Synthetic Protocols of Best-Selling Anxiolytic Therapeutic ‘Diazepam’:
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 plays a pivotalal role in any drug research and development endeavor. The ability to design the elegant and economical synthetic routes to any therapeutic target is often a major factor for making a drug a commercial winner. Retrosynthetic analysis/ Synthon disconnection approach introduced and promoted by Prof. E. J. Corey of Harvard University has emerged as a powerful means on design synthetic routes to any useful molecules of scientific or industrial interest. Exploiting the advantages of this approach, a number of synthetic schemes has been proposed for a potent anxiolytic therapeutic ‘Diazepam’ from the results of its retrosynthetic analysis. Being theoretical propositions, the actual laboratory execution requires a cross examination of so many factors such as reactions, reagents and order of events. The routes that utilise readily available starting materials, convergent, economical, safe and produce maximum yield in short reaction time, are most feasible.
KEYWORDS: Anxiolytic, diazepam, drug synthesis, retrosynthetic analysis, synthon disconnection approach.
1. INTRODUCTION:
Synthesis is an indispensable component of any drug research and development process. Development of novel synthetic routes for convergent and efficient synthesis of pharmaceuticals/drugs to make them suited for therapeutic use is very fundamental to synthetic organic/medicinal chemistry and gives material benefits to mankind. Most of the synthesis before they are executed, is planned carefully with respect to sequence of steps from starting materials to 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 in planning of synthesis is promulgated as a result of Prof.E.J.Corey’s development of Retrosynthetic analysis /Synthon disconnection strategy in design the organic synthesis. Retrosynthetic analysis is a problem solving technique in the planning of organic syntheses. This is achieved by transforming a target molecule into simpler precursor structures by the disconnection of strategy bonds and functional group transformations without assumptions regarding starting materials. Each precursor material is examined using the same method.
This procedure is repeated until simple or commercially available structures are reached.1,2,3,4. Among the possible synthetic routes, the routes those utilise readily available starting materials, convergent, economical, safe and produce maximum yield in short reaction time, are the most plausible.
Anxiety disorders constitutes a group of mental disorders which are characterized by feeling of helplessness, despair, dark premonitions and asthenia, begins to develop with individuals that interfere with activities of daily living5. Anxiety disorders have larger social and economic ramifications such as loss of work place productivity6. Episodes of mild anxiety are common life experiences and do not warrant treatment. Treatment approaches to anxiety disorders include psychoanalytic, cognitive and pharmacologic therapies. Pharmacologic therapies mainly rely on anxiolytic (anti-anxiety) pharmaceuticals. At present three groups of drugs such as benzodiazepine, barbiturates and barbiturate-like substances are used as anxiolytic. The benzodiazepine group of medications is usually a first choice medication for short-term relief of severe and disabling anxiety and has largely replaced barbiturates and meprobamate in the treatment of anxiety, because of their specificity, uniqueness, efficiency and safty7. ‘Diazepam’ (Fig: 1) marketed as ‘Valium’ is one of the members of benzodiazepine group of anxiolytic. It reduces the frequency, severity, and duration of anxiety symptoms in individuals who have medical or disorders associated with anxiety. Diazepam appears to act on area of the limbic system, thalamus and hypothalamus inducing anxiolytic effects. Its actions are due to enhancement of GABA activity8. The high potentiality of Diazepam against multifarious anxiety disorders deserves an adequate place in ‘Best-Selling Drug List.’9
Figure: 1
Few synthetic approaches to Diazepam although well placed in literature, alternative synthetic protocols are still required for making this drug a commercial winner. Keeping an overview on the published works both in journals 10-14 and patent literatures 15-16, we focus our research diligence to propose a good number of synthesis schemes for a potent anxiolytic therapeutic Diazepam based on Retrosynthetic analysis/ Synthon disconnection approach. To our current knowledge, this type of work is certainly a virgin approach in this regard. The choice of this molecule for synthesis planning is obvious as Diazepam is one of the most commonly prescribed medications as anti-anxiety agent. Again the pharmaceutical industries are unquestionably vibrant today in search of alternative, cost-effective, scale-up synthesis for potent anti-anxiety drugs for their commercial success. So with the availability of new reactions, reagents, sophisticated new methods for laboratory execution and application of retrosynthetic analysis to analyse the target structure leading to several routes, deserve it to rethink the existing methodologies for its commercial winner.
2. MATERIAL AND METHODS:
The structure and information regarding Diazepam as anti-anxiety drug candid has been collected from different books17-21 . 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 terms, abbreviations and symbols used during synthesis planning are synonymous to that represented in different books22, 23,24. The analysis–synthesis schemes being theoretical propositions, obviously the synthesis have not been executed in the laboratory. Most of the retrosynthesis schemes have been derived taking in to account the synthesis earlier done for its preparation as found from different literatures. 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 AND DISCUSSION:
Retrosynthetic Analysis-1
Synthesis-1
Scheme: 1
Reaction of 4-chloro-N-methyl aniline 8 with acetic anhydride forms an amide 7 where the 20 N atom of 8 is protected .Friedel-Craft acylation of protected amine with benzoyl chloride 6 forms 5.Aq. alkali hydrolysis of 5 deprotects the 20 N atom of 5 and affords 4. Reaction of amino group of 4 with chloroacetyl chloride 3 forms its acetyl derivative 2.Heating 2 with NH3 forms a 10 amine 1.Intramolecular reaction between ketone and primary amine group of 1 provides the target molecule( TM ) Diazepam(Scheme:1).
Retrosynthetic Analysis:-2
Synthesis:-2
Scheme: 2
Friedel-Craft acylation of p-chloroaniline 14 with benzoyl chloride 6 affords the aminoketone 13.Oximination of 13 with hydroxylamine produces the oxime derivative 12.Methylation of 12 with dimethyl sulfate protects the 10 amine group which on acetylating with chloroacetyl chloride 3 forms 10.Heating 10 with alkali splits out HCl and cyclises to form the amine oxide ring 9.Reduction of the amine oxide with H2 gives out the target molecule(TM) Diazepam (Scheme: 2).
Retrosynthetic Analysis-3
Synthesis-3
Scheme: 3
Double acylation of p-chloroaniline 14 with benzoyl chloride 6 forms intermediate II via intermediate I. Reaction of the 2nd equivalent p-chloroaniline 14 with II leads to the formation of a six membered cyclic intermediate III with two nitrogens. This is hydrolytically opened to form amino ketone 13.Reaction of 13 with amino ester 17 yields 16.Internal cyclisation of 16 forms seven membered cyclic amide 15.Methylation of amide nitrogen of 15 with (CH3)2SO4 forms target molecule(TM) Diazepam (Scheme:3).
Retrosynthetic Analysis-4
Synthesis-4
Scheme: 4
2-Amino-5-chloro benzophenone 13 formed by the double acylation of p-chloro aniline14 and subsequent hydrolysis as in scheme-3, reacts with hydroxyl amine hydrochloride to form corresponding oxime12.Methylation of amine group of 12 by (CH3)2SO4 produces 11.Reaction of 11 with chloroacetyl chloride 3 affords 10.Heating 10 with alkali cyclises it to form seven membered amine oxide ring 9.Catalytic hydrogenation of 9 forms the target molecule (T M) Diazepam (Scheme: 4).
Retrosynthetic Analysis-5
Synthesis-5
Scheme: 5
Reaction of ethyl acetoacetate 25 with benzyl chloride 26 in presence of C2H5ONa in ethanol forms µ-benzyl acetoacetic ester 24.Diazotization of p-chloro aniline 14 with NaNO2 in HCl forms its diazonium salt 23 which undergoes azocoupling with ethyl µ-benzyl acetoacetic ester 24 in an alkaline solution and affords 4-chlorophenyl hydrazone 22. Fischer Indole Synthesis reaction of 22 in presence of HCl transforms in to the ethyl ester of 5-chloro-3-phenylindollyl–2-carboxylic acid 21.Alkylation of the resulting indole at the N-atom using dimethyl sulphate gives N-methyl-5-chloro-3-phenyl indole-2-carboxylic acid ethyl ester 20.Hydrolysis of the resulting product followed by chlorination and subsequent amination gives respective amide, which is then reduced by LiAlH4 to give 1-methyl-3-phenyl-5-chloro-2-aminomethylindole 19.Oxidative opening of the indole ring by CrO3 produces its aminobenzophenone derivative 18.Cyclisation of 18 under the reaction conditions provides the target molecule(TM) Diazepam (Scheme:5)
Retrosynthetic Analysis-6
Synthesis-6
Scheme: 6
5-Chloroanthranilic acid 36 reacts with phosgene hydrochloride 37 to form 5- chloroisatonic anhydride 35.N-methylation of isotonic anhydride with CH3/DMF in presence of Na2CO3 forms 34.Reaction of 34 with glycine in Et3N forms 7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine -2,5-dione 33. Acetylation of 33 by Ac2O protect 10-amine group which then on treatment with phenyl magnesium chloride 31 forms 5-chloro-2-(glycylmethylamino)-benzophenone 29 via a cyclic intermediate 30. Conversion of 29 into its oxime devt.by treatment with NH2-OH.HCl followed by reflux with NaHSO3 forms the target molecule (TM) Diazepam (Scheme: 6).
Retrosynthetic Analysis-7
Synthesis-7
Scheme: 7
Reaction of p-Chloro nitrobenzene 39 with benzyl cyanide 40 in presence of NaOH in alcohol produces 5-chloro-3-phenyl-benzo [c]isoxazole 38.Benzisoxazole undergoes acid medium reduction to form aminoketone 13. N-methylation of 13 with dimethyl sulphate gives 2-methylamino-5-chloro-benzophenone 4. Reaction of 4 with chloroacetyl chloride 3 in dichloromethane forms 2.The chloroacetyl residue 2 is then reduced with (CH2)6N4 followed by reflux with p- toluenesulphonic acid in toluene forms the target molecule (TM ) Diazepam(Scheme:7).
4. CONCLUSION:
Retrosynthetic analysis is a technique for solving problems in the planning of organic synthesis. The overall goal of this approach is the structure simplification. It is a paper exercise and a full analysis of this type will provide many new and innovative synthetic strategies in a logical fashion for design, ececution and development of new synthesis or improvements in existing processes. Utilising this technique, we have proposed a good number of synthesis schemes for a potent anxiolytic Diazepam. Scalable synthetic routes to pharmaceuticals or useful molecules that are extremely scarce in nature or molecules that have previously thought impossible to achieve, can be best provided by this approach. Through retrosynthetic analysis and introduction of new synthetic reactions and reagents, it is now time to rethink the synthesis of top-selling drugs for the improvement of the existing process for commercial winner.
5. ACKNOWLEDGMENTS:
The author CB acknowledges UGC, ERO, Kolkata, India for providing financial grants as Teacher Fellowship. The author also thanks the authorities of IIT Kharagpur, IIT Bhubaneswar, IMMT Bhubaneswar and NISER Bhubaneswar for their 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. Corey, E.J.; “Retrosynthetic Thinking - Essentials and Examples". Chem. Soc. Rev., 1988, 17, 111–133.
3. Corey E.J.; “Multistep Synthesis of Complex Carbogenic Molecules (Nobel Lecture)" (Reprint). Angew. Chem. In.t Ed. Engl., 1999, 30 (5), 455–465. http://nobelprize.org/chemistry/laureates/1990/corey-lecture.pdf.
4. Smith,M.B. ‘Disconnect by the numbers: A beginner's guide to synthesis’J. Chem. Educ.1990, 67 (10),848-856.
5. “Anxiolytic (tranquilizerz) Memidex (WordNet) Dictionary/Thesaurus. Retrieved 2010-12-02.
6. Schneider, F.R.; Johnson, J.; Homig, C.D.; Liebowitz, M.R.; Weissman, M.M. ‘Social phobia: comobidity and morbidity in a epidemiologic sample.’ Arch Gen Psychiat. 1992, 49,282-288.
7. Nutt ,D.J.; ‘Overview of diagnosis and drug treatments of anxiety disorders.’ CNS Spectr. 2005a, 10, 49-56.
8. Ashton, H. ‘Guidelines for the rational use of benzodiazepines: when and what to use.’ Drugs 1994, 48, 25-40.
9. http://en.wikipedia.org/wiki/List of bestselling drugs.
10. .Sternbach,L.H.;Reeder,E.‘Quinazolines and 1,4-Benzodiazepines. IV. Transformations of 7-Chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-Oxide’ J. Org. Chem., 1961, 26 (12), 4936–4941.
11. Yamamoto, H.; Inaba,S.; Hiroheashi, T.; Ishizumi, K.; Benzodiazepine, 2. Notiz über ein neues Verfahren zur Herstellung von 1.4-Benzodiazepin-Derivaten aus 2-Aminomethyl-indol-Derivaten Chem.Ber. 1968, 101(12), 4245-4247.
14. Vejdělek, Z.; Polívka, Z.; Protiva, M. ‘Synthesis of 7-chloro-5-(4-chlorophenyl)-1-methyl-1,3-dihydro-1,4-benzodiazepin-2-one’ Collect. Czech. Chem. Commun. 1985, 50, 1064-1069.
15. Nutley, K.B.; Sternbach, L.H.; U.S.Pat.3.109.843, 1963.
16. Reeder, E.; Sternbach, L.H.; U.S.Pat.3.371.085, 1968.
17. Lednicer,D.;Mitscher,L.A. ‘The Organic Chemistry of Drug synthesis’. Vol.1, Wiley, New York. 1977, p- 365.
18. .Briley,M.;Nutt,D.J.Briley’Anxiolytics’ Birkhauser Vergel,Basel, Switzerland 2000, p- 80
19. Lemke, T.L.; Williams, D.A.;Roche V.F.;Zito, S.W. ‘Foye's Principles of Medicinal Chemistry’(7/e) Lippincott Williams & Wilkins, 2012.p- 478
22. Corey E.J., Chang X.M “The Logic of Chemical Synthesis.” Wiley, New York, 1989.
23. .S.Waren,’Organic Synthesis- The Disconnection Approach” John Wiley and Sons, New York, 1981.
24. Fuhrhop, J-H., Li, G., “Organic Synthesis: Concepts and Methods”Wiley-VC GmbH and Co.KGaA, 2003.
Received on 08.10.2012 Modified on 18.10.2012
Accepted on 27.10.2012 © AJRC All right reserved
Asian J. Research Chem. 5(11): Nov., 2012; Page 1338-1345
S