阅读说明：本技术 从头孢呋辛酸废渣液中回收头孢呋辛酸的方法 (Method for recovering cefuroxime acid from cefuroxime acid waste residue liquid ) 是由 付凯 孙铎 代建建 于 2020-12-29 设计创作，主要内容包括：本发明涉及医药合成技术领域,具体涉及一种从头孢呋辛酸废渣液中回收头孢呋辛酸的方法。将头孢呋辛酸废渣液溶于溶剂中,过滤,滤液中加入高分子负载型催化剂,反应,减压蒸馏,得到头孢呋辛酸。本发明将反式异构体副产品直接转换为顺式产品,不仅解决了废渣带来的环保问题,又提高了产品收率,反应过程中的顺式产物未经破坏,可由反应体系全部回收,反应过程简单,中间不消耗其他反应原材料,工艺简单,生产成本低。(The invention relates to the technical field of medicine synthesis, in particular to a method for recovering cefuroxime acid from waste residue liquid of cefuroxime acid. Dissolving the cefuroxime acid waste residue liquid in a solvent, filtering, adding a polymer supported catalyst into the filtrate, reacting, and distilling under reduced pressure to obtain the cefuroxime acid. The invention directly converts the trans-isomer byproduct into the cis-product, thereby not only solving the environmental protection problem caused by waste residue, but also improving the product yield, the cis-product in the reaction process is not damaged and can be completely recovered by a reaction system, the reaction process is simple, other reaction raw materials are not consumed in the middle, the process is simple, and the production cost is low.)

1. A method for recovering cefuroxime acid from waste residue liquid of cefuroxime acid is characterized by comprising the following steps: dissolving the cefuroxime acid waste residue liquid in a solvent, filtering, adding a polymer supported catalyst into the filtrate, reacting, and distilling under reduced pressure to obtain the cefuroxime acid.

2. The method for recovering cefuroxime acid from waste cefuroxime acid liquid as claimed in claim 1, wherein the method comprises the steps of: the preparation method of the macromolecule supported catalyst comprises the following steps: soaking the high molecular material in absolute ethyl alcohol, adding Lewis acid, refluxing, filtering, washing and drying the filter cake to obtain the catalyst.

3. The method for recovering cefuroxime acid from waste cefuroxime acid liquid as claimed in claim 2, wherein the method comprises the steps of: the dosage ratio of the high polymer material to the Lewis acid to the absolute ethyl alcohol is 5-6: 2-3: 50, wherein the high polymer material and the Lewis acid are counted in g, and the absolute ethyl alcohol is counted in ml; the Lewis acid is TiCl₄、AlCl₃Or BBr₃(ii) a The high polymer material is one or two of polyvinyl chloride or polystyrene.

4. The method for recovering cefuroxime acid from waste cefuroxime acid liquid as claimed in claim 2, wherein the method comprises the steps of: the dosage of the high-molecular load type catalyst is 0.1-2 wt% of the total mass of the filtrate.

5. The method for recovering cefuroxime acid from waste cefuroxime acid liquid as claimed in claim 1, wherein the method comprises the steps of: the dosage ratio of the cefuroxime acid waste residue liquid to the solvent is 1: 5-15, wherein the cefuroxime acid waste residue liquid is counted by g, and the solvent is counted by ml.

6. The method of claim 5, wherein the cefuroxime acid is recovered from the waste cefuroxime acid residue solution by the following steps: the dosage ratio of the cefuroxime acid waste residue liquid to the solvent is 1: 5-10, wherein the cefuroxime acid waste residue liquid is counted by g, and the solvent is counted by ml.

7. The method of claim 6, wherein the cefuroxime acid is recovered from the waste cefuroxime acid residue liquid: the solvent is one or more of water, acetone, acetonitrile, methanol, tetrahydrofuran, ethanol or DMF.

8. The method of claim 7, wherein the cefuroxime acid is recovered from the waste cefuroxime acid residue solution by the following steps: the solvent is one or two of water or acetone.

9. The method for recovering cefuroxime acid from waste cefuroxime acid liquid as claimed in claim 1, wherein the method comprises the steps of: the reaction temperature is 15-50 ℃, and the reaction time is 5-30 h.

10. The method of claim 9, wherein the cefuroxime acid is recovered from the waste cefuroxime acid residue solution by the following steps: the reaction temperature is 25-30 ℃, and the reaction time is 5-10 h.

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a method for recovering cefuroxime acid from waste residue liquid of cefuroxime acid.

Background

Cefuroxime acid is an intermediate for synthesizing cefuroxime axetil and cefuroxime sodium which are second-generation cefuroxime antibiotics. The cefuroxime antibiotics have broad-spectrum antibacterial action and wide application range, can be used for respiratory tract infection, otorhinolaryngology infection, urinary system infection, skin and soft tissue infection, bone and joint infection, gonorrhea, septicemia, meninges and other infections caused by sensitive bacteria, and are the lead varieties of the second-generation cefuroxime antibiotics.

Chinese patent CN101928292A discloses a method for preparing cefuroxime acid. The method comprises the steps of using 7-aminocephalosporanic acid (7-ACA) and methoxyimino furan acetate as raw materials, performing chloric acylation reaction, performing deacetylation to synthesize DCCF, performing nucleophilic addition of DCCF and a strong carbamylation agent chlorosulfonyl isocyanate (CSI) to obtain chlorosulfonylated cefuroxime, and hydrolyzing to obtain cefuroxime acid.

Chinese patent CN101289456A discloses a method for synthesizing cefuroxime acid, which comprises the following steps: (1) taking 7-aminocephalosporanic acid and methoxyimino furan ammonium acetate as raw materials, firstly carrying out N-acylation reaction, then hydrolyzing the acetyl at the 3-position of a reaction product, and finally crystallizing and separating MDCC in a water phase by using hydrochloric acid; (2) performing nucleophilic addition on MDCC and a strong carbamylation reagent chlorosulfonyl isocyanate in an organic solvent to obtain chlorosulfonylated cefuroxime, hydrolyzing to obtain cefuroxime acid, and crystallizing the product.

In the conventional synthesis process of cefuroxime acid, about 5-10% of trans-isomer (E-furoic acid) is generated as a by-product. In addition, a small amount of cefuroxime acid product (Z-furoic acid) is mixed into the waste liquid of cefuroxime acid. The waste residue liquid not only reduces the yield of the cefuroxime acid product, but also causes great pressure to enterprises because of the environmental protection problems of large smell, difficult treatment and the like.

The waste residue liquid of cefuroxime acid generated in the existing cefuroxime acid synthesis process is not recycled and is directly treated as micro-waste, which causes resource waste and environmental pollution. Therefore, there is a need to develop a method for recovering cefuroxime acid from cefuroxime acid waste residue liquid, which can improve the yield of cefuroxime acid and has low production cost.

Disclosure of Invention

The invention aims to provide a method for recovering cefuroxime acid from cefuroxime acid waste residue liquid, which directly converts a trans-isomer byproduct into a cis-product, solves the environmental protection problem caused by waste residue, improves the product yield, does not consume other reaction raw materials in the middle, and has low production cost.

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

the method for recovering cefuroxime acid from the waste residue liquid of cefuroxime acid comprises the following steps: dissolving the cefuroxime acid waste residue liquid in a solvent, filtering, adding a polymer supported catalyst into the filtrate, reacting, and distilling under reduced pressure to obtain the cefuroxime acid.

Wherein:

the preparation method of the macromolecule supported catalyst comprises the following steps: soaking the high molecular material in absolute ethyl alcohol for 2-3 h, adding Lewis acid under the protection of nitrogen, carrying out reflux reaction for 2-2.5 h, cooling to room temperature, filtering to remove the solvent by suction filtration, washing the filter cake with acetone, and drying at room temperature to obtain the high-molecular material.

The dosage ratio of the high polymer material to the Lewis acid to the absolute ethyl alcohol is 5-6: 2-3: 50, wherein the high polymer material and the Lewis acid are counted in g, and the absolute ethyl alcohol is counted in ml; the Lewis acid is TiCl₄、AlCl₃Or BBr₃Preferably AlCl₃(ii) a The high polymer material is one or two of polyvinyl chloride or polystyrene.

The dosage of the high-molecular load type catalyst is 0.1-2 wt% of the total mass of the filtrate.

The dosage ratio of the cefuroxime acid waste residue liquid to the solvent is 1: 5-15, preferably the dosage ratio of the cefuroxime acid waste residue liquid to the solvent is 1: 5-10, wherein the cefuroxime acid waste residue liquid is counted by g, and the solvent is counted by ml.

The solvent is one or more of water, acetone, acetonitrile, methanol, tetrahydrofuran, ethanol or DMF; preferably, the solvent is one or both of water or acetone.

The reaction temperature is 15-50 ℃, and the conversion efficiency of the trans-isomer of furoctanoic acid to Z-furoctanoic acid is the highest at the temperature. The reaction time is 5-30 h; preferably, the reaction temperature is 25-30 ℃ and the reaction time is 5-10 h.

The main components of the cefuroxime acid waste residue liquid are trans-isomer E-furoic acid and a small amount of Z-furoic acid products. The reaction scheme for the conversion of the trans-isomeric E-furoic acid to the Z-furoic acid product is shown below:

TiCl in the invention₄、AlCl₃Or BBr₃Are all Lewis acid, and under the acidic environment of the existence of the Lewis acid, the oxime ether structure C of the cefuroxime acid is N-O-CH₃The N in (2) is protonated to form N⁺And due to the strong electron-withdrawing mediated effect of O negative ions, the pi bonds on the carbon-nitrogen double bonds are polarized to form dipole bodies, so that the E-configuration in the oxime ether structure is promoted to be converted to the Z-configuration, and the trans-cefuroxime acid is converted into the cis-cefuroxime acid.

The invention has the following beneficial effects:

(1) the invention overcomes the defects of the prior art, only a small amount of polymer supported catalyst is added in the process of converting the trans-form byproduct of cefuroxime acid into cis-form product to promote the trans-form cefuroxime acid to be converted into the cis-form cefuroxime acid, no three wastes are generated in the whole conversion process, the invention is environment-friendly, and the product obtained by the method has better quality.

(2) The Lewis acid is loaded on high molecular material polyvinyl chloride (PVC) or Polystyrene (PS) to prepare the high molecular load type catalyst. The macromolecule supported catalyst is not easy to hydrolyze and simple to recover, and solves the problems of easy hydrolysis, long reaction time and difficult recovery caused by using a single catalyst. Under the action of the macromolecular supported catalyst, the purity of the cefuroxime acid product is improved.

(3) The cis-product in the reaction process of the invention is not destroyed and can be completely recovered from the reaction system, the product yield is high, the reaction process is simple, other reaction raw materials are not consumed in the middle, the process is simple, and the production cost is low.

Drawings

FIG. 1 is an HPLC chromatogram of the cefuroxime acid product of example 1;

FIG. 2 is an HPLC chromatogram of the cefuroxime acid product of comparative example 1;

FIG. 3 is an HPLC chromatogram of the cefuroxime acid product of comparative example 2;

FIG. 4 is an HPLC chromatogram of the cefuroxime acid product of comparative example 3.

Detailed Description

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

The preparation method of the polymer supported catalyst in the examples is as follows:

soaking 5-6 g of high polymer material in 50ml of absolute ethyl alcohol for 2-3 h, adding 2-3 g of Lewis acid under the protection of nitrogen for reflux reaction for 2-2.5 h, cooling to room temperature, filtering to remove the solvent by suction filtration, washing a filter cake by acetone, and drying at room temperature to obtain the high-molecular-weight organic silicon/inorganic composite material. Wherein the Lewis acid is TiCl₄、AlCl₃Or BBr₃(ii) a The high molecular material is one or two of polyvinyl chloride or polystyrene.

Example 1

Dissolving 40g of cefuroxime acid waste residue liquid (the peak area ratio of trans-isomer detected by HPLC is 6%) in 200ml of water, filtering to obtain a clear solution, and adding a high-molecular supported catalyst PVC-AlCl into the clear solution₃，PVC-AlCl₃The dosage of the cefuroxime axetil is 1 wt.% of the total mass of the clear solution, the mixture is stirred and reacted for 5 hours at the temperature of 20 ℃, and the reaction product is distilled under reduced pressure to obtain 15g of cefuroxime acid product. The chromatogram of the cefuroxime acid product detected by HPLC is shown in figure 1: the peak area ratio of the trans isomer was 0.131%. Based on the total mass of the cefuroxime acid waste residue liquid, the yield of the cefuroxime acid product is 37.5 percent, and the purity is 99.441 percent.

Examples 2 to 7

The procedure for recovering cefuroxime acid from the waste residue of cefuroxime acid was the same as in example 1, and the reaction temperature, the reaction time, the amount of the waste residue of cefuroxime acid, the type and amount of the solvent, and the type and amount of the polymer-supported catalyst were adjusted, as shown in table 1.

TABLE 1 data tables in examples 2 to 7

The quality of the cefuroxime acid products obtained in the embodiments 1 to 7 is tested, the products obtained in the embodiments 1 to 7 are all white crystalline powder, which all meet the product requirements, and the content of trans-isomer is less than 0.5%.

Comparative example 1

PVC-AlCl without adding high molecular load type catalyst₃The reaction temperature, the reaction time, the amount of the cefuroxime acid waste residue liquid, the kind and the amount of the solvent are the same as those in example 1, and the specific steps are as follows:

40g of cefuroxime acid waste residue liquid (the peak area ratio of trans-isomer detected by HPLC is 6%) is dissolved in 200ml of water, a clear solution is obtained by filtration, the clear solution is stirred and reacted for 5 hours at the temperature of 20 ℃, and the reaction is carried out under reduced pressure to obtain 14.4g of cefuroxime acid product. The chromatogram of the cefuroxime acid product detected by HPLC is shown in FIG. 2: the peak area ratio of the trans isomer was 6.0072%. Based on the total mass of the cefuroxime acid waste residue liquid, the yield of the cefuroxime acid product is 36%, and the purity is 93.5269%.

Comparative example 2

PVC-AlCl without adding high molecular load type catalyst₃The reaction temperature, the reaction time, the amount of the cefuroxime acid waste residue liquid, the kind and the amount of the solvent are the same as those in example 4, and the specific steps are as follows:

40g of cefuroxime acid waste residue liquid (the peak area ratio of trans-isomer detected by HPLC is 6%) is dissolved in 200ml of acetone/water (the volume ratio of acetone to water is 10:1), a clear solution is obtained by filtration, the clear solution is stirred and reacted for 5 hours at 25 ℃, and reduced pressure distillation is carried out, thus obtaining 13.0g of cefuroxime acid product. The chromatogram of the cefuroxime acid product detected by HPLC is shown in FIG. 3: the peak area ratio of the trans isomer was 4.6550%. Based on the total mass of the cefuroxime acid waste residue liquid, the yield of the cefuroxime acid product is 32.5 percent, and the purity is 94.8732 percent.

Comparative example 3

Mixing AlCl₃The reaction temperature, reaction time, the amount of the cefuroxime acid waste residue liquid, and the kind and amount of the solvent used as the catalyst are the same as those in example 1, and the specific steps are as follows:

dissolving 40g of cefuroxime acid waste residue liquid (the peak area ratio of trans-isomer detected by HPLC is 6%) in 200ml of water, filtering to obtain a clear solution, and adding AlCl into the clear solution₃As catalyst, AlCl₃The dosage of the cefuroxime axetil is 1 wt.% of the total mass of the clear solution, the mixture is stirred and reacted for 5 hours at the temperature of 20 ℃, and the reaction product is distilled under reduced pressure to obtain 14.0g of cefuroxime acid product. The chromatogram of the cefuroxime acid product detected by HPLC is shown in FIG. 4: the peak area ratio of the trans isomer was 1.4495%. Based on the total mass of the cefuroxime acid waste residue liquid, the yield of the cefuroxime acid product is 35%, and the purity is 98.3063%.

By comparing example 1 with comparative example 1 and example 4 with comparative example 2, when no catalyst is added, although the yield of cefuroxime acid products of comparative example 1 and comparative example 2 is not much different from that of example 1, the purity of the products is obviously lower than that of example 1; it can be seen from the comparison of example 1 with comparative example 3 that when the catalyst has only lewis acid, the yield and purity of the product of comparative example 3 are lower than those of example 1. Therefore, under the action of the macromolecular supported catalyst, the quality of the cefuroxime acid product is obviously improved, and the product quality is good.