An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

This review which is the second in this series summarises the most common synthetic routes as applied to the preparation of many modern pharmaceutical compounds categorised as containing a six-membered heterocyclic ring. The reported examples are based on the top retailing drug molecules combining synthetic information from both scientific journals and the wider patent literature. It is hoped that this compilation, in combination with the previously published review on five-membered rings, will form a comprehensive foundation and reference source for individuals interested in medicinal, synthetic and preparative chemistry.

[1]  J. Barreto,et al.  Antiretroviral Drugs , 2007, Journal of clinical pharmacology.

[2]  J. Deisenhofer,et al.  Structural Mechanism for Statin Inhibition of HMG-CoA Reductase , 2001, Science.

[3]  V. Chandregowda,et al.  Improved Synthesis of Gefitinib and Erlotinib Hydrochloride‐ Anticancer Agents , 2007 .

[4]  K. Rossen,et al.  A general and efficient method for the formylation of aryl and heteroaryl bromides. , 2005, Angewandte Chemie.

[5]  G. Singh,et al.  A Novel Method for Large-Scale Synthesis of Lamivudine through Cocrystal Formation of Racemic Lamivudine with (S)-(−)-1,1′-Bi(2-naphthol) [(S)-(BINOL)] , 2009 .

[6]  Steven V Ley,et al.  The synthesis of Bcr-Abl inhibiting anticancer pharmaceutical agents imatinib, nilotinib and dasatinib. , 2013, Organic & biomolecular chemistry.

[7]  Lester A. Mitscher,et al.  The Organic Chemistry of Drug Synthesis , 1993 .

[8]  Bioisosteric replacement strategy for the synthesis of 1-azacyclic compounds with high affinity for the central nicotinic cholinergic receptors. , 2000, Bioorganic & medicinal chemistry.

[9]  Thomas H. Lane.  WE’RE ALL IN THIS TOGETHER: Each of us has a personal stake in the advancement of chemistry and letting others know THE VALUE OF OUR SCIENCE , 2009 .

[10]  B. Kutscher,et al.  Synthese und Kristallstrukturanalyse von Azelastin , 1988 .

[11]  W. Bretz,et al.  Red Marine Algae Lithothamnion calcareum Supports Dental Enamel Mineralization , 2023, Marine drugs.

[12]  M. Alves,et al.  Synthesis of 5-amino-4-(cyanoformimidoyl)-1H-imidazole: a reactive intermediate for the synthesis of 6-carbamoyl-1,2-dihydropurines and 6-carbamoylpurines , 1990 .

[13]  I R Baxendale,et al.  Polymer-supported reagents for multi-step organic synthesis: application to the synthesis of sildenafil. , 2000, Bioorganic & medicinal chemistry letters.

[14]  H. Ploegh,et al.  Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. , 2006, Structure.

[15]  David Haigh,et al.  The synthesis of BRL 49653 : a novel and potent antihyperglycaemic agent , 1994 .

[16]  J. Al.  Contemporary drug synthesis , 2013 .

[17]  S. Redshaw,et al.  The design and synthesis of the Angiotensin Converting Enzyme inhibitor Cilazapril and related bicyclic compounds , 1986 .

[18]  N. Narender,et al.  Zeolite catalysed synthesis of 5-ethyl-2-methylpyridine under high pressure , 2009 .

[19]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[20]  S. Gaonkar,et al.  Microwave-assisted synthesis of the antihyperglycemic drug rosiglitazone , 2010 .

[21]  G. Sachs,et al.  Review article: the clinical pharmacology of proton pump inhibitors , 2006, Alimentary pharmacology & therapeutics.

[22]  I. Sircar,et al.  An improved and efficient synthesis of 2-substituted 1,4-dihydropyridine derivatives via regiospecific bromination , 1988 .

[23]  P. Herdewijn,et al.  Discovery of 7-N-piperazinylthiazolo[5,4-d]pyrimidine analogues as a novel class of immunosuppressive agents with in vivo biological activity. , 2011, Journal of medicinal chemistry.

[24]  A. Tolmachev,et al.  N-Substituted Ureas and Thioureas in Biginelli Reaction Promoted by Chlorotrimethylsilane: Convenient Synthesis of N1-Alkyl-, N1-Aryl-, and N1,N3-Dialkyl-3,4-Dihydropyrimidin-2(1H)-(thi)ones , 2007 .

[25]  M. Sanguinetti,et al.  hERG potassium channels and cardiac arrhythmia , 2006, Nature.

[26]  G. Barbe,et al.  Preparation of 1,5-methano-2,3,4,5- tetrahydro-1H-3-benzazepine via Pd-catalyzed cyclization. , 2004, Organic letters.

[27]  R. Leino,et al.  Synthesis of pharmaceutically active compounds containing a disubstituted piperidine framework. , 2008, Bioorganic & medicinal chemistry.

[28]  S. Ley,et al.  Magnesium nitride as a convenient source of ammonia: preparation of dihydropyridines. , 2008, Organic letters.

[29]  Jonathan S. Dordick,et al.  MICROWAVE ASSISTED COMBINATORIAL CHEMISTRY SYNTHESIS OF SUBSTITUTED PYRIDINES , 1998 .

[30]  De novo synthesis of substituted pyridines , 2004 .

[31]  P. Dunn.  Synthesis of Commercial Phosphodiesterase(V) Inhibitors , 2005 .

[32]  S F Campbell,et al.  Science, art and drug discovery: a personal perspective. , 2000, Clinical science.

[33]  D. Anderson,et al.  Ligands for brain cholinergic channel receptors: synthesis and in vitro characterization of novel isoxazoles and isothiazoles as bioisosteric replacements for the pyridine ring in nicotine. , 1994, Journal of medicinal chemistry.

[34]  C. Wermuth.  Are pyridazines privileged structures , 2011 .

[35]  Steven V Ley,et al.  An expeditious synthesis of imatinib and analogues utilising flow chemistry methods. , 2013, Organic & biomolecular chemistry.

[36]  U. Jordis,et al.  Improved synthesis of substituted 6,7-dihydroxy-4-quinazolineamines: tandutinib, erlotinib and gefitinib. , 2006, Molecules.

[37]  Kenneth M. Johnson,et al.  Pharmacophore-based discovery of substituted pyridines as novel dopamine transporter inhibitors. , 2003, Bioorganic & medicinal chemistry letters.

[38]  P. Suzdak,et al.  The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate. , 1993, Journal of medicinal chemistry.

[39]  T. Langer,et al.  On the bioisosteric potential of diazines: diazine analogues of the combined thromboxane A2 receptor antagonist and synthetase inhibitor Ridogrel. , 1996, Journal of medicinal chemistry.

[40]  K. Nicolaou,et al.  Molecules That Changed the World , 2008 .

[41]  Brian T. O’Neill,et al.  Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation , 2005 .

[42]  A. Börner,et al.  A New Approach to the Total Synthesis of Rosuvastatin , 2008 .

[43]  A. F. Crowther.  Heterocyclic Chemistry , 1964, Nature.

[44]  K. E. Bashford,et al.  The Bohlmann–Rahtz route to functionalised pyridine scaffolds and their use in library synthesis , 2003 .

[45]  Rainer E. Martin,et al.  The Kondrat'eva reaction in flow: direct access to annulated pyridines. , 2013, Organic letters.

[46]  C. Cheong,et al.  Synthesis of Amlodipine Using Aza Diels-Alder Reaction , 2002 .

[47]  V. Andriole.  Overview of the fluoroquinolones focus on moxifloxacin , 2002 .

[48]  J. Scannell,et al.  Diagnosing the decline in pharmaceutical R&D efficiency , 2012, Nature Reviews Drug Discovery.

[49]  K. Hirai,et al.  Synthesis and biological activity of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors. , 1997, Bioorganic & medicinal chemistry.

[50]  J. Peters.  11 Years of cyanopyrrolidines as DPP-IV inhibitors. , 2007, Current topics in medicinal chemistry.

[51]  I. Davies,et al.  An efficient preparation of vinamidinium hexafluorophosphate salts. , 2000, The Journal of organic chemistry.

[52]  H. Vorbrüggen,et al.  Nucleoside syntheses, XXII1) Nucleoside synthesis with trimethylsilyl triflate and perchlorate as catalysts , 1981 .

[53]  V. Chandregowda,et al.  Convergent Approach for Commercial Synthesis of Gefitinib and Erlotinib , 2007 .

[54]  M. F. Proença,et al.  Synthesis of 9-aryl-6-carbamoyl-1,2-dihydropurines and a study of their tautomerism , 1994 .

[55]  H. Gohlke,et al.  Synthesis and nicotinic binding studies on enantiopure diazine analogues of the novel (2-chloro-5-pyridyl)-9-azabicyclo[4.2.1]non-2-ene UB-165. , 2002, Journal of medicinal chemistry.

[56]  A. Heim-Riether,et al.  A novel method for the synthesis of imidazo[5,1-f][1,2,4]triazin-4(3H)-ones. , 2005, The Journal of organic chemistry.

[57]  S. Ley,et al.  Modern Synthetic Methods for Copper‐Mediated C(aryl) ? O, C(aryl) ? N, and C(aryl) ? S Bond Formation , 2003 .

[58]  P. Knochel,et al.  Phosphorodiamidate-directed metalation of N-heterocycles using Mg- and Zn-TMP bases. , 2010, Organic letters.

[59]  A. Katritzky,et al.  The mechanisms of heterocyclic ring closures , 1988 .

[60]  D. Powell,et al.  Pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as novel antiproliferative agents: exploration of core and headpiece structure-activity relationships. , 2007, Bioorganic & medicinal chemistry letters.

[61]  C. Abell,et al.  Polymer-assisted solution phase synthesis of the antihyperglycemic agent Rosiglitazone (Avandia). , 2003, Organic & biomolecular chemistry.

[62]  C. Seto,et al.  Enantioselective synthesis of 1-aryltetrahydroisoquinolines. , 2010, Organic letters.

[63]  J. Ellman,et al.  Asymmetric copper-catalyzed synthesis of alpha-amino boronate esters from N-tert-butanesulfinyl aldimines. , 2008, Journal of the American Chemical Society.

[64]  A. Bush,et al.  3‐Cyano‐4,6‐di­methyl‐2‐pyridone (Guareschi pyridone) , 2004 .

[65]  A. Goel,et al.  Synthesis of aminonicotinonitriles and diaminopyridines through base-catalyzed ring transformation of 2H-pyran-2-ones. , 2003, The Journal of organic chemistry.

[66]  D. Hazuda,et al.  Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. , 2008, Journal of medicinal chemistry.

[67]  Holger Fischer,et al.  Discovery of carmegliptin: a potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. , 2010, Bioorganic & medicinal chemistry letters.

[68]  H. Mitsuya,et al.  Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists. , 2006, Journal of medicinal chemistry.

[69]  W. Pitt,et al.  Heteroaromatic rings of the future. , 2009, Journal of medicinal chemistry.

[70]  G. Carlson,et al.  Comparison of the effects of pyridine and its metabolites on rat liver and kidney. , 1996, Toxicology letters.

[71]  K. Houk,et al.  A polar radical pair pathway to assemble the pyrimidinone core of the HIV integrase inhibitor raltegravir potassium. , 2008, Angewandte Chemie.

[72]  Steven V Ley,et al.  Flow and batch mode focused microwave synthesis of 5-amino-4-cyanopyrazoles and their further conversion to 4-aminopyrazolopyrimidines. , 2007, Organic & biomolecular chemistry.

[73]  S. Ley,et al.  An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals , 2011, Beilstein journal of organic chemistry.

[74]  D. Hooper.  Mode of Action of Fluoroquinolones , 2012, Drugs.

[75]  Mao Chen,et al.  Asymmetric Hydrogenation of Pyridines: Enantioselective Synthesis of Nipecotic Acid Derivatives , 2006 .

[76]  Divya K. Nair,et al.  Synthesis of imidazopyridines from the Morita-Baylis-Hillman acetates of nitroalkenes and convenient access to Alpidem and Zolpidem. , 2012, Organic letters.

[77]  F. Krebs,et al.  Combinatorial Approaches to the Prevention and Treatment of HIV-1 Infection , 2011, Antimicrobial Agents and Chemotherapy.

[78]  K. Schofield.  Pyridine and its Derivatives , 1967 .

[79]  G. Pabst,et al.  A new and simple ‘LEGO’ system for the synthesis of branched oligopyridines , 1998 .

[80]  H. V. Pechmann.  Ueber die Spaltungsproducte der α‐Oxysäuren , 1891 .

[81]  Blair Jarvis,et al.  Temozolomide A Review of its Use in the Treatment of Malignant Gliomas, Malignant Melanoma and Other Advanced Cancers , 2002 .

[82]  Stephen A. Smith,et al.  [[omega-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents. , 1994, Journal of medicinal chemistry.

[83]  W. Jones,et al.  Attempted synthesis of 2,4,8,10-tricyclo[5.4.0.01,6]undecatetraene: bis(norcaradiene) , 1978 .

[84]  Deepak Dalvie,et al.  Aldehyde oxidase: an enzyme of emerging importance in drug discovery. , 2010, Journal of medicinal chemistry.

[85]  M. Billah,et al.  Dual antagonists of platelet activating factor and histamine. Identification of structural requirements for dual activity of N-Acyl-4-(5,6-dihydro-11H-benzo [5,6]cyclohepta-[1,2-b]pyridin-11-ylidene)piperidines. , 1991, Journal of medicinal chemistry.

[86]  Yijun Huang,et al.  Piperazine scaffolds via isocyanide-based multicomponent reactions , 2010 .

[87]  R. Kloner,et al.  Relationships between structure and effects of ACE inhibitors: comparative effects in myocardial ischaemic/reperfusion injury. , 1989, British journal of clinical pharmacology.

[88]  R. Chuck.  Technology development in nicotinate production , 2005 .

[89]  D. Josić,et al.  Pharmacokinetic behaviour of R-(+)- and S-(-)-amlodipine after single enantiomer administration. , 1997, Journal of chromatography. B, Biomedical sciences and applications.

[90]  Steven V. Ley,et al.  Flow chemistry synthesis of zolpidem, alpidem and other GABAA agonists and their biological evaluation through the use of in-line frontal affinity chromatography , 2013 .

[91]  A. Yahyazadeh,et al.  SYNTHESIS OF ARYL(OR BENZYL)-(Z)-N-[2-AMINO-1,2-DICYANOVINYL]FORMAMIDINES , 2001 .

[92]  B. Roth,et al.  Contemporary Drug Synthesis: Li/Drug Synthesis , 2004 .

[93]  G. Hitchings,et al.  Studies on Condensed Pyrimidine Systems. IX. The Synthesis of Some 6-Substituted Purines , 1952 .

[94]  K. Rossen,et al.  A practical synthesis of a COX-2-specific inhibitor. , 2000, The Journal of organic chemistry.

[95]  L. Adhikary,et al.  Microwave induced synthesis of the thiazolidine-2,4-dione motif and the efficient solvent free-solid phase parallel syntheses of 5-benzylidene-thiazolidine-2,4-dione and 5-benzylidene-2-thioxo-thiazolidine-4-one compounds , 2006 .

[96]  P. Wakeley,et al.  Synthesis , 2013, The Role of Animals in Emerging Viral Diseases.

[97]  Toni L. Ripley,et al.  Etoricoxib: A Highly Selective COX-2 Inhibitor , 2005, The Annals of pharmacotherapy.

[98]  T. Vortherms,et al.  In vitro SAR of pyrrolidine-containing histamine H3 receptor antagonists: trends across multiple chemical series. , 2008, Bioorganic & medicinal chemistry letters.

[99]  T. Ohkuma,et al.  Asymmetric hydrogenation of bicyclic ketones catalyzed by BINAP/IPHAN-Ru(II) complex. , 2010, Organic letters.

[100]  Stephanie C. Licata,et al.  Abuse and dependence liability of benzodiazepine-type drugs: GABAA receptor modulation and beyond , 2008, Pharmacology Biochemistry and Behavior.

[101]  S. Ley,et al.  Pharmaceutical Strategy and Innovation: An Academics Perspective , 2007, ChemMedChem.

[102]  Steven V Ley,et al.  A flow-based synthesis of imatinib: the API of Gleevec. , 2010, Chemical communications.

[103]  R. Frank,et al.  5‐Ethyl‐2‐methylpyridine , 2003 .

[104]  P. Ravenscroft,et al.  Diastereoselective Synthesis of the Potent Antiviral Agent (-)-2'-Deoxy-3'-thiacytidine and Its Enantiomer , 1995 .

[105]  K. Broadley,et al.  Muscarinic Receptor Agonists and Antagonists , 2001, Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry.

[106]  H. Mitsuya,et al.  Spirodiketopiperazine-based CCR5 antagonists: Lead optimization from biologically active metabolite. , 2007, Bioorganic & medicinal chemistry letters.

[107]  S. Hildbrand,et al.  An Efficient Process for the Manufacture of Carmegliptin , 2011 .

[108]  R. Hüttenrauch,et al.  Mechanical Activation of Pharmaceutical Systems , 1985, Pharmaceutical Research.