阅读说明：本技术 一种头孢西丁酸的制备方法 (Preparation method of cefoxitin acid ) 是由 贾全 胡利敏 任峰 刘树斌 田洪年 孙玉双 杨梦德 魏宝军 贺娇 张建丽 于 2021-01-22 设计创作，主要内容包括：本发明公开了一种头孢西丁酸的制备方法,属于医药技术领域,步骤包括：将头孢西丁钠粗品中加入酸性溶解液中,连续超声萃取；分相,得到头孢西丁酸萃取液；通入氧化铝层析柱中,解吸,收集头孢西丁酸解吸液；浓缩解吸液,加入溶析剂结晶,加晶种养晶；离心过滤后,洗涤、干燥,得到头孢西丁酸。得到的头孢西丁酸纯度高、杂质少、色级低；同时本发明的制备方法还用于头孢西丁酸标准品的制备,具有工艺简单、节能环保、适合大规模工业化生产等优点。(The invention discloses a preparation method of cefoxitin acid, belonging to the technical field of medicines and comprising the following steps: adding the cefoxitin sodium crude product into an acidic dissolving solution, and continuously performing ultrasonic extraction; phase separation is carried out to obtain cefoxitin acid extract; introducing into an alumina chromatographic column, desorbing, and collecting the acidolysis solution of cefoxitin; concentrating the desorption solution, adding a dissolving agent for crystallization, and adding seed crystals for crystal growth; and after centrifugal filtration, washing and drying to obtain cefoxitin acid. The obtained cefoxitin acid has high purity, less impurities and low color grade; meanwhile, the preparation method is also used for preparing the cefoxitin acid standard substance, and has the advantages of simple process, energy conservation, environmental protection, suitability for large-scale industrial production and the like.)

1. A preparation method of cefoxitin acid is characterized by comprising the following steps: the method comprises the following steps:

1) adding the cefoxitin sodium crude product into an acidic dissolving solution, and continuously performing ultrasonic extraction;

2) separating phases, reserving a light phase, and filtering solid particles to obtain cefoxitin acid extract;

3) introducing the cefoxitin acid extract into an alumina chromatographic column, performing column desorption by using an elution reagent, and collecting cefoxitin acid hydrolysis imbibition;

4) concentrating the cefoxitin acid hydrolysis liquid to obtain cefoxitin acid concentrated solution;

5) controlling the temperature of the cefoxitin acid concentrated solution, adding a dissolving-out agent for crystallization, and adding seed crystals for crystal growth;

6) and centrifugally filtering, washing and drying to obtain cefoxitin acid.

2. The process for the preparation of cefoxitin acid as claimed in claim 1, wherein: the acidic dissolving solution in the step 1) is a mixed solution of 2mol/L hydrochloric acid and dimethyl carbonate, and the volume ratio of the hydrochloric acid to the dimethyl carbonate is 1 (100-150).

3. The process for the preparation of cefoxitin acid as claimed in claim 2, wherein: in the step 1), the solid-to-liquid ratio (g/mL) of the cefoxitin sodium crude product to the dimethyl carbonate is 1: (10-20).

4. The process for the preparation of cefoxitin acid as claimed in claim 2, wherein: in the step 3), the alumina is neutral alumina, and the column volume ratio of the dimethyl carbonate to the alumina chromatographic column is (3-5): 1, wherein the height-diameter ratio of the alumina chromatographic column is (5-10): 1.

5. the process for the preparation of cefoxitin acid as claimed in claim 1, wherein: the elution reagent in the step 3) is ethanol, and the solid-to-liquid ratio (g/mL) of the cefoxitin sodium crude product to the ethanol is 1: (10-20) the desorption flow rate is 0.5-2.0 BV/h.

6. The process for the preparation of cefoxitin acid as claimed in claim 1, wherein: the concentration condition in the step 4) is 30-50 ℃, vacuum concentration is carried out, and the concentration time is 1-2 h.

7. The process for the preparation of cefoxitin acid as claimed in claim 1, wherein: cooling to 10-15 ℃ in the step 5); the elution agent is 10-15% of salt water, and the solid-to-liquid ratio (g/mL) of cefoxitin sodium to the elution agent is 1 (10-15).

8. The process for the preparation of cefoxitin acid as claimed in claim 1, wherein: and 5) the seed crystal is cefoxitin acid, the seed amount is 3-5% of the cefoxitin sodium crude product, and the crystal growing time is 0.5-1 h.

9. The process for the preparation of cefoxitin acid as claimed in claim 1, wherein: washing the filter cake 1-2 times with pre-cooled water of 2-8 ℃ in the step 6), and carrying out vacuum drying for 3-4 h at 30-40 ℃ to obtain cefoxitin acid.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of cefoxitin acid.

Background

Cefoxitin sodium is the second generation cephalosporin antibiotic developed by Merck, USA, and has balanced antibacterial spectrum and is stable to beta-lactamase. At present, due to the increasing bacterial drug resistance of cephalosporins, cefoxitin, which is different from cephalosporins of the first and third generations, has attracted attention again. Is a second generation cephalosporin antibiotic developed by Merck company in the United states, has balanced antibacterial spectrum and is stable to beta-lactamase. At present, due to the increasing bacterial drug resistance of cephalosporins, cefoxitin, which is different from cephalosporins of the first and third generations, has attracted attention again.

Cefoxitin sodium (Cefoxitin sodium) with the chemical name: (6R, 7S) -3- (carbamoyloxymethyl) -7-methoxy-8-oxo-7- [2- (2-thienyl) acetylamino ] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, sodium salt. The chemical structural formula is as follows:

the preparation method of cefoxitin acid is not described much, and the methods described in main patents and documents are as follows:

the patent "preparation method of cefoxitin acid" (CN200910074959.9) provides a preparation method of cefoxitin acid, relates to a method for preparing cefoxitin acid by using acetone as a reaction solvent and 7-alpha-methoxy-3-deacetyl cefoxitin benzathine salt as a starting material, and introduces a complex synthetic process and operation process.

Therefore, a preparation method for improving the purity and the color grade of cefoxitin acid is an urgent problem to be solved.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a preparation method of cefoxitin acid, which can improve the purity and the color grade of cefoxitin acid.

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

a preparation method of cefoxitin acid comprises the following steps:

1) adding the cefoxitin sodium crude product into an acidic dissolving solution, and continuously performing ultrasonic extraction;

2) separating phases, reserving a light phase, and filtering solid particles to obtain cefoxitin acid extract;

3) introducing the extract into an alumina chromatographic column, performing column desorption by using an elution reagent, and collecting an acidolysis imbibition of cefoxitin;

4) carrying out acidolysis and imbibition on cefoxitin to obtain a cefoxitin acid concentrated solution;

5) controlling the temperature of the cefoxitin acid concentrated solution, adding a dissolving-out agent for crystallization, and adding seed crystals for crystal growth;

6) and after centrifugal filtration, washing and drying to obtain cefoxitin acid.

The technical scheme of the invention is further improved as follows: the acidic dissolving solution in the step 1) is a mixed solution of 2mol/L hydrochloric acid and dimethyl carbonate, and the volume ratio of the hydrochloric acid to the dimethyl carbonate is 1 (100-150).

The technical scheme of the invention is further improved as follows: the solid-to-liquid ratio (g/mL) of cefoxitin sodium to dimethyl carbonate in the step 1) is 1: (10-20).

The technical scheme of the invention is further improved as follows: the alumina in the step 3) is neutral alumina, and the column volume ratio of the dimethyl carbonate to the alumina chromatographic column is (3-5): 1, wherein the height-diameter ratio of the alumina chromatographic column is (5-10): 1.

the technical scheme of the invention is further improved as follows: the elution reagent in the step 3) is ethanol, and the solid-to-liquid ratio (g/mL) of cefoxitin sodium to ethanol is 1: (10-20) the desorption flow rate is 0.5-2.0 BV/h.

The technical scheme of the invention is further improved as follows: the concentration in the step 4) is vacuum concentration at the temperature of 30-50 ℃, and the concentration time is 1-2 h.

The technical scheme of the invention is further improved as follows: cooling to 10-15 ℃ in the step 5); the elution agent is 10-15% of salt water, and the solid-to-liquid ratio (g/mL) of cefoxitin sodium to the elution agent is 1 (10-15).

The technical scheme of the invention is further improved as follows: the seed crystal in the step 5) is cefoxitin with qualified quality, the seed crystal amount is 3-5% of cefoxitin sodium, and the seed crystal grows for 0.5-1 h.

The technical scheme of the invention is further improved as follows: and 6) washing the filter cake 1-2 times with pre-cooled water at 2-8 ℃, and carrying out vacuum drying for 3-4 h at 30-40 ℃ to obtain cefoxitin acid.

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

the method has good impurity removal effect through the alumina, and the obtained cefoxitin acid has high purity, less impurities, low color grade, simple process, energy conservation and environmental protection, and is suitable for large-scale industrial production.

According to the invention, through optimizing the selection of various solvent types in the refining preparation process, the purity and the color grade of the cefoxitin acid are improved, the crystal particles are uniform and good in fluidity, the content of impurities is reduced, and the quality of the cefoxitin acid is further improved. Meanwhile, the preparation method is also used for preparing the cefoxitin acid standard substance, and has the advantages of simple process, energy conservation, environmental protection, suitability for large-scale industrial production and the like.

Detailed Description

The present invention will be described in further detail with reference to the following examples:

example 1

Adding 1mL of 2mol/L hydrochloric acid and 100mL of dimethyl carbonate into a dissolving tank, starting stirring, adding 10g of cefoxitin sodium crude product, and continuously performing ultrasonic extraction for 20 min; standing for phase separation, reserving a light phase, and filtering solid particles to obtain a cefoxitin acid extract; introducing the extract into a neutral alumina chromatographic column with the volume of 20mL, performing column desorption by using 100mL of ethanol at the flow rate of 0.5BV/h, and collecting an acidolysis solution of cefoxitin; vacuum-pumping and concentrating for 2h at 40 ℃ to obtain cefoxitin acid concentrated solution; controlling the temperature of the cefoxitin acid concentrated solution to be 15 ℃, adding 100mL of 10% saline solution, adding 0.2g of seed crystal, and growing the crystal for 1 h; and after centrifugal filtration, washing the filter cake for 2 times in pre-cooled water with the temperature of 2 ℃, and carrying out vacuum drying for 3 hours at the temperature of 30 ℃ to obtain cefoxitin acid.

Example 2

Adding 1mL of 2mol/L hydrochloric acid and 150mL of dimethyl carbonate into a dissolving tank, starting stirring, adding 10g of cefoxitin sodium, and continuously performing ultrasonic extraction for 20 min; standing for phase separation, reserving a light phase, and filtering solid particles to obtain a cefoxitin acid extract; introducing the extract into a neutral alumina chromatographic column with the volume of 20mL, performing column desorption by using 150mL of ethanol at the flow rate of 2.0BV/h, and collecting an acidolysis solution of cefoxitin; vacuum-pumping and concentrating for 2h at 40 ℃ to obtain cefoxitin acid concentrated solution; controlling the temperature of the cefoxitin acid concentrated solution to be 15 ℃, adding 150mL of 10% saline solution, adding 0.5g of seed crystal, and growing the crystal for 1 h; and after centrifugation, washing the filter cake for 2 times in pre-cooled water with the temperature of 8 ℃, and performing vacuum drying for 4 hours at the temperature of 40 ℃ to obtain cefoxitin acid.

Example 3

Adding 1mL of 2mol/L hydrochloric acid and 120mL of dimethyl carbonate into a dissolving tank, starting stirring, adding 10g of cefoxitin sodium, and continuously performing ultrasonic extraction for 20 min; standing for phase separation, reserving a light phase, and filtering solid particles to obtain a cefoxitin acid extract; introducing the extract into a neutral alumina chromatographic column with the volume of 20mL, performing column desorption by using 120mL of ethanol at the flow rate of 1.5BV/h, and collecting an acidolysis solution of cefoxitin; vacuum-pumping and concentrating for 2h at 40 ℃ to obtain cefoxitin acid concentrated solution; controlling the temperature of the cefoxitin acid concentrated solution to be 15 ℃, adding 120mL of 10% saline solution, adding 0.3g of seed crystal, and growing the crystal for 1 h; after centrifugation, the filter cake is washed for 2 times in precooled water with the temperature of 5 ℃, and vacuum drying is carried out for 3.5 hours at the temperature of 35 ℃ to obtain cefoxitin acid.

Comparative examples 1 to 3

The process steps and process parameters of comparative examples 1-2 were selected differently from example 1. Comparative example 3 was prepared according to the method of example 1 described in the patent "method for preparing cefoxitin acid" (CN 200910074959.9).

Comparative example 1

Adding 1mL of 2mol/L hydrochloric acid and 50mL of ethyl acetate into a dissolving tank, starting stirring, adding 10g of cefoxitin sodium, and continuously performing ultrasonic extraction for 30 min; standing for phase separation, reserving a light phase, and filtering solid particles to obtain a cefoxitin acid extract; introducing the extract into a neutral alumina chromatographic column with the volume of 10mL, performing column desorption by using 120mL of acetone at the flow rate of 2.5BV/h, and collecting an acidolysis solution of cefoxitin; vacuum-pumping and concentrating for 2h at 40 ℃ to obtain cefoxitin acid concentrated solution; controlling the temperature of the cefoxitin acid concentrated solution to be 25 ℃, adding 120mL of purified water, adding 0.3g of seed crystal, and growing the crystal for 1 h; and after centrifugation, washing and drying to obtain cefoxitin acid.

Comparative example 2

Adding 1mL of 5mol/L phosphoric acid and 50mL of dichloromethane into a dissolving tank, starting stirring, adding 10g of cefoxitin sodium, and continuously performing ultrasonic extraction for 10 min; standing for phase separation, reserving a light phase, and filtering solid particles to obtain a cefoxitin acid extract; introducing the extract into a silica gel chromatographic column with the volume of 10mL, performing column desorption by using 120mL of acetone at the flow rate of 2.5BV/h, and collecting an acidolysis solution of cefoxitin; vacuum-pumping and concentrating for 2h at 40 ℃ to obtain cefoxitin acid concentrated solution; controlling the temperature of the cefoxitin acid concentrated solution to be 25 ℃, adding 120mL of purified water, adding 0.3g of seed crystal, and growing the crystal for 1 h; and after centrifugation, washing and drying to obtain cefoxitin acid.

Cefoxitin acid prepared in examples 1-3 and comparative examples 1-3 was tested, and the test results are shown in the following table.

TABLE 1 test results of cefoxitin acid in each example and comparative example

As can be seen from the detection results in Table 1, the cefoxitin acid prepared by the invention has a color grade, maximum single impurity, total impurity and the like which are obviously lower than those of the comparative example. The cefoxitin acid prepared by the method has high purity and low impurity content, can completely remove impurities, has equivalent content, color grade and impurity level in each embodiment, and has good process reproducibility.

In order to better verify the use effect of cefoxitin acid prepared by the invention, the inventor respectively prepares cefoxitin acid prepared in examples 1-3 and comparative examples 1-3 into cefoxitin sodium, and detects various indexes of cefoxitin sodium, wherein the detection results are shown in the following table 2.

TABLE 2 detection results of cefoxitin sodium prepared in each example and comparative example

As can be seen from the detection results in Table 2, cefoxitin sodium obtained by continuously preparing cefoxitin acid 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 cefoxitin sodium. Meanwhile, the preparation method is also used for preparing the cefoxitin acid standard substance, and has the advantages of simple process, energy conservation, environmental protection, suitability for large-scale industrial production and the like.