Field of the invention:
The present invention relates to an improved process for the preparation of Lansoprazole substantially free from its residual impurities & impurities due to over oxidation of the product.
Background of the invention:
A number of substituted 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazole derivatives are reported as gastric proton pump inhibitors. These benzimidazole derivatives include lansoprazole, omeprazole, pantoprazole, and rabeprazole. The lansoprazole is generally represented by the following chemical formula I:


OCH2CF3 CH3

US 4,628,098 & 4,689,333 describes lansoprazole having its chemical name (2-[[[3-methyl-4-(2, 2,2-trifluoro-ethoxy)-2-pyridinyl] methyl] sulfinyl]-lH-benzimidazole. As a characteristic shared with other benzimidazole derivatives (e.g., omeprazole and pantoprazole), lansoprazole can inhibit gastric acid secretion, and thus commonly used as an antiulcer agent. Several methods for preparing lansoprazole are known. The majority of these methods involve the use of a lansoprazole precursor that contains a thioether group. The thioether group is oxidized in the last step of preparation to form the lansoprazole. These patents ('098 and '333) further describes the oxidation of the thioether group using m-chloroperbenzoic acid, per acid, sodium bromite, sodium hypochlorite, or hydrogen peroxide as the oxidizing agent and the reaction solvent is halogenated hydrocarbon, ether, amide, alcohol, or water.
EP 0 302 720 and US 5,578,732 further describes an oxidation method with hydrogen peroxide (H2O2) in the presence of a specific vanadium catalyst. However, the second process has drawbacks in that the amount of the vanadium compound should be increased to enhance the low reactivity, and the production rate of N-oxide impurity (IV) is high.

ES 2105953 describes the conditions for oxidation of thioether to sulfoxide based on the use of hydrogen peroxide in a medium of sodium bicarbonate, catalyzed by phosphotungstenic acid
H3(P(W30,o)4).H20.
ES 2060541 describes a procedure for oxidation of sulfur to sulfoxide with potassium peroxymonosulfate, with or without the presence of a ketone, or with hydrogen peroxide, in the presence of catalysts of Mo and V acetylacetonate.
ES 2063705 describes the oxidation of sulfur to sulfoxide with t-butyl hydroperoxide catalyzed by vanadium.
US 5,374,730 describes an oxidation stage of sulfur to sulfoxide with hydrogen peroxide and catalyzed by vanadium acetylacetonate.
ES 2036948 also describes a procedure for the synthesis of lansoprazole, in which the oxidation of the thioether precursor of lansoprazole to sulfoxide, with m-chloroperbenzoic acid or magnesium monoperoxyphthalate in the presence of a quaternary ammonium salt, or hydrogen peroxide, with a W or molybdenum catalyst.
Despite this, there are unsolved drawbacks in these procedures such as the fact that vanadium compounds are relatively toxic, and that MMPP is expensive to use industrially, as well as generating phthalic acid as a reaction byproduct.
WO 02/074766 describe the process for preparing "lansoprazole", which comprises the steps of reacting 2-hydroxy methyl-3-methyl-4 (2,2,2-trifluoroethoxy) pyridine or its salt with 2-mercaptobenzimidazole in the presence of a halogenating agent and additives to obtain2- 3-methyl-4- (2, 2,2trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole in good yield and oxidizing the reaction product with hydrogen peroxide in the presence of a benzeneseleninic acid catalyst to obtain lansoprazole.

Other patents such as ES 2105953, WO 01/21617, ES 2063705, US 6,313,303, WO 99/47514, WO 01/68594 describes the use of other oxidation reagents and/or other catalysts. None of these oxidation methods result in selective oxidation of the thioether group. The preparation of lansoprazole by conventional methods is always accompanied by the formation of small quantities of the corresponding sulfone derivative as an impurity.
US 6,180,652 describes the presence of sulfone derivative. Formation of sulfone derivative brings about the drawback of low yield of the desired sulfoxide. Although attempts have been made to separate the sulfone derivative from lansoprazole, it is not a simple task, given their very similar structures and physicochemical properties. This patent also describes a method for separation of lansprazole from its sulfone derivative, by converting to an acetone complex of the lansoprazole salt & hence is purified in this method. Lansoprazole and other 2-(2-pyridylmethyl) sulfinybenzimidazole derivatives tend to lose stability and undergo decomposition when contaminated with traces of a solvent, particularly water, in their crystal structure. It is desirable that the benzimidazole crystals be solvent free (i.e., residual solvent should be reduced to a minimum).
US 6,002,011 describes the crystallization of lansoprazole from the same ethanol: water system, containing traces of ammonia. This patent discloses a reslurry method in water, which permits to obtain more stable "solvent free" lansoprazole. This patent fails to disclose the level of purity for lansoprazole. In addition, the ethanol and water are difficult to eliminate. Even after intensive drying, lansoprazole still contains solvent and is unstable under storage.
US 6,909,004 describes the method of purifying lansoprazole, comprising the steps of: a) providing a solution of lansoprazole in a solvent selected from an organic solvent or a mixture of organic solvent and water in the presence of an amine compound; b) combining the provided solution with an acid, and c)isolatin$ the purified lansoprazole. The amine compound is present in 1:1, mole: mole, ratio relative to the lansoprazole. Solution is in an organic solvent selected

from the group consisting of alcohols, acetone, 2-butanone, dimethylformamide and tetrahydrofuran. The alcohol consisting of ethanol, methanol, n-propanol, & iso-propanol. WO 2004/046135 describe the process for preparing a stable lansoprazole compound, comprising the steps of: a) crystallizing a lansoprazole from an organic solvent or a mixture of organic solvent and water in the presence of an amine; and b) isolating a stable lansoprazole compound, wherein the stable lansoprazole compound comprises greater than 500 ppm and not more than about 3,000 ppm water.
Recent U S patents no 7022859 & 7060837 provides a method for preparing a substantially pure lansoprazole containing less than about 0.2% (wt/wt) impurities including sulfone/sulfide derivatives. The present invention also provides a process for recrystallizing lansoprazole to obtain a lansoprazole containing less than about 0.1% (wt/wt) water.
US 2005/020638 describe the process of preparing a stable lansoprazole, comprising the steps of: a) crystallizing a lansoprazole from an organic solvent or a mixture of organic solvent and water in the presence of a weak base; and b) isolating a stable lansoprazole. An amorphous form of lansoprazole prepared by spray drying method has been described (Farm. Vest. vol. 50, p. 347 (1999)). Curin et al. describe an ethanole solvate form and an ethanole-hydrate form of lansoprazole (Farm. Vest. vol. 48, pp. 290-291 (1997). Kotar et al. describe two lansoprazole polymorphs, designated as crystalline lansoprazole forms A and B, (Eur. J. Pharm. Sci. vol. 4, p. 182 (1996 Supp). According to Kotar, each of the crystalline lansoprazole forms A and B exhibits a different DSC curve. In fact, crystalline lansoprazole form B is unstable and can undergo a solid-solid transition to form crystalline lansoprazole form A. No XRD data for crystalline lansoprazole forms A and B, and fails to disclose processes for preparing these crystalline forms. No indication was found in the literature regarding the existence of other crystalline lansoprazole forms other than the known forms A, B, ethanolate and ethanolate-hydrate.
US 2004/010151& WO 03/082857 disclose a method of preparing crystalline lansoprazole form A, comprising the steps of: a) preparing a solution of lansoprazole in a solvent selected from the

group consisting of methanol, n-butanol, acetone, methylethylketone, ethyl acetate, dimethyl sulfoxide, dimethylformamide and their mixtures optionally with water; and b) isolating crystalline lansoprazole form A. WO 00/78729 is disclosed a phenomenon of polymorphism in lansoprazole. The crystalline forms I and II. The form I find application as an active ingredient of pharmaceutical compositions.
Since proton pump inhibitors of the benzimidazole-type are very susceptible to degradation under acidic or neutral conditions, the reaction mixture is usually worked-up under basic conditions. These basic conditions may decompose any unwanted oxidizing agent still present in the reaction mixture and may also neutralize any acid formed when the oxidizing agent is consumed in the oxidation reaction. The main problem with the oxidation reaction to convert the sulfide intermediates of formula (II) into the sulfoxide compounds of formula (I) is over-oxidation, i.e. oxidation from sulfoxides of formula (I) to sulfones of formula (III) ; N-Oxide of formula (IV) & Chlorinating impurities (V).
The formation of sulfones of formula (III) due to over-oxidation is almost impossible to avoid and can be kept to a minimum by performing the oxidation reaction at a low temperature and restricting the amount of oxidizing agent. Typically the amount of oxidizing agent is less than 1 molar equivalent of the starting material, i.e. sulfide intermediates of formula (II), which inevitably results in a less than 100% conversion of starting material. Usually the amount of oxidizing agent is a compromise between maximum conversion of starting material, maximum formation of sulfoxides of formula (I) and minimum formation of unwanted sulfones of formula (III). Chlorinating impurities (V) are observed when chlorinating oxidizing agent such as sodium hypochlorite is used for oxidation reaction. Furthermore removal of the sulfones of formula (III) & Chlorinating impurities (V) has often proved to be difficult, time-consuming and costly, in particular when high performance chromatography on an industrial scale is needed. Another problem with the benzimidazole-type is very susceptible to degradation when expose to high temperatures for removal of solvents during distillation. There is continuing need to obtain 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazoles (e.g., lansoprazole) that are free of contaminants

including sulfone and sulfide derivatives. There has also been a long-felt need for a method to prepare lansoprazole having reduced water content (<0.1% v^^wt water).
The present inventors found that "solvent free" lansoprazole can be obtained by the crystallization from mixture of solvents, avoiding exposing to high temperatures needed for removal of solvents during distillation. Lansoprazole obtained by this method of crystallization can be dried to <0.1% water.
This process has the following advantage:
• Simple Reaction condition & isolation
• Minimize side product formation (product III to V)
• Isolation by Cooling , avoiding heating the compound
• Simple Maceration procedure using Sodium bicarbonate solution
Summary of the invention:
The main object of the present invention is to provide a process for the isolation of (2-[[[3-methyl-4-(2,2, 2-trifluoro-ethoxy)-2-pyridinyl] methyl] sulfmyl]-lH-benzimidazole from chloroform (water immiscible solvent /halogenated hydrocarbon) layer by avoiding the need for distillation.
Another object of the present invention is to provide a process for the isolation of (2-[[[3-methyl-4-(2, 2, 2-trifluoro-ethoxy)-2-pyridinyl]methyl] sulfmyl]-lH-benzimidazole from chloroform (water immiscible solvent/ halogenated hydrocarbon) layer by cooling in presence of water.
Yet another object of the present invention is to provide a commercially feasible, eco-friendly process for the isolation of (2-[[(3-methyl-4-(2, 2, 2-trifluoro-ethoxy)-2-pyridinyl] methyl] sulfinyl]-lH-benzimidazole from chloroform (water immiscible solvent/ halogenated hydrocarbon) layer by cooling in presence of water & base.

Yet another object of the present invention is to provide a process for the isolation of (2-[[[3-methyl-4-(2, 2, 2-trifluoro-ethoxy)-2-pyridinyl]methyl] sulfmyl]-lH-benzimidazole from chloroform (water immiscible solvent/ halogenated hydrocarbon) layer by cooling in presence of water & base.
Yet another object of the present invention is to provide a process for the isolation of (2-[[[3-
methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1 H-benzimidazole from
chloroform (water immiscible solvent/ halogenated hydrocarbon) layer by cooling in presence of water & amide.
Yet another object of the present invention is to provide a process for the isolation of (2-[[[3-methyl-4-(2, 2, 2-trifluoro-ethoixy)-2-pyridinyl]methyl] sulfmyl]-l H-benzimidazole from chloroform (water immiscible solvent/ halogenated hydrocarbon) layer by cooling in presence of base.
It is another feature of the present invention to provide a process for the preparation of lansoprazole, which is suitable for large-scale production. It has surprisingly been found that it is possible the isolation of (2-[[[3-methyl-4-(2, 2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfmyl]-1 H-benzimidazole from chloroform (water immiscible solvent/ halogenated hydrocarbon) layer by cooling in presence of either of water, base ,amide of mixture thereof substantially free from its residual impurities & impurities due to over oxidation of the product.
The above features and another feature may be accomplished by the detailed description of the invention set forth hereinafter.
Detailed description of the invention
The process of the present invention comprises of the following steps:
• Reaction of 2-[[(3-methyl-4-(2,2, 2-trifluoroethoxy)pyridinyl]methyl]thio]-1H-benzimidazole in Chloroform (water immiscible organic solvent/ halogenated

hydrocarbon) with oxidizing agent (m-CPBA/ Sodium hypochlorite) at low temperature (-10 to 10 °C).
• Washing the reaction mass with aqueous solution of buffer, alkali bicarbonate & alkali thiosulphate.
• Isolation of product by cooling to low temperature in presence of water, base, amide or mixture thereof.
• Slurry/crystallizing from water immiscible organic solvent in presence of water, base, amide or mixture thereof
• Slurry the product with sodium bicarbonate solution.
• Drying of the product at 35-45 °C under reduced pressure.
• Optionally storing the product in presence of base.
Scheme 1 describes the reaction of Lansoprazole
SCHEME:I
>-S'^0 OXIDATION ^^^^ Q N^ ^^^ O N
N "■ Y OCH2CF3 ^|j[^>-s'"V^orHrF + IL J- >"«'"V^orH PF
(H) CH3 "--^^N ^H3 ^^^N b XHS
LANSOPRAZOLE (I) SULPHONE (III)
+
H 0_
%-N 0 N^
>-S ^y^oCHjCFj CH3
N-OXIDE (IV)
>-S ^y^oCH2CF3 CHj SULPHIDE (H)
+ Chlorinated Impurities
(V)
by reacting sulphide derivative i.e., 2- [3-methyl-4- (2, 2,2-trifluoroethoxy)-2-pyridyl] methylthio-lH-benzimidazole is oxidized with oxidizing agents in the presence of reaction solvent to give lansoprazole.

The reaction solvent is halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, preferably dichloromethane or chloroform. The Oxidizing agents used in reaction are such as m-Cloroperbenzoic acid/ Sodium Hypochlorite/ HaOa-The resulting product thus obtained may be subject to terminate its oxidation reaction with a conventional method for decomposing excess buffer solution of (pH between 10-14), organic or inorganic base, aqueous solution of inorganic base, by adding an aqueous solution of sodium thiosulfate of mixture thereof
The layers are separated after washing with aqueous solution of inorganic base & aqueous solution of sodium thiosulfate and finally to crystallize by using an aqueous solution chloroform in presence of dimethyl amide & base. To obtain reaction products with a higher quality, a conventional purification method such as recrystallization by using aqueous solution chloroform in presence of dimethyl amide & bage may be used. The crystallisation temperature is between -20°C and 25°C, preferably between -5°C and 20°C.
According to the present invention, lansoprazole (I) can be obtained by oxidation of 2 [3-methyl-4- (2, 2, 2-trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole (II) in good yield and high quality.
The invention is illustrated in more detail in the following Examples and Comparative Examples, and the following Examples illustrate the invention but are not intended to limit the scope of the invention or claims thereof The procedure of the present invention presents a number of improvements on the previous procedures, such as the following the reagents used are commercially affordable, the pH of the reaction mixture is slightly basic and thus adequate for stability of compounds such as lansoprazol in a solution, the formation of N-oxide as an impurity is unappreciable or appreciable at negligible amounts, the percentage of sulfone & chlorinating in the produced are low, the oxidized product can be isolated by precipitation in the reaction medium in presence of other solvents, base, amine & amide as mentioned in Table -1, a first purification of the sample can be performed by a fractionated precipitation at a controlled pH. The crystallisation temperature is between -10°C and 25''C, preferably between -5°C and 20°C.

The wet precipitates are stirred in a dilute solution of sodium bicarbonate & dried to give pure stable Lansoprazole.
The above process can be used for the preparation of benzimidazole derivatives (e.g., omeprazole; rabeprazole and pantoprazole etc )
The following examples are provided for purposes of illustration only and should not be understood as a definition of the limits of the invention.
Example 1:
2-((3-methyl-4-(2, 2, 2-trifluoroethoxy) pyrid-2-ylmethylthio] benzimidazole flOO g) is
suspended in a mixture of chloroform (2.0 L) & N, N-Dimethyl acetamide (20 ml) at room
temperature & cool to 0-10 °C. Add sodium hydroxide solution (IN, 100 ml)) to the suspension.
Add slowly a solution of Aq Sodium hypochlorite (-1%, 21t) at ~5 °C. Progress reaction is
monitored by HPLC. Add a solution of Aq Sodiimi hypochlorite (-1%, 2 x 150 ml) at ~5 °C if
starting material is present in the reaction. Stir and maintain at 0 -10°C till reaction is over. Add
hypo solution (100ml, 10%) at 0 -10°C to quench the reaction. Raise the temperature & add 50%
aq Ammonium sulphate (50%, 500 mL) at room temperature. Separate the two layers. Wash
chloroform layer with sodium bicarbonate solution (0.5%; 500 ml) at room temperature. Add N,
N-Dimethyl Acetamide (10 ml) to organic layer cool slowly to 0 °C. Filter; wash with chilled
chloroform (100 ml) & slurry with sodium bicarbonate solution (0.5%, 500 ml) «fe dried to get off
white Lansoprazole
Purity (by HPLC) = 99.8% Yield (w/w) = 90 g
Off-white Lansoprazole is dissolved in acetone: water (7:3) at pH 10-12 & re-precipitating at pH 7-8 using dil. acetic acid solution. The wet Lansoprazole is slurry washed with sodium bicarbonate solution (0.5%) & dried to get white colour pure compound

Example 2
25 g of 2- [3-methyl-4- (2, 2,2-trifluoroethoxy)-2-pyridyl]methyIthio-lH-benzimidazole is
suspended in 500 ml chloroform. Cool the suspension to -5 to -10°C. Slowly add to the above
suspension 17 g m-Chloroperbenzoic acid solution in chloroform over a period of 3 hrs at -10°C.
After completion of reaction is added Buffer & sodium bicarbonate solution (200 ml). Separate
the layers. Wash organic layer with 2 x 50 ml of hypo solution followed by washing with 3 x 200
ml sodium bicarbonate solution. Separate the two layers. Wash chloroform layer with sodium
bicarbonate solution (0.5%; 500 ml) at room temperature. Add N, N-Dimethyl Acetamide (1 ml)
to organic layer cool slowly to 0 °C. Filter; wash with chilled chloroform (10 ml) & slurry with
Ethyl acetate (10 ml) followed by sodium bicarbonate solution (0.5%, 50 ml) & dried to get pure
Lansoprazole
Purity (by HPLC) = 99.6% Yield (w/w) = 7 g
General Example
10 g of 2- [3-methyl-4- (2, 2, 2-trifluoroethoxy)-2-pyridyl] methylthio-lH-benzimidazoIe is suspended in 100 ml chloroform. Cool the suspension to -IO°C. Slowly add to the above suspension 3.4 g m-Chloroperbenzoic acid solution in chloroform over a period of 2 hrs at -lO^C. After completion of reaction is added sodium bicarbonate solution (500 ml). Separate the layers. Wash organic layer with 2 x 50 ml of hypo solution followed by washing with 3 x 200 ml sodium bicarbonate solution. Separate the two layers. Wash chloroform layer with sodium bicarbonate solution (0.5%); 500 ml) at room temperature. Add various co solvents mentioned in Table-1 to organic layer cool slowly to -10 -lOOC. Filter; wash with chilled chloroform (10 ml) followed by sodium bicarbonate solution (0.5%, 100 ml) & dried to get pure Lansoprazole.

WE CLAIM:
1. A process for the preparation of Lansoprazole which comprises;
a) reaction of 2-[[(3-methyl-4-(2, 2, 2-trifluoroethoxy)pyridinyl]methyl]thio]-lH-
benzimidazole in halogenated hydrocarbon with oxidizing agent,
b) washing the reaction mass with aqueous solution of buffer, alkali bicarbonate & alkali thiosulphate, and
c) isolation of product by cooling to low temperature in presence of co solvent, base or mixture thereof

2. The process according to claim 1 step (a) wherein the halogenated hydrocarbon is selected from chloroform, carbon tetrachloride, dichloromethane.
3. The process according to claim 1, step (b) wherein the alkali bicarbonate employed is sodium bicarbonate, potassium bicarbonate.

4. The process according to claim 1, step (b) wherein the alkali thiosulfate employed is sodium thiosulfate.
5. The process according to claim 1, step (c) wherein the co solvent is dimethyl acetamide^ dimethyl formamide, acetone, triethylamine, heptane, tertiary butyl methyl ether, tetrahydrofuran, toluene, water methanol, ether, acetonitrile or mixtures
6. The process according to claim 1 step (c) wherein the base employed is sodium bicarbonate.
7. A process for the preparation of lansoprazole which comprises

a) suspending lansoprazole in an halogenated hydrocarbon solvent medium
b) adding co-solvent or base to the solvent medium
c) isolating the lansoprazole
8. The process according to claim 7 step (a), wherein the halogenated
hydrocarbon is selected from dichloromethane, chloroform, carbon
tetrachloride.
9. The process according to claim 7, step (b) wherein the co-solvent is selected
from water, triethylamine, acetone, dimethyl acetamide, dimethyl formamide, heptane, t-butyl methyl ether, ethanol, acetonitrile or mixtures thereof.
10.The process according to claim 7 step (b), wherein the base employed is sodium bicarbonate.