An improved and single-pot process for the production of pantoprazole substantially free from sulfone impurity

Article abstract of DOI:10.1021/op034157y

Pantoprazole (1), a substituted benzimidazole derivative, is an irreversible proton pump inhibitor, essentially used for the prevention and treatment of gastric acid-related diseases. The process for its preparation generally suffers from the drawback of producing a potential sulfone impurity (5). The present work details a report of the journey towards the development of a simple, single-pot process for the production of pantoprazole, substantially free from sulfone impurity (5). The detailed study of the different parameters affecting the purity and yield of the compound has been presented.

Full text of DOI:10.1021/op034157y

Organic Process Research & Development 2004, 8, 266−270
Communications to the Editor
An Improved and Single-Pot Process for the Production of Pantoprazole
Substantially Free from Sulfone Impurity
Vijayavitthal T. Mathad,* Shanmugam Govindan, Naveen Kumar Kolla, Madhavi Maddipatla, Eswaraiah Sajja, and
Venkataraman Sundaram
Department of Research and DeVelopment, Dr. Reddy’s Laboratories Ltd., Bulk ActiVes, Unit III, Plot No. 116,
S. V. Co-Op. Ind. Estate, Bollaram, Jinnaram, Medak Dist 502 325, Andhra Pradesh, India
Abstract:
Scheme 1
Pantoprazole (1), a substituted benzimidazole derivative, is an
irreversible proton pump inhibitor, essentially used for the
prevention and treatment of gastric acid-related diseases. The
process for its preparation generally suffers from the drawback
of producing a potential sulfone impurity (5). The present work
details a report of the journey towards the development of a
simple, single-pot process for the production of pantoprazole,
substantially free from sulfone impurity (5). The detailed study
of the different parameters affecting the purity and yield of
the compound has been presented.
Pantoprazole (1) is an oral, pharmaceutically active
1
compound having promising anti-ulcer activity and belongs
to the class of 2-[[(2-pyridinyl)methyl]sulfinyl]-1H-benz-
imidazoles. In general this class are used for the prevention
and treatment of gastric acid-related diseases. Literature
the later is generated due to the over-oxidation of the
sulfoxide derivative (1). However the N-oxide impurity was
observed always in the range from 0.02 to 0.05% in the lab
experimental studies, whereas sulfone was seen as a potential
impurity. Due to similarity of the sulfone compound structure
with that of the parent compound, complete removal of 5
proved problematic.
2
studies reveal different methods for the preparation of
3
2
pantoprazole. The general process for the preparation of
pantoprazole involves condensation of thiol derivative 2 with
chloromethyl pyridine derivative 3 in the presence of
inorganic base to yield 5-(difloromethoxy)-2-[[(3,4-dimethoxy-
5
Different oxidizing agents such as peracids, peresters,
2
-pyridinyl)methyl]thio-1H-benzimidazole (4), which upon
and peroxides were employed for the conversion of the
sulfide derivative (4) to the sulfoxide derivative (1); preferred
conditions mentioned in the literature included oxidizing the
sulfide derivative (4) with an approximately equimolar
quantity of the oxidizing agent in an organic solvent. The
further oxidation with a suitable oxidizing agent leads to the
desired pantoprazole (1) as shown in Scheme 1.
The most important and critical step in the process is the
oxidation wherein there are chances of formation of two
impurities viz., pantoprazole N-oxide (6) and pantoprazole
sulfone (5) as these are mentioned in the recently published
6
most recent version of the process involved the oxidation
4
of 4 using tert-butyl hydroperoxide and VO(acac) . Yet
4
7
analytical drug profile. The former is formed due to the
oxidation at the nitrogen center of the pyridine moiety, and
another version involved oxidation of 4 with m-chloroperoxy
benzoic acid followed by successive pH adjustments to yield
pantoprazole in the organic layer. Concentration of the
organic solvent followed by crystallization in acetone resulted
in the formation of fine solid crystals. All the processes
described previously suffered from the drawback of produc-
ing a considerable amount of 5. Also, a second major
drawback in many of the previous processes was the usage
of heavy metal reagents, such as vanadium, which may prove
*
Corresponding author. Fax: 91 8458 279619. Telephone: 91 8458 279713.
E-mail: vijayavitthalm@drreddys.com.
(
1) (a) Kormer, W.; Postius, S.; Riedel, R.; Simon, W. A.; Hanauer, G.; Brand,
U.; Goenne, S.; Parsons, M. E. J. Pharmacol. Exp. Ther. 1990 1, 254. (b)
Bernhard, K.; Ernst, S.; Joerg, S. B.; Alexander, W. S.; Uwe, K.; Hartmann,
S.; Georg, R.; Volker, F.; Kurt, K. J. Med. Chem. 1992, 35, 1049.
2) Kohl, B.; Sturm, E.; Rainer, G. U.S. Patent 4758579, 1985; EP Patent
(
(
1
66287, 1985.
3) (a) Kormer, W.; Kohl, B. Drugs Future 1990, 15, 801. (b) Bekhazi, M.;
Zoghbi, M.; WO 97/29103, 1997. (c) Brennan, J. P.; Turner, A. T. WO
9
9/47514 A1, 1999. (d) Cheng, M.; Wang, Q.; Pan, L. Faming zhuanli
(5) Alan, E. M.; Daniel, P. B.; Daniel, L. F.; Hui, L.; Clara, I. V. U.S. Patent
5,945,425, 1999.
(6) Ilya, A.; Marioara, M. U.S. Patent 0036554 A1, 2003.
(7) Broeckx, R.; Laurent, M.; De Smaele, D.; Leurs, S.; Marcel, H. WO 03/
008406 A1.
gongkai shuomingshu, 1, 102, 411 (Cl. COID4501/12), 10 May 1995.
4) Adnan, A. B.; Lina, N. N.; Al Omari, M. M.; Nidal, H. D.; Mahmoud, K.
A.; Ahmad, M. A.; Jaber, A. M. Y. Anal. Profiles Drug Subst. Excipients
(
2
002, 29, 213.
2
66
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Vol. 8, No. 2, 2004 / Organic Process Research & Development
10.1021/op034157y CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/03/2004

Table 1. Measured solubilities of 1, 5, and 4
its subsequent oxidation using peracetic acid in the same
vessel after removal of the aqueous layer without its isolation.
The brief outline of the process is described below.
solventsa
b
pH (acetonitrile-water)
cmpd MeOH IPA ACN CHCl
3
9.0 9.2 9.5 9.8 10.5 11.5
The present reaction involves the condensation of the key
raw materials 2 and 3 in water in the presence of sodium
hydroxide, wherein compound 4 is precipitated out in the
reaction mass as a solid. Further, the obtained sulfide (4) is
dissolved in an organic solvent and is subjected to oxidation
after removal of the aqueous layer in the same vessel using
peracetic acid as an oxidizing agent. The peracetic acid
1
5
4
+++
+
+
+
++
++++ +++
++ ++++
+++
-
-
-
-
+
-
-
+
-
-
+
-
+
+
-
+
+
-
+++
++++
a
Notations used in case of solvents: + ) very slightly soluble, ++ ) slightly
b
soluble, +++ ) sparingly soluble, and ++++ ) soluble. Notations used
incase of pH: + ) soluble, and - ) insoluble.
(
PAA) was added slowly to a solution of 4 in an organic
solvent, water, and methanol at temperature of -10 to -5
C. The intention behind the usage of methanol (0.5 times
difficult to remove. No other relevant references disclosed
pantoprazole with sulfone impurity less than 0.10%. Hence,
there has been a need for an efficient, impurity-free, robust,
and plant-friendly process for the preparation of pantoprazole
and its pharmaceutically acceptable salts.
The optimization of the various parameters involved in
the oxidation step resulted in a dramatic improvement in the
purity of the compound. The workup further involved the
exploitation of a fine difference in the solubility of the
sodium salts of sulfone and sulfoxide at a given pH range
in a solvent system. The measured solubilities of compounds
°
with respect to dichloromethane) is to enhance the effect of
depression of the freezing point of water as the reaction is
being carried out at lower temperatures. After the mainte-
nance of the reaction for around 30-45 min, the reaction
mixture was quenched in 10% sodium hydroxide solution,
and the pH was adjusted between 9.0 and 9.5. Further, the
organic layer is separated, which comprises within itself
many components including sulfoxide (1), unreacted sulfide
(4), and sulfone impurity 5, along with some other minor
1
, 4, and 5 in different solvents and different pH are given
in Table 1.
The pure form of the sulfoxide 1 (containing sulfone
impurities. This organic layer is added to the sodium
hydroxide solution and stirred for 10-15 min. Further, the
two layers are separated, and the pantoprazole free base is
precipitated in the form of a fine solid by adjusting the pH
of the aqueous layer between 9.3 and 9.7 in a suitable solvent.
Different parameters such as the mole ratio of the peracetic
acid, the temperature of the reaction, and the workup condi-
tions were studied thoroughly. The details of the optimization
of the various parameters are discussed below in detail.
As per the chemistry involved, an equimolar quantity
impurity 5 less than 0.05%) is precipitated as a fine solid by
adjusting the pH of reaction mixture to a specific range of
9.3-9.7. The sulfone impurity 5 is left behind in the mother
liquor in the form of sodium salt, and it is thus easily
removed during the filtration. Described below is an im-
proved and single-pot approach for the synthesis of 1 with
exceptionally high purity. The present process is a result of
the optimization of the various parameters involved in the
reaction as well as the workup. The process is highly efficient
in consistently producing good-quality product. The percent-
age of the sulfone impurity 5 obtained in this process was
always less than 0.1% in the worst case, and it was observed
to be less than 0.05% in the production samples.
In addition to the reduction in the sulfone impurity 5, the
present work also provides a simple and plant-friendly
process for the preparation of pantoprazole (1). The process
is a single-pot reaction in the sense that 1 is isolated in a
single shot from the key raw materials. There are no other
intermediates isolated in the process. Classical industrial
processes involved the isolation of 4 in the form of a solid.
It is a low-melting compound, and a large amount of time is
consumed in the plant for its drying to proceed to the next
step. The present process avoids this problem by dissolving
the obtained sulfide (4) in an organic solvent followed by
(with respect to 4) of the oxidizing agent is required for the
conversion of 4 to 1. The wide range of studies carried out
in this direction has thrown light on the fact that the mole
ratio of the peracetic acid used plays a vital role in achieving
the high purity of the product 1. The experiments with equi-
molar quantities of the peracetic acid in the reaction resulted
in considerable amounts of 5. Studies revealed the direct
proportionality between the amount of the peracetic acid used
and the content of the 5. A mole ratio of 0.7 equiv of the
peracetic acid was found to be the most ideal quantity for
the attainment of the required compound 1 with high purity
and good yield (Table 2). This table shows the influence of
mole ratio of peracetic acid on sulfone (5) in a given range
of pH (9.3-9.7) and temperature (-10 to -5 °C) at which
satisfactory results were obtained during preliminary studies.
Even though the yields of 1 were found to be high when 1.0
Table 2. Effect of mol equiv of peracetic acid
purity by HPLC
exp.
no
peracetic acid
(mol equiv)
sulfide
(mol equiv)
reaction temp
yield
(%)
pH of
isolation
1
(%)
5 (sulfone impurity)
4
(%)
(°C)
(%)
1
2
3
4
1.0
0.9
0.7
0.7
1.0
1.0
1.0
1.0
-5 to 0
84.37
78.20
76.0
9.70
9.46
9.48
9.54
98.29
99.42
99.73
99.79
1.29
0.27
0.03
0.02
0.004
ND
-10 to -5
-10 to -5
-10 to -5
ND
76.2
ND
Vol. 8, No. 2, 2004 / Organic Process Research & Development
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267

Table 3. Effect of temperature on the purity of the compound
purity by HPLC
expt
no
temp
(°c)
PAA
(mol equiv)
pH of
isolation
1
(%)
5 (sulfone impurity)
4
(%)
(%)
5
6
7
8
9
0 to 5
0 to 5
0.7
0.7
0.7
0.7
0.7
9.5
98.29
98.59
98.80
99.81
99.77
1.09
1.10
0.02
0.03
0.06
ND
9.0
0.03
0.05
0.01
0.01
-5 to 0
9.5
9.32
9.62
-10 to - 5
-10 to - 5
Table 4. Effect of pH on the purity % and sulfone content
purity by HPLC
expt
no.
pH at
isolation
PAA
(mol equiv)
temp
(°C)
yield
(%)
1
(%)
5 (sulfone impurity)
4
(%)
(%)
10
11
12
13
14
15
10.10
10.09
9.72
9.58
9.32
9.00
0.7
0.7
0.7
0.7
0.7
0.7
-10 to -5
-10 to -5
-10 to -5
-10 to -5
-10 to -5
-10 to -5
44.70
42.19
68.20
61.60
68.20
69.80
99.89
99.93
99.78
99.77
99.81
99.34
0.06
0.01
0.07
0.06
0.03
0.20
ND
ND
0.02
0.01
0.01
ND
into the organic layer. The removal of the unreacted 4 was
based on the fact that it has no inclination for the formation
of the sodium salt and is left behind in the organic layer,
whereas the corresponding sodium salts of compounds 1 and
5
are carried on in the aqueous layer. Further, the aqueous
layer containing the salts of 1 and 5 is subjected to pH
adjustment in the presence of suitable solvent wherein the
compound 1 was selectively isolated in high purity leaving
behind the impurity 5 in the aqueous layer due to its solubility
at that particular pH, whereas the unreacted 4 is recovered
from the organic layer. This process of workup of the reaction
was highly efficient in cutting down the unreacted 4. Studies
in the laboratory clearly indicated that compound 4 is
removed almost completely from the reaction mixture. In
most of the production batches, the compound 4 was not at
all detected (see Table 6).
To standardize the optimum pH, a screening study on the
pH for isolation of the desired compound 1 was conducted
at various pH ranges. At the pH range around 9.3-9.7 the
purity of the sulfoxide 1 isolated was good, and the sulfone
(5) content was found to be negligible. The yields of
compound 5 obtained at this pH range were found to be
reasonable, but as the pH became more neutral, yields of 1
were high and the percentage of the sulfone impurity 5 was
observed to be greater in the precipitated compound (entry
no. 15 in Table 4). However, at pH greater than 9.7 there
were no adverse affects on the purity of the compound, but
the obtained yields were less, as shown in Table 3.
Figure 1. Graphical representation of experimental results.
mol of peracetic acid was used, the purity of the compound
1
was not satisfactory. The results of the experiments are
depicted in the form of a graph (Figure 1).
After the optimization of the mole equivalents, the next
task was the study of the effect of the temperature on the
reaction. It was found that the temperature at which the
reaction was carried out also proved to be a very important
factor in controlling the levels of the impurity 5. The rate of
the formation of impurity 5 is directly proportional to the
temperature at which it is carried out. The reaction proceeds
very well at even lower temperatures and minimizes the
chances of the formation of the sulfone impurity 5 (Table
3). The percent of sulfone impurity 5 was found to be
increasing with the increase in temperature. A thorough study
made to understand the effect of temperature on the purity
of the compound led to the observation that the oxidation
carried out at temperatures of -10 to -5 °C produces high-
quality compound.
Despite the precautions taken with respect to the mole
ratio of the peracetic acid and temperature of the reaction,
still there are chances of sulfone impurity 5 remaining in
the compound. To ensure the removal of the traces of
impurity 5, unreacted sulfide 4, and the other unwanted
impurities, we have developed a workup process which
involves the addition of the reaction mass into a solution of
sodium hydroxide, wherein unreacted 4 is extracted neatly
This parameter clearly indicates that, the percent content
of impurity 5 in the product 1 and the yields of 1 are
inversely proportional to the pH of isolation (as shown in
Figure 2, a and b). Meanwhile isolation of the compound
by pH adjustment in water alone proved problematic. The
nature of the solid obtained was found to be gummy;
therefore, simultaneous studies regarding the choice of a
suitable solvent for the isolation of the compound in the form
of the fine solid crystals were carried out. The results of the
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Vol. 8, No. 2, 2004 / Organic Process Research & Development

Table 5. Effect of pH sulfone content during in situ purification
HPLC purity/sulfone content
a
b
BP (%)
AP (%)
expt
no.
batch size
(g)
temp
(°C)
pH of
isolation
pH of in situ
purification
yield
(%)
1
5
1
5
16
17
18
19
50
50
50
50
-10 to -5
-10 to -5
-10 to -5
-10 to -5
9.54
9.62
9.08
9.52
80
73
73
55
99.72
99.66
99.66
99.65
0.07
0.13
0.09
0.10
99.77
99.76
99.78
99.93
0.06
0.06
0.04
0.01
9.64
9.72
10.18
10.09
a
BP ) Before in situ purification. b AP ) After in situ purification.
Table 6. Results of the production batches
HPLC purity
expt.
no.
batch input
of 3 (Kgs)
temp
(°C)
PAA
(mol equiv)
yield
(%)
pH of
isolation
1
(%)
5 (sulfone impurity)
4
(%)
(%)
20
21
22
23
24
50
50
50
50
50
-10 to -5
-10 to -5
-10 to -5
-10 to -5
-10 to -5
0.7
0.7
0.7
0.7
0.7
79.10
74.20
74.20
74.50
75.40
9.3-9.7
9.3-9.7
9.3-9.7
9.3-9.7
9.3-9.7
99.92
99.92
99.90
99.90
99.87
ND
ND
0.02
0.01
0.02
0.02
ND
ND
0.007
ND
as fine solid crystals. The purity of the resulting compound
was found to be extremely good, and the results were
consistent. The in situ purification is just a replica of the
above conditions, which involves the pH adjustment of the
isolated product (wet solid) in the same conditions with
respect to the solvent system used (acetonitrile-water). This
in situ process has been incorporated as a measure of
prevention to remove any remaining traces of impurity 5 in
the product. The criticality of the pH range (9.3-9.7) and
solvent (acetonitrile) holds well here also as we discussed
in the earlier section. However, Table 5 depicts some of the
variations of pH during the process of purification, and the
results support the observations made.
All the above optimized parameters, viz. mole ratio of
the peracetic acid, temperature of the reaction, pH of the
isolation, solvent and in situ purification in combination,
produced excellent results. The level of the sulfone impurity
5
was found to be always less than 0.05% in all the plant
production batches. The results of some of the batches are
depicted below in Table 6. The detailed process is described
in the Experimental Section.
Figure 2. (a) Graphical presentation of effect of pH on yield
and purity. (b) Graphical presentation of effect of pH on
impurity 5.
Conclusions
In conclusion, an efficient and plant-friendly process for
the preparation of pantoprazole substantially free from
sulfone impurity is described. The fine difference in the
nature of compounds 1 and 4 has provided an understanding
in the selection of appropriate parameters for the optimization
of the process to achieve pantoprazole substantially free from
sulfone.
experiments clearly proved that the solvent that satisfied the
need to the best possible extent is acetonitrile. Usage of
acetonitrile not only resulted in fine solid crystals but also
helped in the minimization of the sulfone impurity. Although
the other solvents such as methanol, 2-propanol, butanol, and
acetone helped in attaining fine solid, the purity of the
compound was found to be best in acetonitrile and water.
Thus, acetonitrile was selected in the process.
Experimental Section8
Synthesis of Compound 1. Into a clean and dry 3-L
round-bottom flask was charged sodium hydroxide (44.6 g)
followed by water (1 L); the contents were stirred to obtain
a clear solution. To the obtained solution was added
5-difluromethoxy-2-mercapto-1H-benzimidazole (2, 99.3 g,
Further, an in situ purification process comprising the
formation of the sodium salt of the compound 1 in aceto-
nitrile and water followed by the pH adjustment between
9.3 and 9.7 resulted in the precipitation of the compound 1
Vol. 8, No. 2, 2004 / Organic Process Research & Development
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269

0
.46 mol); and the contents were stirred to obtain a clear
and the organic extract was combined with the main organic
layer. Further, the combined organic layer was charged into
the sodium hydroxide solution (15 g in 1000 mL of water).
The contents were stirred for 30-45 min, aqueous and
organic layers were separated, and the aqueous layer was
extracted with dichloromethane (3 × 300 mL). Acetonitrile
(230 mL) was added to the aqueous layer, and the contents
were cooled to 10-15 °C. The pH of the resulting solution
was adjusted to 9.3-9.7 using acetic acid. The precipitated
solid was maintained for 2-3 h at 0-5 °C, filtered, washed,
and sucked dry. The wet solid was recharged into a round-
bottomed flask containing a solution of sodium hydroxide
(22 g in 600 mL). Acetonitrile was charged (113.0 mL) and
the solution stirred for 30-45 min. The pH of the resulting
solution was adjusted to 9.3-9.7 using acetic acid at
temperatures 10-15 °C. The solid precipitated and was
maintained at 0-5 °C for 2-3 h, filtered, washed, and dried.
solution. A solution of 2-chloromethyl-3,4-dimethoxy-pyri-
dinium chloride (3, 100 g, 0.47 mol) in water (500 mL) was
added dropwise for a period of 1.5-2 h. The contents were
stirred for 3-4 h at a temperature of 25-35 °C. Dichlo-
romethane (750 mL) was added, and the contents were stirred
to obtain a clear biphasic solution. The aqueous layer was
separated and extracted with dichloromethane (300 mL). To
the combined organic layer was charged water (600 mL) and
methanol (150 mL), and the contents were cooled to -10 to
-
5 °C. Peracetic acid (148 mL, 0.7 mol equiv with respect
to the theoretical yield of 4 obtained in situ) was added over
a period of 1-1.5 h, and the contents were stirred for 30-
45 min. The reaction mixture was quenched with 10%
sodium hydroxide solution (805 mL), and the resulting
aqueous and the organic layers were separated. The obtained
aqueous layer was extracted with dichloromethane (300 mL),
9
Yield 86%; purity 99.71%; sulfone 0.06%.
(
8) Peracetic acid is an effective oxidizing agent having an immense affinity
to release nascent oxygen. The product may gradually lose some of its
oxidizing power over time. It may get decomposed at elevated temperatures,
possibly leading to a hazardous condition. Further, the reagent has mild ill
effects on the health of the personnel handling it. It is an irritant and causes
strong nasal burns if exposure is not mitigated. Appropriate precautions
were taken during its handling in the plant. The substance was stored in a
cool and dry location to reduce the chances of exposure to temperature.
The reagent was transferred into the reaction mass in a closed system, and
general safety measures were taken.
Acknowledgment
We thank the management of Bulk Actives SBU, Dr.
Reddy’s Laboratories Ltd. for supporting this work. Coop-
eration from the colleagues from Analytical Research
Development and production facility is highly appreciated.
(
9) The percent yields of 1 were calculated by considering 70% conversion of
the in situ obtained 4 into 1, as we are using 0.7 mol equiv of peracetic
acid with respect to 4 for oxidation.
Received for review November 6, 2003.
OP034157Y
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