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Lewis acids in the preparation of the heterocyclic compounds: synthesis and characterization of the impurities of API

SCHOOL OF ADVANCED STUDIES. Doctorate course in Chemical Sciences. PhD thesis. Lewis acids in the preparation of the heterocyclic compounds: synthesis and characterization of the impurities of API. Cycle XX Scientific-sector CHIM/06. PhD Candidate: Dr. Melissa Paoletti . Tutors:

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Lewis acids in the preparation of the heterocyclic compounds: synthesis and characterization of the impurities of API

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  1. SCHOOL OF ADVANCED STUDIES Doctorate course in Chemical Sciences PhD thesis Lewis acids in the preparation of the heterocyclic compounds: synthesis and characterization of the impurities of API Cycle XX Scientific-sector CHIM/06 PhD Candidate: Dr. Melissa Paoletti Tutors: Prof. Enrico Marcantoni Dr. Gianluca Paniccià 2004/05 – 2006/07

  2. PhD thesis – Cycle XX Lewis acids in the preparation of the heterocyclic compounds: synthesis and characterization of the impurities of API 17 March 2008

  3. PhD thesis – Cycle XX Collaboration with Pfizer, Ascoli Piceno Plant Characterization of Reference Standards - Analysis Identification of unknown impurities Synthesis of impurities New methodologies for the synthesis of compounds of pharmaceutical interest - Synthesis 17 March 2008

  4. PhD thesis – Cycle XX Lewis acids CeCl3•7H2O/NaI on SiO2 TiCl4 CeCl3•7H2O – NaI Synthesis of β-hydroxy esters - Garcia Gonzàlez reaction - Friedel-Crafts reaction - Knoevenagel condensation - Azides transformation to Primary Amines 17 March 2008

  5. PhD thesis – Cycle XX Titanium Compounds TiX4derivates are the most commonly used and X anions largely influence the strength of the acid; in fact, if X is an alkoxy group the Lewis acid is a weak while with halogens or triflates its strength increases dramatically. TiCl4 ability to chelate oxyphilic character favourite octahedral structure 17 March 2008

  6. Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok,2006, 49-58 PhD thesis – Cycle XX Diastereoselective synthesis of tertiary alcohols by nucleophilic addition to α–substituted-β-keto esters The synthetic strategy adopted for the stereoselective addition of RMgX-CeCl3species to β-keto amides was based on their conversion into the corresponding titanium cyclic complexes. 17 March 2008

  7. Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok,2006, 49-58 PhD thesis – Cycle XX Diastereoselective synthesis of tertiary alcohols by nucleophilic addition to α–substituted-β-keto esters 17 March 2008

  8. High diastereoselectivity • moderate-to-good efficiency PhD thesis – Cycle XX Diastereoselective synthesis of tertiary alcohols by nucleophilic addition to α–substituted-β-keto esters Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok,2006, 49-58 17 March 2008

  9. The nature of the carbonyl-substituent in the β-keto ester substrate. PhD thesis – Cycle XX Diastereoselective synthesis of tertiary alcohols by nucleophilic addition to α–substituted-β-keto esters Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok,2006, 49-58 17 March 2008

  10. PhD thesis – Cycle XX Cerium salts Discovered in 1803 by Berzelius and Hisinger Lanthanide Ce Oxidation state III and IV CeCl3 CeCl3.7H2O Low Toxicity Ready availability at low cost High stability towards water FRIENDLY LEWIS ACID 17 March 2008

  11. “Friendly” Lewis acid Solvent-free conditions Solid support Formation of new bonds PhD thesis – Cycle XX CeCl37H2O-NaI CeCl3·7H2O NaI Chemo- and regioselectivity 17 March 2008

  12. Increased the potentialities of CeCl3.7H2O-NaI system • major restriction to the broad application of the Knoevenagel reaction PhD thesis – Cycle XX The CeCl3.7H2O-NaI system as promoter in the synthesis of functionalized trisubstituted alkenes via Knoevenagel condensation CeCl3.7H2O-NaI system promotes the addition of CH-acidic compounds to different electrophiles. Building blocks useful for the synthesis of natural and non-natural bioactive compounds Bartoli, G.; Beleggia, R.; Giuli, S., Giuliani, A., Marcantoni, E.; Massaccesi, M., Paoletti, M., Tetrahedron Letters, 2006, 47, 6501-6504. 17 March 2008

  13. 1:1.2 ratio between 4a and 5 in a ca. 0.1 M solution in acetonitrile • 1.35 equiv of CeCl3.7H2O • 1.35 equiv of NaI PhD thesis – Cycle XX The CeCl3.7H2O-NaI system as promoter in the synthesis of functionalized trisubstituted alkenes via Knoevenagel condensation Bartoli, G.; Beleggia, R.; Giuli, S., Giuliani, A., Marcantoni, E.; Massaccesi, M., Paoletti, M., Tetrahedron Letters, 2006, 47, 6501-6504. 17 March 2008

  14. malonate mono acid 7 as unique product isolated • no evidence of ,-unsaturated malonic acids. PhD thesis – Cycle XX Knoevenagel condensation fairly stereoselective affording E-isomers in high yields Bartoli, G.; Beleggia, R.; Giuli, S., Giuliani, A., Marcantoni, E.; Massaccesi, M., Paoletti, M., Tetrahedron Letters, 2006, 47, 6501-6504. 17 March 2008

  15. PhD thesis – Cycle XX Microwave-Assisted Azides Trasformation to Primary Amines Using Mild and Easily Accessible CeCl3.7H2O/NaI System Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem. 2008, 73, 1919-1924. 17 March 2008

  16. PhD thesis – Cycle XX Microwave-Assisted Azides Trasformation to Primary Amines Using Mild and Easily Accessible CeCl3.7H2O/NaI System Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem. 2008, 73, 1919-1924. 17 March 2008

  17. PhD thesis – Cycle XX Microwave-Assisted Azides Trasformation to Primary Amines Using Mild and Easily Accessible CeCl3.7H2O/NaI System Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem. 2008, 73, 1919-1924. 17 March 2008

  18. PhD thesis – Cycle XX Azides Trasformation to Primary Amines • Diminution of the reaction time • Higher yields Microwave technology Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem 2008, 73, 1919-1924. 17 March 2008

  19. Starting material Glycosidase inhibitors PhD thesis – Cycle XX GarciaGonzàlezreaction [2] [2] F. Garcia Gonzàles, Adv. Carbohydr. Chem.1956, 11, 97 17 March 2008

  20. PhD thesis – Cycle XX Garcia Gonzàlez reaction [3] [3] A.K. Misra, G. Aghihotri Carbohydrate Research 2004, 339, 1381 17 March 2008

  21. PhD thesis – Cycle XX Garcia Gonzàlez reaction 17 March 2008

  22. Solvent-free • 0,3 eq of promoter system • 0,5 g SiO2/mmol D-glucose PhD thesis – Cycle XX Garcia Gonzàlez reaction solvent-free Bartoli, G.; Fernàndez-Bolanõs, J.G.; Di Antonio, G.; Foglia, G.; Giuli S.; Gunnella, R.; Mancinelli, M.; Marcantoni, E.; Paoletti, M. J. Org. Chem. 2007, 72, 6029-6036. 17 March 2008

  23. NaI is essential for the reaction H2O is essential for the reaction • gives a better yield of product • facilitates the work up of the reaction mixture • permits the reaction to be accomplished without solvent PhD thesis – Cycle XX CeCl3•7H2O-NaI-SiO2 The solid support SiO2 Bartoli, G.; Fernàndez-Bolanõs, J.G.; Di Antonio, G.; Foglia, G.; Giuli S.; Gunnella, R.; Mancinelli, M.; Marcantoni, E.; Paoletti, M. J. Org. Chem. 2007, 72, 6029-6036. 17 March 2008

  24. PhD thesis – Cycle XX The CeCl3.7H2O-NaI-SiO2 as efficient promoter for Friedel-Crafts reaction of Indoles to Nitroalkenes in solvent-free conditions Bartoli, G.; Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008,2, 320-324. 17 March 2008

  25. PhD thesis – Cycle XX Friedel-Crafts reaction of Indoles to Nitroalkenes • 0.3 eq CeCl3.7H2O • 0.3 equiv of NaI • SiO2 (0.5 g/mmol of nitroalkene) • solvent-free conditions Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324. 17 March 2008

  26. PhD thesis – Cycle XX The CeCl3.7H2O-NaI-SiO2 as efficient promoter for Friedel-Crafts reaction of Indoles to Nitroalkenes in solvent-free conditions -carboline ringof the (-)-(S)-Brevicolline Carex Brevicollis Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324. 17 March 2008

  27. PhD thesis – Cycle XX Friedel-Crafts reaction of Indoles to Nitroalkenes Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324. 17 March 2008

  28. PhD thesis – Cycle XX Synthesis and Chracterization of Impurities 17 March 2008

  29. PhD thesis – Cycle XX Collaboration with Pfizer, Ascoli Piceno Plant Characterization of Reference Standards - Analysis Identification of unknown impurities Synthesis of impurities New methodologies for the synthesis of compounds of pharmaceutical interest - Synthesis 18 December 2007

  30. ORDINARY TOXIC PhD thesis – Cycle XX Impurities If a material previously considered to be pure can be resolved into more than one component, that material can be redefined into new terms of purity and impurity. ORGANIC INORGANIC RESIDUAL SOLVENT 17 March 2008

  31. PhD thesis – Cycle XX Synthesis of Impurities II and III of Etofamide N-[4-(4-nitrophenoxy)benzyl]-N-(2-ethoxyethyl)amine N,N-di-[4-(4-nitrophenoxy)benzyl]-N-(2-ethoxyethyl)amine 17 March 2008

  32. PhD thesis – Cycle XX Etofamide API of Kitnos 18 December 2007

  33. PhD thesis – Cycle XX Synthesis of Etofamide The tertiary base impurity is the product of the reaction of 4-chloromethyl-4’-nitrodiphenyl ether with N-(2-ethoxyethyl)-N-[4-(4-nitrophenoxy)benzyl]amine intermediate. 17 March 2008

  34. PhD thesis – Cycle XX Impurity II of Etofamide • INTRODUCTION • Chemical name (based on IUPAC rules): • N-(2-ethoxyethyl)-N-[4-(4-nitrophenoxy)benzyl] amine. • Chemical Abstract Services (CAS) Registry Number: 101588-13-0. • Molecular Formula: C17H20N2O4. • Structural Formula: 17 March 2008

  35. J. Am. Chem. Soc., 1953, 75, 5877-5880 Il Farmaco- Ed. Sc.-, 1957, XIII,139-151 PhD thesis – Cycle XX Synthesis of Impurity II of Etofamide 17 March 2008

  36. PhD thesis – Cycle XX Impurity III of Etofamide INTRODUCTION Chemical name (based on IUPAC rules): N-(2-ethoxyethyl)-N,N-di-[4-(4-nitrophenoxy)benzyl] amine Molecular Formula:C30H29N3O7 Structural Formula: 17 March 2008

  37. PhD thesis – Cycle XX Synthesis of Impurity III of Etofamide 17 March 2008

  38. PhD thesis – Cycle XX Isomaltitol INTRODUCTION Chemical name (based on IUPAC rules): (2R, 3S, 4S, 5S)-6-{[( 2R, 3S, 4R, 5R, 6S)- 3,4,5- trihydroxy-6-(hydroxymethyl) terahydro-2H-2 pyranyl] oxy}hexane-1,2,3,4,5- pentaol Trivial name: 6-O-α-(D)-Glucopyranosyl-D-glucitol. Chemical Abstract Services (CAS) Registry Number:534-73-6. Molecular Formula:C12H24O11 Structural Formula: 17 March 2008

  39. PhD thesis – Cycle XX Synthesis of Isomaltitol Thermochimica Acta1996, 271, 149-153. 17 March 2008

  40. Thermochimica Acta1996, 271, 149-153. PhD thesis – Cycle XX Isomalt 17 March 2008

  41. PhD thesis – Cycle XX Isomaltitol Commercial Isomaltitol Synthesized Isomaltitol 17 March 2008

  42. RFT METODO 1 RIDUZIONE COSTI DI APPROVVIGIONAMENTO PER ISO-MALTITOLO DEFINIZIONE PROBLEMA: Elevato costo del reagente iso-maltitolo utilizzato nel metodo 6500QW vs 3 per la determinazione delle sostanze correlate del Mannitolo mediante HPLC(Entrata in vigore del nuovo metodo di Pharmacopeia Europea ) OBIETTIVO: Riduzione costi per l’acquisto del reagente necessario all’analisi MISURA • QUANTITA’ ANNUA NECESSARIA: • 5.000 mg per analisi • 5.000 mg scorta • TOT = 10.000 mg COSTO REAGENTE: • 1.340,00 Euro ogni 50mg COSTO TOTALE: 268.000,00 Euro all’anno IMPLEMENTAZIONE ANALISI Materiali Persone Misura • Sintesi del reagente in esame, per riduzione dell’isomaltoso (600 euro al grammo), effettuata dal gruppo di ricerca del Prof. Marcantoni (Dip.di Scienze Chimiche,Università degli Studi di Camerino, Responsabile Scientifico: Prof. R. Ballini) Purezza Reagente Fornitore (Sigma) BENEFICI Costo Reagente ALTO COSTO REAGENTE • Modifica metodo mediante cambio della pesata (riduzione Pesata) Quantità ordine Metodo Analitico EP • Stabilità della soluzione di iso-maltitolo Metodi Macchine Ambiente • Altro fornitore COSTI IL TEAM CONTROLLO • SOLUZIONI 1 E 2 APPLICATE IN MODO SINERGICO: • RISPARMIO DI 267.700,00 EURO all’anno • _______________ • SOLUZIONI 3 IN CORSO DI VALUTAZIONE • SOLUZIONE 4 = NESSUN VANTAGGIO

  43. PhD thesis – Cycle XX Cabergoline N-Oxide INTRODUCTION Chemical name (based on IUPAC rules): (3-{{[(6aR,9R,10aR)-7-Allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9yl]carbonyl}[(ethylamino)carbonyl]amino}propyl)(dimethyl)ammoniumolate. Empirical Formula:C26H37N5O2 Structural Formula: 17 March 2007

  44. PhD thesis – Cycle XX Cabergoline • API of DOSTINEX: • Hyperprolactinemia (dosage: 0.25mg and 0.5mg per tablets) • Anti-Parkinson(dosage: 1, 2 and 4mg per tablets) 9,10-dihdrolysergic acid 17 March 2008

  45. PhD thesis – Cycle XX Chracterization of Impurities 17 March 2008

  46. PhD thesis – Cycle XX PABA PABA is an essential nutrient for some bacteria and is considered to be in the B-complex vitamin family (Vitamin Bx). Be-Total HDsugar-coated tablets p-Aminobenzoic Acid 17 March 2008

  47. PhD thesis – Cycle XX Impurity of PABA 17 March 2008

  48. PhD thesis – Cycle XX Impurity of PABA 17 March 2008

  49. PhD thesis – Cycle XX PABA The intake of PABA and PABA ester is associated with the same efficacy and safety as free PABA alone. 17 March 2008

  50. Prof. Enrico Marcantoni • Prof. Roberto Ballini • Dott.ssa Sandra Giuli • Dr. Gianluca Paniccià • Dr. Orenzo Agostini • Sig. Terenzio De Angelis PhD thesis – Cycle XX Acknowledgements Colleagues at the laboratory and all the people that have collaborated in the development of the projects 17 March 2008

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