
The inventionDisclosed is a method for preparing high-purity cefpodoxime proxetil, comprising: under the action of carbonate and alkaline ionic liquid, cefpodoxime acid and iodoester react in an organic solvent, and the cefpodoxime proxetil is obtained through post-treatment after the reaction is finished. The cefpodoxime proxetil product obtained by the method has less than 3 percent of total impurities and delta3Less than 1.5 percent of isomer (total impurities are less than 4 percent according to EP7.0 and less than 6 percent according to USP 35), good product stability, high yield, high molar yield of 78.3 to 83.7 percent, simple operation and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing high-purity cefpodoxime proxetil by using cefpodoxime acid as a raw material through a one-step method.
Background
Cefpodoxime Proxetil, CPDX-PR, (6R,7R) -7- [2- (2-aminothiazol-4-yl) -2- (z) - (methoxyimino) -acetamido ] -3-methoxymethyl-8-oxo-5-thio-1-azabicyclo- [4.2.0] oct-2-ene-2-carboxylic acid isopropoxycarbonyloxyethyl ester, of the formula (I), is a prodrug of Cefpodoxime ester which, when administered orally, is converted to Cefpodoxime by rapid hydrolysis by esterases present on the intestinal wall, Cefpodoxime being an antibacterial agent. Cefpodoxime exhibits a broad range of antibacterial activity against gram-positive and gram-negative bacteria, such as staphylococcus aureus, streptococcus aureus, escherichia coli, klebsiella pneumoniae, and proteus vulgaris, while also having high stability against beta-lactamase. Cefpodoxime proxetil belongs to the third generation oral cephalosporin drugs.
The literature (J.of Antibiotics, Vol40,370(1987)) reports the preparation of cefpodoxime proxetil by reacting cefpodoxime acid (of formula II) with an iodoester (of formula III) in the presence of a strong organic base such as dicyclohexylamine. The product obtained by this process, in particular the isomer Δ3Relatively high, typically above 3%. Due to structural similarity, it is difficult to separate such undesirable by-products from the product. Attempts have been made to convert the isomer Δ3Relative conversion to body Delta2Isomers, but this method requires a series of reactions and is therefore economically unfeasible.
Chinese patent (CN1305876C) discloses a method for preparing high-purity cefpodoxime proxetil by a one-step method, which takes cefpodoxime (acid) as a raw material, and after organic alkalescent salts such as sodium acetate, sodium propionate, sodium isooctanoate, potassium acetate, potassium propionate or potassium isooctanoate react, iodoester is added to prepare cefpodoxime proxetil, the product yield is 70-75%, and cis-trans isomer R/(R + S) < 0.5 of the obtained cefpodoxime proxetil product is found to be not in accordance with pharmacopoeia regulations when Chinese patent (CN1305876C) is repeated. (the pharmacopoeia stipulates that the ratio of the peak area of the cefpodoxime proxetil B isomer to the peak area of the cefpodoxime proxetil A, B isomer in a chromatogram of a test solution recorded under the content measurement item is 0.50-0.60).
Patent application publication No. WO01/34611 discloses the preparation of cefpodoxime proxetil from cefpodoxime salt using a crown ether as catalyst. First, the use of crown ethers is required for the preparation of cefpodoxime proxetil, which is not only costly, but also the toxicity of the crown ethers is disadvantageous for the final product, and, without the crown ethers, the isomers formed will reach the range of 6-8% by weight, and thus there are still disadvantages in the preparation.
U.S. Pat. No. 5,498,787 discloses a process for the preparation of cefpodoxime proxetil from cefpodoxime proxetil using a quaternary ammonium salt phase transfer catalyst, such as tetrabutylammonium hydrogen sulfate, in an amount of 35 to 120 mole percent based on cefpodoxime. The method can effectively inhibit isomer delta3But has a problem of low yield of the desired product, ranging from 50% to 60%, and the use of expensive quaternary ammonium salt is required.
Further, according to the method disclosed in Korean laid-open No.99-54751, cefpodoxime proxetil is prepared by reacting a cephem compound of cefpodoxime with an alkyl carbonate to obtain an ester, and then acylating the obtained ester with an active ester form of aminothiazolylacetic acid in the presence of a large amount of quaternary ammonium salt. This method also requires the use of expensive quaternary ammonium salts and results in low yield due to the long reaction process requiring about 3 days.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects and provide a simple and convenient method for preparing high-purity cefpodoxime proxetil, and the product stability is good.
A process for preparing high purity cefpodoxime proxetil comprising:
under the action of carbonate and alkaline ionic liquid, reacting cefpodoxime acid with iodoester in an organic solvent, and performing post-treatment after the reaction to obtain cefpodoxime proxetil;
the cation of the carbonate is selected from alkali metal ions or alkaline earth metal ions;
the alkaline ionic liquid is 1-butyl-3-methylimidazolium hydroxide ([ bmlm ] OH).
The synthetic route is as follows:
the cefpodoxime proxetil prepared by the method has high purity and is subjected to HPLC (high performance liquid chromatography) of European pharmacopoeia EP7.0Method of detecting a therein3Less than 1.5% isomer, less than 3% total impurities, and less than 4% total impurities as specified in European pharmacopoeia EP7.0, and less than 6% total impurities as specified in United states pharmacopoeia USP35, indicating that the product produced by the process of the present invention is superior to both European and United states standards.
In the invention, the weight ratio of the alkaline ionic liquid to the carbonate is 0.001-1.0: 1, preferably 0.2: 1.
in the invention, the dosage of the used alkaline ionic liquid is 0.001-0.2 times of the weight of cefpodoxime acid. The reaction temperature is-20 to-5 ℃, and the preferable temperature range is-20 to-10 ℃. The reaction time is from 0.5 to 2.5 hours, preferably from 0.5 to 1.5 hours.
In the present invention, the organic solvent used is selected from acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethyl sulfoxide, N-dimethylacetamide and a mixture thereof; n, N-dimethylacetamide is preferred.
Preferably, the carbonate is potassium carbonate or sodium carbonate.
In the present invention, the amount of iodo-ester employed is 1 to 3 molar equivalents, preferably 1 to 1.2 equivalents, based on the amount of cefpodoxime acid. When the amount of iodo ester is increased, an increase in impurities or an increase in cost may be caused.
Preferably, the post-treatment comprises: decolorizing the reaction solution with active carbon, filtering, adding the filtrate into a mixed solution of alcohol and water for crystallization, and obtaining the high-purity cefpodoxime proxetil after the crystallization is finished. More preferably, in the mixed solution, the weight ratio of the alcohol to the water is 0.01-0.1: 1;
the alcohol is methanol or ethanol.
Compared with the prior art, the invention has the beneficial effects that:
the cefpodoxime proxetil product obtained by the method has less than 3 percent of total impurities and delta3Less than 1.5 percent of isomer (total impurities are less than 4 percent according to EP7.0 and less than 6 percent according to USP 35), good product stability, high yield, high molar yield of 78.3 to 83.7 percent, simple operation and suitability for industrial production.
Detailed Description
The present invention is further illustrated below in conjunction with specific examples, which are set forth for purposes of illustration only and are not intended to limit the scope of the present invention.
Example 1
In a 250ml reaction flask, 10g (0.0234moL) of cefpodoxime acid B was put into 50ml of DMAc (N, N-dimethylacetamide) under the protection of nitrogen, stirred and cooled to-20 ℃ to dissolve, and [ bmlm ] OH0.05g and 3.5g of potassium carbonate were added and stirred for 20 minutes. 6.5g (0.0253mol) of alpha-iodoethyloxycarbonate is dropwise added, the temperature is controlled between 18 ℃ below zero and 19 ℃ below zero, after 30 minutes of reaction, HPLC controls the content of cefpodoxime acid B which is a raw material to be less than or equal to 0.5 percent, after the esterification reaction is finished, 1g of medicinal activated carbon is added for decolorization, after the decolorization is finished, the esterification reactant is slowly pressed into 400mL of 1 percent methanol/purified water solution which is pre-cooled to 5 ℃, after the filter pressing is finished, the stirring is continued for 30 minutes, the filter is thrown, 50mL of purified water is used for washing the product, and the vacuum drying is carried out, so that 10.5g of white powder solid is.
Product (R + S) HPLC 99.2%, R/(R + S) 0.51, Δ3＝0.35％。
Example 2
In a 250ml reaction flask, 10g (0.0234moL) of cefpodoxime acid B was put into 50ml of DMAc under the protection of nitrogen, stirred and cooled to-20 ℃ to dissolve, and then [ bmlm ] OH0.1g and sodium carbonate 3.1g were added and stirred for 20 minutes. Dripping 6.5g0.0253mol of alpha-iodoethyl oxygen isopropyl carbonate), controlling the temperature between 18 ℃ below zero and 19 ℃ below zero, reacting for 30 minutes,
controlling the raw material cefpodoxime acid B by HPLC (high performance liquid chromatography) to be less than or equal to 0.5 percent, finishing the esterification reaction, adding 1g of medicinal activated carbon for decolorization, slowly pressing the esterification reactant into 400mL of 1 percent methanol/purified water solution which is pre-cooled to 5 ℃, continuing stirring for 30 minutes after the pressure filtration is finished, performing filter-throwing, washing the product with 50mL of purified water, and performing vacuum drying to obtain 10.2g of white powder solid (the molar yield is 78.3 percent).
The product (R + S) HPLC ═ 99.1%, R/(R + S) ═ 0.53, and Δ 3 ═ 0.36%.
Example 3
20g (0.0468moL) of cefpodoxime acid B was put into 100ml of DMF in a 250ml four-neck flask under nitrogen protection, and then dissolved by cooling to-15-18 ℃ under stirring, and [ bmlm ] OH0.2g and potassium carbonate 6.3g were added and stirred for 20 minutes. 13g (0.0505mol) of alpha-iodoethyloxycarbonate isopropyl ester is dripped, after the heat preservation reaction is carried out for 30 minutes, HPLC is used for controlling the cefpodoxime acid B raw material to be less than or equal to 0.5 percent, after the esterification reaction is finished, 2g of medicinal activated carbon is added for decolorization, the esterification reactant is slowly pressed into 800ml of 2 percent ethanol/purified water solution which is pre-cooled to 5 ℃, the solid is separated out after the filter pressing is finished, and the stirring is continued for 30 minutes. The mixture was filtered by shaking, washed with 50mL of purified water, and dried in vacuo to obtain 18.9g of a white powdery solid (yield: 94.5%).
Product (R + S) HPLC 99.2%, R/(R + S) 0.51, Δ3＝0.37％。
Example 4
In a 250ml reaction bottle, 10g (0.0234moL) of cefpodoxime acid B is put into 50ml of DMAc under the protection of nitrogen, stirred and cooled to minus 19 ℃ to minus 20 ℃ to be dissolved, and 1.5g of [ bmlm ] OH and 3.0g of sodium carbonate are added and stirred for 20 minutes. Dropping 6.5g (0.0253mol) of alpha-iodoethyl oxycarbonate, controlling the temperature to be between-17 ℃ and-19 ℃, reacting for 30 minutes, controlling the cefpodoxime acid B raw material to be less than or equal to 0.5% by HPLC, finishing the esterification reaction, adding 1g of medicinal activated carbon for decolorization, slowly pressing the esterification reactant into 400ml of 1% ethanol/purified water solution which is pre-cooled to 5 ℃, continuing stirring for 30 minutes after the filter pressing is finished, throwing and filtering, washing a product by 50mg of purified water, and drying in vacuum to obtain 10.9g of white powder solid (the molar yield is 83.7%).
Product (R + S) HPLC 99.1%, R/(R + S) 0.53, Δ3＝0.36％。
Example 5
20g (0.0468moL) of cefpodoxime acid B was put into 100ml of DMF in a 250ml four-neck flask under nitrogen protection, stirred and cooled to-18 ℃ to-15 ℃ to dissolve, and then 1.1g of [ bmlm ] OH and 5.5g of potassium carbonate were added and stirred for 20 minutes. 13.3g (0.0517mol) of alpha-iodoethyloxycarbonate is dripped, after the heat preservation reaction is carried out for 30 minutes, HPLC is used for controlling the content of cefpodoxime proxetil B which is a raw material to be less than or equal to 0.5 percent, 2g of medicinal activated carbon is added for decolorization after the esterification reaction is finished, the esterification reactant is slowly pressed into 800ml of 2 percent ethanol/purified water solution which is pre-cooled to 5 ℃, solid is separated out after the pressure filtration is finished, and the stirring is continued for 30 minutes. Filtration by shaking, 50mL of purified water was washed, and vacuum dried to obtain 21.4g of a white powdery solid (molar yield 82.2%).
Product (R + S) HPLC 99.2%, R/(R + S) 0.52, Δ3＝0.38％。
Example 6
In a 250ml reaction flask, under the protection of nitrogen, 10g (0.0234moL) of cefpodoxime acid B was put into 50ml of DMAc, stirred and cooled to-20 ℃ to dissolve, and 0.9g of [ bmlm ] OH and 2.5g of sodium carbonate were added and stirred for 20 minutes. Dropwise adding 6.5g (0.0253mol) of alpha-iodoethyloxycarbonate, controlling the temperature to be between 18 ℃ below zero and 17 ℃ below zero, reacting for 30 minutes, controlling the cefpodoxime acid B serving as a raw material to be less than or equal to 0.5% by HPLC, finishing the esterification reaction, adding 1g of medicinal activated carbon for decolorization, slowly pressing the esterified reactant into 400mL of 1% ethanol/purified water solution which is pre-cooled to 5 ℃, continuing stirring for 30 minutes after the filter pressing is finished, performing filter throwing, washing 50mL of purified water to obtain a product, and drying in vacuum to obtain 10.4g (the molar yield is 80.0%) of white powder solid.
Product (R + S) HPLC 99.2%, R/(R + S) 0.54, Δ3＝0.38％。
COMPARATIVE EXAMPLE 7 (REFERENCE TO CN1305876C CULTURE)
In a 250ml reaction flask, 20g (0.0468moL) of cefpodoxime acid B was put into 120ml of DMAc, and dissolved by stirring, and 4.6g of anhydrous sodium acetate and 1g of water were added and stirred at room temperature for 30 minutes. Cooled to 5 ℃, added with 15g (0.0584mol) of alpha-iodoethyloxycarbonate and reacted for 1.5 hours at 5 ℃ to 10 ℃. After the esterification reaction, the mixture is poured into a mixture of 200ml of ethyl acetate and 1005% NaHCO3, stirring is carried out, an organic phase is separated, an aqueous phase is extracted by 100ml of ethyl acetate, the organic phases are combined and washed twice by saturated saline solution, 10g of anhydrous magnesium sulfate and 10g of activated carbon are added into the organic phase for decolorization for 30min, filtration and reduced pressure concentration are carried out until the organic phase reaches 80g, 500ml of isopropyl ether is rapidly added, stirring is carried out vigorously and then filtration is carried out, and vacuum drying is carried out, so that 18.8g of white off-white powder is obtained (the weight yield is 94.0%, the molar yield is 72.2%). The results were determined using the european pharmacopoeia EP7.0HPLC: the HPLC (R + S) of the product is 96.23 percent, R/(R + S) is 0.497 and is less than 0.5 (not meeting the pharmacopeia requirement of 0.5-0.6), and delta 3 is 0.54 percent.
The products of examples 1, 3 and 7 were subjected to stability tests, the results of which are shown in table 1:
TABLE 1 stability test results for the products of the different examples
Claims (4)
1. A process for preparing high purity cefpodoxime proxetil comprising:
under the action of carbonate and alkaline ionic liquid, reacting cefpodoxime acid with iodoester in an organic solvent, and performing post-treatment after the reaction to obtain cefpodoxime proxetil;
the cation of the carbonate is selected from alkali metal ions or alkaline earth metal ions;
the alkaline ionic liquid is 1-butyl-3-methylimidazolium hydroxide;
the post-treatment comprises the following steps: decolorizing the reaction solution with active carbon, filtering, adding the filtrate into a mixed solution of alcohol and water for crystallization, and obtaining the high-purity cefpodoxime proxetil after the crystallization is finished;
in the mixed solution, the weight ratio of alcohol to water is 0.01-0.1: 1;
the alcohol is methanol or ethanol;
the carbonate is potassium carbonate or sodium carbonate;
the weight ratio of the alkaline ionic liquid to the cefpodoxime acid is 0.01-0.2: 1;
the reaction temperature is-20 ℃ to-5 ℃.
2. The method according to claim 1, wherein the weight ratio of the basic ionic liquid to the carbonate is 0.001-1.0: 1.
3. the process according to claim 1, wherein the reaction temperature is from-20 ℃ to-10 ℃.
4. The process of claim 1 wherein the organic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, and mixtures thereof.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5498787A (en) * | 1994-04-20 | 1996-03-12 | Standard Chemical & Pharmaceutical Co., Ltd. | Method for preparing cephalosporin derivatives |
| CN1160361C (en) * | 1999-11-08 | 2004-08-04 | 韩美药品工业株式会社 | Method for prepairng highly purity cefpodoxime proxetil |
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| AT413383B (en) * | 1998-01-09 | 2006-02-15 | Sandoz Ag | METHOD OF ISOLATING A DIASTEREOISOMER MIXTURE OF CEFPODOXIM PROXETIL |
| US20080255200A1 (en) * | 2007-04-11 | 2008-10-16 | Auspex Pharmaceuticals, Inc. | Substituted benzimidazoles |
| WO2010097675A1 (en) * | 2009-02-27 | 2010-09-02 | Dhanuka Laboratories Ltd. | An improved preparation process for cefpodoxime proxetil |
| CN101843599A (en) * | 2009-03-23 | 2010-09-29 | 杭州锐思医药科技有限公司 | Oral cephalosporin ester capsule |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5498787A (en) * | 1994-04-20 | 1996-03-12 | Standard Chemical & Pharmaceutical Co., Ltd. | Method for preparing cephalosporin derivatives |
| CN1160361C (en) * | 1999-11-08 | 2004-08-04 | 韩美药品工业株式会社 | Method for prepairng highly purity cefpodoxime proxetil |
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