KR20110094751A - An improved process for preparing telmisartan - Google Patents

Abstract

PURPOSE: A method for preparing telmisartan is provided to easily remove inorganic salt using a reaction solvent and to simplify reaction process without a separate process. CONSTITUTION: A method for preparing telmisartan of chemical formula 1 comprises: a step of condensing a compound of chemical formula 2 and a compound of chemical formula 3 using dimethyl sulfoxide and isopropanol to prepare a compound of chemical formula 4; and a step of hydrolyzing the compound of chemical formula 4 in a mixture solvent of methanol and purified water.

Description

An improved process for preparing telmisartan}

The present invention relates to an improved method for preparing telmisartan, which is used as an angiotensin II receptor antagonist.

Telmisartan is represented by the following formula (1).

<Formula 1>

Telmisartan has been produced by the method described in Scheme 1 or by the method described in Scheme 2 below.

Preparation methods that can be represented by the following scheme 1 are known from U.S. Patent No. 5,591,762 and European Patent No. 1,912,975. The following Reaction Scheme 1 is a condensation reaction of the following Chemical Formula 2 compound with the following Chemical Formula 5 compound to prepare a t -butyl ester compound of the formula (6), and to hydrolyze the compound of the formula (6) to produce the desired compound telmisartan.

<Scheme 1>

U.S. Patent No. 5,591,762 discloses a t -butyl ester compound of Formula 6 as a N, N -dimethylformamide reaction solvent in the step of preparing telmisartan, which is a compound of Formula 1, from the compound of Formula 6, which is an intermediate compound. The compound of formula 1 is prepared by hydrolysis using trifluoroacetic acid.

By the way, the prior art hydrolyzed trifluoroacetic acid, which is a toxic strong acid, to remove sodium trifluoroacetate, which is an inorganic salt produced as a by-product, because an excess base must be used to neutralize it. After work-up process (reduced distillation under reduced pressure, purified water and organic solvent, adjust pH, separate the layers, wash the organic layer with purified water, and distill the extracted organic layer), and after completion of the reaction, telmisartan was purified using silica gel column chromatography. Because of the separation, not only is the manufacturing process complicated, but also has a large disadvantage of low yield.

In the above scheme 1, the European Patent Publication No. 1912975, an intermediate compound of formula (VI) compound, i.e., t - in using butyl ester for the production of a telmisartan compound of formula I, an intermediate compound is t - butyl ester compound with hydrochloric acid Treatment to obtain a t -butyl ester hydrochloride compound, hydrolyzed with hydrochloric acid to obtain a telmisartan dihydrochloride compound and then adjusting the pH with an aqueous ammonia solution to prepare the target compound telmisartan.

However, the prior art has a complicated manufacturing process for preparing telmisartan as the target compound from the compound of formula (6), which is an intermediate compound, and the total yield of the three processes for producing telmisartan as the target compound from the intermediate compound is very low as 54.5%. Not suitable for mass production

In addition, the method for producing telmisartan which can be represented by the following scheme 2 is US Patent No. 7,501,448, European Patent Publication No. 1,748,990, European Patent Publication No. 1,805,146, International Patent Publication WO 2009/006860, US Patent Application Publication No. 2006/276525, Chinese Patent No. 1,344,712, and US Patent Application Publication No. 2006/211866. That is, the compound of formula 2 and the compound of formula 3 are condensed to prepare a compound of formula 4, and the compound of formula 4 is hydrolyzed to prepare telmisartan.

<Scheme 2>

U.S. Patent No. 7,501,448 in the above Reaction Scheme 2, wherein the compound of formula 2 and the compound of formula 3 in the same process to perform the condensation reaction and hydrolysis reaction to produce the desired compound telmisartan, condensation reaction and hydrolysis In order to proceed with the reaction at the same time, an excess of base (6.5 ~ 8 equivalents) is used, and after completion of the reaction, the layers are separated and the organic layer is treated separately, characterized by adjusting the pH with acetic acid.

Since the preparation method requires a work-up process to remove inorganic salts formed as by-products due to excessive use of basic compounds in order to proceed with condensation and hydrolysis reactions in one process, a lot of time is required to obtain a target compound. This takes a disadvantage in that the manufacturing process is complicated and the yield is low, such as dividing the organic layer in order to obtain the target compound.

European Patent Publication No. 1,748,990 also condenses and hydrolyzes a compound of Formula 2 and a compound of Formula 3 in one process to produce telmisartan as a target compound, using an excess of base (5.4 to 7.6 equivalents). After completion of the reaction, the mixture was extracted with dichloromethane, reduced pressure, acetone was added and filtered to obtain the desired compound telmisartan.

However, the preparation method also takes a lot of time to obtain the target compound because the work-up process has to go through due to the excessive use of the basic compound in order to proceed the condensation reaction and hydrolysis reaction in one process, dichloromethane There is a big disadvantage that the compound telmisartan remains as a residual solvent, which is not suitable for mass production.

In European Patent Publication No. 1,805,146, telmisartan is prepared by performing a condensation reaction and a hydrolysis reaction in two steps, and in the condensation reaction step, methyl 2- [4- (bromomethyl) phenyl ] By benzoate compound is used in excess (1.6 equivalents) to prepare compound (4), which is an intermediate compound. After completion of the reaction, telmisartan methyl ester hydrochloride compound is prepared using hydrochloric acid dissolved in methanol. . In the hydrolysis step, telmisartan salt is obtained by using potassium hydroxide in an acetonitrile solvent in an excess (5.3 equivalents) to obtain telmisartan potassium salt, and adjusting the pH with acetic acid in a mixed solvent of acetonitrile and water to prepare telmisartan.

By the way, in the above production method, the excessive use of the compound of formula (3) during the condensation reaction may exist as an impurity of the intermediate compound itself after the reaction of the compound of formula (3), work-up by using an excess of the basic compound to proceed the hydrolysis reaction It takes a long time to obtain the target compound because it has to go through the process, the manufacturing process for producing the target compound telmisartan from the compound of formula 4 intermediate compound has a disadvantage of low yield.

In International Patent Publication No. WO 2009/006860, in the reaction scheme 2, the amount of water is maintained at 1% or less during the hydrolysis reaction to prepare telmisartan, the target compound, and potassium hydroxide is excessively added to the compound of formula 3 which is an intermediate compound. 3.5 equivalents) was added, and the mixture was stirred under reflux for 24 hours in methanol solvent. After completion of the reaction, pH was adjusted with acetic acid or formic acid to prepare telmisartan.

However, this method uses excessive amounts of basic compounds in the hydrolysis reaction, takes a long reaction time, and slows the filtration rate during the filtration (in the case of the hydrolysis reaction, the reaction is carried out in a methanol solvent (containing less than 1% of water). After the pH adjustment, the inorganic salts, potassium acetate or potassium formate, are precipitated together, so the filtration rate is slowed down and inorganic salts remain in the filtered solid.) have.

The preparation method of U.S. Patent Application Publication No. 2006/276525 uses the compound of formula 4, which is an intermediate compound, to prepare telmisartan as the target compound, wherein the aqueous solution of sodium hydroxide in methanol 6 times and a small amount of water (3.3) is used. After the reaction was completed, and the reaction part was concentrated under reduced pressure, and then, 10 parts of water was added at 85 ° C. to filter the undissolved material, and neutralized with acetic acid to filter to produce telmisartan.

However, the prior art requires a work-up process by using an excessive amount of a basic compound during the hydrolysis reaction, and because crystals are precipitated only in water, the actual filtration rate is very slow, and the purity of the target product is low, requiring several times of purification. This is very low as 62.3%, and there are many manufacturing steps, which is not suitable for mass production.

In the preparation method of Chinese Patent Publication No. 1,344,712, in the above Scheme 2, an intermediate compound telmisartan methyl ester compound is prepared by using an excess amount (3 equivalents) of potassium carbonate from a compound of Formula 2 and a compound of Formula 3, and a target compound telmisartan Was prepared using 3.8 times of ethanol and 4M aqueous sodium hydroxide solution, and after completion of the reaction, the residue was distilled until the residue became 2.3 times, and then the pH was adjusted with hydrochloric acid, and the crystals were filtered and purified with N, N-dimethylformamide. It is.

However, this method requires a work-up process by using an excessive amount of a basic compound in the condensation reaction, and since a small amount of water may be used, inorganic salts may be present in the crystal and have a low yield of 75.1%.

In the preparation method of U.S. Patent Application Publication No. 2006/211866, in the reaction scheme 2, methylisobutyl ketone is added in the production of intermediate telmisartan methyl ester by adding an excess of potassium hydroxide (4 equivalents) and a small amount of t-butylammonium bromide as a phase transfer catalyst. / Purified water = 4/5, the target compound telmisartan is prepared by reaction in aqueous methanol solution using an excess of potassium hydroxide (4 equivalents) during the hydrolysis reaction.

By the way, in the above method, in order to remove the inorganic salt which is a by-product included in the telmisartan solid obtained by adjusting the pH after the hydrolysis reaction, telmisartan containing the inorganic salt was dissolved in dichloromethane / methanol = 8/2 and then filtered. , It is necessary to separate the telmisartan from the methanol solvent by concentration, and as a result has a disadvantage of obtaining a low yield of 73.0%.

Therefore, the present inventors in the method for producing telmisartan according to Scheme 2, while studying the process for easily removing inorganic salts by-products generated by the base added during the condensation reaction and hydrolysis reaction 4 A mixed solvent of dimethyl sulfoxide and isopropanol was used as a reaction solvent based on the amount of -methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole. The intermediate compound was prepared using sulfoxide 0.5-1.5 times and isopropanol 1.5-4.5 times, and the hydrolysis reaction was carried out in a mixed solvent of methanol 7-9 times and purified water 5-7 times based on the intermediate compound to produce telmisartan. By doing so, there is no need for a separate process for removing inorganic salts, which are by-products, and have completed an improved method for producing telmisartan, which is suitable for mass production and can be manufactured with high purity and high yield.

The present invention relates to 4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole compound and methyl 2- [4- (bromomethyl) phenyl ] Methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -as an intermediate compound by condensation reaction from a benzoate compound In the method for producing a benzimidazol-1-yl] methyl} phenyl) benzoate compound, and producing it by the hydrolysis reaction,

It is an object of the present invention to provide a method for preparing telmisartan, a desired compound, which can easily remove inorganic salts, which are by-products generated during condensation and hydrolysis reactions, in high yield and high purity.

The present invention relates to a method for preparing telmisartan, which is a compound of Formula 1.

<Formula 1>

Telmisartan according to the present invention is prepared according to the method according to Scheme 2 below mentioned in the prior art.

<Scheme 2>

Scheme 2 is 4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole compound, which is a compound of Formula 2, and methyl 2- [ Condensation reaction of 4- (bromomethyl) phenyl] benzoate compound to yield methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl- 1H -benzimidazol-1-yl] methyl} phenyl) benzoate compound was prepared, which was prepared as a compound of formula 1 by the hydrolysis reaction as an intermediate compound of telmisartan as the target compound. do.

The present invention is a method for preparing telmisartan prepared by the above Scheme 2, that is, a method of preparing an intermediate compound by condensation of a compound of Formula 2 with a compound of Formula 3, and producing Telmisartan as a compound of Formula 1 by hydrolysis. To

Condensation reaction and purpose using a mixed solvent of dimethyl sulfoxide and isopropanol as a reaction solvent using dimethyl sulfoxide 0.5 to 1.5 times and isopropanol 1.5 to 4.5 times based on the amount of the compound In the preparation step of the compound telmisartan, it provides a hydrolysis reaction in a mixed solvent of methanol 7-9 times and purified water 5-7 times based on the amount of the compound of formula (4).

In the conventional method for preparing telmisartan according to Scheme 2, most of the bases are used in the preparation of the intermediate telmisartan methyl ester compound, which is a compound of Formula 4, and a process for removing the inorganic salts generated as a by-product has a disadvantage. .

In contrast, the condensation reaction for preparing the compound of formula 4, which is an intermediate compound according to the present invention, is carried out under a nitrogen stream, and a mixed solvent of dimethyl sulfoxide and isopropanol as a reaction solvent is based on the amount of the compound of formula 2 dimethyl sulfoxide 0.5. 1.5-4.5 times isopropanol is used, and potassium t-butoxide is reacted using 1-1.2 equivalents as a base. After completion of the reaction, 4-7 times purified water was injected and stirred, and the resulting crystals were filtered, washed successively with purified water and acetone, and dried to obtain the compound of formula 4 as an intermediate. The reaction temperature is maintained in the range of 10 ° C to 80 ° C, preferably 25 ° C to 50 ° C.

Experimental results of determining the ratio of the reaction solvent and the precipitation solvent in the condensation reaction to prepare the compound of formula 4 as an intermediate compound are as follows.

First, in order to determine the amount of dimethyl sulfoxide, isopropanol and purified water were fixed at 3: 5, and the amount of dimethyl sulfoxide was changed to 0.1, 0.5, 1.5, and 2.5 times to obtain the chemical formula obtained by the same method as in Example 1 below. Yield and purity for the 4 compound are shown in Table 1 below.

When the dimethyl sulfoxide was used 0.1 times as shown in Table 1, the purity of the compound of formula 4, which is an intermediate compound, was low as 93.0%, and when 2.5 times was used, the yield of the compound of formula 4, which is an intermediate compound, was low as 87.5%. In order to prepare the desired compound of Formula 4 in high yield and high purity, the amount of dimethyl sulfoxide should be 0.5 to 1.5 times based on the amount of the compound of Formula 2 used.

Secondly, in order to determine the amount of isopropanol, dimethyl sulfoxide and purified water were fixed at 1: 5, and the amount of isopropanol was changed to 0.5, 1.5, 4.5, and 6 times to prepare the compound according to the same method as in Example 1 below. Yield and purity for Table 2 are as follows.

When 0.5 times isopropanol was used as shown in Table 2, the stirring state and purity (90.8%) were poor according to the preparation of the compound of formula 4, which is an intermediate compound, and the yield of the compound of formula 4, which is an intermediate compound, was 80.2 when 6 times was used. In order to prepare the compound of formula 4 desired in the present invention in high yield and high purity, the amount of isopropanol should be 1.5 to 4.5 times based on the amount of the compound of formula 2 used.

Third, in order to determine the amount of purified water, dimethylsulfoxide and isopropanol were fixed to 1: 3, and the amount of purified water was changed to 2, 4, 7, 9 times when precipitated, and was prepared in the same manner as in Example 1 below. Yield and purity for the compound 4 are shown in Table 3.

As shown in Table 3, when the purified water was used twice, the yield of the compound of formula 4, which is an intermediate compound, was low as 85.4%, and when 9 times was used, the purity of the compound of formula 4, which is an intermediate compound, was lowered to 92.1%. In order to prepare the compound of Formula 4 in high yield and high purity, the amount of purified water should be 4 to 7 times based on the amount of the compound of Formula 2 used.

Therefore, the condensation reaction according to the present invention uses 1 to 1.2 equivalents of potassium t-butoxide, which is a basic compound, in the reaction solvent of dimethyl sulfoxide: isopropanol 0.5 to 1.5: 1.5 to 4.5 times based on the amount of the compound of formula (2). After the reaction was completed and the reaction was completed, 4-7 times of purified water was added to precipitate crystals and filtered. Thus, the compound of formula 4, which is an intermediate telmisartan methyl ester compound, can be obtained with a high yield of 95.1% by a very simple process. useful.

On the other hand, the hydrolysis reaction for preparing the compound of Formula 1, which is the target compound according to the present invention, uses about 2 equivalents of sodium hydroxide, and based on the amount of the compound of Formula 4, the reaction solvent 5-7 times purified water and methanol 7-9 The reaction is carried out using an appropriate ratio of about 2 times. After completion of the reaction, hydrochloric acid was added to the reaction mixture, while sufficient amount of purified water and methanol were used, followed by filtration and washing with sufficient amount of purified water to prepare a compound of formula 1 as a target compound.

In the prior art using Scheme 2, since an excess base or acid is used in the step of producing telmisartan by hydrolysis, a process for removing inorganic salts generated as a by-product is required, and the solid precipitated in the solvent used is Slow filtration speed during filtration In addition, in the prior art using the reaction formula 1 by using a strong acid trifluoroacetic acid in order to remove the inorganic salts generated as by-products through the work-up after completion of the separation by silica gel column chromatography to produce telmisartan, etc. The manufacturing process is very complicated.

Therefore, the prior arts require a process for removing inorganic salts, which are by-products generated by using an excess of base in the condensation and hydrolysis reactions, and are not suitable for mass production methods due to problems such as slow filtration rate.

On the other hand, the hydrolysis reaction for preparing the compound of Formula 1, which is the target compound according to the present invention, uses about 2 equivalents of sodium hydroxide, and based on the amount of the compound of Formula 4, the reaction solvent is 5 to 7 times purified water and 7 to methanol. Another process for removing inorganic salts by removing inorganic salts by using a sufficient amount of purified water and methanol while the crystals are precipitated and reacting with an appropriate ratio of about 9 times and washing with a sufficient amount of purified water during filtration and washing. Since it is not necessary, telmisartan can be produced with a high yield of 94.2% and high purity (HPLC purity of 99.9% or more) by a simple process, which is particularly useful as a mass production method.

Experimental results for determining the proportion of the reaction solvent in the hydrolysis reaction to prepare the compound of formula 1 according to the present invention are as follows.

First, in order to determine the amount of purified water, the fixed amount of methanol was fixed 8 times based on the amount of the compound of Formula 4, and the amount of purified water was changed to 3, 5, 7, 9 times to prepare the same method as in Example 2 below. Yields and purity for the compounds are shown in Table 4 below.

As shown in Table 4, when 3 times purified water was used, the yield of the compound of formula 1, which is the target compound, was low as 87.5%, and the stirring state was poor. When 9 times was used, the filtered state was poor, and when methanol was 8 times, purified water was used. The amount of must be 5-7 times.

Secondly, in order to determine the amount of purified water, the ratio of the reaction solvent in the hydrolysis reaction for preparing the compound of Formula 1, which is the target compound according to the present invention, is fixed 6 times based on the amount of the compound of Formula 4, and the amount of methanol To 5, 7, 9, 11 times the yield and purity for the compound of Formula 1 obtained by the same method as in Example 2 is obtained in Table 5.

As shown in Table 5, when 5 times methanol was used, the stirring state and the filtration state for preparing the compound of Formula 1, which is the target compound, were poor, and the unknown impurity was also detected by HPLC at 0.1% or more (0.1% or less). In the case of using, the yield is low as 84.4% in order to manufacture the compound of formula 1 desired in high yield and high purity in the present invention, when the purified water is 6 times based on the amount of the compound of formula 4, the amount of methanol is 7 to 9 times. shall.

Therefore, the hydrolysis reaction according to the present invention is based on the amount of the compound of formula 4 and reacted in a mixed solvent of methanol 7-9 times and purified water 5-7 times and filtered to obtain the effect of removing other impurities and inorganic salts without a separate process And impurities can be easily removed at the same time to obtain the compound of formula 1 as a target compound with a high yield of 94.2% and high purity (at least 99.9% HPLC purity).

In addition, the present invention may proceed with the hydrolysis reaction in a wet state without drying the compound of formula (4) which is an intermediate compound. In the hydrolysis reaction, a basic compound may be added in a mixed solvent of purified water and alcohol to react, and after completion of the reaction, neutralization using an acid may be performed to filter the precipitated solid, thereby preparing telmisartan.

When the preparation method of the present invention described above is carried out, the compound of formula 2 is prepared by condensation reaction of the compound of formula 2 and compound of formula 3, and then the hydrolysis reaction is performed to produce the desired compound of formula 1, telmisartan. The overall reaction yield is as high as 89.6% and can be obtained with high purity (99.9% or more HPLC purity), and the process is simple and is particularly useful as a mass production method.

In the present invention, a compound of formula (2) and compound (3) are condensed to prepare compound (4), which is an intermediate, and then hydrolyzed to produce telmisartan, the compound of formula (1). It is easy to remove inorganic salts, which are by-products, and does not require a separate process to remove inorganic salts, and can produce telmisartan as a target compound with high yield and high purity. It is particularly useful as a method.

The manufacturing method of the present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

< Example  1> methyl  2- (4-{[4- methyl -6- (1- methyl -1H- Benzimidazole -2-yl) -2-propyl-1H- Benzimidazole -1 day] methyl } Phenyl ) Benzoate Preparation of (Formula 4)

50 ml of 4-dimethyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole was added to 150 ml of isopropanol under nitrogen stream and 50 ml of dimethyl sulfoxide and potassium were stirred. After 20.28 g of t-butoxide was added thereto, the mixture was slowly heated and stirred at 40 to 45 ° C. for 1 hour. The reaction solution was cooled to 30-35 ° C., 55.14 g of methyl 2- [4- (bromomethyl) phenyl] benzoate was injected, stirred for 6 hours, and 250 ml of purified water was injected for 1 hour at 20-25 ° C. Stirred. The resulting crystals were filtered off, washed successively with 50 ml of purified water and 50 ml of acetone, and dried to give methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2- 82.58 g of propyl-1 H -benzimidazol-1-yl] methyl} phenyl) benzoate was obtained (yield 95.1%).

m / e 528.6 (parent ion); ¹ H NMR (DMSO-d ₆ ) δ 0.99 (t, 3H, J = 7.24 Hz), 1.73-1.88 (m, 2H), 2.64 (s, 3H), 2.92 (t, 2H, J = 7.42 Hz) , 3.50 (s, 3H), 3.84 (s, 3H), 5.64 (s, 2H), 7.12-7.32 (m, 6H), 7.33-7.82 (m, 8H)

< Example  2> Of telmisartan (Formula 1)  Produce

12.1 g of sodium hydroxide was added to 80 ml of purified water, and 160 ml of methanol and methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 were stirred with stirring. 80 g of H -benzimidazol-1-yl] methyl} phenyl) benzoate was added thereto, and the mixture was heated at 70 to 75 ° C. and stirred under reflux for 4 hours. The reaction solution was filtered hot, the filtrate was cooled, 480 ml of methanol was added at 20-25 ° C., hydrochloric acid (20%) was added dropwise to pH 7.0, and then stirred for 2 hours. 400 ml of purified water was added to the reaction mixture, followed by stirring for 2 hours. The resulting crystals were filtered, washed sequentially with 320 ml of purified water and 80 ml of methanol, and dried to give 73.36 g of the target compound telmisartan as an almost white solid (yield 94.2%).

mp 269.2 ° C. (DSC); m / e 514.6 (parent ion); ¹ H NMR (DMSO-d ₆ ) δ1.00 (t, 3H, J = 7.32 Hz), 1.76-1.88 (m, 2H), 2.64 (s, 3H), 2.93 (t, 2H, J = 7.48 Hz) , 3.82 (s, 3H), 5.63 (s, 2H), 7.15 ~ 7.37 (m, 7H), 7.41 ~ 7.61 (m, 4H), 7.67 ~ 7.75 (m, 3H)

< Example  3> Of telmisartan (Formula 1)  Produce

17.0 g of potassium hydroxide was added to 80 ml of purified water and 160 ml of methanol and methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 were stirred with stirring. 80 g of H -benzimidazol-1-yl] methyl} phenyl) benzoate was added thereto, and the mixture was heated at 70 to 75 ° C. and stirred under reflux for 4 hours. The reaction solution was filtered hot, the filtrate was cooled, 480 ml of methanol was added at 20 to 25 ° C., and hydrochloric acid (20%) was slowly added dropwise to pH 6.8, followed by stirring for 2 hours. 400 ml of purified water was added to the reaction mixture, which was then stirred for 2 hours. The resulting crystals were filtered, washed sequentially with 320 ml of purified water and 80 ml of methanol, and dried to give 73.2 g of the target compound telmisartan as an almost white solid (yield 94.0%).

< Example  4> Of telmisartan (Formula 1)  Produce

50 ml of 4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole was added to 150 ml of isopropanol under nitrogen stream and 50 ml of dimethyl sulfoxide was stirred. After adding 20.28 g of potassium t-butoxide, the mixture was slowly heated and stirred at 40 to 45 ° C. for 1 hour. The reaction solution was cooled to 30-35 ° C., 55.14 g of methyl 2- [4- (bromomethyl) phenyl] benzoate was injected, stirred for 6 hours, and 250 ml of purified water was injected for 1 hour at 20-25 ° C. Stirred. The resulting crystals were filtered, washed sequentially with 50 ml of purified water and 50 ml of acetone, and then wetted with methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2 -Propyl- 1H -benzimidazol-1-yl] methyl} phenyl) benzoate compound was obtained. 12.5 g of sodium hydroxide was added to 80 ml of purified water, followed by stirring, 160 ml of methanol and the wet solid obtained above were heated and stirred at 70 to 75 ° C. for 4 hours. The reaction solution was filtered hot, the filtrate was cooled, 480 ml of methanol was added at 20-25 ° C., and hydrochloric acid (20%) was slowly added dropwise to pH 7.3, followed by stirring for 2 hours. 400 ml of purified water was added to the reaction mixture, which was then stirred for 2 hours. The resulting crystals were filtered, washed sequentially with 320 ml of purified water and 80 ml of methanol, and dried to obtain 75.66 g of the target compound telmisartan as an almost white solid (yield 89.5%).

< Example  5> Of telmisartan (Formula 1)  Produce

50 ml of 4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2-propyl-1 H -benzimidazole was added to 150 ml of isopropanol under nitrogen stream and 50 ml of dimethyl sulfoxide was stirred. After adding 20.28 g of potassium t-butoxide, the mixture was slowly heated and stirred at 40 to 45 ° C. for 1 hour. The reaction solution was cooled to 30-35 ° C., 55.14 g of methyl 2- [4- (bromomethyl) phenyl] benzoate was injected, stirred for 6 hours, and 250 ml of purified water was injected for 1 hour at 20-25 ° C. Stirred. The resulting crystals were filtered, washed sequentially with 50 ml of purified water and 50 ml of acetone, and then wetted with methyl 2- (4-{[4-methyl-6- (1-methyl-1 H -benzimidazol-2-yl) -2 -Propyl- 1H -benzimidazol-1-yl] methyl} phenyl) benzoate compound was obtained. 17.5 g of potassium hydroxide was added to 80 ml of purified water, and 160 ml of methanol and the wet solid obtained above were added with stirring, followed by heating and stirring at 70-75 ° C. for 4 hours. The reaction solution was filtered hot, the filtrate was cooled, 480 ml of methanol was added at 20 to 25 ° C., and hydrochloric acid (20%) was slowly added dropwise to pH 6.8, followed by stirring for 2 hours. 400 ml of purified water was added to the reaction mixture, which was then stirred for 2 hours. The resulting crystals were filtered, washed sequentially with 320 ml of purified water and 80 ml of methanol, and dried to obtain 75.49 g of the target compound telmisartan as an almost white solid (yield 89.3%).

Claims (3)

In the method of preparing a compound of the general formula (1) and telmisartan by the condensation reaction of the compound of formula (2) and the compound of formula (3) to produce a compound of formula (4) as an intermediate compound
In the condensation reaction, a mixed solvent of dimethyl sulfoxide and isopropanol is used as a reaction solvent to prepare a compound of formula 4, which is an intermediate compound, using 0.5 to 1.5 times of dimethyl sulfoxide and 1.5 to 4.5 times of isopropanol based on the amount of the compound of formula (2). The decomposition reaction is a method for preparing telmisartan, which is a compound of Formula 1, characterized in that the reaction is carried out in a mixed solvent of 7 to 9 times methanol and 5 to 7 times purified water based on the amount of the compound of Formula 4 as a reaction solvent.

<Formula 1>

<Formula 2>

<Formula 3>

<Formula 4>

The method of claim 1, wherein after the completion of the condensation reaction, 4 to 7 times the amount of purified water is added based on the amount of the compound of formula 2 to prepare a telmisartan compound of the formula (1) characterized in that to precipitate and crystallize the crystal of the compound of formula (4) Way.
The method for preparing telmisartan according to claim 1, wherein the compound of Formula 1 is hydrolyzed using the compound of Formula 4 in a wet state without drying after preparing the compound of Formula 4.