WO2002074766A1

WO2002074766A1 - Method of preparing lansoprazole and its intermediate

Info

Publication number: WO2002074766A1
Application number: PCT/KR2002/000261
Authority: WO
Inventors: Wan Joo Kim; Kyoung Soo Kim; Myung Hwa Kim; Yong Gu Baek; Jong Yek Park; Jung Min Jang; Jae Won Choi; Yong Sang Yoo
Original assignee: Chemtech Research Incorporation; Hansol Chemience Co., Ltd.
Priority date: 2001-02-21
Filing date: 2002-02-20
Publication date: 2002-09-26
Also published as: KR100430575B1; KR20020068592A; EP1368338A4; JP2004525927A; EP1368338A1

Abstract

The present invention relates to a process for preparing lansoprazole of the following formula (I) and its intermediate, 2-[3-methyl-4(2,2,2-trifluoroethoxy)-2-pyridil]methylthio-1H-benzimidazole of the following formula (II), which comprises reacting 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine or its salt with 2-mercaptobenzimidazole in the presence of a halogenating agent and reaction solvent, and then oxidizing the resulting compound (II) with hydrogen peroxide in the presence of a benzeneseleninic acid catalyst and reaction solution to obtain lansoprazole(I).

Description

Method of Preparing Lansoprazole and Its Intermediate

FIELD OF THE INVENTION

The present invention relates to a novel process for preparing 2-[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl- 1 H-benzimidazole (hereinafter also called "lansoprazole"), which is an anti-ulcer agent having an excellent gastric acid secretion inhibiting action and a gastric mucous membrane protecting action, and its intermediate. More particularly, the present invention relates to a process for preparing lansoprazole which comprises the steps of reacting 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy)pyridine or its salt with 2-mercaptobenzimidazole in the presence of a halogenating agent and additives to obtain 2-[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridyl]methylthio-l H-benzimidazole in good yield (not less than 96%), and oxidizing the reaction product with hydrogen peroxide in the presence of a benzeneseleninic acid catalyst to obtain lansoprazole.

BACKGROUND OF THE INVENTION

2-[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfmyl-lH- benzimidazole, also called lansoprazole, having the following formula (I), is well known as a major component of an anti-ulcer agent having excellent gastric acid secretion inhibiting action and gastric mucous membrane protecting action. Various processes for preparing lansoprazole (I) or its intermediate, 2-[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridyl]methylthio-l H-benzimidazole having the following structural formula {IT), are disclosed in European Patent Nos. 0 302 720 (Kato et al.) and 0 446 961 (Makino et al.), U.S. Patent Nos. 4,689,333 (Nohara et al.) and 5,374,730 (Slemon et al.), WO 97/29103 (Bekhazi et al.), Tetrahedron, 42/17, 5459(1986), Chemical Abstract, 97/5, 547(1982), etc.

(I) <«)

The processes described in the above-mentioned references may be summarized as follows:

The intermediate, 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio- 1 H-benzimidazole (II) is prepared by reacting 2-mercaptobenzimidazole of the formula (IV) with 3-methyl-4-(2,2,2-trifluoroethoxy)pyridine derivative of the formula (V), or by reacting benzimidazole derivative of the formula (VI) with 2-mercaptomethyl-3- methyl-4-(2,2,2-trifluoroethoxy)pyridine of the formula (VII), as shown in the following Reaction Scheme 1 (U.S. Patent No. 4,689,333).

Reaction Scheme 1

(V) (VII)

wherein X is a leaving group such as a halogen atom, arylsulfonyloxy, C₁.₄ alkylsulfonyloxy, or organic phosphoryloxy group. In this process, base such as alkali metal, alkali metal hydride, alkali metal carbonate, sodium alcoholate, or organic amines, and reaction solvent such as alcohol or dimethylformamide are used to enhance the reactivity. One of the disadvantages associated with this process is that it substantially requires two steps which comprise obtaining the said compound (V) from 2- hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine of the following formula (III) and then reacting said compound (V) with 2-mercaptobenzimidazole (TV). For example, if X of the compound (V) is a chlorine atom, additional isolation or purification steps are needed to remove the remaining thionyl chloride after 2- hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (III) is reacted with thionyl chloride.

(I«)

There are some other disadvantages: bases should be used to enhance the reactivity, the use of a column chromatography is not suitable for large-scale production, and the final product has a low yield (about 64.5%).

In the meantime, lansoprazole (I) is prepared by oxidizing 2-[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole (II) as shown in the following Reaction Scheme 2.

Reaction Scheme 2

(") (l)

This oxidation reaction may be summarized to two processes as follows: The first process is disclosed in U.S. Patent No. 4,689,333, in which lansoprazole (I) is prepared by oxidizing 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-lH-benzimidazole (II). The oxidizing agent used in this process is exemplified by peracid, sodium bromite, sodium hypochlorite, or hydrogen peroxide, and the reaction solvent is halogenated hydrocarbon, ether, amide, alcohol, or water.

The above first process has the following disadvantages. Firstly, 2-[3-methyl- 4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl-lH-benzimidazole N-oxide (VIII) produced by the oxidation of nitrogen of the pyridine ring in the object compound (I), is obtained in a considerable amount as a by-product during the oxidation reaction of the above process.

(VIII)

Secondly, it is difficult to remove the discoloration of the crude compound (I) even though it is isolated from the reaction solution since the reaction solution is discolored into violet during the process. Thirdly, the yield of the final product is very low (about 77%), and fourthly, it is not suitable for large-scale production since the purification of the objective compound is carried out by a column chromatography.

The second process for preparing the compound (I) is disclosed in European Patent No. 0 302 720 and is more improved than the first process, hi this process, 2-(3- methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl-lH-benzimidazole (I) is prepared by oxidizing 2-(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylthio-lH- benzimidazole (II) with an inexpensive oxidizing agent, i.e. hydrogen peroxide, instead of an expensive oxidizing agent (m-chloroperbenzoic acid), in the presence of vanadium compound as a catalyst. In comparison with prior art, this process enables the yield of the final product to be enhanced and reduces the production of by-products such as 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl-lH- benzimidazole N-oxide (VIE).

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 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl-lH- benzimidazole N-oxide (VIH) is still high (approximately 4%).

Therefore, the present inventors have developed a novel process, by which 2- [3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio- lH-benzimidazole (II) may be obtained in good yield from 2-hydroxymethyl-3-methyl-4-(2,2,2- trifluoroethoxy)pyridine (III) by using a more simple process, and lansoprazole (I) may be then obtained in good yield from the compound (II). It is difficult to separate the byproduct such as 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfmyl-lH- benzimidazole N-oxide (VIII) from lansoprazole (I) by conventional purification methods e.g. recrystallization because the compound (VIII) has similar physical properties with lansoprazole (I). Thus, the present inventors have extensively studied the conditions for producing a low amount of by-products (about 1% more or less) at the reaction step.

Consequently, the present inventors have developed the process comprising the steps of reacting 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (III) or its salt with 2-mercaptobenzimidazole in the presence of a halogenating agent, without using any base to obtain 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyljmethylthio-lH-benzimidazole (II) in good yield, and then oxidizing the resulting compound (II) with hydrogen peroxide in the presence of benzeneseleninic acid as a catalyst to obtain lansoprazole (I). According to the present invention, the reaction may be carried out effectively without using any base, and 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-lH-benzimidazole (II) may be obtained only in one step with a better yield than the prior art which is subjected to additional isolation or concentration. Furthermore, according to the present invention, lansoprazole (I) may be produced in good quality with a good yield by oxidizing the said compound (II) with hydrogen peroxide in the presence of a benzeneseleninic acid catalyst. Thus, the present process leads to low production of by-product such as 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylsulfinyl-l H-benzimidazole N-oxide (VIII) by a simple and economic oxidation method. It is a feature of the present invention to provide a novel process for the preparation of lansoprazole, which is an anti-ulcer agent having an excellent gastric acid secretion inhibiting action and a gastric mucous membrane protecting action.

It is another feature of the present invention to provide a process for preparation of an intermediate of lansoprazole (I), i.e. 2-[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole (II), in which the reaction may be carried out effectively without using any base in only one step in good yield than the prior art which is subjected to additional isolation or concentration.

It is another feature of the present invention to provide a process for the preparation of lansoprazole and its intermediate with a good quality and a good yield by using a simple and economic reaction.

It is another feature of the present invention to provide a process for the preparation of lansoprazole, which is suitable for large-scale production.

The above features and another features may be accomplished by the detailed description of the invention set forth hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparing lansoprazole and its intermediate. The process comprises the steps of reacting 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy)pyridine (III) or its salt with 2-mercaptobenzimidazole (IN) in reaction solvent in the presence of a halogenating agent, and oxidizing 2-[3-methyl-4- (2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole (II) obtained from the above step with hydrogen peroxide in reaction solvent in the presence of benzeneseleninic acid as a catalyst to obtain lansoprazole as shown in the Reaction Scheme 3. Reaction Scheme 3

(I)

The present invention is described in detail as follows:

Step 1: Preparation of 2-[3-methyl-4-(2,2,2-trifluoroethoxyV2-pyridyl]methyl thio-lH- benzimidazole (IT)

2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole

(II) as an intermediate of lansoprazole is prepared by simultaneously or sequentially adding a halogenating agent and 2-mercaptobenzimidazole (IV) to 2-hydroxymethyl-3- methyl-4-(2,2,2-trifluoroethoxy)pyridine (HT) or its salt in the reaction solvent.

The reaction solvent is preferably halogenated hydrocarbon such as dichloromethane, chloroform, or carbon tetrachloride; or ether such as tetrahydrofuran, or dioxane, more preferably dichloromethane or chloroform.

2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (III) may be prepared from 2,3-lutidine as disclosed in U.S. Patent No.4,689,333, and the compound

(III) may be used in the form of its salts combined with acid, for example, its hydrochloride, hydrobromide, or hydroiodide.

The amount of 2-mercaptobenzimidazole (IV) used is usually one or more equivalent of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (III), preferably 1 to 4 equivalents, more preferably 1 to 1.5 equivalents of the compound

(in). The reaction temperature is usually from about 0^°C to the boiling point of the reaction solvent, preferably about 20 to 85 ^°C, more preferably about 35 to 60 ^°C. The reaction time is usually between initial start of the reaction and 24 hours, preferably about 10 minutes to 3 hours. If a halogenating agent and 2-mercaptobenzimidazole (IV) are sequentially added, the preferable time interval is between just after introducing the halogenating agent and 8 hours, more preferably about 5 minutes to 3 hours.

The halogenating agent used in the reaction includes phosphorus halide, for example phosphorous tribromide (PBr ), phosphorous trichloride (PC1 ), phosphorous pentabromide (PBr₅), phosphorous pentachloride (PC1₅), phosphorous oxybromide (POBr₃), phosphorous oxychloride (POCl₃), or mixtures thereof, preferably phosphorous trihalide. The amount of the halogenating agent is usually 1 (1/3 as a molar ratio) to 15 equivalents (5 as a molar ratio), preferably 2 to 3 equivalents of the compound (HI).

Optionally, conventional additives may be added to the reaction medium. Thiosulfate compound as an additive allows the yield of the product to enhance about 2%. Such thiosulfate compound includes sodium thiosulfate (Na₂S O₃), potassium thiosulfate (K₂S₂O₃), calcium thiosulfate (CaS₂O ), or tetrabutylammonium thiosulfate ((Bu₄N)₂S₂O₃), and sodium thiosulfate is preferred among these compounds. The amount of thiosulfate compound is usually 0.001 to 0.5 equivalent, preferably 0.01 to 0.2 equivalent of the compound (HI).

The intermediate of lansoprazole (II) produced by the reaction described above may be collected by filtrating it to an organic layer by basification after cooling the reaction medium, followed by concentration, and then be further purified by conventional methods, e.g. by using ethyl acetate or hexane. According to the present invention, 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-lH-benzimidazole (II) may be prepared in high purity and good yield of not less than about 96% from reacting 2-hydroxymethyl-3-methyl-4-(2,2,2- trifluoroethoxy)pyridine (III) or its salt. Especially, the present invention is characterized in that 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH- benzimidazole (II) may be prepared only in one step under the same acidic condition as the reaction solution without adding any base, and also without carrying out an additional concentration or purification process an intermediate, 2-halomethyl-3- methyl-4-(2,2,2-trifluoroethoxy)pyridine of the formula (V).

(V)

wherein X is a halogen atom, e.g. bromine and chlorine.

Step 2: Preparation of lansoprazole (I)

2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole (II) obtained from the above step 1 is oxidized with hydrogen peroxide in the presence of reaction solvent and catalyst to form a lansoprazole(I). The reaction solvent in the second step is halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride; or ether such as tetrahydrofuran, dioxane; or water, preferably dichloromethane or chloroform.

The catalyst used is benzeneseleninic acid (PhSeO H), and the amount of the catalyst is usually 0.0001 to 0.2 equivalent, preferably 0.001 to 0.1 equivalent, more preferably, 0.002 to 0.01 equivalent of the compound (H).

Hydrogen peroxide is used as its aqueous solution of about 20 to 50 %, but not limited thereto. The amount of hydrogen peroxide is usually 0.95 to 2.0 equivalents, preferably 0.95 to 1.4 equivalents, more preferably, 1.0 to 1.1 equivalents of the compound (IT). The reaction temperature is usually about 0 to 50 ^°C, preferably about 5 to

35 ^°C , more preferably about 10 to 25 ^°C . The reaction time is usually about 5 minutes to 48 hours, preferably about 30 minutes to 10 hours, more preferably about 1 to 6 hours.

The resulting product thus obtained may be subject to terminate its oxidation reaction with a conventional method for decomposing excess hydrogen peroxide (for example, by adding an aqueous solution of sodium thiosulfate), and then to extract with solvent such as dichloromethane, followed by concentrating, and finally to crystallize by using an aqueous solution of acetonitrile or ethanol. To obtain reaction products with a higher quality, a conventional purification method such as recrystallization by ethanol or water may be used.

According to the present invention, lansoprazole (I) can be obtained from 2- [3 -methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-l H-benzimidazole (II) in good yield (approximately 90% or more) and high quality. Furthermore, the yield of by-products such as 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfiny_- 1 H-benzimidazole N-oxide may be reduced to 1.5% or less. A conventional purification process as disclosed in Examples 7 and 8 may be further carried out, if necessary, and thus the amount of the resulting by-products can be reduced to about 0.1% or less.

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.

Examples

Examples 1 to 5 and Comparative Example 1: Preparation of 2-[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridyl] methylthio-lH-benzimidazole (II)

Example 1 23g (0.10 mole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine was dissolved in 1L of dichloromethane, cooled at 4^°C, to which was sequentially added 9.9ml (O.lOmole) of phosphorous tribromide (PBr₃), 15.6g (O.lOmole) of 2-mercaptobenzimidazole, and 3.3g (0.02 mole) of sodium thiosulfate at a temperature of below 10^°C, and then allowed to reflux for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, to which was added 4N-sodium hydroxide to make the pH of the reaction mixture 13.5 to 14. The reaction mixture was stirred vigorously for about 20 minutes, and an organic layer was then separated therefrom. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. After the organic layer was separated, the residue was crystallized with a mixture of ethyl acetate and hexane (1:6, 630ml) to yield 34.2g of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-lH-benzimidazole as an off-white crystal. The yield of crystal was 93%.

Example 2 23g (0.10 mole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine was dissolved in 1L of dichloromethane, cooled at 4^°C, to which was gradually added 9.9ml (O.lOmole) of phosphorous tribromide (PBr₃) at a temperature of below 10°C, and then allowed to reflux for 1 hour. The temperature of reaction solution was cooled to room temperature, to which was added 15.6g (O.lOmole) of 2- mercaptobenzimidazole, and 3.3g (0.02 mole) of sodium thiosulfate, and then allowed to reflux for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then was added 4N-sodium hydroxide to make the pH of the reaction mixture 13.5 to 14. The reaction mixture was stirred vigorously for about 20 minutes, and an organic layer was then separated. The organic layer thus separated was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized with a mixture of ethyl acetate-hexane (1:6, 630ml) to yield 35.3g of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-l H-benzimidazole as an off-white crystal. The yield of the crystal was 96%o. Example 3

26.8g (0.10 mole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine hydrochloride was dissolved in 1L of dichloromethane, cooled at 4^°C, to which was sequentially added 9.9ml (O.lOmole) of phosphorous tribromide (PBr ), 15.6g (O.lOmole) of 2-mercaptobenzimidazole, and 3.3g (0.02 mole) of sodium thiosulfate at a temperature of below 10^°C, and then allowed to reflux for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then was added 4N-sodium hydroxide to make the pH of the reaction mixture 13.5 to 14. The reaction mixture was stirred vigorously for about 20 minutes, and an organic layer was then separated. The organic layer thus separated was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized with a mixture of ethyl acetate-hexane (1:6, 630ml) to yield 33.8g of 2-[3- methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole as an off- white crystal. The yield of the crystal was 92.1%. Example 4 lOg (0.0452 mole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine was dissolved in 400ml of dichloromethane, cooled at 4^°C, to which was gradually added 3.94ml (0.0452mole) of phosphorous trichloride (PC1₃) at a temperature of below 10^°C, and then allowed to reflux for 1 hour. The temperature of the reaction mixture was cooled to room temperature, to which was added 6.79g (0.0452mole) of 2-mercaptobenzimidazole, and 1.43g (0.00904mole) of sodium thiosulfate, and then allowed to reflux for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then was added 4N-sodium hydroxide to make the pH of the reaction mixture 13.5 to 14. The reaction mixture was stirred vigorously for about 20 minutes, and an organic layer was then separated. The organic layer thus separated was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized with a mixture of ethyl acetate-hexane (1:6, 280ml) to yield 4.9g of 2-[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazoleas as a off-white crystal. The yield of the crystal was 93%. Example 5

2.0g (9.04mmole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine was dissolved in 80ml of dichloromethane, cooled at 4^°C, to which was gradually added 2.59g (9.04mmole) of phosphorous oxybromide (POBr₃) at a temperature of below 10^°C, and then allowed to reflux for 1 hour. The reaction mixture was cooled to room temperature, to which was added 1.36g (9.04mmole) of 2- mercaptobenzimidazole, and 0.29g (1.81mmole) of sodium thiosulfate, and then allowed to reflux for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and then was added 4N-sodium hydroxide to make the pH of the reaction mixture 13.5 to 14. The reaction mixture was stirred vigorously for about 20 minutes, and an organic layer was then separated. The organic layer thus separated was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized with a mixture of ethyl acetate-hexane (1:6, 56ml) to yield 2.69g of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-l H-benzimidazole as a off-white crystal. The yield of the crystal was 84.3%.

Comparative Example 1

5g (0.0226mole) of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy) pyridine was dissolved in 200ml of dichloromethane, cooled at 4^°C, to which was sequentially added 1.65ml (0.0226mole) of thionyl chloride (SOCl₂), 3.39g (0.0226mole) of 2-mercaptobenzimidazole, and 0.72g (0.00452mole) of sodium thiosulfate, and then allowed to reflux for 2.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, to which was added 4N-sodium hydroxide to make the pH of the reaction mixture 13.5 to 14. The reaction mixture was stirred vigorously for about 20 minutes, and an organic layer was then separated. The organic layer thus separated was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized with a mixture of ethyl acetate-hexane (1:7, 140ml) to yield 3.86g of 2-[3-methyl-4-(2,2,2- trifluoroethoxy)-2-pyridyl]methylthio-lH-benzimidazole as a light-pink crystal. The yield of the crystal was 48.3%. ^'When the Comparative Example 1, which uses conventional thionyl chloride as a halogenating agent, is compared with the Examples 1 to 5, it has been found that the yields of the resulting products in the Examples are very higher than that of the Comparative Example. Example 6: Preparation of lansoprazole 1.5g (4.24mmole) of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl thio-1 H-benzimidazole obtained in Example 2 was suspended in 30ml of dichloromethane, to which was added 2.01mg (0.0106mmole) of bezeneseleninic acid (PhSeO₂H), and then cooled to 10^°C . To the reaction mixture, 2ml of tert-butanol and 0.376ml (4.46mmole) of 35.7% hydrogen peroxide were added at a temperature of below 10^°C. The reaction mixture was stirred for 5 hours with the temperature maintaining at 15 to 20 ^°C. After completion of the reaction, the reaction mixture was cooled to 5 ^°C , gradually added dropwise an aqueous solution of sodium thiosulfate (0.4g/20ml) at a temperature of below 10^°C, and then stirred vigorously for about 30 minutes at a temperature of about 10^°C . The organic layer was separated from the mixture, and it was washed with 20ml of water. The washed organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, dissolved in about 5ml of ethanol before a crystal is crystallized out, and then crystallized with reconcentration. The crystals thus obtained were dried under vacuum to give 1.51g of a light beige color solid product. The yield of the product was 95.1%. Reference Examples 1-2: Preparation of lansoprazole according to prior art process Reference Example 1

1.68g of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH- benzimidazole was dissolved in 30ml of dichloromethane, to which was added dropwise at 15 to 20 ^°C a solution of hydrogen peroxide in t-butanol (2.75ml corresponding to 0.2g of hydrogen peroxide) containing vanadium pentoxide (5mg), and then allowed to react at 20 to 25 ^°C for about one hour. After completion of the reaction, an aqueous solution of sodium thiosulfate (0.5g/30ml) was added to the reaction mixture, which was stirred vigorously for about 10 minutes, allowed to stand still, and separated into layers. The dichloromethane layer was washed with water (30ml), and dried with magnesium sulfate, and then concentrated under reduced pressure and dissolved in about 5ml of ethanol before a crystal is crystallized out, and then crystallized with reconcentration. The crystals thus obtained were dried under vacuum to give 1.63g of a light brown-violet color object compound (the yield of the products: 93.0%).

Reference Example 2

1.5g of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-lH- benzimidazole was dissolved in 20ml of chloroform, and cooled at 5 ^°C , to which was added dropwise at below 5 ^°C a solution of m-chloroperbenzoic acid in chloroform (15ml corresponding to l.Og of m-chloroperbenzoic acid). The mixture was stirred to complete the reaction at 0 to 5 ^°C for about one hour. After completion of the reaction, the reaction mixture was washed with an aqueous solution of sodium hydrogen carbonate. The organic layer thus separated was dried with magnesium sulfate, and then concentrated under reduced pressure and dissolved in about 5ml of ethanol before a crystal was crystallized out, and then recrystallized with reconcentration. The crystals thus obtained were dried under vacuum to give 1.6 lg of an object compound as a violet color (the yield of the products: 103%).

Each resulting product obtained in Example 6 according to the present invention and Reference Examples 1 and 2 according to prior art process (European Patent No. 0 302 720) was analyzed by High Performance Liquid Chromatography (HPLC) and the yield and content of resulting product and the results of analysis were shown in the following Table 1.

The conditions of HPLC are as follows: - Equipment used: YOUNG-LIN High Performance Liquid Chromatograph

Type M930

- Column: Kromasil ODS2(4.6 x 250mm i.d.)

- Detector: YOUNG-LIN Ultraviolet Absorption Photometer Type M720

- Data processor: Autochro-Win - Measurement wavelength: 254nm

- Mobile phase: A mixture of methanol:water:triethylamine (60:40:1) of which pH has been adjusted to 7.0 by addition of phosphoric acid

- Flow rate: 0.7ml/min

- Time required for analysis: 50 minutes - Column temperature: a fixed temperature of about 25 ^°C

In Table 1, "content" is a content of each product sample obtained from the Examples on the basis of commercially available standard sample, which is calculated by the following formula.

Content (%) = [weight of the standard sample (g)/weight of the product sample (g)] x [area of the standard sample (g)/area of the product sample in HPLC] x [weight of water in the standard sample/weight of water in the product sample] x 100

Table 1

Example 6 Reference Example 1 Reference Example 2

Yield^a 95.1% 93.0% 103%

Content 97.5% 92.1% 74.4%

Compound (II)^b 1.34% 1.35% 1.67%

Compound (I) 96.8% 93.6% 93.3% Compound (VLT)^b 1.21% 4.19% 4.53% a: Theoretical yield of the product which has not been purified b: Ratio of area in HPLC

As shown in Table 1, there is no great difference in the theoretical yield of between the product sample obtained in Example 6 and those of Reference Examples 1 and 2. However, it can be found that the purity and the yield of the product obtained from Example 6 are more excellent than those of the products obtained from Reference Examples in comparison with contents of standard samples and the ratio of area in HPLC. Especially, it can also be found from the results of the HPLC analysis that the amount of by-product such as N-oxide compound (VIII) may be significantly reduced to about 1% according to Example 6 of the present invention. Examples 7-8: Purification of lansoprazole Example 7

1.5 lg of the crude product of lansoprazole obtained from Example 6 was added to 12.1ml of ethanol, and then heated at 45 to 50 ^°C to dissolve thoroughly the crystal. To the mixture, 4.03ml of water was added, and then slowly cooled to 5 ^°C . After maintaining the mixture at 5 ^°C for about 3 hours, the resulting crystals were collected by filtration and washed with a mixture of ethanol- water (3:1) of 5 ^°C . The collected crystals were dried under vacuum to obtain 1.45g of lansoprazole as a white crystal. The yield of the crystal was 96.1%). The crystal thus obtained was added again 11.6ml of ethanol, and then heated at 45 to 50^°C in order to thoroughly dissolve the crystal. The insoluble matters were removed by hot filtration, and 1.66ml of water was added, and then gradually cooled to 5 ^°C. After maintaining the mixture at 5^°C for about 3 hours, the resulting crystal was collected by filtration and washed with a mixture of ethanol-water (7:1) of 5^°C . The crystal was dried under vacuum to obtain 1.40g of lansoprazole as a white crystal. The yield of the crystal was 96.3%>. Example 8

1.5 lg of the crude product of lansoprazole obtained in Example 6 was added 52.9ml of acetonitrile, and then heated at 50 to 55 ^°C to dissolve thoroughly the crystal. To the mixture, 5.29ml of water was added, and then gradually cooled to room temperature, followed by concentration under reduced pressure to remove 48ml of the reaction solvent. After maintaining the mixture at 5 ^°C for about 3 hours, the resulting crystal was collected by filtration and washed with a mixture of acetonitrile-water (10:1) of 5 °C . The crystal was dried under vacuum to obtain 1.48g of lansoprazole as a white crystal. The yield of the crystal was 98.0%. The crystal thus obtained was added again 11.8ml of ethanol, and then heated at 45 to 50°C to dissolve thoroughly the crystal. The insoluble matters were removed by hot filtration, and 1.69ml of water was added, and then gradually cooled at 5 ^°C . After maintaining the mixture at 5 ^°C for about 3 hours, the resulting crystal was collected by filtration and washed with a mixture of ethanol-water (7:1) of 5 ^°C . The crystal was dried under reduced pressure to obtain 1.4 lg of lansoprazole as a white crystal. The yield of the crystal was 95.0%».

While the present invention has been described with reference to the preferred embodiment thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. A process for preparing lansoprazole (I) comprising the steps of reacting 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (III) or its salt with 2- > mercaptobenzimidazole (TV) in the presence of a halogenating agent and reaction solvent; and then oxidizing the resulting 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-lH-benzimidazole (II) with hydrogen peroxide in the presence of a benzeneseleninic acid catalyst and reaction medium.

2. A process for preparing 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methylthio-1 H-benzimidazole (II), which comprises reacting 2-hydroxymethyl-3- methyl-4-(2,2,2-trifluoroethoxy)pyridine (III) or its salt with 2-mercaptobenzimidazole (IV) in the presence of a halogenating agent and reaction solvent.

(II) (HI) (IV)

3. The process according to claim 1 or 2, wherein the said 2- mercaptobenzimidazole (TV) is used in an amount of about 1 to 4 equivalents to 2- hydroxymethyl-3 -methyl-4-(2,2,2-trifluoroethoxy)pyridine (HI) .

4. The process according to claim 1 or 2, wherein a thiosulfate compound selected from the group consisting of sodium thiosulfate (Na₂S₂O₃), potassium thiosulfate (K₂S₂O ), calcium thiosulfate (CaS O₃), and tetrabutylammonium thiosulfate ((Bu₄N)₂S O₃) is added in an amount of about 0.001 to 0.5 equivalent of the compound (III) when the said compound (III) or its salt is reacted with 2- mercaptobenzimidazole (IV).

5. The process according to claim 1 or 2, wherein the said halogenating agent is selected from the group consisting of phosphorous tribromide (PBr₃), phosphorous trichloride (PC1 ), phosphorous pentabromide (PBr₅), phosphorous pentachloride (PC1₅), phosphorous oxybromide (POBr₃), phosphorous oxychloride (POCl ), and mixtures thereof.

6. The process according to claim 5, wherein the said halogenating agent is used in an amount of 1 to 15 equivalents of said compound (DI).

7. The process according to claim 1, wherein the said benzeneseleninic acid is used in an amount of 0.0001 to 0.2 equivalents of said compound (Et).

8. The method according to claim 1, wherein the said hydrogen peroxide is used in an amount of 0.95 to 2.0 equivalents of said compound (H).