Relazione annuale lavoro

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
CeCl37H2O/NaI on SiO2
TiCl4
CeCl37H2O NaI
Synthesis of ß-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
TiX4 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.
TiCl4
ability to chelate
oxyphilic character
favourite octahedral structure
17 March 2008
6
PhD thesis Cycle XX
Diastereoselective synthesis of tertiary alcohols
by nucleophilic addition to asubstituted-ß-keto
esters
The synthetic strategy adopted for the
stereoselective addition of RMgX-CeCl3 species to
ß-keto amides was based on their conversion into
the corresponding titanium cyclic complexes.
17 March 2008
7
PhD thesis Cycle XX
Diastereoselective synthesis of tertiary alcohols
by nucleophilic addition to asubstituted-ß-keto
esters
17 March 2008
8
PhD thesis Cycle XX
Diastereoselective synthesis of tertiary alcohols
by nucleophilic addition to asubstituted-ß-keto
esters
Marcantoni, E., Massaccesi, M., Paoletti, M.,
Sambri, L. Arkivok, 2006, 49-58
17 March 2008
9
PhD thesis Cycle XX
Diastereoselective synthesis of tertiary alcohols
by nucleophilic addition to asubstituted-ß-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
PhD thesis Cycle XX
CeCl3?7H2O-NaI
CeCl37H2O NaI
Chemo- and regioselectivity
17 March 2008
12
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
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
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
Entry NaI CeCl3.7H2O Conditions/Time (min) Temp.(C) Yields ()
1 1.00 eq 1.50 eq 5W EtOH / 30 90 31
2 2.00 eq 1.50 eq 5W EtOH / 30 70 20
3 2.00 eq 1.50 eq 40W EtOH / 30 90 35
4 9.00 eq 1.50 eq 40W EtOH / 30 100 36
5 9.00 eq 1.50 eq 40W H2O / 60 100 0
6 2.00 eq 1.50 eq 40W CH3CN / 30 100 38
7 9.00 eq 1.50 eq 10W CH3CN / 20 100 86
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
PhD thesis Cycle XX
Garcia Gonzàlez reaction 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
Entry D-Glucose Ethyl acetoacetate CeCl3.7H2O NaI Time (h) Temperature (C) Yield ()
1 1 eq 1 eq 0,1 eq - 1,5 60 -
2 1 eq 1 eq 1 eq - 1,5 60 18,5
3 1 eq 1,2 eq 1 eq 0,1 eq 1,5 60 54
17 March 2008
22
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
PhD thesis Cycle XX
CeCl37H2O-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 ring of 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
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)amin
e
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
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-nitrophenox
y)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 oxyhexane-1,2,3,4,5-
pentaol Trivial name 6-O-a-(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 Acta 1996, 271, 149-153.
17 March 2008
40
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 lacquisto del reagente
necessario allanalisi
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 allanno

IMPLEMENTAZIONE
ANALISI
Materiali
Persone
Misura

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)

Fornitore (Sigma)
Purezza Reagente
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 allanno
• _______________
• 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,7,8,9,1
0,10a-octahydroindolo4,3-fgquinolin-9ylcarbonyl
(ethylamino)carbonylaminopropyl)(dimethyl)ammo
niumolate. 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 HD sugar-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
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