阅读说明：本技术 利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法 (Method for synthesizing 3-decarbamoyl cefuroxime acid by using graphene-supported copper catalyst ) 是由 梁寒冰 刘明仁 朱伟 谢博 于 2020-12-30 设计创作，主要内容包括：本发明涉及医药合成技术领域,具体涉及一种利用石墨烯负载铜催化剂合成3-去氨甲酰基头孢呋辛酸的方法。在石墨烯负载铜催化剂的作用下,呋喃铵盐与7-氨基头孢烷酸发生酰胺化反应,再加入碱液,发生水解反应,过滤,滤液析晶得到3-去氨甲酰基头孢呋辛酸。本发明大幅缩短了目标化合物的合成步骤,且避免了三氯氧磷或五氯化磷等酰胺化试剂的使用,降低了目标产物中反式异构杂质的含量,提高了产物收率,并且催化剂回收率高,减少了石墨烯负载铜催化剂的用量,具有工艺操作简单,成本低,安全性可靠的特点。(The invention relates to the technical field of medicine synthesis, and particularly relates to a method for synthesizing 3-decarbamoyl cefuroxime acid by using a graphene-supported copper catalyst. Under the action of a graphene supported copper catalyst, carrying out amidation reaction on furan ammonium salt and 7-aminocephalosporanic acid, adding alkali liquor, carrying out hydrolysis reaction, filtering, and crystallizing filtrate to obtain the 3-decarbamoyl cefuroxime acid. The method greatly shortens the synthesis steps of the target compound, avoids the use of amidation reagents such as phosphorus oxychloride or phosphorus pentachloride and the like, reduces the content of trans-isomeric impurities in the target product, improves the product yield, has high catalyst recovery rate, reduces the using amount of the graphene-supported copper catalyst, and has the characteristics of simple process operation, low cost and reliable safety.)

1. A method for synthesizing 3-decarbamoyl cefuroxime acid by using a graphene-supported copper catalyst is characterized by comprising the following steps: under the action of a graphene supported copper catalyst, carrying out amidation reaction on furan ammonium salt and 7-aminocephalosporanic acid, adding alkali liquor, carrying out hydrolysis reaction, filtering, and crystallizing filtrate to obtain the 3-decarbamoyl cefuroxime acid.

2. The method for synthesizing 3-decarbamoyl cefuroxime acid by using graphene-supported copper catalyst according to claim 1, wherein the method comprises the following steps: the molar ratio of the furan ammonium salt to the 7-aminocephalosporanic acid is 1.1-1.3: 1.

3. The method for synthesizing 3-decarbamoyl cefuroxime acid by using graphene-supported copper catalyst according to claim 1, wherein the method comprises the following steps: the dosage of the graphene-loaded copper catalyst is 30-55% of the mass of the furan ammonium salt.

4. The method for synthesizing 3-decarbamoyl cefuroxime acid by using graphene-supported copper catalyst according to claim 1, wherein the method comprises the following steps: the temperature of the amidation reaction is 10-30 ℃, and the time of the amidation reaction is 2-8 h.

5. The method for synthesizing 3-decarbamoyl cefuroxime acid by using graphene-supported copper catalyst according to claim 1, wherein the method comprises the following steps: the hydrolysis reaction temperature is-20 to-10 ℃, and the hydrolysis reaction time is 10 to 20 min.

6. The method for synthesizing 3-decarbamoyl cefuroxime acid by using the graphene-supported copper catalyst according to any one of claims 1 to 5, wherein: adding furan ammonium salt and a graphene loaded copper catalyst into a solvent, and stirring to obtain a first mixture; dissolving 7-aminocephalosporanic acid in a sodium hydroxide solution to obtain a second mixture; adding the second mixture into the first mixture to perform amidation reaction; then adding alkali liquor for hydrolysis reaction, filtering, and crystallizing the filtrate to obtain the 3-decarbamoyl cefuroxime acid.

7. The method for synthesizing 3-decarbamoyl cefuroxime acid using a graphene-supported copper catalyst according to claim 6, wherein: the solvent is toluene, acetone, tetrahydrofuran, N-dimethylformamide or dichloromethane.

8. The method for synthesizing 3-decarbamoyl cefuroxime acid using graphene-supported copper catalyst according to claim 7, wherein: the using amount ratio of the solvent to the furan ammonium salt is 3-10: 1, wherein the solvent is calculated by ml, and the furan ammonium salt is calculated by g.

9. The method for synthesizing 3-decarbamoyl cefuroxime acid using a graphene-supported copper catalyst according to claim 6, wherein: the mass ratio of the sodium hydroxide solution to the 7-aminocephalosporanic acid is 1.6-3: 1, and the sodium hydroxide solution is 15 wt.% of sodium hydroxide aqueous solution.

10. The method for synthesizing 3-decarbamoyl cefuroxime acid using a graphene-supported copper catalyst according to claim 6, wherein: adding 10 wt.% hydrochloric acid into the filtrate for crystallization, and filtering to obtain a filter cake which is a graphene-supported copper catalyst for recycling.

Technical Field

The invention relates to the technical field of medicine synthesis, and particularly relates to a method for synthesizing 3-decarbamoyl cefuroxime acid by using a graphene-supported copper catalyst.

Background

3-Decarbamoylcefuroxime acid is an intermediate product in the synthesis of cefuroxime acid. At present, the compound is synthesized by amidating and condensing 7-aminocephalosporanic acid (7-ACA) and N-methoxyimino furan acetyl chloride (SMIF-Cl) at the 7-position, and then hydrolyzing to remove acetyl at the 3-position. Wherein, amidation condensation reaction at 7 position is the key of the process synthesis. The synthesis method uses SMIF-Cl as an amidation reagent and has the following problems: 1. the SMIF-Cl synthesis process is complicated and has a long route, and the SMIF-Cl is synthesized by firstly synthesizing furan acetic acid from furan ammonium salt, then acylating the furan acetic acid with an acylating reagent to synthesize SMIF-Cl, and finally synthesizing a target product through amidation. 2. Phosphorus oxychloride OR phosphorus pentachloride is used as an acylation reagent in the SMIF-Cl synthesis process, so that Z-methoxyimino (C ═ N-OR) on furan ammonium salt is easy to isomerize in an acidic environment, and E-isomer impurities are generated and are difficult to remove. 3. Since SMIF-Cl has high activity, it is easily decomposed at room temperature, and is not suitable for long-term storage, which causes great difficulty in production. 4. The synthesis temperature is-20 to-40 ℃, the process energy consumption is high, and a large amount of waste water and solid phosphate micro-waste are generated.

For example, Chinese patent CN102702231A discloses a preparation method of 3-decarbamoyl-cefuroxime acid: (1) dissolving 7-ACA in water or methanol solution to prepare 7-ACA solution, and performing hydrolysis reaction to obtain 7-DACA solution; (2) dissolving an acyl chlorination reagent in a solvent, adding a cosolvent, then adding SMIA, filtering after reaction, adding water or performing rotary evaporation to remove excessive acyl chlorination reagent, then performing vacuum rotary evaporation, and adding a homogenization reagent to dissolve to prepare a SMIF-Cl solution; (3) adding a homogenization reagent into the 7-DACA solution, then dropwise adding an SMIF-Cl solution, adjusting the pH value, and carrying out heat preservation reaction to obtain a reaction solution; (4) decolorizing the reaction solution, regulating pH value, adding purified water, growing crystal, filtering, and vacuum drying.

Chinese patent CN111440196A discloses a method for synthesizing 3-decarbamoyl cefuroxime acid by nickel-based catalysis, which comprises the steps of placing 2-furyl-2-methoxyimino acetic acid and a nickel-based catalyst in a reaction device, adding a solvent, and uniformly stirring to obtain a first mixture; dissolving 3-aminocephalosporanic acid in a sodium hydroxide solution to obtain a second mixture; and adding the second mixture into the first mixture to perform a first reaction, and then adding an alkali liquor to perform a second reaction to obtain the 3-decarbamoyl cefuroxime acid. The catalyst adopted by the patent is a nickel-based organic compound, the market price is expensive, the 3-decarbamoyl cefuroxime acid synthesized by the catalyst is easy to form metal element residues in human bodies, the body health is affected, and the recovery rate of the catalyst is low.

Disclosure of Invention

The invention aims to provide a method for synthesizing 3-decarbamoyl cefuroxime acid by using a graphene supported copper catalyst, which avoids the isomerization of furan ammonium salt, reduces the content of trans-isomer impurities in a product, improves the product yield and has high recovery rate of the graphene supported copper catalyst under the action of the graphene supported copper catalyst.

The technical scheme adopted by the invention for solving the technical problems is as follows:

the method for synthesizing 3-decarbamoyl cefuroxime acid by using the graphene supported copper catalyst comprises the following steps: under the action of a graphene supported copper catalyst, carrying out amidation reaction on furan ammonium salt and 7-aminocephalosporanic acid, adding alkali liquor, carrying out hydrolysis reaction, filtering, and crystallizing filtrate to obtain the 3-decarbamoyl cefuroxime acid.

Wherein:

the molar ratio of the furan ammonium salt to the 7-aminocephalosporanic acid is 1.1-1.3: 1.

The dosage of the graphene-loaded copper catalyst is 30-55% of the mass of the furan ammonium salt.

The temperature of the amidation reaction is 10-30 ℃, and preferably 25-30 ℃; the amidation reaction time is 2-8 h, preferably 4-6 h.

The hydrolysis reaction temperature is-20 to-10 ℃, and the hydrolysis reaction time is 10 to 20min, preferably 15 min.

The method for synthesizing 3-decarbamoyl cefuroxime acid by using the graphene supported copper catalyst specifically comprises the following steps:

(1) putting furan ammonium salt and a graphene loaded copper catalyst into a reaction device, adding a solvent, and stirring to obtain a first mixture;

(2) dissolving 7-aminocephalosporanic acid in a sodium hydroxide solution to obtain a second mixture;

(3) adding the second mixture into the first mixture to perform amidation reaction; then adding alkali liquor for hydrolysis reaction, filtering, and crystallizing the filtrate to obtain the 3-decarbamoyl cefuroxime acid.

Wherein:

the solvent is toluene, acetone, tetrahydrofuran, N-dimethylformamide or dichloromethane, preferably tetrahydrofuran or N, N-dimethylformamide.

The using amount ratio of the solvent to the furan ammonium salt is 3-10: 1, wherein the solvent is calculated by ml, and the furan ammonium salt is calculated by g.

The mass ratio of the sodium hydroxide solution to the 7-aminocephalosporanic acid is 1.6-3: 1, and the sodium hydroxide solution is 15 wt.% of sodium hydroxide aqueous solution.

The alkali liquor is 15 wt.% of sodium hydroxide solution, and the mass ratio of the alkali liquor to the 7-aminocephalosporanic acid is 1.6-3: 1; the purpose of the addition of lye is to remove the formyl groups by hydrolysis, which is the hydrolysis of the ester.

Adding 10 wt.% hydrochloric acid into the filtrate for crystallization, filtering to obtain a filter cake which is a graphene-supported copper catalyst, washing with dichloromethane, drying, and recycling.

The furan ammonium salt and the graphene loaded copper catalyst are placed in a reaction device, and the device is closed and needs to be dried in advance.

The loading amount of copper in the graphene loaded copper catalyst is 15-20 wt% of the mass of graphene, and the preparation method comprises the following steps:

dispersing 20-25 g of graphite oxide in 10L of distilled water, performing ultrasonic treatment to form a dispersion liquid, stirring for 10-15 min, adding a sodium hydroxide solution to adjust the pH value to 10, adding 24-26 g of ascorbic acid, and stirring for 20-30 min to form a reaction liquid; dissolving 7-8 g of copper sulfate in 0.5L of distilled water to prepare a copper sulfate solution, slowly dropwise adding the copper sulfate solution into the reaction solution, and reacting at 100-110 ℃ for 1.5-2 hours. And adding distilled water after the reaction is finished, standing for layering, retaining the solution at the lower layer, respectively washing and centrifuging for 3 times by using distilled water and absolute ethyl alcohol solution, and drying the obtained solid in vacuum at 50-55 ℃ for 10-12 hours to obtain the graphene supported copper catalyst.

The reaction equation of the invention is as follows:

the invention has the following beneficial effects:

the graphene-supported copper catalyst adopted by the invention is a space three-dimensional catalyst formed by graphene oxide and copper nanoparticles. The acidic microenvironment provided by abundant carboxyl groups on the graphene oxide promotes furan ammonium salt to form a furan carboxylic acid molecular structure on the surface of the graphene under a mild environment, and then the furan ammonium salt and the amino group at the 7-amino-cephalosporanic acid position are subjected to an amidation reaction to construct a carbon-nitrogen bond under the catalysis of copper nanoparticles, so that an amidated product is finally obtained. According to the invention, the copper element is loaded on the graphene to form the co-catalysis of the copper element and the graphene, so that the method has the characteristics of high efficiency and high recycling, and the separation method is simple, is not easy to generate residues, is clean and environment-friendly, and has low comprehensive cost.

The method takes furan ammonium salt as an initial raw material, under the action of a graphene loaded copper catalyst, the furan ammonium salt is catalyzed in one step to directly carry out amidation reaction with amino on 7-ACA, and then alkali liquor is added for hydrolysis reaction, so that the 3-decarbamoyl cefuroxime acid is synthesized. The method greatly shortens the synthesis steps of the target compound, avoids the use of amidation reagents such as phosphorus oxychloride OR phosphorus pentachloride and the like, avoids the isomerization of Z-methoxyimino (C-N-OR) on the furan ammonium salt, reduces the content of trans-isomeric impurities in the target product to be below 0.05 percent, improves the product yield, has the purity of over 99 percent, has high catalyst recovery rate, can be recycled, reduces the use amount of the graphene-loaded copper catalyst, and has the characteristics of simple process operation, low cost, and reliable safety.

Drawings

Fig. 1 is a schematic structural diagram of graphene in a graphene-supported copper catalyst according to the present invention;

FIG. 2 is a hydrogen spectrum of 3-decarbamoyl cefuroxime acid product obtained in example 1 of the present invention.

Detailed Description

The present invention is further described below with reference to examples.

Example 1

Adding 22.6g (0.121mol, 1.1equiv.) of furan ammonium salt and 10g of graphene-supported copper catalyst into a closed reaction container dried in advance, adding 150mL of dichloromethane, and fully stirring at room temperature for 30 minutes to obtain a first mixture; dissolving 30g (0.11mol) of 7-aminocephalosporanic acid in 50g of 15 wt.% aqueous sodium hydroxide solution to obtain a second mixture; the second mixture was slowly added to the first mixture and the reaction was continued for 4h at 20 ℃. And then, cooling to-20 ℃, adding 50g of 15 wt.% sodium hydroxide solution, continuing to react for 20min, filtering, washing a filter cake obtained by filtering, namely the graphene-supported copper catalyst, with dichloromethane, drying, and recycling. Continuously dropwise adding 10 wt.% hydrochloric acid into the filtrate for crystallization, and filtering to obtain 37.2g of 3-decarbamoyl cefuroxime acid; the yield was 88.6%, the trans-isomeric impurity content was 0.01%, and the purity was 99.3%. The catalyst recovery was 99.6 wt.%. The hydrogen spectrum of 3-decarbamoyl cefuroxime acid is shown in FIG. 2:¹H NMR(600MHz,(CD₃)₂SO,δppm):9.77(d,J＝7.8Hz,1H),7.84(dd,J＝1.8Hz,J＝0.6Hz,1H),6.70(dd,J＝4.2Hz,J＝0.6Hz,1H),6.64-6.63(m,1H),5.76-5.74(m,1H),5.14(d,J＝4.8Hz,1H),4.29-4.22(m,2H),3.89(s,3H),3.58(dd,J＝48.6Hz,J＝18Hz,2H).

example 2

Adding 53.6g (0.288mol, 1.2equiv.) of furan ammonium salt and 20g of graphene-supported copper catalyst into a closed reaction container dried in advance, adding 300mL of acetone, and fully stirring at room temperature for 30 minutes to obtain a first mixture; dissolving 65g (0.24mol) of 7-aminocephalosporanic acid in 110g of 15 wt.% aqueous sodium hydroxide solution to obtain a second mixture; the second mixture was slowly added to the first mixture and the reaction was continued for 5h at 25 ℃. Then, cooling to-10 ℃, adding 110g of 15 wt% sodium hydroxide solution, continuing to react for 10min, filtering, obtaining a filter cake as the graphene-supported copper catalyst, washing with dichloromethane, drying, and recycling. Continuously dropwise adding 10 wt.% hydrochloric acid into the filtrate for crystallization, and filtering to obtain 85.8g of 3-decarbamoyl cefuroxime acid; the yield was 94.3%, the trans-isomeric impurity content was 0.03%, and the purity was 99.2%. The catalyst recovery was 99.7 wt.%.

Example 3

Adding 58.0g (0.312mol, 1.3equiv.) of furan ammonium salt and 25g of graphene-supported copper catalyst into a closed reaction vessel dried in advance, adding 200mLN, N-dimethylformamide, and fully stirring at room temperature for 30 minutes to obtain a first mixture; dissolving 65g (0.24mol) of 7-aminocephalosporanic acid in 130g of 15 wt.% aqueous sodium hydroxide solution to obtain a second mixture; the second mixture was slowly added to the first mixture and the reaction was continued at 10 ℃ for 8 h. And then, cooling to-10 ℃, adding 130g of 15 wt.% sodium hydroxide solution, continuing to react for 10min, filtering, washing a filter cake obtained by filtering, namely the graphene-supported copper catalyst, with dichloromethane, drying, and recycling. Continuously dropwise adding 10 wt.% hydrochloric acid into the filtrate for crystallization, and filtering to obtain 84.5g of 3-decarbamoyl cefuroxime acid; the yield was 92.9%, the trans-isomeric impurity content was 0.01%, and the purity was 99.1%. The catalyst recovery was 99.7 wt.%.

Example 4

Adding 58.0g (0.312mol, 1.3equiv.) of furan ammonium salt and 30g of graphene-supported copper catalyst into a closed reaction container dried in advance, adding 250mL of tetrahydrofuran, and fully stirring at room temperature for 30 minutes to obtain a first mixture; dissolving 65g (0.24mol) of 7-aminocephalosporanic acid in 120g of 15 wt.% aqueous sodium hydroxide solution to obtain a second mixture; the second mixture was slowly added to the first mixture and the reaction was continued for 2h at 30 ℃. Then, cooling to-15 ℃, adding 120g of 15 wt.% sodium hydroxide solution, continuing to react for 10min, filtering, obtaining a filter cake as a graphene-loaded copper catalyst, washing with dichloromethane, drying, and recycling. Continuously dropwise adding 10 wt.% hydrochloric acid into the filtrate for crystallization, and filtering to obtain 83.2g of 3-decarbamoyl cefuroxime acid; the yield was 91.4%, no trans-isomeric impurities were detected, and the purity was 99.4%. The catalyst recovery was 99.6 wt.%.

Comparative example 1

The procedure of example 1 was followed without adding the graphene-supported copper catalyst. 0g of 3-decarbamoyl cefuroxime acid is obtained; the yield was 0 wt.%, and the reaction did not proceed.

Comparative example 2

The procedure of example 2 was followed without adding the graphene-supported copper catalyst. 0g of 3-decarbamoyl cefuroxime acid is obtained; the yield was 0 wt.%, and the reaction did not proceed.

The loading amount of copper in the graphene-supported copper catalyst disclosed in embodiments 1-4 of the present invention is 20 wt.% of the mass of graphene, and the preparation method thereof is as follows:

dispersing 20g of graphite oxide in 10L of distilled water, performing ultrasonic treatment to form a dispersion liquid, stirring for 10min, adding a sodium hydroxide solution to adjust the pH value to 10, then adding 25g of ascorbic acid, and stirring for 25min to form a reaction liquid; copper sulfate solution was prepared by dissolving 8g of copper sulfate in 0.5L of distilled water, and the copper sulfate solution was slowly dropped into the reaction solution to react at 110 ℃ for 1.5 hours. And adding distilled water after the reaction is finished, standing for layering, retaining the lower layer solution, respectively washing and centrifuging for 3 times by using distilled water and absolute ethyl alcohol solution, and drying the obtained solid for 10 hours in vacuum at 50 ℃ to obtain the graphene supported copper catalyst.