Preparation method of polymer impurity of 7-aminocephalosporanic acid

Abstract

The invention relates to a preparation method of a polymer impurity of 7-aminocephalosporanic acid, and belongs to the technical field of chemical pharmacy, the preparation method comprises the following steps: condensing 7-aminocephalosporanic acid with acetonitrile, tetrahydrofuran, a hydrochloric acid solution and EDCI to generate a 7-aminocephalosporanic acid dimer; and adding a methanol aqueous solution and a sodium hydroxide solution for hydrolysis and crystallization, and pulping with an acetonitrile aqueous solution to obtain a polymer impurity I compound finished product of 7-aminocephalosporanic acid. According to the invention, 7-aminocephalosporanic acid is adopted as a raw material and is subjected to self condensation and hydrolysis to directionally generate a polymer impurity I compound finished product of 7-aminocephalosporanic acid; compared with the preparation method on the market, the preparation method provided by the invention has the advantages that the reaction condition is mild, and ultralow-temperature reaction is not involved; meanwhile, tedious process steps are simplified, the required finished product can be synthesized through simple steps, and the method is suitable for pilot scale-up in a laboratory. The finished product prepared by the method is high in yield and high in purity.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a method for preparing a polymer impurity of 7-aminocephalosporanic acid. Background Art

[0002] 7-aminocephalosporanic acid (7-ACA) is a key intermediate of cephalosporin drugs and a common parent nucleus of cephalosporins. It has three active groups, 2-carboxyl, 3-acetoxy and 7-amino. The carboxyl and amino groups are easy to condense, and the 3-acetoxy is also easy to degrade, so various polymer impurities will be produced. However, the sources of cephalosporin drug polymers are different. There are side reactions introduced during the synthesis process, starting materials and intermediates, degradation, etc., which cause the quality of the drug to decline. At the same time, such impurities can cause reactions such as antibiotic allergies, which can even endanger life in severe cases. Therefore, it is particularly important to study the quality control of polymers from the source 7-aminocephalosporanic acid, provide a control for the quality research of drug impurities, control the safety limit of impurities, and improve the quality and safety of drugs. Since the polymer content in 7-aminocephalosporanic acid is low and it is difficult to separate directly, it is prepared by synthesis.

[0003] However, at present, the methods for preparing 7-aminocephalosporanic acid polymer impurities that are currently available on the market have many drawbacks. Most traditional processes have strict requirements on reaction conditions and often involve ultra-low temperature reaction environments. Ultra-low temperature conditions not only mean high equipment cost investment, but also expensive refrigerants such as liquid nitrogen and dry ice used to maintain the low temperature state. It also greatly increases the complexity and difficulty of the operation. If you are not careful, the reaction will fail due to temperature fluctuations. Furthermore, the traditional preparation process is cumbersome and involves multiple complex steps. The links are closely connected and the fault tolerance rate is low. The complex process is even more of an obstacle for laboratory tests and subsequent pilot scale-up, and it is difficult to achieve rapid and efficient results transformation. Therefore, in order to solve the above problems, a method for preparing a polymer impurity I compound of 7-aminocephalosporanic acid with mild reaction conditions, no ultra-low temperature reaction, and few process steps is provided to lay a solid technical foundation for the quality research of 7-aminocephalosporanic acid, which has extremely important practical significance. Summary of the invention

[0004] The purpose of the present invention is to provide a method for preparing polymer impurities of 7-aminocephalosporanic acid which has mild reaction conditions, does not involve ultra-low temperature reaction, has fewer process steps, and is suitable for laboratory pilot scale-up, thereby solving the problems of ultra-low temperature reaction and complicated process steps in the existing preparation method technology.

[0005] The purpose of the present invention can be achieved by the following technical solutions: A preparation method of a polymer impurity I compound of 7-aminocephalosporanic acid comprises the following steps: condensing 7-aminocephalosporanic acid with acetonitrile, tetrahydrofuran, hydrochloric acid solution and EDCI to generate a 7-aminocephalosporanic acid dimer, then adding a methanol aqueous solution and a sodium hydroxide solution to hydrolyze and crystallize, and beating with an acetonitrile aqueous solution to obtain a finished product of the polymer impurity I compound of 7-aminocephalosporanic acid.

[0006] Furthermore, the structural formula of the 7-aminocephalosporanic acid is as shown in Formula 1: Formula 1; The structural formula of the 7-aminocephalosporanic acid dimer is shown in Formula 2: Formula 2; The structural formula of the polymer impurity I compound of 7-aminocephalosporanic acid is shown in Formula 3: Formula 3.

[0007] As a preferred technical solution of the present invention, the polymer impurity I compound of 7-aminocephalosporanic acid has the molecular formula: 6 H 18 N 4 O 7 S 2 , exact mass: 442.06169, molecular weight: 442.46100.

[0008] As a preferred technical solution of the present invention, the preparation method of the polymer impurity I compound of 7-aminocephalosporanic acid specifically comprises the following steps: S1, adding acetonitrile, tetrahydrofuran and hydrochloric acid solution to 7-aminocephalosporanic acid, stirring once, adding EDCI, stirring twice, adjusting pH, and performing rotary evaporation under temperature control to obtain a rotary evaporation liquid; S2. Refrigerate the rotary evaporation liquid to precipitate solids, filter to obtain 7-aminocephalosporanic acid dimer, add methanol aqueous solution to 7-aminocephalosporanic acid dimer, dissolve, cool, add sodium hydroxide solution to control temperature and stir, adjust pH, refrigerate to crystallize, filter, take crystals, control temperature and pulp with acetonitrile aqueous solution, filter, take the filter residue and dry to obtain the finished product of polymer impurity I compound of 7-aminocephalosporanic acid.

[0009] As a preferred technical solution of the present invention, the usage ratio of 7-aminocephalosporanic acid, acetonitrile, tetrahydrofuran, hydrochloric acid solution and EDCI in step S1 is 10g:100-200mL:50-100mL:20-30mL:18g.

[0010] Furthermore, the concentration of the hydrochloric acid solution includes 1-3 mol / L; the EDCI is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, CAS: 25952-53-8.

[0011] As a preferred technical solution of the present invention, the temperature of the first stirring in step S1 is room temperature, and the time is 10-15 minutes; the temperature of the second stirring is room temperature, and the time is 1-2 hours; the pH is adjusted by adding sodium hydroxide at room temperature to adjust the solution pH to 6; the temperature-controlled rotary evaporation is to control the temperature at 35-40°C and rotary evaporation until the volume of the remaining solution is 1 / 3 of the volume of the original solution.

[0012] As a preferred technical solution of the present invention, the usage ratio of the 7-aminocephalosporanic acid dimer, methanol aqueous solution, sodium hydroxide solution and acetonitrile aqueous solution in step S2 is 5g:200-400mL:20-30mL:20-50mL.

[0013] Furthermore, the mass concentration of the methanol aqueous solution is 50%; the concentration of the sodium hydroxide solution is 1-3 mol / L.

[0014] As a preferred technical solution of the present invention, the cooling in step S2 is cooling to 0°C; the temperature of the temperature-controlled stirring is 0°C, and the time is 0.5-2h; the pH is adjusted by adding acetic acid aqueous solution to adjust the pH to 7; the temperature of the temperature-controlled slurrying with acetonitrile aqueous solution is 0°C, and the time is 0.5-1h.

[0015] Furthermore, the mass concentration of the acetic acid aqueous solution is 20%; the mass concentration of the acetonitrile aqueous solution is 30-50%.

[0016] As a preferred technical solution of the present invention, the present invention also provides a method for preparing a polymer impurity of 7-aminocephalosporanic acid and a finished product of a polymer impurity I compound of 7-aminocephalosporanic acid.

[0017] Beneficial effects of the present invention: (1) The present invention innovatively uses 7-aminocephalosporanic acid as a raw material, and then condenses and hydrolyzes the raw material to form a polymer impurity I of 7-aminocephalosporanic acid. Compared with the traditional preparation methods currently available on the market, the preparation method provided by the present invention has mild reaction conditions and does not involve ultra-low temperature reaction. At the same time, it also simplifies the cumbersome process steps, and the desired finished product can be synthesized through simple steps, which is suitable for laboratory pilot scale-up.

[0018] (2) The polymer impurity I of 7-aminocephalosporanic acid obtained by the preparation method provided by the present invention has a high yield and a purity of 95%, which can meet the quality research requirements of 7-aminocephalosporanic acid and provide a technical basis for improving the national quality standard of 7-aminocephalosporanic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for describing the embodiments are briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0020] Figure 1 This is the HPLC detection spectrum of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in Example 1 of the present invention; Figure 2 The 1HNMR hydrogen spectrum of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in Example 1 of the present invention; Figure 3 The carbon spectrum detected by NMR of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in Example 1 of the present invention; Figure 4 This is the HRMS detection mass spectrum of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0021] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0022] The EDCI used in the embodiment of the present invention is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, CAS: 25952-53-8; it will not be described in detail later.

[0023] Example 1 A method for preparing a polymer impurity I compound of 7-aminocephalosporanic acid, comprising the following steps: S1, to 10g of 7-aminocephalosporanic acid, add 100mL of acetonitrile, 50mL of tetrahydrofuran and 20mL of 3mol / L hydrochloric acid solution, stir at room temperature for 10min, add 18g of EDCI after stirring, stir at room temperature for 1.5h, then add sodium hydroxide at room temperature to adjust the solution pH=6, control the temperature at 35°C and evaporate until the remaining solution volume is 1 / 3 of the original solution volume, to obtain a rotary evaporated liquid; The structural formula of the 7-aminocephalosporin acid is as follows: S2, placing the rotary evaporation liquid in a refrigerator to refrigerate the solid, filtering to obtain 7-aminocephalosporanic acid dimer, adding 200mL of 50% methanol aqueous solution to 5g of 7-aminocephalosporanic acid dimer to dissolve, cooling to 0°C, adding 20mL of 1mol / L sodium hydroxide solution to control the temperature at 0°C and stirring for 1h, adding 20% ​​acetic acid aqueous solution to adjust the pH to 7, refrigerating in a refrigerator to crystallize, filtering, taking the crystals to control the temperature at 0°C and beating with 35mL of 30% acetonitrile aqueous solution for 0.5h, filtering, taking the filter residue and drying, and obtaining the finished product of polymer impurity I compound of 7-aminocephalosporanic acid; The structural formula of the 7-aminocephalosporanic acid dimer is as follows: The chemical structure of the finished product of the polymer impurity I compound of 7-aminocephalosporanic acid is shown below: ; The polymer impurity I compound of 7-aminocephalosporanic acid has a molecular formula of C6H18N4O7S2, an exact mass of 442.06169, and a molecular weight of 442.46100.

[0024] After testing, the finished product purity of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in this example was 95%, and the yield was 35.4%.

[0025] The HPLC detection spectrum of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in this example is shown in Figure 1 ; The 1HNMR spectrum of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in this example can be found in Figure 2 ; Among them, detection instrument: BRUKER AVANCE Ⅲ 500MHz superconducting nuclear magnetic resonance spectrometer; actual irradiation frequency: 500.13MHz; solvent: DMSO-D 6 ; Spectral range: δ0-15ppm spectrum; The NMR carbon spectrum of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in this example is shown in Figure 3 ; Instrument: BRUKER AVANCE Ⅲ 500MHz superconducting nuclear magnetic resonance spectrometer; actual irradiation frequency: 125.77MHz; decoupling field frequency: 500.13MHz; solvent: DMSO-D 6 ; Spectrum range: δ0-220ppm spectrum; The HRMS mass spectrum of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in this example is shown in Figure 4; Among them, instrument: Q EXACTIVE HF (ThermoFisher Scientific); mode: ESI-; resolution: 120000; scanning range: 120-1800 m / z; spray voltage: 3.5KV; metal capillary temperature: 350℃; sheath gas flow: 60arb; auxiliary gas flow: 10arb; spray temperature: 350℃; S-lens RF level: 55.

[0026] Example 2 A method for preparing a polymer impurity I compound of 7-aminocephalosporanic acid, comprising the following steps: S1, add 200mL acetonitrile, 75mL tetrahydrofuran and 25mL 2mol / L hydrochloric acid solution to 10g 7-aminocephalosporanic acid, stir at room temperature for 12.5min, add 18g EDCI after stirring, stir at room temperature for 1h, then add sodium hydroxide at room temperature to adjust the solution pH=6, control the temperature at 40℃ and evaporate until the remaining solution volume is 1 / 3 of the original solution volume, to obtain a rotary evaporated liquid; S2. The rotary evaporation liquid was placed in a refrigerator to precipitate a solid, which was filtered to obtain a 7-aminocephalosporanic acid dimer. 400 mL of a 50% methanol aqueous solution was added to 5 g of the 7-aminocephalosporanic acid dimer to dissolve it, and the temperature was lowered to 0°C. 25 mL of a 3 mol / L sodium hydroxide solution was added to control the temperature at 0°C and stirred for 0.5 h. A 20% acetic acid aqueous solution was added to adjust the pH to 7. The crystal was refrigerated and crystallized, and the solid was filtered. The crystal was taken and the temperature was controlled at 0°C, and the solid was beaten with 20 mL of a 40% acetonitrile aqueous solution for 1 h. The solid was filtered and the residue was dried to obtain the finished product of the polymer impurity I compound of 7-aminocephalosporanic acid.

[0027] After testing, the finished product purity of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in this example was 95%, and the yield was 33.2%.

[0028] Example 3 A method for preparing a polymer impurity I compound of 7-aminocephalosporanic acid, comprising the following steps: S1, add 150mL acetonitrile, 100mL tetrahydrofuran and 30mL 1mol / L hydrochloric acid solution to 10g 7-aminocephalosporanic acid, stir at room temperature for 15min, add 18g EDCI after stirring, stir at room temperature for 2h, then add sodium hydroxide at room temperature to adjust the solution pH=6, control the temperature at 37.5℃ and evaporate until the remaining solution volume is 1 / 3 of the original solution volume, to obtain a rotary evaporated liquid; S2. The rotary evaporation liquid is placed in a refrigerator to precipitate a solid, which is filtered to obtain a 7-aminocephalosporanic acid dimer. 300 mL of a 50% methanol aqueous solution is added to 5 g of the 7-aminocephalosporanic acid dimer to dissolve it, the temperature is lowered to 0°C, 30 mL of a 2 mol / L sodium hydroxide solution is added to control the temperature at 0°C and stir for 2 hours, a 20% acetic acid aqueous solution is added to adjust the pH to 7, the crystal is refrigerated in a refrigerator for crystallization, filtered, the crystals are controlled at 0°C and slurried with 50 mL of a 50% acetonitrile aqueous solution for 1 hour, filtered, and the filter residue is dried to obtain a finished product of a polymer impurity I compound of 7-aminocephalosporanic acid.

[0029] After testing, the finished product purity of the polymer impurity I compound of 7-aminocephalosporanic acid prepared in this example was 95%, and the yield was 34.5%.

[0030] In the description of the specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0031] The above contents are merely examples and explanations of the concept of the present invention. The technicians in this technical field may make various modifications or additions to the specific embodiments described or replace them in a similar manner. As long as they do not deviate from the concept of the invention or exceed the scope defined by the claims, they should all fall within the protection scope of the present invention.

Claims

1. A method for preparing a polymer impurity of 7-aminocephalosporanic acid, characterized in that: The following steps are involved: 7-aminocephalosporanic acid is condensed with acetonitrile, tetrahydrofuran, hydrochloric acid solution and EDCI to generate 7-aminocephalosporanic acid dimer, and then methanol aqueous solution and sodium hydroxide solution are added for hydrolysis and crystallization, and acetonitrile aqueous solution is used for slurrying to obtain a finished product of polymer impurity I compound of 7-aminocephalosporanic acid, wherein the structural formula of the polymer impurity I compound of 7-aminocephalosporanic acid is: 。 2. The method for preparing the polymer impurities of 7-aminocephalosporanic acid according to claim 1, characterized in that: The structural formula of the 7-aminocephalosporin acid is as follows: ； The structural formula of the 7-aminocephalosporanic acid dimer is as follows: 。 3. The method for preparing the polymer impurities of 7-aminocephalosporanic acid according to claim 2, characterized in that: The polymer impurity I compound of 7-aminocephalosporanic acid has the molecular formula: C6H 18 N4O7S2, exact mass: 442.06169, molecular weight: 442.46100.

4. The method for preparing the polymer impurity of 7-aminocephalosporanic acid according to claim 1, characterized in that: The preparation method of the polymer impurity I compound of 7-aminocephalosporanic acid specifically comprises the following steps: S1, adding acetonitrile, tetrahydrofuran and hydrochloric acid solution to 7-aminocephalosporanic acid, stirring once, adding EDCI, stirring twice, adjusting pH, and performing rotary evaporation under temperature control to obtain a rotary evaporation liquid; S2. Refrigerate the rotary evaporation liquid to precipitate solids, filter to obtain 7-aminocephalosporanic acid dimer, add methanol aqueous solution to 7-aminocephalosporanic acid dimer, dissolve, cool, add sodium hydroxide solution to control temperature and stir, adjust pH, refrigerate to crystallize, filter, take crystals, control temperature and pulp with acetonitrile aqueous solution, filter, take the filter residue and dry to obtain the finished product of polymer impurity I compound of 7-aminocephalosporanic acid.

5. The method for preparing the polymer impurity of 7-aminocephalosporanic acid according to claim 4, characterized in that: The usage ratio of 7-aminocephalosporanic acid, acetonitrile, tetrahydrofuran, hydrochloric acid solution and EDCI in step S1 is 10 g: 100-200 mL: 50-100 mL: 20-30 mL: 18 g.

6. The method for preparing the polymer impurity of 7-aminocephalosporanic acid according to claim 4, characterized in that: In step S1, the temperature of the first stirring is room temperature and the time is 10-15 minutes; the temperature of the second stirring is room temperature and the time is 1-2 hours; the pH adjustment is to add sodium hydroxide at room temperature to adjust the solution pH to 6; the temperature-controlled rotary evaporation is to control the temperature at 35-40°C to rotary evaporation until the remaining solution volume is 1 / 3 of the original solution volume.

7. The method for preparing the polymer impurity of 7-aminocephalosporanic acid according to claim 4, characterized in that: The usage ratio of the 7-aminocephalosporanic acid dimer, methanol aqueous solution, sodium hydroxide solution and acetonitrile aqueous solution in step S2 is 5 g: 200-400 mL: 20-30 mL: 20-50 mL.

8. The method for preparing the polymer impurity of 7-aminocephalosporanic acid according to claim 4, characterized in that: The mass concentration of the methanol aqueous solution is 50%; the concentration of the sodium hydroxide solution is 1-3 mol / L.

9. The method for preparing the polymer impurity of 7-aminocephalosporanic acid according to claim 4, characterized in that: The cooling in step S2 is cooling to 0°C; the temperature of the temperature-controlled stirring is 0°C, and the time is 0.5-2h; the pH is adjusted by adding acetic acid aqueous solution to adjust the pH to 7; the temperature of the temperature-controlled acetonitrile aqueous solution for slurrying is 0°C, and the time is 0.5-1h; the mass concentration of the acetic acid aqueous solution is 20%; the mass concentration of the acetonitrile aqueous solution is 30-50%.

Images