lewis acids in the preparation of the heterocyclic compounds: synthesis and characterization of the...
TRANSCRIPT
Lewis acids in the preparation of the heterocyclic compounds: synthesis
andcharacterization of the impurities of
API
2004/05 – 2006/07
SCHOOL OF ADVANCED STUDIES
Doctorate course in Chemical Sciences
PhD thesis
Cycle XXScientific-sector CHIM/06
PhD Candidate:Dr. Melissa Paoletti
Tutors:Prof. Enrico MarcantoniDr. Gianluca Paniccià
Lewis acids in the preparation of the
heterocyclic compounds: synthesis and
characterization of the impurities of API
PhD thesis – Cycle XX
17 March 2008
Characterization of Reference Standards
Identification of unknown impurities
Collaboration with Collaboration with Pfizer,Pfizer,
Ascoli Piceno PlantAscoli Piceno Plant
- Analysis
- Synthesis New methodologies for the synthesis of compounds of pharmaceutical interest
Synthesis of impurities
PhD thesis – Cycle XX
17 March 2008
PhD thesis – Cycle XX
17 March 2008
Lewis acidsLewis acids
TiCl4
Synthesis of β-hydroxy esters
CeCl3•7H2O – NaI
- Knoevenagel condensation- Azides transformation to Primary Amines
CeCl3•7H2O/NaI on SiO2
- Garcia Gonzàlez reaction- Friedel-Crafts reaction
PhD thesis – Cycle XX
17 March 2008
Titanium CompoundsTitanium 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
oxyphilic character
favourite octahedral structure
ability to chelate
Diastereoselective synthesis of tertiary Diastereoselective synthesis of tertiary alcohols by nucleophilic addition to α–alcohols by nucleophilic addition to α–
substituted-β-keto esterssubstituted-β-keto esters
PhD thesis – Cycle XX
17 March 2008
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 titanium cyclic complexes. complexes.
R OR1
O O
TiCl4
R2MgX-CeCl3R OR1
OHO
R2
Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok, 2006, 49-58
Diastereoselective synthesis of tertiary Diastereoselective synthesis of tertiary alcohols by nucleophilic addition to α–alcohols by nucleophilic addition to α–
substituted-β-keto esterssubstituted-β-keto esters
PhD thesis – Cycle XX
17 March 2008
R OR1
O O
TiCl4
R2MgX-CeCl3; -78°CR OR1
OHO
R2
Marcantoni, E., Massaccesi, M., Paoletti, M., Sambri, L.; Arkivok, 2006, 49-58
Diastereoselective synthesis of tertiary Diastereoselective synthesis of tertiary alcohols by nucleophilic addition to α–alcohols by nucleophilic addition to α–
substituted-β-keto esterssubstituted-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
Diastereoselective synthesis of tertiary Diastereoselective synthesis of tertiary alcohols by nucleophilic addition to α–alcohols by nucleophilic addition to α–
substituted-β-keto esterssubstituted-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
Ce
FRIENDLY LEWIS ACIDFRIENDLY LEWIS ACID
Discovered in 1803 by Berzelius and Hisinger
Lanthanide
Oxidation state III and IV
CeCl3
High stability towards water
Low Toxicity
Cerium saltsCerium saltsPhD thesis – Cycle XX
17 March 2008
Ready availability at low cost
CeCl3.7H2O
PhD thesis – Cycle XX
17 March 2008
CeClCeCl337H7H22O-NaIO-NaI
Solvent-freeconditions
Formation of new bonds
Solidsupport
Chemo- and regioselectivity
“Friendly” Lewis acid
CeCl3·7H2ONaI
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, 6501-6504.
The CeClThe CeCl33..7H7H22O-NaI system as promoter in O-NaI system as promoter in
the synthesis of functionalized the synthesis of functionalized trisubstituted alkenes viatrisubstituted alkenes via
Knoevenagel condensationKnoevenagel condensationCeCl3
.7H2O-NaI system promotes the addition of CH-acidic compounds to different electrophiles.
R1 H
O EWG1
EWG2
R1 EWG1
EWG2
+cat.
1 2 3
Building blocks useful for the synthesis of natural and non-natural bioactive compounds
• Increased the potentialities of CeCl3.7H2O-
NaI system• major restriction to the broad application of the Knoevenagel reaction
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, 6501-6504.
The CeClThe CeCl33..7H7H22O-NaI system as promoter in O-NaI system as promoter in
the synthesis of functionalized the synthesis of functionalized trisubstituted alkenes viatrisubstituted alkenes via
Knoevenagel condensationKnoevenagel condensation
ArCO2Et
CO2But
6a-fAr H
O CO2Et
CO2But+
4a-f 5
ArCO2Et
COOH
7a-f
CeCl3.7H2O
NaI
CH3CN, r.t.
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
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, 6501-6504.
Knoevenagel condensationKnoevenagel condensationEntry Time/h Productb Yield (%)c
1
2
3
4
5
6
5480
40
37
62
64
42
95
97
90
85
91
4a
4f
4b
4c
4d
4e
7a
Aldehydea
CHO
CHO
F3C
CHO
O2N
CHO
H3C
CHO
H3CO
N
CHO
2.5
1.5
0.5
3.5
4.0
1.5
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
reflux
reflux
reflux
reflux
reflux
reflux
CO2Et
COOH
7b
CO2Et
COOHF3C
7c
CO2Et
COOHO2N
7d
CO2Et
COOHH3C
7e
CO2Et
COOHH3CO
7f
N
CO2Et
COOH
E : Zd
77:23
90:10
93:07
75:25
80:20
60:40
Conditions
• malonate mono acid 7 as unique product isolated • no evidence of ,-unsaturated malonic acids.
fairly stereoselective affording E-isomers in high yields
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, 1919-1924.
Microwave-Assisted Azides Microwave-Assisted Azides Trasformation to Primary Amines Trasformation to Primary Amines Using Mild and Easily Accessible Using Mild and Easily Accessible
CeClCeCl33..7H7H22O/NaI SystemO/NaI System
CeCl3.7H2O (1.5 eq)
CH3CNR N3
NaI (9 eq)
reflux or MW
R NH2
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, 1919-1924.
Microwave-Assisted Azides Trasformation to Microwave-Assisted Azides Trasformation to Primary Amines Using Mild and Easily Primary Amines Using Mild and Easily
Accessible CeClAccessible CeCl33..7H7H22O/NaI SystemO/NaI System
CeCl3.7H2O (1.5 eq)
SiO2
R N3
NaI (1.5 eq)
r.t. or reflux
R NH2
CeCl3.7H2O (1.5 eq)
CH3CNR N3
NaI (9 eq)
reflux; 24h
R NH2
(1 eq)
PhD thesis – Cycle XX
17 March 2008
Microwave-Assisted Azides Trasformation to Microwave-Assisted Azides Trasformation to Primary Amines Using Mild and Easily Primary Amines Using Mild and Easily
Accessible CeClAccessible CeCl33..7H7H22O/NaI SystemO/NaI System
Entry Product Yield (%)
1
2
3
75
Starting Material
O2N
N3
O2N
NH2
4
75N3 NH2
75
N3 NH2
90N3 NH2H3CO H3CO
O O
Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem. 2008, 73, 1919-1924.
PhD thesis – Cycle XX
17 March 2008
Azides Trasformation to Primary AminesAzides Trasformation to Primary Amines
Bartoli, G., Di Antonio, G., Giovannini, R., Giuli, S., Lanari, S., Paoletti, M., Marcantoni, E., J. Org. Chem 2008, 73, 1919-1924.
N3 NH2
CeCl3.7H2O
solvent, MW
NaI
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
• Diminution of the reaction time• Higher yields
GarciaGarcia GonzàlezGonzàlez reaction reaction [2][2]
O
OH
HOHO
OH OH
O O
+
90°C, Reflux
ZnCl2, EtOH
O
O
HO
OH
OH
OH
Starting
material
Glycosidase inhibitors
O
COOEt
HO
OH
HO
HO
PhD thesis – Cycle XX
17 March 2008
[2] F. Garcia Gonzàles, Adv. Carbohydr. Chem. 1956, 11, 97
O
O
X
RHO
OHLipophilicity
ChiralityFlexibility
HydrophilicityRigidity
n
O
OH
HOHO
OH OH
O O
O+
O
T=90°C, 5h
CeCl3 7 H2O, H2OO
OHHO
(93%)
6 87
Sugar Time (h) Product1,3-dione
D-GlusoseOEt
O O
O
OOEt
O
OHHO
8 82D-GalactoseOEt
O O
O
OOEt
O
OHHO
7 90D-Arabinose
O O
O
O
HO
HO
OH
Yield(%)
PhD thesis – Cycle XX
17 March 2008
Garcia Gonzàlez Garcia Gonzàlez reaction reaction [3][3]
[3] A.K. Misra, G. Aghihotri Carbohydrate Research 2004, 339, 1381
O
OH
HOHO
OH OHOEt
O O
O+
OOEt
CH3CN, 60°C, 1,5h
1 eq CeCl3. 7H2O
0,1 eq NaI
HO
OH
HO
OH
Entry D-GlucoseEthyl
acetoacetateCeCl3
.7H2O NaITime
(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
Garcia Gonzàlez Garcia Gonzàlez reactionreaction
PhD thesis – Cycle XX
17 March 2008
• Solvent-free
• 0,3 eq of promoter system
• 0,5 g SiO2/mmol D-glucose
2429
40
53
80
95
7570
0
1020
3040
50
6070
8090
100
0,05 0,12 0,25 0,35 0,45 0,5 0,55 0,65
grams of Silica gel for 1 mmol of D-Glucose
yiel
d %
HP
LC
of
5aa
O
O
HO
OH
OH
OH
O
OH
HOHO
OH OH
O O
+
SiO2 T=50°C
CeCl3 7 H2O - NaI
Garcia Gonzàlez reaction Garcia Gonzàlez reaction solvent-freesolvent-free
PhD thesis – Cycle XX
36 85
Sugar Time (h) Yield(%)1,3-dione
O OD-Glusose
Temperature (°C)
50
D-Mannose
O O36 8850
D-Galactose
O O48 8550
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, 6029-6036.
The solid supportSiO2
NaI is essential for the reaction
PhD thesis – Cycle XX
17 March 2008
CeClCeCl33•7H•7H22O-NaI-SiOO-NaI-SiO22
• 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, 6029-6036.
H2O is essential for the reaction
PhD thesis – Cycle XX
17 March 2008
Bartoli, G.; Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324.
The CeClThe CeCl33..7H7H22O-NaI-SiOO-NaI-SiO22 as efficient as efficient
promoter for Friedel-Crafts reaction of promoter for Friedel-Crafts reaction of Indoles to Nitroalkenes in solvent-free Indoles to Nitroalkenes in solvent-free
conditionsconditions
NH
NH
CeCl3.7H2O
NaI, SiO2
+R
NO2
X XR
NO2
PhD thesis – Cycle XX
17 March 2008
Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324.
Friedel-Crafts reaction of Indoles to Friedel-Crafts reaction of Indoles to NitroalkenesNitroalkenes
NH
NH
CeCl3.7H2O
NaI, SiO2
+Ph
NO2
X XPh
NO2
Entry Time (h) Yield(%)
1
Product
4
3
2
NH
Indole
NH
Ph
NO2
NH
Ph
NO2
H3CO
NH
Ph
NO2
NC
NH
NH
NH
NH
Ph
NO2
HO
8
4
18
24
96
92
85
74
H3CO
NC
HO
• 0.3 eq CeCl3.7H2O
• 0.3 equiv of NaI • SiO2 (0.5 g/mmol of nitroalkene)• solvent-free conditions
PhD thesis – Cycle XX
17 March 2008
Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324.
NH
NH
CeCl3.7H2ONaI, SiO2
1a 2b
+
3ab
N NO2
Boc
NBoc
NO2
H
r.t., 2h, 89%
N
NCH3
CH3
NH7
3-(2-nitroethyl)indolyl derivative
The CeClThe CeCl33..7H7H22O-NaI-SiOO-NaI-SiO22 as efficient promoter for as efficient promoter for
Friedel-Crafts reaction of Indoles to Nitroalkenes Friedel-Crafts reaction of Indoles to Nitroalkenes in solvent-free conditionsin solvent-free conditions
-carboline ring of the (-)-(S)-Brevicolline
Carex Brevicollis
PhD thesis – Cycle XX
17 March 2008
Bartoli, G.;Di Antonio, G.; Giuli, S.; Marcantoni, E.; Marcolini, M.; Paoletti, M., Synthesis, 2008, 2, 320-324.
Friedel-Crafts reaction of Indoles to Friedel-Crafts reaction of Indoles to NitroalkenesNitroalkenes
NH
NH
R1
CeCl3.7H2O
NaI, SiO21 2
+
3
XR1
H
R2NO2 X NO2
R2
NH
R1
4
X R2
NH2NH5
NH
XR1
R2
R3
NH
6
N
XR1
R2
R3
Reduction
Cyclization
R3CHO
Aromatizationtetrahydro- carboline tryptamine derivative
PhD thesis – Cycle XX
17 March 2008
Synthesis and Synthesis and Chracterization of ImpuritiesChracterization of Impurities
Characterization of Reference Standards
Identification of unknown impurities
Collaboration with Collaboration with Pfizer,Pfizer,
Ascoli Piceno PlantAscoli Piceno Plant
- Analysis
- Synthesis New methodologies for the synthesis of compounds of pharmaceutical interest
Synthesis of impurities
PhD thesis – Cycle XX
18 December 2007
PhD thesis – Cycle XX
17 March 2008
ImpuritiesImpuritiesIf 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
TOXIC ORDINARY
Synthesis of Impurities II and III of Synthesis of Impurities II and III of EtofamideEtofamide
O
NH
OO2N
N-[4-(4-nitrophenoxy)benzyl]-N-(2-ethoxyethyl)amine
O
NO2N
O
NO2
O
N,N-di-[4-(4-nitrophenoxy)benzyl]-N-(2-ethoxyethyl)amine
PhD thesis – Cycle XX
17 March 2008
PhD thesis – Cycle XX
18 December 2007
EtofamideEtofamide
O
NO2N
O
Cl
Cl
O
API of Kitnos
Synthesis of EtofamideSynthesis 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
• 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:
O
NH
OO2N
Impurity II of EtofamideImpurity II of Etofamide
PhD thesis – Cycle XX
17 March 2008
Synthesis of Impurity II of EtofamideSynthesis of Impurity II of Etofamide
PhD thesis – Cycle XX
17 March 2008
O
NH
OO2N
O
O2NCl H2N
O
1
23
Free solvent;r.t.
O
O2N
(CH2O)n; H3PO4
HCl conc; CH3CO2Hrif. 85°C (50h)
4 90%
J. Am. Chem. Soc., 1953, 75, 5877-5880 Il Farmaco- Ed. Sc.-, 1957, XIII, 139-151
Impurity III of EtofamideImpurity 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: C30H29N3O7
Structural Formula:
O
NO2N
O
NO2
O
Synthesis of Impurity III of Synthesis of Impurity III of EtofamideEtofamide
PhD thesis – Cycle XX
17 March 2008
O
NH
OO2N
O
O2NCl
1
3
Et3N,DMF dry,rif.
O
NO2N
O O
NO2
2
80%
IsomaltitolIsomaltitol
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: 534-73-6.
Molecular Formula: C12H24O11
Structural Formula:
O
OH
HO
HO
OOH
OH
OH
OH
OH
OH
Synthesis of IsomaltitolSynthesis of Isomaltitol
PhD thesis – Cycle XX
17 March 2008
O
OH
HO
HO
O
OH
OH
OH
OH
OH
OO
OH
HO
HO
O
OH
OH
OH
OH
OH
OHNaBH4
r.t.; 48h
Thermochimica Acta 1996, 271, 149-153.
IsomaltIsomalt
PhD thesis – Cycle XX
17 March 2008
Thermochimica Acta 1996, 271, 149-153.
IsomaltitolIsomaltitol
PhD thesis – Cycle XX
17 March 2008
Commercial Isomaltitol Synthesized Isomaltitol
RFT METODO 1RFT METODO 1RIDUZIONE COSTI DI APPROVVIGIONAMENTO RIDUZIONE COSTI DI APPROVVIGIONAMENTO
PER ISO-MALTITOLOPER ISO-MALTITOLO
OBIETTIVO:OBIETTIVO: Riduzione costi per l’acquisto del reagente necessario all’analisi Riduzione costi per l’acquisto del reagente necessario all’analisi
PROBLEMA: 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 )
MMISURAISURAQUANTITA’ ANNUA NECESSARIA:QUANTITA’ ANNUA NECESSARIA: 5.000 mg per analisi 5.000 mg scorta TOT = 10.000 mg
COSTO REAGENTE:COSTO REAGENTE: 1.340,00 Euro ogni 50mg
COSTO TOTALE: 268.000,00 Euro all’annoCOSTO TOTALE: 268.000,00 Euro all’anno
DDEFINIZIONEEFINIZIONE
CONTROLLOCONTROLLO•SOLUZIONI 1 E 2 APPLICATE IN MODO SINERGICO:
RISPARMIO DI 267.700,00 EURO all’annoRISPARMIO DI 267.700,00 EURO all’anno
______________________________
•SOLUZIONI 3 IN CORSO DI VALUTAZIONE
•SOLUZIONE 4 = NESSUN VANTAGGIO
COSTI
ANALISIANALISI
ALTO COSTO REAGENTE
Materiali Persone Misura
Metodi Macchine Ambiente
Quantità ordine
Costo Reagente
Fornitore (Sigma)Purezza Reagente
Metodo Analitico EP
IIMPLEMENTAZIONEMPLEMENTAZIONE
BE
NE
FIC
I
2. Modifica metodo mediante cambio della pesata (riduzione Pesata)
4. Altro fornitore
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)
3. Stabilità della soluzione di iso-maltitolo
IL TEAM
Cabergoline N-OxideCabergoline N-OxidePhD 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: C26H37N5O2
Structural Formula:
N
N
O N N
CH3
CH3
OHN CH3
H
H
H
O
CabergolineCabergolinePhD thesis – Cycle XX
17 March 2008
HN
N
O N N
CH3
CH3
OHN CH3
H
H
HN
N
O
H
OH
9,10-dihdrolysergic acid
API of DOSTINEX:•Hyperprolactinemia (dosage: 0.25mg and 0.5mg per tablets)• Anti-Parkinson (dosage: 1, 2 and 4mg per tablets)
PhD thesis – Cycle XX
17 March 2008
Chracterization of Chracterization of ImpuritiesImpurities
PABAPABA
PhD thesis – Cycle XX
17 March 2008
Be-Total HDBe-Total HD sugar-coated tabletssugar-coated tablets
O OH
NH2
p-Aminobenzoic Acid
PABA is an essential nutrient for some bacteria and is considered to be in the B-complex vitamin family (Vitamin Bx).
Impurity of Impurity of PABAPABA
PhD thesis – Cycle XX
17 March 2008
Impurity of Impurity of PABAPABA
PhD thesis – Cycle XX
17 March 2008
PABAPABA
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.
Acknowledgements
Colleagues 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