Preparation method of S-(+)-naproxen fatty acyl glyceride prodrug

A technology for prodrugs of fatty acylglycerols and esters, applied in the field of preparation of S--naproxen prodrugs, can solve the problems of harsh reaction conditions, many by-products, and no stereoselectivity, so as to reduce toxic and side effects and improve drug production. effect, and the effect of expanding the scope of drug safety

Inactive Publication Date: 2014-07-23
HARBIN UNIV OF COMMERCE
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  • Summary
  • Abstract
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Problems solved by technology

But the synthesis of above-mentioned prodrug generally all uses chemical method to carry out esterification reaction after naproxen carboxylic acid chlorination first, and reaction condition is harsh, and by-product is many, also does not have stereoselectivity simultaneously, can't be in the synthesizing naproxen prodrug Simultaneous resolution of racemic (R, S)-naproxen

Method used

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  • Preparation method of S-(+)-naproxen fatty acyl glyceride prodrug
  • Preparation method of S-(+)-naproxen fatty acyl glyceride prodrug

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specific Embodiment approach 1

[0023] Specific embodiment one: the preparation method of the present embodiment S-(+)-naproxen fatty acylglyceride prodrug, carry out according to the following steps:

[0024] 1. Use molecular sieves to remove water from the vegetable oil so that the water activity is less than 0.01, then add (R, S)-naproxen to the dewatered vegetable oil, and use a homogenizer to homogenize (R, S)-naproxen Disperse in vegetable oil, add Candida columnar lipase, and then add molecular sieves, carry out enzyme-catalyzed reaction at 32°C and 300 rpm stirring conditions, and react for 3 to 6 days to obtain a mixture;

[0025] Two, adopt the method for centrifugation or filtration to remove solid, obtain oily liquid product, promptly complete the preparation of S-(+)-naproxen fatty acylglyceride prodrug; Wherein the substrate (R, S)-naproxen in step 1 The molar ratio of raw material and vegetable oil is 0.1-2:1; the mass ratio of candida cylindrica lipase and substrate (R, S)-naproxen is 1:5-10....

specific Embodiment approach 2

[0026] Embodiment 2: This embodiment differs from Embodiment 1 in that: in step 1, the molar ratio of the substrate (R, S)-naproxen to vegetable oil is 0.5-1.5:1. Others are the same as the first embodiment.

specific Embodiment approach 3

[0027] Embodiment 3: The difference between this embodiment and Embodiment 1 or 2 is that in step 1, the mass ratio of Candida cylindrica lipase to the substrate (R, S)-naproxen is 1:7-8. Others are the same as those in Embodiment 1 or 2.

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Abstract

The invention provides a preparation method of an S-(+)-naproxen fatty acyl glyceride prodrug, and relates to a preparation method of an S-(+)-naproxen prodrug. The invention aims to overcome the defect of a racemic (R,S)-naproxen concentrate and provide a method for preparing a fat-soluble S-(+)-naproxen prodrug by taking natural food raw material vegetable oil as a substrate through enzyme-catalyzed asymmetric acidolysis and esterification reaction. The method comprises the following steps: 1, dewatering the vegetable oil with a molecular sieve, adding (R,S)-naproxen, adding candida rogusa lipase, adding the molecular sieve, and reacting to obtain a mixture; and 2, removing the solids to obtain the oily liquid product. According to the invention, the carboxyl esterification of the naproxen is shielded, the gastrointestinal irritation is reduced, and the fat solubility of the naproxen is increased; and meanwhile, the splitting of the S-(+)-naproxen and the R-(+)-naproxen is realized, thereby being beneficial to improving the drug effect of the naproxen, reducing the toxic or side effect and widening the safe medication range. The method provided by the invention is used for preparing the S-(+)-naproxen prodrug.

Description

technical field [0001] The invention relates to a preparation method of S-(+)-naproxen prodrug. Background technique [0002] 2-Arylpropionates are a class of NSAIDs widely used to manage connective tissue disorders in humans, including ibuprofen, carprofen, ketoprofen, flurbiprofen, and naproxen etc. Among them, the products marked mainly include ibuprofen and naproxen, which are basic chemical drugs for antipyretic and analgesic, anti-inflammatory and anti-rheumatic. However, because it contains a carboxyl group in its structure, it is an acidic drug and has a stimulating effect on the gastric mucosa. Naproxen can cause gastrointestinal adverse reactions (having a stimulating effect on the gastric mucosa, causing gastric bleeding, ulcers, etc.), which limits its further development. application. In addition, the alpha position of naproxen contains a chiral carbon atom, and there is a pair of optically active enantiomers. The S-(+)-configuration activity of naproxen is 2...

Claims

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Application Information

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IPC IPC(8): C12P7/64
Inventor 辛嘉英王艳陈林林姜佳雯王喜军徐丹
Owner HARBIN UNIV OF COMMERCE
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