WO2008087665A2

WO2008087665A2 - Process for preparation of lansoprazole

Info

Publication number: WO2008087665A2
Application number: PCT/IN2008/000034
Authority: WO
Inventors: Mohan Bandari; Chandra Ray Purna; Kumar Sethi Madhuresh; Venkata Lakshmi Narayana Chebolu Veera; Ramakrishna Kamatam
Original assignee: Matrix Laboratories Ltd
Priority date: 2007-01-18
Filing date: 2008-01-18
Publication date: 2008-07-24
Also published as: WO2008087665A3

Abstract

The present invention provides a process for the preparation of Lansoprazole comprising the steps of oxidizing 2-[[(3-methyl-4-(2,2,2-trifluoroethoxy)pyridinyl]methyl]thio]-lH- benzimidazole with an oxidizing agent, 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 followed by drying yields Lansoprazole.

Description

Title: Process for Preparation of Lansoprazole"

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

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.

US 6,002,011 describe 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 6,180,652 describe 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) sulfinylbenzimidazole 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 6,909,004 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)isolating 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.

US 7022859 & US 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 2004/010151 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, dimethylforniamide and their mixtures optionally with water; and b) isolating crystalline Lansoprazole form A.

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.

WO 00/78729 is discloses a phenomenon of polymorphism in Lansoprazole. The crystalline forms , I and II. The form I find application as an active ingredient of pharmaceutical compositions.

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 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.

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 exposed to high temperatures for removal of solvents during distillation.

Thus, there is continuing need to obtain 2-(2-pyridylmethyl) sulfϊnyl-lH-benzirnidazoles (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% wt/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 advantages: ^"

• Simple reaction condition & isolation

• Minimized 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] sulfinyl] - 1 H-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] sulfinyl]- 1 H-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] -1 H-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 & 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]-lH-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-ethoxy)-2-pyridinyl]methyl] sulfinyl] - 1 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 to isolate the (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 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]-lH-benzimid- azole in 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. Scheme 1 describes the reaction of Lansoprazole

SCHEME : ]

LANSOPRAZOLE (I) SULPHONE (III)

N-OXIDE (IV)

SULPHIDE (II)

+ Chlorinated Impurities

(V)

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-chloroperbenzoic acid/ sodium hypochlorite/ hydrogen peroxide. The resulting product thus obtained may be subjected to terminate 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 crystallized by using aqueous solution of chloroform in presence of co-solvent & 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 & base 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-benziniidazole (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 illustrated the invention but are not intended to limit the scope of the invention or claims thereof. The procedure of the present invention discloses the 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 Lansoprazole 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 is isolated by precipitation in the reaction medium by addition of co-solvents, base, amine & amide as mentioned in table -1, The wet precipitate is stirred in a dilute solution of sodium bicarbonate & dried to give pure stable Lansoprazole.

Normally in the prior art process after the oxidation is completed, the organic solvent is removed by distillation which results in the formation of impurities. The inventors have avoided distillation and instead precipitated the product by the addition of cosolvents mentioned in the table- 1. By doing the ^"precipitation the inventors have unexpectedly found obtained pure Lanosprazole which meets the regulatory specifications.

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 (10Og) was suspended in a mixture of chloroform (2.0 L) & N, N-dimethyl acetamide (20 ml) at room temperature & cooled to 0-10 ⁰C. sodium hydroxide solution (IN, 100 ml)) was added to the suspension followed by slowly addition of solution of aq. sodium hypochlorite (~1%, 2It) at ~5 ⁰C. Progress of reaction was monitored by HPLC. Stirred and maintained at 0 -10⁰C till reaction is over. After completion of reaction, sodium thiosulphate solution (100ml, 10%) was added at 0 -10 ⁰C to quench the reaction. The temperature of reaction raised & 50% aq. ammonium sulphate (50%, 500 mL) was added at room temperature. The two layers were separated. Chloroform layer was washed with sodium bicarbonate solution (0.5%; 500 ml) at room temperature. N, N- dimethyl acetamide (10 ml) was added to organic layer and cooled slowly to 0 ⁰C. Filtered; washed with chilled chloroform, slurry was washed with sodium bicarbonate solution & dried to get off white Lansoprazole.

Purity (by HPLC) = 99.8% Yield (w/w) = 90 g

Lansoprazole was dissolved in acetone: water (7:3) at pH 10-12 & re-precipitated at pH 7-8 using dil. acetic acid solution. The wet Lansoprazole was 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]methylthio-lH-benzimidazole was suspended in 500 ml chloroform and cooled to -5 to -10⁰C. Slowly to the above suspension 17 g m-chloroperbenzoic acid solution in chloroform was added over a period of 3 hrs at -10⁰C. After completion of reaction, buffer & sodium bicarbonate solution (200 ml) was added. Both layers were separated. Organic layer was washed with 2 x 50 ml of hypo solution followed by with 3 x 200 ml sodium bicarbonate solution. Again both layers were separated. Chloroform layer was washed with sodium bicarbonate solution (0.5%; 500 ml) at room temperature. Then N, N-- dimethyl acetamide (1 ml) was slowly added to organic layer and cooled to 0 ⁰C. Filtered; washed with chilled chloroform (10 ml) & slurried 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-benzimidazole was suspended in 100 ml chloroform and cooled to -10⁰C. To the above suspension 3.4 g m- chloroperbenzoic acid solution in chloroform was added over a period of 2 hrs at -10 C. After completion of reaction, reaction mass was added to sodium bicarbonate solution (500 ml) and both layers were separated. Organic layer was washed with 2 x 50 ml of hypo solution followed by washing with 3 x 200 ml sodium bicarbonate solution. Both the layers were separated. Chloroform layer was washed with sodium bicarbonate solution (0.5%; 500 ml) at room temperature. Various co-solvents mentioned in Table- 1 were added to organic layer cool slowly to -10 to 10⁰C. Filtered and washed with chilled chloroform (10 ml) followed by sodium bicarbonate solution (0.5%, 100 ml) & dried to get pure Lansoprazole.

Table-1

Claims

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 b) adding co-solvent or base to the solvent and 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 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

10. The process according to claim 7 step (b), wherein the base employed is sodium bicarbonate.