FORM 2
THE PATENTS ACT, 1970 (39 of 1970)

PROVISIONAL SPECIFICATION /
(See section 10 and rule 13)

:ATION

1. TITLE OF THE INVENTION
Process for purification of Rabeprazole


2. APPLICANT(S)
(a) NAME
(b) NATIONALITY
(c) ADDRESS
CADILA PHARMACEUTICALS LIMITED An INDIAN Company
"Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad -382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION
PROVISIONAL SPECIFICATION
The following specification describes the invention.
COMPLETE SPECIFICATION
The following specification particularly describoc the invontion and the mannor m which it is to bo performed
4. DESCRIPTION
(Description starts from next page)


FIELD OF THE INVENTION
The present invention relates to a novel process for purification of Rabeprazole of formula-l. The invention discloses the use of 2-butanone for improving the quality of Rabeprazole by removal of impurities.

BACKGROUND OF THE INVENTION
Rabeprazole sodium, chemical named as 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-7H-benzimidazole sodium salt, is a gastric secretion inhibitor used for the treatment of peptic ulcer.
US 5,045,552 disclose pyridine derivatives having anti-ulcerative activity and their process of preparation. Example 32 of the specification particularly descnbes a method of producing Rabeprazole free base and examp'e-33 describes a method for preparing corresponding sodium salt. The example-32 of US 5,045,552 discloses that 2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl} methylthiofl H-benzimidazole is oxidized with m-chloroperbenzoic acid to give Rabeprazole.
EP997461B1, EP1270555B1, EP1363901A1, EP1466897A1 and EP1575935B1 describe preparation of Rabeprazole, by oxidizing 2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthio]-1 H-benzimidazole with a suitable oxidizing agent. In some cases, the reaction does not stop at intermediate stage of sulfoxide. The reaction results with a problem of side reaction on further oxidation a part of the formed sulfoxide into sulfone, as shown in the following reaction.
As a matter of course, formation of the sulfone brings about the drawback of lower yield of the desired sulfoxide, and another problem is that it is difficult to separate and purify the two compounds because of their very similar physicochemical properties. During this procedure, further oxidation of the sulfoxide of the Rabeprazole causes the problem, so called "over-oxidation" resulting in sulfone impurities in the final product which is difficult to control with classical methods in the state of the art.
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Sulfone
US6180652 describes the acetone complex of the Rabeprazole and its sodium salt. By using these acetone complexes, Rabeprazole and its sodium salt can be purified in high yield and high purity and further it can be stored as raw material (bulk) stably for a prolonged period of time.
There is a need in the art for Rabeprazole and its pharmaceutically acceptable salt, having a higher purity, as well as purification processes for obtaining the same.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a novel process for purification of Rabeprazole in good yield and high purity.
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In one aspect, the present invention provides a process for purifying Rabeprazole comprising treating Rabeprazole with 2-butanone wherein the total purity of the purified Rabeprazole is higher than the total purity of the starting Rabeprazole.
In another aspect, the present invention provides a process to obtain pure Rabeprazole sodium by using purified Rabeprazole from crude Rabeprazole using 2-butanone.
In another aspect, the present invention provides a process for removing sulfone from Rabeprazole.
DETAILED DESCRIPTION OF THE INVENTION
We have surprisingly found that a 2-butanone can be used advantageously in purification of Rabeprazole. Typically in the process of the present invention the Rabeprazole to be purified is added in the solvent 2-butanone and isolating Rabeprazole from the same. The purified Rabeprazole thus obtained can be further transformed in to a pharmaceutically acceptable salt thereof, preferably to a sodium salt of Rabeprazole conforming to purity as ICH guidelines.
In accordance with the present invention which provides a process for purifying Rabeprazole. The process comprises, crystallizing Rabeprazole using 2- butanone, thus obtained product is preferably recovered by filtering, washing of the obtained solid product, and drying, preferably under reduced pressure. Purified Rabeprazole thus obtained is further converted to Rabeprazole sodium comprising following steps:
a) treating Rabeprazole with potassium tertiary butoxide using tertiary butanol as solvent,
b) removing tertiary butanol to provide Rabeprazole sodium,
c) treating Rabeprazole sodium with Dichloromethane to provide a solution,
d) Treating the solution of Rabeprazole sodium in dichloromethane with diisopropyl ether to precipitate the Rabeprazole sodium, followed by filtration and drying.
Rabeprazole obtained by the above process preferably contains sulfone impurity in an amount of less than about 0.2%. The above crystallization process may be repeated in order to further purify the obtained Rabeprazole, so that the sulfone impurity levels may be reduced to less than about 0.1%.
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The total purity of the Rabeprazole obtained by the above process is at least about 98%, more preferably, at least about 99% and most preferably 99.7% or more.
The total purity of the Rabeprazole sodium, prepared by using the above purified Rabeprazole, is of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.7%.
As used herein, the term "sulfide" or "rabesulfide" refers to 2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl} methylthio]-1 H-benzimidazole
As used herein, the term "sulfoxide" refers to 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyi]-methyl] sulfinyl]-1H-benzimidazole.
As used herein, the term "sulfone" refers to 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl] sulfonyl]- 1H-benzimidazole.
The present invention can be illustrated by the following non-limiting examples. Exampfe-1 Purification of crude Rabeprazole
The crude Rabeprazole was obtained by oxidation of 2-[{4-(3-methoxypropoxy)-3-methylpyridine-2-yl} methylthio]-1 H-benzimidazole using dichloromethane as solvent, and mCPBA as oxidizing agent, using prior art process.
After the oxidation was over, the solution of Rabeprazole in dichloromethane containing ethanol amine was distilled out under vacuum below 40°C. The residue obtained was treated with methyl ethyl ketone (MEK- also known as 2-butanone), the solvent was stripped off below 45°C under vacuum. The residual mass was treated with methyl ethyl ketone and treated with charcoal and stirred at 50°C-55°C for 60 minutes, and filtered, washed with 2- butanone and cooled to 25°C-35°C, further cooled to 0°C-5°C with stirring. The reaction mass was filtered washed with 2- butanone and dried under vacuum to yield pure Rabeprazole, with limits of not more than 0.5% water content, not more than 600 ppm dichloromethane, and not more than 5000 ppm MEK.
Purified Rabeprazole was converted to Rabeprazole sodium using sodium tert. Butoxide in tert. Butanol.

For Cadila Pharmaceuticals Ltd.,
Dr. Bakulesh Khamar Executive Director - Research
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