CN105603037A - Method for preparing cephalosporin through enzyme catalytic acylation - Google Patents

Abstract

The invention relates to a method for preparing cephalosporins by enzyme-catalyzed acylation, comprising: A. acylation reaction, performing acylation reaction with an acylation reagent and a β-lactam core under the action of a catalytic enzyme to obtain a product slurry; B. Vibration separation, control the viscosity of the product slurry, use a vibrating sieve to vibrate and separate the product slurry under certain process conditions, and obtain the catalytic enzyme filter residue and cephalosporin suspension filtrate; C. Refining the product, mixing the cephalosporin The suspension filtrate was filtered to obtain wet powder of cephalosporin, which was washed and dried to obtain a refined product. By optimizing the process flow and process parameters, the present invention solves the problems of difficult enzyme separation, high preparation cost, and serious environmental pollution in the existing process. While ensuring product quality, it simplifies the process flow, improves separation efficiency and production efficiency. efficiency and reduce production costs.

Description

A method for preparing cephalosporins by enzyme-catalyzed acylation

technical field

The invention relates to the technical field of antibiotic synthesis, in particular to a novel preparation method of cephalosporins.

Background technique

Cephalosporins (cephalosporins) is a semi-synthetic antibiotic containing cephem in the molecule obtained by semi-synthetic modification of the side chain of the natural cephalosporin C obtained from the culture of Cephalosporus coronaris, which has a similar bactericidal mechanism. This class of drugs can destroy the cell wall of bacteria and kill bacteria during the reproduction period. It has a strong selective effect on bacteria, but has almost no toxicity to humans. It has the advantages of broad antibacterial spectrum, strong antibacterial effect, penicillinase resistance, and allergic reactions are rare compared with penicillins. Therefore, it is an important antibiotic with high efficiency, low toxicity and wide clinical application.

Currently, the green process for the synthesis of cephalosporins is enzymatic, and this process has been extensively described in patent literature. Compared with traditional chemical methods, enzymatic synthesis has obvious advantages in terms of cost reduction, process simplification, and environmental friendliness. But it still has many unsatisfactory parts, such as: there are more serious enzyme separation difficulties in the enzymatic condensation reaction process of the process of the existing enzymatic synthesis of cephalosporins, for this reason the patent document CN203569090U elaborates on the enzyme separation process. In addition, currently reported patent documents, such as patent document CN103805671B and patent document CN102656274A, have recrystallization in the production process, and the operation is relatively cumbersome.

Therefore, it is urgent to improve the enzymatic synthesis process of cephalosporins, simplify the process flow, and improve the separation efficiency and production efficiency.

Contents of the invention

The technical problem to be solved in the present invention is to provide a method for preparing cephalosporins by enzyme-catalyzed acylation, so as to solve the problems of difficult enzyme separation, high preparation cost and serious environmental pollution in the existing technology, simplify the process flow and improve the separation efficiency and production efficiency.

In order to solve the problems of the technologies described above, the technical solution adopted in the present invention is:

A method for preparing cephalosporins by enzyme-catalyzed acylation, said method comprising the following steps,

A. Acylation reaction, acylating the acylating agent and the β-lactam core under the action of a catalytic enzyme to obtain a product slurry;

B. Vibration separation, control the viscosity of the product slurry, use a vibrating sieve to vibrate and separate the product slurry under certain process conditions, and obtain the catalytic enzyme filter residue and cephalosporin suspension filtrate;

C. Refining the product, filtering the suspension filtrate of the cephalosporin to obtain wet powder of the cephalosporin, washing and drying to obtain the refined product.

The further improvement of the technical solution of the present invention lies in: the specific process of the step A is that the acylating agent is slowly added to the aqueous solution of the β-lactam nucleus within a certain period of time, the pH of the aqueous solution of the β-lactam nucleus is controlled, and then the catalytic The enzyme performs the acylation reaction at a certain temperature, controls the pH of the acylation reaction during the reaction process, and obtains a product slurry after the acylation reaction for a certain period of time.

The further improvement of the technical solution of the present invention is: in the step A, the molar ratio of the acylating agent to the β-lactam core is 1.05:1 to 1.2:1, and the mass ratio of the catalytic enzyme to the β-lactam core is 0.3 :1～2:1, the mass concentration of β-lactam nucleus aqueous solution is 30～60%, the pH of β-lactam nucleus aqueous solution is 6.5～8.5, the acylation reaction pH is 6.0～7.2, and the acylation reaction temperature is 15～ At 25°C, the feeding time of the acylating reagent is 30-120 minutes.

The further improvement of the technical solution of the present invention is: during the acylation reaction process of the step A, the pH of the acylation reaction is controlled by ammonia water, and the time from the start of the reaction to the turbidity of the reaction solution is recorded as t, when the reaction time is 2t ~ 3t , slowly add water to the reaction solution, the volume ratio of the added water to the reaction solution is 0.3:1-0.5:1; the process of adding water takes 20-60 minutes, and the HPLC method is used to judge the reaction end point during the process of adding water.

The further improvement of the technical solution of the present invention is: in the step A, the acylating agent is D-phenylglycine ester, D-phenylglycine ester salt, derivative of D-phenylglycine ester, derivative salt of D-phenylglycine ester , one of aminothioxamate and aminothioxate salts.

The further improvement of the technical solution of the present invention lies in that: in the step A, the β-lactam nucleus is one of penicillin acid derivatives and cephalosporin acid derivatives.

The further improvement of the technical solution of the present invention lies in: in the step A, the catalytic enzyme is penicillin acylase.

The further improvement of the technical solution of the present invention lies in: in the step B, the viscosity of the product slurry is controlled at 10-400 mPa·s, the filter mesh of the vibrating screen is 80-120 mesh, and the vibration frequency of the vibrating screen is 1000-3000 rpm.

The further improvement of the technical solution of the present invention is: in the step C, the solvent for washing the wet cephalosporin powder is one or more of water, acetone, and ethanol, and the drying temperature is 30-50°C.

Owing to having adopted above-mentioned technical scheme, the technical progress that the present invention obtains is:

A method for preparing cephalosporins by enzyme-catalyzed acylation of the present invention solves the problems of difficult enzyme separation, high preparation costs, and serious environmental pollution in the existing process by optimizing the process flow and process parameters, and can ensure product quality. At the same time, the process flow is simplified, the separation efficiency and production efficiency are improved, and the production cost is reduced.

By controlling the process conditions of the acylation reaction, the invention improves the conversion rate of the acylation reaction, reduces the generation of by-products, reduces the complexity of product slurry components, and lays a good foundation for the subsequent separation process.

The present invention analyzes the characteristics of the product slurry, controls the viscosity of the product slurry, creatively uses a vibrating screen to separate the components in the product slurry, solves the problem of difficult purification in the traditional process, and can make the product slurry It is separated into catalytic enzyme filter residue and cephalosporin suspension filtrate, and the cephalosporin suspension filtrate product does not need to go through a recrystallization step, and only needs simple washing to obtain a product that meets the requirements of the Pharmacopoeia. The technological process is greatly simplified and the product purity is improved.

A method for preparing cephalosporins by enzymatic acylation of the present invention can be used to prepare β-lactam antibiotics, such as cephalexin, cefadroxil, cefaclor, penicillin ampicillin, amoxicillin, cephradine, cefotaxime etc. production.

detailed description

The invention discloses a method for preparing cephalosporins by enzyme-catalyzed acylation, which comprises the following steps:

A. Acylation reaction, acylating the acylating agent and the β-lactam core under the action of a catalytic enzyme to obtain a product slurry.

The specific process of step A is that the acylating agent is slowly added to the aqueous solution of the β-lactam nucleus within a certain period of time, the pH of the aqueous solution of the β-lactam nucleus is controlled, and then a catalytic enzyme is added to carry out the acylation reaction at a certain temperature. During the reaction process, the pH of the acylation reaction is controlled, and the product slurry is obtained after the acylation reaction for a certain period of time.

Wherein, the molar ratio of the acylating agent to the β-lactam nucleus is 1.05:1-1.2:1, and the mass ratio of the catalytic enzyme to the β-lactam nucleus is 0.3:1-2:1. The mass concentration of the β-lactam nucleus aqueous solution is 30-60%, and the pH of the β-lactam nucleus aqueous solution is 6.0-8.5, preferably 7.8-8.0. The pH of the acylation reaction is 6.0-7.2, preferably 6.5-7.0. The acylation reaction temperature is 15-25° C., and the feeding time of the acylating reagent is 30-120 minutes.

During the acylation reaction, the pH of the acylation reaction was controlled by ammonia water, and the reaction end point was judged by HPLC.

Specifically, the acylating agent is one of D-phenylglycine ester, D-phenylglycine ester salt, D-phenylglycine ester derivative, D-phenylglycine ester derivative salt, aminothioxate, and aminothioxate salt.

Preferably, when the acylating agent is a derivative of D-phenylglycine ester, it may be D-p-hydroxyphenylglycine ester or D-dihydrophenylglycine ester. When the acylating agent is thioxamate, it is ethyl thioxamate.

Further preferably, the acylating agent is preferably D-phenylglycine ester salt and derivative salt of D-phenylglycine ester, and the salt-forming agent is preferably hydrochloric acid or sulfuric acid to form hydrochloride and sulfate, specifically: D-phenylglycine methyl Ester hydrochloride, D-phenylglycine ethyl ester hydrochloride, D-p-hydroxyphenylglycine methyl ester hydrochloride, D-bisphenylglycine methyl ester hydrochloride, D-phenylglycine methyl sulfate, D-benzene Glycine ethyl sulfate, D-hydroxyphenylglycine methyl sulfate, D-dihydrophenylglycine methyl sulfate, aminothioxamic acid ethyl ester hydrochloride.

The reagent type of the acylating reagent is further preferably: solid particle, solution or suspension.

Specifically, the β-lactam core is one of penicillin acid derivatives and cephalosporin acid derivatives.

Preferably, the β-lactam core can be various penicillin acid derivatives, such as 6-aminopenicillin acid (6-APA); the β-lactam core can be various cephalosporin acid derivatives, such as 7-aminocephalosporin Acidic acid (7-ACA), 7-aminodesacetoxycephalosporinic acid (7-ADCA) and 7-amino-3-chlorocephalosporinic acid (7-ACCA).

Specifically, the catalytic enzyme is penicillin acylase.

B. Oscillating separation, controlling the viscosity of the product slurry, using a vibrating sieve, and vibrating and separating the product slurry under certain process conditions to obtain catalytic enzyme filter residue and cephalosporin suspension filtrate.

In step B, the viscosity of the product slurry is controlled at 10-400 mPa·s, preferably 100-300 mPa·s, the filter screen of the vibrating screen is 80-120 mesh, and the vibration frequency of the vibrating screen is 1000-3000 rpm, preferably 2000-2500 rpm.

C. Refining the product, filtering the suspension filtrate of the cephalosporin to obtain wet powder of the cephalosporin, washing and drying to obtain the refined product.

In the step C, the solvent for washing the wet cephalosporin powder is one or more of water, acetone and ethanol, and the vacuum drying temperature is 30-50°C.

A method for preparing cephalosporins by enzymatic acylation of the present invention can be used to prepare β-lactam antibiotics, such as cephalexin, cefadroxil, cefaclor, penicillin ampicillin, amoxicillin, cephradine, cefotaxime etc. production.

Below in conjunction with embodiment the present invention is described in further detail:

Example 1

The method for preparing cephalosporins by enzyme-catalyzed acylation in this embodiment is used for preparing cephalexin.

In the present embodiment, the selected raw materials are as follows: the acylating agent selects D-phenylglycine methyl ester hydrochloride solid, the β-lactam core selects 7-aminodesacetoxycephalosporin acid (7-ADCA), and the catalyst Enzyme selection Penicillin acylase.

Specifically include the following steps:

A. Acylation reaction, acylating the acylating agent and the β-lactam core under the action of a catalytic enzyme to obtain a product slurry. The specific process is, add 60Kg (about 0.2800mol) of 7-ADCA in the reaction tank, add 80L of water, adjust the pH at 8.0 ± 0.2, obtain a 7-ADCA suspension solution with a mass concentration of 75%, and then mix it with 7-ADCA Add 30Kg of penicillin acylase to the suspension solution, then slowly add 63Kg (about 0.3124mol) of D-phenylglycine methyl ester hydrochloride solid to the 7-ADCA suspension solution within 60 minutes, and carry out at 20±1°C For the acylation reaction, ammonia water was used to control the pH of the acylation reaction at 7.0 ± 0.1 during the reaction, and the reaction liquid was a suspension throughout, and the reaction end point was judged by HPLC.

B. Oscillation separation, control the viscosity of the product slurry at 250±20mPa·s, use the filter screen as a 100-mesh vibrating sieve, and vibrate and separate the product slurry under the technological conditions of 20±2°C and the vibration frequency of the vibrating screen at 2500rpm , after shaking and separating for 1 hour, the catalytic enzyme filter residue and cephalosporin suspension filtrate were obtained.

C. the product is refined, and the cephalosporin suspension filtrate is filtered to obtain a cephalosporin wet powder filter cake. The filter cake is washed once with 50L water, then twice with 50L acetone, and dried at 40 ± 2°C. 90Kg of cephalexin was obtained, the weight yield was 150%, and the measured purity was 99.9%.

Example 2

The method for preparing cephalosporins by enzyme-catalyzed acylation in this embodiment is used for preparing cefadroxil.

In this embodiment, the selected raw materials are as follows: the acylating agent is selected from D-p-hydroxyphenylglycine methyl ester hydrochloride solid, and the β-lactam nucleus is selected from 7-aminodesacetoxycephalosporin acid (7-ADCA) , The catalytic enzyme selects penicillin acylase.

Specifically include the following steps:

A. Acylation reaction, acylating the acylating agent and the β-lactam core under the action of a catalytic enzyme to obtain a product slurry. The specific process is, add 60Kg (about 0.2800mol) of 7-ADCA in the reaction tank, add 80L of water, adjust the pH at 7.5 ± 0.2, obtain a 7-ADCA suspension solution with a mass concentration of 75%, and then mix it with 7-ADCA Add 30Kg of penicillin acylase to the suspension solution, and then slowly add 65Kg (about 0.2986mol) of D-p-hydroxyphenylglycine methyl ester hydrochloride solid to the 7-ADCA suspension solution within 60min, at 20±1℃ The acylation reaction was carried out under the following conditions. During the reaction, ammonia water was used to control the pH of the acylation reaction at 6.8 ± 0.1. The reaction solution was a suspension from beginning to end. The end point of the reaction was judged by HPLC.

B. Oscillation separation, control the viscosity of the product slurry at 200±20mPa·s, use the filter screen as a 100-mesh vibrating sieve, and vibrate and separate the product slurry under the technological conditions of 20±2°C and the vibration frequency of the vibrating screen at 2000rpm , after shaking and separating for 1 hour, the catalytic enzyme filter residue and cephalosporin suspension filtrate were obtained.

C. the product is refined, and the cephalosporin suspension filtrate is filtered to obtain a cephalosporin wet powder filter cake. The filter cake is washed once with 50L water, then twice with 50L acetone, and dried at 40 ± 2°C. 90Kg of cefadroxil was obtained, the weight yield was 150%, and the measured purity was 99.9%.

Example 3

The method for preparing cephalosporins by enzyme-catalyzed acylation in this embodiment is used for preparing amoxicillin.

In this embodiment, the selected raw materials are as follows: solid D-p-hydroxyphenylglycine methyl ester is selected as the acylating agent, 6-aminopenicillinic acid (6-APA) is selected as the β-lactam nucleus, and penicillin acylase is selected as the catalytic enzyme.

Specifically include the following steps:

A. Acylation reaction, acylating the acylating agent and the β-lactam core under the action of a catalytic enzyme to obtain a product slurry. The specific process is, add 60Kg (about 0.2778mol) of 6-APA in the reaction tank, add 100L of water, adjust the pH at 7.0 ± 0.1, obtain a 6-APA suspension solution with a mass concentration of 60%, and then mix it with 6-APA Add 30Kg of penicillin acylase to the suspension solution, then slowly add 54Kg (about 0.2986mol) of D-p-hydroxyphenylglycine methyl ester solid to the 6-APA suspension solution within 50 minutes, and carry out acylation at 20±1°C During the reaction, ammonia water is used to control the pH of the acylation reaction at 6.5 ± 0.1, the reaction solution is a suspension from beginning to end, and the end point of the reaction is judged by HPLC.

B. Oscillation separation, control the viscosity of the product slurry at 300±20mPa·s, use the filter screen as a 100-mesh vibrating sieve, and vibrate and separate the product slurry under the technological conditions of 20±2°C and the vibration frequency of the vibrating screen at 3000rpm , after shaking and separating for 1 hour, the catalytic enzyme filter residue and cephalosporin suspension filtrate were obtained.

C. The product is refined, and the cephalosporin suspension filtrate is filtered to obtain a cephalosporin wet powder filter cake. The filter cake is washed once with 30L water, then twice with 50L ethanol, and dried at 40 ± 2°C. 99Kg of amoxicillin was obtained, the weight yield was 165%, and the measured purity was 99.9%.

Example 4

The method for preparing cephalosporins by enzyme-catalyzed acylation in this embodiment is used for preparing cefaclor.

In the present embodiment, the selected raw materials are as follows: the acylating agent selects D-phenylglycine methyl ester hydrochloride, the β-lactam nucleus selects 7-amino-3-chlorocephalosporin acid (7-ACCA), and the catalytic enzyme Select penicillin acylase.

Specifically include the following steps:

A. Acylation reaction, acylating the acylating agent and the β-lactam core under the action of a catalytic enzyme to obtain a product slurry. The specific process is, add 60Kg (about 0.2557mol) of 7-ACCA in the reaction tank, add 80L of water, adjust the pH at 8.0 ± 0.2, obtain a 7-ACCA suspension solution with a mass concentration of 75%, and then mix it with 7-ACCA Add 60Kg of penicillin acylase to the suspension solution, and then slowly add 58Kg (about 0.2886mol) of D-phenylglycine methyl ester hydrochloride solid to the 7-ACCA suspension solution within 90 minutes at 20±1°C For the acylation reaction, ammonia water was used to control the pH of the acylation reaction at 7.0 ± 0.1 during the reaction, and the reaction liquid was a suspension throughout, and the reaction end point was judged by HPLC.

B. Oscillation separation, control the viscosity of the product slurry at 100±20mPa·s, use the filter screen as a 100-mesh vibrating sieve, and vibrate and separate the product slurry under the technological conditions of 20±2°C and the vibration frequency of the vibrating screen at 1000rpm , after shaking and separating for 1 hour, the catalytic enzyme filter residue and cephalosporin suspension filtrate were obtained.

C. The product is refined, and the cephalosporin suspension filtrate is filtered to obtain a cephalosporin wet powder filter cake. The filter cake is washed once with 10L water, then twice with 20L acetone, and dried at 45 ± 2°C. 87Kg of cefaclor was obtained, the weight yield was 145%, and the measured purity was 99.9%.

Example 5

The method for preparing cephalosporins by enzyme-catalyzed acylation in this embodiment is used for the preparation of penicillin ampicillin.

In this example, the selected raw materials are as follows: D-phenylglycine methyl ester hydrochloride was selected as the acylating agent, 6-aminopenicillinic acid (6-APA) was selected as the β-lactam nucleus, and penicillin acylase was selected as the catalytic enzyme.

Specifically include the following steps:

A. Acylation reaction, acylating the acylating agent and the β-lactam core under the action of a catalytic enzyme to obtain a product slurry. The specific process is as follows: add 10Kg (about 0.046mol) of 6-APA into the reaction tank, add 25L of water, adjust the pH at 8.0±0.2, and obtain a 6-APA suspension solution with a mass concentration of 40%. Then add 5Kg of penicillin acylase to the 6-APA suspension solution. Add 9.6Kg (about 0.048mol) of D-phenylglycine methyl ester hydrochloride into 15L aqueous solution to dissolve. Then slowly add the D-phenylglycine methyl ester hydrochloride solution into the 6-APA suspension solution within 90 minutes, and carry out the acylation reaction at 20±1°C. During the reaction, the pH of the acylation reaction is controlled by ammonia water. 7.0 ± 0.2, the reaction solution is a suspension from beginning to end, and the reaction end point is judged by HPLC method.

B. Vibration separation, control the viscosity of the product slurry at 200±20mPa·s, use the filter screen as a 100-mesh vibrating sieve, and vibrate the product slurry at 20±2°C, and the vibrating frequency of the vibrating screen is 2000rpm Separation, shaking and separation for 1 hour, the catalytic enzyme filter residue and cephalosporin suspension filtrate were obtained.

C. The product is refined, and the cephalosporin suspension filtrate is filtered to obtain a cephalosporin wet powder filter cake. The filter cake is washed once with 5L water, then twice with 10L acetone, and dried at 40 ± 2°C. Penicillin ampicillin 16.68Kg was obtained, the weight yield was 166.8%, and the determined purity was 99.9%.

Example 6

The method for preparing cephalosporins by enzyme-catalyzed acylation in this embodiment is used for preparing cephradine.

In this embodiment, the selected raw materials are as follows: the acylating agent is selected from D-dihydrophenylglycine methyl ester hydrochloride, the β-lactam nucleus is selected from 7-aminodesacetoxycephalosporin acid (7-ADCA), Catalytic enzyme selection penicillin acylase.

Specifically include the following steps:

A. Acylation reaction, acylating the acylating agent and the β-lactam core under the action of a catalytic enzyme to obtain a product slurry. The specific process is, add 60Kg (about 0.2804mol) of 7-ADCA in the reaction tank, add 120L of water, adjust the pH at 8.0 ± 0.2, obtain a 7-ADCA suspension solution with a mass concentration of 50%, and then mix it with 7-ADCA Add 60Kg of penicillin acylase to the suspension solution. Add 64.9Kg (about 0.3197mol) of D-dihydrophenylglycine methyl ester hydrochloride into 90L of water to dissolve. Then slowly add the solution of D-dihydrophenylglycine methyl ester hydrochloride into the 7-ADCA suspension solution within 60 minutes, and carry out the acylation reaction at 20±2°C, and use ammonia water to control the acylation reaction during the reaction The pH is 6.8±0.1, the reaction solution is a suspension throughout, and the reaction end point is judged by HPLC.

B. Oscillation separation, control the viscosity of the product slurry at 280±20mPa s, use the filter screen as a 100-mesh vibrating sieve, and vibrate and separate the product slurry under the technological conditions of 20±2°C and the vibration frequency of the vibrating screen at 2800rpm , after shaking and separating for 1 hour, the catalytic enzyme filter residue and cephalosporin suspension filtrate were obtained.

C. The product is refined, and the cephalosporin suspension filtrate is filtered to obtain a cephalosporin wet powder filter cake. The filter cake is washed once with 10L water, then twice with 20L acetone, and dried at 40 ± 2°C. 90Kg of cephradine was obtained, the weight yield was 150%, and the measured purity was 99.9%.

Example 7

The method for preparing cephalosporins by enzyme-catalyzed acylation in this embodiment is used for preparing cefotaxime.

In this embodiment, the selected raw materials are as follows: ethyl acetioxamate is selected as the acylating agent, 7-aminocephalosporanic acid (7-ACA) is selected as the β-lactam nucleus, and penicillin acylase is selected as the catalytic enzyme.

Specifically include the following steps:

A. Acylation reaction, acylating the acylating agent and the β-lactam core under the action of a catalytic enzyme to obtain a product slurry. The specific process is, add 10Kg (about 0.037mol) of 7-ACA in the reaction tank, add 20L of water, adjust the pH at 8.0 ± 0.2, and obtain a 7-ACA suspension solution with a mass concentration of 50%, and then mix it with 7-ACA Add 10Kg of penicillin acylase to the suspension solution. Add 10.8Kg (about 0.044mol) of ethyl thioxamate to 20L of water to dissolve, then slowly add the solution of ethyl thioxamate to the 7-ACA suspension within 90 minutes, and carry out the acylation reaction at 20±2°C During the reaction process, ammonia water is used to control the pH of the acylation reaction at 6.5 ± 0.1, the reaction solution is a suspension throughout, and the reaction end point is judged by HPLC.

B. Vibration separation, control the viscosity of the product slurry at 300±20mPa·s, use the filter screen as a 100-mesh vibrating sieve, and vibrate the product slurry at 20±2°C, and the vibrating frequency of the vibrating screen is 3000rpm Separation, shaking and separation for 1 hour, the catalytic enzyme filter residue and cephalosporin suspension filtrate were obtained.

C. the product is refined, and the cephalosporin suspension filtrate is filtered to obtain the cephalosporin wet powder filter cake. The filter cake is washed once with 5L, then washed twice with 10L acetone, and dried at 45 ± 2°C to obtain Cefotaxime 14.3Kg, the weight yield is 143%, and the determined purity is 99.9%.

Claims (9)

1. enzyme-catalysed acylation is prepared a method for cynnematin, it is characterized in that: said method comprising the steps of,

A. acylation reaction is carried out acylation reaction by acylating reagent and beta-lactam core under the effect of catalyzing enzyme, obtains product slip;

B. concussion separates, and controls product slip viscosity, adopts shaking screen, under certain process conditions, product slip is shaken to separation, obtains catalyzing enzyme filter residue and cynnematin suspendible filtrate;

C. product is refining, and cynnematin suspendible filtrate is filtered, and obtains cynnematin wet-milling, through washing, dry, obtains refined products.

2. a kind of enzyme-catalysed acylation according to claim 1 is prepared the method for cynnematin; it is characterized in that: the detailed process of described steps A is; acylating reagent is slowly joined within a certain period of time in the beta-lactam core suspension solution that contains catalyzing enzyme; control the pH of beta-lactam core suspension solution; carry out at a certain temperature acylation reaction; in course of reaction, control the pH of acylation reaction, after acylation reaction certain hour, obtain product slurry.

3. a kind of enzyme-catalysed acylation according to claim 2 is prepared the method for cynnematin; it is characterized in that: in described steps A; the mol ratio of acylating reagent and beta-lactam core is 1.05:1～1.2:1; catalyzing enzyme is 0.3:1～2:1 with the mass ratio according to beta-lactam core; the mass concentration of beta-lactam core suspension solution is 30～60%; the pH of beta-lactam core suspension solution is 6.5～8.5; acylation reaction pH is 6.0～7.2; acylation reaction temperature is 15～25 DEG C, and the feed time of acylating reagent is 30～60min.

4. a kind of enzyme-catalysed acylation according to claim 3 is prepared the method for cynnematin, it is characterized in that: in the acylation reaction process of described steps A, by ammoniacal liquor control acylation reaction pH, use HPLC method to judge reaction end.

5. a kind of enzyme-catalysed acylation according to claim 3 is prepared the method for cynnematin; it is characterized in that: in described steps A, acylating reagent is derivative salt, cefotaxime acid esters, cefotaxime acid esters salt wherein a kind of of derivative, the D-PG ester of D-PG ester, D-PG ester salt, D-PG ester.

6. a kind of enzyme-catalysed acylation according to claim 3 is prepared the method for cynnematin, it is characterized in that: in described steps A, beta-lactam core is the wherein a kind of of penicillinic acid derivative, cynnematin acid derivative.

7. a kind of enzyme-catalysed acylation according to claim 3 is prepared the method for cynnematin, it is characterized in that: in described steps A, catalyzing enzyme is PA ase.

8. a kind of enzyme-catalysed acylation according to claim 1 is prepared the method for cynnematin; it is characterized in that: in described step B; product slurry viscosity is controlled at 10～400mPas, filter screen 80～120 orders of shaking screen, and the frequency that shakes of shaking screen is 1000～3000rpm.

9. a kind of enzyme-catalysed acylation according to claim 1 is prepared the method for cynnematin, it is characterized in that: in described step C, the solvent of washing cynnematin wet-milling be water, acetone, ethanol wherein one or more, baking temperature is 30～50 DEG C.