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Catalytic synthesis of cefprozil by immobilized penicillin acylase in a reusable two-phase aqueous system

A technology of penicillin acylase catalysis and penicillin acylase, which is applied in the direction of fermentation, can solve the problems of restricting large-scale production, inability to recycle, difficult to recycle, etc., and achieve increased yield, reduced by-products, and synthesis/hydrolysis ratio Improved effect

Inactive Publication Date: 2015-09-30
南通康鑫药业有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are few studies on the catalytic synthesis of cefprozil by penicillin acylase, and the two-phase aqueous system used for enzyme-catalyzed synthesis is also a relatively expensive and difficult-to-recover polyethylene glycol and salt system
The traditional chemical synthesis method of cefprozil has disadvantages and needs to be improved urgently. Although the enzyme-catalyzed synthesis has certain advantages, it also has certain defects. The traditional two-phase aqueous system cannot be recycled, which limits large-scale production

Method used

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  • Catalytic synthesis of cefprozil by immobilized penicillin acylase in a reusable two-phase aqueous system
  • Catalytic synthesis of cefprozil by immobilized penicillin acylase in a reusable two-phase aqueous system
  • Catalytic synthesis of cefprozil by immobilized penicillin acylase in a reusable two-phase aqueous system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] at P NB / P ADB Enzyme-catalyzed synthesis of cefprozil in a reusable two-phase aqueous system:

[0037]To P NB / P ADB A mixture with a total volume of 10 ml was formed in the two aqueous solution. Two polymers P NB with P ADB The concentration in the system is 2.5% (w / w). Then, add 3g (780u) of penicillin G acylase, add 60mmol / L ammonium sulfate to adjust the distribution coefficient of the product cefprozil in the two aqueous phases, adjust the pH of the system to 6.5, and shake the reaction mixture at 15°C After reacting for 80 hours, the yield of cefprozil as determined by liquid chromatography reached 78%, and the post-treatment was carried out by acid precipitation. The final yield was consistent with the yield determined by liquid chromatography, and the solid cefprozil product was obtained by filtration.

[0038] cefprozil 1 HNMR spectrum, mass spectrum and infrared spectrum (such as figure 1 shown). of which cefprozil 1 The HNMR data are shown in Tabl...

Embodiment 2

[0070] at P ADB / P ADBA Enzyme-catalyzed synthesis of cefprozil in a reusable two-phase aqueous system:

[0071] To P ADB / P ADBA A mixture with a total volume of 10 ml was formed in the two aqueous solution. Two polymers P ADB with P ADBA The concentration in the system is 2.5% (w / w). Then, add 3g (780u) of penicillin G acylase, add 60mmol / L ammonium sulfate to adjust the distribution coefficient of the product cefprozil in the two aqueous phases, adjust the pH of the system to 5.0, and shake the reaction mixture at 20°C After reacting for 80 hours, the yield of cefprozil determined by liquid chromatography reached 73%, and the post-treatment was carried out by acid precipitation method. The final yield was consistent with the yield determined by liquid chromatography, and the solid cefprozil product was obtained by filtration.

[0072] Cefprozil obtained through testing 1 HNMR data, mass spectral data and infrared spectrum data are the same as in Example 1.

Embodiment 3

[0074] at P ADB / Sodium citrate reusable enzyme-catalyzed synthesis of cefprozil in two-phase aqueous system:

[0075] To P ADB A mixture with a total volume of 10ml was formed in the aqueous sodium citrate two-phase solution, and the concentration of the two phase-forming substances in the system was 2.5% (w / w). Then, add 3g (780u) of penicillin G acylase, add 60mmol / L sodium dihydrogen phosphate to adjust the distribution coefficient of the product cefprozil in the two aqueous phases, adjust the pH of the system to 6.5, and place the reaction mixture at 20 The reaction was shaken at ℃ for 80 hours, and the yield of cefprozil as determined by liquid chromatography reached 75%. The acid precipitation method was used for post-treatment, and the final yield was consistent with the yield determined by liquid chromatography. The solid cefprozil product was obtained by filtration.

[0076] Cefprozil obtained through testing 1 HNMR data, mass spectral data and infrared spectrum d...

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Abstract

The invention discloses a method for catalyzing the synthesis of cefprozil by immobilized penicillin acylase in a reusable two-water phase system, which comprises dissolving cefprozil mother nucleus and acylating agent in the two-water phase polymer solution, and dissolving the mother nucleus The molar ratio to the acylating reagent is 1:1~4, add the immobilized penicillin G acylase and then add the two-phase partition regulator, adjust the pH=4.5~7, react at 5~30°C for 1~80h, the enzyme is in the reaction The concentration in the system is 50~150U / ml. The method of the invention can effectively inhibit the hydrolysis activity of the penicillin acylase, thereby reducing the hydrolysis degree of the acylating reagent and the hydrolysis product. Compared with the method using water as the medium, this method allows the product and the enzyme to be distributed in two different water phases, the reactants are fully in contact with the enzyme, the synthesis / hydrolysis ratio is greatly improved, and the yield of cefprozil can be increased 20%, the highest yield reached 78%. The invention adopts a novel reusable two-water phase system, the system is recycled and reused, and the production cost is reduced.

Description

technical field [0001] The invention relates to a preparation method of cefprozil, in particular to a method for catalyzing the synthesis of cefprozil by using immobilized penicillin acylase in a reusable two-water phase system. Background technique [0002] Cefprozil (Cefprozil), is a broad-spectrum cephalosporin antibacterial drug. It has strong antibacterial activity against G+, G-bacteria and anaerobic bacteria, especially against G+ bacteria, and is stable against β-lactamase. It is mainly used for the treatment of otitis media, respiratory tract infections, skin and skin soft tissue infections, etc. Cefprozil has high bioavailability, complete gastrointestinal absorption, broad antibacterial spectrum and good stability. It is a semi-synthetic cephalosporin drug with good development prospects. [0003] The chemical synthesis of cefprozil mainly contains two kinds of methods, and one is to use the cephalosporin mother nucleus as starting material, introduce propenyl at...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P35/04
Inventor 曹学君祝超慧唐子安赵志炎李玉丹陈佳伶
Owner 南通康鑫药业有限公司
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