FORM 2
THE PATENTS ACT, ,1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
•t
(See section 10, rule 13)
"PROCESS FOR PREPARATION OF S-PANTOPRAZOLE"
EMCURE PHARMACEUTICAL LIMITED of Emcure House, T-184, MIDC, Bhosari, Pune, Maharashtra 411 018, India
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention relates to improved process for the preparation of pharmaceutically acceptable salts of S-pantoprazole or its hydrated forms.
BACKGROUND OF THE INVENTION:
There are a large number of patents and patent applications disclosing different substituted 2-(2-pyridinylmethylsulphinyl)-lH-benzimidazoles. This class of compounds has properties making the compounds useful as inhibitors of gastric acid secretion. For example, the compound (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] -sulphonyl]-lH-benzimidazole) with the generic name omeprazole, described in i.e. EP 0005129, is useful as an antiulcer agent. Other compounds of interest are for instance the compounds with the generic names lansoprazole, pantoprazole, pariprazole and leminoprazole.
Pantoprazole, 5-(difluoromethoxy)-2-(((3,4-dimehoxypyridine-2yl) methyl) sulphinyl)-lH-benzimidazole of formula (I) has the following structure formula.
MeO OMe

Formula (I)
PANTOPRAZOLE (PROTONIX®) prevents the production of acid in the stomach. It reduces symptoms and prevents injury to the esophagus or stomach in patients with gastroesophageal reflux disease (GERD) or ulcers. Pantoprazole is also useful in conditions that produce too much stomach acid such as Zollinger-Ellison syndrome.
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Pantoprazole has a stereogenic centre at the sulphur atom and thus exists as two optical isomers, i.e. enantiomers. The single enantiomer of pharmacologically active compounds has a improved pharmacokinetic and biological properties. Such are the current requirement from the regulatory authorities.
(Ref: http://www.fpharm.uniba.sk/Dokumenty/Acta .Fiacul"tatis/L/Pharm-02%20Hutt% 20%20AJ - Valentov%C3%Al%20J.pdf). Therefore, there is a demand and need for an enantioselective process that can be used in large scale for the manufacture of the single enantiomer of pharmacologically active compound, such as S- pantoprazole.
The optically pure S-pantoprazole is an effective agent for treating ulcers of the stomach, duodenum and esophagus, gastroesophageal reflux diseases, Zollinger-Ellison Syndrome and other disorders, including those that would benefit from an inhibitory action on H+, K+-ATPase. The optically pure S-pantoprazole provides this effective treatment, while substantially reducing the adverse effects of racemic pantoprazole including, but not limited to, hepatocellular neoplasia, gastric' carcinoids, headache, diarrhea and skin alterations.
DE 4035455 patent discloses (Scheme-I) process for the preparation of enantiomerically pure pantoprazole, wherein 5-difiuoromethoxy-lH-benzimidazole-2-thiol of formula (II) is reacted with 2-chloromethyl-3,4-dimethoxypyridine of formula (III) in the presence of sodium hydroxide in methanol to get 5-(difluoromethoxy)-2-(((3,4-dimehoxy pyrolidine-2-yl)methyl)thio)-lH-benzimidazole of formula (IV), which is subjected to oxidation reaction in the presence of m-chloro perbenzoic acid to get racemic 5-[difluoromethoxy]-2[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole of formula (I).
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OMe
Sodium hydroxide Methanol
F,HCO
m-chloroperbenzoic acid
MeO OMe
\—( Sodium hydroxide
AA
F,HCO
F,HCO

(III)
(II)
S^z^-U Na
-S N=/
0

(V)
Fencyl chloromethyl ether Dichloro methane Sulphuric acid
MeO
OMe

(I)

S-pantoprazole (VI)
Scheme-I
The formula (I) is converted into sodium salt by conventional method to get sodium salt of formula (V), which is subjected to resolution by reacting with enantiomeric pure fencyl chloroethyl ether followed by hydrolysis to get S- pantoprazole.
Above process involves more synthetic and purification steps such as
a) Condensation of formula (II) and formula (III) followed by isolation and purification to get formula (IV).
b) Condensed product is subjected to oxidation reaction and followed by salt formation and purification to get formula (I).
c) Racemic pantoprazole of formula (I) is "converted into diastereomeric intermediate, which involves complicated steps, and formation of more impurities, further it needs repeated crystallizations" to get desired quality of diastereomeric intermediate.
d) The diasteeomeric intermediate is subjected to hydrolysis to get S-pantoprazole.

This process involves more synthetic and purification steps in different solvents. Therefore this process demands more utilities, manpower leading to increase in the cost of the final product.
US 5,948,789 patent revels process for the preparation of S-pantoprazole (Scheme-II), wherein formula (II) is reacted with formula (III) in the presence of base in a solvent medium to get condensed product of formula (IV), which is purified. The purified compound of formula (IV) is reacted with excess amount of cumene hydroperoxide in the presence of titanium (IV) isopropoxide, (-) diethyl D-tartarate and N, N-diisopropylethylamine in methylene chloride. After completion of the reaction, the reaction mass is subjected to acid base work up followed by purification to get S-pantoprazole.
The major draw backs of this process are follows:
a) Condensation of formula (II) with Formula (III) in the presence of base in a
solvent medium followed by isolation and essential purification to get formula
(IV). The purification at this stage becomes a limiting step in view of yield and
time cycle.
b) Oxidation reaction is carried out with excess amount of cumene hydroperoxide.
Hence, formation of impurities is more in the final product (Ref: EP 07773940)
c) The impure final product needs repeated crystallizations in different solvents to get desired quality of final product of pharmaceutical grade quality. It leads to yield loss of the final product.
d) Usage of excess quantity of cumene hydroperoxide in the plant level is dangerous. (Ref: http://physchem.ox.ac.uk/MSDS/CU/cumerie hydroperoxide.htmP
All the above activities demand more utilities and manpower. Therefore, cost of the final Active pharmaceutical ingredient (API) will be increased.
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(II)

OMe
(III)

Sodium hydroxide Methanol
F2HCO

MeO OMe
/>—S N^
N
(IV)

Dichloro methane (-)-diethyl D-tartarate Titanium (IV) isopropoxide Cumene Hydroperoxide Ammonium Solution Acetic acid


MeO OMe
,. . Purification
'/ \ Salt formation
N ' "*
r^^N

Pure S -Pantoprazole

S- Pantoprazole (VI)

Scheme-ll
Considering the prior art references and the limitations therein such as
a) Increased hazards on the manufacturing side with respect to high molar ratio of cumene hydroperoxide.
b) Loses incurred due to purification of the condensed product in the early stage.
c) Requirement of repeated crystallization to achieve the desired pharmaceutical grade purity.
d) The increased time cycle for a manufacturing batch, due to unavoidable purifications.
e) Use of different solvents in different steps increases the requirement of procuring, storing various solvents along with the limitation in recovery.
f) Increased utilities, manpower and cost due to the above factors.
Thus, this is a need to develop the comparatively safe, economical and pharmaceutically acceptable salt of S -pantoprazole or its hydrated form.
Herein is developed an improved and industrially feasible process for preparation of Pharmaceutically acceptable salts of S (-) pantoprazole to its hydrated forms, without isolation and purification of intermediate stages.
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OBJECT OF THE INVENTION:
The main object of the invention is to provide an improved process for preparation of S-patoprazole with reduced synthetic and purification steps
Another object of the invention is to carry out all the reaction steps in a single solvent.
Yet another object of the present invention is to use minimum quantity of cumene hydroperoxide and minimize the formation of impurities
Further, object of the invention is to avoid the purification in final stage to improve the yield and reduce the time cycle.
A still further object of the invention is to recover and reuse of the formula (IV) to reduce the raw material cost.
SUMMARY OF THE INVENTION:
The present invention provides all the reaction steps are carried out in a single solvent, without isolation and purification of intermediate stages.
The present invention further provides improved process for preparation of S-pantoprazole with minimum quantity of cumene hydroperoxide.
The present invention provides another advantage of recovery and reusability of the formula (IV).
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DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides improved and commercially feasible process for the preparation of S- pantoprazole, which comprises the steps of:
a) reacting 5-difluoromethoxy-lH-benzimidazole-2khiol of formula (II) with 2-chloromethyl-3,4-dimethoxypyridine salt of formula (III) in presence of phase transfer catalyst and base in a solvent medium to get 5-(difluoromethoxy)-2-(((3,4-dimehoxypyridine-2yl)methyl)sulphinyl)-lH-benzimidazole of formula (IV).
b) reacting formula (IV) in-situ with peroxides / oxidizing agent in presence of stereo selective reagent and base to get S- pantoprazole of formula (VI)
c) optionally purifying formula (VI) in the presence' of basic medium to get pure S-pantoprazole.
d) reacting S-pantoprazole with alkaline solution in a solvent medium to get pharmaceutically acceptable salts of S-pantoprazole or its hydrated forms.
According to the present invention, condensation reaction of 5-difluoromethoxy-l-H-benzimidazole-2-thiol of formula (I) with 2-chloromethyl-3,4-dimethoxypyridine salt of formula (II) in presence of phase transfer catalyst and base in solvent medium to get 5-(difluoromethoxy)-2-(((3,4-dimehoxypyridine-2 yl) methyl) thio)-l-H-benzimidazole of formula (III).
2-Chloromethyl-3,4-dimethylpyridine salt is selected from the group comprising of hydrochloride, sulphate and acetate etc. The preferred salt is hydrochloride.
The condnesataion reaction is carried out in the presence of phase transfer catalyst (PTC), which helps in progress of the reaction. The phase transfer catalyst is selected from the

group comprising of tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, benzyltriethyl ammonium chloride, methyltrioctyl ammonium chloride, hexadecyl trimethyl ammonium chloride, crown ethers, and mixtures thereof. Most preferably, the phase transfer catalyst is tetrabutyl ammonium bromide, tetrabutyl ammonium chloride or benzyltriehyl ammonium chloride.
The condensation reaction is carried out in a solvent medium and it can be mixture of water and water immiscible organic solvent. Water immiscible organic solvent selected from the group comprising of toluene, xylene, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, dichloro methane, dichloro ethane etc and mixtures thereof. The preferred water immiscible organic solvent is toluene and dichloromethane or mixture thereof.
The condensation reaction is carried out in the presence of base, which is selected from the group comprising of hydroxides, carbonates of alkali or alkaline earth metals, but preferably the hydroxide of an alkali metal. The preferred alkali metal hydroxide is sodium hydroxide.
The condensation reaction is carried out at temperature between 40-70° C and preferred reaction temperature is 50-60° C. After completion of the reaction, the reaction mass is
r
diluted with water and separated organic and aqueous layers. The organic layer is as such taken for stereo selective oxidation reaction, without isolation and purification of the compound (IV). Thus, bypassing isolation and purification, which saves on time cycle, manpower, utilities and loss in the yield, where by reducing the cost of the production.
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MeO
F2HCO

xx>
(II)

SH +

OMe
(III)

/> N
(IV)

OMe