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Insight into microwave assisted enzyme catalysis in process intensification of reaction and selectivity: Kinetic resolution of (R,S)-flurbiprofen with alcohols
Molecular Catalysis ( IF 3.9 ) Pub Date : 2017-07-23 , DOI: 10.1016/j.mcat.2017.06.020
Surbhi M. Gupta , Manoj P. Kamble , Ganapati D. Yadav

Biocatalysis has potential applications in pharmaceuticals, fine chemicals and drug industries for the synthesis and separation of chiral compounds. The current work deals with the kinetic resolution of (R,S)-flurbiprofen using immobilized Candida antarctica lipase B under the influence of microwave irradiation. Flurbiprofen (R,S)-[2-(3-fluro-4-phenyl) phenyl] propionic acid is one of the most widely used non-steroidal anti-inflammatory drugs (NSAID). It exists in two enantiomeric forms as (R,S)-flurbiprofen because it has a single stereogenic center. Pharmacological action of flurbiprofen resides with the S form by inhibiting Cox-2 activity and results in anti-inflammatory action and hence (R)-flurbiprofen causes gastrointestinal infection. Novozym 435 was found to be most active among others for the stereoselective esterification of the R-enantiomer in organic reaction media. Microwave irradiation shows a synergistic effect on enzyme catalysis by enhancing both rate of the reaction and conversion of R-enantiomer into an ester. Effects of various reaction parameters such as solvent, speed of agitation, mole ratio, type of alcohol, temperature, catalyst loading, and reusability were studied. Maximum conversion of R-flurbiprofen ester under microwave irradiation was found to be ∼44.4% with enantioselectivity (E) of 478, eeP = 98.9% and eeS = 79.07% in 6 h, whereas in conventional heating the maximum conversion was 17% with enantioselectivity (E) of 126, and eeS = 20.12% in 6 h. The ping-pong bi–bi mechanism with inhibition by methanol was proposed for the kinetic resolution of (R,S)-flurbiprofen and validated against experimental data.



中文翻译:

深入了解微波辅助酶催化反应和选择性的过程:(R,S)-氟比洛芬与醇的动力学拆分

生物催化在制药,精细化工和制药行业中具有潜在的应用,用于手性化合物的合成和分离。当前的工作涉及在微波辐射的影响下,使用固定化的南极假丝酵母脂肪酶B动力学拆分(R,S)-氟比洛芬。氟比洛芬(R,S)-[2-(3-氟-4-苯基)苯基]丙酸是最广泛使用的非甾体抗炎药(NSAID)之一。它以(R,S)-氟比洛芬两种对映体形式存在,因为它具有单个立体生成中心。氟比洛芬的药理作用通过抑制Cox-2活性而呈S形式存在,并具有抗炎作用,因此(R氟比洛芬引起胃肠道感染。已发现Novozym 435在有机反应介质中对R-对映异构体的立体选择性酯化活性最高。微波辐射通过提高反应速率和将R-对映异构体转化为酯均显示出对酶催化的协同作用。研究了各种反应参数的影响,例如溶剂,搅拌速度,摩尔比,醇类,温度,催化剂负载量和可重复使用性。发现R-氟比洛芬酯在微波辐射下的最大转化率约为44.4%,对映选择性(E)为478,ee P  = 98.9%,ee S 在6小时内达到79.07%,而在常规加热条件下,最大转化率为17%,对映选择性(E)为126, 在6小时内ee S = 20.12%。提出了具有甲醇抑制作用的乒乓bi-bi机理用于(R,S)-氟比洛芬的动力学拆分,并针对实验数据进行了验证。

更新日期:2017-07-23
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