CeCl 3 •7H 2 O - Università degli Studi di Camerino

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
PhD thesis – Cycle XX
Lewis acids in the preparation of the
heterocyclic compounds: synthesis and
characterization of the impurities of API
17 March 2008
PhD thesis – Cycle XX
Collaboration with Pfizer,
Ascoli Piceno Plant
- Analysis
Characterization of Reference Standards
Identification of unknown impurities
Synthesis of impurities
- Synthesis
New methodologies for the
synthesis of compounds of pharmaceutical interest
17 March 2008
PhD thesis – Cycle XX
Lewis acids
TiCl4
CeCl3•7H2O – NaI
Synthesis of β-hydroxy esters
CeCl3•7H2O/NaI on SiO2
- Garcia Gonzàlez reaction
- Friedel-Crafts reaction
- Knoevenagel condensation
- Azides transformation to Primary Amines
17 March 2008
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
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-CeCl3 species to
β-keto amides was based on their conversion into the corresponding titanium cyclic
complexes.
O
O
HO
R
1
OR
TiCl4
R2MgX-CeCl3
R
R2
O
OR1
Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok, 2006, 49-58
17 March 2008
PhD thesis – Cycle XX
Diastereoselective synthesis of tertiary alcohols by
nucleophilic addition to α–substituted-β-keto esters
O
O
HO
R
TiCl4
OR1
R
R2
O
OR1
2
R MgX-CeCl3; -78°C
Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok, 2006, 49-58
17 March 2008
PhD thesis – Cycle XX
Diastereoselective synthesis of tertiary alcohols by
nucleophilic addition to α–substituted-β-keto esters
• High diastereoselectivity
• moderate-to-good efficiency
Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri,
L.; Arkivok, 2006, 49-58
17 March 2008
PhD thesis – Cycle XX
Diastereoselective synthesis of tertiary alcohols by
nucleophilic addition to α–substituted-β-keto esters
The nature of the carbonylsubstituent in the β-keto ester
substrate.
Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok, 2006, 49-58
17 March 2008
PhD thesis – Cycle XX
Cerium salts
Discovered in 1803 by Berzelius and Hisinger
Ce
Lanthanide
Oxidation state III and IV
CeCl3.7H2O
CeCl3
Low Toxicity
Ready availability at low cost
High stability towards water
FRIENDLY LEWIS ACID
17 March 2008
PhD thesis – Cycle XX
CeCl37H2O-NaI
“Friendly”
Lewis acid
Solvent-free
conditions
CeCl3·7H2O
NaI
Solid
support
Chemo- and
regioselectivity
Formation of
new bonds
17 March 2008
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.
O
EWG1
cat.
+
R1
H
1
EWG1
R1
EWG2
EWG2
2
3
• Increased the potentialities of CeCl3.7H2ONaI system
• major restriction to the broad application of
the Knoevenagel reaction
Building blocks useful for the
synthesis of natural and nonnatural 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
PhD thesis – Cycle XX
The CeCl3.7H2O-NaI system as promoter in the synthesis
of functionalized trisubstituted alkenes via
Knoevenagel condensation
O
Ar
CO2Et
H
4a-f
CeCl3.7H2O
NaI
+
CO2But
CO2Et
Ar
CO2But
CH3CN, r.t.
6a-f
5
Reflux
• 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
CO2Et
Ar
COOH
7a-f
Bartoli, G.; Beleggia, R.; Giuli, S., Giuliani, A., Marcantoni, E.; Massaccesi,
M., Paoletti, M., Tetrahedron Letters, 2006, 47, 6501-6504.
17 March 2008
PhD thesis – Cycle XX
Knoevenagel condensation
Aldehydea
Entry
CHO
1
Time/h
Productb
Conditions
54
r.t.
2.5
reflux
2
F3C
40
r.t.
77:23
1.5
reflux
95
90:10
97
93:07
90
75:25
85
80:20
91
60:40
CO2Et
COOH
F3C
• malonate mono acid 7 as unique
product isolated
• no evidence of ,-unsaturated
malonic acids.
7b
4b
CHO
3
O2N
37
r.t.
0.5
reflux
CO2Et
COOH
O2N
7c
4c
CHO
4
H3C
62
r.t.
3.5
reflux
CO2Et
COOH
H3C
7d
4d
CHO
5
H3CO
64
r.t.
4.0
reflux
fairly stereoselective affording
E-isomers in high yields
CO2Et
COOH
H3CO
7e
4e
CHO
4f
80
COOH
7a
CHO
N
E : Zd
CO2Et
4a
6
Yield (%)c
42
r.t.
1.5
reflux
CO2Et
COOH
N
7f
17 March 2008
Bartoli, G.; Beleggia, R.; Giuli, S., Giuliani, A., Marcantoni,
E.; Massaccesi, M., Paoletti, M., Tetrahedron Letters, 2006,
47, 6501-6504.
PhD thesis – Cycle XX
Microwave-Assisted Azides Trasformation to
Primary Amines Using Mild and Easily Accessible
CeCl3.7H2O/NaI System
CeCl3.7H2O (1.5 eq)
NaI (9 eq)
R
N3
R
CH3CN
reflux or MW
NH2
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
PhD thesis – Cycle XX
Microwave-Assisted Azides Trasformation to Primary
Amines Using Mild and Easily Accessible
CeCl3.7H2O/NaI System
CeCl3.7H2O (1.5 eq)
NaI (1.5 eq)
R
N3
R
NH2
SiO2
r.t. or reflux
CeCl3.7H2O (1.5 eq)
NaI (9 eq)
R
N3
(1 eq)
R
NH2
CH3CN
reflux; 24h
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
PhD thesis – Cycle XX
Microwave-Assisted Azides Trasformation to Primary Amines
Using Mild and Easily Accessible CeCl3.7H2O/NaI System
Entry
Starting Material
Product
N3
1
Yield (%)
NH2
75
O2N
O2 N
N3
2
NH2
N3
NH2
75
3
O
O
4
75
H3CO
N3
H3CO
NH2
90
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
PhD thesis – Cycle XX
Azides Trasformation to Primary Amines
• Diminution of the reaction time
• Higher yields
CeCl3.7H2O
N3
NH2
NaI
solvent, MW
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
PhD thesis – Cycle XX
Garcia Gonzàlez reaction [2]
OH
O
ZnCl 2, EtOH
+
OH
OH
O
O
HO
HO
O
OH
90°C, Reflux
O
HO
OH
Flexibility
OH
Chirality O
COOEt
X
OH
HO
O
HO
OH
Hydrophilicity
n
R
Rigidity
HO
Lipophilicity
O
HO
Starting
material
Glycosidase inhibitors
[2] F. Garcia Gonzàles, Adv. Carbohydr. Chem. 1956, 11, 97
17 March 2008
PhD thesis – Cycle XX
Garcia Gonzàlez reaction [3]
OH
O
O
O
HO
HO
O
CeCl 3 7 H2O, H2O
+
OH
OH
O
O
T=90°C, 5h
HO
OH
(93%)
Sugar
1,3-dione
Time (h)
Yield(%)
Product
O
O
O
OEt
D-Glusose
6
87
O
OEt
O
HO
OH
O
O
O
OEt
D-Galactose
8
82
O
OEt
O
HO
OH
O
O
D-Arabinose
O
HO
7
90
HO
O
OH
[3] A.K. Misra, G. Aghihotri Carbohydrate Research 2004, 339, 1381
17 March 2008
PhD thesis – Cycle XX
Garcia Gonzàlez reaction
OH
O
1 eq CeCl3. 7H2O
0,1 eq NaI
O
O
HO
HO
+
OH
OH
OEt
O
OEt
HO
O
CH3CN, 60°C, 1,5h
OH
HO
OH
Entry D-Glucose
Ethyl
CeCl3.7H2O
acetoacetate
NaI
Time Temperature
(h)
(°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
PhD thesis – Cycle XX
Garcia Gonzàlez reaction solvent-free
OH
O
CeCl 3 7 H2O - NaI
+
OH
OH
O
O
HO
HO
O
OH
SiO2 T=50°C
O
HO
OH
OH
• Solvent-free
• 0,3 eq of promoter system
Sugar
1,3-dione
O
D-Galactose
Yield(%)
100
90
80
70
60
50
40
30
20
10
0
95
80
75
70
53
40
29
36
50
85
36
50
88
grams of Silica gel for 1 mmol of D-Glucose
85
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.
O
D-Mannose
O
Temperature (°C)
O
D-Glusose
O
Time (h)
yield % HPLC of 5aa
• 0,5 g SiO2/mmol D-glucose
24
0,05
O
48
50
17 March 2008
0,12
0,25
0,35
0,45
0,5
0,55
0,65
PhD thesis – Cycle XX
CeCl3•7H2O-NaI-SiO2
NaI is essential for
the reaction
H2O is essential
for the reaction
The solid support
SiO2
• gives a better yield of product
• facilitates the work up of the reaction
mixture
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.
• permits the reaction to be accomplished
without solvent
17 March 2008
PhD thesis – Cycle XX
The CeCl3.7H2O-NaI-SiO2 as efficient promoter for
Friedel-Crafts reaction of Indoles to Nitroalkenes in
solvent-free conditions
X
NO2
+
N
H
R
CeCl3.7H2O
NaI, SiO2
R
X
N
H
NO2
Bartoli, G.; Di Antonio, G.; Giuli, S.; Marcantoni, E.;
Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324.
17 March 2008
PhD thesis – Cycle XX
Friedel-Crafts reaction of Indoles to Nitroalkenes
X
NO2
+
N
H
Ph
Ph
X
N
H
Indole
Entry
CeCl3.7H2O
NaI, SiO2
Yield(%)
Product
Time (h)
NO2
Ph
1
8
96
N
H
N
H
H3CO
2
4
18
NO2
Ph
NC
85
N
H
NO2
N
H
HO
4
24
N
H
• 0.3 equiv of NaI
• SiO2 (0.5 g/mmol of nitroalkene)
• solvent-free conditions
92
N
H
NC
• 0.3 eq CeCl3.7H2O
Ph
H3CO
N
H
3
NO2
Ph
HO
74
N
H
NO2
Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.;
Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324.
17 March 2008
PhD thesis – Cycle XX
The CeCl3.7H2O-NaI-SiO2 as efficient promoter for Friedel-Crafts
reaction of Indoles to Nitroalkenes in solvent-free conditions
+
Boc
N
N
1a H
-carboline ring of the (-)-(S)-Brevicolline
Carex Brevicollis
2b
N
N
H
7
N
CH3
CH3
CeCl3.7H2O
NaI, SiO2
NO2
r.t., 2h, 89%
N
H
N
H
Boc
NO2
3ab
3-(2-nitroethyl)indolyl derivative
Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.;
Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324.
17 March 2008
PhD thesis – Cycle XX
Friedel-Crafts reaction of Indoles to Nitroalkenes
+
X
1
H
NO2
R2
1
R
N
H
2
R1
CeCl3.7H2O
NO2
X
NaI, SiO2
N
H
R2
3
Reduction
R1
X
R2
N
H
5
NH
R1
3
R CHO
R2
X
Cyclization
N
H 4
3
R
tetrahydro-carboline
Aromatization
NH2
tryptamine derivative
R1
X
R2
N
N
H
R3
6
Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.;
Paoletti, M., Synthesis, 2008, 2, 320-324.
17 March 2008
PhD thesis – Cycle XX
Synthesis and
Chracterization of Impurities
17 March 2008
PhD thesis – Cycle XX
Collaboration with Pfizer,
Ascoli Piceno Plant
- Analysis
Characterization of Reference Standards
Identification of unknown impurities
Synthesis of impurities
- Synthesis
New methodologies for the
synthesis of compounds of pharmaceutical interest
18 December 2007
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
TOXIC
RESIDUAL SOLVENT
ORDINARY
17 March 2008
PhD thesis – Cycle XX
Synthesis of Impurities II and III of Etofamide
O2 N
O
N
H
O
N-[4-(4-nitrophenoxy)benzyl]-N-(2-ethoxyethyl)amine
O2N
NO2
N
O
O
O
N,N-di-[4-(4-nitrophenoxy)benzyl]-N-(2-ethoxyethyl)amine
17 March 2008
PhD thesis – Cycle XX
Etofamide
O
O2N
Cl
N
Cl
O
O
API of Kitnos
18 December 2007
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
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:
O2 N
O
N
H
O
17 March 2008
PhD thesis – Cycle XX
Synthesis of Impurity II of Etofamide
O2N
O
1
(CH2O)n; HCl conc;
H3PO4
CH3CO2H
rif. 85°C (50h)
O2 N
Cl
H2N
O
O
3
2
Free solvent;
r.t.
O2 N
O
N
H
O
4
90%
J. Am. Chem. Soc., 1953, 75, 5877-5880
Il Farmaco- Ed. Sc.-, 1957, XIII, 139-151
17 March 2008
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:
O2N
NO2
N
O
O
O
17 March 2008
PhD thesis – Cycle XX
Synthesis of Impurity III of Etofamide
O2N
Cl
O2N
N
H
O
1
O
2
Et3N,
DMF dry,
rif.
O2N
NO2
N
O
O
O
3
80%
17 March 2008
O
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
OH
Structural Formula:
OH
OH
O
HO
OH
OH
O
OH
HO
OH
17 March 2008
PhD thesis – Cycle XX
Synthesis of Isomaltitol
OH
OH
OH
O
O
HO
OH
OH
O
HO
O
OH
r.t.; 48h
OH
OH
O
NaBH4
OH
HO
OH
OH
HO
OH
OH
Thermochimica Acta 1996, 271, 149-153.
17 March 2008
PhD thesis – Cycle XX
Isomalt
Thermochimica Acta 1996, 271, 149-153.
17 March 2008
PhD thesis – Cycle XX
Isomaltitol
Commercial Isomaltitol
Synthesized Isomaltitol
17 March 2008
RFT METODO 1
RIDUZIONE COSTI DI APPROVVIGIONAMENTO
DEFINIZIONE
PER ISO-MALTITOLO
PROBLEMA:
OBIETTIVO:
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 )
Riduzione costi per l’acquisto del reagente necessario all’analisi
QUANTITA’ ANNUA NECESSARIA:
 5.000 mg per analisi
MISURA
 5.000 mg scorta
 TOT = 10.000 mg
COSTO REAGENTE:
 1.340,00 Euro ogni 50mg
COSTO TOTALE: 268.000,00 Euro all’anno
BENEF
ICI
IMPLEMENTAZIONE
ANALISI
Materiali
1. 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)
2. Modifica metodo mediante cambio della pesata
(riduzione Pesata)
Persone
Purezza Reagente
Costo Reagente
Misura
Fornitore (Sigma)
ALTO COSTO
REAGENTE
Quantità ordine
Metodo Analitico EP
3. Stabilità della soluzione di iso-maltitolo
Metodi
4. Altro fornitore
COSTI
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
Macchine
Ambiente
IL TEAM
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]quinolin9yl]carbonyl}[(ethylamino)carbonyl]amino}propyl)(dimethyl)ammoniumolate.
Empirical Formula: C26H37N5O2
Structural Formula:
H
N
O
O
N
H
N
H
N
H
17 March 2007
CH3
CH3
O
N
CH3
PhD thesis – Cycle XX
Cabergoline
H
N
O
API of DOSTINEX:
•Hyperprolactinemia (dosage:
0.25mg and 0.5mg per tablets)
• Anti-Parkinson (dosage: 1, 2
and 4mg per tablets)
O
N
N
CH3
H
N
O
CH3
CH3
OH
H
HN
N
H
HN
9,10-dihdrolysergic acid
17 March 2008
PhD thesis – Cycle XX
Chracterization of
Impurities
17 March 2008
PhD thesis – Cycle XX
PABA
O
OH
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
NH2
p-Aminobenzoic Acid
17 March 2008
PhD thesis – Cycle XX
Impurity of PABA
17 March 2008
PhD thesis – Cycle XX
Impurity of PABA
17 March 2008
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
PhD thesis – Cycle XX
Acknowledgements
 Prof. Enrico Marcantoni
 Prof. Roberto Ballini
 Dott.ssa Sandra Giuli
 Dr. Gianluca Paniccià
 Dr. Orenzo Agostini
 Sig. Terenzio De Angelis
Colleagues at the laboratory and all the
people that have collaborated in the
development of the projects
17 March 2008