KR100430575B1 - Method of Preparing Lansoprazole and Its Intermediate - Google Patents

Abstract

The present invention provides 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole represented by the following general formula (I) 2- (3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl], represented by the following formula (II), and lansoprazole) A method for preparing methylthio-1H-benzimidazole, the method comprising: 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt thereof in a reaction solvent; Halogenating agent and additive are added to the mercaptobenzimidazole, and 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio- of formula (II) It is a method for preparing lansoprazole by preparing 1H-benzimidazole in high yield and oxidizing it with hydrogen peroxide under a reaction solvent and a benzeneselenic acid catalyst.

Description

Method for preparing lansoprazole and its intermediates {Method of Preparing Lansoprazole and Its Intermediate}

The present invention is an anti-ulcer agent 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl, which is an anti-ulcer agent having an excellent effect on gastric acid secretion and gastric mucosal protection A novel process for preparing -1H-benzimidazole and its intermediates. More specifically, the present invention relates to halogenated 2-mercaptobenzimidazole in 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt thereof in a reaction solvent. The reaction was carried out with the addition of an additive to yield 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole in high yield (96% or more). Prepared and oxidized with hydrogen peroxide under benzeneselenine acid catalyst to 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimi The present invention relates to a method for preparing a dozol.

2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole (Formula I) is used to inhibit gastric acid secretion and gastric mucosal protection. It is a compound known as an anti-ulcer agent that shows excellent effects. 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole and its intermediate 2- [3- Method for preparing methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole (Formula II) is disclosed in Korean Patent Publication No. 92-2128 (Takeda) , Republic of Korea Patent Publication No. 96-0047 (Takeda), Republic of Korea Patent Publication No. 97-6299, European Patent No. 0,174,726 (Takeda), European Patent No. 0,446,961 (Takeda), United States Patent No. 4,689,333 (Takeda), United States Patent 5,374,730, WO 95/12590, and WO 97/29103 (PDI Research Laboratories). In addition, methods for preparing such compounds are also described in various academic documents, such as Tetrahedron, 42/17, 5459 (1986), Chemical Abstract, 97/5, 547 (1982), Chemical Abstract, 68/1, 658 (1968), and the like. have.

The manufacturing methods disclosed in the above document are summarized as follows.

The compound represented by formula (II) is 2-mercaptobenzimidazole represented by formula (IV) and 3-methyl-4- (2,2, represented by formula (V) as shown in Scheme 1 below. Through the coupling reaction of 2-trifluoroethoxy) pyridine derivative, or 2-mercaptomethyl-3-methyl-4- represented by the benzimidazole derivative represented by the following general formula (VI) and the following general formula (VII) It can be prepared through the coupling reaction of (2,2,2-trifluoroethoxy) pyridine (Korean Patent Publication No. 92-2128).

In the above scheme, X is a leaving group, specifically, a halogen atom, an arylsulfonyloxy group, a C _1-4 alkylsulfonyloxy group, or an organic phosphoryloxy group.

In this method, a base such as alkali metal, alkali metal hydride or carbonate, sodium alcoholate, or organic amine is used to increase reactivity, and alcohol or dimethylformamide is used as a reaction solvent.

Disadvantages of this method are firstly obtained from the compound of formula (V) from 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine (Formula III) It is necessary to carry out the coupling reaction with the compound of), which requires substantially two steps. For example, when X is a chlorine atom in formula (V), a separation operation or a concentration process is necessary to remove the remaining thionyl chloride after reacting formula (III) with thionyl chloride. Second, the base should be used to increase the reactivity. Third, the separation process is performed through column chromatography, which is inappropriate for mass synthesis. Fourth, the yield of the final product (64.5%) is low.

The preparation method of the compound represented by the formula (I) can be summarized in two ways as follows by oxidizing the compound of the formula (II) as shown in Scheme 2 below.

The first method is a method of synthesizing the compound represented by the formula (I) through the oxidation reaction of the compound represented by the formula (II) as disclosed in the Republic of Korea Patent Publication No. 92-2128. The oxidant is peracid, sodium bromide, sodium hypochloride, or hydrogen peroxide and the reaction solvent is a halogenated hydrocarbon, ether, amide, alcohol, or water.

The disadvantages of this method are, firstly, not only the desired compound (I), which is a desired compound in the oxidation reaction, but 2- [3-methyl of formula (VIII) 4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide is obtained in significant amounts as a reaction byproduct.

Second, it is difficult to completely remove the color even when the color of the reaction solution is changed to dark purple to separate the compound of formula (I) therefrom. Third, the yield of the product is as low as 77%, and fourth, is separated by column chromatography, which is not suitable for mass synthesis.

The second production method of formula (I) is a method described in Korean Patent Publication No. 96-0047, which is a further improvement of the first method. In the presence of a vanadium compound as a catalyst, a compound of formula (I) is prepared by oxidizing a compound of formula (II) with hydrogen peroxide, which is a low-cost oxidant, instead of an expensive oxidant (m-chloroperbenzoic acid). This method has the advantage of increasing the yield of the product and the amount of N-oxide compound of the general formula (VIII) by-products can be reduced than the conventional method. However, in order to solve this problem, the vanadium compound must be increased to synthesize the compound of formula (I), and the reaction by-product, 2- [3-methyl-4- (2,2,2) The disadvantage is that trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide is produced in large amounts of about 4%.

The inventors have found that high quality 2- [3-methyl-4- (2,2,2,2,2,2,2,2-trifluoroethoxy) pyridine 2-Trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole was prepared in high yield and 2- [3-methyl-4- (2,2,2-trifluoro) was obtained from this compound. By-products such as loethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide are less produced and the desired product is 2- [3-methyl-4- (2,2,2-trifluoro Ethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole has led to the development of a process for high yield. In particular, by-products such as 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide of formula (VIII) Is finally the desired product with 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole of formula (I) General purification methods such as recrystallization due to similar physical properties include 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole Since it is difficult to remove from the present inventors, the inventors invented 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole in the reaction step. The research focused on finding conditions that produce less than 1% of N-oxide.

As a result, the present inventors added a halogenating agent and 2-mercaptobenzimidazole from a compound of formula (III) as well as a salt thereof without using a base to prepare 2- [3-methyl-4- (2,2) of formula (II). , 2-Trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole was prepared in high yield, which was oxidized with hydrogen peroxide under a reaction solvent and a benzeneselenic acid catalyst to afford 2- [3-methyl. A method for preparing -4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole has been developed.

Therefore, according to the present invention, it is possible to effectively proceed the reaction without using any base, and unlike the conventional reaction process, which undergoes a two-step process, only a one-step process that does not require a separate separation process or a concentration process than the known method. The compound of formula (II) can be prepared in high yield, and the oxidation reaction can be progressed to hydrogen peroxide under a benzene selenic acid catalyst to increase the reaction completeness while generating less by-products such as formula (VIII). It is possible to prepare high quality, high yield 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole in a simple and economical way. have.

An object of the present invention is an anti-ulcer agent 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl, which has an excellent effect on inhibiting gastric acid secretion and gastric mucosal protection. It is to provide a new method for preparing sulfinyl-1H-benzimidazole.

Another object of the present invention, unlike the known art, is 2- [3-methyl-4- (2,2) as a one-step reaction under acidic conditions in a reaction liquid state without a separate concentration operation or separation process and without using a base. 2- [3-methyl-4- (2,2,2-trifluoroethoxy), a reaction intermediate of, 2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole To provide a method for producing 2-pyridyl] methylthio-1H-benzimidazole.

Still another object of the present invention is to provide a simpler and more economical way of purifying 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimi It is to provide a method for producing a high yield of the doazole and its intermediates.

Another object of the present invention is 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole, a reaction byproduct that is difficult to separate. Less production of N-oxide from the reaction step yields high yield of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole To provide a method for producing.

It is another object of the present invention to prepare 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole in large quantities. It is to provide a suitable method.

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

The present invention relates to 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole (hereinafter referred to as' lansoprazole) (lansoprazole) 'and its intermediate 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H- of formula (II) It relates to a process for preparing benzimidazole. The lansoprazole is 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt compound thereof, and 2-mercapto of formula (IV) Reacting benzimidazole under a reaction solvent and a halogenating agent, and 2- [3-methyl-4- (2,2,2-trifluoroethoxy)-of the formula (II) And oxidizing the 2-pyridyl] methylthio-1H-benzimidazole compound with hydrogen peroxide under a reaction solvent and a benzeneselenic acid catalyst. In the oxidation step, benzene seleninic acid 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.

In the present invention, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole of formula (II) and (I) Lansoprazole is prepared according to Scheme 3 below.

First Step: Preparation of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole

In the reaction solvent, a halogenating agent and 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt compound thereof represented by the above formula (III) and the above formula (IV) 2-mercaptobenzimidazole represented by the above reaction was carried out simultaneously or sequentially to react 2- (3-methyl-4- (2,2,2-trifluoroethoxy) represented by the formula (II) as an intermediate of lansoprazole. ) -2-pyridyl] methylthio-1H-benzimidazole is prepared.

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

2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine of Formula (III) may be prepared as described in Korean Patent Publication No. 92-2128 (Takeda). It can be prepared from 3-lutidine, and the compound of formula (III) can also be used in the form of its salt in combination with an acid, for example in the form of a hydrochloride salt, bromic acid salt, or iodic salt.

2-mercaptobenzimidazole of formula (IV) used in the reaction is equivalent to or greater than 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine. Used, preferably 1 to 4 equivalents, more preferably 1 to 1.5 equivalents. 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 10 minutes to 3 hours. When the halogenating agent and 2-mercaptobenzimidazole are added sequentially, an appropriate time interval is from 8 hours immediately after incorporation of the halogenating agent, preferably 5 minutes to 3 hours.

Halogenating agents used in the reaction are halogenated phosphorus compounds, for example phosphorus tribromide (PBr ₃ ), phosphorus trichloride (PCl ₃ ), phosphorus pentabromide (PBr ₅ ), phosphorus pentachloride (PCl ₅ ) , Phosphorus oxybromide (POBr ₃ ), phosphorus oxychloride (POCl ₃ ); Or mixtures thereof, preferably phosphorus trihalides. The halogenating agent is 1 equivalent (1/3 times in molar ratio) to 15 equivalents (5 times in molar ratio) based on 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine It is used, More preferably, 2 to 3 equivalents are used.

Optionally, additives can be added to the reaction. When the thiosulfate compound is used as an additive, there is a yield increase effect of about 2%, and the thiosulfate compound used here is sodium thiosulfate (Na ₂ S ₂ O ₃ ), potassium thiosulfate (K ₂ S ₂ O ₃ ), calcium Thiosulfate (CaS ₂ O ₃ ), or tetrabutylammonium thiosulfate ((Bu ₄ N) ₂ S ₂ O ₃ ), most preferably sodium thiosulfate. The thiosulfate compound is used in an amount of 0.001 equivalents to 0.5 equivalents, preferably 0.01 equivalents to 0.2 equivalents, relative to 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine. .

The compound of formula (II) synthesized as described above may be recovered by cooling the reaction solution, basifying it, extracting it into an organic layer, and concentrating, and purifying with a higher purity using a general purification method, in particular, ethyl acetate and hexane. Can be.

According to the preparation method of the present invention, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole is 2-hydroxymethyl- It can be prepared from 3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt thereof in high yield and high purity of 96% or more. In particular, 2-halomethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine of the formula (V), which is a reaction intermediate produced during the reaction, is prepared without a separate concentration or separation process. And 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H as a one-step reaction under acidic conditions in a reaction solution state without using a base. It is characterized by the possibility of synthesis of benzimidazole.

In the above formula, X is a halogen atom, ie bromine or chlorine.

Second Step: Preparation of Lansoprazole

2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole produced in the first step of the present invention is reacted with Lansoprazole represented by the formula (I) is prepared by oxidation with hydrogen peroxide in the presence of a catalyst.

The reaction solvent used in the second step of the present invention may be halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; Or ethers such as tetrahydrofuran and dioxane, of which dichloromethane and chloroform are preferred.

The catalyst used in the reaction is benzeneseleninic acid (PhSeO ₂ H), and the amount of use is 0.0001 to 0.2 equivalents, preferably 0.001 to 0.1 equivalents, and most preferably 0.002 to 0.01 based on the compound of formula (II). It is equivalent.

Hydrogen peroxide is generally used in 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 2.0 equivalents, preferably 0.95 to 1.4 equivalents, most preferably 1.0 to 1.1 equivalents based on the compound of formula (II).

Reaction temperature is 0-50 degreeC, Preferably it is 5-35 degreeC, More preferably, it is 10-25 degreeC. The reaction time is 5 minutes to 48 hours, preferably 30 minutes to 10 hours, and more preferably 1 to 6 hours.

Compounds of formula (I) synthesized by the methods described above are terminated by a common method of decomposing hydrogen peroxide (e.g. by addition of aqueous sodium thiosulfate solution), extracted with a solvent such as dichloromethane, concentrated and aceto It can be crystallized with an aqueous solution of nitrile or an aqueous solution of ethanol. Also, in order to obtain a better quality product, it may be purified by a general purification method such as recrystallization using a solvent such as ethanol or water.

According to the present invention as described above, the lansoprazole from 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole is prepared with high quality and It can be produced in high yield (about 90% or more). In particular, the amount of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide produced as a byproduct during the reaction Can be significantly reduced to less than 1.5%. If necessary, a general purification procedure such as Example 7-8 below may be carried out to form 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl in the product. The amount of -1H-benzimidazole N-oxide can be reduced to 0.1% or less.

The invention can be better understood by the following examples and reference 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 1-6 Preparation of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole

Example 1

23 g (0.10 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 1 L of dichloromethane, cooled to 4 ° C, and phosphorus tribromide (PBr ₃ ) 9.9 ml (0.10 mol), 2-mercaptobenzimidazole 15.6 g (0.10 mol), and sodium thiosulfate 3.3 g (0.02 mol) were sequentially added at 10 ° C. or lower, and refluxed for 2.5 hours. After the reaction was completed, the reaction solution heated by the reflux process was cooled to room temperature and 4 N -caustic soda was added so that the pH of the reaction solution was 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After the organic layer was separated, the remaining solution was crystallized from 630 ml of a mixture of ethyl acetate: hexane = 1: 6, which was a light white crystal, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-. 34.2 g of pyridyl] methylthio-1H-benzimidazole was obtained. The yield of crystals was 93%.

Example 2

23 g (0.10 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 1 L of dichloromethane, cooled to 4 ° C, and phosphorus tribromide (PBr ₃ ) 9.9 ml (0.10 mol) was slowly added at 10 ° C or less, and then refluxed for 1 hour. The reaction solution heated by reflux was cooled to room temperature, 15.6 g (0.10 mol) of 2-mercaptobenzimidazole and 3.3 g (0.02 mol) of sodium thiosulfate were added thereto, and the mixture was refluxed for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature again and 4N -caustic soda was added to bring the pH of the reaction solution to 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 630 ml of a mixture of ethyl acetate: hexane = 1: 6 to yield a light white crystal, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio- 35.3 g of 1H-benzimidazole was obtained. The yield of crystals was 96%.

Example 3

26.8 g (0.10 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine hydrochloride were suspended in 1 L of dichloromethane and then cooled to 4 ° C., followed by phosphorus 9.9 ml (0.10 mol) of tribromide (PBr ₃ ), 15.6 g (0.10 mol) of 2-mercaptobenzimidazole, and 3.3 g (0.02 mol) of sodium thiosulfate were sequentially added at 10 ° C. or below and refluxed for 2.5 hours. . After the reaction was completed, the reaction solution was cooled to room temperature and the pH of the reaction solution was adjusted to 13.5-14 using 4 N -caustic soda. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 630 ml of a mixture of ethyl acetate: hexane = 1: 6 to yield a light white crystal, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio- 33.8 g of 1H-benzimidazole was obtained. The yield of crystals was 92.1%.

Example 4

10 g (0.0452 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 400 ml of dichloromethane, cooled to 4 ° C, and phosphorus trichloride (PCl ₃ ) 3.94 ml (0.0452 mol) was slowly added at 10 ° C. or lower, and then refluxed for 1 hour. The reaction solution was cooled to room temperature, and 6.79 g (0.0452 mol) of 2-mercaptobenzimidazole and 1.43 g (0.00904 mol) of sodium thiosulfate were refluxed for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and 4N -caustic soda was added to bring the pH of the reaction solution to 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 280 ml of a mixture of ethyl acetate: hexane = 1: 6 to yield a light white crystal, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio- 4.9 g of 1H-benzimidazole was obtained. The yield of crystals was 93%.

Example 5

2.0 g (9.04 mmol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 80 ml of dichloromethane, cooled to 4 ° C., and phosphorus oxybromide ( 2.59 g (9.04 mmol) of POBr ₃ was slowly added at 10 ° C. or lower, and then refluxed for 1 hour. The reaction solution was cooled to room temperature, 1.36 g (9.04 mmol) of 2-mercaptobenzimidazole and 0.29 g (1.81 mmol) of sodium thiosulfate were added thereto, and the mixture was refluxed for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature again and 4N -caustic soda was added to bring the pH of the reaction solution to 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 56 ml of a mixture of ethyl acetate: hexane = 1: 6 to yield white-white crystals 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H 2.69 g of benzimidazole were obtained. The yield of crystals was 84.3%.

Comparative Example 1

5 g (0.0226 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 200 ml of dichloromethane, cooled to 4 ° C, and thionyl chloride (SOCl ₂ ) 1.65ml (0.0226mol), 2-39-capcapbenzimidazole 3.39g (0.0226mol) and 0.72g (0.00452mol) sodium thiosulfate were added in this order and refluxed for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and 4N -caustic soda was added to bring the pH of the reaction solution to 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 140 ml of a mixture of ethyl acetate: hexane = 1: 7 to give pale pink crystals of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio 3.86 g of -1H-benzimidazole were obtained. The yield of crystals was 48.3%.

As a halogenating agent, when comparing Comparative Example 1 to which thionyl chloride which is generally used is added compared with Example 1-5 according to the present invention, it was confirmed that there is a significant difference in product yield.

Example 6: Preparation of Lansoprazole

1.5 g (4.24 mmol) of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole prepared in Example 2 was prepared. After suspended in 30 ml of dichloromethane, 2.01 mg (0.0106 mmol) of benzene selenic acid (PhSeO ₂ H) was added thereto, and the suspension was cooled to 10 ° C. 2 ml of tert -butanol and 0.376 ml (4.46 mmol) of 35.7% hydrogen peroxide solution were added below 10 ° C. After the reaction was completed by stirring for 5 hours while maintaining the temperature of the reaction solution at 15 to 20 ° C., the reaction solution was cooled to 5 ° C. and 0.4 g of sodium thiosulfate dissolved in 20 ml of water was slowly added dropwise at 10 ° C. The mixture was stirred vigorously for about 30 minutes at about ℃. The organic layer was separated and washed with 20 ml of water. The washed organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, dissolved in about 5 ml of ethanol before crystals were precipitated, and then concentrated and recrystallized. The crystals were collected and dried in vacuo to yield 1.51 g of a pale beige solid product. The yield of the product was 95.1%.

Reference Example 1-2: Preparation of Lansoprazole by Known Technology

Reference Example 1

1.68 g of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole was suspended in 30 ml of dichloromethane and 15 to 20 ° C. Hydrogen peroxide solution dissolved in tert -butanol (2.75 ml for 0.2 g of hydrogen peroxide) containing 5 mg of vanadium pentaoxide was added dropwise, followed by reaction at 20 to 25 ° C. for about 1 hour. After the reaction was completed, aqueous sodium thiosulfate solution (0.5 g / 30 ml) was added to the reaction mixture, stirred vigorously for about 10 minutes and left to separate into layers. The dichloromethane layer was washed with 30 ml of water, dried over magnesium sulfate, concentrated under reduced pressure, dissolved in about 5 ml of ethanol before crystals were precipitated, and then concentrated and recrystallized. The crystals were collected and dried in vacuo to yield 1.63 g of the target compound as a light brown-purple solid (yield: 93.0%).

Reference Example 2

1.5 g of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole was suspended in 20 ml of chloroform and cooled to 5 ° C. A solution in which 1.0 g of m-chloroperbenzoic acid was dissolved in 15 ml of chloroform at 5 ° C. or lower was slowly added dropwise for 30 minutes. It stirred at 0-5 degreeC until completion of reaction (about 1 hour). After the reaction was completed, the reaction was washed with aqueous sodium hydrogen carbonate solution. The separated organic layer was dried over magnesium sulfate, concentrated under reduced pressure, dissolved in about 5 ml of ethanol before precipitation of crystals, and then concentrated and recrystallized. The crystals were collected and dried in vacuo to yield 1.61 g of the target compound as a purple solid (yield: 103%).

Yield, content, and high performance liquid chromatography (HPLC) analysis results of the respective lansoprazole products prepared according to Reference Examples 1 and 2 according to Example 6 according to the present invention and known techniques (Korean Patent Publication No. 96-0047) The comparison is shown in Table 1 below.

High performance liquid chromatography (HPLC) analysis conditions are as follows.

Equipment used: YOUNG-LIN High Performance Liquid Chromatograph Type M930

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

Detector: Young UV absorbance photometer type M720

Data Processing Unit: Autochro-Win

Measurement wavelength: 254nm

Mobile phase: A mixture of methanol: water: triethylamine adjusted to pH 7.0 by adding phosphoric acid (60: 40: 1)

Flow rate: 0.7ml / min

Time required for analysis: 50 minutes

Column temperature: fixed temperature of about 25 ° C

In Table 1, the content represents the content of the product sample obtained as a result of the experiment on the basis of a commercial standard, which was obtained according to the following formula:

Content (%) = [Standard Weight (g) / Sample Weight (g)] × [Standard Product Area / Sample Area in HPLC] × [Water Weight of Sample / Water Weight of Sample] × 100

Manufacturing method 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) ^b 96.8% 93.6% 93.3% Compound (VIII) ^b 1.21% 4.19% 4.53%

a: theoretical yield before purification

b: area ratio in high performance liquid chromatography

As shown in Table 1 above, the theoretical yield of the product was not different between Example 6 and Reference Examples 1-2. However, comparing the content with respect to the external standard, and the area ratio in high performance liquid chromatography, it can be seen that the case of Example 6 is superior to the purity and actual yield of the product than the case of the reference example carried out according to the known technology. In particular, as a result of high performance liquid chromatography analysis, according to the present invention, the amount of N-oxide compound of the general formula (VIII), which is a reaction byproduct, was significantly reduced to about 1%.

Example 7-8 Purification of Lansoprazole

Example 7

12.1 ml of ethanol was added to 1.51 g of lansoprazole which was not subjected to the purification obtained in Example 6, and heated to 45 to 50 ° C. to completely dissolve the crystals. 4.03 ml of water was added thereto, and the mixture was slowly cooled to 5 ° C. The mixture was left for 3 hours at 5 ° C. to completely precipitate the crystals, and then the obtained crystals were filtered and washed with a 5 ° C. ethanol: water = 3: 1 mixture. The crystals were collected and dried in vacuo to yield 1.45 g of lansoprazole, a white crystal. The yield of the crystal was 96.1%. 11.6 ml of ethanol was further added to the obtained crystals, and the mixture was heated to 45 to 50 ° C to completely dissolve the solid. After the insoluble matters were removed by thermal filtration, 1.66 ml of water was added thereto and slowly cooled to 5 ° C. After standing at the same temperature for 3 hours to completely precipitate the crystals, the obtained crystals were filtered and washed with a ethanol: water = 7: 1 mixture at 5 ° C. The crystals were collected and dried in vacuo to give 1.40 g of lansoprazole as white crystals. The yield of crystals was 96.3%.

Example 8

52.9 ml of acetonitrile was added to 1.51 g of lansoprazole, which was not subjected to the purification obtained in Example 6, and heated to 50 to 55 ° C to completely dissolve the solid. 5.29 ml of water is added, and after cooling slowly to room temperature, about 48 ml are concentrated and removed under reduced pressure. After standing at 5 ° C. for 3 hours to completely precipitate crystals, the obtained crystals were filtered and washed with acetonitrile: water = 10: 1 mixture at 5 ° C. The crystals were collected and dried in vacuo to give 1.48 g of lansoprazole as a white crystal. The yield of the crystal was 98.0%. 11.8 ml of ethanol was further added to the obtained crystals, and the mixture was heated to 45 to 50 ° C to completely dissolve the solid. After thermal filtration to remove the insoluble matter, 1.69 ml of water was added and slowly cooled to 5 ° C. After standing at 5 ° C. for 3 hours to completely precipitate the crystals, the obtained crystals were filtered and washed with 5 ° C. ethanol: water = 7: 1 mixture. The crystals were collected and dried in vacuo to yield 1.41 g of lansoprazole as a white crystal. The yield of the crystal was 95.0%.

The present invention provides a large amount of lansoprazole and its intermediates, which are anti-ulcer agents that exhibit superior effects on gastric acid secretion inhibition and gastric mucosa protection with high purity and yield in a simpler and more economical way than the prior art by reducing the reaction step and using a low-cost oxidant. It has the effect of providing the manufacturing method.

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 (10)

2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or its salt compound of formula (III) and 2-mercaptobenzimidazole of formula (IV) Reacting under a reaction solvent, a halogenated phosphorus compound, and a thiosulfate compound; And 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole compound of formula (II) Oxidizing with hydrogen peroxide under a reaction solvent and a benzeneselenic acid catalyst; Preparation of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole (lansoprazole) having the following formula (I) Way. 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or its salt compound of formula (III) and 2-mercaptobenzimidazole of formula (IV) Is reacted under a reaction solvent, a halogenated phosphorus compound, and a thiosulfate compound to yield 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] of formula (II) A process for preparing a methylthio-1H-benzimidazole compound. The 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole produced according to claim 2 is reacted with a reaction solvent and benzeneselenin. A process for preparing lansoprazole of formula (I) by oxidation with hydrogen peroxide under an acid catalyst. The process according to any one of claims 1 to 3, wherein the reaction solvent is a halogenated hydrocarbon or ether. The method according to claim 1 or 2, wherein the 2-mercaptobenzimidazole is 1 to 4 relative to 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine. The equivalent method is used, The manufacturing method characterized by the above-mentioned. The method of claim 1 or 2, wherein the thiosulfate compound in the step of preparing the compound of formula (II) is sodium thiosulfate (Na ₂ S ₂ O ₃ ), potassium thiosulfate (K ₂ S ₂ O ₃ ), calcium Thiosulfate (CaS ₂ O ₃ ), and tetrabutylammonium thiosulfate ((Bu ₄ N) ₂ S ₂ O ₃ ), which is used in an amount of 0.001 to 0.5 equivalents based on the compound of formula (III) The manufacturing method characterized by the above-mentioned. According to claim 1 or 2, wherein the halogenated phosphorus compound is phosphorus tribromide (PBr ₃ ), phosphorus trichloride (PCl ₃ ), phosphorus pentabromide (PBr ₅ ), phosphorus pentachloride (PCl ₅ ), phosphorus oxybromide (POBr _3), phosphorus oxychloride (POCl _3), and is selected from the group consisting of a mixture thereof, to 1 equivalent of one-third times (molar ratio of a compound represented by the above formula (III)) The manufacturing method characterized by using 15 equivalent (5 times molar ratio). The method of claim 1, wherein the halogenated phosphorus compound is phosphorus tribromide (PBr ₃ ), and the thiosulfate compound is sodium thiosulfate (Na ₂ S ₂ O ₃ ). The method according to claim 1 or 3, wherein the benzene selenine acid is used in an amount of 0.0001 to 0.2 equivalents based on the compound of formula (II). The method according to claim 1 or 3, wherein the hydrogen peroxide is used in an amount of 0.95 to 2.0 equivalents based on the compound of formula (II).