DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Dexlansoprazole (Formula 1) substantially free of sulphide (Formula 2) and sulphone (Formula 3) impurities.

BACKGROUND OF THE INVENTION
Dexlansoprazole is chemically described as 2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-yl]methyl}sulfinyl]-1H-benzimidazole as represented by Formula 1.

US6462058 discloses crystalline dexlansoprazole, its salts and methods of their preparation. The process discloses in this patent has several drawbacks such as:
(i) Multiple extraction steps
(ii) Several purification steps
(iii) Use of excess reagents
(iv) Generation of large amount of effluent

US5948789 discloses a process for the preparation of R-isomer of lansoprazole by chiral oxidation of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole compound using titanium(IV) isopropoxide and (+)-diethyl L-tartrate. The crude R-isomer of lansoprazole is isolated as oil. The workup procedure involves extraction, evaporation and flash chromatography techniques. The obtained oil compound is treated with acetonitrile three times to achieve chiral purity. The process discloses in this patent has several drawbacks such as:

(i) Longer reaction hours i.e. 16 hours.
(ii) Unreacted starting material i.e. sulphide content more than 10%.
(iii) Sulphone content more than 5%.
(iv) Repeated purification steps to achieve desired optical purity.
(v) Low chiral purity i.e. 55%.

The structures of the sulphide (Formula 2) and sulphone (Formula 3) impurities are mentioned below:

SUMMARY OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of Dexlansoprazole.
Yet another object of the present invention is to provide an improved process for the preparation of Dexlansoprazole with substantially free of sulphide and sulphone impurities.
Yet another object of the present invention is to provide a method to produce Dexlansoprazole without repeated purification.
Yet another object of the present invention is to provide a method to produce Dexlansoprazole with high yield and purity.

The term “substantially free of impurities” means less than 0.1 % sulphone, sulphide and unknown impurities as measured by area percentage HPLC., preferably less than 0.08 % of sulphone, sulphide and unknown impurities as measured by area percentage HPLC, most preferably 0.03% level of sulphone, sulphide and unknown impurities as measured by area percentage HPLC.

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention for the preparation of Dexlansoprazole comprises steps:
a) treating the organic layer containing dexlansoprazole with aqueous solution of base to form biphasic medium,
b) separating the layers,
c) washing the aqueous layer with mixture of acetonitrile and toluene,
d) adjusting the pH of aqueous layer to 9-9.5 using acidic solution,
e) filtering the formed solid and washing with toluene and MTBE,
f) treating the wet solid with base in water, and
g) filtering the solid mass and drying to get the highly pure dexlansoprazole.

In step-a, base is used during reaction is selected from sodium hydroxide, ammonia, preferably sodium hydroxide.

In step-c, the pH is adjusted using acetic acid, hydrochloride, preferably acetic acid. The preferable pH is 9.3.

In step-e, the obtained solid is washed by using toluene & MTBE, wherein the ratio of tolune:MTBE is preferably 20:80 (v/v).

In step-f, the solid obtained in step e), is further treated with aqueous solution containing the base selected from sodium hydroxide, sodium carbonate, sodium bicarbonate and ammonia, preferably sodium hydroxide and ammonia, more preferably ammonia.

The present invention is illustrated with following examples without limiting the scope of the invention.

Example 1 Preparation of lansoprazole sulphide
To a solution of sodium hydroxide (79 g, in 1000 ml water), was added 2-Mercapto benzimidazole (142 g), and the mixture is stirred at 30-40°C for homogeneous solution. To this mixture add 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine hydrochloride (250 g, in 1500 ml water) solution for about 2.0-2.5 h and stirred at 25-30°C for 2-2.5 h. The solid was filtered and washed with water (500 ml) to afford wet cake; subsequently the wet solid was suspended in water (1250 ml) at 50-55°C and stirred for 30-45 min. Then the solid was filtered at 25-30°C and wash with water (500 ml); dry under vacuum at 50-55°C to obtain thio ether as off-white solid. Yield: 98.43%; HPLC purity: 99.72%.

Example 2 Preparation of crude dexlansoprazole sesquihydrate
A mixture of lansoprazole sulphide [53 g] and toluene (500 ml) are heated to reflux temperature (108-112°C) under N2-atmosphere and then collect the water azeotropically through Dean-Stork apparatus. The resulting clear solution is cooled to 65-70°C, add DM water (0.3 ml), (R,R)-DET (12.9 g) followed by Ti(OiPr)4 (Assay 97%, 8.3 g) and continue stirring at 65-70°C for 50-60 min. Reaction mass is slowly cooled to 10-15°C, add N, N-Diisopropylethylamine (6.4 g) and then slowly add solution of cumene hydroperoxide (assay 79%, 41 g) drop wise to the above reaction mass at 10-15°C over a period of 30-45 min and stirred at same temperature for 2 h under N2-atmosphere for reaction completion. After reaction completion, reaction mass was quenched by slow adding of 20% aqueous sodium thiosulphate solution (100 ml) at 10-15°C. Thereafter, temperature is raised to 25-35°C, add MTBE (200 ml) and stir for addition 15 min. at 25-35°C. The resulting organic layer is separated and extracted with acetonitrile (300 ml) and solution of sodium hydroxide (7 g in water (500 ml) solution and one more time extracted with acetonitrile (125 ml) and solution of sodium hydroxide (3.5 g in water (250 ml) at 25-35°C. All the aqueous extracts are combined, add acetonitrile (50 ml), and washed with toluene (150 ml). Resulting aqueous layer, cooled to 10-15°C and then adjusted the pH of the solution between 9.0-9.3 using 20% aqueous acetic acid solution. The resulting slurry is stirred for 1-2 h at 10-15°C. The precipitated solid is filtered, wash with toluene: MTBE (20:80, 100 ml) to obtain wet cake; subsequently the wet solid was suspended in basified water (400 ml) at 15-20°C and stirred for 20-30 min and then washed with basified water (50 ml) and dry at 30-35°C under vacuum for 12-16 h to afford enantiomerically enriched crude dexlansoprazole. Yield: 61.45%; HPLC purity: 98.6%.

Example 3 Purification of crude dexlansoprazole sesquihydrate
A mixture of water (540 ml) and DMF (270 ml) are added to crude dexlansoprazole (30 g) and stir for 10-20 min. Reaction mass is cooled to 20-25°C and added aqueous ammonium hydroxide solution (90 ml), and stirred the mixture at 30-35oC for 30-40 min to get clear solution. The clear mass carbon (3 g) is charged and stirred at 50-55°C for 20-30 min. Reaction mass is filtered over Hyflo bed, and washed the bed with water (50 ml). To the resulting filtrate acetonitrile (105 ml) was charged and cooled to 10-15°C and then adjusted the pH of the solution to 9.0-9.5 using 10% acetic acid solution. The resulting heterogeneous mass is stirred at 10-15°C for 1-2 h to ensure the total solid precipitation. Subsequently, the solid is filtered to afford wet cake, and re-slurry the wet cake in basified water (375 ml). Finally, the wet cake was dried at 30-35°C under vacuum for 10-12 h to afford (R)-(+)-2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1H-benzimidazole. Yield: 61.33%; HPLC purity: 99.87%.
The below mentioned table-1 clearly indicates that the dexlansoprazole of formula (I) prepared according to the present invention provides the highly pure dexlansoprazole without using chromatographic purification.
Table-1: HPLC results of the final product:
No. % of Sulphone % of Sulphide % of Unknown
impurity %Purity of Dexlansoprazole
By HPLC

1 0.08 0.01 0.02 99.88
2 0.07 0.03 0.02 99.87
3 0.07 0.03 0.02 99.87

,CLAIMS:We Claim:
1. An process for the purification of dexlansoprazole comprising the following steps:
a)treating the organic layer containing dexlansoprazole with aqueous solution of base to form biphasic medium,
b)separating the layers,
c)washing the aqueous layer with mixture of acetonitrile and toluene,
d)adjusting the pH of aqueous layer to 9-9.5 using acidic solution,
e)filtering the formed solid and washing with toluene and MTBE,
f)treating the wet solid with base in water, and
g)filtering the solid mass and drying to get the highly pure dexlansoprazole.

2. A process according to claim 1, wherein the base is sodium hydroxide, ammonia or a mixture thereof.

3. A process according to claim 1, wherein the pH is 9.3.

4. A process according to claim 1, wherein the acid used for pH adjustment is acetic acid, hydrochloride or a mixture thereof.

5. A process according to claim 1, wherein ratio of toluene:MTBE ratio is 20:80 (v/v).

6. A process according to claim 1, wherein solid obtained in step e) is further treated with aqueous solution containing the base selected from sodium hydroxide, sodium carbonate, sodium bicarbonate and ammonia, preferably sodium hydroxide and ammonia.