FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and mlel3)
1. TITLE OF THE INVENTION:
"NOVEL PROCESS FOR PREPARATION OF DEXLANSOPRAZOLE AND
SALT THEREOF"
2. APPLICANT:
(a) NAME: CIPLA LIMITED
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

Technical field of the Invention
The present invention relates to novel process for preparation of dexlansoprazole and salt and purification thereof.
Background of the Invention
Racemic lansoprazole is chemically known as 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]sulfinyl]-lH-benzimidazole and represented as follows :

Lansoprazole has 2 isomers namely S-lansoprazole and R-lansoprazoIe. R-lansoprazole is known as dexlansoprazole.
EP0773940 describes preparation of (+) lansoprazole and (-) lansoprazole.
US6462058 describes crystalline dexlansoprazole characterized by XRD. Further, this patent simply mentions various alkali metal salts such as sodium & potassium; alkaline earth metal salts such as calcium, magnesium, barium & salts with various organic bases. This patent also describes preparation of amorphous dexlansoprazole and crystalline dexlansoprazole sesquihydrate and characterizes crystalline dexlansoprazole sesquihydrate by (d) spacing values in XRD.
US7271182 describes crystalline lithium, potassium, magnesium, sodium & calcium salts of R-lansoprazole and preparation thereof. However, the process described in this patent is not reproducible, material is not obtained upon repeated purification and also the crystalline form is not stable on storage.
WO2010079504 claims alkylamine salt of R-lansoprazole.
WO2009087672 & WO2009117489 claim amorphous dexlansoprazole.

Pantoprazole and rabeprazole are used commercially as their sodium salts while esomeprazole is used as its magnesium salt. Lansoprazole as well as dexlansoprazole are not preferred in the form of their salts. However, it has been observed that amorphous salts of dexlansoprazole have advantageous properties over crystalline dexlansoprazole salt.
Summary of the Invention:
According to the first aspect of the present invention, there are provided amorphous salts of dexlansoprazole.
In another aspect of the present invention, there is provided process for the preparation of amorphous salts of dexlansoprazole. The process comprises following steps:
a) contacting dexlansoprazole with suitable inorganic base or an inorganic salt,
b) distilling off the solvent to get amorphous dexlansoprazole salt.
According to another aspect of the present invention, there is provided an improved process for preparation of crystalline dexlansoprazole sesquihydrate. The process comprises contacting 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole with a chiral agent and titanium isopropoxide in a suitable organic solvent in presence of water, followed by oxidation using an oxidizing agent to get dexlansoprazole sesquihydrate.
Another aspect of the invention provides a process for purification of dexlansoprazole sesquihydrate. The process comprises following steps :
1) dissolving dexlansoprazole sesquihydrate in a suitable organic solvent,
2) adding base
3) adding water or mixture of water and organic solvent to the above solution,
4) adjusting the pH of the solution to 8.5-9.5,
5) filtering and washing the product with the chilled water and drying
Brief Description of Drawings:
Figure 1 describes an X-ray diffraction pattern of amorphous dexlansoprazole sodium. Figure 2 describes an X-ray diffraction pattern of amorphous dexlansoprazole potassium.

Figure 3 describes an X-ray diffraction pattern of crystalline dexlansoprazole
sesquihydrate.
Figure 4 describes an Infra-red absorption spectrum of crystalline dexlansoprazole
sesquihydrate.
Figure 5 describes an X-ray diffraction pattern of anhydrous crystalline lansoprazole
sulphide.
Detailed Description of the Invention:
The present invention provides amorphous salts of dexlansoprazole.
Amorphous dexlansoprazole sodium and amorphous dexlansoprazole potassium are characterized by XRD patterns showing no sharp peaks as described in figures 1 & 2 respectively.
In another aspect of the present invention, there is provided process for the preparation of amorphous salts of dexlansoprazole. The process comprises following steps :
a) contacting dexlansoprazole with suitable inorganic base or an inorganic salt,
b) distilling off the solvent to get amorphous dexlansoprazole salt.
Inorganic salt used for preparation of salt of dexlansoprazole are selected from sodium chloride, potassium chloride, potassium acetate, sodium acetate etc. Inorganic base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate etc.
Typically inorganic base or an inorganic salt is dissolved in a solvent which solvent is selected from methanol, ethanol, isopropanol, water, t-butanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, methyl acetate, butyl acetate, acetone or mixture thereof.
Dexlansoprazole used for preparation of amorphous salt can be anhydrous or a hydrate.
Optionally, dexlansoprazole may be added as a solution in a suitable solvent which is selected from acetone, t-butanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, methanol,

ethanol, isopropanol, ethyl acetate, methyl acetate, butyl acetate, methylene chloride or mixture thereof.
After mixing dexlansoprazole with inorganic base or its salt, the solvent is distilled off to get amorphous dexlansoprazole salt.
This amorphous dexlansoprazole salt may optionally be further purified by dissolving in suitable solvent and then isolating the pure product.
The amorphous dexlansoprazole salt is dissolved in a hydrocarbon solvent such as methylene dichloride, ethylene dichloride and toluene, preferably methylene dichloride.
The solvent used to isolate the amorphous dexlansoprazole salt is a suitable hydrocarbon solvent such as cyclohexane, toluene, n-hexane, n-heptane, preferably n-heptane.
In an embodiment the salt is isolated at low temperature such as -2 to 7°C.
It has been found that amorphous sodium salt of dexlansoprazole prepared according to the process of the present invention is more stable w.r.t hygroscopic ity and enantiomeric purity and has advantageous properties compared to the crystalline form and hence, is well suited for formulating in a suitable dosage form.
Further, dexlansoprazole amorphous salt obtained by the process of the present invention may be converted into another salt.
According to another aspect of the present invention, there is provided a process for preparation of dexlansoprazole sesquihydrate. The process comprises contacting 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole with a (+)-diethyl-L-tartrate & titanium isopropoxide in a suitable organic solvent in presence of water, followed by oxidation using an oxidizing agent to get dexlansoprazole sesquihydrate.

Typically (+)-diethyl-L-tartrate is added about 0.25 to 1.0 equivalent preferably 0.61 to 0.64 equivalents per mole of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methy l]thio]-1 H-benzimidazole.
Suitable organic solvent is selected from methylene chloride, toluene, ethyl acetate, xylene, methyl ethyl ketone, methyl isobutyl ketone, diethyl carbonate, tetrahydrofuran and the like. The preferred solvent is toluene.
In an embodiment, (+)-diethyl-L-tartrate and titanium isopropoxide are added first followed addition of water and 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyI]thio] -1 H-benzimidazole.
In another embodiment, before addition of an oxidizing agent, the reaction mixture is heated to get a clear solution then cooled to -15 to 5°C and then oxidizing agent is added at-15to5°C.
Oxidizing agent used for oxidation is selected from hydrogen peroxide, cumene hydroperoxide, tert. butyl hydroperoxide, peracetic acid, m-chloro perbenzoic acid, sodium hypochlorite, sodium hypobromite, preferably cumene hydroperoxide.
Typically oxidizing agent added is about 3 to 4 molar equivalents per mole of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-l H-benzimidazole.
Oxidation is carried out at a lower temperature ranging from -15 to 5°C, preferably -1 to -10°C.
Optionally oxidation is carried out in presence of a base. The base is selected from organic or inorganic bases. Inorganic base is selected from alkali metal carbonate like sodium carbonate, potassium carbonate; alkali metal bicarbonate like sodium bicarbonate, potassium bicarbonate; alkali metal hydroxides like potassium hydroxide, sodium hydroxide, lithium hydroxide and the like.

Organic base is selected from pyridine, triethyl amine, dicyclohexylamine, diisopropyl amine, diisopropyl ethyl amine, monomethyl amine, morpholine, preferably diisopropyl ethyl amine.
Crystalline dexlansoprazole sesquihydrate has water content in the range of 6.5 to 8.5%. The XRPD of the crystalline dexlansoprazole sesquihydrate is measured on a Rigaku DMAX2200 X-ray powder diffractomer using a Cu Ka radiation source and is characterized by its XRPD pattern as shown in Figure 3.
Infra-red absorption spectrum of crystalline dexlansoprazole sesquihydrate pattern is as shown in Figure 4.
Another aspect of the invention provides a process for purification of dexlansoprazole sesquihydrate. The process comprises following steps :
1) dissolving dexlansoprazole sesquihydrate in a suitable first organic solvent,
2) adding base to the solution obtained in step 1),
3) mixing water or mixture of water and first organic solvent with above solution obtained in step 2),
4) adjusting the pH of the solution obtained in step 3) to 8.5-9.5,
5) filtering the product and washing with the chilled water and drying.
The first organic solvent used for dissolving the dexlansoprazole sesquihydrate is selected from acetone, methanol, ethanol, isopropanol, n-butanol, iso-butanol, t-butanol, methyl ethyl ketone, methyl isobutyl ketone, preferably acetone.
In an embodiment, the solution of dexlansoprazole sesquihydrate in a first organic solvent is cooled to-3 to 7°C.
The base used is an organic base selected from pyridine, triethyl amine, dicyclohexylamine, diisopropyl amine, diisopropyl ethyl amine, monomethyl amine, morpholine, preferably triethyl amine.
Typically, the solution is cooled to 2-12°C after adjusting the pH.

The purified dexlansoprazole sesquihydrate obtained as per the process of the present invention and dexlansoprazole sesquihydrate prepared according to the example 3 of US6462058. Example 3 does not provide any details of sulfide and sulphone impurities and enantiomeric purity. However, the products of US'058 were analyzed for sulfide and sulphone impurities and enantiomeric purity and the results obtained are given in table below.

Product Duration of Enantiomeric Sulfide Sulphone
storage at
25°C purity (%) impurity (%) impurity (%)
Dexlansoprazole initial 99.70 0.03 0.22
sesquihydrate prepared
by the process of the
present invention
Dexlansoprazole initial 96.40 1.32 1.81
sesquihydrate prepared as
per example 3 of
US6462058
Dexlansoprazole sesquihydrate prepared as per the process of the present invention and prior art patent (US'058) were monitored on stability at 25°C for 2 months and were studied for impurity profile and it was found that dexlansoprazole sesquihydrate prepared by the process of the present invention is more stable with respect to impurity than the prior art process.

Product Duration of storage at 25°C Impurity profile (single max. at l.2 RRT)
Dexlansoprazole sesquihydrate Initial 0.02

After 1 month 0.02

After 2 months 0.05
Dexlansoprazole anhydrous crystalline form prepared as per US6462058 Initial 0.02

After 1 month 0.56

After 2 months 1.69

The results of the above stability study indicates that dexlansoprazole obtained by the process of the present invention is more stable compared to the prior art process.
The single maximum impurity observed at 1.2 RRT was increasing during stability which has a mass of 267.05. The chemical name of this impurity is 1-Methyl-12-thioxopyrido[1,2':3,4]imidazo-[l,2a]benzimidazol-2(12H)-one (thioxo impurity). The chemical formula of the impurity is C14H9N3OS and the structure was identified as below.

Lansoprazole sulphide used for preparation of dexlansoprazole is in an anhydrous form. The anhydrous lansoprazole sulphide compound is obtained by drying the monohydrate
of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyI]thio]-lH-benzimidazole at 110° to 118°C under vacuum for 24 hours.
The anhydrous lansoprazole sulphide compound is also obtained by azeotropic removal of water from a solution of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole monohydrate in a hydrophobic solvent.
Hydrophobic solvents that are used include toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, more preferably toluene at reflux temperature, under Nitrogen atmosphere, followed by cooling to 25 - 30°C, filtration and drying at 55 - 65°C under vacuum.
Optionally, the anhydrous 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI]-methyI]thio]-lH-benzimidazole after cooling to 25-30°C is isolated using a mixture of solvents which are selected from ethyl acetate, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene.
The anhydrous crystalline lansoprazole sulphide is characterized by its XRPD pattern as shown in Figure 5.

The details of the invention are given in the examples which are provided below for illustration only and therefore these examples should not be construed to limit the scope of the invention.
Examples
Example 1: Preparation of anhydrous 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-
pyridinyl]-methyl]thio]-lH-benzimidazole
50 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI]-methyl]thio]-lH-benzimidazole was added to 750 ml of toluene and heated to dissolve. Water was removed by azeotropic distillation for 3 - 5 hours followed by distillation of 500 ml of toluene, cooled to 25 - 30°C and stirred for 30 minutes. Anhydrous 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole was filtered under Nitrogen atmosphere and dried under vacuum at 55 - 65°C for 6 - 10 hours to yield 45 g of anhydrous compound. Purity is 99.92%.
Example 2: Preparation of anhydrous 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazoIe
50 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole was added to 750 ml of toluene and heated to dissolve. Water was removed by azeotropic distillation for 3 - 5 hours followed by complete distillation of toluene and cooled to 60°C. 100 ml of ethyl acetate and 200 ml of hexane were added under Nitrogen atmosphere, cooled to 25 - 30°C and stirred for 30 minutes. Anhydrous 2-[[[3-methyl-4-(2;2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole was filtered under Nitrogen atmosphere and dried under vacuum at 55 - 65 °C for 6 - 10 hours to yield 47 g of anhydrous compound. Purity is 99.93%.
Example 3: Preparation of anhydrous 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole
50 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole was added to 750 ml of xylene and heated to dissolve. Water was removed by azeotropic distillation for 3 - 5 hours followed by distillation of 500 ml of xylene, cooled to 25 - 30°C and stirred for 30 minutes. Anhydrous 2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole was filtered under Nitrogen

atmosphere and dried under vacuum at 55 - 65°G for 6-10 hours to yield 44.5 g of anhydrous compound. Purity is 99.86%.
Example 4: Preparation of anhydrous 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole
50 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI]-methyl]thio]-lH-benzimidazole was dried at 110 to 118°C under vacuum for 20 - 24 hours to yield 47.5 g of anhydrous sulphide and purity 99.85% (HPLC).
Example 5: Preparation of (+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphinyI]-lH-benzimidazole sesquihydrate, without using an organic base
36.19 g of (+)-diethyl L-tartrate and 24.15 g of titanium (IV) isopropoxide were added to toluene 950 ml under nitrogen. To this solution, 0.4 g of water was added and stirred at 25-30°C for 10-15 minutes. 100 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzirnidazole was introduced. The mixture was heated to 60 - 65°C for 30 minutes and then cooled to -10°C. 158.6 g of cumene hydroperoxide (80%) in 200 ml of toluene was added at -10 to -5°C. The reaction mixture was quenched with 500 ml of 5% aqueous potassium hydroxide (KOH) solution at about -10°C, 250 ml of methanol was charged and the reaction mixture was stirred for 10 minutes at 30 - 35°C. Layers were separated, toluene layer was extracted with a mixture of 300 ml of 5% aqueous KOH and 150 ml of methanol. The combined aqueous layers were washed with 500 ml of methylene dichloride (MDC). To the aqueous layer, toluene 400 ml was added. pH was adjusted to 8.0 to 8.2 with 20% acetic acid (AcOH) and layers were separated. To the toluene layer, 400 ml of water was added and stirred for 10 minutes. 400 ml of n-hexane was added to the above mixture and cooled to 5 - 10°C. The solid thus obtained was filtered, washed with 200 ml of chilled water.
The wet material was taken in 400 ml of acetone followed by addition of 0.5 ml of triethylamine. The reaction mass was stirred for 10 minutes, 1000 ml of water was charged and stirred for 15 minutes. The pH was adjusted to 8.0 to 8.2, stirred for 30 minutes and filtered and dried to yield 82 g.

Dried material was dissolved in 200 ml of acetone, filtered through hyflo bed. Triethylamine 0.5 ml was added to the filtrate. This filtrate was added slowly to a mixture of 400 ml of water and 80 ml of acetone. The pH was checked and adjusted to 8.0 to 8.2. This mixture was cooled to 5 - 10°C, filtered and washed with chilled water. The material was dried under vacuum till water content is 6.5 to 8.5 % w/w to yield 42.5 g with purity 99.16% (HPLC) and enantiomeric purity 99.97%.
Example 6: Preparation of (+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphiny!]-lH-benzimidazole sesquihydrate, without using an organic base (Azeotropic removal of water)
105 g of 2-[[[3-methyl4-(2,2,24rifluoroethoxy)-2-pyridinyl]-rnethyl]thio]-lH-benzimidazole having water content 5.0% was taken in 750 ml of toluene and heated to reflux. Water was distilled azeotropically and 200 ml of toluene was distilled. The reaction mass was cooled to 25 - 30°C and stirred for 10 minutes. To the other reaction vessel, toluene 350 ml was added, followed by 36.19 g of (+)-diethyl L-tartrate, 24.15 g of titanium (IV) isopropoxide, stirred for 15 minutes and 0.4 g of water was added and stirred for 15 minutes at 25 - 30°C. The mixture was added to the sulphide solution, heated to 70-75°C for 5 minutes. This reaction mass was then cooled -10°C. 158.6 g of cumene hydroperoxide (80%) in 200 ml of toluene was added slowly at -10 to -5°C. The reaction mixture was quenched with 500 ml of 5% aqueous KOH solution at about -10°C, 250 ml of methanol was charged, stirred for 10 minutes and the pH adjusted to 12.5 -13.0 with 5% aqueous KOH solution and stirred for 10 minutes at 30 - 35°C. Layers were separated, toluene layer was extracted with a mixture of 300 ml of 5% aqueous KOH and 150 ml of methanol. The combined aqueous layers were washed with 400 ml of MDC and the reaction mass was cooled to 25 - 30°C. Toluene 200 ml was added, pH was adjusted to 8.0 to 8.2 with 20% AcOH, cooled to 5 - 10°C and stirred for 30 - 45 minutes. The solid thus obtained, was filtered and washed with 200 ml of chilled water.
The wet material was taken in 400 ml of acetone, stirred for 10 minutes, 0.5 ml of triethylamine was added, 1000 ml of water was charged and stirred for 15 minutes. The pH was adjusted to 8.0 to 8.2, stirred for 30 minutes and filtered and dried to yield 88 g.

Dried material was dissolved in 200 ml of acetone, filtered through hyflo bed. Triethylamine 0.5 ml was added to the filtrate. This filtrate was added slowly to a mixture of 500 ml of water and 40 ml of acetone. The pH was checked, adjusted to 8.0 to 8.2, cooled to 5 - 10°C, filtered and washed with chilled water. The material was dried under vacuum till water content is 6.5 to 8.0 % w/w to yield 40 g with purity 99.54% (HPLC) and enantiomeric purity 99.32%.
Example 7: Preparation of (+)-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphinyl]-lH-benzimidazole sesquihydrate, with using an organic base (Azeotropic removal of water).
52.5 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole having water content 5.0 %w/w was taken in 350 ml of toluene, followed by flushed with 50 ml of toluene, heated to reflux, water was distilled azeotropically and 100 ml of toluene was distilled and cooled to about 25 - 30°C. 18.09 g of (+)-diethyl L-tartrate, 12.09 g of titanium (IV) isopropoxide and water 0.3 ml were added under nitrogen, stirred for 15 minutes and the mixture was heated to 70 - 75°C for 5 minutes, cooled to 25 - 30°C. 11.71 g of DIPEA was charged, stirred for 30 minutes and then cooled to -5 to -1°C. 73.94 g of cumene hydroperoxide (80%) in 50 ml of toluene was added. The reaction mixture was quenched with 250 ml of 5% aqueous KOH solution at about -5 to -1°C and 125 ml of methanol was charged. pH was adjusted to 12.5-13.0 by 20% KOH solution and stirred for 10 minutes at 30 - 35°C. Layers were separated, toluene layer was extracted with a mixture of 150 ml of 5% aqueous KOH and 75 ml of methanol. The combined aqueous layers were washed with 250 ml of MDC. The reaction mass was then cooled to 25 - 30°C. Toluene 100 ml was added, pH was adjusted to 8.0 to 8.2 with 20% AcOH, stirred for 30 minutes and cooled to 5 - 10°C and stirred for 30 minutes. The solid thus obtained was filtered, washed with 100 ml of chilled water.
The wet material was taken in 100 ml of acetone, stirred for 10 minutes, 0.25 ml of triethylamine was added, 300 ml of water was charged and stirred for 15 minutes. The pH was adjusted to 8.0 to 8.2 at 25 - 30°C, stirred for 30 minutes, filtered and dried to yield 49 g.

Dried material was dissolved in 100 ml of acetone, filtered through hyflo. Triethylamine 0.25 ml was added to the filtrate. This filtrate was added slowly to a mixture of 300 ml of water and 20 ml of acetone, stirred for 15 minutes and the pH was checked and adjusted to 8.0 to 8.2. This mixture was cooled to 5 - 10°C, filtered, washed with chilled water. The material was dried under vacuum till water content is 6.5 to 8.5 % w/w to yield 40.0 g with purity 99.64% (HPLC) and enantiomeric purity 99.63%.
Example 8: Preparation of (+)-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphinyl]-lH-benzimidazole sesquihydrate, with using an organic base
36.19 g of (+)-diethyl L-tartrate and 24.15 g of titanium (IV) isopropoxide were added to toluene 750 ml at 25 - 30°C. 0.6 g of water was added to the solution, stirred for 15 minutes and 100 g of 2-[[[3-methyl-4-(2,2,2-trilluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole was introduced. The mixture was heated to 70 - 75°C for 5 minutes, cooled to 25 - 30°C. 23.42 g of diisopropylethyl amine was added, stirred for 30 minutes and then cooled to -5 to 0°C. 147.88 g of cumene hydroperoxide (80%) in 100 ml of toluene was added. The reaction mixture was quenched with 500 ml of 5% aqueous KOH solution at about -5 to 0°C, 250 ml of methanol was charged and pH was adjusted to 12.5 - 13.0 with 20% aqueous KOH solution and stirred for 10 minutes at 30 - 35°C. Layers were separated, the toluene layer was extracted with a mixture of 300 ml of 5% aqueous KOH and 150 ml of methanol at 30 - 35°C. The combined aqueous layers were washed with 500 ml of MDC. To the aqueous layer, toluene 200 ml was added, pH was adjusted to 8.0 to 8.2 with 20% aqueous AcOH solution at 25 - 30°C, stirred for 30 minutes, cooled to 5 - 10°C and stirred for 30 - 45 minutes. The solid thus obtained, was filtered and washed with 200 ml of chilled water.
The wet material was taken in 200 ml of acetone, 0.5 ml of triethylamine was added, 600 ml of water was charged and stirred for 15 minutes. The pH was adjusted to 8.0 to 8.2, stirred for 30 minutes and filtered and dried yield 97 g.
Dried material was dissolved in 200 ml of acetone at about 25°C, cooled to 0 - 5°C, filtered through hyflo bed. Triethylamine 0.5 ml was added to the filtrate. This filtrate was added slowly to a mixture of 600 ml of water and 40 ml of acetone. The pH was

checked, adjusted to 8.0 to 8.2. the reaction mass was cooled to 5 - 10°C, filtered and washed with chilled water. The material was dried under vacuum till water content is 6.5 to 8.0 % w/w to yield 88 g with purity 99.66% (HPLC) and enantiomeric purity 99.91%.
Example 9 : Purification of Dexlansoprazole sesquihydrate
100 g of dried material of Dexlansoprazole prepared as detailed in above examples, was dissolved in 200 ml of acetone at about 25°C, cooled to 0 - 5°C, filtered through hyflo bed. Triethylamine 0.5 ml was added to the filtrate. This filtrate was added slowly to a mixture of 800 ml of water and 40 ml of acetone. The pH was checked, adjusted to 9.0 to 9.5. The reaction mass was cooled to 5 - 10°C, filtered and washed with chilled water. The material was dried under vacuum till water content is 6.5 to 8.0 % w/w to yield 93.76 g with purity 99.73% and enantiomeric purity 99.70%.
Example 10: Preparation of amorphous sodium salt of (+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI]methyl]sulphinyl]-lH-benzimidazoIe.
2.78 g of sodium hydroxide was dissolved in 75 ml of methanol and 25.0 g of dexlansoprazole sesquihydrate was added at 25 - 30°C. Solution was stirred for 15 minutes and methanol was distilled completely under vacuum at 45 - 50°C. 25 ml of MDC was added and stripped off completely. Residue was dissolved in 125 ml of MDC, stirred for 15 minutes, added to a pre-cooled n-Heptane (625 ml) having about 0 - 5°C, stirred, filtered under nitrogen atmosphere, suck-dried and dried under vacuum at 60 -65°C for 20 hours to yield 24.3 g. Purity is 99.65%.
Example 11: Preparation of amorphous sodium salt of (+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphinyl]-lH-benzimidazole.
2.5 g of sodium hydroxide was dissolved in 25 ml of methanol and a solution of 25.0 g of dexlansoprazole sesquihydrate in acetone 250 ml was added at 25 - 30°C. Solution was stirred for 15 minutes and the solvent was distilled completely under vacuum at 35 -50°C. Residue was dissolved in 125 ml of MDC, stirred for 15 minutes, added to a pre-cooled n-Heptane (625 ml) having temperature about 0 - 5°C, stirred, filtered under nitrogen atmosphere, suck-dried and dried under vacuum at 60 - 65°C for 22 - 24 hours to yield 24.8 g. Purity is 99.67%.

Example 12: Preparation of amorphous potassium salt of (+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI]methyl]suIphinyI]-lH-benzimidazole.
3.0 g of potassium hydroxide was dissolved in 75 ml of methanol and 25.0 g of dexlansoprazole sesquihydrate was added at 25 - 30°C. Solution was stirred for 15 minutes and methanol was distilled completely under vacuum at 45 - 50°C. 25 ml of MDC was added and stripped off completely. Residue was dissolved in 125 ml of MDC, stirred for 15 minutes, added to a pre-cooled n-Heptane (625 ml) having about 0 - 5°C, stirred, filtered under nitrogen atmosphere, suck-dried and dried under vacuum at 60 -65°C for 22 - 24 hours to yield 25.1 g. Purity is 99.73%.
Example 13: Preparation of amorphous sodium salt of (+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphinyI]-lH-benzimidazole from anhydrous dexlansoprazole
1.112 g of sodium hydroxide was dissolved in 30 ml of methanol and 10.0 g of anhydrous dexlansoprazole was added at 25 - 30°C. Solution was stirred for 15 minutes and methanol was distilled completely under vacuum at 45 - 50°C. 10 ml of MDC was added and stripped off completely. Residue was dissolved in 50 ml of MDC, stirred for 15 minutes, added to a pre-cooled n-Heptane (250 ml) having about 0 - 5°C, stirred, filtered under nitrogen atmosphere, suck-dried and dried under vacuum at 60 - 65°C for 22 - 24 hours to yield 9.92 g. Purity is 99.67%.
Example 14: Preparation of amorphous potassium salt of (+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphinyl]-lH-benzimidazole from anhydrous dexlansoprazole
1.2 g of potassium hydroxide was dissolved in 30 ml of methanol and a solution of anhydrous dexlansoprazole (10 g of anhydrous dexlansoprazole dissolved in 100 ml of acetone) was added at 25 - 30°C. Solution was stirred for 15 minutes and distilled completely under vacuum at 45 - 50°C. 10 ml of MDC was added and stripped off completely. Residue was dissolved in 50 ml of MDC, stirred for 15 minutes, added to a pre-cooled n-heptane (250 ml) having about 0 - 5°C, stirred, filtered under nitrogen atmosphere, suck-dried and dried under vacuum at 60 - 65°C for 22 - 24 hours to yield 10.32 g. Purity is 99,66%.

WE CLAIM:
1. A process for preparation of dexlansoprazole sesquihydrate which process comprises contacting 2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole with a (+)-diethyl-L-tartrate & titanium isopropoxide in a suitable organic solvent in presence of water, followed by oxidation using an oxidizing agent to get dexlansoprazole sesquihydrate.
2. The process according to claim 1, wherein suitable organic solvent used is selected from the group consisting of methylene chloride, toluene, ethyl acetate, xylene, methyl ethyl ketone, methyl isobutyl ketone, diethyl carbonate, tetrahydrofuran.
3. The process according to claim 2, wherein suitable organic solvent used is toluene.
4. The process according to claim 1, wherein (+)-diethyl-L-tartrate used is 0.25 to 1.0 equivalent per mole of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyI]thio]-lH-benzimidazole.
5. The process according to claim 4, wherein (+)-diethyl-L-tartrate used is 0.61 to 0.64 equivalents per mole of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-1 H-benzimidazole.
6. The process according to claim 1, wherein (+)-diethyl-L-tartrate and titanium isopropoxide are added first followed addition of water and 2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole.
7. The process according to claim 1, wherein oxidizing agent used is selected from the group consisting of hydrogen peroxide, cumene hydroperoxide, tert. butyl hydroperoxide, peracetic acid, m-chloro perbenzoic acid, sodium hypochlorite, sodium hypobromite.

8. The process according to claim 7, wherein oxidizing agent used is cumene hydroperoxide.
9. The process according to claim 1, wherein before addition of an oxidizing agent, the reaction mixture is heated to get a clear solution and then cooled to -15 to 5°C.
10. The process according to claim 1, wherein oxidizing agent is added at -15 to 5°C.
11. The process according to claim 1, wherein oxidizing agent added is 3 to 4 molar equivalents per mole of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl]thio]-lH-benzimidazole.
12. A process for purification of dexlansoprazole sesquihydrate which process comprises following steps:

1) dissolving dexlansoprazole sesquihydrate in a suitable first organic solvent,
2) adding base to the solution obtained in step 1),
3) mixing water or mixture of water and first organic solvent with solution obtained in step 2),
4) adjusting the pH of the solution obtained in step 3) to 8.5-9.5,
5) filtering the product and washing it with the chilled water and drying.

13. The process according to claim 12, wherein the first organic solvent is selected from the from the group consisting of acetone, methanol, ethanol, isopropanol, n-butanol, iso-butanol, t-butanol, methyl ethyl ketone, methyl isobutyl ketone.
14. The process according to claim 12, wherein the base is selected from the group consisting of pyridine, triethyl amine, dicyclohexylamine, diisopropyl amine, diisopropyl ethyl amine, monomethyl amine, morpholine.
15. The process according to claim 14, wherein the base selected is triethyl amine.

16. The process according to claim 12, wherein solution of dexlansoprazole sesquihydrate in first organic solvent is cooled to -3 to 7°C.
17. The process according to claim 12, wherein the solution is cooled to 2-12°C after adjusting the pH.