SYNTHESIS OF OMEPRAZOLE, LANSOPRAZOLE AND PANTOPRAZOLE
IMPURITIES
M. Paz Matía, J. Luis. Novella, Juan J. Vaquero, Julio Alvarez-Builla*
Planta Piloto de Química Fina. Universidad de Alcalá. Ctra. Madrid-Barcelona Km. 33,600. 28871 Alcalá de Henares.
Madrid. España.
INTRODUCTION
The final step in the pathway for acid secretion from the parietal cell into the gastric lumen is the so-called
‘proton pump’. The proton pump is an active transport system powered by the enzyme H+/K+-ATPase, which
catalyzes the exchange of intra-cellular hydrogen ions for extracellular potassium ions. The inhibition of proton
1
pump prevents acid secretion from the parietal cell .
Omeprazole, pantoprazole and lansoprazole (figure 1) are three irreversible proton pump inhibitors (PPIs). The
benzimidazole PPIs are essentially prodrugs, that in the acidic biophase of the parietal cell form an active
metabolite that irreversibly interact with an essential thiol (SH) function on ATPase of the proton pump.
CHF2
H
N
O
CH 3
O
CH 3
H
N
S
H 3C
CH 3
O
H
N
O
CF 3
O
S
N
O
O
CH 3
O
O
CH 3
S
N
Figure 1
N
N
N
Omeprazole
Lansoprazole
CH3
N
Pantoprazole
OBJETIVE AND RESULTS
In the present work we have prepared2 and analyzed by HPLC-MS3,4 some of the different impurities of omeprazole,
lansoprazole and pantoprazole. Compounds 1a, 1b, 1c were commercially available and the corresponding sulfones, the more
common impurities, were obtained by oxidation with peracetic acid (Scheme 1).
H
N
R2
R3
S
N
R
Scheme 1
H
N
CH3CO3H
R2
R3
N
R
N
2a omeprazole sulfone 90% R 4
2b lansoprazole sulfone 92%
2c pantoprazole sulfone 85%
N
R4
1a omeprazole sulfide
1b lansoprazole sulfide
1c pantoprazole sulfide
O O
S
Additionally, the omeprazole impurities B and E were prepared following the synthesis indicated in the schemes 2 and 3.
H3C
CH 3
H 3C
CH 3
Ac2O
H3CCO3H (35%)
CH 3
N
CH 3
+
O_
94%
O
CH 3
OH -/H 2O
DCM
N
H3C
H3C
OH
Cl 2SO
90%
N
H
H 3C
80%
H 3C
O
N
Impurity B
N
O
H3C
CH3
DCM
35 ºC, 1.5h
Cl
N
+
O_
H
N
Scheme 3
CH 3
H3C
CH3
CH3
Scheme 2
H3C
87%
H
N
O
CH3
O
CH3
O
Impurity E
CH3
N
O_
+
K2CO3
CH 3
2
3
4
O
CH3
S
H 3C
O
N
DCM/MeOH
80%
N
H
REFERENCES:
1
N
O
H
N
H 3CCO3H (15%)
N
SH
NaOH 1M
S
N
O
Cl
N
H
N
O
H
N
H3CCO3H (35%)
CH3
CH 3
SH
S
DCM
K2CO3
O
CH3
N
S
H
N
Cl
H3CCO3H (35%)
H 3C
Cl
H
N
NaOH/BNTC
H3C
CH3
CH3
65%
60%
CH3
O
N
H
47%
HCl
H3C
CH3
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CH3
N
+
O_