WO2010095144A2 - Process for the preparation of proton pump inhibitors - Google Patents

Abstract

An improved process for the preparation of proton pump inhibitors, such as 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole and pharmaceutically acceptable salts thereof is disclosed. The process involves protecting lansoprazole sulphide with D (+)-camphor sulphonyl chloride, followed by stereo selective oxidation using meta-chloroperbenzoic acid to obtain the camphor sulphonyl protected sulfoxide derivative, and stereo dexlansoprazole with high enantiomeric excess is prepared through deprotection of the camphor sulphonyl protected sulfoxide derivative.

Description

Process for the preparation of proton pump inhibitors Related Application:

This application claims the benefit of priority of our Indian patent application numbers 243/CHE/2009 filed on 4^th February and 2339/CHE/2009 filed on 29^th September 2009, which are incorporated herein by reference.

Field of the invention:

The present invention related to novel and improved processes for the preparation of proton pump inhibitors such as Dexlansoprazole and its pharmaceutically acceptable salts thereof. Dexlansoprazole is chemically known as 2-[(i?)-[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole represented as compound of formula- 1.

Formula- 1

Dexlansoprazole is the R-enantiomer of lansoprazole and belongs to benzimidazole type proton pump inhibitors which work by undergoing a rearrangement to form a thiophilic species which then conveniently bind to gastric Η K-ATPase, the enzyme involved in the final step of proton production in parietal cells and there by inhibit the enzyme subsequently inhibiting the secretion of the gastric acid. Therefore they are useful in the treatment of diseases which include peptic ulcer, heartburn, non- ulcer dispepsia, reflux esophagitis, and erosive esophagitis. Background of the Invention:

Some of the benzimidazole compounds capable of inhibiting the gastric Η K ATPase enzyme have found substantial use as drugs in human medicine and are known under such names as lansoprazole (US Pt No: 4,628,098), omeprazole (US Pt No: 4,255,431 and US 5,693,818), pantoprazole (US Pt. No. 4,758,579) and rabeprazole (US Pt No: 5,045,552). These compounds are structurally related sulphoxides having stereogenic center at sulphur atom and thus exist as two optical isomers i.e. enantiomers. The synthesis of racemic mixtures of these compounds has been disclosed in the earlier years, the synthesis of single enantiomer has become prominent.

The single enantiomer of pharmacologically active compounds has met an increased interest in the last few years because of improved pharmacokinetic and biological properties, but there is not yet any efficient asymmetric process described for the synthesis of the single enantiomer thereof.

Though processes for resolution of racemic mixture are described in DE 4,035,455 and WO 94/27988, these processes are lengthy, cumbersome and involve the loss of unwanted stereoisomer which is not economically viable.

US 5,948,789 disclose a process for enantioselective synthesis of single enantiomer of omeprazole and other structurally related compounds. The example-22 of this patent particularly disclosed the preparation of dexlansoprazole by asymmetric oxidation. The said process involves the oxidation of 2-[[[3-methyl-4-(2,2,2- trifiuoroethoxy)-2-pyridinyl]methyl]thio]- 1 H-benzimidazole using cumenehydroperoxide (in 1 molar ratio with respect of benzimidazole compound) in presence of diethyl tartrate, titanium isopropoxide, water and diisopropylethylamine in toluene medium for the period of 16 hours at room temperature provides the dexlanoprazole as an oil with 13% of sulfide, 8% of sulfone and 76% of sulfoxide by achiral HPLC. The oil compound further purified using flash chromatography to provide the dexlansoprazole as oil with the optical purity of 99.6%ee. The said patent involves flash chromatography for purification and the formation of sulfone is also high, hence this process is commercially not suitable. Moreover the said process involves the usage of unprotected nitrogen group in oxidation reaction process which leads to the formation of unwanted impurities.

US 6,982,275 disclose a process for optically active sulfoxide derivatives by employing kagan oxidation conditions. But the process involves the use of excess mole ratio of oxidizing agent (i.e. cumene hydroperoxide) in 2.5 to 10 molar equivalents relative to the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH- benzimidazole and the reaction is carried out at low temperatures between -20 to 20⁰C. The said application disclosed that the excess amount of oxidation agent used in the reaction helps to reduce the sulfone formation. However the usage of high amount of oxidation agent increases the over all cost of product and at the same time excess amount of base required for the decomposition of unreacted oxidizing agent substantially led to the increase in the formation of unwanted impurities. Moreover the oxidation reaction was carried out at low temperatures, which in general commercially not recommendable. H.B.Kagan et.al. in their research publications namely Tetrahedron Vol.43, No.

21, page 5135-5144, 1987 and J.Am.Chem. Soc, 1984, 106, 8188-8193, have disclosed the process for asymmetric oxidation of sulfides to sulfoxides using modified Sharpless reagent i.e. a combination of titanium isopropoxide, diethyl tartrate, and tertiary butyl hydroperoxide in the presence of water. But the reactions produced maximum yield while performed at -20° C and its makes not preferable for large scale industrial process.

In tetrahedron letters (1994), 35, 485 Pitchen and co-workers disclosed the process for the asymmetric oxidation of 4,5-diphenyl-2-imidazolyl methyl sulphide and its structurally related compounds into their corresponding sulphoxides. The process involved attaching a protective group to one of the nitrogen atoms in the imidazole moiety followed by asymmetric oxidation under Kagan oxidation conditions. It was observed that when two large substituents were present on the sulphur atom the enantiomeric excess of the sulphoxide formed was 0 %(racemic mixture). Hence it is not suitable for preparation of substituted sulfoxides.

WO 2005/116011 discloses a process for the preparation of S-omeprazole and

R-omeprazole, which involves the protection of sulfide, followed by oxidation with m-chloroperbenzoic acid and subsequent deprotection to provide the product. Even though the other prazoles have been generically described in the patent, none of them have been exemplified in this application. It is known to any person skilled in the art that until and unless one reaction is performed on a specific molecule it is difficult to really ascertain whether it behaves in the similar manner as omeprazole and gives the similar results. In most of the cases it has been observed that different molecules behave in a different manner in similar reaction conditions. Therefore there is a demand and a need for an enantioselective process that can be used in the large scale for manufacture of the enantiomers of pharmacologically active compounds.

The present invention was devised based on the above teachings and in order to overcome the disadvantages of prior art. The process involves the use of Kagan oxidation conditions but the oxidizing agent cumene hydroperoxide was replaced with m-chloroperbenzoic acid, and the reaction was carried out in presence of a base which improved the reaction yields and enantiomeric purity substantially. The route for the preparation of dexlansoprazole in the present invention involves the protection of lansoprazole sulphide with D (+)-camphor sulphonyl chloride followed by stereo selective oxidation using kagan oxidation conditions using meta chloroperbenzoic acid to provide camphor sulphonyl protected sulfoxide derivative which on deprotection provides stereo specifically dexlansoprazole with high enantiomeric excess and yield. During the present invention, after extensive experimentation it was discovered that by using a base in the oxidation reaction improved the yield and purity substantially. When the reaction was performed according to WO 2005/116011 wherein the N-protected sulphanyl derivative of omeprazole and other prazoles, were oxidized with meta chloro per benzoic acid in the absence of a base provided the products which were enantiomeric mixture with nearly equivalent quantities of the enantiomers. Whereas when the reaction was performed with N-protected sulphanyl intermediate of lansoprazole using diisopropylethyl amine base and meta chloro perbenzoic acid, it gave the product with >85% enantiomeric excess. Hence the use of a base in the reaction is a novel concept introduced by the present inventors.

Extensive literature search on D (+)-camphor sulphonyl protected sulfide and sulfoxide intermediates of dexlasoprazole revealed that these compounds have not been reported till date. We the present inventors has synthesized camphor sulfonyl protected sulfide and sulfoxide intermediates of dexlasoprazole and isolated them as novel crystalline solids and used them for the synthesis of enantiomerically pure R & S lansoprazole with substantial yield, high enantiomeric excess and fine quality. This has decreased the production cost drastically; hence it is easy to scale up to industrial level.

WO 2008/18091 particularly disclosed a process for the preparation of omeprazole salts, by the asymmetric oxidation of 5-methyoxy-2-[(4-methoxy-3,5- dimethyl-2-pyridinyl)-methyl]thio]-lH-benzimidazole with a oxidizing agent in presence of chiral transition metal complex without using organic solvent and a base.

Anhydrous and hydrated crystalline forms of dexlansoprazole are disclosed in US 6462058. The said patent also disclosed a process for the preparation of both forms. As dexlansoprazole is an important proton pump inhibitor available in the market it is advantageous to have an alternate process for the preparation of anhydrous and hydrated dexlansoprazole crystalline forms. US 2006/57095 disclosed a process for the preparation of amorphous dexlansoprazole by heating the hydrated crystalline dexlansoprazole at high temperatures for longer hours. The process requires high temperature for longer hours for the conversion of crystalline into amorphous form as well as the chemical purity of the obtained substance is not satisfactory. Hence this process is not suitable for the commercial scale up. There is a need in the art for the preparation of amorphous dexlansoprazole.

There is a demand and a need for an enantioselective process that can be used in the large scale for the manufacture of the enantiomers of pharmacologically active compounds. The present invention provides an efficient process for the preparation of dexlansoprazole using kagan conditions with the optimum amount of oxidation agent at ambient temperature, which provides high yields, purity with low levels of sulfones.

Brief description of the Invention: The first aspect of the present invention is to provide a novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]- lH-benzimidazole compound of formula-2 with D(+) camphorsulfonyl chloride in presence of an alkali metal base in a suitable solvent to provide N-camphor sulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH- benzimidazole compound of formula-3, which is optionally purified using a suitable solvent, b) oxidizing the N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole compound of formula-3 with a suitable oxidizing agent in presence of diethyl tartrate, titanium isopropoxide and a base in a suitable solvent provides N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4, c) treating the N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4 with aqueous alkali metal base in a suitable solvent provides 2-[(R)-[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinyl]methyl]sulfiny I]- 1 H-benzimidazole compound of formula- 1 , d) optionally purifying the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfϊnyl]-l H-benzimidazole compound of formula- 1 in a suitable solvent provides pure 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl] -lH-benzimidazole compound of formula- 1. The second aspect of the present invention is to provide a novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]- lH-benzimidazole compound of formula-2 with D(+) camphorsulfonyl chloride in presence of an alkali metal base in a suitable solvent provides N-camphor sulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH- benzimidazole compound of formula-3, which is optionally purified using a suitable solvent, b) oxidizing the N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole compound of formula-3 with a suitable oxidizing agent in presence of a base in a suitable solvent provides N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinyl]- lH-benzimidazole compound of formula-4, c) treating the N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl] methyl]sulfϊnyl]-lH-benzimidazole compound of formula-4 with aqueous alkali metal base in a suitable solvent provides 2-[(R)-[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridiny l]methyl]sulfiny I]- 1 H-benzimidazole compound of formula- 1 , d) optionally purifying the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-lH-benzimidazole compound of formula-1 in a suitable solvent provides pure 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl]-! H-benzimidazole compound of formula-1. The third aspect of the present invention is to provide a crystalline camphor sulphonyl protected sulfide intermediate i.e., N-camphorsulfonyl-2-[[[3-methyl-4- (2,2,2 -trifluoroethoxy)-2-pyridiny l]methy l]sulphanyl]- 1 H-benzimidazole compound of formula-3.

The fourth aspect of the present invention is to provide a crystalline camphor sulphonyl protected sulfoxide intermediate, i.e. N-camphorsulfonyl-2-[(R)-[[3-rnethyl-4- (2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfϊnyl]-lH-benzimidazole compound of formula-4.

The fifth aspect of the present invention is to provide an improved process for the preparation of dexlansoprazole compound of formula- 1, which comprise of oxidizing 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-2 with an oxidizing agent in presence of a chiral titanium complex and a base, characterized in that the oxidizing agent used in the ratio of 1.1 to 1.4 with respect to the compound of formula-2.

The sixth aspect of the present invention is to provide one pot process for the preparation of dexlansoprazole compound of formula- 1, which comprises of reacting the 2-mercaptobenzimidazole with 2-(chloromethyl)-3-methyl(4-(2,2,2,-trifluoroethoxy) pyridine hydrochloride in presence of a suitable base in a suitable polar solvent then extracting the obtained compound of formula-2 in a suitable solvent followed by oxidizing it with a suitable oxidizing agent in presence of a chiral titanium complex and a base to provide the compound of formula- 1.

. The further aspects of the present invention is to provide an improved process for the preparation of anhydrous, sesquihydrate crystalline forms and amorphous form of dexlansoprazole compound of formula- 1 and also provide a solvated form of dexlansoprazole.

Brief description of the drawings:

Figure-1: Illustrates the powder X-Ray diffractogram of crystalline N-camphorsulfonyl- 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-3. Figure-2: Illustrates the powder X-Ray diffractogram of crystalline N-camphor sulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH- benzimidazole compound of formula-4.

Figure-3: Illustrates the powder X-Ray diffractogram of IPA solvated dexlansoprazole.

Detailed description of the Invention:

Accordingly the present invention provides novel and improved processes for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts thereof.

Formula- 1

The first aspect of the present invention provides a novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]- lH-benzimidazole compound of formula-2

Formula-2 with D(+)camphorsulfonyl chloride in presence of an alkali metal base in a suitable solvent, to provide N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-3, which is optionally purified using a suitable solvent,

b) oxidizing the N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole compound of formula-3 with a suitable oxidizing agent in presence of diethyl tartrate and titanium isopropoxide in a suitable solvent in the presence of a base to provide N-camphorsulfonyl-2-[(R)-[[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4,

Formula-4 c) treating the N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4 with aqueous alkali metal base in a suitable solvent to provide 2-[(R)-[[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]- lH-benzimidazole compound of formula- 1, d) optionally purifying the 2-[(R)-[[3-rnethyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]suIfϊnyl]-lH-benzimidazole compound of formula- 1 in a suitable solvent provides pure 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl]-lH-benzimidazole compound of formula- 1.

Wherein in step a) the suitable alkali metal base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like or mixtures thereof; preferably potassium carbonate and the solvent is selected from chloro solvents such as methylenechloride, ethylene dichloride, carbon tetra chloride, chloroform and the like or mixtures thereof, preferably methylenechloride. The suitable solvent for the purification of compound of formula-3 is selected from alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like or mixtures thereof; preferably methanol.

In step b) the oxidizing reagent is selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; preferably m-chloro perbenzoic acid; the base is selected from organic bases such as tertiary butylamine, triethyl amine, N,N-diisopropyl-ethylamine, n-methyl glucamine, thiophene alkyl amine and the like or mixtures thereof; preferably N₅N- diisopropyl ethylamine and the solvent is selected from hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane and the like or mixtures there of; preferably toluene.

In step c) the alkali metal base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like or mixtures thereof; preferably sodium hydroxide and the solvent is selected from alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like or mixtures thereof; preferably methanol

In step d) the solvent used for purification is selected from keto solvents such as acetone, methyl ethyl ketone and the like; and polar solvents like water or mixture there of, preferably acetone/water mixture. The second aspect of the present invention provides a novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]- lH-benzimidazole compound of formula-2 with D (+) camphorsulfonyl chloride in presence of an alkali metal base in a suitable solvent, to provide N-camphor sulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH- benzimidazole compound of formula-3, which is optionally purified using a suitable solvent, b) oxidizing the N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole compound of formula-3 with a suitable oxidizing agent in a suitable solvent in the presence of a base to provide N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl]- 1 H-benzimidazole compound of formula-4, c) treating the N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulfinyl]-l H-benzimidazole compound of formula-4 with aqueous alkali metal base to provide 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfϊnyl]-lH-benzimidazole compound of formula-l, d) optionally purifying the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-lH-benzimidazole compound of formula-l in a suitable solvent provides pure 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl]- 1 H-benzimidazole compound of formula-l. Wherein in step a) the suitable alkali metal base and the solvent used are similar to the one described in step a) of first aspect of the invention.

In step b) the oxidizing reagent is selected from hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; preferably m-chloro perbenzoic acid ; the base is selected from organic bases such as tertiary butylamine, triethyl amine, N,N-diisopropyl-ethylamine, n-methyl glucamine, thiophene alkyl amine and the like; preferably N,N-diisopropyl ethylamine and the solvent is selected from hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane and the like; preferably toluene. After extensive experimentation it was discovered that by using a base in the reaction improved the yield and purity of the product substantially. When the reaction was performed according to WO 2005/116011 wherein the N-protected sulphanyl intermediate of omeprazole and other prazoles, were oxidized with meta chloro perbenzoic acid in the absence of a base provided the products which were enantiomeric mixture with nearly equivalent quantities of the enantiomers. Whereas when the reaction was performed with meta chloro perbenzoic acid in presence of diisopropylethyl amine as a base to prepare N-protected sulfinyl intermediate of dexlansoprazole, it gave the product with >85% enantiomeric excess. The alkali metal base and solvent used in step c) and d) used are similar to the bases and solvent described in step c) and d) of first aspect of the invention. In a similar manner if L-(-)-camphorsulfonyl chloride is used in place of D(+)-camphorsulfonyl chloride in the above processes provides S-Lansoprazole.

The third aspect of the present invention provides a crystalline camphorsulfonyl protected sulfide intermediate, i.e. N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-3, which is characterized by its strong powder X-ray diffractogram peaks at about 7.05, 8.29, 8.95, 9.66, 10.45, 13.33, 14.04, 14.95, 16.66, 18.81, 23.89, 24.76, 26.86, 31.35 ± 0.2 degrees two theta (represented in Figure-1). The novel crystalline form of compound of formula-3 of the present invention is used to prepare highly pure dexlansoprazole or its intermediates and pharmaceutically acceptable salt thereof. The fourth aspect of the present invention provides a crystalline camphor sulphonyl protected sulfoxide intermediate, i.e. N-camphorsulfonyl-2-[(R)-[[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4, which is characterized by its strong powder X-ray diffractogram peaks at about 5.83, 6.27, 8.01, 8.26, 9.00,10.20, 12.63, 13.86, 16.54, 17.33, 18.28, 18.75, 19.84, 21.38, 23.58, 28.02 ± 0.2 degrees two theta (represented in Figure-2). The novel crystalline form of compound of formula-4 of the present invention is used to prepare highly pure dexlansoprazole or its pharmaceutically acceptable salts thereof

The fifth aspect of the present invention provides an improved process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of asymmetrically oxidizing the 2-[[[3-methyl-4-

(2,2,2 -trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-2

Formula-2 with an optimum amount of oxidizing agent in presence of a chiral transition metal complex, an organic solvent and a base, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar equivalents relative to the 2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]-lH-benzimidazole compound of formula-2, optionally converting the obtained compound of formula- 1 into its pharmaceutically acceptable salts. According to the present invention, the oxidation is carried out in the presence of a suitable oxidizing agent selected from cumene hydroperoxide, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; preferably the oxidizing agent used in the process is cumene hydroperoxide. As per the prior art, the asymmetric oxidation of sulfide derivative is carried out using either one equivalent (US 5948789) or more equivalents of oxidizing agent (US 6982275) with respect to sulfide, in presence of a base, organic solvent, chiral metal ligand to provide the corresponding sulfoxide compound. If less amount of oxidizing agent is used, the reaction is incomplete and the sulphide compound used as starting material remains unreacted and contaminates with the sulfoxide product. If excess amount of oxidizing agent used leads to the increase in cost of over all production as well as the sulfone impurity formation due to over oxidation. Whereas the present invention utilizes the optimum amount of oxidizing agent for the said reaction avoids the prior art problems. According to the present invention, the asymmetric oxidation is carried out in the presence of a chiral transition metal complex, which is prepared from a transition metal catalyst and a chiral ligand. The transition metal is selected from the group comprising titanium, vanadium, molybdenum and tungsten, preferably titanium and vanadium compound. Preferred transition metal compound is titanium (IV) isopropoxide, titanium (IV)propoxide, titanium(IV)ethoxide, titanium(IV)methoxide, vanadium oxy tripropoxide or vanadium oxy triisopropoxide and the like. The chiral ligand used is selected from chiral diols which are esters of tartaric acid particularly (+)-diethyl L-tartarate or (-)- diethyl D-tartarate, (+)-dimethyl L- tartarate or (-)- dimethyl D-tartarate and the like. Further, the asymmetric oxidation of the present invention is carried out in presence of catalytic amount of water. The oxidation reaction of the present invention is carried out at a temperature in the range of 20 to 30°C, preferably between 21-28°C more preferably between 21-25°C, for a period of about 1-6 hours, preferably between 1-3 hours.

According to the present invention, the base used in the oxidation reaction is selected from a group comprising of but not limited to tertiary butylamine, triethyl amine, N,N-diisopropyl-ethylamine, n-methyl glucamine, thiophene alkyl amine and the like preferably N,N-diisopropylethylamine.

The asymmetric oxidation in the present invention is carried out in a suitable solvent and the solvent is selected from hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane and the like; preferably toluene.

The dexlansoprazole obtained after the asymmetric oxidation may be further converted into its pharmaceutically acceptable salts by the conventional methods. The starting material 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH- benzimidazole compound of formula-2 can be prepared as per the process known in the art.

The sixth aspect of the present invention provides one pot process for the preparation of compound of formula- 1, which comprises of reacting the 2- mercaptobenzimidazole with 2-(chloromethyl)-3-methyl(4-(2,2,2,-trifluoroethoxy) pyridine hydrochloride in presence of a suitable alkali metal hydroxides base like sodium hydroxide or potassium hydroxide, preferably sodium hydroxide in a suitable polar solvent such as water followed by extracting the obtained compound of formula-2 in a suitable solvent selected from chloro solvents like methylenechloride, ethylene dichloride, carbon tetra chloride, chloroform or hydrocarbon solvent like toluene, heptane, cyclohexane and hexane, preferably methylene chloride and then treating it with an optimum amount of oxidizing agent in presence of a chiral transition metal complex and a base and catalytic amount of water, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar equivalents relative to the 2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]-lH-benzimidazole compound of formula-2. Further the reaction conditions, base used for the oxidation of compound of formula-2 are similar to one described in the fifth aspect of the invention. The further aspect of the present invention provides a process for the preparation of amorphous dexlansoprazole compound of formula- 1, which comprises of the following steps, a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture and filtering the solid, g) adding suitable chloro solvents like methylene chloride or chloroform to the obtained solid, h) separating water from the organic layer, i) distilling off the solvent from the organic layer under reduced pressure, j) adding a suitable ketone solvent selected from acetone or methyl isobutyl ketone to obtained amorphous solid and co-distilling off the acetone from the reaction mixture under reduced pressure to get the amorphous dexlansoprazole.

In a preferred embodiment of the present invention, the process for the preparation of amorphous dexlansoprazole compound of formula- 1 comprises of the following steps; a) dissolving dexlansoprazole in acetone at room temperature, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture for 30 minutes at 25-30⁰C and filtering the solid, g) adding methylene chloride to the obtained solid, h) separating water from the organic layer, i) distilling off methylene chloride from the organic layer under reduced pressure, j) adding acetone to the obtained solid and co-distilled off the solvent from the reaction mixture under reduced pressure to get the amorphous dexlansoprazole. Further aspect of the present invention provides a process for the preparation of anhydrous crystalline form of dexlansoprazole compound of formula- 1, which comprises of the following steps, a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof, b) adding the obtained solution to a suitable hydrocarbon solvent selected from toluene, heptane, cyclohexane, hexane or mixtures thereof at a suitable temperature ranges from 0°C to reflux temperature of the solvent, c) stirring the reaction mixture at a suitable temperature, d) filtering the solid, washing with suitable hydrocarbon solvent as defined above, e) drying the solid to get the anhydrous form of dexlansoprazole.

The addition of hydrocarbon solvent in step b) of the present aspect of the invention can be done in either ways i.e., adding a suitable hydrocarbon solvent to a solution of dexlansoprazole or adding a solution of dexlansoprazole in suitable solvent to the hydrocarbon solvent at a suitable temperature.

In a preferred embodiment of the present invention, the anhydrous crystalline form of dexlansoprazole compound of formula- 1 comprises of the following steps; a) Dissolving the amorphous dexlansoprazole in acetone, b) adding the obtained solution to heptane at 35-45°C, c) stirring the reaction mixture for an hour at 35-45°C, d) filtering the solid, washing with heptane, e) drying the solid to get the anhydrous crystalline form of dexlansoprazole.

Another aspect of the present invention provides a process for the preparation of crystalline sesquihydrate of dexlansoprazole compound of formula- 1, which comprises of the following steps, a) dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture and filtering the solid, g) drying the solid to get the sesquihydrate of dexlansoprazole. In a preferred embodiment of the present invention, the process for the preparation of crystalline sesquihydrate of dexlansoprazole compound of formula- 1 comprises of the following steps; a) dissolving the dexlansoprazole in acetone at room temperature, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture for 30 minutes and filtering the solid, g) drying the solid at less than 40°C to get the crystalline sesquihydrate of dexlansoprazole.

The present invention also provides crystalline IPA solvated dexlansoprazole, which is characterized by its strong powder X-ray diffractogram peaks at about 5.87, 9.19, 9.98, 11.00, 13.39, 14.95, 15.69, 17.66, 19.70, 20.96, 24.90, 25.45 ± 0.2 degrees two theta and the same has been represented in Figure-3. The novel IPA solvated form of dexlansoprazole of the present invention can used to prepare highly pure dexlansoprazole in amorphous and other available crystalline forms.

The dexlansoprazole which is used for the preparation of crystalline and amorphous form of the present invention may be in crude dexlansoprazole obtained directly from the reaction mixture or crystalline material or amorphous material or a mixture of crystalline and amorphous material prepared by the conventional methods.

The present invention further provides a process for the preparation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-2, which comprises of reacting the 2-mercaptobenzimidazole with 2-(chloromethyl)-3-methyl(4-(2,2,2,-trifluoroethoxy)pyridine hydrochloride in presence of a suitable alkali metal hydroxides base such as sodium hydroxide in a suitable polar solvent such as water to provide the compound of formula-2, which is optionally purified from suitable hydrocarbon solvents such as toluene to provide the highly pure compound of formula-2.

The anhydrous crystalline dexlansoprazole particles prepared by the present invention having the mean particle size D[4,3] in the range from 2 to 35 microns and having D(0.9) in the range of 2 to 80 microns.

The crystalline sesquihydrate dexlansoprazole particles prepared by the present invention having the mean particle size D[4,3] in the range from 1 to 50 microns and having D(0.9) in the range of 2 to 120 microns.

Dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts thereof can be milled or micronized by the conventional methods to obtain the required particle size.

The anhydrous and sesquihydrate crystalline dexlansoprazole as prepared by the present invention is characterized by its powder X-ray diffractogram values, which are similar to the PXRD values of anhydrous and sesquihydrate crystalline dexlansoprazole disclosed in US 6462058 respectively.

As used herein the present invention the term "highly pure" refers to the compound with purity greater than 99.50% by HPLC, preferably > 99.70 % by HPLC and more preferably > 99.95% by HPLC. Dexlansoprazole prepared as per any aspect of the present invention can be micronized or milled to get the desired particle size. The particle size distribution (P.S.D) of dexlansoprazole can be measured using Malvern Mastersizer 2000 instrument.

The related substance of dexlansoprazole were analyzed by HPLC using the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and Column: YMC-PAK ODS-A Flow rate: 1.0 ml/min; wavelength: 285 nm;

Temperature: Ambient; Load: 10 μl; Run time: 50 min; Elution: Gradient; and using water and acetonitrile as a mobile phase. The isomer content of dexlansoprazole were analyzed by chiral HPLC using the following conditions: A liquid chromatograph equipped with variable wavelength UV detector and intergrator Column: Chiralpak-IC, Flow rate: 1.0 ml/min; wavelength: 285 nm; Temperature: Ambient; Load: 10 μl; Run time: 50 min; Elution: Gradient; and using a mixture of acetonitrile:TFA:DEA as a mobile phase and diluent.

XRD analysis of Dexlansoprazole intermediates was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A⁰ and continuous scan speed of 0.0457min.

The present invention is schematically represented by the following scheme:

Pure Oexlaπsoprazolβ

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:

Reference Example:

19.8 g of residue containing mixture of l-(R)-camphorsulfonyl-5-methoxy-2- [(3,5-dimethyl4-methoxy-2-pyridyl)methylthio]-lH-benzimidazole and l-(R)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-lH- benzimidazole was mixed with methylene chloride (200 ml) at 30°C-35°C, cooled to -5°C. and then the solution of m-chloro perbenzoic acid (8.0 g) in methylene chloride (80 ml) was added drop wise for 30 minutes at -5°C. The contents were stirred for 3 hours at -5°C, then the reaction mass was filtered and washed with 5 % sodiumbicarbonate (80 ml). The organic layer was dried and distilled to give the residue containing the diastereomeric mixture of l-(R)-camphorsulfonyl-(5-and6-)-methoxy-2-[(3,5-dimethyl-4- methoxy-2-pyridyl)methyl-(R)-sulfinyl]-lH-benzimidazole (18 g) (the ratio of diastereomeric mixture of 1-(R)- camphorsulfonyl-(5-and 6)-methoxy-2-[(3,5-dimethyl- 4-methoxy-2-pyridyl)methy l-(S)-sulfinyl]- 1 H-benzimidazole and 1 -(R)-camphor sulfonyl-(5and6)-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R)-sulfϊnyl]- 1 H-benzimidazole was 4.4: 1 ).

Example-1: Preparation of N-camphorsulfonyl 2-[[[3-methyl-4-(2,2,2-trifIuoro ethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole of formuIa-3:

To the solution of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]-l H-benzimidazole (100 g) present in methylenechloride (1500 ml) added potassium carbonate (58.5g) and heated the reaction mixture to reflux temperature.

Added a solution of D-(+)-camphorsulfonyl chloride (106 g) in methylenechloride

(500 ml) to the reaction mixture slowly at the same temperature. Stirred the reaction mixture for 6 hrs. Cooled the reaction mixture and added water to it. Separated the both aqueous and organic layers. Distilled off the solvent completely under reduced pressure from the organic layer. To the residue added n-heptane (400 ml) and stirred for 45 min. Filtered the precipitated solid and washed with n-heptane. The title compound obtained as a crystalline solid.

Yield: 225 grams; MR: 125-135°C ExampIe-2: Purification of N-camphor sulfonyl 2-[[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazoIe of formula-3:

To the compound obtained in example- 1, added methanol (900 ml) and stirred for 45 minutes. Filtered the solid and washed with methanol. To the wet compound added methanol (700 ml) and stirred for 45 minutes. Filtered the compound and washed with methanol then dried to get the pure title compound. Yield: 95 grams

Example-3: Preparation of N-camphorsulfonyI-2-[(R)-[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridinyl] methyI]suIfinyl]-LH-benzimidazole of formula-4: To 5 g of N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole obtained in example-2, added 25 ml of toluene, D-(+)-diethyl tartrate (1.39g) and heated the reaction mixture to 65°C. Stirred the reaction mixture for 15 minutes at same temperature. Added 0.90 g of titanium isopropoxide to the reaction mixture and stirred for 1 hr. at 65°C. Cooled the reaction mixture to 25°C and diisopropyl ethyl amine (0.74 g) was added to it. Cooled the reaction mixture to 0 to -5°C, added a solution of m-chloro perbenzoic acid (9.1 g) in toluene (100 ml) to it slowly. Stirred the reaction mixture for 3 hrs. Quenched the reaction mixture using 10% aqueous sodium bicarbonate solution. Raised the temperature to 35°C. Separated the both aqueous and organic layers. To the organic layer added 80 ml of n-heptane and stirred for 30 minutes at 28°C. Filtered the solid precipitated and washed with n-heptane. The title compound obtained as a crystalline solid. Yield: 3 grams; MR: 100-105°C; (ee of R-isomer = 90%)

ExampIe-4: Preparation of N-camphorsuIfonyl-2-[(R)-[[3-inethyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl] methyI]sulfinyl]-LH-benzimidazoIe of formula-4:

To 10 g of the compound obtained in example-2 added 50 ml of toluene, added diisopropyl ethyl amine (1.48 g) and stirred the reaction mixture for 5 minutes at same temperature. Cooled the reaction mixture to 0 to 5°C, added a solution of m-chloro per benzoic acid (9.1 g) in toluene (150 ml) to it slowly. Stirred the reaction mixture for 1 hr. Quenched the reaction mixture using 10% aqueous sodium bicarbonate solution. Raised the temperature to 28°C. Separated the both aqueous and organic layers. To the organic layer added 500 ml of n-heptane and stirred for 1.5 hrs at 28°C. Filtered the precipitated solid and washed with n-heptane. The title compound obtained as a crystalline solid. Yield: 7.5 grams; MR: 100-105⁰C; (ee of R-isomer = 80%)

Example-5: Purification of N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-triflιioro ethoxy)-2-pyridinyl] methyI]sulfϊnyl]-lH-benzimidazoIe of formula-4: 5.0 g of N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole obtained as per example-3 or example-4 was dissolved in 15 ml of acetone. Added 30 ml of water to the reaction mixture and stirred for 20 minutes. Filtered the precipitated solid and washed with water. Yield: 4.0 grams; M.R: 120-130⁰C.

Example-6: Preparation of dexlansoprazole

2.5 g of compound obtained as per example-5 was taken in 12.5 ml of methanol and stirred for 10 minutes. Added aqueous sodium hydroxide solution to the reaction mixture and stirred for 45 minutes at 30⁰C. Adjusted the pΗ to neutral conditions by using 10% acetic acid. Filtered the precipitated solid and washed with water and dried to get the title compound. Yield: 1.3 grams

ExampIe-7: Purification of dexlansoprazole To 1 g of dexlansoprazole compound obtained in example-5 added 20 ml of acetone, stirred for 10 minutes at 25°C. Filtered the reaction mixture and the filtrate is saturated with water (100 ml). Filtered the compound obtained and washed with water then dried to get the title compound.

Yield: 0.5 grams Particle size Distribution: D(0.1): 0.997 μm; D(0.5): 4.731 μm; D(0.9): 18.865 μm;

D[4,3]: 8 μm

Purity by ΗPLC: 99.72 %; Sulfone Impurity: 0.21%; Single maximum unknown impurity: 0.07% Example-8: Preparation of crystalline IPA solvated dexlansoprazole.

To 50 g of wet dexlansoprazole taken in 200 ml of isopropyl, alcohol and stirred for 15 minutes for obtaining clear solution. Distilled off the solvent under reduced pressure at below 40°C up to 80%. Cooled the reaction mixture to 25°C. Filtered the compound and washed with cyclohexane. Dried the compound at 25-30⁰C and the title compound obtained as crystals. Yield: 15 grams: MR: 70-80°C.

Example-9: Preparation of lansoprazole sulphide protected with L-(-)-camphor sulfonyl chloride.

To the solution of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfanyl]-lH-benzimidazole (100 g) present in methylenechloride (1500 ml) added potassium carbonate (58.5g) and heated the reaction mixture to reflux temperature. Added a solution of L-(-)-camphorsulfonyl chloride (106 g) in methylenechloride (500 ml) to the reaction mixture slowly at the same temperature. Stirred the reaction mixture for 6 hrs. Cooled the reaction mixture and added water to the reaction mixture. Separated the both aqueous and organic layers. Distilled off the solvent completely under reduced pressure from the organic layer. To the reaction mixture n-heptane (400 ml) was added and stirred for 45 min. Filtered the solid precipitated and washed with n-heptane. The title compound obtained as a crystalline solid. Yield: 220 grams

Example-10: Purification of lansoprazole sulphide protected with L-(-)-camphor sulfonyl chloride. Take the obtained compound in example-9, added methanol (880 ml) and stirred for 45 minutes. Filtered the solid and washed with methanol. Dried the compound to get the title compound. Yield: 95 grams

Example-11: Preparation of N-camphorsulfonyl protected (S)-Lansoprazole.

To 25 g of the compound obtained in example-10 added 125 ml of toluene, D(-)diethyltartrate (6.9g) and heated the reaction mixture to 65°C. Stirred the reaction mixture for 15 minutes at same temperature. Added 4.5 g of titanium iso propoxide to the reaction mixture and stirred for 1 hr. at 65°C. Cooled the reaction mixture to 25°C and diisopropyl ethyl amine (3.6 g) was added to it. Cooled the reaction mixture to 0 to -5°C, added a solution of m-chloro per benzoic acid (29 g) in toluene (375 ml) to it slowly. Stirred the reaction mixture for 3 hrs. Quenched the reaction mixture using 10% aqueous sodium bicarbonate solution. Raised the temperature to 35°C. Separated the both aqueous and organic layers. To the organic layer added 375 ml of n-heptane and stirred for 2 hrs at 35°C. Filtered the solid precipitated and washed with n-heptane. The title compound obtained as a crystalline solid. Yield: 11 grams

Example-12: Preparation of S-Iansoprazole

14 g of compound obtained as per example- 11 added 75 ml of methanol and stirred for 10 minutes. Added aqueous sodium hydroxide solution to the reaction mixture and stirred for 45 minutes at 30°C. Adjusted the pH to neutral by using 10% acetic acid. Filtered the precipitated solid and washed with water. Yield: 6.0 grams

Example-13: Purification of S-lansoprazole

To 10 g of S-Lansoprazole compound obtained in example-12 added 50 ml of acetone, stirred for 10 minutes at 25°C. Filtered the reaction mixture and the filtrate was saturated with water (150 ml). Filtered the precipitated solid and washed with water. Dried the compound to get the title compound. Yield: 5.0grams Example-14: Preparation of Dexlansoprazole:

Mixture of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methy l]thio]- 1 H- benzimidazole (50 grams) and toluene (400 ml) was heated to reflux temperature and water was removed by azeotropic distillation. The reaction mixture was cooled to room temperature under nitrogen atmosphere. Water (0.4 ml) and L(+)-diethyltatarate (22.4 grams) were added to the reaction mixture under nitrogen atmosphere. The reaction mixture was heated to 55-60°C and stirred for 15 minutes. Titanium isopropoxide (14.4 grams) was added to the reaction mixture, stirred for 60 minutes at 55-60°C and then cooled to 21-25°C. Diisopropyl ethyl amine (11.8 grams) and cumene hydroperoxide (29.61 grams) were added to the reaction mixture and stirred for 2 hours at 20-25⁰C. The reaction mixture was quenched with sodium thiosulphate solution and the layers were separated. The organic layer washed with sodium thiosulphate solution and water (100 ml) was added to it. Methyl tertiary butyl ether (200 ml) followed by cyclohexane (1 L) was added to the organic layer and stirred for 2 hours at 25-35°C. The solid obtained was filtered and washed with methyl tertiary butyl ether. Acetone (250 ml) was added to the wet solid and stirred for 15 minutes at 25-35°C. Water (750 m) was added to reaction mixture at 25-30°C and stirred for 30 minutes. The solid obtained was filtered washed with water. Yield: 75 grams

Chiral Purity by HPLC: 99.00 %; other isomer: 0.34%; sulfone: 0.49%; sulfide: 0.07%

Example-15: Preparation of Dexlansoprazole:

The title compound was prepared in a similar manner to example- 14 except that 31 grams of cumene hydroperoxide was used instead of 29.61 grams and the reaction mixture was stirred for 5 hours. Yield: 73 grams

Example-16: Preparation of amorphous dexlansoprazole: 1% aqueous ammonia (100 ml) was added to a solution of dexlanosprazole

(75 grams) obtained as per example- 14 in acetone (200 ml) and the reaction mixture was subjected to carbon treatment. The reaction mixture was filtered through hyflow and the bed was washed with acetone. Aqueous ammonia (500 ml) solution was added to the filtrate and stirred for 45 minutes at room temperature. The solid obtained was filtered, washed with aqueous ammonia. Methylene chloride (400 ml) was added to the obtained wet solid and stirred. The organic layer was separated and dried over sodium sulphate. The dried organic layer was distilled off under reduced pressure at below 40⁰C. Acetone (100 ml) was added to the obtained amorphous solid and co-distilled off the reaction mixture completely under reduced pressure to get the amorphous dexlansoprazole. Yield: 20 grams;

Purity by HPLC: 99.75%

Chiral Purity: 99.82%; other isomer: 0.04%; sulfone: 0.05%; sulfide: 0.01% Example-17: Preparation of anhydrous dexlansoprazole

Amoφhous dexlansoprazole (25 grams) was dissolved in acetone (50 ml) and filtered for particle free. The filtrate was added to the n-heptane (500 ml) at 38-42°C. The reaction mixture was stirred for an hour at 38-42°C. The solid was filtered and washed with n-heptane. The solid was dried at 38-42°C under reduced pressure until the water content to reach below 0.5% w/w to get the title compound Yield: 20.2 grams

Chiral Purity by HPLC: 99.90 %; other isomer: 0.01%; sulfone: 0.03%; sulfide: 0.06% Purity by HPLC: 99.80%; sulfone: 0.03%; sulfide: 0.06% Particle Size Distribution:

Before micronization: D(0.1): 2.26 μm; D(0.5): 9.59 μm; D(0.9):56.12 μm; D[4,3]: 20.46 μm;

After micronization: D(0.1): 1.26 μm; D(0.5):4.54 μm; D(0.9):9.93; D[4,3]: 5.18 μm;

Example-18: Preparation of crystalline sesquihydrate of dexlansoprazole:

1% aqueous ammonia (100 ml) was added to a solution of dexlanosprazole (75 grams) obtained as per example- 14 in acetone (200 ml) and the reaction mixture was subjected to carbon treatment. The reaction mixture was filtered through hyflow and the bed was washed with acetone. Aqueous ammonia (500 ml) solution was added to the filtrate and stirred for 45 minutes at room temperature. The solid obtained was filtered and washed with aqueous ammonia. The solid was dried at below 40°C under reduced pressure until the water content to reach below 6-8% w/w to get the title compound. Yield: 24 grams Chiral Purity by HPLC: 99.81 %; other isomer: 0.03%; sulfone: 0.04%; sulfide: 0.05% Purity by HPLC: 99.77%; sulfone: 0.04%; sulfide: 0.05% Particle Size Distribution:

Before micronization: D(0.1): 1.44 μm; D(0.5): 8.90 μm; D(0.9):88.35 μm; D[4,3]: 27.57 μm; After micronization: D(0.1): 0.67 μm; D(0.5):2.06 μm; D(0.9):5.25; D[4,3]: 2.57 μm; Example-19: Preparation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI] methyl] sulphanyl]-l//-benzimidazole of formula-2:

2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridinehydrochloride(96.49 grams) was dissolved in water (600 ml) and subjected to carbon treatment. The solution was filtered through high flow. The filtrate was added to a mixture of 2-mercarptobenzimidazole (50 grams), sodium hydroxide (32 grams) and water (600 ml) at 25-35°C. The reaction mixture stirred for 2 hours and the obtained solid was filtered, washed with water. The obtained wet solid was purified from toluene to get the title compound. Yield: 106 grams

Example-20: One pot process for dexlansoprazole:

2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridinehydrochloride (49 grams) was dissolved in water (300 ml) and subjected to carbon treatment. The solution was filtered through high flow. The filtrate was added to a mixture of 2-mercarptobenzimidazole (25 grams), sodium hydroxide (16 grams) and water (300 ml) at 25-35°C. The reaction mixture stirred and 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]thio]-lH-benzimidazole compound was extracted into methylene chloride. Water (0.4 ml) and L(+)-diethyltatarate (22.4 grams) were added to the methylene chloride layer under nitrogen atmosphere. The reaction mixture was heated to 55-60°C and stirred for 15 minutes. Titanium isopropoxide (14.4 grams) was added to the reaction mixture, stirred for 60 minutes at 55-60°C and then cooled to 21-25°C. Diisopropyl ethyl amine (11.8 grams) and cumene hydroperoxide (29.61 grams) were added to the reaction mixture and stirred for 2 hours at 20-25⁰C. The reaction mixture was quenched with sodium thiosulphate solution and the layers were separated. The organic layer washed with sodium thiosulphate solution and water (100 ml) was added to it. Methyl tertiary butyl ether (200 ml) followed by cyclohexane (1 L) was added to the organic layer and stirred for 2 hours at 25-35°C. The solid obtained was filtered and washed with methyl tertiary butyl ether. Acetone (250 ml) was added to the wet solid and stirred for 15 minutes at 25-35°C. Water (750 m) was added to reaction mixture at 25- 30⁰C and stirred for 30 minutes. The solid was filtered washed with water. Yield: 70 grams

Claims

We Claim:

1) The novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts,

Formula- 1 which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]-lH-benzimidazole compound of formula-2

Formula-2 with D-(+)-camphorsulphonyl chloride in presence of potassium carbonate in methylenechloride, to provide N-camphorsulfonyl 2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]-lH-benzimidazole compound of formula-3 which is optionally purified using methanol.

Formula-3 b) oxidizing the N-camphorsufonyl 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-3 with meta chloro perbenzoic acid in presence of diethyl tartrate and titanium isopropoxide in toluene in presence of diisopropylethylamine to provide

N-camphorsulfonyl2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-lH-benzimidazole compound of formula-4,

Formula-4 c) treating the N- camphor sulphonyl 2-[(R)-[[3-methyl-4-(2,2,2-trifiuoroethoxy)-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4 with aqueous sodium hydroxide in methanol to provide 2-[(R)-[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-lH-benzimidazole compound of formula- 1, d) optionally purifying the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfϊnyl]-lH-benzimidazole compound of formula- 1 in water and acetone mixture provides pure 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfϊnyl]-lH-benzimidazole compound of formula- 1.

2) The novel process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of the following steps; a) Reacting the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]-lH-benzimidazole compound of formula-2 with D-(+)- camphorsulphonyl chloride in presence of potassium carbonate in methylenechloride, to provide N-camphor sulfonyl 2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]-lH-benzimidazole compound of formula-3 which is optionally purified using methanol, b) oxidizing the N-camphorsufonyl 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl] methyl]sulphanyl]-lH-benzimidazole compound of formula-3 with meta chloro perbenzoic acid in toluene in the presence of diisopropylethyl amine to provide N-camphorsulfonyl 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4, c) treating the N- camphor sulphonyl 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4 with aqueous sodium hydroxide in methanol to provide 2-[(R)-[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-lH-benzimidazole compound of formula- 1, d) optionally purifying the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfϊnyl]-lH-benzimidazole-Compound of formula- 1 in water and acetone mixture provides pure 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinyl]-lH-benzimidazole compound of formula-1.

3) The process for the oxidation of N-camphorsulfonyl 2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]- lH-benzimidazole compound of formula-3, using meta chloro perbenzoic acid in the presence of a organic base in toluene solvent to provide N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole compound of formula-4.

4) The process according to claim-3, wherein the organic base used is selected from tertiary butylamine, triethyl amine, N,N-diisopropyl ethylamine, n-methyl glucamine and thiophene alkyl amine.

5) N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl] -lH-benzimidazole compound of formula-3 as a solid.

6) N-camphorsulphonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinyl]-lH-benzimidazole compound of formula-4 as a solid.

7) Use of the compound of formula-3 and formula-4 as claimed in claim 5 & 6 in the preparation of dexlansoprazole, its intermediate and pharmaceutically acceptable salts thereof.

8) Crystalline N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole compound of formula-3.

9) Crystalline compound of formula-3 according to claim-8 is characterized by its strong powder X-ray diffractogram peaks at about 7.05, 8.29, 8.95, 9.66, 10.45, 13.33, 14.04, 14.95, 16.66, 18.81, 23.89, 24.76, 26.86, 31.35 ± 0.2 degrees two theta as illustrated in figure- 1.

10)Crystalline N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl] methyl]sulfinyl]-lH-benzimidazole compound of formula-4.

11) Crystalline compound of formula-4 according to claim 10, is characterized by its strong powder X-ray diffractogram peaks at about 5.83, 6.27, 8.01, 8.26, 9.00, 10.20,

12.63, 13.86, 16.54, 17.33, 18.28, 18.75, 19.84, 21.38, 23.58, 28.02 ± 0.2 degrees two theta as illustrated in figure-2.

12) Use of crystalline form of compound of formula-3 & 4 as claimed in claim 8 to 11 in the preparation of dexlansoprazole, its intermediate and pharmaceutically acceptable salts thereof.

13) Dexlansoprazole IPA solvate. 14) IPA solvated form according to claim 13 is characterized by its strong powder X-ray diffractogram peaks at about, 5.87, 9.19, 9.98, 11.00,

13.39,

14.95,

15.69, 17.66, 19.70, 20.96, 24.90, 25.45 ± 0.2 degrees two theta as illustrated in fϊgure-3.

15) Use of IPA solvated form of dexlansoprazole as claimed in claim 13 & 14 in the preparation of other crystalline and amorphous formse of dexlansoprazole.

16) Dexlansoprazole having the particle size of Dio in the range of 0.1 - 8 μm; D₅₀ in the range of 2 - 20 μm; D₉₀ in the range of 10 -100 μm. 17) An improved cost effective and commercially feasible process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of asymmetrically oxidizing the 2-[[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-2

Formula-2 with an optimum amount of oxidizing agent in presence of a chiral transition metal complex, an organic solvent, a base and catalytic amount of water, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar equivalents relative to 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH- benzimidazole compound of formula-2 and the oxidation is carried out at a temperature of 22 to 28°C. 18) The process as claimed in claim 17, where in the oxidizing agent used is cumene hydroperoxide in an amount of 1.1 to 1.4 molar equivalents with respect to 2-[[[3- methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-2. 19) The process as claimed in claim 17, wherein the organic solvent used is toluene or methylene chloride and the base used is diisopropyl ethyl amine.

20) The process according to claim 17, where in the chiral transition metal complex comprises of titanium isopropoxide and L(+)-diethyl tartarate.

2I)An improved cost effective process for the preparation of dexlansoprazole compound of formula- 1 and its pharmaceutically acceptable salts, which comprises of asymmetrically oxidizing the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulphanyl]-lH-benzimidazole compound of formula-2 with cumene hydroperoxide in presence of a titanium isopropoxide, L(+)-diethyl tartarate, diisopropyl ethyl amine and a catalytic amount of water in toluene medium to provide the dexlansoprazole compound of formula- 1, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar equivalents relative to compound of formula-2 and the oxidation is carried out at a temperature of 22 to 28°C.

22) A process for the preparation of amorphous dexlansoprazole compound of formula- 1, which comprises of the following steps, a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture and filtering the solid, g) adding suitable chloro solvents like methylene chloride or chloroform to the obtained solid, h) separating the water from organic layer, i) distilling off the solvent from the organic layer under reduced pressure, j) adding a suitable ketone solvent selected from acetone or methyl isobutyl ketone to the obtained amorphous solid and co-distilling the solvent from the reaction mixture under reduced pressure to get the amorphous dexlansoprazole. 23) A process for the preparation of amorphous dexlansoprazole compound of formula- 1, which comprises of the following steps, a) Dissolving dexlansoprazole in acetone at room temperature, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture for 30 minutes and filtering the solid, g) adding methylene chloride to the obtained solid, h) separating water from the organic layer, i) distilling off the methylene chloride from the organic layer under reduced pressure, j) adding acetone to the obtained amorphous solid and co-distilling the acetone from the reaction mixture under reduced pressure to get the amorphous dexlansoprazole.

24) A process for the preparation of anhydrous crystalline form of dexlansoprazole compound of formula- 1, which comprises of the following steps, a) Dissolving dexlansoprazole in a suitable ketone solvent like acetone, methyl isobutyl ketone or mixtures thereof, b) adding above obtained solution to a suitable hydrocarbon solvent selected from toluene, heptane, cyclohexane, hexane or mixtures thereof at a temperature from 0⁰C to reflux temperature of the solvent, c) stirring the reaction mixture at a suitable temperature d) filtering the solid, washing with suitable hydrocarbon solvent as defined above, e) drying the solid to get the anhydrous form of dexlansoprazole. 2I)A process for the preparation of anhydrous crystalline form of dexlansoprazole compound of formula- 1, which comprises of the following steps, a) Dissolving amorphous dexlansoprazole in acetone, b) Adding the above obtained solution to heptane at 35-45°C, c) stirring the reaction mixture for an hour at 35-45°C, d) filtering the solid and washing with heptane, e) drying the solid to get the anhydrous crystalline form of dexlansoprazole.

22) A process for the preparation of crystalline sesquihydrate of dexlansoprazole compound of formula- 1, which comprises of the following steps, a) Dissolving the dexlansoprazole in acetone at room temperature, b) treating the reaction mixture with aqueous ammonia, c) subjecting the reaction mixture to carbon treatment, d) filtering the reaction mixture through hyflow, e) treating the filtrate with aqueous ammonia, f) stirring the reaction mixture for 30 minutes and filtering the solid, g) drying the solid at below 40⁰C to get the crystalline sesquihydrate of dexlansoprazole having water content of 6-8 %w/w.

23) A process comprises of oxidizing the crystalline N-camphorsufonyl 2-[[[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole compound of formula-3 with suitable oxidizing agent in a suitable solvent and in the presence of a base to provide crystalline N-camphorsulfonyl 2-[(R)-[[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]- 1 H-benzimidazole compound of formula-4.

24) A process for the preparation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-l H-benzimidazole compound of formula-2, which comprises of reacting the 2-mercaptobenzimidazole with 2-(chloromethyl)-3-methyl(4-(2,2,2,- trifiuoroethoxy)pyridine hydrochloride in presence of a suitable alkali metal hydroxides base such as sodium hydroxide in a suitable polar solvent such as water to provide the compound of formula-2, which is optionally purified from suitable hydrocarbon solvents such as toluene to provide the highly pure compound of formula-2.

25) One pot process for the preparation of dexlansoprazole compound of formula- 1, which comprises of reacting the 2-mercaptobenzimidazole with 2-(chloromethyl)-3- methyl(4-(2,2,2,-trifluoroethoxy)pyridine hydrochloride in presence of a suitable alkali metal hydroxides base like sodium hydroxide or potassium hydroxide in a suitable polar solvent such as water followed by extracting the obtained compound of formula-2 in a suitable chloro solvent like methylenechloride or hydrocarbon solvent like toluene and then treating it with optimum amount of oxidizing agent in presence of a chiral transition metal complex, a base and in presence of catalytic amount of water, characterized in that the oxidizing agent used in an amount of 1.1 to 1.4 molar equivalents relative to the 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-lH-benzimidazole compound of formula-2.