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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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slide1

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

slide2

PhD thesis – Cycle XX

Lewis acids in the preparation of the heterocyclic compounds: synthesis and

characterization of the impurities of API

17 March 2008

slide3

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

slide4

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

slide5

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

slide6

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

slide7

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

slide8

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

slide9

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

slide10

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

slide11

“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

slide12

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

slide13

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

slide14

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

slide15

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

slide16

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

slide17

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

slide18

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

slide19

Starting material

Glycosidase inhibitors

PhD thesis – Cycle XX

GarciaGonzàlezreaction [2]

[2] F. Garcia Gonzàles, Adv. Carbohydr. Chem.1956, 11, 97

17 March 2008

slide20

PhD thesis – Cycle XX

Garcia Gonzàlez reaction [3]

[3] A.K. Misra, G. Aghihotri Carbohydrate Research 2004, 339, 1381

17 March 2008

slide21

PhD thesis – Cycle XX

Garcia Gonzàlez reaction

17 March 2008

slide22

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

slide23

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

slide24

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

slide25

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

slide26

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

slide27

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

slide28

PhD thesis – Cycle XX

Synthesis and

Chracterization of Impurities

17 March 2008

slide29

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

slide30

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

slide31

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

slide32

PhD thesis – Cycle XX

Etofamide

API of Kitnos

18 December 2007

slide33

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

slide34

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

slide35

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

slide36

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

slide37

PhD thesis – Cycle XX

Synthesis of Impurity III of Etofamide

17 March 2008

slide38

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

slide39

PhD thesis – Cycle XX

Synthesis of Isomaltitol

Thermochimica Acta1996, 271, 149-153.

17 March 2008

slide40

Thermochimica Acta1996, 271, 149-153.

PhD thesis – Cycle XX

Isomalt

17 March 2008

slide41

PhD thesis – Cycle XX

Isomaltitol

Commercial Isomaltitol

Synthesized Isomaltitol

17 March 2008

slide42

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
slide43

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

slide44

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

slide45

PhD thesis – Cycle XX

Chracterization of

Impurities

17 March 2008

slide46

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

slide47

PhD thesis – Cycle XX

Impurity of PABA

17 March 2008

slide48

PhD thesis – Cycle XX

Impurity of PABA

17 March 2008

slide49

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

slide50

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