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Lewis acids in the preparation of the heterocyclic compounds: synthesis and characterization of the impurities of API 2004/05 – 2006/07 SCHOOL OF ADVANCED.

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Presentation on theme: "Lewis acids in the preparation of the heterocyclic compounds: synthesis and characterization of the impurities of API 2004/05 – 2006/07 SCHOOL OF ADVANCED."— Presentation transcript:

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

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

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

4 PhD thesis – Cycle XX 17 March 2008 Lewis acids TiCl 4 Synthesis of β-hydroxy esters CeCl 3 7H 2 O – NaI - Knoevenagel condensation - Azides transformation to Primary Amines CeCl 3 7H 2 O/NaI on SiO 2 - Garcia Gonzàlez reaction - Friedel-Crafts reaction

5 PhD thesis – Cycle XX 17 March 2008 Titanium Compounds TiX 4 derivates 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. TiCl 4 oxyphilic character favourite octahedral structure ability to chelate

6 Diastereoselective synthesis of tertiary alcohols by nucleophilic addition to α–substituted-β-keto esters PhD thesis – Cycle XX 17 March 2008 titanium cyclic complexes. The synthetic strategy adopted for the stereoselective addition of RMgX-CeCl 3 species to β-keto amides was based on their conversion into the corresponding titanium cyclic complexes. Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok, 2006, 49-58

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

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

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

10 Ce FRIENDLY LEWIS ACID Discovered in 1803 by Berzelius and Hisinger Lanthanide Oxidation state III and IV CeCl 3 High stability towards water Low Toxicity Cerium salts PhD thesis – Cycle XX 17 March 2008 Ready availability at low cost CeCl 3. 7H 2 O

11 PhD thesis – Cycle XX 17 March 2008 CeCl 3 7H 2 O-NaI Solvent-free conditions Formation of new bonds Solid support Chemo- and regioselectivity Friendly Lewis acid CeCl 3 ·7H 2 O NaI

12 PhD thesis – Cycle XX 17 March 2008 Bartoli, G.; Beleggia, R.; Giuli, S., Giuliani, A., Marcantoni, E.; Massaccesi, M., Paoletti, M., Tetrahedron Letters, 2006, 47, The CeCl 3. 7H 2 O-NaI system as promoter in the synthesis of functionalized trisubstituted alkenes via Knoevenagel condensation Knoevenagel condensation CeCl 3. 7H 2 O-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 Increased the potentialities of CeCl 3. 7H 2 O- NaI system major restriction to the broad application of the Knoevenagel reaction

13 PhD thesis – Cycle XX 17 March 2008 Bartoli, G.; Beleggia, R.; Giuli, S., Giuliani, A., Marcantoni, E.; Massaccesi, M., Paoletti, M., Tetrahedron Letters, 2006, 47, The CeCl 3. 7H 2 O-NaI system as promoter in the synthesis of functionalized trisubstituted alkenes via Knoevenagel condensation Knoevenagel condensation 1:1.2 ratio between 4a and 5 in a ca. 0.1 M solution in acetonitrile 1.35 equiv of CeCl 3. 7H 2 O 1.35 equiv of NaI

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

15 PhD thesis – Cycle XX 17 March 2008 Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem. 2008, 73, Microwave-Assisted Azides Trasformation to Primary Amines Using Mild and Easily Accessible CeCl 3. 7H 2 O/NaI System

16 PhD thesis – Cycle XX 17 March 2008 Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem. 2008, 73, Microwave-Assisted Azides Trasformation to Primary Amines Using Mild and Easily Accessible CeCl 3. 7H 2 O/NaI System

17 PhD thesis – Cycle XX 17 March 2008 Microwave-Assisted Azides Trasformation to Primary Amines Using Mild and Easily Accessible CeCl 3. 7H 2 O/NaI System Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem. 2008, 73,

18 PhD thesis – Cycle XX 17 March 2008 Azides Trasformation to Primary Amines Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem 2008, 73, EntryNaICeCl 3. 7H 2 OConditions/Time (min) Temp.(°C)Yields (%) eq1.50 eq5W; EtOH / eq1.50 eq5W; EtOH / eq1.50 eq40W; EtOH / eq1.50 eq40W; EtOH / eq1.50 eq40W; H 2 O / eq1.50 eq40W; CH 3 CN / eq1.50 eq10W; CH 3 CN / Diminution of the reaction time Higher yields

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

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

21 EntryD-Glucose Ethyl acetoacetate CeCl 3. 7H 2 ONaI Time (h) Temperature (°C) Yield (%) 11 eq 0,1 eq-1, eq -1,56018,5 31 eq1,2 eq1 eq0,1 eq1,56054 Garcia Gonzàlez reaction PhD thesis – Cycle XX 17 March 2008

22 Solvent-free 0,3 eq of promoter system 0,5 g SiO 2 /mmol D-glucose Garcia Gonzàlez reaction solvent-free PhD thesis – Cycle XX 17 March 2008 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,

23 The solid support SiO 2 NaI is essential for the reaction PhD thesis – Cycle XX 17 March 2008 CeCl 3 7H 2 O-NaI-SiO 2 gives a better yield of product facilitates the work up of the reaction mixture permits the reaction to be accomplished without solvent 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, H 2 O is essential for the reaction

24 PhD thesis – Cycle XX 17 March 2008 Bartoli, G.; Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, The CeCl 3. 7H 2 O-NaI-SiO 2 as efficient promoter for Friedel-Crafts reaction of Indoles to Nitroalkenes in solvent-free conditions

25 PhD thesis – Cycle XX 17 March 2008 Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, Friedel-Crafts reaction of Indoles to Nitroalkenes 0.3 eq CeCl 3. 7H 2 O 0.3 equiv of NaI SiO 2 (0.5 g/mmol of nitroalkene) solvent-free conditions

26 PhD thesis – Cycle XX 17 March 2008 Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, The CeCl 3. 7H 2 O-NaI-SiO 2 as efficient promoter for Friedel-Crafts reaction of Indoles to Nitroalkenes in solvent-free conditions -carboline ring of the (-)-(S)-Brevicolline Carex Brevicollis

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

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

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

30 PhD thesis – Cycle XX 17 March 2008 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. ORGANICINORGANICRESIDUAL SOLVENT TOXICORDINARY

31 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 PhD thesis – Cycle XX 17 March 2008

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

33 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. PhD thesis – Cycle XX 17 March 2008

34 INTRODUCTION Chemical name (based on IUPAC rules): N-(2-ethoxyethyl)-N-[4-(4-nitrophenoxy)benzyl] amine. Chemical Abstract Services (CAS) Registry Number: Molecular Formula: C 17 H 20 N 2 O 4. Structural Formula: Impurity II of Etofamide PhD thesis – Cycle XX 17 March 2008

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

36 Impurity III of Etofamide PhD thesis – Cycle XX 17 March 2008 INTRODUCTION Chemical name (based on IUPAC rules): N-(2-ethoxyethyl)-N,N-di-[4-(4-nitrophenoxy)benzyl] amine Molecular Formula: C 30 H 29 N 3 O 7 Structural Formula:

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

38 Isomaltitol PhD thesis – Cycle XX 17 March 2008 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: Molecular Formula: C 12 H 24 O 11 Structural Formula:

39 Synthesis of Isomaltitol PhD thesis – Cycle XX 17 March 2008 Thermochimica Acta 1996, 271,

40 Isomalt PhD thesis – Cycle XX 17 March 2008 Thermochimica Acta 1996, 271,

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

42 RFT METODO 1 RIDUZIONE COSTI DI APPROVVIGIONAMENTO PER ISO-MALTITOLO OBIETTIVO: Riduzione costi per lacquisto del reagente necessario allanalisi 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 ) M ISURA QUANTITA ANNUA NECESSARIA: mg per analisi mg scorta TOT = mg COSTO REAGENTE: 1.340,00 Euro ogni 50mg COSTO TOTALE: ,00 Euro allanno D EFINIZIONE CONTROLLO SOLUZIONI 1 E 2 APPLICATE IN MODO SINERGICO: RISPARMIO DI ,00 EURO allanno _______________ SOLUZIONI 3 IN CORSO DI VALUTAZIONE SOLUZIONE 4 = NESSUN VANTAGGIO COSTI ANALISI ALTO COSTO REAGENTE MaterialiPersoneMisura MetodiMacchineAmbiente Quantità ordine Costo Reagente Fornitore (Sigma)Purezza Reagente Metodo Analitico EP I MPLEMENTAZIONE BENEF ICI 2.Modifica metodo mediante cambio della pesata (riduzione Pesata) 4.Altro fornitore 1.Sintesi del reagente in esame, per riduzione dellisomaltoso (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) 3.Stabilità della soluzione di iso-maltitolo IL TEAM

43 Cabergoline N-Oxide PhD thesis – Cycle XX 17 March 2007 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: C 26 H 37 N 5 O 2 Structural Formula:

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

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

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

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

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

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

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


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