A novel process for the preparation of Dexlansoprazole
Field of the invention:
The present invention provides a novel process for the preparation of Dexlansoprazole and its pharmaceutical!}1 acceptable salts thereof. Dexlansoprazole is chemically known as 2-[(#)-[|>methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl]-I#-benzimidazole, represented as compound of formula-1.

Background of the Invention:
Dexlansoprazole is the R-enantiomer of lansoprazole. It belongs to benzimidazole type proton pump inhibitors which work by undergoing a rearrangement to form a thiophilic species which then conveniently bind to gastric H 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.
Some of the benzimidazole compounds capable of inhibiting the gastric H 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 9427988. But these processes are lengthy, cumbersome and involve the loss of unwanted stereoisomer which is not economically viable.
US 5,948,789 discloses a process for enantioselective synthesis of the single enantiomer of omeprazole and other structurally related compounds, by asymmetric oxidation of the unprotected sulfide intermediate, using diethyl tartrate, titanium isopropoxide and cumene hydroperoxide (kagan oxidation conditions), to provide the sulfoxide product. Since the nitrogen group is not protected it may involve in the oxidation process leading to the formation of impurities
US 6,982,275 disclose a process for optically active sulfoxide derivatives employing the kagan oxidation conditions. But the process involves the use of high molar ratio of the oxidizing agent i.e. cumene hydroperoxide in concentrations between 3 to 10 molar equivalents relative to the starting material. The reaction is carried out at low temperatures between -20 to 20°C. Since the process involves the use of higher concentrations of selective oxidizing agent, employing low temperatures the process cost would increase substantially.
H.B.Kagan et.al. in their research publications namely tetrahedron Vol.43, No 21, pp 5135 to 5144, 1987 and JAm.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, which is not preferred in 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 the patent. 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 hydorperoxide was replaced with m-chlorobenzoic 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 tbe 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 derivative 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 dexlansoprazole 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.
Brief description of the Invention:
The present invention provides a novel process for the preparation of dexlansoprazole compound of formula-1 and its pharmaceutically acceptable salts thereof. Dexlansoprazole is chemically known as 2-[(fl)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfmyl]-lH-benzimidazole

The first aspect of the present invention is to provide a novel process foe 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]-l//-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]sulphanyi]-l//-benzimidazole compound of formula-3, which is purified using a suitable solvent,
b) oxidizing the N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-l//-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-trifluoroethoxy)-2-pyridinyl]memyl]sulfinyl]-l//-benzimidazole compound of formula-4,
c) treating the N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyi]suifinyi]-l/f-benzimidazole compound of formula-4 with aqueous alkali metal base provides 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methy!]sulfinyl]-l//-benzimidazole compound of formula-l,
d) recrystallizing the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-l//-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 //-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-l 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]-1//-benzimidazole compound of formula-2 with D(+) camphorsulfonyl chloride in presence of an alkali metal base in a suitable solvent provides N- camphorsulfonyl-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-l/f-benzimidazole compound of formula-3, which is purified using a suitable solvent,
b) oxidizing the N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-l//-benzimidazole compound of formula-3 with a suitable oxidizing agent in presence of a base in a suitable solvent provides N-camphorsulfonyI-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinyl]-1//-benzimidazole compound of formula-4,
c) treating the N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-l//-benzimidazole compound of formula-4 with aqueous alkali metal base provides 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethox.y)-2-pyridinyl]methyl]sulfinyl]-l//-benzimidazole compound of formula-l,

d) recrystallizing the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinyl]-l#-benzimidazole compound of formula-1 in a suitable solvent provides pure 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinyl]-ltt-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-pyridinyl] methyI]su!phanyl]-l//-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-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyI] methyl] sulfinyl]-l#-benzimidazole compound of formula-4.
The fifth aspect of the present invention is to provide a solvated 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-triftuoroethoxy)-2-pyridinyl]methyl]sulphanyl]-l//-benzimidazole
compound of formula-3.
Figure-2: Illustrates the powder X-Ray diffractogram of crystalline N-camphorsulfonyl-
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:
The present invention provides a novel process for the preparation of Dexlansoprazole compound of formula-1 and its pharmaceutically acceptable salts thereof. Dexlansoprazole is chemically known as 2-[(.#)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl]-l#-benzimidazole


Formula-3 b) oxidizing the N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyI]-l//-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]-l^-benzimidazole compound of formula-4,


d) recrystallizing the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyl]-l-tf-benzimidazole compound of formula-1 in a suitable solvent provides pure 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfmyl]-!//-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; preferably potassium carbonate and the solvent is selected from chloro solvents such as methylenechloride, ethylene dichloride, carbon tetra chloride, chloroform and the like 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; preferably methanol.

In step b) the oxidizing reagent is selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracefic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium permanganate, chromic acid, chromium trioxide, selenium dioxide, sodium hypochlorite, sodium metaperiodate 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.
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 bicarbonales such as sodium bicarbonate, potassium bicarbonate and the like; preferably sodium hydroxide and the solvent is selected from alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; preferably methanol
In step d) the solvent for recrystallization 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]-
l#-benzimidazole compound of formula-2 with D {+)
camphorsulfonyl chloride in presence of an alkali metal base in a suitable solvent, to
provide N-camphorsuIfonyl-2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-
pyridinyl]methyl]sulphanyl]-l/f-benzimidazole compound of formula-3, which is purified using a suitable solvent,

b) oxidizing the N-camphorsu]fony]-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-l//-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]-l//-benzimidazoie compound of formuia-4,
c) treating the N-campborsuJfonyl- 2-[(R)-[[3 -methyl -4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-l//-benzimidazole compound of formula-4 with aqueous alkali metal base to provide 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-l//-benzimidazole compound of formula-1,
d) recrystallizing the 2-[(R)-[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-l//-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; preferably potassium carbonate and the solvent is selected from chloro solvents such as methylenechloride, ethylene dichloride, carbon tetra chloride, chloroform and the like 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; preferably methanol.
In step b) the oxidizing reagent is selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium permanganate, chromic acid, chromium trioxide, selenium dioxide, sodium hypochlorite, sodium metaperiodate 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 lansoprazole, 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.
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; preferably sodium hydroxide and the solvent is selected from alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; preferably methanol.
In step d) the solvent for recrystallization 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.
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 third aspect of the present invention provides a crystalline camphor sulfonyl protected sulfide intermediate, i.e. N-camphorsulfonyl-2-[[[3-methy!-4-(2,2,2-trifiuoroethoxy)-2-pyridinylj methyl]suIphanyI]-l//-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 A 24.76, 26.86, 31.35 ± 0.2 degrees two theta (Figure-1).
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]-l//-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 (Fig-2).
The fifth aspect of the present invention provides a IPA solvated dexlansoprazoie, 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 (Fig-3).
In a similar manner if L-(-)-camphorsulfonyl chloride is used in the above processes it provides S-Lansoprazole.
XRD analysis of Dexlansoprazoie intermediates was carried out using S1EMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.
Analysis of particle size distribution: A Malvern laser diffraction instrument (Malvern Mastersizer 2000) was used to characterize the particle size distribution of dexlansoprazoie. The instrument (Scirocco 2000) parameters are as follows: Material RI: 1.500; absorption: 0.1. Dispersant name: air; Dispersant RI: 1; Sensitivity: Normal; Depressive air pressure: 3 bar; obscuration Range: 0.5-6.5%; vibration feed rate: 50%.
The related substance of dexlansoprazoie and its intermediate compounds were analyzed by HPLC using the following conditions:
A liquid chromatograph equipped with variable wavelength detector and integrator.Column: Chiralpak-IC, 250 X 4.6 mm; Flow rate: 1.0 ml/min; wavelength: 285

nm; Temperature: Ambient; Load: 20 ul; Run time: 25 min; Elution: Isocratic and using as Acetonitrile: TFA: DEA in 1000:0.5:1.0 (v/v) as a mobile phase/diluent.


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 1 -(R)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-lH-benzimidazole was mixed with methylene chloride (200 mi) 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 -5aC. 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-t(3,5-dimethyl-4-methoxy-2-pyridyl) methyl-(R)-sulfinyl]-lH-benzimidazole (18 g) (the ratio of diastereomeric mixture of I-(R)- camphorsuifonyi-(5- and 6-)-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(S)-sul finyl]-1 H-benzimidazole and 1 -(R)-camphorsulfonyl-(5- and 6-)-methoxy-2-[(3,5-dimethy!-4-methoxy-2-pyridyl)methyl-(R)-su!finyl]-lH-benzimidazole was 4.4:1).
Example-1: Preparation of N-camphor sulfonyl 2-([[3~methyl-4-(2,2,2-trifluoroethoxy) -2-pyridinyl] m ethyl] sulph any l]-ltf-benzirnidazole
To the solution of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl]-l//-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 g; MR: 12S-135°C
ExampIe-2: Purification of N-camphor sulfonyl 2-[[[3-methyl-4-(2,2,2-tnfluoro ethoxy)-2-pyridinyl] methyl] sulphanyl]-l//-benzimidazole.
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. Dried the compound to get the title compound. Yield: 95 g
Example-3: Preparation of N-camphorsulfony]-2-[{R)-[[3-methy]-4-(2,2,2-trifluoro ethoxy)-2-pyridinyl] methyl]sulflnyl]-l//-benzimidazole.
To 5 g of N-camphorsulfonyl-2-t[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulphanyl]-l//-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 g; MR: 100-105°C (eeofR-isomer = 90%)

Example-4: Preparation of N-camphorsulfonyl-2-[(R)-|[3-methyl-4-{2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinyl]-li/-benzimidazole.
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 2S°C. Filtered the precipitated solid and washed with n-heptane. The title compound obtained as a crystalline solid. Yield: 7.5 g; MR: 100-105°C (eeofR-isomer=80%)
Example-5: Purification of N-camphorsulfonyI-2-((R)-[[3-methyi-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinyl]-l//-benzimidazole.
5.0 g of N-camphorsuifonyl-2-[(R)-[[3-meihyl-4-(2,2,2-trifluoroethoxy) -2-pyridinyl] methyl]sulfinyl]-l//-benzimidazole obtained as per example-3 or example-4 was dissolved in 15 ml of acetone. Stirred the reaction mixture for clear solution, 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 g; M.R: 120-130°C.
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 30°C. Adjusted the pH to neutral conditions by using 10% acetic acid. Filtered the precipitated solid and washed with water. Yield: 1.3 g
Example-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.
Dried the compound to get the title compound.
Yield: 0.5 g
Particle size Distribution: D(0.1): 0.997 um; D(0.5): 4.731 urn; D(0.9): 18.865 um;
D[4,3]: 8 um
Purity by HPLC: 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 25-30°C and the title compound obtained as crystals. Yield: 15g: MR: 70-80°C.
Example-9: Preparation of lansoprazole sulphide protected with L-(-)-camphor sulfony) chloride.
To the solution of 2-[[[3-methyl-4-(2!2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfanyTJ-li/-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-(-)-camphorsulfony] chloride (106 g) in methyletiechloride (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 g
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 g
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-(-)-di ethyl tartrate (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 firs. 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 g
Example-12: Preparation of S-lansoprazole
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 g
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: 5.0g

We Claim:
1) A 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-trifiuoroethoxy)-2-pyridinyl]methyl]
sulphanyl]-l#-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 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-(2,212-trifluoroethoxy)-2-pyridinyl]
methyl]sulfmyl]-lH-benzimidazole compound of formula-4,


Formula-4
c) treating the N- camphor sulphonyl 2-[(R)-[[3-methyM-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinyI] -lH-benzimidazole compound of formula-4 with aqueous sodium hydroxide in methanol to provide 2-[(R)-[[3-methyi-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfmyl]-ltf-benzimidazole compound of formula-1,
d) recrystallizing the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyI]-l/f-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.
2) A novel process for the preparation of dexlansoprazole compound of formula-1 and its pharmaceutical\y 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


with D-(+)-camphorsulphonyl chloride in presence of potassium carbonate in methyl enechloride, 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 purified using methanol,

Formula-3
b) oxidizing the N-camphorsufonyl 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-
pyridinyl] methyl]su]phanyl]-lH-benzimJdazole compound of formula-3 with
meta chloro perbenzoic acid in toluene in the presence of diisopropylethyl amine
to provide N-camphorsulfonyl 2-[(RJ-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-
pyridinyl]methyl]sulfinyl]-l#-benzimidazole compound of formula-4,

Formula-4
c) treating the N- camphor sulphonyl 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-l#-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) recrystallizing the 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfmy!]-lH-benzimidazoie compound of formula-1 in water and acetone mixture provides pure 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulfinyi]-lH-benzimidazoIe compound of formula-1.

3) The process for the oxidation of N-caraphorsuifonyl 2-[[[3-methyI-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulphanyl]-3H-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]sulfmyl]-lH-benzimidazole compound of formula-4.
4) The process of claim-3, the organic base is selected from tertiary butylamine, triethyl amine, N,N-diisopropyl ethylamine, n-methyl glucamine, thiophene alkyl amine.
5) N-camphorsufonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl] sulphanyl] -ltf-benzimidazole compound of formula-3 as a solid.
6) N-camphorsu!phonyl-2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulfinylJ-l-H-benzimidazole compound of formula-4 as a solid.
7) Crystalline N-camphorsulfonyl-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-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 as illustrated in figure-1.
8) Crystalline N-camphorsulfonyl-2-[(R)-[[3-methyl-4-(2!2,2-trifluoroethoxy)-2-pyridinyl] methyl]sulfinyl]-l#-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 as illustrated in figure-2.

9) 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 as illustrated in figure-3.
10)Dexlansoprazole having the particle size of DJO in the range of 0.1 - 8 um; D5o in the range of 2 - 20 um; D90 in the range of 10 -100 um.