阅读说明：本技术 一种头孢呋辛酸的制备方法 (Preparation method of cefuroxime acid ) 是由 任峰 胡利敏 贾全 刘树斌 田洪年 孙玉双 魏宝军 乔俊华 杨梦德 贺娇 于 2021-01-22 设计创作，主要内容包括：本发明公开了一种头孢呋辛酸的制备方法,属于医药中间体制备领域,以头孢呋辛钠粗品为原料,投入溶解剂中搅拌溶清,再加入吸附剂搅拌,过滤后,使用酸性试剂析晶,得到头孢呋辛酸；本发明制备得到的头孢呋辛酸具有含量高、杂质少、稳定性好的优点,制备方法简单、节能环保,适合大规模工业化生产。(The invention discloses a preparation method of cefuroxime acid, which belongs to the field of preparation of medical intermediates, and is characterized in that cefuroxime sodium crude product is taken as a raw material, added into a dissolving agent for stirring and dissolving, then added with an adsorbent for stirring, filtered, and crystallized by using an acidic reagent to obtain cefuroxime acid; the cefuroxime acid prepared by the invention has the advantages of high content, less impurities and good stability, and the preparation method is simple, energy-saving and environment-friendly and is suitable for large-scale industrial production.)

1. A preparation method of cefuroxime acid is characterized by comprising the following steps: the cefuroxime sodium crude product is used as a raw material, is put into a dissolving agent to be stirred and dissolved, is added with an adsorbent to be stirred, is filtered, and is crystallized by using an acid reagent to obtain cefuroxime acid, and the method comprises the following specific steps:

A. preparing a mixed solution, controlling the temperature, adding the cefuroxime sodium crude product, and stirring and dissolving until the solution is clear to obtain a cefuroxime sodium solution clear solution;

B. adding activated carbon loaded with phosphoric acid into the clear solution, stirring, controlling the pH value of the solution, and filtering the activated carbon to obtain filtered solution;

C. dripping phosphoric acid into the filtered solution for the first time to adjust the pH value, then adding seed crystals to grow crystals, continuously dripping phosphoric acid for the second time to adjust the pH value, and cooling to grow crystals;

D. the crystallized solution is filtered, washed and dried under reduced pressure to obtain the refined cefuroxime acid.

2. The method for preparing cefuroxime acid according to claim 1, wherein the cefuroxime acid is prepared by the following steps: the quality index of the cefuroxime sodium crude product meets any one or combination of more of total impurities less than or equal to 5.0 percent, maximum single impurities less than or equal to 2.0 percent or solution color less than or equal to No. 7.

3. The method for preparing cefuroxime acid according to claim 1, wherein the cefuroxime acid is prepared by the following steps: the mixed solution in the step A is selected from methanol, isopropanol and acetonitrile, and the combination of two of the methanol, the isopropanol and the acetonitrile and water; the volume of each organic solvent in the mixed solution and the water ratio are 1:1: 2; the ratio of the volume milliliter of the mixed solvent to the weight gram of the cefuroxime sodium crude product is 20-30: 1, and the temperature is controlled to be 10-15 ℃ during stirring.

4. The method for preparing cefuroxime acid according to claim 1, wherein the cefuroxime acid is prepared by the following steps: in the step B, the mass percentage of the phosphoric acid in the activated carbon is 10-20%, and the dosage of the activated carbon is 10-20% of the cefuroxime sodium crude product.

5. The method for preparing cefuroxime acid according to claim 1, wherein the cefuroxime acid is prepared by the following steps: and in the step B, the pH range of the solution is controlled to be 4.5-5.0.

6. The method for preparing cefuroxime acid according to claim 1, wherein the cefuroxime acid is prepared by the following steps: the concentration of the phosphoric acid in the step C is 30-60%; adjusting the pH value to 3.6-4.0 for the first time, and adjusting the pH value to 1.9-2.1 for the second time; the seed crystal is cefuroxime acid with qualified quality, and the dosage of the seed crystal is 3-5% of that of the cefuroxime sodium crude product.

7. The method for preparing cefuroxime acid according to claim 1, wherein the cefuroxime acid is prepared by the following steps: and C, cooling to 5-10 ℃.

8. The method for preparing cefuroxime acid according to claim 1, wherein the cefuroxime acid is prepared by the following steps: in the step D, the washing reagent is a mixed solution of acetone and ethanol (3-5): 1, and the dosage of the washing reagent is 3 times (mL/g) of the cefuroxime sodium crude product.

9. The method for preparing cefuroxime acid according to claim 1, wherein the cefuroxime acid is prepared by the following steps: and D, drying under reduced pressure in the step D at the temperature of 30-40 ℃.

Technical Field

The invention belongs to the technical field of medicines, relates to a recovery and preparation method of cephalosporin, and more particularly relates to a one-step recovery and preparation method of cefuroxime sodium.

Background

Cefuroxime sodium is a semi-synthetic second-generation cephalosporin, and has high antibacterial effects on staphylococcus aureus, streptococcus, meningococcus, bacillus influenzae, klebsiella, escherichia coli, proteus mirabilis, salmonella, shigella and the like. The product can be used for resisting beta-lactamase and penicillin-resistant Staphylococcus aureus. The traditional Chinese medicine composition is mainly used for respiratory tract infection, pyelonephritis and urinary tract infection caused by sensitive bacteria and infection of bones, joints, ears, noses, throats, soft tissues and the like in clinic. The product can enter into cerebrospinal fluid in sufficient amount during meningitis inflammation, and has remarkable curative effect on meningitis caused by meningococcus. The activity to gram-positive bacteria (including penicillium-resistant grape) is similar to that of the first generation of cephalosporins; has stronger effect on gram-negative bacteria than the first generation of cephalosporins.

The chemical name of cefuroxime sodium is (6R, 7R) -7- [2- (furan-2-yl) -2- (methoxyimino) acetamido]-3-carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0]Octyl-2-ene-2-carboxylic acid sodium salt with molecular formula C₁₆H₁₅N₄NaO₈S, molecular weight 446.37. The chemical structural formula is shown as follows:

the cefuroxime sodium has the problem of poor stability, which is mainly reflected in that the color of the product changes rapidly. In the industrial production of cefuroxime sodium, because of the influence of the process or the production environment, unqualified products sometimes appear in the production, and in addition, the stability of cefuroxime sodium is poor, and the color of the product gradually rises to unqualified products in the storage process of cefuroxime sodium in the commercial circulation field. The recovery of cefuroxime sodium is a difficult problem because the unqualified cefuroxime sodium in the production process or the storage process needs to be recovered.

The methods for recycling and preparing unqualified cefuroxime sodium and the aseptic crystallization process are not introduced much, and the methods introduced in the patent and literature mainly comprise the following steps:

the patent "a method for recrystallizing cefuroxime sodium" (cn201010290808.x) provides a method for recrystallizing cefuroxime sodium, which is used for solving the refining problem of cefuroxime sodium raw material medicines with darker colors. Is suitable for recrystallization of crude drugs with unqualified color grades. The document is not suitable for recrystallization preparation of unqualified products with excessive impurities.

The patent "a new industrial crystallization technology of cefuroxime sodium" (CN201510330842.8) discloses a new industrial crystallization technology of cefuroxime sodium, which realizes the recrystallization of cefuroxime sodium by combining the supercritical fluid extraction technology and the traditional crystallization technology. In the whole crystallization system, under the combined action of the supercritical fluid, the solvent, the extraction tank and the crystallization tank, the processes of extraction, adsorption, crystallization and drying are completed under the specific conditions of temperature and pressure, and the recrystallization of cefuroxime sodium is realized. However, the method uses special equipment for operation, needs to modify the existing equipment, and has higher production cost.

In order to overcome the above disadvantages, a method for recovering and preparing cefuroxime sodium, which is more suitable for industrial production, needs to be found.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a preparation method of cefuroxime acid, which can fully recycle cefuroxime sodium which does not meet the quality standard, and the prepared cefuroxime acid has the advantages of high content, less impurities and good stability, and the preparation method is simple, energy-saving and environment-friendly and is suitable for large-scale industrial production.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows:

a preparation method of cefuroxime acid comprises the following steps of taking a cefuroxime sodium crude product as a raw material, adding a dissolving agent, stirring for dissolving, adding an adsorbent, stirring, filtering, and crystallizing by using an acidic reagent to obtain cefuroxime acid, wherein the preparation method comprises the following specific steps:

A. preparing a mixed solution, controlling the temperature, adding the cefuroxime sodium crude product, and stirring and dissolving until the solution is clear to obtain a cefuroxime sodium solution clear solution;

B. adding activated carbon loaded with phosphoric acid into the clear solution, stirring, controlling the pH value of the solution, and filtering the activated carbon to obtain filtered solution;

C. dripping phosphoric acid into the filtered solution for the first time to adjust the pH value, then adding seed crystals to grow crystals, continuously dripping phosphoric acid for the second time to adjust the pH value, and cooling to grow crystals;

D. the crystallized solution is filtered, washed and dried under reduced pressure to obtain the refined cefuroxime acid.

The technical scheme of the invention is further improved as follows: the quality index of the cefuroxime sodium crude product meets any one or combination of more of total impurities less than or equal to 5.0 percent, maximum single impurities less than or equal to 2.0 percent or solution color less than or equal to No. 7.

The technical scheme of the invention is further improved as follows: the mixed solution in the step A is selected from methanol, isopropanol and acetonitrile, and the combination of two of the methanol, the isopropanol and the acetonitrile and water; the volume of each organic solvent in the mixed solution and the water ratio are 1:1: 2; the ratio of the volume milliliter of the mixed solvent to the weight gram of the cefuroxime sodium crude product is 20-30: 1, and the temperature is controlled to be 10-15 ℃ during stirring.

The technical scheme of the invention is further improved as follows: in the step B, the mass percentage of the phosphoric acid in the activated carbon is 10-20%, and the dosage of the activated carbon is 10-20% of the cefuroxime sodium crude product.

The technical scheme of the invention is further improved as follows: and in the step B, the pH range of the solution is controlled to be 4.5-5.0.

The technical scheme of the invention is further improved as follows: the concentration of the phosphoric acid in the step C is 30-60%; adjusting the pH value to 3.6-4.0 for the first time, and adjusting the pH value to 1.9-2.1 for the second time; the seed crystal is cefuroxime acid with qualified quality, and the dosage of the seed crystal is 3-5% of that of the cefuroxime sodium crude product.

The technical scheme of the invention is further improved as follows: and C, cooling to 5-10 ℃.

The technical scheme of the invention is further improved as follows: in the step D, the washing reagent is a mixed solution of acetone and ethanol (3-5): 1, and the dosage of the washing reagent is 3 times (mL/g) of the cefuroxime sodium crude product.

The technical scheme of the invention is further improved as follows: and D, drying under reduced pressure in the step D at the temperature of 30-40 ℃.

Due to the adoption of the technical scheme, the invention has the technical progress that:

the preparation method of cefuroxime acid provided by the invention can fully recycle cefuroxime sodium which does not meet the quality standard, and the prepared cefuroxime acid has the advantages of high content, less impurities and good stability, and is simple, energy-saving and environment-friendly, and suitable for large-scale industrial production.

The invention takes cefuroxime sodium as raw material, especially the total impurity is less than or equal to 5.0%, the biggest single impurity is less than or equal to 2.0% or the solution color is less than or equal to 7 arbitrary one or more of the cefuroxime sodium which does not meet the quality standard, the cefuroxime sodium which does not meet the quality standard usually adopts a degradation treatment method, the use value is greatly reduced, and the cefuroxime acid in the cefuroxime sodium is re-extracted to be used as the raw material for preparing the cefuroxime sodium, so that the value of the cefuroxime sodium which does not meet the quality standard is fully utilized, and the production cost is saved.

Compared with the traditional synthesis preparation process, the cefuroxime acid prepared by dissolving, separating out, decoloring and crystallizing the cefuroxime sodium which does not meet the quality standard has the advantages of easily obtained raw materials, simple preparation process, simple and convenient operation, no pollution in the production process, stable process control, no byproduct generation, high content of the obtained product, less impurities and stable property.

The invention adopts the activated carbon loaded with phosphoric acid to slowly release phosphoric acid to adjust the pH value of the feed liquid, reduce the solubility of impurities, effectively adsorb the separated impurities by the activated carbon, remove related substances in the cefuroxime sodium and reduce the color grade of the product. When the mass percent of the activated carbon-loaded phosphoric acid is 10-20% and the addition amount of the decolorizing agent is 10-20% of the mass of the cefuroxime sodium, the phosphoric acid release process is mild, the precipitated impurities are immediately adsorbed by the activated carbon and cannot be dissolved again, the decolorizing effect is best, and the obtained product has low related substances.

The mixed solution is added during the dissolution, so that the cefuroxime is kept relatively stable in the system, and impurities are separated out successively along with the low solubility of the adjusted pH in the solution; when the mixed solution is crystallized, the cefuroxime acid can be uniformly dispersed in a crystallization system, the obtained crystal has uniform particle size and good crystal form, and simultaneously, the impurity precipitation is inhibited, and the prepared product has the advantages of high purity, low impurity content and good stability.

The invention adopts a secondary crystallization mode, and gradually separates out crystals by adjusting pH, thereby ensuring that the obtained crystals have higher purity and complete crystallization, and the product yield is high. When the pH value of the first crystallization is adjusted to 3.6-4.0, the solubility of cefuroxime acid is greatly reduced, most of cefuroxime acid in a crystallization system can be separated out in a crystal form, at the moment, purified water is added into the crystallization system to increase the solubility of cefuroxime acid in the system, and when the pH value of the second crystallization is adjusted to 1.9-2.1, the cefuroxime acid which is not crystallized in the system during the first crystallization can be crystallized out, so that the yield of cefuroxime acid crystals is improved.

The invention adopts the mixed solvent for washing, effectively removes impurities in the crystallization mother liquor, loosens the wet powder, has less moisture occluded in the wet powder, does not need high-temperature drying, and prolongs the drying time. When the washing liquid is mixed liquid of acetone and ethanol, and the ratio of the acetone to the ethanol is (3-5): 1, the mother liquid and most of water in the wet powder can be taken away, the subsequent drying is facilitated, and the finally obtained product has high purity and less impurities.

The preparation method of cefuroxime acid in the invention is energy-saving and environment-friendly, the organic solvent can be recycled, the operation is simple, the prepared cefuroxime acid has the advantages of low impurity content, low color grade, uniform crystal particles, good fluidity, high purity and high yield, can be used as a raw material for preparing cefuroxime sodium, the prepared cefuroxime sodium has low impurity content, high purity and good stability, and the problem of recycling of cefuroxime sodium which does not meet the quality standard is effectively solved.

Detailed Description

The following are some specific embodiments of the present invention for further detailed description.

A preparation method of cefuroxime acid is characterized by comprising the following steps: using unqualified cefuroxime sodium as a raw material, adding the unqualified cefuroxime sodium into a dissolving agent, stirring and dissolving the cefuroxime sodium clearly, adding an adsorbent, stirring, filtering, and crystallizing by using an acidic reagent to obtain cefuroxime acid.

The quality index of the cefuroxime sodium satisfies any one or combination of more of total impurities less than or equal to 5.0 percent, maximum single impurities less than or equal to 2.0 percent or solution color less than or equal to No. 7.

The method comprises the following steps:

A. preparing a mixed solution, controlling the temperature, adding unqualified cefuroxime sodium products, stirring and dissolving until the cefuroxime sodium products are clear, and obtaining a cefuroxime sodium solution clear solution;

the mixed solution is selected from methanol, isopropanol and acetonitrile, and the combination of two of the methanol, the isopropanol and the acetonitrile and water; the volume of each organic solvent in the mixed solution and the water ratio are 1:1: 2; the ratio of the volume milliliter of the mixed solvent to the weight gram of the cefuroxime sodium is 20-30: 1, and the temperature is controlled to be 10-15 ℃ during stirring.

B. Adding activated carbon loaded with phosphoric acid into the clear solution, stirring, controlling the pH value of the solution, and filtering the activated carbon to obtain filtered solution;

the mass percentage of the phosphoric acid in the active carbon is 10-20%, and the using amount of the active carbon is 10-20% of that of the cefuroxime sodium; controlling the pH range of the solution to be 4.5-5.0.

C. Dripping primary phosphoric acid into the filtered solution, adding seed crystals for growing crystals, continuously dripping secondary phosphoric acid, and cooling for growing crystals;

the concentration of phosphoric acid is 30-60%; adjusting the pH value to 3.6-4.0 for the first time by using phosphoric acid, and adjusting the pH value to 1.9-2.1 for the second time; the seed crystal is qualified cefuroxime acid, and the dosage of the seed crystal is 3-5% of that of cefuroxime sodium; cooling to 5-10 ℃.

D. Filtering, washing and drying the crystal liquid under reduced pressure to obtain refined cefuroxime acid;

the washing reagent is a mixture of (3-5) and 1 of acetone and ethanol, the dosage of the washing reagent is 3 times (mL/g) of that of cefuroxime sodium, and the temperature is 30-40 ℃ during reduced pressure drying.

Example 1

Adding 100mL of methanol-isopropanol-water mixed solution into a dissolving tank, starting stirring, controlling the temperature to be 10 ℃, adding 5g of cefuroxime sodium crude product, stirring to dissolve, adding 1g of activated carbon loaded with 10% phosphoric acid, detecting the pH value in the tank, filtering when the pH value is reduced to 4.5, dropwise adding 30% phosphoric acid into the filtrate until the pH value is 3.6, adding 0.15g of cefuroxime acid, growing crystals for 1h, continuously dropwise adding 30% phosphoric acid until the pH value is 1.9, cooling to 5 ℃, filtering the crystallization liquid, washing wet powder with 15mL of acetone-ethanol (3:1), placing in a reduced pressure drying oven, drying at 30 ℃ until the water content is qualified, and obtaining 4.61g of cefuroxime acid product.

Examples 2 to 4

Examples 2-4 were the same as example 1 except for the selection of the process parameters, as shown in table 1 below.

Comparative examples 1 to 3

The process steps and process parameters of comparative examples 1-3 were selected differently from example 1, as shown in Table 1 below, wherein "-" indicates the absence of such steps or parameters.

TABLE 1 Experimental parameters for the examples and comparative examples

In order to better verify the superiority of the cefuroxime acid prepared by the present invention, the inventors tested the cefuroxime acid obtained in examples 1-4 and comparative examples 1-3, and the test results are shown in table 2 below.

TABLE 2 quality comparison of cefuroxime acid prepared in each example and comparative example

Detecting items	Example 1	Example 2	Example 3	Example 4	Comparative example 1	Comparative example 2	Comparative example 3
								Color grade	Number 1	Number 1	Number 1	Number 1	Number 4	Number 4	Number 4
Moisture (%)	4.6	4.8	5.0	5.1	5.3	4.9	5.1
								Maximum single impurity (%)	0.08	0.07	0.11	0.09	0.51	0.63	0.74
Total impurities (%)	0.34	0.35	0.35	0.34	0.78	0.77	1.05
								Content (%)	99.6	99.5	99.5	99.3	97.5	97.1	97.7
Yield (%)	92.2	91.9	91.8	91.5	87.5	86.2	85.3

According to the detection results in table 2, compared with comparative examples 1 to 3, the color grade, maximum single impurity, total impurity, impurity A and the like of the cefuroxime acid prepared by the invention are obviously lower than those of the comparative examples, the content of the cefuroxime acid reaches 99.0 percent and is obviously higher than that of the comparative examples 97.1 to 97.7 percent, the yield reaches 91.2 to 92.2 percent, and the comparison ratio is 85.3 to 87.5 percent and is 4.0 to 6.9 percent higher. The cefuroxime acid prepared by the invention has high purity and low impurity content, can completely remove impurities, has equivalent moisture, content, color grade and impurity level in each embodiment, and has good process reproducibility.

In order to better verify the usage effect of the cefuroxime acid prepared by the present invention, the inventors prepared the cefuroxime acid prepared in examples 1 to 4 and comparative examples 1 to 3 into cefuroxime sodium respectively, and examined various indexes of the cefuroxime sodium, and the examination results are shown in table 3 below.

TABLE 3 mass comparison of cefuroxime sodium

As can be seen from the detection results in Table 3, compared with the cefuroxime sodium prepared in the comparative examples 1 to 3, cefuroxime sodium prepared by continuing to prepare cefuroxime acid prepared by the method is obviously reduced in indexes such as related substances and the like, and the content is obviously improved. The product prepared by the preparation process has high purity and low impurity content, and is beneficial to improving the quality of cefuroxime sodium.