JP6091339B2 - Method for producing olmesartan medoxomil - Google Patents

Description

  The present invention relates to olmesartan medoxomil (chemical name: (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [ 2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate).

  Following formula (1)

Olmesartan medoxomil represented by the formula is useful as an antihypertensive agent having an excellent effect as an angiotensin II receptor antagonist.

  Olmesartan medoxomil used as such a therapeutic agent is desired to have a very high purity. Olmesartan medoxomil usually has the following formula (2)

4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (5- Methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester (hereinafter also referred to as trityl olmesartan medoxomil) at 60 ° C. in the presence of 1.5 times (mass) of water relative to trityl olmesartan medoxomil. The product is produced by deprotection reaction (detritylation reaction) by allowing acetic acid to act (see Patent Document 1).

Japanese Examined Patent Publication No. 7-121918

  However, when the present inventors produced olmesartan medoxomil according to the method of the above-mentioned patent document, in this method, the medoxomil group was eliminated by the hydrolysis reaction proceeding even at the ester group of olmesartan medoxomil, and the following formula (3) )

4- (2-hydroxypropan-2-yl) -2-propyl-1-{[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5 -It became clear that many carboxylic acids (hereinafter also referred to as olmesartan) are by-produced as impurities. Furthermore, by-product olmesartan reacts with olmesartan medoxomil etc. in the reaction system, and the following formula (4)

It was found that many low-polar impurities derived from olmesartan are by-produced, such as the dimer represented by (hereinafter also referred to as olmesartan dimer). Such low-polar impurities are difficult to remove once produced, and in order to obtain high-purity olmesartan medoxomil, complicated operations such as repeated purification are required. Since it falls, it was a serious problem for industrial production.

  Accordingly, an object of the present invention is to provide a method for easily producing a high-purity olmesartan medoxomil crystal in which the content of low-polar impurities such as the olmesartan dimer is reduced.

  In order to solve the above-mentioned problems, the present inventor diligently studied conditions for deprotecting trityl olmesartan medoxomil in an acetic acid aqueous solution. As a result, the deprotection reaction of trityl olmesartan medoxomil is performed at a temperature lower than 60 ° C. in the conventional method, particularly 45 ° C. or less, and by using a specific pKa acid, hydrolysis at the ester group of olmesartan medoxomil is performed. It became clear that it can be suppressed. Furthermore, by setting the temperature in the range of 30 to 45 ° C., it has been found that the deprotection reaction proceeds sufficiently to obtain high-purity olmesartan medoxomil, and the present invention has been completed.

That is, the present invention relates to 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid. (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, an acid with a pKa of 2.5 to 6.0 and 4- (1-hydroxy-1-methylethyl) -2-propyl- 1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester were mixed at a temperature 3 5 to 45 ° C. water 0.3~1.3g for, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy - - methylethyl) -2-propyl -1- [2 '- (1H- tetrazol-5-yl) biphenyl-4-ylmethyl] deprotection reaction to obtain a solution containing an imidazole-5-carboxylate
And by removing the aqueous layer from the mixture obtained by mixing the liquid property of the solution obtained in the deprotection reaction step with a pH of 3.0 to 4.5 and a water-insoluble organic solvent, (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5- Yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy) This is a method for producing -1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate.

Also, from the organic layer obtained in the extraction step, by precipitating directly olmesartan medoxomil crystals (crystallization step), it can be efficiently obtain olmesartan medoxomil crystals.

  According to the method of the present invention, in particular, a high-purity olmesartan medoxomil having a reduced content of low-polar impurities such as the olmesartan dimer is efficiently and easily produced without repeating the purification operation. be able to.

  This invention is a manufacturing method of olmesartan medoxomil including the deprotection reaction process which mixes the olmesartan medoxomil, the acid of pKa2.5-6.0, and water at the temperature of 30-45 degreeC, and obtains olmesartan medoxomil. In the present invention, it is preferable to perform the extraction step after the deprotection reaction step, and more preferably to perform the crystallization step. Details of each step will be described below.

(Deprotection reaction process)
In the present invention, the deprotection reaction step is a step of obtaining olmesartan medoxomil by mixing trityl olmesartan medoxomil, pKa 2.5 to 6.0 acid and water at a temperature of 30 to 45 ° C.

  The trityl olmesartan medoxomil used in the present invention is not particularly limited, and those produced by a known method can be used. In order to obtain higher purity olmesartan medoxomil, it is preferable to use one purified by the following method. That is, the trityl olmesartan medoxomil is a crystal of trityl olmesartan medoxomil obtained by recrystallizing trityl olmesartan medoxomil using an organic solvent such as acetone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and toluene. In particular, it is preferable to recrystallize using ethyl acetate.

  In the recrystallization of trityl olmesartan medoxomil, the amount of the solvent to be used may be appropriately determined depending on the type of the solvent, and usually 5 to 15 mL is used per 1 g of trityl olmesartan medoxomil. The temperature at which trityl olmesartan medoxomil is dissolved is appropriately determined depending on the type and amount of the solvent used, and is usually dissolved at a temperature 5 to 10 ° C. lower than the reflux temperature of the solvent used. Moreover, when precipitating a crystal | crystallization, it is preferable to cool to the temperature of 0-10 degreeC, for example, and to precipitate a crystal | crystallization. At this time, a seed crystal can also be used. The obtained crystals can be separated by a known separation method, specifically, a method such as decantation, filtration or centrifugal filtration. Moreover, the crystals of trityl olmesartan medoxomil separated by these methods can be washed with the organic solvent used. By performing the recrystallization operation, the high polarity impurity group contained in trityl olmesartan medoxomil can be reduced, and the high polarity impurity group of olmesartan medoxomil crystals obtained when this is used as a raw material is also reduced. Can do. The recrystallization operation may be repeated for the purpose of reducing the highly polar impurity group.

  In this step, an acid having a pKa (acid dissociation constant) of 2.5 to 6.0 is used. In the present invention, the value of pKa is a value at 25 ° C. unless otherwise specified. Specific examples of acids used in the present invention include formic acid (pKa 3.55), acetic acid (pKa 4.56), citric acid (pKa 5.69), tartaric acid (pKa 3.95), oxalic acid (pKa 3.82), Fluoroacetic acid (pKa 2.59), fumaric acid (pKa 4.10) and the like are exemplified, but not limited thereto. These can be used alone or in combination. Moreover, a reagent, an industrial raw material, etc. can be used without a restriction | limiting, and can also be used as aqueous solution. In the present invention, the amount of acid used is not particularly limited and must be adjusted according to the type and concentration of the acid, but usually 2 to 10 g is used per 1 g of trityl olmesartan medoxomil. By using this amount, the reaction proceeds sufficiently and operations such as post-treatment can be performed efficiently.

  In this process, it is necessary to use water. In the present invention, the amount of water used is not particularly limited, and the presence of water in the reaction solution increases the reaction rate, increases the reaction conversion rate, and allows the reaction to proceed sufficiently. Further, in the present invention, by strictly adjusting the amount of water present in the reaction solution, the by-product of the olmesartan can be suppressed, and the by-product of low-polar impurities such as the olmesartan dimer can be suppressed. It is preferable. That is, the amount of water present in the reaction solution is preferably 0.3 to 1.3 g, more preferably 0.4 to 1.2 g with respect to 1 g of trityl olmesartan medoxomil. By using this amount of water, olmesartan medoxomil of higher purity can be obtained.

  In the present invention, the method and order of mixing trityl olmesartan, acid and water are not particularly limited. However, if a specific method is exemplified, trityl olmesartan and acid are mixed and heated to 30 to 45 ° C. After dissolution, it is preferable to add and mix water. By using this method, the amount of the acid used can be reduced.

  In the present invention, the greatest feature is that the temperature at the time of mixing is 30 to 45 ° C. in this step. By carrying out the reaction in the temperature range, the deprotection reaction proceeds, and the production of low-polar impurities such as the olmesartan dimer is suppressed, so that high-purity olmesartan medoxomil can be obtained. When the reaction temperature is higher than 45 ° C., it is not preferable because generation of low-polar impurities such as the olmesartan dimer cannot be sufficiently suppressed. On the other hand, when the reaction temperature is lower than 30 ° C., the reaction does not proceed and olmesartan medoxomil cannot be obtained. Moreover, in this invention, since the said reaction temperature shall be 35-45 degreeC, since a reaction conversion rate becomes higher and a yield improves, reaction rate becomes quick and efficient, it is preferable. Further, the reaction time is not particularly limited, but is usually performed in the range of 1 to 10 hours.

(Extraction process)
In the present invention, after the deprotection reaction step, the liquid property of the solution obtained in the deprotection reaction step is adjusted to pH 3.0 to 4.5, and the mixture obtained by mixing with a water-insoluble organic solvent is used. It is preferable to further perform an extraction step of obtaining an organic layer containing olmesartan medoxomil by removing the aqueous layer. By adjusting the liquidity of the aqueous layer to pH 3.0 to 4.5, low-polar impurities such as olmesartan dimer can be reduced.

  In the extraction step, the liquidity of the obtained solution is adjusted by mixing with an alkaline aqueous solution. As the alkaline aqueous solution used in the present invention, an aqueous solution of ammonia, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or the like is used. Reagents or industrial materials can be used without any limitation. The concentration and use amount of these alkaline aqueous solutions are determined by adjusting the pH of the aqueous layer to be 3.0 to 4.5 depending on the type of alkali.

  In addition, the water-insoluble organic solvent in the step is preferably an organic solvent having low compatibility with water and sufficiently high solubility of olmesartan medoxomil. The compatibility with water is not particularly limited as long as it is generally known as a solvent that is not miscible with water. Specifically, the solubility in water at 100 ° C. at 20 ° C. is 10 g or less. Can be used. Specific examples of water-insoluble organic solvents used in the process include acetates such as methyl acetate, ethyl acetate, butyl acetate, and isopropyl acetate, aromatic hydrocarbons such as toluene and xylene, methylene chloride, chloroform, and the like. Among these, acetate esters are preferred because they extract olmesartan medoxomil most effectively. In addition, acetates are particularly preferable in the case where the crystallization process described in detail below is carried out continuously, so that they can be efficiently crystallized in the process. These water-insoluble organic solvents can be used alone or as a mixture of a plurality of types. Moreover, although the usage-amount of the water-insoluble organic solvent in the said extraction process is based also on the kind of organic solvent to be used, 0.5 mL-50 mL, Preferably 1 mL-40 mL are used with respect to 1 g of olmesartan medoxomil.

  In the extraction step, the method and order of mixing the solution obtained in the deprotection reaction step, the alkaline aqueous solution and the organic solvent are not particularly limited. When the amount of the alkaline aqueous solution used to adjust the pH of the aqueous layer to 3.0 to 4.5 is unknown, the organic solution is first adjusted by bringing the alkaline solution into contact with the obtained solution and adjusting the liquidity. Although it is necessary to mix with a solvent, when the usage-amount of alkaline aqueous solution is decided, the method and order in which the obtained solution, alkaline aqueous solution, and organic solvent are mixed are not specifically limited. The contact with the alkaline aqueous solution can be performed in a plurality of times. Moreover, although the temperature which mixes these also depends on the kind of organic solvent, it should just be 0-60 degreeC, and it is preferable that it is 5-50 degreeC.

  Moreover, in this invention, it is preferable to perform the said extraction process about the solution which removed solids, such as triphenyl methanol byproduced at the said deprotection reaction process, from the reaction liquid obtained at the said deprotection reaction process. By removing the solid before the extraction step, the step can be performed efficiently. The method for removing solids such as triphenylmethanol is not particularly limited. Specifically, the temperature of the reaction solution obtained in the deprotection reaction step is cooled to 10 to 30 ° C., preferably 15 to 25 ° C. As a result, a solid such as triphenylmethanol is precipitated in the reaction solution and can be easily removed. Furthermore, it is preferable to add water to the reaction solution because a solid such as triphenylmethanol is more efficiently precipitated in the reaction solution. The amount of water to be added may be 1 to 20 mL, and preferably 2 to 10 mL. Thereby, most of triphenylmethanol by-produced in the reaction is precipitated in the reaction solution. The precipitated solid such as triphenylmethanol can be removed from the reaction solution by a general separation method such as decantation, filtration, and centrifugal filtration.

(Crystallization process)
In the present invention, olmesartan medoxomil crystals can be efficiently obtained by performing a crystallization step in which olmesartan medoxomil crystals are directly precipitated from the organic layer obtained in the extraction step.

  In the crystallization step, the solvent for crystallizing olmesartan medoxomil is preferably an acetate such as ethyl acetate, butyl acetate, isopropyl acetate, and propyl acetate. Particular preference is given to using ethyl. Therefore, when performing the said crystallization process, it is preferable to use these organic solvents as an organic solvent in the said extraction process.

  Moreover, in the said process, it is preferable that the quantity of the solvent which coexists when crystallizing olmesartan medoxomil is 5-100 mL with respect to 1 g of olmesartan medoxomil contained, and it is especially preferable that it is 8-30 mL. Therefore, when the amount of the solvent in the organic layer obtained in the extraction step is not within the range when performing the crystallization step, it is possible to appropriately adjust the addition or distillation of the solvent so as to be the amount. preferable.

  Further, in the present invention, without performing the crystallization step, the solvent is distilled off from the organic layer obtained in the extraction step to obtain a crude product, and the crude product is purified or crystallized by a known method such as recrystallization. It is also possible to make it. When recrystallizing such a crude product, the same solvent as in the crystallization step can be used. Specifically, the crude product is dissolved in a solvent at 60 ° C. to reflux temperature, and then The obtained solution is preferably cooled to 0 to 10 ° C. at a cooling rate of 5 to 60 ° C. per minute and kept at the temperature for an appropriate time to precipitate crystals, and if necessary, seeds are used. Crystals may be used. The precipitated crystals can be separated by a known separation method, specifically, a method such as decantation, filtration or centrifugal filtration. Such a recrystallization operation can also be performed for the purpose of purifying the olmesartan medoxomil crystals obtained in the crystallization step.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited by these Examples. In addition, Examples 7 to 9 and 12 to 13 described later are Reference Examples 1 to 3 and 4 to 5, respectively.

  In addition, the measurement of the purity of olmesartan medoxomil and the content of olmesartan dimer obtained in Examples and Comparative Examples (high performance liquid chromatography measurement) was performed using the following method.

<Measurement of purity of olmesartan medoxomil and content of olmesartan dimer>
Measuring method: High performance liquid chromatography (HPLC)
Apparatus: High-performance liquid chromatograph apparatus WATERS detector: UV absorption height detector WATERS (measurement wavelength: 220 nm)
Column: GL Science Co., Ltd. product name Inertsil ODS-3, inner diameter 4.6 mm, length 25 cm (particle diameter 5 μm, pore diameter 12 nm)
Column temperature: 25 ° C., constant temperature Sample temperature: 25 ° C., constant temperature mobile phase A: acetonitrile mobile phase B: 25 mM sodium perchlorate aqueous solution (pH = 2.5, adjusted with perchloric acid)
Transfer of mobile phase: The concentration gradient is controlled by changing the mixing ratio of mobile phases A and B as shown in Table 1.
Flow rate: 1.5 ml / min Measurement time: 45 minutes

Under the above conditions, a peak is observed at about 15.8 minutes for olmesartan medoxomil and at about 26.5 minutes for olmesartan dimer. In the following Examples and Comparative Examples, the purity of olmesartan medoxomil and the content of olmesartan dimer are all the values of each compound relative to the sum of all peak area values (excluding solvent-derived peaks) measured under the above conditions. It is the ratio of the peak area value. In the present invention, the low polarity impurity group has a peak in the range of 16.0 to 40.0 minutes under the above conditions.

Example 1
40 g of trityl olmesartan medoxomil, 180 ml of acetic acid and 40 g of water (1.0 times volume) were added to a 500 mL four-necked flask equipped with two stirring blades with a diameter of 7.5 cm, and the mixture was stirred at 40 ° C. for 2 hours for deprotection reaction. (Reaction conversion: 98.4%, olmesartan medoxomil purity: 98.95%, olmesartan dimer: 0.047%). Next, the reaction solution was cooled to 20 ° C., 80 g of water was added, and the mixture was stirred at 20 ° C. for 1 hour. The precipitated triphenylmethanol was removed by filtration under reduced pressure, and 240 ml of 10% sodium bicarbonate was added to the obtained filtrate. In addition, the liquidity of the aqueous layer was adjusted to pH 3.5, 400 ml of ethyl acetate was added and stirred vigorously, and then the aqueous layer was separated to obtain an organic layer containing olmesartan medoxomil (olmesartan medoxomil purity: 99.35% Dimer: 0.011%). 200 ml of ethyl acetate was distilled off from the organic layer, the mixture was stirred at 20 to 30 ° C. for 1 hour, and the precipitated solid was collected as a wet body by vacuum filtration. The obtained wet body was dried at 40 ° C. for 14 hours to obtain 24 g of olmesartan medoxomil crystals (yield: 86%, olmesartan medoxomil purity: 99.71%, dimer: 0.010%).

Examples 2-9
The same operation as in Example 1 was carried out except that the reaction temperature of Example 1 and the amount of water used in the reaction were changed as described in Table 1. Table 1 shows the reaction conversion rate in the deprotection reaction step and the physical properties of the obtained olmesartan medoxomil crystals.

Examples 10 and 11
The same operation as in Example 1 was performed except that the liquidity of the aqueous layer of Example 1 was changed as described in Table 2. The physical properties of the obtained organic layer are shown in Table 2.

Examples 12 and 13
The same operation as in Example 1 was performed except that sodium hydroxide was used in place of the sodium hydrogen carbonate in Example 1 and the liquidity of the aqueous layer was changed as described in Table 2. As a result, there was almost no difference between the purity of olmesartan medoxomil in the reaction solution after the reaction and the purity of olmesartan medoxomil in the organic layer. The physical properties of the obtained organic layer are shown in Table 2.

Examples 14-17
The same operation as in Example 1 was performed except that the acid shown in Table 3 was used in place of the acetic acid in Example 1. Table 3 shows the reaction conversion rate in the deprotection reaction step and the physical properties of the obtained olmesartan medoxomil crystals.

Comparative Example 1 (Examination of Japanese Patent Publication No. 7-121918, Example 78 (a))
40 g of trityl olmesartan medoxomil, 180 ml of acetic acid and 60 g of water (1.5 times the amount) were added to a 500 mL four-necked flask equipped with two stirring blades with a diameter of 7.5 cm, and the reaction was stirred at 60 ° C. for 1.5 hours. (Olmesartan medoxomil purity: 97.75%, olmesartan dimer: 0.277%). Next, the reaction solution was cooled to 20 ° C., 75 g of water was added, and the mixture was stirred at 20 ° C. for 1 hour. After the precipitated triphenylmethanol was removed by filtration under reduced pressure, the obtained filtrate was concentrated and dried, and toluene was added to the residue and dried again. 200 ml of ethyl acetate was added to the residue, and the mixture was stirred at 20 to 30 ° C. for 1 hour. Subsequently, the wet body was separated by filtration under reduced pressure, and the obtained wet body was dried at 40 ° C. for 14 hours to obtain 25 g of a crude product of olmesartan medoxomil (yield: 90%, purity of olmesartan medoxomil: 98.62). %, Dimer: 0.196%).

Comparative Examples 2-6
The same operation as in Example 1 was performed except that the reaction temperature of Example 1 and the amount of water used were changed as described in Table 1. The results are shown in Table 1. In Comparative Example 6, the reaction conversion rate was low, and olmesartan medoxomil could not be obtained.

Comparative Example 7
The same operation as in Example 1 was performed except that water was used in place of the sodium hydrogen carbonate in Example 1. As a result, no layer was formed in the extraction step, and olmesartan medoxomil could not be obtained.

Claims (2)

4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid (5-methyl-2 -Oxo-1,3-dioxolen-4-yl) methyl ester, an acid with a pKa of 2.5 to 6.0 and 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [ 2- (trityltetrazol-5-yl) phenyl] phenyl} methylimidazole-5-carboxylic acid 0.3 to 1 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester the 1.3g of water were mixed at 3 5 ~45 ℃, (5- methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl -2-propyl -1- [2 '- (1H- tetrazol-5-yl) biphenyl-4-ylmethyl] deprotection reaction to obtain a solution containing an imidazole-5-carboxylate
And by removing the aqueous layer from the mixture obtained by mixing the liquid property of the solution obtained in the deprotection reaction step with a pH of 3.0 to 4.5 and a water-insoluble organic solvent, (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5- Yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy) -1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate. From the organic layer obtained in the extraction step, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [ The method according to claim 1 , comprising a crystallization step of precipitating crystals of 2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate.