JP6147546B2 - Method for producing telmisartan A-type crystals with reduced acetic acid - Google Patents

Description

  The present invention relates to a novel process for producing telmisartan Form A crystals.

  Following formula (1)

(Chemical name: 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl- 2-Carboxylic acid) is used as an angiotensin II receptor antagonist in antihypertensive drugs and the like (see Patent Document 1).

  Since telmisartan is a drug substance and is required to have high purity, it is necessary to finally purify and purify the crude telmisartan obtained by the conventional synthesis method. Therefore, various methods have been disclosed as methods for purifying telmisartan. Among them, a crystal form called A-type crystal can be stably produced, and the following method, that is, telmisartan is allowed to act with a base from the reason that a small amount of solvent can be efficiently produced, A method is widely used in which a base salt of telmisartan is dissolved in a solvent, neutralized with an acid, and crystallized as telmisartan. In this method, acetic acid is often used as the acid because it is easy to remove a salt produced as a by-product by neutralization. In Patent Document 1, as a method for purifying telmisartan, a crude product of telmisartan is reacted with 25% aqueous ammonia in an ethanol solvent to dissolve it as an ammonium salt of telmisartan. After the resulting solution is treated with activated carbon, acetic acid is used. Is added to crystallize telmisartan.

Japanese Patent No. 4700813

  However, when the present inventors examined the above purification method, when acetic acid was used as the acid, the purity of telmisartan could be improved efficiently, but a large amount of acetic acid remained in the obtained telmisartan A type crystal. Moreover, it has been clarified that the acetic acid is difficult to remove by drying. Therefore, in order to reduce the acetic acid content to an amount that is acceptable for use as an active pharmaceutical ingredient, drying at a high temperature for a long time is necessary, especially as the production scale increases, There arises a problem that time is conspicuous.

  Accordingly, an object of the present invention is to provide a method for efficiently producing telmisartan A-type crystals with a reduced amount of acetic acid.

  In order to solve the above-mentioned problems, the present inventors have conducted extensive research. Specifically, whether or not the amount of acetic acid in the crystal can be reduced by performing operations such as recrystallization and dispersion in a solvent (reslurry) on a crude telmisartan A-type crystal containing acetic acid was examined. As a result, in recrystallization, although the amount of acetic acid of telmisartan A-type crystals can be reduced, when crystallizing from a solution, part or all of the A-type crystals are crystal forms other than A-type crystals or amorphous forms. In addition, since the solubility of telmisartan is low, a large amount of solvent is required for recrystallization, the recovery rate is low, and there is a problem in industrial production. Therefore, when a method (reslurry) in which a crude telmisartan A-type crystal is dispersed in a solvent to obtain a suspension is studied, the amount of acetic acid can be reduced to some extent by dispersing, but the solvent to be dispersed (hereinafter referred to as reslurry). The amount of acetic acid and its reproducibility vary greatly depending on the type of the solvent), and a part of the A-type crystal may change to a crystal form other than the A-type crystal or an amorphous form. Was a problem. Therefore, when the solvent to be used was further examined, when a mixture of methanol and water obtained by mixing at a specific ratio was used as the reslurry solvent, acetic acid was not changed from the A-type crystal to another crystal. The inventors have found that the amount can be stably reduced to a desired amount, and have completed the present invention. The reason for this is not clear, but in a mixture of methanol and water, telmisartan is likely to take the form of A-type crystals and acetic acid is easily extracted from the crystals, and telmisartan A-type. It is presumed that the separation efficiency between the crystal and the mixture of methanol and water is high, and the mother liquor containing acetic acid hardly remains in the telmisartan A-type crystal after separation.

That is, the present invention relates to 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benz] having an acetic acid content of 0.05 to 10% by mass. In X-ray diffraction (XRD) using Cu-Kα rays of imidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid (telmisartan) , the diffraction angle 2θ is 6.9 ± 0.2 °, 13.9 ± 0.2 °, 14.3 ± 0.2 °, 15.1 ± 0.2 °, 18.3 ± 0.2 °, 19.1 ± 0.2 °, 22.3 ± 0 Coarse of type A crystals having peaks at .2 °, 23.2 ± 0.2 °, 23.9 ± 0.2 °, 25.0 ± 0.2 ° and 37.6 ± 0.2 ° The volume ratio of methanol is 50 or more and 99 or less, assuming that the total volume of methanol and water of 5 to 50 mL per gram of telmisartan is 100. Obtaining a suspension by mixing the mixture of Lumpur and water at a temperature of 20 to 50 ° C., to comprise the step of obtaining the Telmisartan Form A crystals to remove the liquid from the suspension This is a method for producing a telmisartan A-type crystal having an acetic acid content of less than 0.05% by mass.

  Further, in the present invention, a telmisartan A-type crystal crude product having an acetic acid content of 0.05 to 10% by mass is mixed with a telmisartan crude product and a base to prepare a salt solution of telmisartan and a base. It is preferable that it is manufactured by the method of including the process of obtaining, the process of mixing the said solution and acetic acid, and precipitating telmisartan.

  According to the present invention, 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benz] has an acetic acid content of 0.05 to 10% by mass. A large amount of solvent is used for recrystallization by dispersing a crude form of A-type crystals of imidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid (telmisartan) in a mixture of methanol and water Thus, telmisartan A-type crystals with a reduced amount of acetic acid can be efficiently produced at a high recovery rate. The telmisartan A-type crystals obtained by dispersing in a mixture of methanol and water have a greatly reduced amount of acetic acid, so that it is not necessary to perform drying at a high temperature and for a long time, which has been essential in the past.

3 is an XRD profile of a crude telmisartan crystal obtained in Production Example 1. 2 is an XRD profile of telmisartan crystals obtained in Example 1. FIG.

  The present invention relates to 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazole] having an acetic acid content of 0.05 to 10% by mass. 1-yl] -methyl] -biphenyl-2-carboxylic acid (telmisartan) A-form crystal (hereinafter also referred to as acetic acid-containing telmisartan A-form crystal) and 5-50 mL of methanol per gram of telmisartan And a mixture of methanol and water (hereinafter also simply referred to as a mixture of methanol and water) having a methanol volume ratio of 50 or more and 99 or less when the total volume of water is 100. And a step of obtaining a telmisartan A-type crystal by removing the liquid from the suspension to obtain a suspension. Is Telmisartan Form A method for producing a crystal is less than%.

  First, an acetic acid-containing telmisartan A-type crystal coarse body and a mixture of methanol and water, which are reslurry solvents, will be described.

(Rough body of acetic acid-containing telmisartan type A crystal)
In the present invention, the telmisartan A-type crystal crude body (acetic acid-containing telmisartan A-type crystal crude body) having an acetic acid content of 0.05 to 10% by mass is not particularly limited. The crystal form is not particularly limited, and may contain impurities other than acetic acid) and a step of mixing a base to obtain a salt solution of telmisartan and a base, and the solution and acetic acid are mixed to form telmisartan Can be produced by a method comprising a step of depositing. By the above method, a crude telmisartan A-type crystal having a high purity and an acetic acid content of 0.05 to 10% by mass is obtained. Therefore, in the present invention, it is preferable to use telmisartan obtained by the above method because telmisartan A-type crystals with high purity and reduced acetic acid amount can be obtained. In the present invention, the above method may be repeated in order to highly purify the telmisartan A-type crystal finally obtained.

  Here, telmisartan A-type crystals are long, thin or thin needles, and are crystalline polymorphs characterized by a melting point determined by differential scanning calorimetry (DSC) of 269 ± 2 ° C. (patent) Reference 1). Further, when the present inventors measured X-ray diffraction (XRD) using Cu-Kα rays, the A-type crystal has a diffraction angle 2θ of 6.9 ± 0.2 °, 13.9 ±. 0.2 °, 14.3 ± 0.2 °, 15.1 ± 0.2 °, 18.3 ± 0.2 °, 19.1 ± 0.2 °, 22.3 ± 0.2 °, It had characteristic peaks at positions of 23.2 ± 0.2 °, 23.9 ± 0.2 °, 25.0 ± 0.2 ° and 37.6 ± 0.2 °. Being an A-type crystal can be easily identified by the above-described various analyses, and can be clearly distinguished from other crystal forms and amorphous forms.

  In the above method, the base that forms the base salt of telmisartan is not particularly limited as long as it can form a base salt with telmisartan. Specific examples include inorganic bases such as ammonia, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, and potassium hydrogen carbonate, and organic bases such as methylamine, ethylamine, trimethylamine, triethylamine, and diisopropylamine. Moreover, the solvent used for obtaining the salt solution of telmisartan and base may be any solvent that dissolves the base salt of telmisartan. Specifically, alcohols having 1 to 3 carbon atoms such as methanol, ethanol, isopropanol and the like. , Ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran and the like. These may be used alone, in combination of two or more, or a mixture of these and water may be used. Among these, telmisartan base salt has high solubility, has a relatively low boiling point and is easy to remove, and therefore alcohols having 1 to 3 carbon atoms, ethyl acetate, acetone, or a mixture of these with water What was done can be used conveniently.

  Specific examples of the method include the method disclosed in Patent Document 1. That is, telmisartan and 25% aqueous ammonia are stirred and mixed in an ethanol solvent, and activated carbon is added to the solution obtained by dissolving as an ammonium salt of telmisartan and stirred, and then the activated carbon is removed by filtration. The resulting solution was heated to 70 to 80 ° C., acetic acid was added, and the mixture was stirred at 75 to 80 ° C., then the obtained reaction solution was cooled to 0 to 10 ° C. and stirred, and the precipitated telmisartan was collected by filtration. By washing with ethanol and water, a crude wet body of telmisartan A-type crystals usually containing 1 to 10% by mass of acetic acid is obtained.

  In the present invention, as the crude acetic acid-containing telmisartan A-type crystal, the wet telmisartan A-type crystal obtained by the above method can be used, or the wet body can be dried to obtain acetic acid or other What reduced content of the solvent contained can also be used. The drying conditions depend on the amount of acetic acid contained in the wet body and the amount of the other solvent, but may be dried at 70 to 90 ° C. for 1 to 90 hours, whereby the acetic acid content is 0.05 to 2% by mass. A crude product of telmisartan A-type crystals reduced to a low level is obtained. Although drying can be carried out under normal pressure or reduced pressure, the time required for drying can be shortened by carrying out under reduced pressure.

  In the present invention, the method for obtaining a crude product of acetic acid-containing telmisartan A-type crystals is not limited to the above, and the activated carbon treatment in the above method may be omitted, and the temperature and time of the reaction solution in each stage may be used. What is necessary is just to determine suitably by the kind, quantity, etc. of a base and a solvent to perform. As an example of suitable conditions, the temperature at which the base salt solution of telmisartan is obtained is preferably 20 to 80 ° C. from the viewpoint of the reaction rate, and when telmisartan is precipitated, from the viewpoint of the recovery rate of telmisartan. It is preferable to set it as 0-30 degreeC.

  The crude acetic acid-containing telmisartan A-type crystal in the present invention is not limited to those produced by the above-described method, and the telmisartan A-type crystal having an acetic acid content of 0.05 to 10% by mass is used. The effects of the present invention are efficiently expressed.

(Reslurry solvent: a mixture of methanol and water)
In the mixture of methanol and water used as the reslurry solvent in the present invention, the volume ratio of methanol (hereinafter also simply referred to as the volume ratio of methanol) is 50 to 99 when the total volume of methanol and water is 100. It is not particularly limited as long as it is a mixture of methanol and water as described below, and any mixture of methanol and water may be used so that the above ratio is obtained. By setting the volume ratio of methanol to 50 or more and 99 or less, acetic acid can be effectively reduced. When the volume ratio of methanol is less than 50, the viscosity of the suspension obtained by mixing telmisartan, a mixture of methanol and water is increased, the filtration efficiency is lowered, and telmisartan separated by filtration becomes acetic acid or other Since the solvent is contained in a large amount, acetic acid is not effectively reduced. When the volume ratio is greater than 99, acetic acid is relatively difficult to extract from the crystals, and acetic acid is not effectively reduced. In consideration of the reduction efficiency of acetic acid and the recovery rate of telmisartan A-type crystals, it is preferably 55 or more and 99 or less, and more preferably 60 or more and 95 or less.

  The methanol in the present invention can be used without any limitation in grades such as reagents or industrial raw materials. Further, the water in the present invention is not particularly limited, and tap water, ion exchange water, pure water, ultrapure water, and the like can be used. Further, the method for preparing a mixture of methanol and water is not particularly limited, and the mixture may be prepared before being put into a container to be mixed with telmisartan or may be prepared in a container. Furthermore, after mixing telmisartan and methanol or water, water or methanol can be added to the mixture to prepare a mixture.

  Moreover, in this invention, the usage-amount of the mixture of methanol and water is 5-50 mL per 1g of telmisartan. Here, when using the crude wet body of a telmisartan A type crystal | crystallization, the usage-amount is calculated with respect to the pure part of the telmisartan contained in it. If the amount used is less than 5 mL per gram of telmisartan, the efficiency of reducing acetic acid is low, and if it exceeds 50 mL, the recovery rate of telmisartan is low, which is not preferable. In consideration of the reduction efficiency of acetic acid and the recovery rate of telmisartan A-type crystals, the amount used is preferably 7.5 to 40 mL, more preferably 10 to 35 mL, per gram of telmisartan. Most preferably, it is 15-30 mL.

  Next, the details of the method of the present invention will be described.

(Reslurry conditions)
The present invention includes a step of mixing the crude acetic acid-containing telmisartan A-type crystal with a specific amount of a mixture of methanol and water to obtain a suspension, and removing the liquid from the suspension to remove telmisartan A-type. A method for producing a telmisartan A-type crystal having an acetic acid content of less than 0.05% by mass, comprising a step of obtaining a crystal. In the present invention, the acetic acid-containing telmisartan A-type crystal and a mixture of methanol and water are mixed to obtain a suspension in which the crystal is dispersed, thereby obtaining a solid-liquid separation. The content of acetic acid contained in the telmisartan A type crystal can be reduced.

  In the present invention, the acetic acid-containing telmisartan A-type crystal and the mixture of methanol and water are preferably mixed with stirring. In the above mixing operation, a glass container, a stainless steel container, a Teflon (registered trademark) container, a glass lining container, or the like can be used as a reaction container, and it is preferable to attach a thermometer or a temperature sensor to the reaction container. The mixing operation is preferably carried out by stirring with a mechanical stirrer, magnetic stirrer, or the like in such a reaction vessel, and is preferably stirred with a stirring blade or the like for large-scale production.

  The mixing operation may be performed at a temperature of 20 to 50 ° C. If the room temperature at which the operation is performed is in the temperature range, it is efficient and preferable to perform the operation without particularly performing an operation such as heating or cooling. By performing the reaction within the temperature range, acetic acid can be effectively reduced without reducing the yield. In addition, the time for carrying out the above mixing operation is usually 0.01 to 5 hours. However, in order to obtain the effects of the present invention sufficiently, the telmisartan A-type crystals are reacted in the suspension state. It is preferable to be uniformly dispersed therein, and when a lump exists, it is preferable to continue mixing until it is dispersed.

  In the present invention, telmisartan A-type crystals can be obtained by solid-liquid separation of the suspension obtained by mixing as described above and drying the obtained wet body. In the present invention, the method for solid-liquid separation is not particularly limited, and may be carried out by a known method, and examples thereof include vacuum filtration, pressure filtration, and centrifugal separation. It is preferable to sufficiently remove the mother liquor contained in the telmisartan A-type crystal obtained by solid-liquid separation by washing with methanol, water, or a mixture thereof. When washing is not performed, the mother liquor may remain in the telmisartan A-type crystal, and the effect of reducing acetic acid may be reduced. Here, the amount of the solvent used for washing may be appropriately determined depending on the type of the solvent, but is usually 0.5 to 20 mL per 1 g of telmisartan A-type crystal. The telmisartan A-type crystal thus obtained has a reduced acetic acid content. Depending on the acetic acid content in the acetic acid-containing telmisartan and the conditions of the mixing operation, the acetic acid content is 0. Less than 05% by weight is obtained. The acetic acid contained in the wet body is easier to remove than the acetic acid contained in the crude acetic acid-containing telmisartan A-type crystal, and even if the acetic acid content is 0.05% by mass or more, the following drying is performed. By performing the operation, it can be easily made less than 0.05% by mass.

  In the present invention, telmisartan A-type crystals obtained by solid-liquid separation as described above may be dried by an appropriate method. As a result, the amount of acetic acid can be reduced to less than 0.05% by mass, and the amount of solvent used in the above operation can be reduced. The drying method is not particularly limited, and may be performed using a known dryer. For example, a shelf dryer or a conical dryer can be used. Moreover, it is preferable to dry in a nitrogen atmosphere or a vacuum atmosphere, and considering the time required for drying, it is more preferable to dry in a vacuum atmosphere. The temperature at which drying is carried out is usually 20 to 120 ° C., and considering the solvent removal efficiency, it is preferably 30 to 120 ° C., more preferably 40 to 120 ° C. The time for carrying out the drying may be continued until the amount of acetic acid or solvent remaining in the telmisartan A-type crystal is measured and reached the desired amount, and is usually 0.1 to 20 hours.

  According to the method of the present invention, a telmisartan A-type crystal in which the acetic acid content is reduced and the acetic acid is easily removed can be produced from the crude acetic acid-containing telmisartan A-type crystal. Therefore, it is not necessary to dry at high temperature for a long time in order to remove acetic acid, and telmisartan A-type crystals having a high purity and an acetic acid content of less than 0.05% by mass can be easily produced. The telmisartan type A crystal can be used for pharmaceutical use without any problem. Further, the telmisartan A-type crystal is sufficiently high in purity, but by repeating the operation of the present invention, it is possible to obtain a telmisartan A-type crystal with higher purity.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples.
In addition, the measurement of the amount of acetic acid contained in the sample of an Example and a comparative example, the purity of telmisartan, and evaluation of the crystal polymorphism were implemented as follows.

(Measurement of the amount of acetic acid)
The amount of acetic acid contained in the sample was calculated by a calibration curve method from the peak area value of acetic acid measured by gas chromatography (GC). The apparatus used for GC measurement and the measurement conditions are as follows. Here, the acetic acid amount is a percentage of the mass of acetic acid to the mass of the sample. Moreover, the detection limit of the amount of acetic acid in the said evaluation was less than 0.003 mass%.

Apparatus: Gas chromatograph apparatus (Agilent Technologies, Inc.)
Detector: Hydrogen flame ionization detector (manufactured by Agilent Technologies, Inc.)
Column: Capillary column in which the inner surface of a fused silica tube having an inner diameter of 0.53 mm and a length of 30 m is coated with polyethylene glycol for gas chromatography at a thickness of 1 μm Column temperature: After injection at a constant temperature around 40 ° C., at 5 ° C. per minute The temperature was raised to 165 ° C. Subsequently, the temperature was raised to 230 ° C. at 10 ° C. per minute and maintained for 5 minutes.
Inlet temperature: 240 ° C
Detector temperature: 240 ° C
Carrier gas: helium Column pressure: 50 kPa.

(Measurement of telmisartan purity)
The purity of telmisartan was measured by high performance liquid chromatography (HPLC). The apparatus used for the HPLC measurement and the measurement conditions are as follows. In HPLC analysis under the above conditions, the retention time of telmisartan is around 14.6 minutes. In the following examples and comparative examples, the purity of telmisartan is the ratio of the peak area value of telmisartan to the sum of the area values of all peaks (excluding solvents-derived peaks) measured under the following conditions. Moreover, the detection limit in the evaluation was less than 0.003%.

Apparatus: Liquid chromatograph (manufactured by Waters Corporation)
Detector: UV absorptiometer (manufactured by Waters Corporation)
Measurement wavelength: 230 nm
Column: A stainless steel tube having an inner diameter of 4.0 mm and a length of 12.5 cm packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Mobile phase A: A mixed solution in which 2.0 g of sodium dihydrogen phosphate and 3.8 g of sodium 1-pentanesulfonate were added to 1000 mL of water and dissolved, and then phosphoric acid was added to adjust the pH to 3.0.
Mobile phase B: a mixed solution obtained by adding 200 mL of methanol to 800 mL of acetonitrile.
Transfer of mobile phase: Concentration control is performed by changing the mixing ratio of mobile phases A and B as shown in Table 1.
Flow rate: 1.0 mL per minute
Column temperature: constant temperature around 40 ° C Measurement time: 32 minutes

(Evaluation of crystalline polymorph of telmisartan)
The crystals of telmisartan were subjected to differential scanning calorimetry (DSC) measurement and X-ray diffraction (XRD) measurement. The melting point by DSC measurement was 269 ± 2 ° C., and the diffraction angle 2θ was 6.9 ± 0.2 ° in XRD measurement. 13.9 ± 0.2 °, 14.3 ± 0.2 °, 15.1 ± 0.2 °, 18.3 ± 0.2 °, 19.1 ± 0.2 °, 22.3 ± Confirm that there are peaks at 0.2 °, 23.2 ± 0.2 °, 23.9 ± 0.2 °, 25.0 ± 0.2 ° and 37.6 ± 0.2 °. This confirmed that it was an A-type crystal.

Production Example 1
In a 200 mL three-necked flask equipped with a stirring blade and a thermometer, methyl 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazole-1] was added. -Il] -methyl] -biphenyl-2-carboxylate 15.0 g (28.4 mmol) and methanol 30 mL were added and stirred. To the obtained white slurry, an aqueous sodium hydroxide solution prepared from 2.2 g (56.1 mmol) of sodium hydroxide and 15 mL of water was dropped little by little so that the internal temperature would be 22 to 26 ° C. in a water bath, After dropping the whole amount, the mixture was heated and reacted at 80 ° C. for 3 hours. After completion of the reaction, the mixture was cooled to around 25 ° C. and 84 mL of methanol was added. Subsequently, 10.2 g (56.1 mmol) of dilute hydrochloric acid was added so that the internal temperature became 24-28 ° C., and when the pH reached 7, crystals were precipitated. Furthermore, after adding 75 mL of water and stirring for 10 minutes, the crystal | crystallization which precipitated by vacuum filtration was separated by filtration, and the crystal separated by filtration was washed twice with the liquid mixture prepared from 12 mL of methanol and 3 mL of water. The obtained light brown crystals were dried at 60 ° C. under reduced pressure for 14 hours to obtain 13.6 g (26.4 mmol) of crude telmisartan crystals as light brown crystals. When the crystal polymorph was evaluated for the crude body of the crystal, it was confirmed that the melting point by DSC measurement was 270 ° C., and the characteristic peak was found in the A-type crystal in XRD measurement (FIG. 1).

Example 1
After adding and stirring and mixing 5.0 g (9.7 mol) of telmisartan A-type crystals obtained in Production Example 1, 70 mL of methanol, and 5 mL of water to a 200 mL three-necked flask equipped with a stirring blade and a thermometer Then, 1.0 g (14.6 mmol) of 25% aqueous ammonia was added to dissolve the crude telmisartan A-type crystal. Subsequently, 250 mg of activated carbon was added and stirred at around 25 ° C. for 1 hour. After completion of the stirring, the activated carbon was separated by filtration under reduced pressure, and 2.3 g (38.9 mmol) of acetic acid was added to the resulting solution, followed by stirring at around 25 ° C. for 2 hours. The white crystals precipitated by filtration under reduced pressure were filtered off, and the white crystals filtered off with 5 mL of methanol were washed once to obtain 6.8 g of telmisartan crystal wet as white crystals (telmisartan 4.5 g, 8.7 mmol). . When the amount of acetic acid contained in the wet body of this telmisartan crystal was measured, it was 2.1% by mass with respect to telmisartan. The purity was 99.90%.
To a 50 mL three-necked flask equipped with a stirring blade and a thermometer, 6.8 g of the obtained telmisartan crystal wet body and 67 mL of a mixture with a volume ratio of methanol of 80 were added, and the mixture was stirred at around 25 ° C. for 1 hour. . Next, the crystals were separated by filtration under reduced pressure, and the crystals separated by filtration were washed twice with 5 mL of methanol to obtain a wet telmisartan crystal (acetic acid amount: 0.005% by mass). The obtained wet substance was dried at 60 ° C. under reduced pressure for 3 hours to obtain 4.3 g (8.4 mmol) of telmisartan crystals as white crystals. The amount of acetic acid contained in the telmisartan crystal was 0.005% by mass, and the purity was 99.90%. The yield based on the crude telmisartan A-type crystal was 85.9%. Further, when the crystal polymorph was evaluated for the crystal, it was confirmed that the melting point by DSC measurement was 270 ° C. and the characteristic peak was found in the A-type crystal in XRD measurement (FIG. 2).

Examples 2-8
The amount and purity of acetic acid were measured for the obtained telmisartan A-type crystals in the same manner as in Example 1 except that the mixture of methanol and water shown in Table 2 was used and the mixing conditions were changed. The results are shown in Table 2.

Comparative Example 1 (Dry)
6.8 g (telmisartan 4.5 g, 8.7 mmol) of the telmisartan crystal wet body obtained in Example 1 (purity 99.90%, acetic acid amount 2.1% by mass) was dried at 60 ° C. under reduced pressure for 30 hours. The acetic acid content of the wet telmisartan crystal thus obtained was 1.2% by mass. Furthermore, drying was continued under reduced pressure at 90 ° C., and the amount of acetic acid was measured at regular time intervals. As a result of drying at 0.150 mass% for 10 hours after 90 ° C., the amount of acetic acid was 0.090 mass. % And 4.5 g (8.7 mmol) of telmisartan A-type crystals having a purity of 99.90% were obtained. The yield based on the crude telmisartan A-type crystal was 89.5%.

Comparative Example 2 (recrystallization)
Add 6.8 g of wet telmisartan crystals (purity 99.90%, acetic acid amount 2.1% by mass) obtained in Example 1 (telmisartan 4.5 g, 8.7 mmol) and 1360 mL of methanol, and heat to reflux temperature. Warm up. When the mixture was stirred for 15 minutes at the reflux temperature, all the termamyltan was dissolved. The resulting solution was gradually cooled to 25 ° C. and stirred at around 25 ° C. for 2 hours. Next, the crystals were separated by filtration under reduced pressure, and the white crystals separated by filtration were washed twice with 5 mL of methanol to obtain 4.1 g of wet telmisartan A-type crystals (acetic acid amount: 0.031%). The obtained wet body was dried at 60 ° C. under reduced pressure for 5 hours to obtain 2.7 g (5.2 mmol) of telmisartan A-type crystals as white crystals. The amount of acetic acid contained in the telmisartan A-type crystal was 0.019% by mass, and its purity was 99.90%. The yield based on the crude telmisartan type A crystal was 54.8%.

Comparative Examples 3-9
The amount and purity of acetic acid were measured for the obtained telmisartan A-type crystals in the same manner as in Example 1 except that the mixture of the organic solvent and water shown in Table 2 was used and the mixing conditions were changed. The results are shown in Table 2.

Claims (2)

4 '-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] having an acetic acid content of 0.05 to 10% by mass -Methyl] -biphenyl-2-carboxylic acid by X-ray diffraction (XRD) using Cu-Kα rays, the diffraction angle 2θ is 6.9 ± 0.2 °, 13.9 ± 0.2 °, 14.3 ± 0.2 °, 15.1 ± 0.2 °, 18.3 ± 0.2 °, 19.1 ± 0.2 °, 22.3 ± 0.2 °, 23.2 ± 0 A coarse product of type A crystals having peaks at positions of 2 °, 23.9 ± 0.2 °, 25.0 ± 0.2 ° and 37.6 ± 0.2 °, and 4 ′-[[2 Per gram of -n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid A suspension is obtained by mixing a mixture of methanol and water having a methanol volume ratio of 50 or more and 99 or less, assuming that the total volume of methanol of 50 mL and water is 100, at a temperature of 20 to 50 ° C. Removing liquid from the suspension, 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl - characterized in that it comprises the step of obtaining the crystalline form a of biphenyl-2-carboxylic acid, the content of acetic acid is less than 0.05 wt% 4 '- [[2- n- propyl - A process for producing type A crystals of 4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid. Form A of said 4 '-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid As a step of obtaining a crude product of crystals, 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl 2-carboxylic acid and a base were mixed to produce 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl]- A step of obtaining a salt solution of methyl] -biphenyl-2-carboxylic acid and a base, and the solution and acetic acid are mixed to produce 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenz Imidazole-2- Le) - benzimidazol-1-yl] - methyl] - The method according to claim 1, characterized in that it further comprises the step of precipitating the biphenyl-2-carboxylic acid.

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