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Download (725Kb) This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Process Biochemistry 45 (2010) 1587–1604 Contents lists available at ScienceDirect Process Biochemistry journal homepage: www.elsevier.com/locate/procbio Review Single enantiomeric ␤-blockers—The existing technologies Joni Agustian a,b, Azlina Harun Kamaruddin a,∗, Subhash Bhatia a a School of Chemical Engineering, Universiti Sains Malaysia, 14300 Nibong Tebal, Pulau Pinang, Malaysia b Department of Chemical Engineering, Universitas Lampung, Bandar Lampung 35145, Lampung, Indonesia article info abstract Article history: A number of ␤-blocking drugs are available in the world market, only few compounds are found as sin- Received 1 February 2010 gle enantiomers. The need to use the single enantiomeric ␤-blockers affects development of drugs and Received in revised form 30 June 2010 technology. Many processes have been exploited to replace the existing racemates. Two main routes Accepted 30 June 2010 are established: (1) asymmetric syntheses and (2) racemic resolutions. The syntheses give medium-high yields and excellent enantiomeric excess, but the resolutions are limited by 50% yield. Both technolo- Keywords: gies involve new techniques such as dynamic kinetic resolution (DKR) and membrane-based extraction. Single enantiomeric ␤-blockers The synthetic ways utilise various substrates and catalysts. A simultaneous formation is also afforded by Asymmetric synthesis ␤ Racemic resolution these processes. They offer oriented alternatives to the single enantiomeric -blockers. Resolutions of the Enzymatic membrane reactors racemates appear with many attractive separation methods. Direct or indirect resolutions show excel- Dynamic kinetic resolution lent characteristics and produce high enantiomeric excess. The existing processes operate continuously at mild operating temperatures compared to the asymmetric synthesis. In situ separation is also exploited. Development of the single enantiomeric ␤-blockers using the DKR based on enzymatic membrane(s) is encouraged. Integration of acetylation, racemisation and hydrolysis followed by separation of the enan- tiomers in the enzymatic membrane reactors could be a better option in resolution and separation of the ␤-blocker racemates. © 2010 Elsevier Ltd. All rights reserved. Contents 1. Introduction: status of ␤-blockers ................................................................................................................. 1588 2. Single enantiomeric-based processes ............................................................................................................. 1588 2.1. Routes to single enantiomers .............................................................................................................. 1588 2.2. The existing single enantiomeric ␤-blockers: highlight of processes ..................................................................... 1588 3. The asymmetric syntheses: synthetic ways to replace the existing racemic ␤-blockers ......................................................... 1588 3.1. Chemo-catalysis ............................................................................................................................ 1588 3.2. Chemo-enzymatic kinetic resolution catalysis ............................................................................................ 1591 3.3. Chemo-enzymatic dynamic kinetic resolution ............................................................................................ 1593 3.4. Whole-cells reduction...................................................................................................................... 1593 3.5. Chiral pool strategy ........................................................................................................................ 1593 4. Resolutions of the existing racemic ␤-blockers ................................................................................................... 1593 4.1. Enantioselective extraction ................................................................................................................ 1594 4.2. Whole-cells transformation ................................................................................................................ 1594 4.3. Enzymatic kinetic resolution ............................................................................................................... 1594 4.4. Liquid chromatography-based processes .................................................................................................. 1595 4.4.1. Simulated moving bed (SMB) .................................................................................................... 1595 4.4.2. Chiral belt chromatography ...................................................................................................... 1595 4.4.3. High performance liquid chromatography and other methods ................................................................. 1595 4.5. Electromigration techniques ............................................................................................................... 1595 4.6. Diastereomeric formation (DF) ............................................................................................................ 1597 5. Perspectives on the existing processes ............................................................................................................ 1597 ∗ Corresponding author. Tel.: +60 4 5996417; fax: +60 4 5941013. E-mail address: [email protected] (A.H. Kamaruddin). 1359-5113/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.procbio.2010.06.022 Author's personal copy 1588 J. Agustian et al. / Process Biochemistry 45 (2010) 1587–1604 6. Chiral switch via dynamic kinetic resolution using enzymatic membranes ...................................................................... 1599 7. Conclusions ........................................................................................................................................ 1599 Acknowledgements................................................................................................................................ 1599 References ......................................................................................................................................... 1600 1. Introduction: status of ␤-blockers directs syntheses of the single enantiomers and/or resolutions of the racemic compounds are developed [66] through chemical or The need to use single enantiomers in medication forces author- chemo-enzymatic pathways [67]. A general route to the single ities to tighten regulations on drugs. The United States Food and enantiomeric ␤-blockers is presented in Fig. 1. The syntheses use Drug Administration requires enantiomeric studies and justifica- either racemic or chiral compounds as raw materials, whilst the tion for approval of racemic drugs [1,2]. The evaluations lead to the resolution processes consume the racemates or racemic esters or development of drugs and technology [3]. Since then a lot of efforts diastereomeric derivates. The crystallisation processes are not pop- have been exploited to form the single enantiomers [4]. However, ular. Other methods such as whole-cells reduction, dynamic kinetic until 2002 the number of single enantiomeric drugs approved to be resolution and enantioselective extraction have also been inte- sold in the world markets was 39% [5]. In general, the cardiovascu- grated. lar drugs were the highest portion of the sold single enantiomers [6]. 2.2. The existing single enantiomeric ˇ-blockers: highlight of Beta adrenergic receptor blocking agents or popularly known processes as ␤-blockers are a group of drugs consumed in cardiovascular therapies. The drugs treat high blood pressure, heart failure and Various technologies were employed to give the existing single myocardial ischemia diseases [7,8]. They have similar functions to enantiomers [12,68–109].(S)-bunolol was prepared from an oxi- calcium channel- and angiotensin-II-blockers, but are found mostly ranic intermediate without formation or resolution of its racemate as racemates as shown in Table 1 [8–28]. Many ␤-blockers are avail- [110]. Previously the racemic bunolol synthesized from hydroxy- able in the United States and European markets [29,30] since the tetralone and epichlorohydrin was resolved hydrolytically using first launch in 1960s [31], however only few drugs are sold as sin- (−)-tartaric acid [109].(S)-penbutolol was made by methods of gle enantiomers. Hence, major clinical and research purposes are regioselective alkylation of phenol-cyclopentanol, resolution of its based on the racemates. racemate, enzymatic hydrolysis of its acetate derivative or epoxi- The ␤-blocker enantiomers should be used individually [32]. The dation of the allylic alcohol [111–114]. Resolution of
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