Synthesis Planning of a Potent Opioid Analgesic “Fentanyl”: A Retrosynthetic Approach
Chittaranjan Bhanja*, Satyaban Jena
Department of Chemistry, Utkal University, Bhubaneswar-751004, Odisha, India.
*Corresponding Author E-mail: bhanjac@gmail.com
ABSTRACT:
Synthesis of pharmaceuticals/drugs for the process development, reaction condition optimization, and scale-up production is a part and parcel of modern drug discovery process. Design synthetic routes to pharmaceuticals/drugs via retrosynthetic analysis, coined by Nobel Laureate Prof. E.J. Corey of Harvard University, has emerged as a powerful analytical tool in synthetic organic/medicinal chemistry and most responsible for yielding material benefits to mankind. Keeping an overview on the works published in both journals and patent literatures a good number of synthesis schemes have been proposed in a novel way for a potent analgesic “fentanyl” from the results of its retrosynthetic analysis. In actual practice, generally that route is most feasible which is cost-effective, safe, produce maximum yield in a short reaction time under robust conditions.
KEYWORDS: Analgesic, drug synthesis, fentanyl, retrosynthetic analysis, synthesis planning
1. INTRODUCTION:
Organic synthesis occupies a central role in any pharmaceutical development endeavor. The development of new synthetic methodology to synthesize pharmaceuticals/drugs in a more convergent and more efficient manner so as to make them suited for therapeutic use is very fundamental to organic synthesis. Most syntheses before they are executed are carefully planned with respect to sequence of steps from starting material to the final product. Although the sequence is quite logical but the details as to how the chemist first formulated the sequence of steps is not always published. A systematic approach for designing synthetic routes in the synthesis planning of a molecule is promulgated as a result of Prof. E.J. Corey’s developments of retrosynthetic analysis/ synthon disconnection approach. “Retrosynthetic analysis is a problem solving technique for transforming the structure of synthetic target molecule (TM) to a sequence of progressively simpler structures by disconnection of bonds and functional group interchange along the pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis.” 1, 2, 3 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 routes. In actual practice, generally that route is selected which is short, efficient, safe, reproducible, scalable, ecological and economically viable, while assessing alternative synthetic routes to a molecule.
Analgesic or pain reliever is any member of the diverse group of drugs that produces insensibility to pain without blocking the conduction of nerve impulses or markedly altering the function of the sensory apparatus. By the mechanism of their pain-relieving action, analgesics are classified as opioids, which act on receptors in the brain to inhibit pain impulses, or nonopioids, which inhibit the synthesis of prostagladins. The World Health Organization (WHO) has approved opioid analgesics for treating patients with moderate to severe pain.4 The goal of developing analgesic compounds that are potent but not addicting has motivated the synthesis and evaluation of thousands of new molecules. The introduction of ‘Fentanyl’5 [N-(1-phenethyl-4-piperidyl) propionanilide] (Fig: 1) in the 1960’s by Janssen Pharmaceuticals is a momentous milestone in man’s search for the ideal analgesic. It is a simple phenyl piperidine derivatives and is found to be 100 times more potent then morphine having short duration of action, rapid onset and high lipid solubility with very few adverse effect compared to morphine or meperidine.6,7 Fentanyl provides analgesia by stimulating primarily μ-receptors.8 Activation of μ – opioid receptors opens potassium channels to inhibit the firing of actions potential in pain pathways through the central nervous system. It is relatively safe drug and rarely causes hypotention, making it an excellent choice for injured children in severe pain. It is well suited for use in neuroleptanalgesia as it does not cause histamine release on intravenous injection. It has now achieved widespread use in surgical analgesia especially when given in combination with a major tranquilizer. More recently Fentanyl has been used for primary pain relief in patch form. The low molecular weight, high potency, lipid solubility and multiple routes of administration i.e; oral, intravenous, intramuscular, subcutaneous, transdermal, intranasal, epidural, and intrathecal makes it to find adequate position in “Best Selling Drug List.”9
Figure: 1
A few methods of synthesis of Fentanyl although have appeared in the literature,10-17 some alternative synthetic routs are still required for its commercial success. Here in, we propose a good number of synthesis schemes for Fentanyl based on retrosynthetic analysis/ synthon disconnection approach, keeping an overview on the published works both in journals and patent literatures. 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 analgesics are commonly used medications to relieve multifarious pain and Fentanyl is of excellent choice due to its multiple routes of administration. 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. MATERIAL AND METHODS:
The structure and information about Fentanyl as drug candid has been collected from different books.18-23 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 different books.24-29 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, safetyness, short time and scalable synthesis.
3. RESULTS AND DISCUSSION:
Retrosynthetic Analysis-1
Synthesis-1
Scheme:1
Acid catalysed condensation of 1-benzyl -4- piperidone 8 with aniline 7 forms the corresponding Schiff’s base 6.
Reduction of the double bond of the Schiff’s base by LiAlH4 forms 1-benzyl-4-anilinopiperidine 5, which on acylation with anhydride 4 forms the amide 3.Removal of benzyl group of amide by catalytic hydrogenation produces another amide 2. N-alkylation of 2 with 2-phenyl ethyl chloride 1 forms the target molecule (TM).
Retrosynthetic Analysis-2
Synthesis-2
Scheme:2
2-phenyl ethanamine15 obtained from the reduction of 2-phenylacetonitrile 16 condenses with 2-eqv.of methylacrylate 14 to form an intermediate diester 13.Dickman intermolecular condensation of diester produces the ketoester 12 which upon hydrolysis and subsequent decarboxylation forms the piperidone 11.Reductive amination of piperidone with aniline 7 using Na/EtOH forms 9. Acylation of 9 with anhydride 4 in toluene forms the target molecule (TM).
Retrosynthetic Analysis-3
Synthesis-3
Scheme: 3
Condensation of 1-benzoyl-4-piperidone 22 witn aniline 7 in presence of acid forms the Schiff’s base 21.Catalytic reduction of Schiff’s base produces 20. Hydrolytic deprotection of 20 forms the amine 19. Alkylation of this amine with aryl bromide 18 forms 4-anilino-1-phenethyl piperidine 9. Acylation of 9 with propionyl chloride 17 produces the target molecule (TM).
Retrosynthetic Analysis-4
Synthesis-4
Scheme:4
Friedel-Crafts acylation of benzene 26 with chloroacetyl chloride 27 produces 2-chlorp-1-phenylethanone 25 which upon reduction with Zn-Hg/HCl forms 1-(2-chloroethyl) benzene 1.N-alkylation of piperidone 24 with 1 forms 1-phenethylpiperidine-4- one 11.Strecker synthesis of 11 with aniline 7, KCN and AcOH in isopropyl alcohol gives a-aminonitrile 23.Reductive decyanation of 23 with NaBH4 in iPr.alcohol forms 9.Acylation of 9 with anhydride 4 forms the target molecule (TM ).
Retrosynthetic Analysis-5
Synthesis-5
Scheme:5
Reaction of pyridine 31 with aniline 7 in SOCl2 forms 4-anilinopyridine 30.Acylation of 30 with propanoic anhydride 4 affords the amide 29.Alkylation of 29 with 2-phenyl ethyl bromide 18 forms the pyridinium bromide intermediate 28.Hydrogenation of 28 over PtO2 reduces the pyridine ring and also cleaves the propanoyl group, affording 9. Acylation of 9 with anhydride 4 forms target molecule (TM).
Retrosynthetic Analysis-6
Synthesis-6
Scheme:6
Reductive alkylation of piperidone 24 with 2-phenyl acetaldehyde 33 in presence of NaBH(OAc)2 generates 1-(2-phenethyl)-4- piperidone 11.Reductive amination of keto function of 11 with aniline in presence of the same reagent NaBH(OAc)2 forms 4-anilino-1-phenethyl piperidine 9.These two steps are carried out in one-pot condition. Acylation of 9 with propionyl chloride 17 forms the target molecule (TM).
4. CONCLUSION:
The power of retrosynthetic analysis becomes evident in the design of a synthesis. The goal of retrosynthetic analysis is structural simplification. It is a paper exercise; a full analysis of this type will provide many routes and comparing them in a logical and straightforward fashion for synthesizing the target molecule. We have proposed a good number of synthesis schemes for a potent analgesic “Fentanyl” taking the privilege of this approach. Being a theoretical proposition, the synthesis works have not been executed in the laboratory. Scalable synthetic routes for newly discovered drug molecules/drug intermediates , useful compounds not available in adequate quantities from natural resources and even the target molecules that have never been synthesized earlier 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. ACKNOWLEDGMENTS:
The author deeply acknowledges UGC, ERO, Kolkata, India for providing financial support as Teacher Fellow grants. The author also thanks the authorities of IIT, Bhubaneswar, IMMT, Bhubaneswar and NISER, Bhubaneswar for permission to collect information from books and journals from their library.
6. REFERENCES:
1. Corey, E.J. ‘General methods for the construction of complex molecules’ Pure. Appl. Chem., 1967, 14, 19-38.
2. E. J. Corey “Retrosynthetic Thinking - Essentials and Examples". Chem. Soc. Rev., 1988, 17, 111–133.doi:10.1039/CS9881700111.
3. E. J. Corey. “Multistep Synthesis of Complex Carbogenic Molecules (Nobel Lecture)" (Reprint). Angew. Chem. In.t Ed. Engl., 1999, 30 (5), 455–465.doi:10.1002/anie. 199104553. http://nobelprize.org/chemistry/laureates/1990/corey-lecture.pdf.
4. “Framework of the Access to Controlled Medications Programme” World Health Organization. February, 2007.
5. The Merck Index, 12th Ed. Merck and Co., Inc., NJ, 1996.
6. Andrews, C.J.H.; Prys-Roberts, C. “Fentanyl-A review” Clin Anaesthesiol” 1983, 1, 97-122.
7. Stanley, T.H. “The history and development of the fentanyl series’ .Pain.Symptom Manage, 1992, 7, S3-S7.
8. Trescot, A.M.; Datta, S.; Lee, M.; Hansen, H. “Pain Physician: Opioid Special Issue: 2008, 11, S133-S153.
9. http://en.wikipedia.org/wiki/List of bestselling drugs.
10. Francis, G.J.; Janssen, P.A.J., “Method for Producing Analgesia” U.S.Pat.3, 141, 823, 1964.
11. Janssen, P.A.J. “1-Aralkyl-4-(n-AryI-Carbonylamino)-piperidines and Related Compounds," U.S.Pat.3, 164.600,1965.
12. Casy, A.F.; Hassan, M.A.;Simmonds, A.B.; Staniforta, D. “Structureactivity
13. Relations in Analgesics Based on 4-Anilinopiperidine” J Pharm.Pharmac. 1969, 21, 434-440.
14. Zong,R.S.,Yin,D.-X.,Ji,R.-Y., “Synthetic Studies of Potential Analgesics-II.Synthesis of Fentanyl”,Yao Hsueh Pao,1979,14,362-367.
15. Zee, S.H.; Wang, W.K.; “A New Process for the Synthesis of Fentanyl” Chin. Chem. Soc. (Taipei), 1980, 27,147-149.
16. Suh, Y.G.;Cho, K.H.; Shin, D.Y. “Total synthesis of fentanyl.” Arch Pharm Res. 1998, 21(1), 70-72.
17. Gupta,P.K.;Ganesan,K.;Pande.A.;Malhotra,R.C. “A convenient one pot synthesis of Fentanyl” J.Chem.Res.,2005,452-453.
18. Foye, W.O.; Lemke, T.L.; Williams, D.A. “Foye's Principles of Medicinal Chemistry” Lippincott Williams and Wilkins, 2007.
19. Vadivelu,N.; Urman.R.D.; Hines,R.L “Essentials of Pain Management” Springer, 2011.
22. Lednicer, D.; Mitscher,L.A.,“The Organic Chemistry of Drug Synthesis”, Vol.1, Wiley,New York, 1977, p-310.
23. Lednicer, D. “Strategies for Organic Drug Synthesis and Design”.(2/e), John Wiley and Sons,Inc.,New Jersey,2009.
24. Corey E.J., Chang X.M “The Logic of Chemical Synthesis.” Wiley, New York, 1989.
25. Warren S., “Designing Organic Synthesis: A Programme Introduction to Synthon Approach”,John Wiley and Sons,New York,1978.
26. Warren S. “Organic Synthesis-The Disconnection Approach”. John Wiley and Sons,1982.
27. Fuhrhop, J-H., Li, G., “Organic Synthesis: Concepts and Methods”Wiley-VC GmbH and Co.KGaA, 2003.
28. Clayden,J.;Greeves,N.;Warren,S.;Wothers,P.“Retrosynthetic Analysis In Organic Chemistry” Oxford University Press Inc., New York, 2001; pp. 773-778.
29. Kar, R.K.,“Fundamentals of Organic Synthesis: The Retrosynthetic Analysis”. NCBA, Kolkata, India. 2007.
Received on 04.06.2012 Modified on 02.07.2012
Accepted on 18.07.2012 © AJRC All right reserved
Asian J. Research Chem. 5(7): July, 2012; Page 925-931