An improved process for the production of rabeprazole sodium substantially free from the impurities

Article abstract of DOI:10.1021/op900148x

The present work details the journey towards development of a simple and cost-viable process for large-scale synthesis of rabeprazole sodium substantially free from the impurities. The detailed study of different parameters affecting the quality and yield percentage of the compound has been presented. Yield is increased from 40% (reported process) to 75% with the improved process at sulfoxidation stage.

Full text of DOI:10.1021/op900148x

Organic Process Research & Development 2009, 13, 896–899
An Improved Process for the Production of Rabeprazole Sodium Substantially Free
§
from the Impurities
Pingili Ramchandra Reddy,†,‡ Vurimidi Himabindu, Lilakar Jaydeepkumar, Ganta Madhusudhan Reddy,*
‡
†
,†,‡
†
,†
Jonnalagadda Vijaya Kumar, and Ghanta Mahesh Reddy*
Research and DeVelopment, Integrated Product DeVelopment, InnoVation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupally,
Qutubullapur, R. R. Dist. 500 072, Andhra Pradesh, India, and Center for EnVironment, Institute of Science and Technology,
Jawaharlal Nehru Technological UniVersity, Kukatpally, Hyderabad 500 072, Andhra Pradesh, India
Abstract:
an inorganic base. Oxidation of the resulting sulfide derivative
4, with a suitable oxidizing agent to furnish rabeprazole 1a, is
followed by the preparation of rabeprazole sodium 1 as shown
in the Scheme 1.
The present work details the journey towards development of a
simple and cost-viable process for large-scale synthesis of rabepra-
zole sodium substantially free from the impurities. The detailed
study of different parameters affecting the quality and yield
percentage of the compound has been presented. Yield is increased
from 40% (reported process) to 75% with the improved process
at sulfoxidation stage.
Results and Discussion
The most important and critical step in this process is the
oxidation, which suffers from certain disadvantages such as use
of a high volume of chloroform, low yield, and number of
purifications involved. Further, there is a possibility of forming
Introduction
12,13
two major impurities,
namely, rabeprazole sulfone 5 and
Rabeprazole sodium, 2-{[[4-(3-methoxypropoxy)-3-methyl-
rabeprazole N-oxide 6 due to the over-oxidation of rabeprazole
2-pyridinyl]methyl]sulfinyl}-1H-benzimidazole sodium (1) is
1a. The N-oxide impurity 6 was observed in the range of
+
+
a proton pump inhibitor, inhibits the action of H -K ATPase
0.02-0.05% in the lab experimental studies, while sulfone
1-5
in parietal cells, and is used for the prevention and treatment
of gastric acid related diseases. It has also demonstrated efficacy
in healing and symptom relief of gastric and duodenal ulcers
and has shown a high eradication rate of the microorganism,
Helicobacter pylori when associated with antimicrobial therapy.
Literature studies reveal different methods
preparation of rabeprazole sodium (1). The general method for
impurity 5 was seen as major impurity. Due to structural
similarity of sulfone 5 with the parent compound, its complete
removal proved to be problematic.
Reported procedures did not give any better results when
6
,7
9
experiments were conducted with various oxidizing agents such
8
-11
for the
as peracids, peresters, peroxides, and tertiary butylhydroperox-
10
ide with VO(acac)
4
.
8
the preparation of 1 involved condensation of thiol derivative
11
The traditional approach involved oxidation of the sulfide
derivative 4 with m-chloroperoxybenzoic acid (m-CPBA) in
chloroform. Adjustment of pH and extraction of the product
1a into chloroform and dilution with methyl tertiary butyl ether
2
with chloromethyl pyridine derivative 3 in the presence of
§
DRL Communication number: IPDO-IPM000141.
*
To whom correspondence should be addressed. Telephone: +91 9959098098.
E-mail: madhusudanrg@drreddys.com (Madhusudhan Reddy), reddyghanta@
yahoo.com (Mahesh Reddy), DRL Communication number: IPDO-IPM000141.
(MTBE) at low temperature gave fine crystals of 1a. Crude 1a
†
was purified in aqueous basic methanol at pH 8.5-9.0. The
drawback of this process is that the reaction has to be conducted
using 0.8 equiv of m-CPBA, which led to only 60% reaction
completion and consequently poor yield (40%). When the
reaction was conducted with 1.0 equiv of m-CPBA, sulfone 5
was formed at levels of up to 2%. All these reported processes
produced sulfone 5 more, and another major drawback in many
of the previous processes is the usage of heavy metal reagents
such as vanadium, which were proved to be difficult to remove.
Dr. Reddy’s Laboratories Ltd.
Jawaharlal Nehru Technological University.
‡
(
(
1) Morri, M.; Takeguchi, N. J. Biol. Chem. 1993, 268, 21553–21559.
2) Nakai, H.; Shimamura, Y.; Kanazawa, T.; Yasuda, S.; Kayano, M.
J. Chromatogr., Sect. B 1994, 660, 211–220.
(
3) Fujisaki, H.; Shibata, H.; Oketani, K.; Murakami, M.; Fujimoto, M.;
Wakabayashi, T.; Yamatsu, I.; Yamaguchi, M.; Sakai, H.; Takeguchi,
N. Biochem. Pharmacol. 1991, 42, 321–328.
(
4) Takeguchi, N.; Yamanouchi, T.; Sakai, H.; Mora, M. Jpn. J. Physiol.
1
992, 42, 75–88.
(
(
(
5) Carswel, C. I.; Goa, K. L. Drugs 2001, 61, 2327–2356.
6) Barth, J.; Hahne, W. Aliment. Pharmacol. Ther. 2002, 16, 31–33.
7) Garcia, C. V.; Nudelman, N. S.; Steppe, M.; Schapoval, E. E. S.
J. Pharm. Biomed. Anal. 2008, 46, 88–93.
8,14
Sodium hypochlorite was found to be a better reagent
for oxidation of 1a in the presence of alkaline basic medium
where the sulfone impurity 5 was present at less than 0.20%
and two unknown impurities were observed in the range of
(
8) Souda, S.; Ueda, N.; Miyazawa, S.; Tagami, K.; Nomoto, S.; Okita,
M.; Shimomura, N.; Kaneko, T.; Fujimoto, M.; Murakami, M.;
Oketani, K.; Fujisaki, H.; Shibata, H.; Wakabayashi, T. U.S. Patent
5
,045,552, 1991.
(
9) Moormann, A. E.; Becker, D. P.; Flynn, D. L.; Li, H.; Villamil, C. I.
+
+
Method of Using (H /K )ATPase Inhibitors as Antiviral Agents. U.S.
Patent 5,945,425, 1999.
(12) Pingili, R. R.; Jambula, M. R.; Ganta, M. R.; Ghanta, M. R.; Sajja,
E.; Sundaram, V.; Boluggdu, V. B. Pharmazie 2005, 60, 814–818.
(13) (a) Ganta, M. R.; Boluggodu, V. B.; Padi, P. R.; Sudhakar, P.; Moses
Babu, J.; Vyas, K.; Pingili, R. R.; Mukkanti, K. J. Pharm. Biomed.
Anal. 2007, 43, 1262–1269. (b) Ganta, M. R.; Mukkanti, K.;
Boluggodu, V. B.; Padi, P. R. Synth. Commun. 2009, 39, 278–290.
(14) Pathi, S. L.; Kankan, R. N.; Rao, D. R. New Process for the Synthesis
of Proton Pump Inhibitors. WO Patent WO 2006/117802 A2, 2006.
(
(
10) Ilya, A.; Marioara, M. Process for the Production of Substituted 2-(2-
Pyridylmethyl)sulfinyl-1H-benzimidazoles. U.S. Patent 2003/0036554A1,
2
003.
11) Broeckx, R.; Laurent, M.; De Smaele, D.; Leurs, S.; Marcel, H.
Improved Process for Preparing Benzimidazole Type Compounds. WO
Patent 03/008406A1, 2002.
8
96
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Vol. 13, No. 5, 2009 / Organic Process Research & Development
10.1021/op900148x CCC: $40.75  2009 American Chemical Society
Published on Web 08/12/2009

Scheme 1. Scheme for the preparation of 1
Table 1. Effect of mole equivalents of sodium hypochlorite
After the optimization of mole equivalents of sodium
hypochlorite, the next task was to study the effect of 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 sulfone impurity 5. The
percentage of sulfone 5 was found to be increasing with reaction
temperature (Table 2). The reaction proceeded very well at
lower temperatures, as low as 0-5 °C, and this minimized the
formation of sulfone 5. Thus, oxidation carried out at temper-
atures of 0-5 °C produced a compound with minimal levels
of sulfone 5 (entry 1, Table 2).
on quality
purity by HPLC
NaOCl sulfide (4)
purity
sulfide sulfone
entry (equiv) (equiv) T (°C)a (1a) (%) (4) (%) (5) (%)
b
1
2
3
4
0.9
1.0
1.1
1.3
1.0
1.0
1.0
1.0
0-5
0-5
0-5
0-5
97.94
99.12
99.73
99.55
0.30
0.18
0.03
0.03
0.02
0.03
0.05
0.20
a
Temperature of reaction mass. b Rabeprazole.
0
.02-0.9%. Purification in ethyl acetate subsequent to oxidation
To control further the sulfone 5 and other unknown impuri-
ties in the active pharmaceutical ingredient (API), the following
workup process was developed. The workup process involved
quenching the reaction mass with a solution of sodium thio-
sulfate, so that unreacted sodium hypochlorite was quenched
completely. If the reaction mass was not quenched with hypo
solution, then the impurity 5 was enhanced up to 0.27% (entries
and isolation of rabeprazole 1a as rabeprazole sodium 1 helped
in removing the sulfone impurity 5 and unknown impurities.
Cost effectiveness as well as greenness of the process (sodium
chloride is the byproduct) made this sodium hypochlorite-
mediated oxidation an attractive alternative.
No other relevant references disclosed rabeprazole sodium
with sulfone impurity 5 at a level of less than 0.10% and all
1
other unknown impurities at less than 0.10%, which is an
essential criterion of a bulk drug substance. Hence, there is a
call for development of an efficient, impurity-free, cost-viable,
robust, and plant-friendly process for the preparation of ra-
beprazole sodium 1. The optimization of various parameters
involved in the oxidation step resulted in a dramatic improve-
ment in the purity and yield of 1a when using sodium
hypochlorite as the oxidizing agent. Various parameters such
as mole equivalents of the sodium hypochlorite, temperature
of the reaction, workup conditions, and purification process were
studied thoroughly. The details of the optimization and various
parameters are discussed below in this article.
Figure 1. Effect of mole equiv of NaOCl on % of purity.
Table 2. Effect of temperature on purity of rabeprazole
purity by HPLC
During the process optimization, we paid great attention to
optimize the equivalents of NaOCl. When we use 0.9 and 1.0
equiv of NaOCl, reaction did not complete; 1.1 equiv of the
sodium hypochlorite was found to be the most ideal for getting
the required compound 1a with high purity and good yield
NaOCl sulfide (5)
purity
(1a) (%) (5) (%)
sulfone
T (°C)a
b
entry
(equiv)
(equiv)
1
2
3
0-5
10-15
25-30
1.1
1.1
1.1
1.0
1.0
1.0
99.69
99.61
99.30
0.05
0.11
0.29
(Table 1). The results of the experiments are depicted in the
a
Temperature of reaction mass. b Rabeprazole.
form of a graph (Figure 1).
Vol. 13, No. 5, 2009 / Organic Process Research & Development
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897

Table 3. Effect of the sodium thiosulphate solution on
adjustment of the pH to 8.0-8.5 using acetic acid, and then
compound 1a was isolated from the mixture of acetonitrile and
water (3:10) at temperature 0-5 °C. The purity was 98%, and
two unknown impurities were observed with this process at 1.7
relative retention time (RRT) (ranges from 0.02-0.30%) and
formation of impurity 5
purity by HPLC
purity sulfone
entry T (°C)a (equiv) hypo solution (1a) (%) (5) (%)
NaOCl
10% of
b
1
2
3
4
0-5
0-5
0-5
0-5
1.1
1.1
1.1
1.1
used
used
not used
not used
99.56
99.69
99.36
99.25
0.05
0.06
0.25
0.27
5.0 RRT (ranges from 0.60-0.80%). Therefore, a purification
process was developed in ethyl acetate to remove these two
unknown impurities, but the yield loss was 70-90% (entries 1
and 2, Table 5) due to the solubility of compound 1a in ethyl
acetate in the presence of water when the compound 1a was
purified without drying the crude material. Once compound 1a
is filtered, it should be dried thoroughly because it contains
a
Temperature of reaction mass. b Rabeprazole.
Table 4. Effect of isolation in mixture of DCM and MTBE
on yield
purity by HPLC
30-40% of water content. Thus, the drying process has to be
batch
NaOCl
purity sulfone
efficient to remove the entrained water. Hence, a study was
carried out to decrease the water content of compound 1a. Water
content and purity of the compounds were obtained at regular
intervals, and the results are tabulated in Table 5.
In order to identify the suitable solvent for purification, we
have tried in various ICH class three solvents and chosen ethyl
acetate. With this purification in ethyl acetate, impurities at RRT
a
b
entry size (kg) T (°C) (equiv) yield (%) (1a) (%) (5) (%)
1
2
3
0.050
5.0
5.0
0-5
0-5
0-5
1.1
1.1
1.1
63
50
46
99.61
99.71
99.73
0.04
0.03
0.04
a
Temperature of reaction mass. b Rabeprazole.
3
and 4, Table 3) during the workup process, and the results
are tabulated in Table 3.
1.7 and RRT 5.0 in compound 1a were come down to 0.10%
Initially, one process was developed using DCM for extrac-
tion and MTBE as an antisolvent for isolating the compound.
When three batches were executed with the same process in
the pilot plant, what we observed is inconsistency in the yield
and 0.24%, respectively. These two unknown impurities were
further washed out in the next step of sodium salt formation to
less than 0.05%. The results are tabulated in Tables 6 and 7.
When we executed one 25 kg batch in pilot plant, sulfone 5
and other two unknown impurities were observed at the level
of 0.2%. but these impurities were reduced to less than 0.1%
after converting to sodium salt (1). The results are tabulated in
Table 7.
(varied from 46-63%). An alternative process was developed
to get consistency in the yield using water and acetonitrile. The
results are tabulated in Table 4.
An alternative workup process involves, after completion
of the reaction (monitored by thin layer chromatography),
Table 5. Effect of drying before purification in ethyl acetate
purity by HPLC after purification in ethyl acetate
T (°C)a water content (%) yield (%) purity (1a) (%) sulfone (5) (%) U imp (%) U imp (%)
b
c
d
entry
experiment
1
2
3
4
without drying
without drying
with drying
-
-
45
45
31
42
0.3
3.0
29.6
13.1
87.9
86
99.76
99.64
99.56
99.47
0.07
0.17
0.05
0.02
0.01
0.02
0.009
0.01
NDe
0.04
0.06
ND
with drying
a
Temperature of drying. b Rabeprazole. c Unknown impurity at RRT 1.7. d Unknown impurity at RRT 5.0. e Not detected.
Table 6. Effect of purification in ethyl acetate to eradicate unknown impurities at RRT 1.7 and RRT 5.0
purity by HPLC before purification (1a)
purity by HPLC after purification (1a)
a
b
c
a
b
c
entry purity (1a) (%) sulfone (5) (%) U imp (%) U imp (%) purity (1a) (%) sulfone (5) (%) U imp (%) U imp (%)
1
2
3
98.21
98.57
98.29
0.05
0.07
0.08
0.24
0.09
0.14
0.70
0.72
0.67
99.49
99.56
99.28
0.05
0.07
0.08
0.10
0.03
0.10
0.03
0.03
0.13
a
Rabeprazole. b Unknown impurity at RRT 1.7. c Unknown impurity at RRT 5.0.
c
Table 7. U imp Comparison of quality between rabeprazole base and rabeprazole sodium after execution in pilot plant
quality of rabeprazole base (1a)
quality of rabeprazole sodium (1)
batch
sulfone
batch
sulfone
a
b
c
d
b
c
entry size (kg) purity (1a) (%) (5) (%) U imp (%) U imp (%) size (kg) purity (1) (%) (5) (%) U imp (%) U imp (%)
1
2
3
25
25
25
99.51
99.28
99.14
0.20
0.12
0.06
0.05
0.06
0.10
0.03
0.15
0.24
40
40
40
99.84
99.79
99.77
0.06
0.07
0.08
0.03
0.05
0.03
0.02
0.02
0.02
a
Rabeprazole. b Unknown impurity at RRT 1.7. c Unknown impurity at RRT 5.0. d Rabeprazole sodium.
8
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•
Vol. 13, No. 5, 2009 / Organic Process Research & Development

(
75 L) was added compound 4 (25 kg, 72.8 mol) at 25-30 °C.
The contents were cooled to 0 °C, and sodium hypochlorite
47.5 L, 79.3 mol, assay 12.45%) was added at 0-5 °C for
h, and the reaction mass was stirred for 45 min. After
(
1
completion of the reaction (Vide TLC) the reaction mixture was
quenched with a solution of sodium thiosulfate (10 kg in 212.5
L of water). The resulting mixture was cooled to 0 °C, and the
pH of the solution was adjusted to 8.3 with acetic acid. The
precipitated solid was stirred at 0-5 °C for 2 h, filtered, and
washed with water (25 L) followed by drying under suction.
The wet solid was dried in a vacuum oven at 40-45 °C to get
the moisture content less than 5%. The dried solid was purified
in ethyl acetate (125 L) to give a cream-colored powder 1a:
yield 19 kg (72%).
Purification. Compound (1a, 19 kg) was added into ethyl
acetate (95 L) and then stirred at 25-30 °C for 1 h. The
heterogeneous solution was cooled to 5 °C and stirred for 45
min. The solid was filtered at 0-5 °C, and the solid was dried
in a vacuum oven (550 mm/Hg) for 5 h at 45-50 °C to yield
1a. Yield 17.05 kg (90%).
Figure 2. Effect of temperature on purity %.
Conclusion
In conclusion we have developed an efficient and plant-
friendly process by improving the original process for the
preparation of 1 substantially free from sulfone impurity 5 and
all other unknown impurities. The oxidizing reagent, m-CPBA,
was replaced by NaOCl, and we have examined various
possibilities to reduce the identified/unidentified impurities and
optimized several parameters such as temperature, usage of
sodium thiosulphate for quenching the reaction mass, and
amount of oxidant. The purification process in ethyl acetate was
developed, and this process ensures the production of rabepra-
zole sodium 1 with sulfone 5 less than 0.10% and all other
impurities less than 0.05%. This improved process was imple-
mented at the commercial scale with 25 kg batch size of
rabeprazole 1a and 40 kg batch size of rabeprazole sodium 1.
2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]-
sulfinyl]-1H-benzimidazole Sodium (1). To a solution of
sodium hydroxide (4.673 kg, 116.85 mol) in methanol (80 L)
was added compound 1a (40 kg, 111.42 mol), and the mixture
was stirred for 1 h. The reaction mass was filtered through
hyflow to remove particulates; the resulting filtrate was con-
centrated to dryness. n-Butanol (20 L) and MTBE (400 L) were
added to the crude product, and the contents were stirred at
25-30 °C for 5 h. The precipitated solid was stirred at 0-5
°C for 1 h, filtered, and washed with MTBE (80 L). The solid
was dried at 85 °C under vacuum to yield 1. Yield 40.32 kg
(95%). NMR, mass, IR of the compounds 1a and 1 are matching
Experimental Section
Rabeprazole sodium and its impurities were analyzed (Agi-
lent with empower software, 1100 series, G1312A Binary pump,
G1314A variable wavelength detector, Waldbronn, Germany)
with an Inertsil ODS-3 V column, 250 mm × 4.6 mm, 5 µm
(GL Sciences Inc., Japan), with mobile phase A consisting of
8
2 4
0.01 M KH PO , with the pH adjusted to 6.0 with diluted
with the reported values.
potassium hydroxide and acetonitrile in the ratio of 65:35,
mobile phase B consisting of acetonitrile and water in the ratio
of 90:10 with a flow rate of 1.0 mL/min, and UV detection at
Acknowledgment
We thank the colleagues of Analytical Research Department
and the colleagues of Dr. Reddy’s Laboratories Ltd., Integrated
Product Development.
280 nm was used with a timed gradient program. This LC
method was able to detect all these impurities. The solvents
and reagents were used without further purification.
2
-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]-
Received for review June 11, 2009.
OP900148X
sulfinyl]-1H-benzimidazole (1a). To a solution of sodium
hydroxide (7.5 kg, 187.5 mol) in water (30 L) and acetonitrile
Vol. 13, No. 5, 2009 / Organic Process Research & Development
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