Synthon Approach in Designing Organic Synthesis: A Case Study of Rational Synthesis Design of a Potent Antidiabetic Agent “Rosiglitazone.”

 

Chittaranjan  Bhanja¹*, Seetaram Mohapatra²

¹Department of Chemistry, Upendra Nath (Degree) College, Nalagaja, Mayurbhanj-757073, Odisha, India.

²Department of Chemistry, Ravenshaw University, Cuttack-753003,  Odisha, India.

*Corresponding Author E-mail: bhanjac@gmail.com

ABSTRACT:

 

 

1. INTRODUCTION

The heart of organic synthesis is designing synthetic routes to a molecule. The simplest synthesis of a molecule is one in which the target molecule can be obtained by submitting a readily available starting material to a single reaction that converts it to the desired target molecule. However, in most cases the synthesis is not that straightforward; in order to convert a chosen starting material to the target molecule, numerous steps that add, change, or remove functional groups and steps that build up the carbon atom framework of the target molecule may need to be done. A systematic approach for designing synthetic routes to a molecule is promulgated as a result of Prof. E.J. Corey’s developments of synthon disconnection approach/retrosynthetic analysis.^1,2,3 Retrosynthetic analysis is a protocol of stepwise breaking of target molecule to starting materials by disconnection of bonds and functional group interchange to a sequence of progressively simpler structures along a pathways just reverse of actual synthesis. Every disconnected part is an idealized fragment, called ‘synthon.’

 

The synthons when joined by known or conceivable synthetic operations result in the formation of target molecule. Retrosynthetic analysis of a target molecule usually results in more than one possible synthetic route. It is therefore necessary to critically assess each derived route in order to choose the single route that is most feasible. In actual practice, generally that route is selected which is cost-effective, safe (the toxicity and reactivity hazards associated with the reactions involved), easy to carry out and produces maximum yield in a short reaction time, when assessing alternative synthetic routes to a molecule.

 

Diabetes mellitus is one of the world’s most prevalent, debilitating and progressive disease. According to recently compiled data from WHO, approximately 170 millions people have diabetes worldwide and this number may well double by the year 2025 due to population growth, ageing, unhealthy diets, obesity and sedentary lifestyles.⁴ Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both.⁵ It adversely affects the functioning of the kidneys, eyes, nervous and vascular systems. Therefore, once diagnosed, it is essential to control blood glucose levels during the early stages of the disease. The drugs/medicines used to treat diabetes mellitus are known as antidiabetic agent or oral hypoglycemic agent. The most attractive and direct approach to treat diabetes is the administration of orally active hypoglycemic drugs. Members of the thiazolidinedione drug class⁶ are well known as anti-hyperglycemic drugs used for the treatment of diabetes mellitus type II⁷ Rosiglitazone (Fig 1), known as Avandia by GlaxoSmithKline, is one of the most potent drugs in this class.⁸ It works as an insulin sensitizer by binding to the Peroximose Proliferators-Activated Receptors (PPAR) in fat cells and makes the cells more responsive to insulin. Apart from its effect on insulin sensitizer, thiazolidinedione appears to have an anti-inflammtory effect.⁹ Recent research has suggested that rosiglitazone may also be of benefit to a subset of patients with Alzheimer’s disease.¹⁰ The medication may also be effective in the treatment of mild to moderate ulcerative colitis, due to its anti-inflammatory properties as a PPAR ligand.¹¹ Recent studies show that rosiglitazone can be used for the treatment of acute pancreatitis-associated lung injury.¹² Due to its multifarious therapeutic activities, it is now one of the members of “Blockbuster Drug List.”

 

Fig: 1

Although a few methods of synthesis of rosiglitazone are well documented in literature,¹³ some alternative synthetic routs are still required for its commercial success. Keeping an overview on the published works both in journals and patent literatures, an effort has been made to propose a good number of synthesis schemes for “rosiglitazone” based on synthon disconnection approach /retrosynthetic analysis. To the best of our knowledge, this type of work has not been reported earlier. The choice of this molecule for synthesis planning is obvious as diabetics is one of the worlds’ most prevalent, debilitating and progressive disease that covers more than 170 millions peoples worldwide and rosiglitazone is one of the widely used orally active hypoglycemic drugs/anti diabetic agent. In this profit oriented world, the pharmaceutical industries are also vibrant today in search of cost effective scalable synthesis. Moreover with the availability new reagents, chemical reactions, sophisticated new methods of laboratory execution and the application of synthon approach to analyse the target molecules leading to several routes have made it possible to rethink their synthesis for the improvement in existing processes to satisfy the commercial need.

 

2. MATERALS AND METHODS:-

The structure and information about rosiglitazone as drug candid has been collected from different books.^8,9 The proposed synthesis planning are then exploited in a novel way from the result of retrosynthetic analysis of dug structure using the basic principle outlined in the pioneering works of Prof. E.J. Corey. The symbols and abbreviations are synonymous to that represented in book.¹ The analysis–synthesis schemes being a theoretical propositions, obviously the synthesis have not been executed in the laboratory. The actual laboratory execution requires the cross examination of a considerable number of factors such as reagents, reactions, order of events, economical viability, environmental benign, saftyness, short time and scalable synthesis.

 

 

 

3. RESULTS:

 

Retrosynthetic Analysis-1

Synthesis-1

Scheme:1

 

Retrosynthetic Analysis-2

 

Synthesis-2

Scheme:2

 

Retrosynthetic Analysis-3

 

Synthesis-3

 

Scheme: 3

 

Retrosynthetic Analysis-4

 

Synthesis-4

 

Scheme:4

 

Retrosynthetic Analysis-5

 

Synthesis:-5

 

Scheme:5

 

 

4. DISCUSSION AND CONCLUSIONS:

The planning of a multistep synthesis via synthon disconnection approach/ retrosynthetic analysis is a challenging task that requires not only a thorough knowledge of synthetic reactions, but also a logical approach for disconnecting a complex target molecule into simpler or commercially available starting materials for a chemical synthesis. It is a paper exercise; a full analysis of this type will provide many routes for synthesizing the target molecule. Taking the privilege of this approach, we have proposed a good number of synthesis schemes for a potent anti-diabetic agent “rosiglitazone”.Being a theoretical proposition, the synthesis works have not been executed in the laboratory. Strategic application of this approach can determine different routes to synthesize the target molecule even if the target molecule has never been synthesized earlier. Scalable synthetic routes for newly discovered drug molecules/drug intermediates and useful compounds not available in adequate quantities from natural resources can be best provide by this approach. With the advancement and development of new reactions and reagents, the synthesis of best selling drugs can be rethinking for the improvements in existing process through this approach.

 

5. ACKNOWLEDGEMENTS:

The author deeply acknowledges UGC, ERO, Kolkata, India for providing financial support as MRP grant. The author also thanks the authorities of IIT Kharagpur and IMMT Bhubaneswar for permission to collect information from books and journals from their library and Dr. Sabita Nayak of Ravenshaw University, Cuttack for helpful discussion.  

 

6. REFERENCES:

Journals:

1.       Corey, E.J. ‘General methods for the construction of complex molecules’ Pure. Appl. Chem., 1967, 14, 19-38.

2.       Corey, E.J.; Wipke, W.T.; ‘Computer-Assisted designing of Complex Organic Synthesis’ Science, 1969, 166, 3902, 178-192.

3.       Corey, E. J.; ‘Centenary lectur.Computer-assisted analysis of complex synthetic problems’ Q. Rev .Chem. Soc., 1971, 25, 455-482.

4.       WHO expert committee on diabetes mellitus. The effect of intensive treatment of diabetes on the development and the progression of long term complications in IDDM, Second report. Technical Report Series 646, World Health Organization, Geneva, 1980.

5.       Lebovitz, H.E. ‘Therapy for Diabetes Mellitus and Related Disordes,’ 4/e, Alexandria: American Diabetes Association, 2004

6.       Centello, B.C.; Cawthorne, M.A.; Cottam,G.P.; Duff,P.T.; Haigh,D; Hindley, R.M.; Lister,C.A.; Smith,S.A.;Thurlby,P.L. ‘[[.omega.- (Heterocyclylamino) alkoxy] benzyl] -2,4-thiazolidinediones as potent antihyperglycemic agents’ J. Med. Chem, 1994, 37,3977-3985.

7.       Centello,B.C.;Cawthorne,M.A.;Haigh,D;Hindley,R.M.;Lister,C.A.;Smith,S.A.;Thurlby,P.L ‘The synthesis of BRL 49653 - a novel and potent antihyperglycaemic agent Bioorg. Med. Chem .Lett, 1994, 4, 1181-1184.

8.       Reaven, G.M ‘Role of insulin resistance in human disease’ Diabetes, 1988, 37, 1595-1607.

9.       Mohanty,P.;Aljada,A.;Ghanim,H.;Hofmeyer,D.’Tripathy,D.;SyedT,Alhadad,W.;Dhindsa, S.; Dandona, P. ‘Evidence for a Potent Anti-inflammatory Effect of Rosiglitazone’J.Clin.Endicrinol.Metab.2004, 89, 2728-2735.

10.     Risner, M. E.; Saunders, A.M.; Altman, J.F. B.; Ormandy, G.C.; Craft,S.; Foley,I.M.; Zvartau-Hind, M.E.; Hosford, D.A.;Roses, A.D. ‘Efficacy of rosiglitazone in a genetically   defined population with mild-to-moderate Alzheimer's disease’Pharmacogenomics J.   2006, 6, 246-254.

11.     Lewis, J.D.; Lichtenstein, G.R.; Deren,J.J.;Sands,B.E.;Hanauer,S.B.;Katz<g>a.;Lashner,B.;Present,D.H.;Chuai,S.;Ellenberq,J.H.;Nessel,L.;Wu,G.D.‘Rosiglitazone for Active Ulcerative Colitis: A Randomized PlaceboControlledTrial’Gastroenterology,2008,134,688-695.

12.     Chen, C.; Xu, S.; Wang, W.-X.; Dng, Y.-M Yu, K.-H: Wang, B.; Chen, X.Y. ‘Rosiglitazone Attenuates the Severity of Sodium Taurocholate-induced Acute Pancreatitis and Pancreatitis-associated Lung Injury’ Arch .Med .Res, 2009, 40, 79-88.

13.      (a) Xin Li, Chris Abell, Brian H, Warrington and Mark Latlow; ‘Polymer-assisted solution phase synthesis of the antihyperglycemic agent Rosiglitazone(Avandia™)’ Org.Biomol.Chem, 2003, 1, 4392-4395. (b) Radhakrishna,  S.;  Venkatnta Naga,  M.;  Rao, B.; Raju,T.S.; Himabindu,V.;  Reddy G. M.   ‘Isolation, Synthesis and Characterization of Rosiglitazone Maliate Impurities’ E-Journal of Chemistry, 2008 (5),3, 562-566. (c) .Kirefu, T., Landwater, S.W., Letter, A. J., Lawrie, K. W. M., Morecombe, D.J., Willcocks. K., ‘Rosiglitazone maleate (BRL 49653-C); the preparation of [¹⁴C] and [³H]  isotopomers’ J .Label Compd Radiopharm. , 2001, 44, 5, 329-335.

 

Books:

1.       Corey E.J., Chang X.M “The Logic of Chemical Synthesis” Wiley, New York, 1989.

2.       Warren S., “Designing Organic Synthesis: A Programme Introduction to Synthon Approach”,John Wiley and Sons,New York,1978.

3.       Warren S. “Organic Synthesis-The Disconnection Approach”. John Wiley and Sons,1982.

4.       Fuhrhop J-H, Li G, “Organic Synthesis: Concepts and methods” WILEY-VC GmbH and Co.KGaA, 2003.

5.       Clayden, Greeves, Warren and Wothers, “Retrosynthetic analysis, In Organic Chemistry”     Oxford University Press Inc., New York, 2001; pp. 773-778.

6.       Kar R.K., “Fundamentals of Organic Synthesis: The Retrosynthetic Analysis”. NCBA, Kolkata, India. 2007.

7.       Ghosh S.K. “Advanced General Organic Chemistry -A Modern Approach”. New Central Book Agency Ltd., Kolkata, 2007

8.       Foye, W.O.; Lemke, T.L.; Williams, D.A.Foye’s Principle of Medicinal Chemistry (5/e), Lippincott  Williams and Wilkins 2002, pp-1377.

9.       Bhagavan N.V.; Hu C.-E., “Essentials of Medicinal Biochemistry: With Clinical Cases”[KindleEdn.] Academic Press ,2011

10.     Lednicer, D. “Strategies for Organic Drug Synthesis and Design”.(2/e), John Wiley and Sons,Inc.,New Jersey,2009.

11.     Douglas S.J. and Li, J.J., “The Art of Drug Synthesis”.Wiley Inc, 2007, pp-121.

 

 

 

Received on 06.01.2012         Modified on 10.02.2012

Accepted on 12.02.2012         © AJRC All right reserved