Lipase Assisted (S)-Ketoprofen Resolution from Commercially Available Racemic Mixture.
Lipase Assisted (S)-Ketoprofen Resolution from Commercially Available Racemic Mixture.
复制标题
脂肪酶辅助（S）酮酮从市售的外消毒混合物中分辨率。
DOI：
10.3390/ph14100996
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发表时间：
2021-09-29
期刊：
影响因子：
--
通讯作者：
Chávez-Flores D
中科院分区：
文献类型：
--
作者：
Estrada-Valenzuela D;Ramos-Sánchez VH;Zaragoza-Galán G;Espinoza-Hicks JC;Bugarin A;Chávez-Flores D
酮洛芬是一种市售药物，作为外消旋混合物出售，属于非甾体抗炎药家族，称为普罗芬。已经证明（体外）（S）-酮洛芬的效力比其对映体（R）-酮洛芬高约160倍，而（R）-酮洛芬的积累可引起严重的副作用，如消化不良、胃肠道溃疡/出血、疼痛、盐和液体潴留以及高血压。在这项工作中，四个市售脂肪酶进行了系统评估。被认为是参数，如转化率，对映体过量，和对映体选择性。通过对脂肪酶负载量、温度、溶剂和乙醇的综合评价，发现Candida rugosa脂肪酶的对映体选择性E = 185（（S）-对映体参比），酯化转化率c = 47%（50%），对映体过量99%。通过液-液萃取回收未反应的（R）-对映体，并在碱性介质下进行外消旋化，其作为起始原料再循环。最后，（S）-烷基酮洛芬酯被成功地酶解所需的（S）-酮洛芬与c = 98.5%和99%ee。这项工作证明了使用假丝酵母rugosa脂肪酶动力学拆分外消旋酮洛芬的环境友好的协议和回收的不需要的（R）-酮洛芬的好处和效率。
Ketoprofen is a commercially available drug sold as a racemic mixture that belongs to the family of non-steroidal anti-inflammatory drugs known as profens. It has been demonstrated (in vitro) that (S)-ketoprofen is around 160 times more potent than its enantiomer (R)-ketoprofen, while accumulation of (R)-ketoprofen can cause serious side effects, such as dyspepsia, gastrointestinal ulceration/bleeding, pain, salt and fluid retention, and hypertension. In this work, four commercially available lipases were systematically assessed. Parameters such as conversion, enantiomeric excess, and enantioselectivity were considered. Among them, and by evaluating lipase load, temperature, solvent, and alcohol, Candida rugosa lipase exhibited the best results in terms of enantioselectivity E = 185 ((S)-enantiopreference) with esterification conversions of c = 47% (out of 50%) and enantiomeric excess of 99%. The unreacted (R)-enantiomer was recovered by liquid-liquid extraction and racemized under basic media, which was recycled as starting material. Finally, the (S)-alkyl ketoprofen ester was successfully enzymatically hydrolyzed to the desired (S)-ketoprofen with c = 98.5% and 99% ee. This work demonstrated the benefit and efficiency of using Candida rugosa lipase to kinetically resolve racemic ketoprofen by an environmentally friendly protocol and with the recycling of the undesired (R)-ketoprofen.
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DOI：
10.3390/molecules26144322
发表时间：
2021-07-16
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Bui CV;Rosenau T;Hettegger H
通讯作者：
Hettegger H
影响因子：
3.4
作者：
Ong, A. L.;Kamaruddin, A. H.;Kumari, R.
通讯作者：
Kumari, R.
影响因子：
3.8
作者：
FOSTER, RT;JAMALI, F;ALBALLA, SR
通讯作者：
ALBALLA, SR
DOI：
10.1046/j.1365-2885.1999.00193.x
发表时间：
1999-04-01
影响因子：
1.3
作者：
Alkatheeri, NA;Wasfi, IA;Lambert, M
通讯作者：
Lambert, M
影响因子：
2.6
作者：
Huras, Bogumila;Zakrzewski, Jerzy;Michalczyk, Alicja
通讯作者：
Michalczyk, Alicja