[0001]The present invention azilsartan (Chemical Name: 1 - [[2 '- (4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) [1,1'-biphenyl - 4-yl] methyl] -2-ethoxy -1H- benzimidazole-7-carboxylic acid), and a method for producing the same.
BACKGROUND
[0002]The following formula (1)
[0003]
[Formula 1]

[0004]
In azilsartan represented (Chemical Name: 1 - [[2 '- (4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) [1,1'-biphenyl -4 - yl] methyl] -2-ethoxy -1H- benzimidazole-7-carboxylic acid) is a very useful compound as a therapeutic agent showing an excellent effect as angiotensin II receptor antagonists (Patent Document 1).
[0005]
　Azilsartan is synthesized in the following manner.
[0006]
[Formula 2]

[0007]
　That is, the formula (3) represented by the alkyl 2-ethoxy-1 - [[2 '- (hydroxyimino carboxamide) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate (hereinafter, simply, sometimes referred to as "amidoxime compound") or used as it is the cyclization reaction, or performs ester protecting reaction for protecting the hydroxyl group of the amidoxime compound with an ester protecting group, an alkyl 2 represented by the formula (4) - ethoxy-1 - [[2 '- (alkyloxy - carbonyloxy carbamimidoyl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate (hereinafter, simply, "ester protecting group-containing compound" after that it may) and performs cyclization, alkyl ethoxy represented by the formula (2) 1 - [[2 '- (2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (hereinafter, simply, producing in some cases a "azilsartan alkyl ester"). And, finally, by hydrolyzing the azilsartan alkyl esters, azilsartan represented by the formula (1) is produced (e.g., Patent Documents 1-3, Non-Patent Document 1).
[0008]
　Azilsartan obtained in the above manner is quite and high purity that is desired, a variety of synthetic methods, purification methods have been studied.
[0009]
　Further, the azilsartan is known to have a crystal polymorphism. Here, the crystal as having a polymorphism, which means that multiple crystal forms crystal structures are different in the same molecule is present. Each crystal form in the crystal polymorphs, appearance, solubility, melting point, dissolution rate, bioavailability, stability, often differ characteristics related to the quality of the medicament, such as effectiveness.
[0010]
　In Patent Document 1, by crystallization ethyl acetate was added to the resulting residue and the solvent was distilled off from the reaction solution after hydrolysis to obtain azilsartan colorless prisms having a melting point of 156 ~ 157 ° C. it has been described.
[0011]
　Further, Non-Patent Document 1, the crystals obtained by solution after the reaction was neutralized by washing with ethanol, it is described to obtain a azilsartan colorless prisms having a melting point of 212 ~ 214 ° C. ing.
[0012]
　Further, Non-Patent Document 2, after obtaining crude crystals of azilsartan from a mixed solvent of acetone and water, and stirred for 1 hour was suspended in acetone, azilsartan of white crystals of melting point 208 ~ 211 ° C. It describes a method of obtaining.
[0013]
　However, the crystals are relatively low solubility of azilsartan synthesized by these methods have been reported to be a bioavailability (Patent Document 2).
[0014]
　Therefore, in Patent Document 2, with better physicochemical properties, in particular relatively high solubility, describes a process for making the crystalline form A ~ K of azilsartan having bioavailability and / or efficacy .
CITATION
Patent Document
[0015]
Patent Document 1: Japanese Patent 2645962 Publication
Patent Document 2: JP-T 2014-530805 Patent Publication
Patent Document 3: JP-T 2014-505097 Patent Publication
Non-patent literature
[0016]
Non-Patent Document 1: Journal of Medicinal Chemistry, (the United States), 1996, vol. 39, p. 5228-5235
Non-Patent Document 2: Organic Process Research and Development, (the United States), 2013, Vol.17, p. 77-86
Summary of the Invention
Problems that the Invention is to Solve
[0017]
　If the commonly used compound as a pharmaceutical drug is very high purity that is desired. The method of recrystallization or the like using an organic solvent has high purification effect, is preferably employed.
[0018]
　However, the present inventors have synthesized a azilsartan by the method described in Patent Document 1, Non-Patent Documents 1 and 2, each of the obtained crystals azilsartan, it is very poorly soluble in organic solvents It was found. Further the synthesis of crystal form A ~ K of azilsartan by the method described in Patent Document 2, solubility acidic aqueous solution, Patent Document 1, the conventional crystal obtained by the method described in Non-Patent Documents 1 and 2 although an improvement over the solubility in an organic solvent remained low. Therefore, as with the conventional azilsartan crystal, in the case of performing the purification procedure using an organic solvent is required a large amount of organic solvent. Therefore, when performing industrial purification was a big problem.
[0019]
　Therefore, a soluble in an organic solvent, development of recrystallization is adoptable azilsartan crystals using an organic solvent has been desired.
[0020]
　The first object of the present invention is to provide solubility in organic solvents is improved, the crystal of azilsartan having a novel crystal form, and a manufacturing method thereof.
[0021]
　Further, when the present inventors etc. studied, Patent Documents 1-3 and even to produce azilsartan according to the method of Non-Patent Document 1, it was found that there are impurities that are difficult to reduce. Analysis of this impurity,
　the following formula (5)
[0022]
[Formula 3]

[0023]
In azilsartan dimerization impurities shown (hereinafter, sometimes simply referred to as "azilsartan dimer") it was found to be.
[0024]
　The azilsartan dimer was believed to be synthesized as follows. That is, in the cyclization reaction in the production of azilsartan,
　the following formula (3)
[0025]
[Chemical Formula 4]

[0026]
(Wherein, R 1 is an alkyl group)
and amidoxime unreacted compound represented by the
　following formula (1)
[0027]
[Formula 5]

[0028]
And azilsartan shown in is to first react,
　the following formula (6)
[0029]
[Formula 6]

[0030]
(Wherein, R 1 is an alkyl group)
dimers of azilsartan alkyl ester represented by (hereinafter, simply sometimes referred to as "azilsartan alkyl ester dimer") is produced. Then, the azilsartan alkyl ester dimers, was it considered to be hydrolyzed by-product. That is, when manufacturing the azilsartan, was considered that other reactions are prepared by proceeding simultaneously (i.e., but also the raw material or the like with high purity would generate in the reaction).
[0031]
　Further, the impurity (azilsartan dimer), in the conventional method, reduction of the final product is difficult. Further, azilsartan alkyl ester dimer of prehydrolysis was also difficult to removed as well. Therefore, in the conventional method, in order to further reduce the azilsartan dimer, it is necessary to perform repeated purification operations, there is room for industrially improved to manufacture in terms of operability and yield It was.
[0032]
　A second object of the present invention, the crude azilsartan containing azilsartan dimer as an impurity, in particular can be selectively reduce the content of azilsartan dimer method of azilsartan high purity It is to provide a.
Means for Solving the Problems
[0033]
　The present inventors have conducted extensive studies with respect to the first problem. As a result, a solution obtained by dissolving azilsartan dimethylformamide, crystals azilsartan obtained by precipitating by adding a solvent of ketones and / or esters, crystalline forms thereof and the conventional crystalline form found that are different crystalline forms. Then, crystals of the azilsartan include esters such as alcohols or ethyl acetate, such as methanol or ethanol, it found that solubility to various solvents is very high crystallinity, thereby completing the first invention It led to.
[0034]
　That is, the first present invention, the X-ray diffraction using Cu-K [alpha line, at least 2θ = 9.4 ± 0.2 °, 11.5 ± 0.2 °, 13.3 ± 0.2 °, 14.8 ± 0.2 °, a azilsartan having a crystal structure giving the characteristic peaks at 26.0 ± 0.2 °. In this specification, the azilsartan of the present invention having the crystal structure may be referred to as "azilsartan M-type crystal".
[0035]
　Melting point as determined by the first differential scanning calorimetry (DSC) measurement of azilsartan M-type crystals of the present invention is 135 ° C. or less 115 ° C. or higher.
[0036]
　The first of the present invention, the solution obtained by dissolving azilsartan dimethylformamide, adding a solvent of ketones and / or esters, wherein the precipitating azilsartan M-type crystals azilsartan M it is a manufacturing method of the type crystal.
[0037]
　Further, the present inventors have conducted extensive studies to solve the second problem. Specifically, we examined how effectively removing the azilsartan dimer from a solution of the crude azilsartan. As a result, a solution crude azilsartan is dissolved by contacting the activated carbon, found that the content of the azilsartan dimer in solution after removal of the activated carbon is greatly reduced, the second invention the has been completed.
[0038]
　That is, the second invention,
　the following formula (5)
[0039]
[Chemical Formula 7]

[0040]
In a solution coarse azilsartan containing azilsartan dimer is dissolved shown, after contacting the activated carbon,
　the following formula (1)
[0041]
[Formula 8]

[0042]
A azilsartan manufacturing method, characterized by fractionating in crystals azilsartan shown from the solution.
[0043]
　In the second invention, the activated carbon, the ratio was determined by the BET method surface area of 1000 ~ 3500 m 2 it is / g, and the cumulative pore volume is 0.6 ~ 1.5 mL / g preferable.
[0044]
　Further, the coarse azilsartan is
　the following formula (2)
[0045]
[Formula 9]

[0046]
(Wherein, R 1 is alkyl as group)
to azilsartan alkyl ester represented by the case is obtained by hydrolyzing an inorganic base, exhibits a particularly excellent effect.
Effect of the invention
[0047]
　First azilsartan M-type crystal obtained by the method of the present invention has a novel crystal structure, compared to known azilsartan crystal, alcohols, esters, ketones, ethers It is very high solubility in the organic solvent. Therefore, azilsartan M-type crystals, requires only a small amount is necessary amount of the organic solvent at the time of recrystallization, purification operations easily and becomes using purified-efficient organic solvent, the industrial utility value is high. In particular as an intermediate for pharmaceuticals, etc. that requires high purity of the drug substance, optimally can be utilized.
[0048]
　According to the second method of the present invention, in particular, high purity azilsartan of the content is reduced in azilsartan dimer as an impurity, without repeating purification operation, to produce in an efficient and simple method be able to.
BRIEF DESCRIPTION OF THE DRAWINGS
[0049]
FIG. 1 is a X-ray diffraction chart of azilsartan M-type crystals of the present invention prepared in Example 1.
It is a DSC chart of azilsartan M-type crystals of the present invention produced in [2] Example 1.
3 is a X-ray diffraction chart of the conventional azilsartan crystals prepared in Comparative Example 1 (crystal form A in patent document 2).
4 is a DSC chart of a conventional azilsartan crystals prepared in Comparative Example 1 (crystal form A in patent document 2).
DESCRIPTION OF THE INVENTION
[0050]
　Hereinafter, the first present invention and the second invention will be described respectively.
[0051]
1. The first present invention
　(azilsartan M-type crystal)
　azilsartan M-type crystals of the present invention, by X-ray diffraction using Cu-K [alpha line, at least 2θ = 9.4 ± 0.2 °, 11.5 ± 0 .2 °, 13.3 ± 0.2 °, 14.8 ± 0.2 °, is a compound having characteristic peaks at 26.0 ± 0.2 °. Incidentally, ± 0.2 ° is a measurement error of the X-ray diffraction angles, including the range of a ± 0.2 ° due to rounding. The X-ray diffraction measurement results of the azilsartan M-type crystals are shown in FIG.
[0052]
　Here, the characteristic peaks of the present invention, which has a peak intensity becomes a maximum 2θ = 9.4 ± 0.2 °, 2θ = 11.5 ± 0.2 °, 13.3 ± 0 .2 °, 14.8 ± 0.2 °, to 26.0 ± 0.2 °, the maximum peak intensity strength of at least 7% by (2 [Theta] = 9.4 ± peak intensity of 0.2 °) It says that the peak has to appear. Peaks having an intensity of less than 7% of the maximum peak intensity, considered as noise or the like, the characteristic peaks of the present invention shall not be applicable.
[0053]
　Although described in detail in the following examples, azilsartan M-type crystals of the present invention, Patent Documents 1 to 3, in comparison to known azilsartan crystal described in Non-Patent Documents 1 and 2, methanol Ya alcohols such as ethanol, esters such as ethyl acetate, ketones such as acetone; solubility in organic solvents of the ethers such as tetrahydrofuran are improved. Specifically, at room temperature, azilsartan M-type crystals, than the known azilsartan crystals can be dissolved about 7 to 10 times the same amount of methanol.
[0054]
　Further, azilsartan M-type crystal in the present invention shows a lower melting point compared to known azilsartan crystals. Specifically, it is 135 ° C. or less 115 ° C. higher than the melting point as determined by differential scanning calorimetry (DSC) measurements. In the present invention, the melting point as determined by differential scanning calorimetry (DSC) measurements, refers to the peak top temperature of the endothermic peak obtained by the measurement.
[0055]
　(Manufacturing method of azilsartan M-type crystal)
　azilsartan M-type crystal in the present invention, the solution obtained by dissolving azilsartan dimethylformamide, azilsartan M by adding a solvent of ketones and / or esters it can be prepared by precipitating the type crystals.
[0056]
　Azilsartan M-type crystal obtained by the production method of the present invention has a novel crystal structure, compared to known azilsartan crystal, alcohols, esters, ketones, an organic solvent of ethers the solubility is very high.
[0057]
　(Azilsartan)
　azilsartan used in the present invention is not particularly limited, it is possible to use those produced by a known method. For example, the method described in Patent Document 1, i.e., azilsartan methyl ester (chemical name: methyl-1 - [[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol - 3-yl) biphenyl-4-yl] methyl] -2-ethoxy -1H- benzimidazole-7-carboxylate) for 3 hours in a mixed solution of methanol and aqueous lithium hydroxide, by reaction with heating under reflux can be produced (see Patent Document 1, example 1e).
[0058]
　Azilsartan used in the present invention, once to a solution state, such as its crystal form is not particularly limited, for example, crystalline form described in Non-Patent Documents 1 and 2 and Patent Documents 1 and 2, amorphous, organic amines salts, or may be in the form which they are mixed, the powder, lump, or may be they are mixed shape, there anhydride, hydrate, solvate, or form they are mixed it may be. When a hydrate or solvate, number of molecules of water or solvent is not particularly limited. Further, since the use of solvent of dimethylformamide and ketones and / or esters in the production of azilsartan M-type crystal may be a wet material containing the organic solvent, for the other solvents, the crystallization it may remain within a range that does not affect the. Specifically, it may remain in an amount of 50 mass% or less of the azilsartan. And most preferably it contains no solvent other than the organic solvent. Further, it is possible to purity of azilsartan to be used is not particularly limited, as it is obtained by the above production method used. However, in order to further increase the purity of the finally obtained azilsartan M-type crystals, typical purification methods, for example recrystallization or reslurry, by a method such as column chromatography, one or more times if necessary purified were those, it is preferable to use as azilsartan.
[0059]
　Specifically, when measured under the conditions of high performance liquid chromatography as described in the Examples below (HPLC), the peak area ratio of azilsartan is preferably used azilsartan 95% or more. Further, for the purpose of obtaining a high solubility crystal in an organic solvent, in the purity measurement of the HPLC, peak area ratio of azilsartan can also be used which is 100%.
[0060]
　(Azilsartan solution process for the preparation of)
　the production method of the present invention by azilsartan M-type crystals, obtaining azilsartan solution first azilsartan by dissolving in dimethyl formamide. At this time, dimethylformamide used without any particular limitation, it may be used as it is commercially available. The amount of dimethyl formamide, may be suitably determined by the crystalline form of azilsartan used but, with respect to general azilsartan 1g, it may be set to 0.5mL least 10mL less. When the amount of dimethylformamide is increased, since the yield is lowered, it is preferable to 0.5mL or 5mL less. The volume of solvent in the present invention is intended at 25 ° C.. The temperature at which dissolving azilsartan may be appropriately determined by the amount of crystal form or dimethylformamide azilsartan used, it is preferably dissolved in the range of 10 ° C. or higher 50 ° C. or less. As a matter of course, if there is one which does not completely dissolve may also be processed was filtered off does not dissolve. Furthermore, a method of obtaining azilsartan solution in the present invention is not particularly limited, it may be adjusted solution by mixing a azilsartan and dimethylformamide, mixing method and order are not particularly limited.
[0061]
　(Agile crystallization Sultan M-type crystal)
　manufacturing method of the present invention by azilsartan M-type crystals to precipitate azilsartan M-type crystals in addition to the solvent of the ketone to the resulting azilsartan solution and / or esters it is characterized in. By adopting this method, it is possible to obtain the azilsartan M-type crystal solubility is improved in organic solvents in high yield. In the present invention, the solvent added to azilsartan solution, acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone and cyclohexanone; and / or ethyl acetate methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, etc. it can be selected from esters. Preferably adding a solvent of esters to obtain the higher purity azilsartan of, it is most preferable to use ethyl acetate. Among these. In the present invention, it may be added by mixing the solvent for the solvent and esters thereof ketones. In the present invention, by precipitating azilsartan by adding a solvent of ketones and / or esters, it can be precipitated azilsartan M-type crystals solubility is improved in organic solvents.
[0062]
　In the present invention, the amount of the solvent of ketones and / or esters added to azilsartan solution may be appropriately determined by the type of solvent selected. Usually, the relative azilsartan solution dimethylformamide 1mL was used in the preparation of, well if 1mL least 50mL less, yield, be less considering the operability 5mL or 20mL preferred. At this time, the temperature adding solvent ketones and / or esters are not particularly limited, after confirming that azilsartan is dissolved in dimethylformamide, it may also be added immediately at that temperature, 30 ° C. or less it is more preferable to add in. By adding at 30 ° C. or less, it is possible to suppress an increase in impurity due to thermal decomposition, the purity of the resulting azilsartan M-type crystal also becomes higher purity. Further, a method of adding a solvent of ketones and / or esters is not particularly limited, a method of adding the total amount at one time, can be either a method of adding in several divided times adopted. In the present invention, after the addition of solvent ketones and / or esters, to precipitate azilsartan M-type crystals by stirring at constant temperature. Temperature holding at this time may be a -5 ° C. or higher 30 ° C. or less, in order to obtain the azilsartan more high yield, it is preferable to retain at 0 ℃ least 10 ° C. or less. The time for holding can be appropriately determined by a temperature holding, it is preferable to usually 5 hours or more. At this time, when the crystals of azilsartan is hardly precipitated, it may also be added to the seed crystal.
[0063]
　Thus azilsartan M-type crystals precipitated, after solid-liquid separation such as filtration or centrifugal separation, natural drying, air drying, can be isolated by drying by a method such as vacuum drying.
[0064]
　Azilsartan acquired in the method is azilsartan M-type crystal having a novel crystalline structure. Azilsartan M-type crystals of the present invention is improved solubility in an organic solvent, an alcohol as compared with the known crystalline form, esters, ketones, is very high solubility in the solvent of ether. Therefore, when performing the purification procedure as target azilsartan M-type crystals, alcohols, esters, ketones, using the solvent of ethers can be carried out readily purified and recrystallization.
[0065]
2. The second of the present invention
　present invention, a solution of the crude azilsartan containing azilsartan dimer as an impurity, after contacting the activated carbon, azilsartan, characterized in that fractionating crystallization of azilsartan from the solution it is a method of manufacture.
[0066]
　(Crude azilsartan)
　In the present invention, the crude azilsartan means azilsartan containing azilsartan dimer as an impurity. In the present invention, crude azilsartan is not limited in particular, it is possible to use those produced by a known method. For example, it is possible to use azilsartan described in the first invention. Crude azilsartan, in high performance liquid chromatography may be azilsartan of 96.0 to 99.0% purity (HPLC) analysis (the present invention, the purity, the percentage of impurities (%) was determined by HPLC the area% of the value of time.). Such crude azilsartan can be suitably produced by the hydrolysis of azilsartan alkyl esters. Further, the crude azilsartan to be purified, the azilsartan dimer or may be contained from 0.01 to 0.50%. In the present invention, the order of azilsartan dimers can be reduced efficiently, may contain the above proportions azilsartan dimer.
[0067]
　First, the production method of crude azilsartan to be purified will be described. Azilsartan dimer of interest to reduce is considered a by-product in the following manner. That is, amidoxime compound used as starting material (Compound of formula (3)), when cyclizing the amidoxime compound, previously (compounds of formula (1)) azilsartan considered to be generated and is first reacted and, generating a azilsartan alkyl ester dimers. Then, azilsartan dimers are considered to be obtained from the azilsartan alkyl ester dimers. Therefore, first, a method for manufacturing of the azilsartan alkyl esters.
[0068]
　(Starting compound: Synthesis of azilsartan alkyl ester)
　azilsartan alkyl esters used in the hydrolysis reaction is not particularly limited, it is possible to use those produced by a known method. For example, it is possible to accept those produced by the method described in Patent Documents 1-3, Non-patent Document 1. Specifically, it can be prepared according to the following reaction scheme.
[0069]
[Formula 10]

[0070]
　Amidoxime compound represented by the formula (3) are known compounds, their preparation method, non-patent document 1, disclosed in Patent Document 1. That is, the presence of a base, and amidoxime compound represented by the formula (3), XCOOR 2 is reacted with a compound represented by performs ester protecting reaction, the formula (4) ester protecting group-containing compound represented by the after producing performs cyclization reaction to produce azilsartan alkyl ester represented by the formula (2).
[0071]
　According to the method of the present invention efficiently, it is possible to reduce the azilsartan dimer. However, the finally obtained azilsartan is because better high purity, adopts the following method, it is preferable to synthesize the azilsartan alkyl ester (compound of formula (2)).
[0072]
　By producing azilsartan alkyl ester in the following manner, azilsartan alkyl ester dimer which is a precursor of azilsartan dimer, it is possible to reduce the other precursor impurities, azilsartan alkyl as a raw material it can be purified ester. As a result, the purity of the finally obtained azilsartan also a higher purity.
[0073]
　(Ester protecting reaction of amidoxime compound)
　in the reaction formula, XCOOR is reacted with an amidoxime compound represented by the formula (3) 2 is, X is a halogen atom, R 2 ester protection is represented by the formula (4) R in group-containing compound 2 is the same as a protecting group for protecting the hydroxyl group.
[0074]
　Wherein R 2 protects the hydroxyl group, the general protecting group. Specifically, an optionally substituted alkyl group, a benzyl group, and a phenyl group which may have a substituent. Among them, industrially easy availability, its role in the ester protecting group-containing compound, considering such that finally removed, it is preferably a non-substituted alkyl group having 1 to 8 carbon atoms. The unsubstituted alkyl group may be straight-chain alkyl group or may be a branched alkyl group.
[0075]
　The XCOOR 2 if specifically exemplified methyl chloroformate, ethyl chloroformate, propyl, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, amyl, chloroformate, 2-ethylhexyl, hexyl chloroformate, heptyl chloroformate, chloromethyl chloroformate, 2-chloroethyl, benzyl chloroformate, phenyl chloroformate, and a chloroformate 4-chlorophenyl and the like. Among them, industrially easy availability, reactivity, and considering the role or the like in the ester protecting group-containing compound, methyl chloroformate, ethyl chloroformate, it is preferable to use propyl chloroformate and the like.
[0076]
　The XCOOR 2 usage is not particularly limited. Specifically, 1 mol of the compound represented by the formula (3), XCOOR 2 usage may be 1 to 5 moles.
[0077]
　Ester protecting reaction is carried out in the presence of a base. To exemplify the base used, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide inorganic bases like; methylamine, ethylamine, trimethylamine, triethylamine, diisopropylamine, tripropylamine, diisopropylethylamine, pyridine, piperazine, pyrrolidine, aniline, N, N- dimethylaminopyridine, diazabicycloundecene, N- methylmorpholine organic bases like can be mentioned. Among this, progressive reaction, removal easiness, considering the process or the like in a later step, triethylamine, pyridine is preferably an organic base diisopropylethylamine. The base can either be used one type, it is also possible to use multiple kinds of bases. When using a plurality of kinds of bases, the amount of base as a reference is the total amount of a plurality of types of bases.
[0078]
　The amount of the base is not particularly limited. Specifically, with respect to amidoxime 1 mole of the compound represented by the formula (3), the amount of the base may be 1 to 5 moles. As will be described later, when the cyclization of the ester group-containing compound is preferably carried out in the presence of a base. Therefore, an ester group-containing compound obtained by this reaction in the case of cyclization, it is also possible to the base is carried out cyclization reaction while remaining.
[0079]
　The solvent to be used, XCOOR 2 may be selected from among aprotic solvents which do not react with. Specifically, benzene, toluene, methylene chloride, chloroform, 1,4-dioxane and the like. These reaction solvents may be used one type may be used a mixture of two or more solvents.
[0080]
　The reaction in the presence of a base, in a solvent, amidoxime compound represented by the formula (3), and the XCOOR 2 so that contact with the well, it is preferable that stirring and mixing. Procedure for introducing these components into the reaction vessel is not particularly limited. Preferred methods include the formula (3) and said base with amidoxime compound represented by added followed XCOOR diluted with a solvent if necessary in advance in the solvent 2 is preferably going added. At this time, in order to prevent a rapid heat generation, XCOOR 2 it is preferred to dropwise. Other conditions for performing the reaction, is not particularly limited. The reaction temperature is preferably -10 ~ 10 ° C.. The reaction time, while monitoring the remaining amount of amidoxime compound materials may be suitably determined, it is preferred that the remaining amount of amidoxime compound is 0.5% or less. Be carried out usually 0.5 to 15 hours is sufficient.
[0081]
　By reacting the above-described conditions, it is possible to manufacture the above formula (4) ester protecting group-containing compound represented by the. How to retrieve the ester protecting group-containing compound from the reaction system is not particularly limited. Specifically, ethyl acetate the ester protecting group-containing compound, toluene, chloroform, dissolved in water, such as methylene chloride in the hardly soluble solvent, washing with water, concentrated, by drying or the like, containing the ester protecting group it can be taken out compound. Incidentally, in the case of using a sparingly soluble solvent to the water in the solvent, it may be washed with water solutions.
[0082]
　Ester protecting group-containing compound represented by the formula obtained by the above-described condition (4) is not particularly limited, it is possible purity and that of 90.0 to 99.5%. Further, by adjusting the water washing, the ester protecting group-containing compound taken out in a state containing a base, it can also be carried out following the cyclization reaction.
[0083]
　(Cyclization of the ester protecting group-containing compound)
　cyclization reaction is preferably carried out by heating the resulting ester protecting group-containing compound in the reaction in a reaction solvent. By performing the cyclization reaction at the method, removal is difficult impurity formula (6)
[0084]
[Of 11]

[0085]
(Wherein, R 1 is an alkyl group)
or azilsartan alkyl ester dimer represented by the
　following formula (7)
[0086]
[Chem. 12]

[0087]
(Wherein, R 1 is an alkyl group)
azilsartan alkyl ester of the hydrolyzate of the formula (hereinafter, simply sometimes referred to as "azilsartan alkyl esters desethyl body"),
　no further structural clear but the analysis of a liquid chromatograph mass spectrometer (LC-mASS), it is possible to reduce impurities molecular weight plus 10 to the molecular weight of azilsartan methyl ester.
[0088]
　More impurities are difficult to separate the azilsartan alkyl esters, in the end, it is possible that these impurities from the impurities (which was hydrolyzed) is included in the azilsartan. Therefore, do not produce these impurities as much as possible, it is preferable to employ a method described in detail below.
[0089]
　The cyclization reaction by heating, it is possible to proceed the reaction. Specifically, by the ester protecting group-containing compound to heat the reaction solution in the reaction solvent, the cyclization reaction is promoted, the ester protecting group-containing compound may be a azilsartan alkyl esters. During the cyclization reaction, by dissolving the ester protecting group-containing compound in the reaction solvent, it is preferably heated while stirring and mixing. As a matter of course, and heated while stirring to the ester protecting group-containing compound and the reaction solvent and the reaction solution may be directly heating the reaction solution.
[0090]
　The reaction temperature of the cyclization reaction increases the reaction rate, and to reduce the impurities, 50 ° C. or more, is preferably not more than reflux temperature of the reaction solution, 60 ° C. or more and less reflux temperature of the reaction solution it is more preferred, and even more preferably from 70 ° C. or higher, less reflux temperature of the reaction solution. The reflux temperature of the reaction solution, the reaction solvent used, the concentration of the ester protecting group-containing compound, by-produced R 2 because it varies depending on the kinds of -OH, it can not be limited unconditionally. However, in order to suppress the generation of more impurities, the reaction temperature is preferably set to 100 ° C. or less.
[0091]
　In the present invention, it can facilitate the cyclization reaction according to the conditions. Among them, in order to shorten the reaction time is preferably carried out in the presence of a base. Specifically, it may be any condition that includes a base in the reaction solution. Bases which can be employed in the cyclization reaction is not particularly limited, but is sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, sodium hydroxide, water potassium oxide, barium hydroxide, and inorganic bases such as lithium hydroxide. Further, methylamine, ethylamine, trimethylamine, triethylamine, diisopropylamine, tripropylamine, diisopropylethylamine, pyridine, piperazine, pyrrolidine, aniline, N, N- dimethylaminopyridine, diazabicycloundecene, etc. N- methylmorpholine organic base can be used. Among them, purified ease of the obtained azilsartan alkyl esters, in order to improve the operability, triethylamine, pyridine, it is preferred to use an organic base such as diisopropylethylamine. These bases can either be used one type, it is also possible to use multiple kinds of bases. When using a plurality of kinds of bases, the amount of base as a reference is the total amount of a plurality of types of bases. Incidentally, the base is, as described above, when using the base in preparing the ester protecting group-containing compound can also be used bases remaining in retrieving the ester protecting group-containing compound .
[0092]
　In the present invention, without using a base, it is possible to proceed cyclization reaction. However, when using bases, relative to the ester protecting group-containing compound to 1 mole, the amount of base used is preferably 0.01 to 5 mol. Base By using this range, it is possible to increase the reaction rate, and can be increased azilsartan alkyl ester yield and purity. For greater this effect, relative to the ester protecting group-containing compound to 1 mole, the amount of base used is more preferably from 0.1 to 1 mol. In the present invention, when using bases, the reaction solvent can advance bases, and the addition of the ester protecting group-containing compound, also be stirred and mixed with heating. Further, the reaction solution is heated with stirring and mixing, it may be added to the base in order to accelerate the reaction in the middle. If you add the base in the middle is a quantity of the total amount of base used is standard.
[0093]
　By performing the cyclization reaction in the above-described conditions, it is possible to produce a azilsartan alkyl esters. How to retrieve the resulting azilsartan alkyl ester from the reaction system is not particularly limited, non-patent document 1, it is possible to employ a method described in Patent Document 1.
[0094]
　The cyclization reaction is preferably carried out by heating. And, in a more preferred embodiment, the temperature of the reaction solution (reaction temperature) to 50 ° C. or higher. Therefore, the reaction solution after completion of the reaction, it is preferred to cool in a range of 30 ° C. or less, preferably be further cooled to the range of -10 ~ 30 ° C., in particular cooling in the range of -10 ~ 10 ° C. preferable.
[0095]
　The purity of the resulting azilsartan alkyl esters to higher, the reaction solution after completion of the reaction by cooling at a cooling rate of 10 ~ 30 ° C. / time, 30 ° C. or less, preferably 0 ~ 30 ° C., more preferably It is -10 ~ 30 ° C., particularly preferably preferably be a temperature of -10 ~ 20 ° C.. Furthermore, in order to increase the yield of the resulting azilsartan alkyl ester, 1 30 ° C. or less, preferably as 0 ~ 30 ° C., more preferably -10 ~ 30 ° C., especially a temperature of preferably -10 ~ 20 ° C. time or more, preferably to stand for 20 hours or less than 2 hours.
[0096]
　In the present invention, accept hydrolyzing the azilsartan alkyl esters, can also be a coarse azilsartan. However, the azilsartan alkyl esters of crude obtained in this manner, and contains a plurality of impurities in addition to the azilsartan alkyl ester dimer as an impurity, in order to obtain a azilsartan of higher purity preferably, the recrystallized azilsartan alkyl esters obtained by the above method. By performing recrystallization, thereby further reducing the amount of impurities including azilsartan alkyl ester dimers. To exemplify the solvent used, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl butyl ketone, it can be mentioned methyl isobutyl ketone. It These solvents may be used in one kind, it is also possible to use a plurality of types of mixed solvent. The amount of solvent employed is not particularly limited. Specifically, with respect to the crystal 1g of the azilsartan alkyl esters, the amount of solvent is preferably in the 3 ~ 30 ml, it is preferable to further 5 ~ 20 ml.

claims

The X-ray diffraction using Cu-K [alpha line, at least 2θ = 9.4 ± 0.2 °, 11.5 ± 0.2 °, 13.3 ± 0.2 °, 14.8 ± 0.2 °, azilsartan characterized by providing a characteristic peaks at 26.0 ± 0.2 °.
[Requested item 2]
　Azilsartan of claim 1 is melting point as determined by differential scanning calorimetry (DSC) measurement is 135 ° C. or less 115 ° C. or higher.
[Requested item 3]
　The azilsartan to the solution obtained by dissolving in dimethyl formamide, ketones, and / or azilsartan method of manufacturing according to claim 1 or 2, wherein esters solvent by adding to, characterized in that precipitating azilsartan .
[Requested item 4]
　Formula (5) as an impurity
[Chemical Formula 1

with a solution crude azilsartan containing azilsartan dimer represented by was dissolved, after contacting the activated carbon,
　the following formula (1)
[Formula 2]

represented by azilsartan manufacturing method characterized by comprising the step of separating the crystals azilsartan from the solution.
[Requested item 5]
　The activated carbon, the ratio was determined by the BET method surface area of 1000 ~ 3500 m 2 was / g, and, azilsartan method as claimed in claim 4 cumulative pore volume is 0.6 ~ 1.5 mL / g .
[Requested item 6]
　Formula (5) as an impurity
Formula 3]

with a solution crude azilsartan containing azilsartan dimer represented by was dissolved, after contacting the activated carbon,
　the following formula (1)
[Chemical formula 4]

represented by a step of separating the crystals azilsartan from the solution,
　the solution obtained by dissolving the crystals of the azilsartan dimethylformamide, a step of precipitating azilsartan ketones, or by adding a solvent of esters,
azilsartan manufacturing method according to claim 1 or 2, characterized in that it has a.
[Requested item 7]
　The crude azilsartan is,
　the following formula (2)
[Chemical Formula 5]

(wherein, R 1 is an alkyl group)
that is intended to azilsartan alkyl ester represented by, obtained by hydrolysis with an inorganic base azilsartan method according to claim 4 or 5, characterized in.