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Method of preparing semisynthetic antibiotic 6-amino penicillanic acid by ion liquid extraction penicillin and enzymic catalytic reaction coupling

A technology of aminopenicillanic acid and ionic liquids, applied in organic chemistry, fermentation, etc., can solve the problems of reduced penicillin potency, waste of energy, and high content of ionic liquids, and achieve the effect of optimizing the extraction and catalytic process and realizing recycling.

Inactive Publication Date: 2007-04-18
INST OF PROCESS ENG CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are three major disadvantages in this process: one is that the extraction process needs to lower the pH value, resulting in a decrease in the potency of penicillin and the emulsification of proteins; the other is that organic solvents pollute the environment; (Process Biochemistry, vol 8, 146-152, 1989)
However, this method does not consider the separation between the penicillin aqueous phase and the hydrophilic ionic liquid, resulting in an excessively high content of ionic liquid in the penicillin aqueous phase, which reduces the activity of subsequent enzyme catalysis and hinders the penicillin extraction reaction to produce the semi-synthetic drug intermediate 6-APA Realization of coupling process

Method used

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  • Method of preparing semisynthetic antibiotic 6-amino penicillanic acid by ion liquid extraction penicillin and enzymic catalytic reaction coupling
  • Method of preparing semisynthetic antibiotic 6-amino penicillanic acid by ion liquid extraction penicillin and enzymic catalytic reaction coupling
  • Method of preparing semisynthetic antibiotic 6-amino penicillanic acid by ion liquid extraction penicillin and enzymic catalytic reaction coupling

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Get the ionic liquid light phase of 10ml two aqueous phases, contain 47% (w / w) [C 4 mim] BF 4 , 18% (w / w) Na 2 HPO 4 12H 2 O and penicillin 1.4%, add 2ml [C 4 mim]PF 6 , oscillated for 2 minutes, and allowed to stand for stratification. It can be found that the hydrophobic phase was 5.8ml, and 80% of [C 4 mim] BF 4 was extracted into the hydrophobic phase, but less than 4% of the penicillin was extracted. The volume of the upper phase aqueous solution is 6.2ml, containing 1.44% penicillin and a small amount of Na 2 HPO 4 . Take 5ml containing penicillin and Na 2 HPO 4 15 mg of immobilized penicillin acylase was added to the aqueous solution of the solution, reacted at 37° C., and 6-aminopenicillanic acid was isolated. The measured enzyme activity was 162 IU / g, which was 85% of the activity of 190 IU / g in pure water. Get 5ml ionic liquid extraction phase, directly adopt the pure water washing of 1: 1 ratio, about 52% [C 4 mim] BF 4 separated from the hydrop...

Embodiment 2

[0043] Get the ionic liquid light phase of 10ml two-phase aqueous phase, contain 58% (w / w) [C 4 mim] BF 4 , 9.3% (w / w) Na 2 HPO 4 12H 2 O and penicillin 1%, add 1ml [C 4 mim]PF 6 , shake for 2 minutes, stand to separate layers, the hydrophobic phase is 5.5ml, 78% [C 4 mim] BF 4 Extracted into the hydrophobic phase, 6% of the penicillin was extracted. The volume of the upper phase is 5.5ml, containing 1.6% penicillin and a small amount of Na 2 HPO 4 . Take 5ml containing penicillin and Na 2 HPO 4 15 mg of immobilized penicillin acylase was added to the raffinate, reacted at 37° C., and 6-aminopenicillanic acid was isolated. The measured enzyme activity was 145 IU / g, which was 76% of the activity of 190 IU / g in pure water. Get 5ml ionic liquid extractive phase, wash with pure water 70 ℃ of 1: 1 ratio, about 93% [C 4 mim] BF 4 separated from the hydrophobic phase.

Embodiment 3

[0045] Get the ionic liquid light phase of 10ml two-phase aqueous phase, contain 34.5% (w / w) [C 4 mim] BF 4 and 21.4% (w / w) Na 2 HPO 4 12H 2 O, and penicillin 0.8%, add 1ml [C 4 mim]PF 6 , shaking for 2min, standing for stratification, it can be found that the hydrophobic phase is 3.7ml, 82% [C 4 mim] BF 4 was extracted into the hydrophobic phase, but less than 8% of the penicillin was extracted. The volume of the upper phase is 7.5ml, containing 0.9% penicillin and a small amount of Na 2 HPO 4 . Take 5ml containing penicillin and Na 2 HPO 4 15 mg of immobilized penicillin acylase was added to the aqueous solution, reacted at 37°C, and 6-aminopenicillanic acid was isolated. The measured enzyme activity was 164 IU / g, which was 85% of the activity of 190 IU / g in pure water. Get 3.5ml ionic liquid extraction phase, directly adopt the pure water washing of 1: 1 ratio, about 56% [C 4 mim] BF 4 separated from the hydrophobic phase.

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Abstract

The present invention relates to a technological process for preparing semi-synthetic antibiotic 6-aminopenicillanic acid by utilizing integrative process composed of penicillin fermentation liquor extraction and enzymatic catalysis reaction. It is characterized by that it utilizes the aqueous two-phase formed by hydrophilic ionic liquor to make penicillin be extracted into the upper phase containing ionic liquor, then utilizes hydrophobic ionic liquor to make secondary extraction so as to make the hydrophilic ionic liquor be extracted into hydrophobic phase, and the penicillin aqueous solution of raffinate phase can be directly undergone the process of enzymatic catalysis reaction, the enzyme activity can be up to above 80%.

Description

technical field [0001] The present invention relates to a process for preparing a semi-synthetic anti-drug intermediate through the integration of penicillin fermentation broth extraction and enzymatic catalytic reaction, in particular to a method for preparing semi-synthetic antibiotic 6-aminopenicillanic acid by coupling ionic liquid extraction of penicillin and enzymatic catalytic reaction . Background technique [0002] 6-APA (6-aminopenicillanic acid) is an important intermediate in the pharmaceutical industry. It uses penicillin as a raw material and is hydrolyzed under the catalysis of penicillin acylase to generate the target product 6-APA and by-product PAA (phenylacetic acid). [0003] [0004] And 6-APA can continue to synthesize other types of semi-synthetic antibiotics. The existing penicillin production method is to separate the penicillin fermentation liquid from the solid and liquid, then use an organic extraction solvent to extract the penicillin from t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/21C12P37/00
Inventor 夏寒松余江胡雪生刘庆芬刘会洲
Owner INST OF PROCESS ENG CHINESE ACAD OF SCI
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