FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION :
2-[[(3,4-DIMETHOXY-2-PYRIDINYL)METHYL]SULFINYL]-SUBSTITUTED BENZIMIDAZOLES AND SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The invention provides 2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-substituted benzimidazoles and salts thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The invention provides 2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-substituted benzimidazoles and salts thereof and process for isolation of the same. The invention further provides a pharmaceutical composition comprising 2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-substituted benzimidazoles and salts thereof. The invention also provides a pharmaceutical composition of pantoprazole or salts thereof having 2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-substituted benzimidazoles and salts thereof content of 0.5% or less.
Pantoprazole is chemically known as 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1/-/-benzimidazole having structure of formula I.
Formula I
Pantoprazople sodium, marketed under the name PROTONIX®, is a proton pump inhibitor and is indicated for the treatment of erosive esophagitis and pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
There are several patents and patent applications, which refer to pantoprazole or salt thereof and its preparation such as U.S. Patent No. 7,081,534, U.S. Patent No. 7,060,839, U.S. Patent No. 6,686,379, U.S. Patent No. 6,410,569, U.S. Application No. 2006/167262, U.S. Application No. 2005/245578, U.S. Application No. 2004/235904, and International (PCT) Application Nos. WO 2007/017890, WO 2007/026188, WO 2006/064249 and WO 2006/100243.
The inventors while developing a process for the preparation of pantoprazole sodium have surprisingly isolated a compound of formula (II),


MeO OMe

Formula II
wherein -CI may be present at C-4, C-6 or C-7 and salts thereof.
The compound of the formula II is produced by the reaction of a thioether of formula with an oxidizing agent as depicted in scheme 1.

^MeO OMe

F,HCO

MeO
0
OMe

F,HCO

MeO OMe

F,HC0
Formula I

In one aspect of the invention there is provided a compound of formula II,
MeO OMe

Formula II
wherein -CI may be present at C-4, C-6 or C-7 and salts thereof.
The specific compounds of invention include;
6-Chloro-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-
benzimidazole;

7-Chloro-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole;
4-Chloro-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole; and salts thereof.
In this disclosure, the term "salts" refers to pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, mesylic, phenylacetic, mandelic, methanesulfonic, benzenesulfonic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, stearic, algenic, 3-hydroxybutyric galacturonic acid and the like. Suitable pharmaceutically acceptable base addition salts include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like.
In another aspect of the present invention there is provided a process of isolation of compound of formula II, wherein the process includes steps of:

MeO OMe
F O
Formula II
(a) stirring pantoprazole sodium with water and an organic solvent mixture at acidic pH,
(b) concentrating the organic layer,

(c) contacting the solution of residue of step b) with antisolvent and
(d) isolating compound of formula II or salt thereof from the reaction mass thereof.
Pantoprazole sodium can be prepared according to the process known in the art for example as described in International (PCT) Application No. WO 2007/026188. The process of invention involves stirring pantoprazole sodium with water and an organic solvent at a pH 4 to 7. The organic layer is separated, washed with water and concentrated to obtain a residue. The residue is further dissolved in a ketone solvent and the solution is concentrated. The residual solution obtained thereof is stirred with an antisolvent. Solid obtained thereof is separated and the filtrate is concentrated to get compound of formula II or salts thereof.
The organic solvent is selected from the group of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, isopropyl acetate, toluene, xylene, heptane, hexane, pentane, 2,2,4-trimethylpentane and the like or mixture thereof. The antisolvent includes diethyl ether, dimethyl ether, methyl-tert-butyl ether, methoxypropane, heptane, hexane, pentane and the like. Ketone solvent is selected from the group of acetone, ethyl methyl ketone, propanone, methyl iso-butyl ketone and the like.
In yet another aspect of the invention there is provided a pharmaceutical composition containing compound of formula II in association with a pharmaceutically acceptable excipient and/or carrier wherein the composition may comprise a preparation such as solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories for parenteral administration.
The non-limiting examples of solid composition include compressed tablets, pills, capsules, dispersible powders, granules, hard capsules and soft capsules. The non-limiting examples of liquid composition include emulsions, solutions, suspensions,


syrups and elixirs. The non-limiting examples of injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
In yet another aspect of the invention there is provided a pharmaceutical composition of pantoprazole and salts thereof.
In this disclosure, pharmaceutical composition of pantoprazole refer to a pharmaceutical composition of pantoprazole and salts thereof with compound of formula II and salts thereof content of 0.5% or less.
The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Examples
Example 1: Isolation of 6-Chloro-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1 H-benzimidazole
Pantoprazole Sodium (100 gm) was added in water (500 ml) and methylene chloride
(DCM) (300 ml) at room temperature. The pH of the solution was adjusted to 5.5 with
1N hydrochloric acid (260 ml). The organic layer was separated and the aqueous layer
was extracted with DCM (100 ml). The combined organic layer was washed with water
(75 ml) and concentrated. The solid obtained (81.1 g) was dissolved in acetone (600 ml)
at 45 °C with stirring. The organic layer was concentrated to half volume and cooled to
10 °C. Diethyl ether (200 ml) was added and the solution was further stirred for 1 hour.
The solids were removed by filtration and the mother liquor was concentrated. The
residue (12 g) obtained was enriched with the desired compound (0.91%). The desired
compound was then isolated by preparative HPLC.
Yield: 73 mg.
HPLC Purity (% area) : 82.74%.

1H NMR (400 MHz, CD3OD) 5 : 3.84 (3H, s), 3.93 (3H, s), 4.72 (2H, s), 6.87 (1H, t),
7.06(1H, m), 7.56(1H, s), 7.78(1H, s), 8.04(1H, d, J=5.6Hz).
Mass(m/e) : 418 (M+1).
IR(KBr, cm-1) : 3106, 2925,1585,1489,1301, 1115 and 1064.

We claim:
1. A compound of formula II,

F O
Formula II
wherein -CI may be present at C-4, C-6 or C-7 and salts thereof.
2. The compound of claim 1, wherein specific compound includes:
6-Chloro-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-
benzimidazole;
7-Chloro-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole;
4-Chloro-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole; and
salts thereof.
3. A process of isolation of compound of formula II, wherein the process comprises of:
MeO OMe

Formula II
a) stirring pantoprazole sodium with water and an organic solvent mixture at acidic pH,
b) concentrating the organic layer,
c) contacting the solution of residue of step b) with antisolvent and
d) isolating compound of formula II or salt thereof from the reaction mass thereof.

4. The process of claim 3, wherein an organic solvent comprises of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, isopropyl acetate, toluene, xylene, heptane, hexane, pentane, 2,2,4-trimethylpentane and the like or mixture thereof.
5. The process of claim 3, wherein pantoprazole sodium is stirred with water and an organic solvent mixture at a pH of 5.5.
6. The process of claim 3, wherein the solution of residue is prepared in ketone solvent selected from acetone, ethyl methyl ketone, propanone, methyl iso-butyl ketone and the like.
7. The process of claim 3, wherein antisolvent comprises of diethyl ether, dimethyl ether, methyl-tert-butyl ether, methoxypropane, heptane, hexane, pentane and the like.
8. A pharmaceutical composition containing compound of formula II and salts thereof in association with a pharmaceutically acceptable excipient and/or carrier.
9. A pharmaceutical composition of pantoprazole and salts thereof having the
compound of formula II and salt thereof content of 0.5% or less.

Abstract
The invention provides 2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-substituted benzimidazoles and salts thereof and process for isolation of the same. The invention further provides a pharmaceutical composition comprising 2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-substituted benzimidazoles and salts thereof. The invention also provides a pharmaceutical composition of pantoprazole or salts thereof having 2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-substituted benzimidazoles and salts thereof content of 0.5% or less.