Method for preparing (S)-naproxen by enzyme resolution of racemic naproxen ester

A naproxen ester and naproxen technology are applied in the field of enzyme separation of racemic naproxen ester preparation-naproxen, and can solve the problem of poor dispersibility of naproxen ester, slowing down the enzymatic reaction speed, naproxen Problems such as poor solubility of raw esters, to achieve the effects of low production cost, accelerated reaction speed, high chemical purity and optical purity

Inactive Publication Date: 2010-11-10
EAST CHINA UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Therefore, the technical problem to be solved in the present invention is exactly the poor solubility of naproxen ester in a single aqueous reaction medium for the existing enzymatic resolution of racemic naproxen ester to prepare (S)-naproxen. Slow down the speed of enzymatic reaction, need to introduce non-aqueous phase reaction system or add additive, thereby cause environmental pollution and reactant separation difficulty defect, provide a kind of naproxen ester enzymatic resolution preparation (S)-naproxen It is a new method that can promote the dispersion of the substrate naproxen ester in a single aqueous reaction medium, thereby increasing the concentration of the substrate and improving the reaction efficiency.
[0007] The inventor finds through extensive res...

Method used

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  • Method for preparing (S)-naproxen by enzyme resolution of racemic naproxen ester

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Example 1 Preparation of carboxylesterase BsE-NP01

[0030] Design primers:

[0031] Primer 1: 5'-TTCCATATGTCAAACCATTCATCTAGTATTCCCG-3';

[0032] Primer 2: 5'-GGATCCTTACCGTGAAATGCCTGTTTCTGCATTG-3'.

[0033] Using the extracted Bacillus subtilis CGMCC 2548 genomic DNA as a template, PCR amplification was carried out with the above-mentioned primers, and the obtained PCR product was connected to the plasmid pMD 18-T (purchased from Takara Company), transformed into Escherichia coli DH 5α, and screened. positive clone. Nucleotide sequencing was performed on the positive cloned plasmid, and the nucleotide sequence of the carboxylesterase BsE-NP01 gene of the inserted recombinant fragment was shown in SEQ ID NO.1 in the sequence table. The DNA sequence has been registered in GENBANK. The number is GQ868652. Restriction endonucleases NdeI and BamHI (purchased from Takara Company) were used to digest and ligate the recombinant plasmid obtained above and plasmid pET-11a (pu...

Embodiment 2

[0037] Mix 80g of racemic naproxen methyl ester with 500ml of tap water, place it in a high-speed smashing homogenizer JJ-2 (Jintan Experimental Instrument Branch of Shanghai Pudong Physical Optical Instrument Factory), and homogenize it at a high speed (10,000rpm, 20min) mashed. The suspension slurry of the gained racemic naproxen methyl ester was added and placed in a 2-L glass reactor, 600U of the crude carboxylesterase obtained in Example 1 was added, tap water was added to make up to a total volume of 2.0L, and the temperature was kept at 28 ℃ reaction, the stirring speed is 300rpm, the pH of the reaction solution is kept constant at 7.5 by automatic flow of concentrated ammonia water, and the reaction is terminated after 5 hours, and the conversion rate is about 36% at this time.

[0038] After the reaction was terminated, the reaction mixture was suction filtered, the filter cake was (R)-naproxen methyl ester that did not participate in the reaction, and the filtrate co...

Embodiment 3

[0040] The (R)-naproxen methyl ester filter cake collected in Example 2 was dried to about 50 g, 100 ml of methanol and 0.6 g of sodium methoxide were added, heated to reflux, and the reflux reaction was continued for 2 h. After cooling, suction filtration was performed to obtain racemization. Naproxen methyl ester 46.5g. The obtained racemic naproxen methyl ester can be directly mixed with fresh substrate and used for the next batch of enzymatic hydrolysis after homogenization.

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Abstract

The invention discloses a method for preparing (S)-naproxen by enzyme resolution of racemic naproxen ester. The method comprises the following steps of: resolving and hydrolyzing the racemic naproxen ester to form the (S)-naproxen by using esterase or lipase in an aqueous phase medium, wherein the racemic naproxen ester is mechanically disrupted, and dispersed in the aqueous phase medium to form suspended slurry, and the esterase or lipase is added to carry out hydrolysis reaction. In the method, the (R)-naproxen ester is subjected to racemization in the presence of sodium alcoholate serving as a base catalyst so as to reduce production cost and improve reaction yield. The method realizes effective dispersion of the naproxen ester in the single aqueous phase reaction medium, greatly improves the concentration of reactants, quickens reaction speed and improves the reaction yield. The comprehensive yield of the (S)-naproxen can reach 86 percent, and the optical purity can reach over 97 percent. The method has the advantages of simple process, no need of organic solvent or surfactant, and less environmental pollution.

Description

technical field [0001] The invention belongs to the field of biochemical industry, in particular to a method for preparing (S)-naproxen by enzymatic separation of racemic naproxen ester. Background technique [0002] Naproxen is an important 2-arylpropionic acid non-steroidal anti-inflammatory drug, which is widely used in the pharmaceutical industry. The anti-inflammatory activity of (S)-naproxen is 28 times that of (R)-naproxen; in order to improve the efficacy, reduce the toxic and side effects of (R)-naproxen, and expand the scope of drug safety, it is necessary to prepare optically pure Single enantiomer (S)-naproxen. [0003] (S)-naproxen with a single configuration can be obtained by chemical resolution, enzymatic asymmetric synthesis or enzymatic resolution. Considering the product yield, ease of separation and optical purity, esterase-catalyzed enantioselective hydrolysis of racemic naproxen esters has become the preferred method for the preparation of (S)-naproxe...

Claims

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Application Information

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IPC IPC(8): C12P7/40C12P41/00
CPCY02P20/582
Inventor 许建和刘想潘江赵晶
Owner EAST CHINA UNIV OF SCI & TECH
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