Lipase Catalyzed Synthesis Of (S)-Naproxen Starch Ester

Naproxen((S)-(+)-2-(6-methoxy-2-naphthyl) propionic acid) is a non-steroidal anti-inflammatory drug (NSAIDs) derived from propionic acid. It has antipyretic analgesic and anti-inflammatory anti-rheumatic effect. It is popular in clinic. The effect of (S)-naproxen is 28 times better than (R)-naproxen. And (R)-naproxen has toxic side effects. The enantiomeric excess value of (S)-naproxen must be greater than 95%, that could be used in clinical medication. There are some methods had been reported to obtain (S)-naproxen, such as chemical method, chromatography and biological method. Also, the side effects of (S)-naproxen had been showed when using for clinical. Such as vomiting, dyspepsia, constipation, gastrointestinal bleeding and so on. In this thesis the (S)-naproxen starch ester has been synthesized to improve the efficacy and decrease the side effect because of its sustained release property. The synthesis by enzyme method (S)-naproxen starch ester, can improve the efficacy and played the role of sustained release. The main contents are as follows:(l)The reaction system was constructed, the products were analyzed by infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy ('HNMR) and high performance liquid chromatography (HPLC). We eventually determined the reaction substrates for the racemic naproxen methyl ester and NaOH/urea starch; the enzyme was papaya lipase; Reaction solvent was isooctane.(2)In order to make the enantiomeric excess of product higher than 95%, the reaction conditions were optimized. Optimum reaction conditions were determined:The quality ratio of naproxen methyl ester to pretreated starch was 1:1; amount of lipase (10%); the reaction temperature (50?); reaction time (141h); the volume of the organic reagent isooctane (15mL); initial aw(0.57). S-naproxen ester of starch conversion rate was 13.9%, enantiomeric excess was 97.6%.(3) Microwave has been used to promote lipase-catalyzed naproxen ester synthesis reaction. Optimum reaction conditions were determined:at microwave power (200W), reaction time (150 min), the reaction temperature (55?), amount of lipase (10%). Compared with the traditional oil bath heating method, microwave method shortened the reaction process, reduce energy consumption, increase enzyme activity and stereoselectivity, and improve the conversion rate and eep.