FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A NOVEL ONE POT PROCESS FOR PREPARATION
OF PANTOPRAZOLE SODIUM SESQUIHYDRATE
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT
MAHALAXMI CHAMBERS, 2nd FLOOR,
22, BHULABHAI DESAI ROAD, MUMBAI-400 026.
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner
in which it is to be performed.


A NOVEL ONE POT PROCESS FOR PREPARATION OF
PANTOPRAZOLE SODIUM SESQUIHYDRATE
FIELD OF THE INVENTION
The present invention relates to a novel one pot process for the preparation of 5-
(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-l//-benzimidazole
sodium salt, commonly known as pantoprazole sodium.
BACKGROUND OF THE INVENTION
5-(Difluoromethoxy)-2-[[{3,4-dimethoxy-2-pyridinyl)methyl]su[finyl]-1H-benzimidazole
commonly known as pantoprazole having formula (I) is an oral, pharmaceutically active
compound having outstanding anti-ulcer activity and belongs to the class of 2-[[(2-
pyridinyl) methyl]sulfinyl]-lH-benzirnidazoles. It is effectively used in the treatment of
gastric ulcers, duodenal ulcers, gastroesophageal reflux disease (GERD), and Zollinger-
Ellison Syndrome.

Pantoprazole is the active ingredient of a pharmaceutical product marketed in the
United States by Wyeth-Ayerst Inc. under the brand name Protonix®. It contains a
monosodium salt of pantoprazole (hereafter "pantoprazole sodium") in a
sesquihydrate state of hydration, which is represented by the formula (II) and named
as 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methy)]sulfinyl]-1H-
benzimidazole sodium salt sesquihydrate.
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1.5 H20

PRIOR ART
There are various prior art references, which are disclosing the synthesis of
pantoprazole. US Patent No. 4,758,579 claims that pantoprazole and many other
fluoroalkoxy substituted benzimidazoles are inhibitors of gastric acid secretion.
The '579 patent describes that the pantoprazole can be prepared by oxidation of 5-
(difluoromethoxy)-2-(((3,4-dimethoxypyridine-2-yl)methyl)thLo)-lH-benzimidazole
during reaction with m-chloroperbenzoic acid in methylene chloride, yielding
pantoprazole base. Further reaction with aqueous sodium hydroxide solution gives
pantoprazole sodium, which is then purified by crystalisation from methanol. The
drawback of the reaction is that oxidation is carried out with m-chlorobenzoic acid
which is costly as well as forms benzoic acid as a byproduct. The crude pantoprazole
is further purified by crystalisation, which adds one additional step as well as hampers
the yiel'd of the product. Moreover, the patent is silent about the state of hydration,
purity and form of the pantoprazole sodium.
Bernhard Kohl et al. in article J.Med.Chem.1992, 35, 1049-57 describes a process for
the preparation of pantoprazole sodium sesquihydrate by adding 6 N sodium
hydroxide solution to a solution of pantoprazole in a 6:1 ethanol: methylene
dichloride mixture at 20 ° C. After ten minutes, diisopropyl ether was added till the
mixture became turbid. After stirring for next two hours, the precipitate is collected
by filtration. It is washed with diisopropyl ether, and dried under vacuum at 40 ° C.
Thus this process requires a large amount of solvent and anti solvent, which is not
environment friendly.
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WO 2004/056804 describes the preparation of pantoprazole sodium Sesquihydrate by
forming a solution of pantoprazole and sodium hydroxide in a diluents selected from
the group consisting of 2-propanol, tetrahydrofuran, acetonitrile, methanel, ethanol,
water, mixtures of sec-butanol and methylene dichioride, and ethyl acetate,
precipitating crystals of pantoprazole sodium sesquihydrate from the solution, and
separating the crystals from the diluents. In this process pantoprazole sodium
sesquihydrate is prepared from pantoprazole base, which is prepared separately. It
also involves solvents and anti-solvents for the preparation, which increases the
manufacturing cost.
US 2004 / 0186139 Al describes a process for preparing crystalline Form-I of
pantoprazole sodium sesquihydrate. Pantoprazole sodium sesquihydrate Form I is
synthesized by dissolving pantoprazole free base in a sodium hydroxide solution,
filtering the solution and adding an anti-solvent to isolate crystalline Form 1 of
pantoprazole sodium sesquihydrate. The drawback of this process is that pantoprazole
sodium sesquihydrate Form I is prepared from pantoprazole freebase and MaOH
solution. Thus it involves more number of reaction steps as well as it is uneconomical
and not environment friendly as it uses solvents and anti-solvents. More over the
process does not mention the sulfone impurity.
An article, Organic Process Research & Development 2004, 8, 266-270, describes a
single-pot process for the production of Pantoprazole substantially free from sulfone
impurity. It involves four to five times separation of organic and aqueous layer and
reprecipitation with acetonitrile to obtain the pantoprazole base with sulfone impurity
0.06%. Thus this process is lengthy as well as uneconomical. Moreover, It describes
the synthesis of pantoprazole base only, and not of the sodium salt sesquihydrate
Form-I.
It is evident that all the prior art process involves preparation, and isolation of
pantoprazole base, as a first stage & the second stage is conversion of isolated, dried,
pantoprazole base in to pantoprazole sodium salt, which are not economical for
industrial scale synthesis due to number of reaction steps and number of reagents used
by them. The isolation of pantoprazole sodium sesquihydrate is problematic while
using high volume of solvents particularly ethanol. Most of the prior art process uses
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crystalisation for purification, which reduces the yield of the pantoprazole
sesquihydrate.
Thus there is a need of one pot method for the preparation of pantoprazole sodium
sesquihydrate Form-I, of a very high purity, which is obtained without involving any
purification step in turn increasing the yield of the product.
SUMMARY OF THE INVENTION
The present invention provides a novel one pot process for the preparation of
pantoprazole sodium sesquihydrate Form I in pure form with high yield which
involves less number of steps and no purification. Thus the objective is to make the
process simple, cost effective and easily scalable.
The other aspect of the invention is to provide a process for the preparation of
pantoprazole sodium sesquihydrate, which involves less number as well as less
volume of solvents and no use of any anti-solvent. Thus the objective is to make the
process environment friendly.
DESCRIPTION OF DRAWING:
FIG. 1 is characteristic X-ray powder diffraction pattern of crystalline Form-I of
Pantoprazole sodium sesquihydrate prepared by the inventors. Vertical axis: Intensity
(CPS), Horizontal axis; Two Theta (degrees).
The significant two-theta values obtained are 5.348, 7.407, 10.608, 11.522, 12.461,
13.106, and 13.370, 14.552, 15.324, 15.921, 16.184, 16.293, 16.669, 16.877, 17.631,
17.972, 18.478, 18.707, 20.074, 20.583, 21.012, 21.270, 21.602, 21.770, 22.254,
22.880, 23.025, 23.359, 24.105, 24.600, 25.031, 25.387, 25.543, 26.332, 26.749,
27.126, 27.421, 27.866, 28.814, 29.514, 29.729, 30.277, 30.944, 31.758, 32.674,
33.738, 34.235, 34.777, 37.626, 41.363, 43.560, 44.083, 45.502, 46.131
DETAIL DESCRIPTION OF THE INVENTION
The crystalline Form-I of Pantoprazole sodium sesquihydrate of the present invention
is characterized by X-ray powder diffractogram. Differential Scanning Colorimetry
thermogram and Infrared spectra.
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The X-ray powder diffract gram of the crystalline Form-I of pantoprazole sodium
sesquihydrate are measured on PANanalytical XTERT-PRO MPD, with Cu K
alpha-1 Radiation source (1.54060 A°),
The X-ray powder diffractogram of the crystalline Form-I of pantoprazole sodium
sesquihydrate obtained in the present invention is substantially as depicted in FIG. (1)
The characteristic peaks (in 2-theta values) and their relative intensities (in
percentage) of crystalline Form-1 of pantoprazole sodium sesquihydrate, obtained in
the present process are shown in the following Table (1)
TABLE 1

26 (°) Intensity ( %)
5.348 100.00
7.407 3.51
10.608 1.30
11.5227 3.18
12.461 1.31
13.106 5.22
13.370 5.39
14.552 6.34
15.324 1.43
15.921 2.61
16.184 4.09
16.293 1.91
16.669 7.69
16.877 7.86
17.631 5.26
17.972 3.07
1 8.478 1.96
18.707 1.67
20.074 8.82
20.583 18.03
2J.012 3.57
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21.270 5.00
21.602 4.56
21.77 3.68
22.254 16.47
22.880 7.26
23.025 7.06
23.359 5.42
24.105 6.87
24.600 8.95
25.031 6.12
25.387 6.78
25.543 5.51
26.332 8.61
26.749 6.88
27.126 7.97
27.421 8.32
27.866, 9.52
28.814 6.20
29.514 6.51
29.729 5.40
30.277 2.72
30.944 3.02
31.758 50.40
32.674 6.06
33.718 6.27
34.235 3.65
34.777 4.59
37.626 • 6.21
41.363 2.09
43.560 2.14
44.083 3.04
45.502 22.29
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The crystalline Form-1 of pantoprazole sodium sesquihydrate of the present invention
is also characterized by Differential scanning calorimetry. The Differential scanning
calorimetry thermogram exhibits a significant endotherm peak at around 138 ° C.
The crystalline Form-I of pantoprazole sodium sesquihydrate of the present invention
is further characterized by Infrared spectrum having significant IR bands around 453,
523.4, 554.9, 583.4, 643.8, 689.18, 710.17, 775.17, 8)5.3, 837.54: 937.9., 960.1,
985.10, 1041.63, 1072.77, 1089.10, 1119.85, 1170.11, 1276.84, 1305.35, 1362.28,
1376.51, 1427.64, 1465.25, 1491.59, 1589.62, 1653.61, 2072.26, 2602.48, 2846.49,
2997.29, 2942.43, 3186.64., 3364.43, 3487.61, 3552.27
According to this invention, the process for the preparation of pantoprazole sodium
sesquihydrate Form 1 include:
a) condensation of 5-(difluoromethoxy)-2-mercapto-l H-benzimidazole and 2-
chloromethyl-3, 4-dimethoxypyridine hydrochloride in a Sodium hydroxide
solution and acetone to obtain 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-
pyridinyl)methyl]thio-1 H-benzimidazole;
b) in-situ oxidation of thus obtained 5-(difluoromethoxy)-2-[[(3, 4-dimethoxy-2-
pyridinyl) methyl] thio-1 H-benzimidazole to a sodium salt of 5-
(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-
benzimidazole in presence of sodium hypochlorite
c) the removal of impurities by slurring in dichloromethane, and isolating as a
sesquihydrate.
The condensation of 5-(dif!uoromethoxy)-2-mercapto-lH-benzimidazole and 2-
chloromethyl-3, 4-dimethoxypyridine hydrochloride in acetone and water is carried
out in presence of sodium hydroxide solution at 20 to 25 °C. The progress of the
reaction is monitored by TLC and if the 5-(difluoromethoxy)-2-mercapto-lH-
benzimidazole is found unreacted, additional amount of 2-chloromethyl-3, 4-
dimethoxypyridine hydrochloride is added again.
The oxidation of formed 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-
pyridinyl)methyl]thio-11-l-benzimidazole is carried out in 5.7% sodium hypochlorite
solution diluted with equal volume of water by adding it over a period of three hrs. at
20 to 25 ° C. It is stirred for additional half an hour. The progress of the reaction is
checked by TLC and if still incomplete, the required quantity of additional sodium
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hypochlorite solution is added. The reaction is quenched with aqueous sodium
thiosulphate solution, the solution is treated with activated carbon and filtered. After
removal of acetone by distillation under vacuum, the reaction mass was cooled to 20
to 25 ° C.
Dichloromethane was added, and the reaction mass is stirred. Sodium chloride is
added over a period of half an hour and the solid is precipitated. The stirring is
continued for next half an hour and material is filtered off and dried at 30 ° C under
vacuum for overnight. The powdered material slurried with dichloromethane and
filtered, dried under vacuum at 40° C to obtain pantoprazole sodium sesquihydrate
having HPLC purity 99.90% and sulphone impurity 0.07%.
The pantoprazole sodium sesquihydrate obtained as per the above mentioned process
is observed as free flowing, non-solvated crystalline solid, which is well suited for
pharmaceutical applications.
The one pot process of the present invention is simple, involves less number of stages,
non-hazardous and well suited for commercial production.
Thus in brief, all the prior art processes describes the preparation of pantoprazole
sodium sesquihydrate Form I by condensing the 5-(difiuoromethoxy)-2-mercapto-lH-
benzimidazole and 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride to obtain 5-
(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio-lH-benzimidazole
which is oxidized and thus obtained pantoprazole sodium was converted to
pantoprazole free base. The free base is converted to sodium salt. If required the
sodium salt is purified and sesquihydrate is isolated. Although the sodium salt is
formed after oxidation but nobody could isolate it rather they neutralize it to isolate
freebase and again convert it to sodium salt. Thus increasing the process by one more
additional step. But in our inventive process, we isolate the pure pantoprazole sodium
sesquihydrate directly after in-situ oxidation without involving any purification.
The invention can be illustrated by the following example, which is for illustration
purpose only and is not intended to limit the scope of the invention in any way.
EXAMPLE
In a two-litre flask, a solution of 24 g of sodium hydroxide in 150 ml of distilled water
was charged and cooled to 20 to 25 °C. A solution of 5-(difluoromethoxy) -2-
mercapto-lH-benzimidazole (50 g) in acetone (250 ml) was added to it and stirred for
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half an hour. A solution of 2-chloromethy!-3, 4-dimethoxypyridine hydrochloride (56
g) in distilled water (150 ml) was added over a period of one hr while maintaining the
temperature in the range of 23 to 25° C. It was stirred for next half an hour and
progress of the reaction was monitored by TLC. If unreacted 5-(difluoromethoxy) -2-
mercapto-lH-benzimidazole is still present 0.50 g of 2-chloromethyl-3, 4-
dimethoxypyridine hydrochloride was added, and stirring was continued for next half
an hour. Aqueous Sodium hypochlorite solution (5.7%, 300 ml) diluted with equal
volume of water was added to it over a period of three hrs. at 20 to 25 ° C and stirred
for additional half an hour. The progress of the reaction was checked by TLC and if
still incomplete, the required quantity of additional sodium hypochlorite solution was
added. The reaction was quenched with aqueous solution of sodium thiosulphate (8 g
of sodium thiosulphate dissolved in 25 ml of distilled water). It was stirred at RT for
next half an hr. Reaction mass was filtered off on the Celite bed. the insoluble
material were dissolved in 200 ml of acetone and filtered. The solution was treated
with activated carbon, and filtered. Acetone was distilled off under vacuum and
cooled to 25 ° C.
The reaction mass was stirred with 500 ml of dichloromethane. Sodium chloride (17
to 20 % of the volume of aqueous layer) was added over a period of haif an hour and
the solid was precipitated. The stirring was continued for next half an hour and
material was filtered off and dried at 30 ° C for overnight. It was powdered and
slurried with 400 ml of dichloromethane, followed by washing with 2X100 ml of
dichloromethane and dried under vacuum at 40° C to obtain pantoprazole sodium
sesquihydrate (65 g) having HPLC purity 99.90% and sulphone impurity 0.07%. The
water content was 5.90% (measured by TGA). The characteristic X-ray powder
diffraction pattern, and the significant two-theta values confirm that the obtained
product is pantoprazole sodium sesquihydrate.
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We claim:
1. A process for preparation of highly pure pantoprazole sodium sesquihydrate
comprising:
a) condensation of 5-{difluoromethoxy)-2-mercapto-lH-benzimidazole and
2-chloromethyl-3, 4-dimethoxypyridine hydrochloride in aqueous sodium
hydroxide solution and acetone to obtain 5-(difluoromethoxy)-2-[[(3.4-
dimethoxy-2-pyridinyl)methyl]thio-lH-benzirnidazole;
b) the in-situ oxidation of obtained 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-
2-pyridinyl)methyl]thio-1H-benzimidazo!e in presence of sodium
hypochlorite to obtain a reaction mass
c) terminating the oxidation, by adding aqueous solution of sodium
thiosulphate
d) removal of all the water miscible solvent under vacuum
e) addition of chlorinated hydrocarbon solvent or ester solvent
f) precipitation of sodium salt of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-
pyridinyl)methyl]sulfmyl]-lH-benzimidazole by addition of sodium
chloride
g) filtration of the precipitated sodium salt
h) further slurring of the precipitated sodium salt in chlorinated hydrocarbon
solvent or ester solvent
i) filtration of the slurry, followed by drying under vacuum at 25 to 30 ° C, to
get pantoprazole sodium sesquihydrate.
2. A process as claimed in claim 1, wherein the condensation in (a) is carried out
at a temperature between 0 to 35 ° C, preferably 25 to 30° C
3. A process as claimed in claim ], wherein the water miscible solvent in (d) is
selected from the group comprising of acetone, acetonitrile, dioxane,
tetrahydrofuran, preferably acetone.
4. A process as claimed in claim I, wherein the inert chlorinated hydrocarbon
solvent in (e) and (h) is selected from the group consisting of
dichloromethane, dichloroethane, chloroform, preferably dichloromethane &
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the ester solvent is selected from the group consisting of ethyl acetate, methyl
acetate, n-butyl acetate, tert. Butyl acetate etc., preferably ethyl acetate.

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