Synthesis method of cefditoren pivoxil ring-opening impurity

Abstract

The invention discloses a preparation method of a cefditoren pivoxil ring-opening impurity, which comprises the following steps: adding cefditoren pivoxil into organic alcohol and water, carrying out ring-opening reaction under an alkaline condition, after the reaction is finished, regulating the pH value to 7.5-8.5 by using NaHCO3, washing by using an organic solvent, regulating the pH value to 2.5-3.5 by using hydrochloric acid, filtering and drying to obtain the cefditoren pivoxil ring-opening impurity. The method has the advantages of simple operation, mild conditions and high purity, and can be used as an impurity reference substance for quality control of cefditoren pivoxil bulk drugs and preparations.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a method for preparing a ring-opening impurity of cefditoren pivoxil. Background Art

[0002] Cefditoren pivoxil, with a structural formula shown in Formula I, is a third-generation cephem antibiotic developed by Meiji Seika Co., Ltd. of Japan. It is an oral preparation with two dosage forms, tablets and granules. It was first launched in Japan in 1994 and in China in April 2001 under the trade name Meiact.

[0003] I This product has a wide antibacterial spectrum against Gram-positive and Gram-negative bacteria, especially against Gram-positive bacteria such as Staphylococcus, Streptococcus including Streptococcus pneumoniae, Gram-negative bacteria such as Escherichia coli, Branhamella catarrhalis, Klebsiella, Proteus, Haemophilus influenzae, and anaerobic bacteria such as Peptostreptococcus, Propionibacterium acnes, and Bacteroides. It is clinically used to treat various infections such as respiratory tract, skin infections, urinary tract infections, etc. The mechanism of action of Cefditoren is to inhibit bacterial cell wall synthesis, and it has a high affinity with various bacterial penicillin-binding proteins (PBPs) to exert a bactericidal effect.

[0004] The ring-opening impurity of cefditoren pivoxil, whose structural formula is shown in Formula II, is the main synthetic process impurity and degradation impurity of cefditoren pivoxil.

[0005] II The document (CN110143957B) discloses a method for preparing a ring-opening impurity of cefditoren pivoxil. Cefditoren pivoxil is reacted in an organic solvent at 10°C to 20°C under base catalysis. After the reaction is completed, water and ethyl acetate are added to the reaction system, and the pH is adjusted to 3 to 4. The ethyl acetate layer is taken and concentrated, separated and purified by column chromatography, and concentrated twice to obtain the product. The purity of the ring-opening impurity of cefditoren pivoxil is about 95%. The operation is cumbersome, the purity is poor, the yield is low, and the cost is high.

[0006] Any substance that affects the purity of a drug is collectively referred to as an impurity. The study of impurities is an important part of drug development. It includes selecting appropriate analytical methods, accurately distinguishing and measuring the content of impurities, and determining the reasonable limit of impurities based on the results of pharmaceutical, toxicological and clinical studies. This study runs through the entire process of drug development. Impurities not only affect the purity and content of the product, but also have potential toxic and side effects, which has positive practical significance for the quality control and application of drugs.

[0007] The "Technical Guidelines for the Study of Impurities in Chemical Drugs" clearly explains the classification, analysis methods, and limit formulation of impurities. It stipulates that for drugs that have been copied and have national standards, a comprehensive quality comparison study should be conducted with the same type of drugs that have been marketed (it is recommended that the products of the original research and development company within the validity period be preferred), and the types and contents of their impurities should be analyzed. Based on the results of the study and the results of the stability study, it is decided whether the impurities need to be controlled in the quality standards. The identification limit of impurities is specified in the appendix, that is, for drugs with a maximum daily dose of ≤2g, impurities greater than 0.10% need to be identified.

[0008] When identifying impurities, commonly used identification methods include nuclear magnetic resonance and infrared. Both nuclear magnetic resonance and infrared detection require samples to have a purity of at least 95% to meet the test requirements. For nuclear magnetic resonance, a purity of more than 98% is even required to confirm the structure with a higher degree.

[0009] In order to accurately and effectively control quality, easy-to-obtain and high-purity impurity reference substances have become one of the indispensable elements in quality research. Summary of the invention

[0010] One of the purposes of the present invention is to provide a method for preparing a ring-opening impurity of cefditoren pivoxil with high purity and simple operation. The method is simple and easy to operate, has high purity, and is more suitable for the preparation of a reference substance for the ring-opening impurity of cefditoren pivoxil.

[0011] The inventors unexpectedly discovered that adding a small amount of water to the reaction solution can promote the hydrolysis reaction, reduce the formation of impurities under the catalysis of organic bases such as potassium tert-butoxide, and obtain a high-purity target product without column chromatography, thereby avoiding cumbersome operating steps.

[0012] To achieve the above object, the present invention adopts the following technical scheme to prepare the ring-opening impurity (II) of cefditoren pivoxil, comprising the following steps: Cefditoren pivoxil is added to organic alcohol and water to undergo a ring-opening reaction under alkaline conditions; After the reaction was completed, NaHCO was added to the reaction solution. 3 Adjust pH to 7.5-8.5; The aqueous phase is washed with an organic solvent and then adjusted to a pH of 2.5 to 3.5 with hydrochloric acid; The obtained solid is filtered and dried to obtain the ring-opening impurity of cefditoren pivoxil.

[0013] In step (1), the organic alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, and tert-pentanol, preferably tert-butanol.

[0014] In step (1), the alkaline condition is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, preferably potassium tert-butoxide.

[0015] In step (1), the amount of the base used is 0.5 to 3.0 equivalents based on cefditoren pivoxil.

[0016] In step (1), the amount of water used is 1.0 to 5.0 equivalents based on cefditoren pivoxil.

[0017] In step (1), the reaction temperature is 25°C to 60°C.

[0018] In step (3), the organic solvent is one or more of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, dichloromethane, chloroform, tetrachloromethane, 1,2-dichloroethane, preferably n-butyl acetate.

[0019] The beneficial effects of the present invention are: The invention provides a method for preparing a ring-opening impurity of cefditoren pivoxil. The method has simple operation and mild conditions.

[0020] The ring-opening impurities of cefditoren pivoxil prepared by the method provided by the invention have high purity and can meet the quality requirements of an impurity reference substance without the need for column chromatography purification. The impurities can be used for the quality control of cefditoren pivoxil raw materials and preparations, thereby improving the safety of the clinical use of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the MS detection spectrum of the ring-opening impurity of cefditoren pivoxil in Example 1.

[0022] Figure 2 This is a HPLC purity check chart of the ring-opening impurity of cefditoren pivoxil in Example 1.

[0023] Figure 3 This is a HPLC purity check chart of the ring-opening impurity of cefditoren pivoxil in Example 4. Implementation

[0024] The preferred embodiments of the present invention are described in detail below. The embodiments are provided to better illustrate the contents of the present invention. However, the contents of the present invention are not limited to the embodiments. Therefore, those skilled in the art may make non-essential improvements or adjustments to the implementation scheme according to the above-mentioned contents of the invention, which still fall within the protection scope of the present invention.

[0025] Examples 1 to 3 are further descriptions of the technical solution of the present invention, and Example 4 is a comparative example. Example 1

[0026] 6.1 g of cefditoren pivoxil was added to 20 ml of tert-butyl alcohol, 1.1 g of potassium tert-butylate, and 0.3 ml of water, and stirred at 50 °C for 10 hours. After the reaction, 100 ml of purified water and NaHCO were added to the reaction system. 3 Adjust the pH to 8.0, add 100 ml of n-butyl acetate, separate the liquid at rest, collect the aqueous phase, control the temperature at 5-10°C, adjust the pH to about 3.0 with 2N hydrochloric acid, filter, and dry to obtain 5.2 g of the target product with a yield of 90% and a purity of 99.1%. Example 2

[0027] 6.1 g of cefditoren pivoxil was added to 20 ml of tert-butyl alcohol, 1.1 g of sodium tert-butylate, and 0.3 ml of water, and stirred at 50 °C for 10 hours. After the reaction, 100 ml of purified water and NaHCO were added to the reaction system. 3 The pH was adjusted to 8.0, 100 ml of n-butyl acetate was added, the liquid was separated by standing, the aqueous phase was collected, the temperature was controlled at 5-10°C, the pH was adjusted to about 3.0 with 2N hydrochloric acid, filtered, and dried to obtain 4.1 g of the target product with a yield of 65% and a purity of 98.6%. Example 3

[0028] 6.1 g of cefditoren pivoxil was added to 20 ml of isopropanol, 1.1 g of potassium tert-butoxide, and 0.3 ml of water, and the mixture was stirred at 50 °C for 10 hours. After the reaction, 100 ml of purified water and NaHCO were added to the reaction system. 3 The pH was adjusted to 8.0, 100 ml of n-butyl acetate was added, the liquid was separated by standing, the aqueous phase was collected, the temperature was controlled at 5-10°C, the pH was adjusted to about 3.0 with 2N hydrochloric acid, filtered, and dried to obtain 2.9 g of the target product with a yield of 46% and a purity of 98.1%. Example 4

[0029] 6.2 g of cefditoren pivoxil and 50 ml of N, N-dimethylformamide were added to the reaction flask, the temperature was lowered to -15 ° C while stirring, 0.012 mol of potassium hydroxide was slowly added, the temperature was raised to 10 ° C-20 ° C for reaction, and after HPLC inspection, 50 ml of water and 50 ml of ethyl acetate were added, and the pH value was adjusted to 3-4 with 10% hydrochloric acid while stirring, and the layers were allowed to stand for stratification. The aqueous layer was extracted with 20 ml of ethyl acetate, the ethyl acetate layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The purity of the product was 52.70% by HPLC.

[0030] Purity test method for open-ring impurities of cefditoren pivoxil Chromatographic conditions: Chromatographic column: Octadecylsilane bonded silica as filler (YMC-Pack ODS-AM, 4.6mm×150mm, 5μm or chromatographic column with equivalent performance) Detection wavelength: 254nm Flow rate: 1.0 ml / min (adjust the flow rate appropriately so that the main peak retention time is about 26 minutes) Column temperature: 25°C Injection volume: 20µl Mobile phase A: 0.02 mol / L sodium dihydrogen phosphate solution (adjust pH to 3.0 with phosphoric acid) Mobile phase B: acetonitrile-methanol (1:1) Elution procedure: Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 75 25 5 70 30 15 50 50 35 50 50 50 15 85 55 15 85 60 75 25 70 75 25 Diluent: mobile phase A-mobile phase B (1:1) Sample solution: Take about 10 mg of the product, place it in a 10 ml volumetric flask, add mobile phase B to dissolve and dilute to the scale to prepare a 1 mg / ml test solution.

[0031] Determination method: Take the sample solution, inject it into the liquid chromatograph, and record the chromatogram.

Claims

1. A method for synthesizing a ring-opening impurity of cefditoren pivoxil, wherein the impurity has a structural formula as shown in Formula II: II It is characterized in that The following steps are involved: (1) adding cefditoren pivoxil to organic alcohol, water, and alkaline conditions to cause a ring-opening reaction; (2) After the reaction is completed, add NaHCO3 to the reaction solution to adjust the pH to 7.5-8.5; (3) The aqueous phase is washed with an organic solvent and then the pH is adjusted to 2.5-3.5 with hydrochloric acid; (4) The obtained solid is filtered and dried to obtain the ring-opening impurity of cefditoren pivoxil.

2. The preparation method according to claim 1, It is characterized in that In step (1), the organic alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, and tert-pentanol.

3. The preparation method according to claim 1, It is characterized in that In step (1), the organic alcohol is tert-butyl alcohol.

4. The preparation method according to claim 1, It is characterized in that In step (1), the alkaline condition is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

5. The preparation method according to claim 1, It is characterized in that In step (1), the alkaline condition is potassium tert-butoxide.

6. The preparation method according to claim 1, It is characterized in that In step (1), the amount of the base used is 0.5 to 3.0 equivalents based on cefditoren pivoxil.

7. The preparation method according to claim 1, It is characterized in that In step (1), the amount of water used is 1.0 to 5.0 equivalents based on cefditoren pivoxil.

8. The preparation method according to claim 1, It is characterized in that In step (1), the reaction temperature is 25°C to 60°C.

9. The preparation method according to claim 1, It is characterized in that In step (3), the organic solvent is one or more of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, dichloromethane, chloroform, tetrachloromethane, and 1,2-dichloroethane.

10. The preparation method according to claim 1, It is characterized in that In step (3), the organic solvent is n-butyl acetate.

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