KR20060102245A - Method of preparing pantoprazole and its intermediate - Google Patents

Abstract

The present invention relates to a new method for producing pantoprazole represented by the following formula (I) and an intermediate thereof, which are anti-ulcer agents exhibiting excellent effects on gastric acid secretion and gastric mucosal protection. The present invention relates to the reaction of 2-hydroxymethyl-3,4-dimethoxypyridine or salt thereof with 5- (difluoromethoxy) -2-mercaptobenzimidazole with phosphorus tribromide to give 5- (difluorome Methoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole was prepared in high yield and oxidized with hydrogen peroxide under a mixed catalyst of benzene selenic acid and trialkylamine to panto To prepare a prasol.

Pantoprazole, 5- (difluoromethoxy) -2-[[3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 5- (difluoromethoxy)- 2- [3,4-Dimethoxy-2-pyridyl] methylthio-1H-benzimidazole, benzeneselenic acid

Description

Method for Preparing Pantoprazole and Its Intermediate {Method of Preparing Pantoprazole and Its Intermediate}

The present invention relates to 5- (difluoromethoxy) -2-[[3,4-dimethoxy-2-pyridyl) represented by formula (I), which is an anti-ulcer agent showing an excellent effect on gastric acid secretion and gastric mucosal protection. Methyl] sulfinyl] -1H-benzimidazole (hereinafter referred to as pantoprazole) and a novel process for the preparation thereof. More specifically, the present invention relates to 2-hydroxymethyl-3,4-dimethoxypyridine represented by formula (III) or a salt thereof and 5- (difluoromethoxy) -2-mercapto represented by formula (IV). Benzimidazole is reacted with phosphorus tribromide (PBr ₃ ) to 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H represented by formula (II) -Benzimidazole is prepared and oxidized with hydrogen peroxide under a mixed catalyst of benzene selenine acid (PhSeO ₂ H) and trialkylamine to prepare pantoprazole represented by the formula (I).

Pantoprazole represented by formula (I) is very unstable to acids due to its structural properties, so to solve this problem, stable and storeable oral dosage forms (e.g. tablets or capsules) made in the form of sodium salts Used as

Methods of preparing pantoprazole are disclosed in European Patent No. 166287, Australian Patent No. 394368, International Patent Publication Nos. 97/29103, 02/28852 and 03/8406.

European Patent No. 166287, the first patent application describing a method for preparing pantoprazole, introduces a variety of synthetic processes for pantoprazole as shown in Scheme 1.

Scheme 1

Wherein Y and Z are leaving groups and Me is an alkali metal.

In addition, European Patent No. 166287 presents the synthesis process of Scheme 2 in detail, and this method is known as the most economical method of the synthesis of pantoprazole known to date.

Scheme 2

Although the synthesis method shown in Scheme 2 is the best method among the known methods, the reaction yield of the three steps does not reach 90%, and there is a problem that various by-products are detected in the third process. Representative by-products produced at this time include 5- (difluoromethoxy) -2-[[3,4- of formula (VI), which is formed by oxidation of nitrogen present in the pyridine ring of the compound represented by formula (I). Dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole N-oxide or 5- (difluoromethoxy) of formula (VII) in which the sulfinyl group of the compound represented by formula (I) is oxidized ) -2-[[3,4-dimethoxy-2-pyridyl) methyl] sulfonyl] -1H-benzimidazole and the like.

More specifically, in the case of m-chloroperbenzoic acid, which is most commonly used for such a reaction, there is a problem in that the reaction should be carried out at a low temperature of about -30 ° C in order to minimize the generation of by-products. In addition, despite these efforts, by-products are generated, and complex purification processes are required to remove them.

Australian patent 394368 proposes a new method of methylating the hydroxy group at position 4 of the pyridine ring as in Scheme 3. However, this method has a problem that a large amount of unwanted by-products are generated by introducing a methyl group into the benzimidazole ring as well as the pyridine ring during the methylation process.

Scheme 3

International Patent Publication No. 97/29103 discloses a new method for preparing pantoprazole as shown in Scheme 4. However, this method has a problem that the efficiency is less than the process described in Scheme 2.

Scheme 4

International Patent Publication No. 02/28852 proposes a new method for preparing pantoprazole by introducing a methoxy group at the position 4 of the pyridine ring as in Scheme 5. However, this method also has a problem that the efficiency of the synthesis process becomes worse by introducing a methyl group to be introduced at the beginning of the synthesis process at the end of the synthesis process.

Scheme 5

International Patent Publication No. 03/8406 discloses 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by formula (II). A method for preparing pantoprazole has been proposed by oxidizing with chloroperbenzoic acid and then extracting and removing by-product represented by formula (VII) with basic aqueous solution. This method can effectively remove the by-product represented by the formula (VII), but there is a problem that the process is very complicated and the yield is also greatly lowered. The results of this document, after all, explain well how many by-products in the oxidation reaction of the compound represented by the formula (II) in the case of a commonly used oxidant such as m-chloroperbenzoic acid and how many problems.

Therefore, the present inventors have attempted to develop a method for preparing pantoprazole and its intermediates in a high yield in a simpler manner than known methods.

In particular, 5- (difluoromethoxy) -2-[[3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole N-oxide represented by formula (VI) or By-products such as 5- (difluoromethoxy) -2-[[3,4-dimethoxy-2-pyridyl) methyl] sulfonyl] -1H-benzimidazole represented by VII) are the final product Since the physical properties are similar to pantoprazole represented by the formula (I), and thus it is difficult to be removed by a general purification method such as recrystallization, the present inventors focused on finding conditions under which such by-products are produced from the reaction step. It was.

As a result, the inventors of the present invention have shown that 2-hydroxymethyl-3,4-dimethoxypyridine represented by formula (III) and 5- (difluoromethoxy)-represented by formula (IV) and phosphorus tribromide thereof. When 2-mercaptobenzimidazole is added, 5- (difluoromethoxy) -2- [3,4-dimethoxy-2- represented by the formula (II) which is an intermediate of pantoprazole without using any base. It was found that pyridyl] methylthio-1H-benzimidazole could be obtained in high yield. In addition, 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by the formula (II) is reacted with a solvent, benzene selenic acid and trialkyl. Oxidation with hydrogen peroxide under a mixed catalyst of amines was found to yield pantoprazole, represented by formula (I), in high yield. In view of the fact that acids normally used as catalysts for hydrogen peroxide reaction did not proceed normally in the presence of a base, it was found that the benzene selenic acid used in the present invention is exceptionally suitable for this reaction.

According to the present invention, it is possible to effectively proceed the reaction without using any base, and unlike the conventional reaction process that goes through a two-step process, only a one-step process does not require a separate separation process in a higher yield than known methods 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by (II) can be prepared. In addition, according to the present invention, the compound (II) is oxidized with hydrogen peroxide under a mixed catalyst of benzene selenic acid and trialkylamine to prepare pantoprazole in high yield, thereby being represented by 5- (difluoro) represented by the formula (VI) Romethoxy) -2-[[3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole N-oxide or 5- (difluoromethoxy) represented by formula (VII) A simple and economical oxidation process can be carried out with little generation of by-products such as 2-[[3,4-dimethoxy-2-pyridyl) methyl] sulfonyl] -1H-benzimidazole.

It is an object of the present invention to provide a new method for preparing pantoprazole, an anti-ulcer agent which has an excellent effect on gastric acid secretion inhibition and gastric mucosal protection.

Another object of the present invention, unlike the known art, is 5- (difluoromethoxy)-which is a reaction intermediate of pantoprazole in a one-step reaction under acidic conditions in a reaction liquid state without a separate separation process and without using a base. It is to provide a process for preparing 2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole.

It is another object of the present invention to provide a method for producing pantoprazole in high purity and high yield more simply and economically.

Another object of the present invention is to provide a method suitable for producing pantoprazole in large quantities.

The above and other objects of the present invention can be achieved by the present invention described below.

The present invention relates to 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio represented by pantoprazole represented by general formula (I) and intermediates thereof (II). A method for preparing -1H-benzimidazole is provided.

Process for preparing pantoprazole according to the present invention can be represented by the following Scheme 6.

Scheme 6

As shown in Scheme 6, the method for preparing pantoprazole according to the present invention is 2-hydroxymethyl-3,4-dimethoxypyridine represented by formula (III) or a salt thereof and 5 represented by formula (IV). Reacting (difluoromethoxy) -2-mercaptobenzimidazole under a reaction solvent and phosphorus tribromide, and reacting the compound represented by the formula (II) produced by the reaction with a reaction solvent and benzene Oxidizing with hydrogen peroxide under a mixed catalyst of acid and trialkylamine. In the oxidation step, a mixed catalyst of benzene selenic acid and trialkylamine was used as a catalyst to increase reaction completion and minimize generation of by-products.

In the following, the present invention is described in more detail.

First Step: Preparation of 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole (II)

Phosphorus tribromide (PBr ₃ ) and 5- (difluorome) represented by formula (IV) to 2-hydroxymethyl-3,4-dimethoxy pyridine represented by formula (III) or a salt compound thereof under a reaction solvent 5- (difluoromethoxy) -2- [3,4-dimethoxy- represented by the formula (II), which is an intermediate of pantoprazole, by reacting by simultaneously or sequentially adding methoxy) -2-mercaptobenzimidazole 2-pyridyl] methylthio-1H-benzimidazole is prepared.

Solvents used in the reaction include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; Or ethers such as tetrahydrofuran, dioxane, with dichloromethane or chloroform being most preferred.

5- (difluoromethoxy) -2-mercaptobenzimidazole represented by the formula (IV) is equivalent to 2-hydroxymethyl-3,4-dimethoxypyridine or a salt compound thereof represented by the formula (III). Used as

Reaction temperature is the boiling point of 0 degreeC-reaction solvent, Preferably it is 20-85 degreeC, More preferably, it is 35-60 degreeC. The reaction time is from immediately after the start of the reaction to 24 hours, preferably 30 minutes to 3 hours.

Phosphorus tribromide is used in the amount of 1 equivalent (1/3 times molar ratio) to 15 equivalents (5 times molar ratio) relative to 2-hydroxymethyl-3,4-dimethoxypyridine represented by the formula (III), Preferably 2 to 3 equivalents are used.

Compound (II) obtained through the reaction as described above may be recovered by cooling the reaction solution, basifying it, extracting it into an organic layer, concentrating, and further purifying by a general purification method, for example, with ethyl acetate. Can be purified to higher purity with hexane.

According to the invention, 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by formula (II) is represented by formula (III) It can be prepared from the indicated 2-hydroxymethyl-3,4-dimethoxypyridine or its salt in high yield and high purity of 92% or more. In particular, the present invention is a 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyrid represented by the formula (II) in only one step process, unlike the prior art known through a two step process Dyl] methylthio-1H-benzimidazole is characterized in that it can be synthesized under acidic conditions in the reaction state without adding a base or a catalyst.

Second Step: Preparation of Pantoprazole (I)

In the second step, 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by the formula (II) produced in the first step. In the presence of a reaction solvent and a mixed catalyst of benzene selenine acid and trialkylamine, oxidized with hydrogen peroxide to prepare pantoprazole represented by the formula (I).

The reaction solvent used in the second step of the present invention is a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride; Ethers such as tetrahydrofuran, dioxane; Or water, of which dichloromethane and chloroform are preferred.

The catalyst used in the reaction is benzene selenic acid, and the amount used is 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H- represented by the formula (II). It is 0.0001 to 0.2 equivalent, preferably 0.001 to 0.1 equivalent, and most preferably 0.002 to 0.01 equivalent to benzimidazole.

Since pantoprazole, which is a reaction product, is unstable in acid, trialkylamine is used together with benzeneselenic acid to prevent acidification of the reaction solution. The trialkylamines used here are 1-methylpyrrolidine, N, N-diethylmethylamine, 1-methylpiperidine, triethylamine, N, N-diisopropylmethylamine, N, N-diiso Propylethylamine and the like, most preferably triethylamine and N, N-diisopropylethylamine. The amount of the trialkylamine used is 0.01 to 1.0 for 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by the formula (II). It is equivalent, Preferably it is 0.05-0.1 equivalent.

Hydrogen peroxide is generally used in the form of an aqueous solution of about 20 to 50%, but is not limited to the above range. The amount of hydrogen peroxide used is 0.95 to 1.2 equivalents based on 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by formula (II), Preferably it is 1.0-1.1 equivalent.

Reaction temperature is 0-50 degreeC, Preferably it is 5-35 degreeC, More preferably, it is 10-25 degreeC. The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 10 hours, and more preferably 1 to 6 hours.

The product obtained by the above method can be terminated by a general hydrogen peroxide decomposition method (for example, by adding an aqueous sodium thiosulfate solution), extracted with a solvent such as dichloromethane, and then concentrated and crystallized using acetone and hexane. . In addition, it can be purified by a general purification method such as recrystallization using a solvent such as acetone and water in order to obtain a better quality product.

As described above, according to the present invention, a chemical formula is obtained from 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by the formula (II). Pantoprazole represented by (I) can be manufactured with high quality and high yield (87% or more). In particular, 5- (difluoromethoxy) -2-[[3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole N- represented by formula (VI) as a reaction byproduct The amount of oxide and 5- (difluoromethoxy) -2-[[3,4-dimethoxy-2-pyridyl) methyl] sulfonyl] -1H-benzimidazole represented by the formula (VII) was 1.5 It can be significantly reduced below%. If necessary, the general purification process as in Example 3 below may reduce the amount of these by-products in the product to 0.1% or less.

The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection defined by the appended claims.

Example

Example 1: Preparation of 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole (II)

After dissolving 33.836 g (0.20 mol) of 2-hydroxymethyl-3,4-dimethoxypyridine in 1.2 l of dichloromethane, 54.14 g (0.20 mol) of phosphorus tribromide and 5- (difluoromethoxy) -2- 43.24 g (0.20 mol) of mercaptobenzimidazole were sequentially added at room temperature and then refluxed for 2.5 hours. After the reaction was completed, the reaction solution heated by reflux was cooled to room temperature and 4N-caustic soda was slowly added to bring the pH of the reaction solution to 13.5-14. 200 ml of acetone was added to the reaction solution, followed by vigorous stirring for 20 minutes. The organic layer was separated, and the water layer was reextracted with 200 ml of dichloromethane. The combined organic layers were combined, washed with 400 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solvent was removed, the remaining oily residue was suspended in 200 ml of ethyl acetate, and 700 ml of hexane was slowly added to give 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl as a white crystal. ] 67.601 g of methylthio-1H-benzimidazole was obtained. The yield of the crystal was 92.0%.

¹ H NMR (CDCl ₃ ) δ = 3.92 (3H, s), 3.94 (3H, s), 4.40 (2H, s), 6.51 (1H, t, J = 74.6 Hz), 6.86 (1H, d, J _{5 '6'} = 5.7 Hz, H-5 '), 6.98 (1H, dd, J _6,7 = 2.2 Hz, H-6), 7.32 (1H, d, H-4), 7.63 (1H, d, H -7), 8.26 (1H, d, H-6 '), 12.5 (1H, br)

Example 2: Preparation of 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole (II)

After dissolving 41.128 g (0.20 mol) of 2-hydroxymethyl-3,4-dimethoxypyridine hydrochloride in 1.2 l of dichloromethane, 54.14 g (0.20 mol) of phosphorus tribromide and 5- (difluoromethoxy) -2 43.24 g (0.20 mol) of mercaptobenzimidazole were added sequentially at room temperature and then refluxed for 2.5 hours. After the reaction was completed, the reaction solution heated by the reflux process was cooled to room temperature, and 4N-caustic soda was slowly added to make the pH of the reaction solution 13.5-14. 200 ml of acetone was added to the reaction solution, followed by vigorous stirring for 20 minutes. The organic layer was separated, and the water layer was reextracted with 200 ml of dichloromethane. The combined organic layers were combined, washed with 400 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solvent was removed, the remaining oily residue was suspended in 200 ml of ethyl acetate, and 700 ml of hexane was slowly added to give 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl as a white crystal. ] 67.642 g of methylthio-1H-benzimidazole was obtained. The yield of crystals was 92.1%.

¹ H NMR (CDCl ₃ ) δ = 3.92 (3H, s), 3.94 (3H, s), 4.40 (2H, s), 6.51 (1H, t, J = 74.6 Hz), 6.86 (1H, d, J _{5 '6'} = 5.7 Hz, H-5 '), 6.98 (1H, dd, J _6,7 = 2.2 Hz, H-6), 7.32 (1H, d, H-4), 7.63 (1H, d, H -7), 8.26 (1H, d, H-6 '), 12.5 (1H, br)

Example 3: Preparation of Pantoprazole (I)

31.85 g (86.69 mmol) of 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole obtained in Example 1 was dissolved in 600 ml of dichloromethane. Then, 82 mg (0.433 mmol) of benzene selenic acid was added thereto, and the suspension was cooled to 10 ° C. 1.21 mL (8.669 mmol) of triethylamine and 8.92 g (93.625 mmol) of 35.7% hydrogen peroxide solution were added at 10 占 폚 or lower. When the reaction was completed by stirring for 5 hours while slowly raising the temperature of the reaction solution to room temperature, the reaction solution was cooled to 5 ° C and an aqueous solution of 8 g of sodium thiosulfate dissolved in 400 ml of water was slowly added dropwise at 10 ° C or lower. The reaction solution was stirred vigorously at about 10 ° C. for 20 minutes, and the organic layer was separated and washed with 400 ml of water. The washed organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily crude product. 150 ml of acetone was added to the crude oily product, and 300 ml of hexane was slowly added dropwise, followed by stirring for 2 hours to crystallize. The obtained crystals were filtered, washed with 50 ml of a 1: 2 mixed solution of acetone and hexane, followed by vacuum drying to obtain 30.57 g of white crystals. The obtained crystals were again suspended in 150 ml of acetone, and then 50 ml of water was slowly added to completely dissolve the crystals. When 250 ml of water is slowly added dropwise, white crystals are obtained. The white crystals thus obtained were filtered, washed with 50 ml of a 1: 2 mixed solvent of water and acetone, followed by vacuum drying to obtain 28.9 g of white crystals. The yield of crystals was 87.0%.

¹ H NMR (CDCl ₃ ) δ = 3.82 (3H, s), 3.84 (3H, s), 4.82 (2H, AB, J = 13.1 Hz), 6.53 (1H, t, J = 74.2 Hz), 6.78 (1H , d, J _{5'6 '} = 5.5Hz, H-5'), 7.08 (1H, dd, J _6,7 = 8.8Hz, J _6,4 = 2.1Hz, H-6), 7.3 (1H, br , H-4), 7.6 (1H, br, H-7), 8.15 (1H, d, H-6 ′), 12.71 (1H, s)

The present invention relates to 2-hydroxymethyl-3,4-dimethoxypyridine represented by formula (III) or a salt thereof and 5- (difluoromethoxy) -2-mercaptobenzimidazole represented by formula (IV). Is reacted with phosphorus tribromide to yield 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by formula (II) in high yield. And it has the effect of providing a method for easily preparing pantoprazole represented by the formula (I) by oxidizing with hydrogen peroxide under a mixed catalyst of benzene selenine acid and trialkylamine. In the prior art related to the method for preparing pantoprazole, there is a problem that the reaction process is long, the synthesis yield is low, and the purification is difficult because a large amount of impurities are included in the final product. However, the present invention provides a two-step process for obtaining 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole (II) in one step. In addition to using a mixed catalyst of benzene selenic acid and trialkylamine, the yield and purity of the final product were greatly improved, and thus the purification was easy.

Simple modifications and variations of the present invention can be readily understood by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.

Claims (8)

5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by the following formula (II) was reacted with a solvent, benzeneselenic acid and trialkyl. A method for producing pantoprazole represented by the following formula (I) by oxidizing with hydrogen peroxide under a mixed catalyst of amines.

2-hydroxymethyl-3,4-dimethoxypyridine or salt thereof represented by the following formula (III) and 5- (difluoromethoxy) -2-mercaptobenzimidazole represented by the following formula (IV) 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by the following formula (II) by reacting with phosphorus tribromide under a reaction solvent Manufacturing, and, 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole (II) in the reaction solvent and the presence of a mixed catalyst of benzene selenic acid and trialkylamine Oxidized with hydrogen peroxide under: The manufacturing method of pantoprazole represented by following General formula (I) which consists of steps.

The method according to claim 1 or 2, wherein the benzene selenine acid is used in an amount of 0.0001 to 0.2 equivalents based on the compound represented by the formula (II). The compound of claim 1 or 2, wherein the trialkylamine is 1-methylpyrrolidine, N, N-diethylmethylamine, 1-methylpiperidine, triethylamine, N, N-diisopropylmethyl A method selected from the group consisting of amines, N, N-diisopropylethylamine and used in an amount of 0.01 to 1.0 equivalents based on the compound represented by formula (II). The method according to claim 1 or 2, wherein the hydrogen peroxide is used in an amount of 0.95 to 1.2 equivalents based on the compound represented by the formula (II). 2-hydroxymethyl-3,4-dimethoxypyridine or salt thereof represented by the following formula (III) and 5- (difluoromethoxy) -2-mercaptobenzimidazole represented by the following formula (IV) 5- (difluoromethoxy) -2- [3,4-dimethoxy-2-pyridyl] methylthio-1H-benzimidazole represented by the following formula (II) by reacting with phosphorus tribromide under a reaction solvent How to prepare.

The method according to claim 2 or 6, wherein the phosphorus tribromide is used in the range of 1 equivalent (1/3 times in molar ratio) to 15 equivalents (5 times in molar ratio) relative to the compound represented by Formula (III). . The process according to claim 1, 2 or 6, wherein the reaction solvent is a halogenated hydrocarbon or ether.