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

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...

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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 research and repeated tests that naproxen ester is poorly soluble in water, so that the dispersibility of naproxen ester is poor in a single aqueous medium, the concentration in the aqueous medium is very low, and the contact area with the enzyme is small. Thereby cause the problem that reaction rate is slow, therefore, the present inventor adopts the method for mechanical crushing specially, and naproxen ester is dispersed in the aqueous phase reaction medium, forms suspension slurry, thereby greatly increased the particle size of naproxen ester. The surface area effectively increases the rate of the enzymatic reaction, even without the aid of non-aqueous solvents or surfactants and other additives to achieve high-efficiency enzymatic conversion of high-concentration naproxen esters

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