阅读说明：本技术 一种头孢丙烯的制备方法 (Preparation method of cefprozil ) 是由 杨虎星 韩雪英 刘玉良 温雄飞 于 2020-12-29 设计创作，主要内容包括：本发明公开了一种头孢丙烯的制备方法,所述制备方法为首先将APCA与TMC和HMDS发生硅烷化反应,将HPDS与DMF和CBE形成混酐溶液,然后将硅烷化反应后的反应液与混酐溶液发生酰化反应,反应结束后经酸化水解、分层,水相中加入DMF,结晶得到头孢丙烯DMF复合物,然后将头孢丙烯DMF复合物加入水中进行转化反应,结晶得到头孢丙烯；其中,HPDS的投料摩尔量为APCA的投料摩尔量的1.05～1.20倍,CBE的投料摩尔量为HPDS的投料摩尔量的0.95～1.02倍。本发明的制备方法收率高且能够降低杂质(Z)-头孢丙烯乙氧基甲酸酯的产生,使头孢丙烯产品符合欧盟药典标准。(The invention discloses a preparation method of cefprozil, which comprises the steps of firstly, carrying out silanization reaction on APCA, TMC and HMDS, forming mixed anhydride solution by HPDS, DMF and CBE, then carrying out acylation reaction on the reaction solution after silanization reaction and the mixed anhydride solution, carrying out acidification hydrolysis and layering after the reaction is finished, adding DMF into a water phase, crystallizing to obtain a cefprozil DMF compound, then adding the cefprozil DMF compound into water for conversion reaction, and crystallizing to obtain cefprozil; wherein the feeding molar weight of the HPDS is 1.05-1.20 times of that of the APCA, and the feeding molar weight of the CBE is 0.95-1.02 times of that of the HPDS. The preparation method has high yield, can reduce the generation of impurity (Z) -cefprozil ethoxy formate, and ensures that the cefprozil product meets the European Union pharmacopoeia standard.)

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

(1) performing silanization reaction on cefprozil parent nucleus 7-amino-3-propenyl-4-cephalosporanic acid, trimethylchlorosilane and hexamethyldisilazane in dichloromethane,

(2) reacting p-hydroxyphenylglycine dane potassium salt with N, N-dimethylformamide and ethyl chloroformate in dichloromethane to form a mixed anhydride solution,

(3) mixing the reaction liquid obtained after the silanization reaction in the step (1) with the mixed anhydride solution obtained in the step (2) for acylation reaction, after the reaction is finished, acidifying, hydrolyzing and layering, then adding N, N-dimethylformamide into a water phase, separating out a solid, filtering, adjusting the pH of the filtrate to 5.5-6.0 by using ammonia water, crystallizing to obtain a cefprozil DMF compound,

(4) adding the cefprozil DMF compound obtained in the step (3) into water for conversion reaction, crystallizing after the reaction is finished, and washing the crystal with water to obtain cefprozil;

wherein the feeding molar weight of the p-hydroxyphenylglycine dane potassium salt is 1.05-1.20 times of that of the 7-amino-3-propenyl-4-cephalosporanic acid,

the feeding molar weight of the ethyl chloroformate is 0.95-1.02 times of that of the p-hydroxyphenylglycine dane potassium salt.

2. The process for producing cefprozil according to claim 1, wherein: and (3) adding the cefprozil naphthol compound when adding the N, N-dimethylformamide into the water phase.

3. The process for producing cefprozil according to claim 2, wherein: the preparation method of the cefprozil naphthol compound comprises the following steps: and (4) collecting the mother liquor and the washing water in the step (4), adding 2, 7-dihydroxynaphthalene, crystallizing, and drying crystals to obtain the cefprozil naphthol compound.

4. The process for producing cefprozil according to claim 3, wherein: the feeding mass of the 2, 7-dihydroxy naphthalene is 0.5-2 kg per 100L of the mixed solution of the mother liquor and the washing water.

5. The process for producing cefprozil according to claim 1, wherein: and (2) heating the silylation reaction in the step (1) to reflux, and reacting for 3-8 h in a reflux state.

6. The process for producing cefprozil according to claim 1, wherein: in the step (1), the feeding molar weight ratio of the 7-amino-3-propenyl-4-cephalosporanic acid to the trimethylchlorosilane to the hexamethyldisilazane is 1.1-1.3: 0.9-1.1: 1.

7. The process for producing cefprozil according to claim 1, wherein: the step (2) is specifically as follows:

adding the p-hydroxyphenylglycine dane potassium salt into the dichloromethane, cooling to-60-70 ℃, adding the N, N-dimethylformamide, adding the ethyl chloroformate, and controlling the temperature to be-40 +/-2 ℃ to react for 1.5-2.5 h.

8. The process for producing cefprozil according to claim 1, wherein: the reaction temperature of the acylation reaction in the step (3) is-50 to-75 ℃, and the reaction time is 1 to 4 hours.

9. The process for producing cefprozil according to claim 1, wherein: the ratio of the feeding volume of water in the conversion reaction to the feeding mass of the cefprozil DMF compound in the step (4) is 1-3 mL/g, and the temperature of the conversion reaction is 30-38 ℃.

10. The process for producing cefprozil according to claim 1, wherein: the preparation method specifically comprises the following steps:

(1) adding trimethylchlorosilane and hexamethyldisilazane into a cefprozil parent nucleus 7-amino-3-propenyl-4-cephalosporanic acid system in dichloromethane, heating and refluxing to perform a silanization reaction;

(2) adding p-hydroxyphenylglycine dane potassium salt into dichloromethane, cooling to-60-70 ℃, adding N, N-dimethylformamide, adding ethyl chloroformate, and controlling the temperature to be-40 +/-2 ℃ to react to form a mixed anhydride solution;

(3) cooling the reaction liquid obtained in the step (1) after the silanization reaction, dropwise adding the reaction liquid into the mixed anhydride solution obtained in the step (2), controlling the temperature to be between 50 ℃ below zero and 75 ℃ below zero for reaction, adding water and hydrochloric acid for hydrolysis and layering after the reaction is finished, taking water and adding N, N-dimethylformamide and cefprozil naphthol compound, filtering, removing precipitated inorganic salt solid, controlling the temperature to be between 25 ℃ and 28 ℃, dropwise adding ammonia water into the filtrate to adjust the pH value to be between 5.5 and 6.0 to precipitate crystals, and then carrying out crystal growing, filtering and acetone washing on the crystals to obtain a cefprozil DMF compound;

(4) adding the cefprozil DMF compound obtained in the step (3) into water, controlling the temperature to be 30-38 ℃ for conversion reaction, cooling and growing crystals after the reaction is finished, filtering, washing the crystals with water, and drying to obtain cefprozil;

(5) and (3) collecting the mother liquor and the washing water in the step (4), adding 2, 7-dihydroxynaphthalene, reacting for 1.5-2.5 h at 20-25 ℃, cooling to below 10 ℃, growing crystals for 25-35 min, washing the crystals with acetone, and drying to obtain the cefprozil naphthol compound.

Technical Field

The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of cefprozil.

Background

Cefprozil (Cefprozil hydrate) is sold as compound or hundred million, and the main component and the chemical name of the Cefprozil (Cefprozil hydrate) are (6R,7R) -7- [ [ (2R) -2-amino-2- (4-hydroxyphenyl) acetyl ] amino ] -8-oxo-3- [ (E) -prop-1-enyl ] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid hydrate, and the molecular formula is as follows: C18H19N3O5SH2O, molecular weight: 407.44, having the formula:

cefprozil is an oral cephalosporin antibiotic developed by Bristol-Myers, Tokyo research institute, USA, and approved by FDA in 1992 at 12 months. The second generation cephalosporin drugs of cefprozil have broad-spectrum antibacterial action. The bactericidal mechanism of the drug is that the bacterial cell wall synthesis is blocked by combining with Penicillin Binding Proteins (PBPs) on bacterial cell membranes, thereby causing bacterial lysis and death. The common dosage forms of the medicine comprise tablets, capsules, dispersible tablets, chewable tablets, granules, dry suspensions and the like. Is used as bacteriostatic agent. Used for treating upper respiratory tract infection and lower respiratory tract infection caused by sensitive bacteria; staphylococcus aureus (including penicillinase-producing strains) and Streptococcus pyogenes cause uncomplicated skin and skin soft tissue infections, among others.

Regarding the chemical synthesis of cefprozil, two synthetic routes exist in the prior art: the first method is that APCA is used as a starting material and is dissolved by tetramethylguanidine, HPDS and pivaloyl chloride form a mixed anhydride solution, the two are mixed to carry out acylation reaction under the condition of ultralow temperature, then acidification hydrolysis, delamination and DMF crystallization are carried out by adding DMF into a water phase to obtain a cefprozil DMF compound, and the cefprozil DMF compound is converted in hot water to obtain cefprozil. The cefprozil obtained by the method has low yield, the molar yield is less than 80%, the appearance character is faint yellow powder, the quality of the powder accords with the standard of Chinese pharmacopoeia, but the powder has no market advantage, and the powder is not suitable for industrial production. The specific route is as follows:

and the second is to synthesize cefprozil by using APCA as a starting material and carrying out silanization, acylation reaction with mixed anhydride formed by p-hydroxyphenylglycine dane potassium salt, acidification hydrolysis, layering, crystallization of aqueous phase by adding DMF and ammonia water to form DMF solvate, conversion and other main reaction steps. The domestic chemical synthesis method is mainly based on the second route, the yield is about 80 percent, and the quality accords with Chinese pharmacopoeia but does not accord with European Union and United states pharmacopoeia.

The enzymatic synthesis of cefprozil is reported in open at home and abroad, and compared with the prior art, the biological enzymatic synthesis has the characteristics of less pollution, low synthesis cost, less side reaction compared with chemical synthesis and high quality, and only takes water as a medium. The synthesis of cefprozil by a chemical method needs to have new breakthrough in quality and yield so as to have industrial value and market advantage. Through analysis, the items that cefprozil synthesized by a chemical method does not accord with European Union pharmacopoeia are mainly related impurities M, the impurities can not be detected by adopting Chinese pharmacopoeia, the impurities M are detected by using the method of European Union pharmacopoeia (EP) version 8.0, the impurities M exceed the standard by 0.4-0.5%, and other impurities basically accord with the requirements. The structural formula of cefprozil impurity M in EP8.0 is: (Z) -Cefprozil EthoxyformateEP8.0 cefprozil reference substance:

therefore, the existing chemical synthesis method needs to be improved, so that the cefprozil product meets the European Union pharmacopoeia standard and has industrial production value and market advantages.

Disclosure of Invention

The invention aims to solve the technical problem of providing a chemical preparation method of cefprozil, which meets the standards of European Union pharmacopoeia.

In order to solve the technical problems, the invention adopts the following technical scheme:

the invention provides a preparation method of cefprozil, which comprises the following steps:

(1) performing silanization reaction on cefprozil mother nucleus 7-amino-3-propenyl-4-cephalosporanic acid (APCA), Trimethylchlorosilane (TMC) and Hexamethyldisilazane (HMDS) in dichloromethane,

(2) reacting p-hydroxyphenylglycine dane potassium salt (HPDS), N-Dimethylformamide (DMF) and ethyl Chloroformate (CBE) in dichloromethane to form a mixed anhydride solution,

(3) mixing the reaction liquid obtained after the silanization reaction in the step (1) with the mixed anhydride solution obtained in the step (2) for acylation reaction, after the reaction is finished, acidifying, hydrolyzing and layering, then adding N, N-dimethylformamide into a water phase, separating out a solid, filtering, adjusting the pH of the filtrate to 5.5-6.0 by using ammonia water, crystallizing to obtain a cefprozil DMF compound,

(4) adding the cefprozil DMF compound obtained in the step (3) into water for conversion reaction, crystallizing after the reaction is finished, and washing the crystal with water to obtain cefprozil;

wherein the feeding molar weight of the p-hydroxyphenylglycine dane potassium salt (HPDS) is 1.05-1.20 times of that of the 7-amino-3-propenyl-4-cephalosporanic acid (APCA),

the feeding molar weight of the ethyl Chloroformate (CBE) is 0.95-1.02 times of that of the p-hydroxyphenylglycine dane potassium salt (HPDS).

Preferably, the water used in the present invention is purified water, i.e. water containing no or very low amounts of impurities.

Preferably, the cefprozil naphthol complex is also added when the N, N-dimethylformamide is added to the aqueous phase in step (3).

Further preferably, the preparation method of the cefprozil naphthol compound comprises the following steps: and (4) collecting the mother liquor and the washing water in the step (4), adding 2, 7-dihydroxynaphthalene, crystallizing, and drying crystals to obtain the cefprozil naphthol compound.

Further preferably, the preparation method of the cefprozil naphthol compound in the step (3) specifically comprises the following steps: and (3) collecting the mother liquor and the washing water in the step (4), adding 2, 7-dihydroxynaphthalene, reacting for 1.5-2.5 h at 20-25 ℃, cooling to below 10 ℃, growing crystals for 25-35 min, washing the crystals with acetone, and drying to obtain the cefprozil naphthol compound.

More preferably, the amount of the 2, 7-dihydroxynaphthalene charged is 0.5 to 2kg, and still more preferably 0.8 to 1.6kg per 100L of the mixed solution of the mother liquor and the washing water.

Preferably, the silylation reaction in the step (1) is carried out under the condition of heating to reflux and reacting for 3-8 h in a reflux state.

Further preferably, the reflux temperature is 42-44 ℃, and the reflux reaction time is 4-6 h.

Preferably, the feeding molar weight ratio of the 7-amino-3-propenyl-4-cephalosporanic acid, the trimethylchlorosilane and the hexamethyldisilazane in the step (1) is 1.1-1.3: 0.9-1.1: 1.

Preferably, the step (2) is specifically as follows:

adding the p-hydroxyphenylglycine dane potassium salt into the dichloromethane, cooling to-60-70 ℃, adding the N, N-dimethylformamide, adding the ethyl chloroformate, and controlling the temperature to be-40 +/-2 ℃ to react for 1.5-2.5 h.

Preferably, the reaction temperature of the acylation reaction in the step (3) is-50 to-75 ℃, and more preferably-60 to-70 ℃.

Preferably, the reaction time of the acylation reaction in the step (3) is 1-4 h, and further preferably 2-3 h.

Preferably, concentrated hydrochloric acid and water are used for the acidification hydrolysis in step (3).

Further preferably, the feeding volume ratio of the concentrated hydrochloric acid to the water is 4-5: 1.

The concentrated hydrochloric acid described herein is a commercially available concentrated hydrochloric acid having a substance concentration of 12 mol/L.

Preferably, the ratio of the feeding volume of water in the conversion reaction in the step (4) to the feeding mass of the cefprozil DMF complex is 1-3 mL/g, and further preferably 1.5-2.5 mL/g.

Preferably, the temperature of the conversion reaction in the step (4) is 30-38 ℃, and more preferably 32-35 ℃.

According to a particular embodiment, the conversion reaction comprises the following specific steps: and (3) controlling the temperature to be 30-38 ℃, slowly adding the cefprozil DMF compound wet product into water in 90-120 min in several times, separating out a large amount of white crystals in the process, washing the inner wall of the container by using a small amount of water after the addition, reducing the temperature to grow crystals, filtering to obtain crystals, washing the crystals by using water, and finally drying in vacuum.

According to a specific embodiment, the preparation method specifically comprises the following steps:

(1) adding trimethylchlorosilane and hexamethyldisilazane into a cefprozil parent nucleus 7-amino-3-propenyl-4-cephalosporanic acid system in dichloromethane, heating and refluxing to perform a silanization reaction;

(2) adding p-hydroxyphenylglycine dane potassium salt into dichloromethane, cooling to-60-70 ℃, adding N, N-dimethylformamide, adding ethyl chloroformate, and controlling the temperature to be-40 +/-2 ℃ to react to form a mixed anhydride solution;

(3) cooling the reaction liquid obtained in the step (1) after the silanization reaction, dropwise adding the reaction liquid into the mixed anhydride solution obtained in the step (2), controlling the temperature to be between 50 ℃ below zero and 75 ℃ below zero for reaction, adding water and hydrochloric acid for hydrolysis and layering after the reaction is finished, taking water and adding N, N-dimethylformamide and cefprozil naphthol compound, filtering, removing precipitated inorganic salt solid, controlling the temperature to be between 25 ℃ and 28 ℃, dropwise adding ammonia water into the filtrate to adjust the pH value to be between 5.5 and 6.0 to precipitate crystals, and then carrying out crystal growing, filtering and acetone washing on the crystals to obtain a cefprozil DMF compound;

(4) adding the cefprozil DMF compound obtained in the step (3) into water, controlling the temperature to be 30-38 ℃ for conversion reaction, cooling and growing crystals after the reaction is finished, filtering, washing the crystals with water, and drying to obtain cefprozil;

(5) and (3) collecting the mother liquor and the washing water in the step (4), adding 2, 7-dihydroxynaphthalene, reacting for 1.5-2.5 h at 20-25 ℃, cooling to below 10 ℃, growing crystals for 25-35 min, washing the crystals with acetone, and drying to obtain the cefprozil naphthol compound.

In the invention, by controlling the feeding ratio of HPDS and APCA and the feeding ratio of CBE and HPDS and combining the adjustment of the whole process, the obtained cefprozil has white-like appearance and less impurities, the purity reaches more than 99.5 percent (Z + E type), the impurity M detected by the EP8.0 method is less than or equal to 0.10 percent and is far lower than the standard and less than or equal to 0.30 percent, and other items all accord with the European Union standard.

According to the invention, the cefprozil naphthol compound is used after hydrolysis and layering, so that the crystallization amount of the cefprozil DMF compound is increased, the aim of increasing the yield of cefprozil products is finally achieved, the weight yield of the obtained cefprozil is more than 1.45 (calculated by APCA), and the molar yield is more than 85%. In addition, the cefprozil naphthol compound is recovered through mother liquor. The cefprozil naphthol compound is applied mechanically after the next batch of hydrolysis and delamination, thereby further reducing the waste and the cost.

The preparation method has industrial production value, and the obtained product has market advantages.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

the purity of the cefprozil prepared by the invention meets the European Union standard, has obvious economic benefit and is beneficial to realizing industrial production.

Detailed Description

The present invention will be further described with reference to the following examples. However, the present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not mentioned are conventional conditions in the industry. The technical features of the embodiments of the present invention may be combined with each other as long as they do not conflict with each other.

Example 1

Adding 100g (0.4168mol) of APCA and 430ml of dichloromethane into a 1000ml dry reaction bottle, adding 56g (0.3468mol) of HMDS, dropwise adding 37.7g (0.3468mol) of TMC and 10ml of dichloromethane for washing, heating to 42-44 ℃, carrying out reflux, timing reflux for 6h, and cooling to-25-30 ℃; 2000ml of dry reaction flask, 138.8g (0.4576mol) of HPDS, 420ml of dichloromethane, liquid nitrogen cooled to-60-70 ℃, 300ml of DMF, 49g (0.4516mol) of CBE and 20ml of dichloromethane washed, temperature controlled to-40 +/-2 ℃ for reaction for 2 hours, colorless clear liquid. And after the reaction is finished, cooling to-75-80 ℃, transferring the reflux liquid into the mixed anhydride, finishing the reaction for 10min, washing with 20ml of dichloromethane, controlling the temperature to be-60-70 ℃, reacting for 2-3 hours, and measuring 0.48mg/ml of APCA residue by HPLC. And after acylation is qualified, adding a mixed solution of 250ml of purified water and 55ml of concentrated hydrochloric acid, stirring for 30min, standing for layering, slowly adding 1000ml of DMF into the upper water phase, adding about 20g (batch output) of cefprozil naphthol compound, stirring for 20min, filtering, and washing with 100ml of DMF. Dropping ammonia water solution, controlling the temperature at 25-28 deg.c and lowering the temperature below 10 deg.c for crystal growth for 30min to reach pH 5.89 within 2 hr. Filtration, washing with 600ml DMF and washing with 400ml acetone. 230g of cefprozil DMF complex wet product is obtained.

And (3) transformation: and (3) adding 230g of the cefprozil DMF compound wet product into a 1000ml reaction bottle slowly in several times within 90-120 min by controlling the temperature of 32-35 ℃ with 460ml of purified water, washing the bottle wall with 10ml of purified water, filtering, washing with 200ml of purified water, and drying in vacuum to obtain 146.3g of a cefprozil (BX) finished product.

Mother liquor recovery: and (3) converting the mother liquor, adding 10g of 2, 7-dihydroxynaphthalene into about 800ml of water washing liquor, stirring for 2 hours at the temperature of 20-25 ℃, cooling to the temperature below 10 ℃, growing crystals for 30 minutes, filtering, washing with 100ml of acetone, and drying in vacuum to obtain about 20.5g of cefprozil naphthol compound.

Yield: the molar yield is 86.1%; quality: the characters are white, the maximum single impurity content in Chinese pharmacopoeia standards is 0.02%, the total impurity content is 0.13%, and all items meet the Chinese pharmacopoeia standards; eu standard impurity M: 0.05 percent and 99.78 percent of purity, and all the items meet the European Union pharmacopoeia standard.

Example 2:

adding 100g (0.4168mol) of APCA and 430ml of dichloromethane into a 1000ml dry reaction bottle, adding 56g (0.3468mol) of HMDS, dropwise adding 37.7g (0.3468mol) of TMC and 10ml of dichloromethane for washing, heating to 42-44 ℃, carrying out reflux, timing reflux for 5h, and cooling to-25-30 ℃; 2000ml of dry reaction bottle is added with 140g (0.462mol) of HPDS and 420ml of dichloromethane, liquid nitrogen is cooled to-60 to-70 ℃, 300ml of DMF is added, 50g (0.4608mol) of CBE and 20ml of dichloromethane are added for washing, the temperature is controlled to-40 +/-2 ℃ for reaction for 2 hours, and colorless clear liquid is obtained. And after the reaction is finished, cooling to-75-80 ℃, transferring the reflux liquid into the mixed anhydride, finishing the reaction for 10min, washing with 20ml of dichloromethane, controlling the temperature to be-65-70 ℃, reacting for 2-3 hours, and measuring 0.56mg/ml of APCA residue by HPLC. And after acylation is qualified, adding a mixed solution of 250ml of purified water and 55ml of concentrated hydrochloric acid, stirring for 30min, standing for layering, slowly adding 1000ml of DMF into the upper water phase, adding about 20g (batch output) of cefprozil naphthol compound, stirring for 20min, filtering, and washing with 100ml of DMF. Dropping ammonia water solution, controlling the temperature at 25-28 deg.c and lowering the temperature below 10 deg.c for crystal growth for 30min to reach pH 5.63 within 2 hr. Filtration, washing with 600ml DMF and washing with 400ml acetone. 233g of cefprozil DMF complex wet product is obtained.

And (3) transformation: and (3) adding 233g of the cefprozil DMF compound wet product into a 1000ml reaction bottle by steps slowly within 90-120 min with 440ml of purified water and controlling the temperature to be 32-35 ℃, washing the bottle wall by 10ml of purified water after the addition, filtering, washing by 200ml of purified water, and drying in vacuum to obtain 146g of a BX finished product.

Mother liquor recovery: and (3) converting the mother liquor, adding 12g of 2, 7-dihydroxynaphthalene into about 800ml of water washing liquor, stirring for 2 hours at the temperature of 20-25 ℃, cooling to the temperature below 10 ℃, growing crystals for 30 minutes, filtering, washing with 100ml of acetone, and drying in vacuum to obtain about 21g of cefprozil naphthol compound.

Yield: the molar yield is 85.9%; quality: the characters are white, the maximum single impurity content in Chinese pharmacopoeia standards is 0.04%, the total impurity content is 0.13%, and all items meet the Chinese pharmacopoeia standards; eu standard impurity M: 0.07 percent and 99.75 percent of purity, and all the items meet the European Union pharmacopoeia standard.

Example 3:

adding 100g (0.4168mol) of APCA and 430ml of dichloromethane into a 1000ml dry reaction bottle, adding 56g (0.3468mol) of HMDS, dropwise adding 37.7g (0.3468mol) of TMC and 10ml of dichloromethane for washing, heating to 42-44 ℃, carrying out reflux, timing reflux for 4 hours, and cooling to-25-30 ℃; 2000ml of dry reaction flask, adding 145g (0.4785mol) of HPDS and 420ml of dichloromethane, cooling liquid nitrogen to-60-70 ℃, adding 300ml of DMF, adding 51.8g (0.4774mol) of CBE and 20ml of dichloromethane, washing, controlling the temperature to-40 +/-2 ℃ and reacting for 2 hours, and obtaining colorless clear liquid. And after the reaction is finished, cooling to-75-80 ℃, transferring the reflux liquid into the mixed anhydride, after 10min, washing with 20ml of dichloromethane, controlling the temperature to be-60-65 ℃, reacting for 2-3 hours, and measuring 0.73mg/ml of APCA residue by HPLC. And after acylation is qualified, adding a mixed solution of 250ml of purified water and 55ml of concentrated hydrochloric acid, stirring for 30min, standing for layering, slowly adding 1000ml of DMF into the upper water phase, adding about 20g (batch output) of cefprozil naphthol compound, stirring for 20min, filtering, and washing with 100ml of DMF. Dropping ammonia water solution, controlling the temperature at 25-28 deg.c and lowering the temperature below 10 deg.c for crystal growth for 30min to reach pH 5.72 within 2 hr. Filtration, washing with 600ml DMF and washing with 400ml acetone. 225g of cefprozil DMF complex wet product is obtained.

And (3) transformation: and (2) adding 225g of the cefprozil DMF compound wet product into a 1000ml reaction bottle slowly in several times within 90-120 min by controlling the temperature of 32-35 ℃ with 500ml of purified water, washing the bottle wall with 10ml of purified water, filtering, washing with 200ml of purified water, and drying in vacuum to obtain 145.5g of a BX finished product.

Mother liquor recovery: and (3) converting the mother liquor, adding 8g of 2, 7-dihydroxynaphthalene into about 800ml of water washing liquor, stirring for 2 hours at the temperature of 20-25 ℃, cooling to the temperature below 10 ℃, growing crystals for 30 minutes, filtering, washing with 100ml of acetone, and drying in vacuum to obtain about 20.2g of cefprozil naphthol compound.

Yield: the molar yield is 85.6%; quality: the characters are white, the maximum single impurity content in Chinese pharmacopoeia standards is 0.04%, the total impurity content is 0.16%, and all items meet the Chinese pharmacopoeia standards; eu standard impurity M: 0.10 percent and 99.69 percent of purity, and all the items meet the European Union pharmacopoeia standard.

Comparative example 1:

adding 100g (0.4168mol) of APCA and 430ml of dichloromethane into a 1000ml dry reaction bottle, adding 56g (0.3468mol) of HMDS, dropwise adding 37.7g (0.3468mol) of TMC and 10ml of dichloromethane for washing, heating to 42-44 ℃, carrying out reflux, timing reflux for 4 hours, and cooling to-25-30 ℃; 2000ml of dry reaction flask, adding 155g (0.5115mol) of HPDS and 420ml of dichloromethane, cooling liquid nitrogen to-60-70 ℃, adding 300ml of DMF, adding 58g (0.5346mol) of CBE and 20ml of dichloromethane, washing, controlling the temperature to-40 +/-2 ℃ and reacting for 2 hours, and obtaining colorless clear liquid. And after the reaction is finished, cooling to-75-80 ℃, transferring the reflux liquid into the mixed anhydride, after 10min, washing with 20ml of dichloromethane, controlling the temperature to be-60-65 ℃, reacting for 2-3 hours, and measuring 0.86mg/ml of APCA residue by HPLC. And after acylation is qualified, adding a mixed solution of 250ml of purified water and 55ml of concentrated hydrochloric acid, stirring for 30min, standing for layering, slowly adding 1000ml of DMF into the upper water phase, stirring for 20min, filtering, and washing with 100ml of DMF. And (3) dropwise adding an ammonia water solution, controlling the temperature to be 25-28 ℃ in the process until the pH value is 5.92 within 2 hours, and cooling to below 10 ℃ for crystal growth for 30 min. Filtration, washing with 600ml DMF and washing with 400ml acetone. 203g of cefprozil DMF compound wet product is obtained.

And (3) transformation: and (2) adding 203g of the cefprozil DMF compound wet product into a 1000ml reaction bottle by 500ml of purified water, controlling the temperature to be 32-35 ℃, slowly adding 10ml of purified water to wash the bottle wall within 90-120 min, filtering, washing with 200ml of purified water, and drying in vacuum to obtain 133.5g of a BX finished product.

Yield: the molar yield is 78.5%; quality: the characters are white, the maximum single impurity content in Chinese pharmacopoeia standards is 0.06%, the total impurity content is 0.22%, and all items meet the Chinese pharmacopoeia standards; eu standard impurity M: 0.43 percent is higher than 0.30 percent, the purity is 99.38 percent, and the standard of European Union pharmacopoeia is not met.

The present invention has been described in detail in order to enable those skilled in the art to understand the invention and to practice it, and it is not intended to limit the scope of the invention, and all equivalent changes and modifications made according to the spirit of the present invention should be covered by the present invention.