WO2018008219A1 - Azilsartan intermediate, azilsartan, method for producing azilsartan intermediate, and method for producing azilsartan - Google Patents

Abstract

The present invention provides: a method for producing an amidoxime compound, wherein a nitrile compound and hydroxylamine and/or an acid salt of hydroxylamine are reacted with each other in a reaction solvent that contains an alcohol having 2-7 carbon atoms; a method for producing an azilsartan alkyl ester, wherein a compound containing an ester-protecting group is subjected to a cyclization reaction in a reaction solvent that contains an alcohol having 1-8 carbon atoms; a method for producing an azilsartan alkyl ester, wherein an azilsartan alkyl ester is crystallized in acetone or in a mixed solvent of acetone and an alcohol; and a method for producing azilsartan, wherein an azilsartan alkyl ester is hydrolyzed.

Description

Azilsartan intermediate, azilsartan, and production method thereof

The present invention relates to an azilsartan intermediate, azilsartan, and methods for producing them.
More specifically, an alkyl 2-ethoxy-1-[[2 ′-(hydroxyiminocarboxamido) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate, which is an azilsartan intermediate, and Alkyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- Carboxylate; 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] which is azilsartan Methyl] benzimidazole-7-carboxylic acid and methods for producing them.

The following formula (5)

 

 

Azilsartan (also known as: 1-[[2 '-(4,5-dihydro-5-oxo-1,2,4- oxadiazol-3-yl) [1,1'-biphenyl-4- [Il] methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid) is a very useful compound as a therapeutic agent showing an excellent effect as an angiotensin II receptor antagonist (Patent Document 1).

This azilsartan is synthesized by the following manufacturing method.

 

 

That is, first, an alkyl 1-[(2′-cyanobiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxylate represented by the above formula (1) (hereinafter simply referred to as “nitrile compound”) The alkyl 2-ethoxy-1-[[2 ′-(hydroxyiminocarboxamido) biphenyl-4 represented by the above formula (2) is reacted with hydroxylamine and / or hydroxylamine acid salt. -Yl] methyl] -1H-benzimidazole-7-carboxylate (hereinafter sometimes simply referred to as “amidoxime compound”).

Next, the amidoxime compound is used as it is in the cyclization reaction, or an alkyl 2-ethoxy-1-[[2 ′-(alkyloxy) represented by the above formula (3) in which the hydroxyl group of the amidoxime compound is protected with an ester protecting group. -Carbonyloxycarbamimidoyl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate (hereinafter sometimes simply referred to as “ester protecting group-containing compound”), followed by cyclization The alkyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl represented by the above formula (4) was reacted. -4-yl] methyl] benzimidazole-7-carboxylate (hereinafter sometimes simply referred to as “azirsartan alkyl ester”) ).

Finally, the azilsartan alkyl ester represented by the formula (5) is produced by hydrolyzing the azilsartan alkyl ester (see, for example, Patent Documents 1 to 3 and Non-Patent Document 1).

Drug substances like azilsartan are desired to reduce impurities. However, as described above, since it is manufactured through many steps, an impurity different from the target product may be generated in each step. Since this impurity has a structure similar to that of the target product, purification or the like becomes very difficult when the amount thereof increases. Therefore, in the case of producing a drug substance, it is desired to reduce impurities even in the production of an intermediate.

Japanese Patent No. 26459962 Special table 2014-506898 gazette Special table 2014-505097 gazette Special table 2014-530805 gazette

Journal of Medicinal Chemistry, (USA), 1996, vol. 39, p. 5228-5235

(1) The first problem of the present invention According to the study by the present inventors, when producing the amidoxime compound represented by the above formula (2), there is room for improvement in the following points in the prior art. I understood that.

For example, in Patent Document 1, hydroxylamine hydrochloride is used, and the reaction is carried out in a reaction solvent of dimethyl sulfoxide in the presence of sodium methoxide as a base. According to this method, the main product is
Following formula (7)

 

 

A desethyl form of the nitrile compound represented by (hereinafter, sometimes simply referred to as “nitrile desethyl form”), and the production ratio of the amidoxime compound is small.

In the method described in Non-Patent Document 1, hydroxylamine hydrochloride is used, and the reaction is carried out in a reaction solvent of dimethyl sulfoxide in the presence of an organic base such as triethylamine as a base. According to studies by the present inventors, in this method, the production rate of the amidoxime compound is increased. However, at the same time, the same amount as the amidoxime compound (8)

 

 

It was found that the amide compound represented by (hereinafter, sometimes simply referred to as “amide compound”) is by-produced. Furthermore, if you increase the reaction time,
Following formula (9)

 

 

A desethyl derivative of the amidoxime compound represented by the formula (hereinafter sometimes simply referred to as “amidoxime desethyl derivative”), and the following formula (10)

 

 

It was found that the amide desethyl form represented by the formula (hereinafter, sometimes simply referred to as “amide desethyl form”) tends to increase.

In the method described in Patent Document 2, an aqueous solution of hydroxylamine is used, and the reaction is carried out in a reaction solvent such as an aprotic polar solvent such as dimethyl sulfoxide. According to studies by the present inventors, in this method, the amide form is reduced, and the target amidoxime compound can be increased. However, also in this method, the purity of the amidoxime compound is about 70%, and the amide form is contained about 10%. According to the study by the present inventors, even when the amidoxime compound is taken out from the reaction system as a crystal, the purity of the adoxime compound is about 85%, and the amide form is contained about 5%. I understood that. And when reaction time became long, it turned out that the said amidoxime desethyl body and the said amidodes ethyl body tend to increase.

In the present invention, the purity of the amidoxime compound, the purity of other compounds, and the content ratio of impurities are the area% of each peak measured under the measurement conditions of high performance liquid chromatography (HPLC) described in the examples. .

In addition, in the method described in Patent Document 3, hydroxylamine hydrochloride is used, and the reaction is carried out in a reaction solvent of dimethyl sulfoxide in the presence of sodium hydrogen carbonate as a base.

Not only the method described in Patent Document 3, but also the methods described in Non-Patent Document 1, Patent Document 1, and 2, as described above, dimethyl sulfoxide is mainly used as a reaction solvent. According to the study of the present inventor, it has been found that when dimethyl sulfoxide is the main component as a reaction solvent, it is difficult for the amidoxime compound crystals to precipitate. Therefore, in a conventional method using dimethyl sulfoxide as a reaction solvent, a method of crystallizing an amidoxime compound by adding water to the solution after the reaction is generally used. In this method, only crystals of low purity amidoxime compounds could be obtained. And in order to acquire the crystal | crystallization of a highly purified amidoxime compound, refinement | purification operations, such as recrystallization, were needed separately, and there existed a problem that operation became complicated.

Accordingly, a first object of the present invention is to provide a method for producing the amidoxime compound, which can obtain the amidoxime compound with high yield and high purity by a simple operation. Furthermore, it is providing the method of manufacturing a highly purified azilsartan using the said amidoxime compound manufactured by this method.

(2) Second problem of the present invention According to the study by the present inventors, it has been found that there is room for improvement in the following points when producing an azilsartan alkyl ester in the prior art.

For example, in Non-Patent Document 1, an ester protecting group-containing compound in which R ² is a 2-ethylhexyl group is used as a reaction solvent with xylene at a reflux temperature (the reflux temperature of the reaction solution; about 130 ° C.). An azilsartan methyl ester is produced by a chemical reaction. According to this method, azilsartan methyl ester can be obtained in a relatively short reaction time (yield: 52%). However, according to the study by the present inventors, in the method described in Non-Patent Document 1, the structure is not clear, but in the analysis result of the liquid chromatograph mass spectrometer (LC-MASS), the azilsartan methyl ester It was found that impurities having a molecular weight obtained by adding 10 to the molecular weight increased.

On the other hand, in Patent Document 1, an ester protecting group-containing compound in which R ² is an ethyl group is used as a reaction solvent, xylene is used, and the cyclization reaction is performed in the xylene at the reflux temperature (the reflux temperature of the reaction solution; about 130 ° C.). To produce azilsartan methyl ester. However, it has been found that this method also increases the impurities. Furthermore, in the method described in Patent Document 1, the yield is as low as about 23%, and there is room for improvement.

Patent Document 1 also discloses a method of performing a cyclization reaction in ethyl acetate in the presence of a base (potassium carbonate, diazabicycloundecene). However, in this reaction, azilsartan methyl ester is precipitated during the reaction. Therefore, azilsartan methyl ester is obtained as a solid containing the base. As a result, there is room for improvement in that the purification process becomes complicated.

Therefore, the second object of the present invention is to provide a method for producing a high yield and high purity azilsartan alkyl ester. In addition, an object of the present invention is to provide a method for producing an azilsartan alkyl ester that can facilitate a purification step, which is a subsequent step. And finally, it is to provide a method for producing high-purity azilsartan using the azilsartan alkyl ester produced by the method.

(3) Third Problem of the Present Invention Further, according to the study by the present inventors, it has been found that there is room for improvement in the following points when producing an azilsartan alkyl ester in the prior art.

For example, Patent Document 1 describes the following method. First, a cyclization reaction is carried out in xylene for an ester protecting group-containing compound in which R ¹ is a methyl group and R ² is an ethyl group to synthesize azilsartan methyl ester. Next, after adding ethyl acetate to the reaction solution, washing and drying with water, xylene is distilled off, the residue is purified by silica gel chromatography, and the resulting crude crystals are recrystallized from ethyl acetate and isopropyl ether.

Non-Patent Document 1 describes the following method. First, a compound containing an ester protecting group in which R ¹ is a methyl group and R ² is a 2-ethylhexyl group is subjected to a cyclization reaction in xylene to synthesize an azilsartan methyl ester. Next, xylene is distilled off and recrystallization is performed using ethyl acetate.

However, according to the study by the present inventors, in the methods described in Patent Document 1 and Non-Patent Document 1,
Following formula (11)

 

 

(Wherein R ¹ is an alkyl group)
Hydrolyzate of azilsartan alkyl ester represented by the following (hereinafter sometimes simply referred to as “desethyl body”),
Following formula (12)

 

 

(Wherein R ¹ is an alkyl group)
A dimer of an azilsartan alkyl ester represented by (hereinafter sometimes simply referred to as “dimer”),
Furthermore, although the structure is not clear, there is room for improvement in that the impurities of molecular weight obtained by adding 10 to the molecular weight of azilsartan methyl ester cannot be reduced in the analysis results of the liquid chromatograph mass spectrometer (LC-MASS). I understood.

That is, when recrystallization was performed with a solvent containing ethyl acetate, there was room for improvement in terms of reducing impurities.

In addition, the melting point of conventionally known azilsartan methyl ester is as high as 190 to 200 ° C. Therefore, if an azilsartan methyl ester having a lower melting point can be produced, it is considered that it is easily dissolved in a solvent and does not increase unnecessary impurities when used as an azilsartan. Therefore, development of azilsartan methyl ester having a novel crystal form has been demanded.

Accordingly, a third object of the present invention is to provide a method for producing a high-purity azilsartan alkyl ester. In addition, it is to provide a novel crystalline form of azilsartan methyl ester having a low melting point. Finally, high-purity azilsartan alkyl ester produced by the above method and / or high-purity azilsartan methyl ester having a novel crystalline form with high purity is produced. It is to provide a way to do.

The inventors of the present invention have made extensive studies to solve the above problems (1) to (3).
And when manufacturing the said amidoxime compound, in the prior art, the reason for using an aprotic polar solvent like dimethyl sulfoxide was estimated as follows. That is, when a protic solvent or the like is used, the —OR (R; alkyl group having 1 to 4 carbon atoms) and —OEt (Et; ethyl group) moieties in the nitrile compound represented by the formula (1) are transesterified. It was thought that the reaction might become more complicated.

From this, even if a protic polar solvent is used, if the transesterification reaction does not occur in -OR and -OEt, it is considered that a high yield and high purity of the amidoxime compound can be obtained. Proceeded.

As a result, it was found that by using a reaction solvent containing a specific alcohol, the amidoxime compound having a high yield and a high purity can be obtained, and the first present invention has been completed.

Next, when performing the cyclization reaction, the compound has high solubility in the ester protecting group-containing compound and the azilsartan alkyl ester, and the reaction is performed without decomposing the ester protecting group-containing compound and the azilsartan alkyl ester in the cyclization reaction. The conditions that can be promoted were examined. As a result, it was found that the above problem can be solved by carrying out the cyclization reaction in a specific reaction solvent, that is, a reaction solvent containing an alcohol having 1 to 8 carbon atoms, and the second invention has been completed. .

Furthermore, recrystallization of azilsartan alkyl ester was examined using various solvents. As a result, when crystallization of azilsartan alkyl ester was performed using acetone or a mixed solvent of acetone and alcohol, the desethyl isomer and dimer impurity of azilsartan alkyl ester can be efficiently reduced. I understood. In addition, when azilsartan methyl ester is crystallized in acetone or a mixed solvent of acetone and alcohol, it is found that a novel crystal having a low melting point portion, which is not found in conventional crystals, can be obtained. The present invention has been completed.

That is, the first aspect of the present invention is
Following formula (1)

 

 

(Wherein R ¹ is an alkyl group having 1 to 4 carbon atoms)
A nitrile compound represented by
Hydroxylamine and / or hydroxylamine acid salt,
By reacting in a reaction solvent containing an alcohol having 2 to 7 carbon atoms,
Following formula (2)

 

 

(Wherein R ¹ has the same meaning as in formula (1)).
Is a method for producing an amidoxime compound represented by the formula:

In the first aspect of the present invention, the reaction is preferably performed in the presence of a base. By performing the reaction in the presence of a base, the by-production of the amide form and the amide desethyl form can be further suppressed. Among these, in order to suppress the by-product of the amide form and the amide desethyl form more highly and improve operability, the base preferably contains an organic base. The blending amount is preferably 0.01 to 0.5 mol with respect to 1 mol of the nitrile compound represented by the formula (1).

Further, in the present invention, in order to produce the high-purity amidoxime compound and to further improve the operability, the alcohol is a linear or branched alcohol having 3 to 7 carbon atoms. There are preferred. Furthermore, it is preferable that hydroxyamine is used and the reaction solvent contains water.

The amidoxime compound obtained by the method of the present invention has high purity and few impurities. Therefore, the amidoxime compound obtained by the method of the present invention can be suitably used for the production of the azilsartan alkyl ester represented by the formula (4) and the azilsartan represented by the formula (5).

The second aspect of the present invention
Following formula (3)

 

 

(Wherein R ¹ is an alkyl group, and R ² is a protecting group for protecting the hydroxyl group)
By carrying out a cyclization reaction in a reaction solvent containing an alcohol having 1 to 8 carbon atoms.
Following formula (4)

 

 

(In the formula, R ¹ has the same meaning as in formula (3)).
Is a method for producing an azilsartan alkyl ester represented by

In the present invention, in order to further increase the yield, the cyclization reaction is preferably performed at 50 ° C. or higher and the reflux temperature of the reaction solution or lower. The reflux temperature is substantially the same as the temperature at which the reaction solvent refluxes. However, the “reflux temperature of the reaction solution” is slightly different depending on the concentration of by-product R ² —OH (alcohol having R ² group), dissolved azilsartan alkyl ester, etc. This is because there is a difference with temperature. In the present invention, the reaction solution refers to a solution containing R ² —OH produced as a by-product by dissolving an ester group-containing compound and / or an azilsartan alkyl ester in a reaction solvent. In addition, when using a base as needed, a reaction solution contains a base as a matter of course.

In the present invention, the alcohol is preferably a linear or branched alcohol having 3 to 8 carbon atoms. By using this alcohol, not only a high yield and high purity azilsartan alkyl ester can be obtained, but also the azilsartan alkyl ester can be easily crystallized in the reaction solvent after completion of the reaction. As a result, the post-processing process can be facilitated.

Furthermore, in the present invention, in order to increase the yield in a short time, the cyclization reaction is preferably performed in the presence of a base. Among them, the amount of the base used is preferably 0.01 to 5 mol with respect to 1 mol of the ester protecting group-containing compound represented by the formula (3). Furthermore, the base is preferably an organic base.

The azilsartan alkyl ester obtained by the second present invention has a novel crystal structure. Specifically, an azilsartan methyl ester having at least a characteristic peak at 2θ = 9.9 ± 0.2 °, 10.9 ± 0.2 ° in X-ray diffraction using Cu—Kα rays is obtained. Can do.

In addition, the second aspect of the present invention, after producing an azilsartan alkyl ester by this method, hydrolyzing the obtained azilsartan alkyl ester,
Following formula (5)

 

 

The method of manufacturing the azilsartan shown by this is included. According to the present invention, a highly pure azilsartan alkyl ester can be produced, so that a highly purified azilsartan can be obtained.

The third aspect of the present invention provides
Following formula (4)

 

 

(Wherein R ¹ is an alkyl group)
Is a method for producing an azilsartan alkyl ester characterized by crystallizing an azilsartan alkyl ester represented by formula (2) in acetone or a mixed solvent of acetone and alcohol.

The third aspect of the present invention relates to the above formula (4), wherein R ¹ is a methyl group, that is, methyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo- 1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (hereinafter sometimes simply referred to as “azirsartan methyl ester”) Especially effective. The azilsartan methyl ester can be in a quasicrystalline state having a portion with a low melting point.

The azilsartan methyl ester is characterized by at least 2θ = 9.2 ± 0.2 °, 15.8 ± 0.2 °, 22.1 ± 0.2 ° by X-ray diffraction using Cu—Kα ray. Has a typical peak. The azilsartan methyl ester is preferably a compound having at least a melting point in a temperature range of 150 to 165 ° C. and a temperature range of 185 to 195 ° C.

Furthermore, the third present invention includes a method for producing azilsartan by hydrolyzing azilsartan alkyl ester and / or azilsartan methyl ester produced by this method. By using these as raw materials, azilsartan with higher purity can be produced.

The first to third methods for producing azilsartan of the present invention include a method in which a step of removing azilsartan dimers contained as impurities using activated carbon is added.

The first to third methods for producing azilsartan of the present invention include a step of precipitating azilsartan by adding a solvent of ketones or esters to a solution obtained by dissolving azilsartan in dimethylformamide. The manufacturing method to which is added.

Furthermore, the present invention provides the amidoxime compound from the nitrile compound by the production method of the first invention,
Next, the ester protecting group-containing compound is obtained from the amidoxime compound,
By the production method of the second invention, the azilsartan alkyl ester is obtained from the ester protecting group-containing compound,
The manufacturing method of obtaining the said azilsartan from the said azilsartan alkyl ester by the manufacturing method of 3rd this invention is included.

According to the first method of the present invention, an amidoxime compound with high yield and high purity can be obtained by a simpler operation. As a result, by using the amidoxime compound obtained in the present invention to produce an azilsartan alkyl ester and azilsartan, these can also be made highly pure.

According to the second method of the present invention, it is possible to obtain an azilsartan alkyl ester having a high yield and a high purity by a simpler operation. As a result, high-purity azilsartan can be obtained by hydrolyzing the azilsartan alkyl ester obtained in the present invention to produce azilsartan. In addition, since it becomes easier to take out the azilsartan alkyl ester as crystals, the operability can also be improved.

According to the third method of the present invention, a high-purity azilsartan alkyl ester, particularly a high-purity azilsartan methyl ester can be obtained. As a result, high-purity azilsartan can be obtained by hydrolyzing the azilsartan alkyl ester and / or azilsartan methyl ester obtained in the present invention to produce azilsartan. In addition, the azilsartan methyl ester obtained by the method of the present invention can be a quasicrystal having a portion having a low melting point.
Since these methods can increase the purity of azilsartan used as a drug substance, which is finally obtained, its industrial utility value is high.

2 is an X-ray diffraction chart of a novel crystal of azilsartan methyl ester of the present invention produced in Example 10. 6 is an X-ray diffraction chart of a conventional azilsartan methyl ester crystal produced in Comparative Example 4. 19 is an X-ray diffraction chart of a novel crystal (quasicrystal) of azilsartan methyl ester of the present invention produced in Example 18. 6 is an X-ray diffraction chart of a conventional azilsartan methyl ester crystal produced in Comparative Example 5. 19 is a DSC chart of a novel crystal (quasicrystal) of azilsartan methyl ester of the present invention produced in Example 18. 10 is a DSC chart of conventional azilsartan methyl ester crystals produced in Comparative Example 5. 4 is an X-ray diffraction chart of an azilsartan M-type crystal of the present invention produced in Example 33. FIG.

1. 1st this invention 1st this invention is following formula (1).

 

 

(Wherein R ¹ is an alkyl group having 1 to 4 carbon atoms)
A nitrile compound represented by
Reacting with hydroxylamine and / or hydroxylamine acid salt,
Following formula (2)

 

 

(Wherein R ¹ has the same meaning as in formula (1)).
In producing the amidoxime compound represented by
The reaction is carried out in a reaction solvent containing an alcohol having 2 to 7 carbon atoms. In the following, description will be given in order.

(Raw material compound; Nitrile compound)
The nitrile compound represented by the formula (1) is not particularly limited, and can be produced by a known method. Specifically, acetic acid is added to a method described in Patent Document 1, that is, a solution of alkyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl) methyl] amino] benzoate in ethyl orthocarbonate. It can manufacture by making it react at 80 degreeC for 1 hour stirring (refer Example 1b of patent document 1).

(Raw material compound; hydroxylamine and / or hydroxylamine acid salt)
In the present invention, the amidoxime compound is produced by reacting the nitrile part of the nitrile compound with hydroxylamine and / or hydroxylamine acid salt.

The hydroxylamine and / or hydroxylamine salt to be used is not particularly limited, and commercially available products can be used. It should be noted that “and / or” naturally refers to hydroxylamine alone, hydroxylamine acid salt alone, or a mixture of hydroxylamine and hydroxylamine acid salt. Hereinafter, when these are collectively referred to, they may be referred to as hydroxylamines.

Examples of the hydroxylamine salt include hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, hydroxylamine oxalate and the like.
These hydroxylamine salts can also be used as hydroxylamine after neutralizing with a base.

The amount of hydroxylamine and / or hydroxylamine salt to be used is not particularly limited, but is preferably 1 to 10 mol, more preferably 2 to 7 mol, relative to 1 mol of the nitrile compound. It is preferable that

Among hydroxylamine and / or hydroxylamine acid salt, it is preferable to use hydroxylamine in order to reduce the nitrile desethyl body and the amide body and to increase the purity of the obtained amidoxime compound. When hydroxylamine is used, it is preferable to use an aqueous hydroxylamine solution, for example, an aqueous solution having a hydroxylamine concentration of 30 to 50% by mass from the viewpoint of easy availability. In the present invention, the advantage of using hydroxylamine is not clear. However, the present inventors believe that the purity of the amidoxime compound can be increased because the reaction can proceed under an appropriate pH condition in this reaction. When hydroxylamine is used as an aqueous solution for the reaction, the reaction solvent contains at least an alcohol having 2 to 7 carbon atoms and water. The reaction solvent of the present invention may contain this water.

(Reaction solvent)
The greatest feature of the present invention is that a reaction solvent containing an alcohol having 2 to 7 carbon atoms is used. By using the reaction solvent, the amount of by-products of the amide and desethyl compounds can be reduced, and the amidoxime compound with high purity can be produced.

Examples of alcohols having 2 to 7 carbon atoms include ethanol, 1-propanol, isopropanol, 1-butanol, 2-methyl-1-propanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 3- Methyl-1-butanol, 1-hexanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-methyl-2-pentanol, 2,4-dimethyl-3-pentanol, 3- Examples include ethyl-3-pentanol. Among these, linear or branched alcohols having 3 to 7 carbon atoms are preferable from the viewpoints of yield and purity of the obtained amidoxime compound, the ratio of impurities contained therein, and finally removal of the reaction solvent. . Specifically, 1-propanol, isopropanol, 1-butanol and 2-butanol are preferable, and 1-propanol and 1-butanol are particularly preferable.

The alcohols exemplified above can be used singly or in a mixture of two or more. When used as a mixture, the amount used is based on the total amount of the mixture.

In the present invention, the reaction solvent may contain other solvents as long as it contains an alcohol having 2 to 7 carbon atoms. Specifically, as described above, water in the case of using a hydroxylamine aqueous solution, water to be newly added, and other solvents compatible with alcohol having 2 to 7 carbon atoms can be added. In consideration of the post-treatment of the reaction, the content of the other solvent is preferably less than 50% by mass and more preferably 30% by mass or less in the total amount of the reaction solvent of 100% by mass. Preferred (naturally the balance of the reaction solvent is an alcohol having 2 to 7 carbon atoms). The total amount of the reaction solvent may be an alcohol having 2 to 7 carbon atoms. However, when an aqueous hydroxylamine solution is used for the reaction, when the total amount of the reaction solvent is 100% by mass, the alcohol having 2 to 7 carbon atoms is used. It is preferable that the alcohol is 70 to 99% by mass and the water is 1 to 30% by mass.

In the present invention, the amount of reaction solvent used is not particularly limited, and the raw material compound can be sufficiently mixed during the reaction, and the raw material compound and the amidoxime compound to be produced are sufficiently dissolved. Use as much as you can. Among them, in order to make it easy to take out the obtained amidoxime compound as crystals, it is preferable to use 5 to 50 ml of reaction solvent, and more preferably 6 to 30 ml, with respect to 1 g of the nitrile compound. In addition, the usage-amount of this reaction solvent is a volume in 23 degreeC.

(Reaction method)
In the present invention, the reaction can be carried out by contacting the nitrile compound with hydroxylamines in a reaction solvent containing an alcohol having 2 to 7 carbon atoms. Therefore, what is necessary is just to stir and mix the said nitrile compound and hydroxylamines in this reaction solvent, and to make both which are raw material compounds contact.

(base)
In the method of this invention, when making both the raw material compounds contact (react), it can also implement in presence of a base. By using a base, the purity of the amidoxime compound can be further increased, and in particular, the amount of by-products of the amide body and the amide desethyl body can be suppressed.

As the base to be used, a known base can be used. Specifically, 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, etc. Inorganic bases, and methylamine, ethylamine, trimethylamine, triethylamine, diisopropylamine, tripropylamine, diisopropylethylamine, pyridine, piperazine, pyrrolidine, aniline, N, N-dimethylaminopyridine, diazabicycloundecene, N-methylmorpholine Organic bases such as can be used. These can be used singly or a plurality of types can be used simultaneously. When a plurality of types are used at the same time, the reference blending amount is based on the total amount of the plurality of types.

Among the above bases, it is preferable to use an organic base particularly when it is desired to suppress the amount of the amide form and by-product of the amide desethyl form. By using an organic base, the removal of the organic base is facilitated. Among these organic bases, triethylamine, pyridine, and diisopropylethylamine are preferably used in consideration of industrial production.

The amount of base used is not particularly limited, and may be a normal amount of catalyst. In particular, when an organic base is used, the amount of the organic base used is preferably 0.01 to 0.5 mol with respect to 1 mol of the nitrile compound represented by the formula (1). By making the usage-amount of an organic base into the said range, the by-product amount of the said amide body and the said amide desethyl body can be suppressed further. Furthermore, in order to suppress the amount of by-products of the amide compound and the amide desethyl compound, the amount of the organic base used is 0.1 to 1 mol with respect to 1 mol of the nitrile compound represented by the formula (1). The amount is preferably 0.5 mol, particularly preferably 0.2 to 0.5 mol.

(Reaction conditions)
In the present invention, other reaction conditions are not particularly limited, but the reaction is preferably carried out under the following conditions.

The procedure for introducing each component into the reaction vessel when mixing the raw material compound, the reaction solvent, and the base compounded as necessary in the reaction vessel is not particularly limited. Specifically, a method of simultaneously introducing a raw material compound, a reaction solvent, and a base to be blended as necessary into a reaction vessel can be employed. Also, one raw material compound and a reaction solvent are previously introduced into a reaction vessel, and then the other raw material compound (may be diluted with a reaction solvent if necessary), and a base compounded as necessary (Which may be diluted with a reaction solvent) can also be introduced into the reaction vessel. At this time, the raw material compound to be added later may be divided and introduced several times. Among these, in order to make the operation easier, first, the nitrile compound and the reaction solvent are charged into a reaction vessel. Subsequently, the base mix | blended as needed is introduce | transduced, and also hydroxylamines are introduce | transduced. At this time, the hydroxylamines may of course be diluted with a reaction solvent. When hydroxylamine is used, an aqueous solution having a concentration of 30 to 50% by mass can also be used.

In the present invention, the reaction temperature (the temperature of the reaction solution after all the components are mixed) is not particularly limited, but it is preferable to carry out the reaction at 50 ° C. or higher and the reflux temperature of the reaction solution or lower. Since the reflux temperature of the reaction solution varies depending on the type of reaction solvent used, the concentration of the raw material compound, and the like, it cannot be generally limited. However, in order to suppress decomposition of the amidoxime compound, the temperature of the reaction solution is preferably 50 to 100 ° C. or less, and preferably 60 to 95 ° C.

In the present invention, the reaction time (the time after all components are mixed) is not particularly limited, and may be determined while confirming the consumption ratio of the nitrile compound, the formation ratio of the amidoxime compound obtained, and the like. . However, since the amidoxime compound may be decomposed if the reaction time is too long, it is usually preferable to set the reaction time to 1 to 20 hours. In addition, the atmosphere during the reaction is not particularly limited, and the reaction can be performed in the presence of air or in the presence of an inert gas. Further, the reaction can be carried out under reduced pressure, increased pressure, or atmospheric pressure. Among these, in order to improve operability, it is preferable to perform the reaction in the presence of air and atmospheric pressure.

(Post-processing process)
According to the method, the amidoxime compound can be produced. The amidoxime compound produced in the reaction solution is preferably taken out by cooling the reaction solution or distilling off the reaction solvent for crystallization. Among them, when the temperature of the reaction solution is 50 ° C. or higher and lower than the reflux temperature of the reaction solution, it is preferably cooled to a temperature of 30 ° C. or lower, more preferably 10 to 30 ° C. It is preferable to precipitate crystals of the amidoxime compound. In particular, in order to increase the purity of the amidoxime compound obtained, it is preferable to set the cooling rate when the reaction temperature is 30 ° C. or less to 5 to 50 ° C./hour. Further, in order to increase the yield, it is preferable to leave it at a temperature of 30 ° C. or lower for 1 hour or longer, preferably 2 hours or longer and 10 hours or shorter.

The precipitated amidoxime compound crystals can be treated by a known method. Usually, it is preferable to take out the crystals by filtration, wash and dry. In order to obtain a hydroxylamidino compound with higher purity, recrystallization may be performed with a reaction solvent.

According to the present invention, the amidoxime compound obtained has a purity of 90.0 to 98.0%, amide 0.1 to 3.0%, nitrile desethyl 0.0 (undetected) to 0.5 %, The amidoxime desethyl compound 0.1 to 1.0%, and the amido desethyl compound 0.05 to 1.0%. By further adjusting the conditions, the purity is preferably 94.0 to 98.0%, the amide body 0.1 to 2.0%, the nitrile desethyl body 0.0 (undetected) to 0.1% Further, the amidoxime desethyl compound of 0.1 to 1.0% and the amido desethyl compound of 0.05 to 0.5% can be used. More preferably, the purity is 94.0 to 98.0%, the amide compound 0.1 to 1.0%, the nitrile desethyl compound 0.0 (undetected) to 0.1%, the amidoxime desethyl compound 0 .1 to 1.0%, and high purity of the above amidedesethyl compound 0.05 to 0.5%.

In addition, since the purity of the amidoxime compound, the amide body, the nitrile desethyl body, the amidoxime desethyl body, and the amiddesethyl body ratio may include other components, the total is not necessarily 100%. It will not be.

Therefore, the obtained amidoxime compound can be suitably used as a starting material for azilsartan alkyl ester and azilsartan.

(Method for producing azilsartan methyl ester)
In the present invention, from the amidoxime compound obtained by the above method,
Following formula (4)

 

 

(Wherein R has the same meaning as in formula (1)).
The azilsartan alkyl ester shown by these can be manufactured.

As a method for producing an azilsartan alkyl ester, a known method can be adopted without limitation.

For example, Org. Process. As described in Res. Dev 2013, 17, cyclization directly from the amidoxime compound by reaction in a reaction solvent containing 1,1′-carbonylimidazole, diazabicycloundecene, and dimethyl sulfoxide. The reaction can be carried out and the azilsartan alkyl ester can be produced.

Also, the following method can be adopted. This is the method described in Non-Patent Document 1 and Patent Document 1. Specifically, first, the amidoxime compound and an alkyl chloroformate (the alkyl group is a protecting group for a hydroxyl group, specifically, a 2-ethylhexyl group or an ethyl group) are combined with an organic base ( (Pyridine or triethylamine) in the presence of dimethylformamide, tetrahydrofuran / dichloromethane solvent, to give the following formula (3)

 

 

(Wherein R ² is an alkyl group that protects a hydroxyl group, specifically a 2-ethylhexyl group or an ethyl group), thereby obtaining an ester protecting group-containing compound. Next, the resulting ester protecting group-containing compound is placed in a xylene solvent at a reflux temperature (about 130 ° C.), whereby a cyclization reaction is performed to produce an azilsartan alkyl ester.

The obtained azilsartan alkyl ester is not particularly limited. Process. Purification, etc. may be carried out by the methods described in Res. Dev 2013, 17, Non-Patent Document 1, and Patent Document 1.

Specific examples include a method of recrystallization from acetone, ethyl acetate, ethyl acetate / isopropyl ether, chloroform / ethyl acetate. In order to further increase the purity of the resulting azilsartan alkyl ester, it is preferable to select a method of recrystallization from acetone.

(Azilsartan production method)
In the present invention, by hydrolyzing the azilsartan alkyl ester obtained by the above method,
Following formula (5)

 

 

The azilsartan shown by this can be manufactured. The azilsartan alkyl ester to be used may be a novel crystal or may be recrystallized with a solvent containing a ketone solvent.

The conditions for the hydrolysis are not particularly limited, and a known method such as the method described in Patent Document 1 can be employed. Specifically, hydrolysis may be performed in the presence of a base or an acid to convert —COOR ¹ (alkyl ester group) to —COOH (carboxylic acid).

The second aspect of the present invention
Following formula (3)

 

 

(Wherein R ¹ is an alkyl group, and R ² is a protecting group for protecting the hydroxyl group)
A cyclization reaction of the ester protecting group-containing compound represented by
Following formula (4)

 

 

(In the formula, R ¹ has the same meaning as in formula (3)).
Is produced by performing the cyclization reaction in a reaction solvent containing an alcohol having 1 to 8 carbon atoms.

In the above formula, R ¹ is an alkyl group. Considering the stability of the ester protecting group-containing compound as a raw material, the stability of the azilsartan alkyl ester, and the ease of production of azilsartan, R ¹ is preferably an alkyl group having 1 to 4 carbon atoms. Specific examples include a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, a 1-butyl group, and an isobutyl group, and a methyl group is particularly preferable.
In the following, description will be given in order.

(Raw material compound; Ester protecting group-containing compound)
The ester protecting group-containing compound represented by the formula (3) is not particularly limited, and can be produced by a known method. Specifically, it can be produced by the methods described in Non-Patent Document 1 and Patent Document 1. Specifically, it can be produced according to the following reaction formula.

 

 

The amidoxime compound represented by the formula (2) is a known compound, and its production method is described in Non-Patent Document 1 and Patent Document 1. Moreover, it is also preferable to use what was manufactured by 1st this invention. In the presence of a base, the amidoxime compound represented by the formula (2) can be reacted with the compound represented by XCOOR ² to produce an ester protecting group-containing compound represented by the formula (3).

In Reaction Scheme, XCOOR ² is reacted with a compound represented by the formula (2), X is a halogen atom, the same as R ² in the ester protecting group-containing compound represented by R ² is the formula (3) Yes, it is a protecting group for protecting the hydroxyl group.

In XCOOR ² , X includes a chlorine atom, a bromine atom, and an iodine atom. Among them, a chlorine atom is preferable in consideration of industrial availability, reactivity, and the like.

R ² includes a general protecting group for protecting a hydroxyl group. Specific examples include an alkyl group which may have a substituent, a benzyl group, and a phenyl group which may have a substituent. Among these, an unsubstituted alkyl group having 1 to 8 carbon atoms is preferable in view of industrial availability, role in the ester protecting group-containing compound, and finally removal. This unsubstituted alkyl group may be a linear alkyl group or a branched alkyl group.

Specific examples of XCOOR ² include methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, amyl chloroformate, 2-ethylhexyl chloroformate, hexyl chloroformate, chloroformate Examples include heptyl acid, chloromethyl chloroformate, 2-chloroethyl chloroformate, benzyl chloroformate, phenyl chloroformate, and 4-chlorophenyl chloroformate. Among these, it is preferable to use methyl chloroformate, ethyl chloroformate, propyl chloroformate and the like in view of industrial availability, reactivity, role in the ester protecting group-containing compound, and the like.

The amount of XCOOR ² used is not particularly limited. Specifically, the amount of XCOOR ² used may be 1 to 5 mol with respect to 1 mol of the compound represented by the formula (2).

The reaction is performed in the presence of a base. As an example of the base used,
Inorganic bases such as 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;
Organic bases such as methylamine, ethylamine, trimethylamine, triethylamine, diisopropylamine, tripropylamine, diisopropylethylamine, pyridine, piperazine, pyrrolidine, aniline, N, N-dimethylaminopyridine, diazabicycloundecene, N-methylmorpholine Can be mentioned.

Of these, organic bases such as triethylamine, pyridine, and diisopropylethylamine are preferable in consideration of the progress of the reaction, ease of removal, treatment in the subsequent steps, and the like.

The above-mentioned base can be used as a single kind or a plurality of kinds of bases. When a plurality of types of bases are used, the reference base amount is the total amount of the plurality of types of bases.

The amount of the base used is not particularly limited. Specifically, the amount of the base used may be 1 to 5 mol with respect to 1 mol of the compound represented by the formula (2). As will be described later, when the ester group-containing compound is cyclized, it is preferably carried out in the presence of a base. Therefore, when the ester group-containing compound obtained by this reaction is cyclized, the cyclization reaction can be carried out with the base remaining.

The solvent to be used may be selected from among aprotic solvents which do not react with XCOOR ^2. Specific examples include benzene, toluene, methylene chloride, chloroform, 1,4-dioxane and the like. One kind of these reaction solvents may be used, or two or more kinds of mixed solvents may be used.

In the reaction, it is preferable to stir and mix in the presence of a base so that the amidoxime compound represented by the formula (2) and XCOOR ² are in sufficient contact with each other in a solvent. The procedure for introducing these components into the reaction vessel is not particularly limited. As a preferred method, it is preferable to add the amidoxime compound represented by the formula (2) and the base in a solvent in advance, and then add XCOOR ² diluted with a solvent as necessary. At this time, XCOOR ² is preferably added dropwise to prevent sudden heat generation.

In addition, the conditions for carrying out the reaction are not particularly limited. The reaction temperature is preferably −10 to 10 ° C. The reaction time is sufficient if it is 0.5 to 15 hours.

By reacting under the above conditions, the ester protecting group-containing compound can be produced. The method for taking out the ester protecting group-containing compound from the reaction system is not particularly limited. Specifically, the ester protecting group-containing compound is dissolved in a water-insoluble solvent such as ethyl acetate, toluene, chloroform, methylene chloride, washed with water, concentrated, dried, etc. The compound can be removed. When a solvent that is hardly soluble in water is used as the solvent, the solution can be washed as it is.

The ester group-containing compound obtained under the above conditions is not particularly limited, but may have a purity of 90.0 to 99.5%. Moreover, the following cyclization reaction can also be implemented in the state which this extracted ester group containing compound contained the base by adjusting water washing.

(Cyclization reaction)
The feature of the present invention is that the ester protecting group-containing compound is subjected to a cyclization reaction,

 

 

(In the formula, R ¹ has the same meaning as in formula (3)).
Is produced in a reaction solvent containing an alcohol having 1 to 8 carbon atoms. During this cyclization reaction, R ² —OH is by-produced.

This cyclization reaction can proceed by heating. Specifically, by heating a reaction solution in which the ester protecting group-containing compound is dissolved in an alcohol having 1 to 8 carbon atoms, the cyclization reaction is promoted, and the ester protecting group-containing compound is converted to an azilsartan alkyl ester. be able to. In the cyclization reaction, it is preferable that the ester protecting group-containing compound is dissolved in a reaction solvent and heated while being stirred and mixed. As a matter of course, the ester protecting group-containing compound and the reaction solvent may be heated while stirring to form a reaction solution, and the reaction solution may be heated as it is.

(Reaction solvent)
The reaction solvent used in this cyclization reaction is a solvent containing an alcohol having 1 to 8 carbon atoms. Specific examples of alcohols having 1 to 8 carbon atoms include methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-methyl-1-propanol, 2-butanol, 2-methyl-2-propanol, 1 -Pentanol, 3-methyl-1-butanol, 1-hexanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-methyl-2-pentanol, 2,4-dimethyl-3 -Pentanol, 3-ethyl-3-pentanol, octanol and the like.

Among these, a straight-chain or branched alcohol having 3 to 8 carbon atoms is used as a solvent capable of increasing the temperature during the cyclization reaction, increasing the reaction rate, and reducing impurities. Is preferred. Specifically, 1-propanol, isopropanol, 1-butanol and 2-butanol are preferably used, and 1-propanol and 1-butanol are particularly preferable.

These alcohols having 1 to 8 carbon atoms can be used alone or a plurality of kinds of mixed solvents can be used. When a mixed solvent is used, the reference amount of the alcohol is the total amount of the mixed solvent.

The reaction solvent can also contain other solvents other than alcohols having 1 to 8 carbon atoms in a proportion of less than 50% by mass, but considering the ease of purification and the like, the other solvent is 10% by mass. The following is preferable, and 0% by mass is further preferable.

In the present invention, the amount of alcohol having 1 to 8 carbon atoms used in the reaction solvent is not particularly limited. Considering the efficiency of the reaction, reduction of impurities, and operability in the subsequent step, the amount of the alcohol having 1 to 8 carbon atoms in the reaction solvent is 3 to 30 ml with respect to 1 g of the ester protecting group-containing compound. preferable. By satisfying this range, after completion of the cyclization reaction, it becomes easy to cool and take out the azilsartan methyl ester as crystals. In order to further exert the above effects, the amount of the alcohol having 1 to 8 carbon atoms in the reaction solvent is more preferably 5 to 20 ml with respect to 1 g of the ester protecting group-containing compound. In addition, the said volume of a reaction solvent is a volume in 23 degreeC.

The reaction temperature of the cyclization reaction is preferably 50 ° C. or higher and the reflux temperature of the reaction solution or lower, and preferably 60 ° C. or higher and the reaction solution reflux temperature or lower in order to increase the reaction rate and reduce impurities. It is more preferable that the temperature be 70 ° C. or higher and the reflux temperature of the reaction solution or lower. Since the reflux temperature of the reaction solution varies depending on the reaction solvent used, the concentration of the ester protecting group-containing compound, and the type of R ² —OH produced as a by-product, it cannot be generally limited. However, in order to further suppress the generation of impurities, the reaction temperature is preferably 100 ° C. or lower.

(base)
In the present invention, the cyclization reaction can be promoted according to the above conditions. Among these, in order to shorten the reaction time, the reaction is preferably performed in the presence of a base. Specifically, it may be in a state where a base is contained in the reaction solution.

The base that can be used in the cyclization reaction is not particularly limited, and the above-mentioned inorganic bases and organic bases can be used. Among them, it is preferable to use an organic base such as triethylamine, pyridine, or diisopropylethylamine in order to improve the ease of purification and operability of the obtained azilsartan alkyl ester.

These bases can be used alone or in a plurality of types. When a plurality of types of bases are used, the reference base amount is the total amount of the plurality of types of bases.

In addition, as above-mentioned, when using a base when manufacturing the said ester protective group containing compound as above-mentioned, the base which remains when taking out this ester protective group containing compound can also be used. .

In the present invention, the cyclization reaction can proceed without using a base. However, when a base is used, the amount of the base used is preferably 0.01 to 5 mol with respect to 1 mol of the ester protecting group-containing compound. By using a base in this range, the reaction rate can be increased, and the yield and purity of the azilsartan alkyl ester can be increased. In order to further enhance this effect, the amount of the base used is more preferably 0.1 to 1 mol with respect to 1 mol of the ester protecting group-containing compound.

In the present invention, when a base is used, the base and the ester protecting group-containing compound can be added in advance to the reaction solvent, and the mixture can be stirred and mixed while heating. In addition, the base can be added to the reaction solution heated with stirring and mixing in order to promote the reaction from the middle. When a base is added from the middle, the total amount of base used is the standard amount.

(Method for removing azilsartan alkyl ester)
By performing the cyclization reaction under the above conditions, an azilsartan alkyl ester can be produced. The method for taking out the obtained azilsartan alkyl ester from the reaction system is not particularly limited, and the methods described in Non-Patent Document 1 and Patent Document 1 can be employed.

Above all, in the present invention, since the solvent containing 1 to 8 alcohols is used as the reaction solvent, it is preferable to employ the following method. Specifically, the reaction solution is cooled or a part of the reaction solvent is distilled off from the reaction solution to precipitate crystals of azilsartan alkyl ester in a reaction solvent containing an alcohol having 1 to 8 carbon atoms. It is preferable to take out the crystals. In particular, it is preferable to cool the reaction solution to precipitate crystals.

When the crystals of the azilsartan alkyl ester are precipitated in the reaction solvent, there is no particular limitation. Specifically, the amount of alcohol having 1 to 8 carbon atoms is preferably 3 to 30 ml with respect to 1 g of azilsartan alkyl ester. When the alcohol having 1 to 8 carbon atoms satisfies the above range, the operability is improved and the purity can be increased. In order to further enhance this effect, the amount of alcohol having 1 to 8 carbon atoms is preferably 5 to 20 ml with respect to 1 g of azilsartan alkyl ester. The amount of the alcohol having 1 to 8 carbon atoms is a volume at 23 ° C.

The cyclization reaction is preferably performed by heating. In a more preferred embodiment, the temperature of the reaction solution (reaction temperature) is 50 ° C. or higher. Therefore, the reaction solution after completion of the reaction is preferably cooled to a range of 30 ° C. or less, more preferably -10 to 30 ° C., particularly -10 to 10 ° C. preferable. In the present invention, since an alcohol having 1 to 8 carbon atoms is used, crystals of the azilsartan alkyl ester easily precipitate within the cooling temperature range. A seed crystal can also be used when the crystal is precipitated. And in this invention, if it cools and it adjusts so that the crystal | crystallization of an azilsartan alkylester may precipitate, this crystal | crystallization will become difficult to take in a by-product and the base mix | blended as needed.

In order to further increase the purity of the resulting azilsartan alkyl ester, the reaction solution after completion of the reaction is cooled at a cooling rate of 10 to 30 ° C./hour, and is 30 ° C. or less, preferably 0 to 30 ° C., more preferably The temperature is preferably -10 to 30 ° C, particularly preferably -10 to 20 ° C. Furthermore, in order to increase the yield of the obtained azilsartan alkyl ester, the temperature is 30 ° C. or less, preferably 0 to 30 ° C., more preferably −10 to 30 ° C., particularly preferably −10 to 20 ° C. It is preferable to leave it for more than an hour, preferably more than 2 hours and less than 20 hours.

The crystals of the precipitated azilsartan alkyl ester can be processed by a known method. Usually, it is preferable to take out the crystals by filtration, wash and dry. In order to obtain a higher purity azilsartan alkyl ester, it may be recrystallized with an alcohol having 1 to 8 carbon atoms.

(Crystal of novel azilsartan alkyl ester; method for producing novel crystal)
The azilsartan alkyl ester obtained as described above becomes a solvate crystal containing an alcohol having 1 to 8 carbon atoms, even if recrystallized again with an alcohol having 1 to 8 carbon atoms. That is, it is considered that a part of the alcohol having 1 to 8 carbon atoms is taken into the crystal.

Among the alcohols having 1 to 8 carbon atoms, 1-propanol is used, and the azilsartan methyl ester in which R ¹ is a methyl group is at least 2θ = 9. 9 in X-ray diffraction using Cu—Kα ray. A crystal having a characteristic peak at 9 ± 0.2 °, 10.9 ± 0.2 ° can be obtained. In addition, the azilsartan methyl ester is a crystal having peaks at 2θ = 13.6 ± 0.2 °, 17.2 ± 0.2 °, 23.2 ± 0.2 °, and the like. The crystal having the above peak is not in the prior art and is a new crystal form. This crystal may contain 0.5 to 5% by mass of 1-propanol (hereinafter, this crystal may be simply referred to as “new crystal”).

Here, the characteristic peak in the present invention has a peak having a maximum intensity at 2θ = 9.9 ± 0.2 ° and a maximum peak intensity at 2θ = 10.9 ± 0.2 °. It means that a peak having an intensity of 5% or more with respect to (2θ = 9.9 ± 0.2 ° peak intensity) appears. A peak having an intensity of less than 5% with respect to the maximum peak intensity is regarded as noise or the like, and does not correspond to a characteristic peak in the present invention.

(Recrystallization of azilsartan alkyl ester)
In the present invention, azilsartan can also be synthesized by hydrolyzing the azilsartan alkyl ester as it is. However, in order to obtain a higher-purity azilsartan alkyl ester, it is preferable to recrystallize the novel crystal form azilsartan alkyl ester obtained by the above method using a solvent containing a ketone solvent. It will be appreciated that the novel crystalline form of the azilsartan alkyl ester may be a solvate containing 0.5-5% by weight of 1-propanol.

Examples of the ketone solvent to be used include acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl butyl ketone, and methyl isobutyl ketone. Among them, acetone is preferably used in order to improve purity and improve operability. These ketone solvents can be used alone or a plurality of types of mixed solvents can be used. When a mixed solvent is used, the amount of the ketone solvent used as a reference is the total amount of the mixed solvent.

The solvent containing the ketone solvent may contain other solvents other than the ketone solvent at a ratio of less than 50% by mass, but considering the ease of purification, the other solvent is 10% by mass or less. It is preferable that it is 0% by mass.

The amount of ketone solvent to be used is not particularly limited. Specifically, the amount of the ketone solvent is preferably 3 to 30 ml, more preferably 5 to 20 ml, with respect to 1 g of the azilsartan alkyl ester crystal.

As a recrystallization method, the crystal of the azilsartan alkyl ester is dissolved in a solvent containing a ketone solvent. Preferably, the crystals of the azilsartan alkyl ester are dissolved by heating to the reflux temperature of the solution (about 60 ° C.). Then, it is preferably cooled at a cooling rate of 10 to 30 ° C./hour and left standing for a certain time in a temperature range of 0 to 30 ° C., more preferably −10 to 30 ° C., particularly preferably −10 to 20 ° C.

(Method for producing azilsartan)
In the present invention, by hydrolyzing the azilsartan alkyl ester obtained by the above method in the same manner as in the first invention,
Following formula (5)

 

 

The azilsartan shown by this can be manufactured.

The third aspect of the present invention provides
Following formula (4)

 

 

(Wherein R ¹ is an alkyl group)
Is a method for producing an azilsartan alkyl ester characterized by crystallizing the azilsartan methyl ester represented by the formula (1) in acetone or a mixed solvent of acetone and alcohol. Hereinafter, the description will be given in order.

(Target azilsartan alkyl ester)
First, an azilsartan alkyl ester to be crystallized (hereinafter, sometimes referred to as a target azilsartan alkyl ester) will be described. In the above formula, R ¹ is an alkyl group. Considering the stability of the ester protecting group-containing compound as a raw material, the stability of the azilsartan alkyl ester, and the ease of production of azilsartan, R ¹ is preferably an alkyl group having 1 to 4 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group, and a methyl group is particularly preferable.

(Production of target azilsartan alkyl ester)
The target azilsartan alkyl ester used in the present invention is not particularly limited, and those synthesized by a known method can be used. For example, it is preferable to employ one manufactured by the manufacturing method described in the second aspect of the present invention.

That is, in the present invention, the target azilsartan alkyl ester is obtained by performing a cyclization reaction in a reaction solvent containing an alcohol having 1 to 8 carbon atoms as described in the second aspect of the present invention. Is preferred. The target azilsartan alkyl ester obtained by the method can reduce impurities whose structure is unknown compared to the conventional azilsartan alkyl ester that is cyclized in a xylene solvent and precipitated in a solvent containing ethyl acetate. . This conventional azilsartan alkyl ester tends to contain impurities having a molecular weight higher than that of the azilsartan alkyl ester (in the case of azilsartan methyl ester, it tends to contain impurities having a molecular weight of 10 more than that of the azilsartan methyl ester. ). Therefore, in the present invention, it is preferable to use the target azilsartan alkyl ester in which impurities are reduced by performing a cyclization reaction in a reaction solvent containing an alcohol having 1 to 8 carbon atoms. However, in the present invention, as described in detail below, since a high-purity azilsartan alkyl ester can be obtained, a conventional azilsartan alkyl ester containing impurities having an unknown structure and a large molecular weight is used as the target azilsartan alkyl ester. Of course, it is also possible to use an ester.

(Method for crystallizing azilsartan alkyl ester; method for producing quasicrystal)
(Solvent; acetone or a mixed solvent of acetone and alcohol)
In the present invention, in order to increase the purity of the target azilsartan alkyl ester and to change the crystal form into an azilsartan alkyl ester having a low melting point, the target azilsartan alkyl ester is acetone, or acetone and alcohol. It is necessary to crystallize in a mixed solvent. By using acetone or a mixed solvent of acetone and alcohol, it is possible to efficiently reduce the desethyl isomers and dimer impurities of the azilsartan alkyl ester as compared with the conventional method using ethyl acetate.

The solvent used in the present invention is acetone or a mixed solvent of acetone and alcohol. When the total volume of acetone and alcohol is 100, the volume ratio of acetone is 100 to 50, and the volume ratio of alcohol is 0 to What becomes 50 is preferable. According to the study by the present inventors, it is found that even when alcohol is contained in a volume ratio of 50% or less, a new crystal form can be obtained as in the case of containing no alcohol (only acetone). It was. Therefore, it is not necessary to strictly manage the remaining amount of alcohol in the target azilsartan alkyl ester as long as the volume ratio of alcohol does not become larger than the volume ratio of acetone used. That is, when the target azilsartan alkyl ester obtained by carrying out the cyclization reaction in a reaction solvent containing an alcohol having 1 to 8 carbon atoms is used, it is not necessary to remove the alcohol strictly. Can be improved. Therefore, when the target azilsartan alkyl ester is a crude product containing alcohol, the amount of acetone used may be adjusted by measuring the amount of the alcohol.

In the present invention, when alcohol is used, the alcohol is preferably an alcohol having 1 to 8 carbon atoms. Specifically, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-methyl-1-propanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 3-methyl- 1-butanol, 1-hexanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, 2-methyl-2-pentanol, 2,4-dimethyl-3-pentanol, 3-ethyl- Examples include 3-pentanol and octanol. Among these, in consideration of the yield and the effect of reducing impurities of desethyl and dimers of the azilsartan alkyl ester, it is preferable to use a linear or branched alcohol having 3 to 8 carbon atoms. Specifically, 1-propanol, isopropanol, 1-butanol and 2-butanol are preferably used, and 1-propanol and 1-butanol are particularly preferable. One kind of these alcohols can be used, or a plurality of kinds can be mixed and used. In the present invention, when alcohol is used, it is preferable that the volume ratio of acetone is 99 to 51 and the volume ratio of alcohol is 1 to 49. Furthermore, the volume ratio of acetone is 90 to 60, and the volume ratio of alcohol. Is preferably 10 to 40.

(Method of crystallization)
Further, the amount of acetone or the mixed solvent of acetone and alcohol to be used is not particularly limited, but is preferably 3 to 30 ml with respect to 1 g of the target azilsartan alkyl ester crystal, It is preferably 5 to 20 ml. In addition, the said volume of the solvent to be used is a volume in 23 degreeC. When a mixed solvent is used, the reference amount of solvent is the total amount of acetone and alcohol.

As the recrystallization method, the target azilsartan alkyl ester is dissolved in acetone or a mixed solvent of acetone and alcohol, preferably heated to the reflux temperature (about 60 ° C.) of the resulting solution, and then 10 It is preferable to cool at a cooling rate of ˜30 ° C./hour, and hold for a certain time in a temperature range of preferably 0 to 30 ° C., more preferably −10 to 30 ° C., particularly preferably −10 to 20 ° C.

(Azilsartan alkyl ester, novel azilsartan methyl ester)
Among the azilsartan alkyl esters obtained by crystallization in acetone or a mixed solvent of acetone and alcohol, the azilsartan methyl ester in which R ¹ is a methyl group, which is a suitable compound, is obtained by X-ray diffraction using Cu—Kα rays. Thus, a new crystal having a characteristic peak at least at 2θ = 9.2 ± 0.2 °, 15.8 ± 0.2 °, 22.1 ± 0.2 ° is obtained. The other peaks are crystals having peaks at 2θ = 18.2 ± 0.2 °, 25.1 ± 0.2 °, and 27.4 ± 0.2 °.

In addition, azilsartan methyl ester obtained by crystallization in acetone or a mixed solvent of acetone and alcohol has a novel crystal form in which at least two melting points exist (hereinafter referred to as “quasicrystal”). ”). Among them, the azilsartan methyl ester obtained by crystallization in acetone or a mixed solvent of acetone and alcohol has a melting point measured under the conditions of the differential scanning calorimeter shown in the examples at least 150 to 165 ° C., 185 Observed at ~ 195 ° C. The melting point determined by differential scanning calorimetry (DSC) measurement is the peak top temperature of the endothermic peak. This new quasicrystal is considered not to be a complete crystal because it has a lower melting point than the conventionally known azilsartan alkyl ester. Therefore, although the purity is high, since it can be easily dissolved, it can be suitably used for the next hydrolysis reaction.

The heat of fusion of the quasicrystalline azilsartan methyl ester cannot be obtained by drawing a beautiful tangent to the endothermic peak as shown in the chart of FIG. This is presumably due to the fact that the azilsartan methyl ester is an unstable crystal. Therefore, the heat of fusion is not an accurate value, but when the heat of fusion is obtained as shown in FIG. 5, the melting point in the temperature range of 150 to 165 ° C. (hereinafter, sometimes simply referred to as “low melting point”). The heat of fusion with respect to the melting point in the range of 185 to 195 ° C. (hereinafter sometimes simply referred to as “high melting point”) is 40 to 70 J / g. preferable. Further, the heat of fusion related to the low melting point is preferably 4 to 10 J / g, and the heat of fusion related to the high melting point is preferably 50 to 60 J / g.

Thus, by recrystallizing a novel crystal obtained in a solvent containing an alcohol having 1 to 8 carbon atoms with acetone or a mixed solvent of acetone and alcohol, the purity can be easily increased. It is possible to form a quasicrystal having a low melting point that can be dissolved in the quaternary crystal.

(Azilsartan production method)
In the present invention, by hydrolyzing the azilsartan alkyl ester obtained by the above method in the same manner as in the first invention,
Following formula (5)

 

 

The azilsartan shown by this can be manufactured.

The obtained azilsartan is not particularly limited, and may be purified by a known method to obtain a drug substance. For example, the method using methods, such as recrystallization, reslurry, and column chromatography, is mentioned.

(Removal of azilsartan dimer)
The azilsartan produced according to the first to third inventions has the following formula (6) as an impurity:

 

 

The azilsartan dimer shown by may be included. In such a case, after bringing the crude azilsartan solution containing the azilsartan dimer into contact with activated carbon, a step of separating the crystals of azilsartan from the solution may be added.

(Crude azilsartan)
Crude azilsartan means azilsartan containing azilsartan dimers as impurities. The crude azilsartan may be 96.0-99.0% pure azilsartan as determined by high performance liquid chromatography (HPLC) analysis. The crude azilsartan to be purified may contain 0.01 to 0.50% of the azilsartan dimer.

The azilsartan dimer to be reduced is considered to be by-produced as follows. That is, the amidoxime compound (compound of formula (2)) used as a raw material first reacts with azilsartan (compound of formula (5)) that is considered to have been produced when the amidoxime compound is cyclized. do it,
Following formula (12)

 

 

(Wherein R ¹ is an alkyl group)
This produces an azilsartan alkyl ester dimer represented by: Next, it is considered that an azilsartan dimer is obtained from the azilsartan alkyl ester dimer.

(Method of contacting activated carbon with a solution in which crude azilsartan is dissolved)
A method for bringing a solution of crude azilsartan containing azilsartan dimer into contact with activated carbon will be described below.

The activated carbon to be used is not particularly limited, but the specific surface area determined by the BET method is 1000 to 3500 m ² / g and the cumulative pore volume is 0.6 to 1.5 mL / g. Is preferred. By using activated carbon having the physical properties in this range, the azilsartan dimer can be more effectively reduced.

The activation (activation) method of the activated carbon to be used is not particularly limited, and both zinc chloride coal obtained by a chemical activation method and steam coal obtained by a steam activation method can be suitably used. Also, the type of activated carbon is not particularly limited, and any activated carbon can be used as long as it satisfies the above properties, such as powdered coal, crushed coal, granular coal, granulated coal, and formed coal. Among these, considering the ease of handling, the removal efficiency of the activated carbon itself, etc., it is preferable to use powdered coal or granular coal. Specific examples of activated carbon include refined white birch, characteristic white birch, granular white birch, white birch A, white birch P, white birch C, white birch M (above, manufactured by Osaka Gas Chemicals), Dazai A, Dazai CA, Dazai K, Dazai M. (Above, manufactured by Phutamura Chemical).

The solution of the crude azilsartan to be brought into contact with the activated carbon is not particularly limited as long as the crude azilsartan containing the azilsartan dimer as an impurity is dissolved. Therefore, the solvent used in the crude azilsartan solution may be an organic solvent or water as long as the crude azilsartan can be dissolved. Among them, as described above, it is preferable to contact activated carbon with a solution containing crude azilsartan obtained by hydrolyzing an azilsartan alkyl ester (a solution containing crude azilsartan obtained after the hydrolysis reaction). In this case, the solution containing crude azilsartan can contain a base. Further, for the purpose of reducing the azilsartan dimer, the solution obtained by dissolving the azilsartan taken out from the solution in a basic aqueous solution and the activated carbon can be contacted again. However, in consideration of workability, it is preferable to target a solution containing crude azilsartan obtained after the hydrolysis reaction.

The method of bringing the crude azilsartan solution into contact with the activated carbon is not particularly limited. For example, a method of simultaneously mixing crude azilsartan, activated carbon, and a solvent capable of dissolving crude azilsartan, a method of preparing a solution in which crude azilsartan is dissolved, a method of adding activated carbon to the solution and mixing, or a method of filling activated carbon A method of allowing the solution to pass through a column can be employed. Among these, from the viewpoint of ease of operation, it is preferable to employ a method of adding and mixing activated carbon to the solution.

The amount of activated carbon used may be appropriately determined depending on the type of activated carbon, the amount of impurities, and the like. When using a solution in which the crude azilsartan obtained by the above method is used, it is preferable to use 0.03 to 0.2 g of activated carbon per 1 g of the crude azilsartan. At this time, the mixing of the solution and activated carbon is preferably carried out with stirring. Further, the temperature at the time of stirring and mixing is preferably 15 to 35 ° C., particularly preferably 20 to 30 ° C. Further, the contact time with the activated carbon is not particularly limited, and it is usually sufficient to carry out at the temperature in the range of 1 to 5 hours.

(Method for removing activated carbon)
As described above, after bringing the crude azilsartan solution into contact with the activated carbon, the activated carbon is then separated from the mixture and the separated solution is recovered. The method for separating the activated carbon is not particularly limited, and can be carried out by a known method. For example, a separation method such as decantation, filtration, and centrifugal filtration may be employed. At this time, a filter aid such as celite or radiolite may be used for the purpose of improving the efficiency of filtration.

(Separation of azilsartan)
In the present invention, it is necessary to fractionate azilsartan crystals from the separated liquid obtained after the activated carbon treatment. The method for fractionating the crystals of azilsartan from the separated liquid is not particularly limited and can be carried out by a known method. For example, a method of fractionating azilsartan crystals by directly distilling off the solvent from the separated solution, or a method of precipitating azilsartan crystals by neutralizing the separated solution can be employed without particular limitation.

The crystals of azilsartan precipitated by the above method can be separated (sorted) by a known method. Specifically, separation methods such as decantation, reduced pressure / pressure filtration, and centrifugal filtration may be employed. Moreover, it is preferable to wash | clean the isolate | separated crystal | crystallization of azilsartan using the same kind of solvent as the said solvent. The crystals of azilsartan thus obtained are wet bodies, and a dried form of azilsartan crystals is obtained by drying at 30 to 50 ° C. for 3 to 20 hours.

As described above, after bringing crude azilsartan containing an azilsartan dimer as an impurity into contact with activated carbon, the azilsartan dimer content is reduced particularly by separating the crystals of azilsartan from the solution. High-purity azilsartan crystals can be obtained. Further, by using the activated carbon having a specific surface area determined by the BET method of 1000 to 3500 m ² / g and a cumulative pore volume of 0.6 to 1.5 mL / g, The content of the monomer can be further reduced, and crystals of azilsartan with higher purity can be obtained.

(Azilsartan M-type crystal)
Each of the crystals of azilsartan produced according to the first to third inventions is very hardly soluble in an organic solvent. For this reason, when a purification operation is performed using an organic solvent, a large amount of the organic solvent is required. In order to improve this, the crystalline form of the azilsartan produced according to the first to third inventions described above has very high solubility in various solvents including alcohols such as methanol and ethanol and esters such as ethyl acetate. It is also preferable that

Specifically, by X-ray diffraction using Cu—Kα rays, at least 2θ = 9.4 ± 0.2 °, 11.5 ± 0.2 °, 13.3 ± 0.2 °, 14.8 ± Azilsartan having a crystal structure giving characteristic peaks at 0.2 ° and 26.0 ± 0.2 ° is preferred. In addition, in this specification, the azilsartan of this invention which has this crystal structure may be called "Azilsartan M-type crystal". Note that ± 0.2 ° which is a measurement error of the X-ray diffraction angle includes a range of ± 0.2 ° by rounding off. The X-ray diffraction measurement result of this azilsartan M-type crystal is shown in FIG.

Here, the characteristic peak in the present invention has a peak with the maximum intensity at 2θ = 9.4 ± 0.2 °, and 2θ = 11.5 ± 0.2 °, 13.3 ± 0. .2 °, 14.8 ± 0.2 °, 26.0 ± 0.2 ° with an intensity of 7% or more with respect to the maximum peak intensity (2θ = 9.4 ± 0.2 ° peak intensity) It means that a peak having it appears. A peak having an intensity of less than 7% with respect to the maximum peak intensity is regarded as noise or the like, and does not correspond to a characteristic peak in the present invention.

Compared with the known azilsartan crystals described in Patent Documents 1 to 4 and Non-Patent Document 1, the azilsartan M-type crystals are alcohols such as methanol and ethanol; esters such as ethyl acetate; Ketones: The solubility of ethers such as tetrahydrofuran in organic solvents is improved. Specifically, at room temperature, azilsartan M-type crystals can be dissolved about 7 to 10 times in the same amount of methanol than known azilsartan crystals.

Further, the azilsartan M-type crystal has a lower melting point than the known azilsartan crystal. Specifically, the melting point determined by differential scanning calorimetry (DSC) measurement is 115 ° C. or higher and 135 ° C. or lower. In the present invention, the melting point determined by differential scanning calorimetry (DSC) measurement refers to the peak top temperature of the endothermic peak obtained by the measurement.

(Method for producing azilsartan M-type crystal)
Azilsartan M-type crystals can be produced by adding a solvent of ketones and / or esters to a solution obtained by dissolving azilsartan in dimethylformamide to precipitate azilsartan M-type crystals.

When azilsartan is a hydrate or solvate, the number of molecules of water or solvent is not particularly limited. In addition, since a solvent of dimethylformamide and ketones and / or esters is used in the production of azilsartan M-type crystals, it may be a wet body containing the organic solvent, and other solvents may be used during crystallization. It may remain within a range that does not affect the above. Specifically, it may remain in an amount of 50% by mass or less of the azilsartan. Most preferably, no solvent other than the organic solvent is contained. The purity of the azilsartan used is not particularly limited, and those obtained by the first to third inventions can be used as they are.

(Method for preparing azilsartan solution)
In the method for producing azilsartan M-type crystals, azilsartan solution is first obtained by dissolving azilsartan in dimethylformamide. In this case, the dimethylformamide used is not particularly limited, and a commercially available product can be used as it is. The amount of dimethylformamide used may be appropriately determined depending on the crystal form of azilsartan to be used, but is generally 0.5 mL to 10 mL with respect to 1 g of azilsartan. When the amount of dimethylformamide used increases, the yield decreases, so that it is preferably 0.5 mL or more and 5 mL or less. In addition, the volume of a solvent shall be in 25 degreeC. The temperature at which azilsartan is dissolved may be appropriately determined depending on the crystal form of azilsartan used and the amount of dimethylformamide, and it is preferably dissolved in the range of 10 ° C to 50 ° C. As a matter of course, when there is a substance that does not completely dissolve, the substance that does not dissolve can be filtered and processed. Further, the method for obtaining the azilsartan solution is not particularly limited, and the solution may be prepared by mixing azilsartan and dimethylformamide, and the mixing method and order are not particularly limited.

(Crystallization of azilsartan M-type crystal)
The method for producing azilsartan M-type crystals is characterized in that a solvent for ketones and / or esters is added to the obtained azilsartan solution to precipitate azilsartan M-type crystals. By employing this method, azilsartan M-type crystals with improved solubility in organic solvents can be obtained in high yield. Solvents added to the azilsartan solution are from ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone and cyclohexanone; and / or esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate. You can choose. In order to obtain a higher purity azilsartan, it is preferable to add a solvent of an ester, and it is most preferable to use ethyl acetate among them. In the present invention, these ketone solvents and esters can be mixed and added. In the present invention, by adding a solvent of ketones and / or esters to precipitate azilsartan, it is possible to precipitate azilsartan M-type crystals having improved solubility in organic solvents.

The amount of ketones and / or esters used in the azilsartan solution may be appropriately determined depending on the type of solvent selected. Usually, it may be 1 mL or more and 50 mL or less with respect to 1 mL of dimethylformamide used in the preparation of the azilsartan solution, and it is preferably 5 mL or more and 20 mL or less in consideration of yield and operability. At this time, the temperature at which the ketone and / or ester solvent is added is not particularly limited, and after confirming that azilsartan is dissolved in dimethylformamide, it can be added immediately at the temperature, but 30 ° C. or less. It is more preferable to add at. By adding at 30 ° C. or less, an increase in impurities due to thermal decomposition can be suppressed, and the purity of the obtained azilsartan M-type crystal becomes higher. Further, the method of adding the ketone and / or ester solvent is not particularly limited, and either a method of adding the whole amount at once or a method of adding it in several divided portions can be employed. In this method, after adding a solvent of ketones and / or esters, the azilsartan M-type crystals are precipitated by stirring at a constant temperature. The temperature maintained at this time may be −5 ° C. or higher and 30 ° C. or lower. In order to obtain azilsartan with a higher yield, it is preferably maintained at 0 ° C. or higher and 10 ° C. or lower. The holding time may be appropriately determined depending on the holding temperature, but it is usually preferably 5 hours or longer. At this time, if crystals of azilsartan are difficult to precipitate, seed crystals can be added.

The azilsartan M-type crystals thus precipitated can be isolated by solid-liquid separation by filtration, centrifugation, or the like, and then drying by a method such as natural drying, blast drying, or vacuum drying.

The azilsartan obtained by this method is an azilsartan M-type crystal having a novel crystal structure. The azilsartan M-type crystal of the present invention has improved solubility in organic solvents, and the solubility of alcohols, esters, ketones, and ethers in solvents is extremely high compared to known crystal forms. Accordingly, when performing purification operations on azilsartan M-type crystals, purification operations such as recrystallization can be easily performed using solvents of alcohols, esters, ketones, and ethers.

Hereinafter, the present invention will be described in detail with reference to examples, but these are specific examples, and the present invention is not limited thereto.

The purity evaluation in Examples and Comparative Examples was performed by the following method using high performance liquid chromatography (HPLC).

<Measurement conditions for HPLC>
Apparatus: High performance liquid chromatography (HPLC).
Model: 2695-2489-2998 (manufactured by Waters).
Detector: Ultraviolet absorptiometer (measurement wavelength: 210 nm).
Column: Kromasil C18, inner diameter 4.6 mm, length 15 cm (particle diameter 5 μm) (manufactured by Akzo Nobel).
Column temperature: constant 30 ° C.
Sample temperature: constant at 25 ° C.
Mobile phase A: acetonitrile.
Mobile phase B: 15 mM potassium dihydrogen phosphate aqueous solution (pH = 2.5, adjusted with phosphoric 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: 1.0 mL / min.
Measurement time: 0 to 90 minutes.

Under the above conditions, the amidoxime desethyl derivative is about 1.8 minutes, the amidoxime compound is about 2.8 minutes, the amidoxime ethyl form is about 4.0 minutes, the amide form is about 8.5 minutes, the nitrile The desethyl compound is about 11.2 minutes, the nitrile compound is about 25.0 minutes, the ester protecting group-containing compound A (R ¹ : methyl group, R ² : ethyl group) is about 16.2 minutes, the ester protection Group-containing compound B (R ¹ : methyl group, R ² : 2-ethylhexyl group) is about 52.3 minutes, said azilsartan methyl ester is about 14.5 minutes, said desethyl body is about 7.0 minutes, said azil A peak is observed at about 7.3 minutes for sultan, about 49.1 minutes for the dimer, and about 5.5 minutes for impurities whose molecular weight is 10 larger than that of azilsartan methyl ester. In the following Examples and Comparative Examples, the purity values of the amidoxime compound, the ester protecting group-containing compound, the azilsartan methyl ester, and the azilsartan are all the area values of all peaks measured under the above conditions (from the solvent) Is the ratio of the peak area value of each compound to the total.

<Measurement of crystal form of azilsartan alkyl ester and azilsartan>
Apparatus: X-ray diffractometer (XRD).
Model: SmartLab (manufactured by Rigaku Corporation).
Measuring method: ASC6 BB Dtex.
X-ray output: 40 kV-30 mA.
Wavelength: CuKa / 1.541882Å.

<Measurement of melting point of azilsartan alkyl ester>
Apparatus: Differential scanning calorimeter (DSC).
Model: DSC6200 (made by SII Nano Technology).
Temperature rising condition: 10 ° C./min.
Gas: Argon.

<Measurement of melting point of azilsartan>
Apparatus: Differential scanning calorimeter (DSC)
Model: DSC6200 (made by SII Nano Technology)
Temperature rising condition: 5 ° C / min Gas: Argon

A. Example and Comparative Example According to First Invention [Example 1]
The nitrile compound (5 g, 12.2 mmol) was weighed in a 100 mL three-necked flask equipped with two stirring blades with a diameter of 2.5 cm, and 1-propanol (50 mL), a commercially available 50% by mass hydroxylamine aqueous solution (4.0 g, 60.60 mL). 8 mmol) was added, and the mixture was heated to the reflux temperature (about 92 ° C.), and then reacted at the same temperature for 12 hours. The amidoxime compound purity: 82.2%, the amide compound: 9.1%, the nitrile compound: 2.2%, the amidoxime desethyl compound: 6.0%, the amidoxime ethyl compound: 0.3%, Nitrile desethyl compound: 0.05%.

The solution after the reaction was cooled to 20 ° C. at a rate of 30 ° C./hour and stirred at 20 ° C. overnight. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried at 50 ° C., and 4.0 g of the amidoxime compound crystals (purity of the amidoxime compound: 94.7%, the amide Body: 3.0%, nitrile compound: 0.2%, amidoxime desethyl body: 0.7%, amide desethyl body: 0.3%, nitrile desethyl body: undetected) (Yield: 77.1%). The results are summarized in Tables 2 and 3.

[Example 2]
70 g (170.1 mmol) of the nitrile compound was weighed into a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, 700 mL of 1-propanol, 5.16 g (51.0 mmol) of triethylamine, and a commercially available 50% by mass hydroxyl group. After adding 56.2 g (850.5 mmol) of an aqueous amine solution and heating to the reflux temperature (about 92 ° C.), the reaction was carried out at the same temperature for 13 hours. Purity of the amidoxime compound: 83.9%, the amide body: 2.4%, the nitrile compound: 2.4%, the amidoxime desethyl body: 7.6%, the amidoxime ethyl body: 0.2% The nitrile desethyl compound was 0.01%.

The solution after the reaction was cooled to 20 ° C. at a rate of 20 ° C./hour and stirred at 20 ° C. for 13 hours. Subsequently, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried at 50 ° C., and 61.0 g of the amidoxime compound crystals (purity of the amidoxime compound: 96.9%, the amide Body: 0.5%, nitrile compound: 0.1%, amidoxime desethyl body: 0.5%, amide desethyl body: 0.1%, nitrile desethyl body: undetected) (Yield: 81.0%). The results are summarized in Tables 2 and 3.

Example 3
Nitrile compound 5 g (12.2 mmol) was weighed into a 100 mL three-necked flask equipped with two 2.5 cm diameter stirring blades, 1-propanol 50 mL, triethylamine 0.62 g (6.1 mmol), 50% by mass commercially available. After adding 4.0 g (60.8 mmol) of an aqueous hydroxylamine solution and heating to the reflux temperature (about 92 ° C.), the reaction was carried out at the same temperature for 13 hours. Purity of the amidoxime compound: 84.2%, the amide body: 1.8%, the nitrile compound: 2.6%, the amidoxime desethyl body: 7.4%, the amidoxime ethyl body: 0.2% The nitrile desethyl compound was 0.01%.

The solution after the reaction was cooled to 20 ° C. at a rate of 20 ° C./hour and stirred at 20 ° C. for 13 hours. Subsequently, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried at 50 ° C., and 4.1 g of the amidoxime compound crystals (purity of the amidoxime compound: 97.1%, the amide Body: 0.3%, nitrile compound: 0.1%, amidoxime desethyl body: 0.5%, amide desethyl body: 0.1%, nitrile desethyl body: undetected) (Yield: 77.4%). The results are summarized in Tables 2 and 3.

Example 4
In Example 3, the same operation was performed except that the reaction solvent was changed from 1-propanol to 1-butanol and the amount of triethylamine used was changed from 0.62 g (6.1 mmol) to 0.37 g (3.66 mmol). .

4.4 g of crystals of the amidoxime compound (purity of the amidoxime compound: 97.0%, the amide compound: 0.4%, the nitrile compound: 0.1%, the amidoxime desethyl compound: 0.6%, The amide desethyl compound: 0.1%, the nitrile desethyl compound: not detected) was obtained (yield: 81.1%). The results are summarized in Tables 2 and 3.

Example 5
In Example 3, the same operation was performed except that the base used was changed from triethylamine to pyridine and the amount of the base used was changed from 0.62 g (6.1 mmol) to 0.37 g (3.66 mmol).

4.3 g of crystals of the amidoxime compound (purity of the amidoxime compound: 96.5%, the amide compound: 0.4%, the nitrile compound: 0.2%, the amidoxime desethyl compound: 0.6%, The amide desethyl compound: 0.1%, the nitrile desethyl compound: not detected) was obtained (yield: 79.4%). The results are summarized in Tables 2 and 3.

Example 6
In Example 3, the same operation was performed except that the amount of triethylamine used was changed from 0.62 g (6.1 mmol) to 0.12 g (1.22 mmol).

4.3 g of crystals of the amidoxime compound (purity of the amidoxime compound: 95.3%, the amide compound: 1.5%, the nitrile compound: 0.2%, the amidoxime desethyl compound: 0.6%, The amide desethyl compound: 0.3%, the nitrile desethyl compound: not detected) was obtained (yield: 80.2%). The results are summarized in Tables 2 and 3.

Example 7
In Example 1, the same operation was performed except that the amount of 1-propanol used was changed from 50 mL to 75 mL.

3.9 g of crystals of the amidoxime compound (purity of the amidoxime compound: 94.9%, the amide compound: 2.8%, the nitrile compound: 0.2%, the amidoxime desethyl compound: 0.7%, The amide desethyl compound: 0.3% and the nitrile desethyl compound: not detected) were obtained (yield: 73.1%). The results are summarized in Tables 2 and 3.

[Example 8] (Synthesis of azilsartan methyl ester)
40 g of the amidoxime compound obtained in Example 2 was weighed into a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, dimethyl sulfoxide 350 mL, 1,1′-carbonylimidazole 17.5 g, diazabicyclo 15.5 g of undecene was added, and the reaction was carried out with stirring at room temperature for 4 hours. 1500 mL of water was weighed into a separately prepared 3 L three-necked flask, and the reaction solution was slowly added dropwise. After adjusting the pH to about 4 by adding 5% aqueous hydrochloric acid to the resulting solution, the precipitated crystals of azilsartan methyl ester are collected by filtration under reduced pressure, dried at 50 ° C., and then recrystallized from 400 mL of acetone. The obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 50 ° C. to obtain 32.0 g of crystals of azilsartan methyl ester (purity of azilsartan methyl ester: 99. 4%).

[Example 9] (Synthesis of azilsartan)
After weighing 20 g of azilsartan methyl ester obtained in Example 8 into a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, adding 200 mL of a 1.25 M aqueous sodium hydroxide solution and heating to 50 ° C., The reaction was carried out at the same temperature for 3 hours. After cooling the reaction solution to 45 ° C., 100 mL of acetone, 75 mL of acetic acid, and 70 mL of water were added at the same temperature to precipitate azilsartan crystals. The reaction solution was cooled to 20 ° C. at a rate of 20 ° C./hour and then stirred at the same temperature for 5 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 40 ° C. to obtain 16.6 g of azilsartan crystals (purity of azilsartan: 99.4%).

[Comparative Example 1] (Production of the amidoxime compound by the method described in Non-Patent Document 1)
In a 500 mL three-necked flask equipped with two stirring blades with a diameter of 7.5 cm, 5 g (12.2 mmol) of the nitrile compound was weighed, 50 mL of dimethyl sulfoxide, 4.2 g (60.8 mmol) of hydroxylamine hydrochloride, triethylamine 6 .15 g (60.8 mmol) was added, heated to 90 ° C., and reacted at the same temperature for 16 hours. The amidoxime compound purity: 42.6%, the amide compound: 37.0%, the nitrile compound: 4.5%, the amidoxime desethyl compound: 9.3%, the amidoxime ethyl compound: 4.8%, The nitrile desethyl form: 1.0%.

The solution after the reaction was cooled to 20 ° C. and stirred for 12 hours, but no crystals of the amidoxime compound were precipitated. Therefore, 125 mL of water was added to the reaction solution to precipitate crystals of the amidoxime compound. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried at 50 ° C., and 3.1 g of the amidoxime compound crystals (purity of the amidoxime compound: 49.9%, the amide Body: 46.4%, nitrile compound: 0.5%, amidoxime desethyl body: 1.7%, amide desethyl body: 0.9%, nitrile desethyl body: 0.1%) Obtained (yield: 57.1%). The results are summarized in Tables 2 and 3.

[Comparative Example 2] (Production of amidoxime compound by the method described in Patent Document 2)
The nitrile compound (5 g, 12.2 mmol) was weighed into a 500 mL three-necked flask equipped with two stirring blades with a diameter of 7.5 cm, dimethyl sulfoxide (50 mL), and a commercially available 50 mass% hydroxylamine aqueous solution (2.0 g, 30.4 mmol). ) And heated to 90 ° C., followed by reaction at the same temperature for 15 hours. Purity of the amidoxime compound: 72.0%, the amide form: 9.8%, the nitrile compound: 0.5%, the amidoxime desethyl form: 9.3%, the amidoxime ethyl form: 1.0% The nitrile desethyl compound was 0.2%.

The solution after the reaction was cooled to 20 ° C. and stirred for 12 hours, but no crystals of the amidoxime compound were precipitated. Therefore, 125 mL of water was added to the reaction solution to precipitate crystals of the amidoxime compound. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried at 50 ° C., and 4.2 g of the amidoxime compound crystals (the amidoxime compound purity: 85.7%, the amide compound). : 5.1%, the nitrile compound: 0.5%, the amidoxime desethyl compound: 5.9%, the amido desethyl compound: 0.4%, and the nitrile desethyl compound: 0.1%). (Yield: 78.8%). The results are summarized in Tables 2 and 3.

 

 

B. Example and Comparative Example According to Second Invention [Production Example 1] (Ester Protecting Group-Containing Compound A; R ¹ : Methyl Group, R ² : Synthesis of Ethyl Group)
120 g (270.0 mmol) of the amidoxime compound was weighed into a 2 L four-necked flask equipped with two stirring blades having a diameter of 15 cm, 840 mL of methylene chloride and 33.0 g (324.0 mmol) of triethylamine were added, and the mixture was stirred at 0 ° C. Until cooled. A solution prepared by diluting 35.4 g (324.0 mmol) of ethyl chloroformate with 360 mL of methylene chloride was slowly added dropwise to the resulting solution. After the total amount was dropped, the reaction was carried out with stirring at 0 ° C. for 2 hours. The solution after the reaction was heated to 20 ° C., and 480 mL of water was added to extract the organic layer. The obtained organic layer was concentrated under reduced pressure, 1-propanol (600 mL) was added to the residue, and the mixture was stirred at 20 ° C. for 3 hr. The obtained slurry solution was subjected to solid-liquid separation by filtration under reduced pressure, and then dried under reduced pressure at 40 ° C. to obtain 122.86 g of ester protective group-containing compound A (purity of ester protective group-containing compound A: 96.1%). Rate 88.1%).

[Production Example 2] (Ester protecting group-containing compound B; R ¹ : methyl group, R ² : synthesis of 2-ethylhexyl group)
30 g (67.5 mmol) of the amidoxime compound was weighed into a 500 mL four-necked flask equipped with two stirring blades having a diameter of 7.5 cm, and 210 mL of methylene chloride and 8.2 g (81.0 mmol) of triethylamine were added and stirred. Cooled to 0 ° C. A solution obtained by diluting 15.6 g (81.0 mmol) of 2-ethylhexyl chloroformate with 90 mL of methylene chloride was slowly added dropwise to the resulting solution. After the total amount was dropped, the reaction was carried out with stirring at 0 ° C. for 2 hours. The solution after the reaction was heated to 20 ° C., and 120 mL of water was added to extract the organic layer. The obtained organic layer was concentrated under reduced pressure, 150 mL of 1-propanol was added to the residue, and the mixture was stirred at 20 ° C. for 3 hours. The obtained slurry solution was subjected to solid-liquid separation by filtration under reduced pressure, and then dried under reduced pressure at 40 ° C. to obtain 31.9 g of ester protecting group-containing compound B (purity of ester protecting group-containing compound B: 94.5%). (Rate 78.7%).

Example 10
5 g (9.7 mmol) of the ester protecting group-containing compound A obtained in Production Example 1 was weighed into a 100 mL three-necked flask equipped with two stirring blades having a diameter of 3.5 cm, 45 mL of 1-propanol was added, and the reflux temperature was increased. After heating to (about 95 ° C.), the reaction was carried out at the same temperature for 16 hours. The purity of the azilsartan methyl ester was 91.5%, and the ester protecting group-containing compound A was 1.8%. The reaction solution after the reaction was cooled to 0 ° C. at a rate of 20 ° C./hour, and stirred at 0 ° C. for 14 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 3.7 g of crystals of the azilsartan methyl ester (purity of the azilsartan alkyl ester: 97. 3%) (yield: 81.1%). The results are summarized in Table 4. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Further, when XRD was measured using this azilsartan methyl ester as a sample, the X-ray diffraction chart shown in FIG. 1 was obtained. This crystal was found to be a compound having a novel crystal structure that gives characteristic peaks at 2θ = 9.9 °, 10.9 °, 13.6 °, 17.2 °, 23.2 °.

Example 11
10 g (19.4 mmol) of the ester protecting group-containing compound A obtained in Production Example 1 was weighed in a 200 mL three-necked flask equipped with two stirring blades having a diameter of 5 cm, and 90 mL of 1-propanol and 0.4 g of triethylamine (3 g .9 mmol) was added and heated to the reflux temperature (about 94 ° C.), followed by reaction at the same temperature for 9 hours. The purity of the azilsartan methyl ester was 93.0%, and the ester protecting group-containing compound A was 0.7%. The reaction solution after the reaction was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 12 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 7.6 g of crystals of the azilsartan methyl ester (purity of the azilsartan methyl ester: 97. 8%) was obtained (yield: 83.4%). The results are summarized in Table 4. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. In addition, when XRD is measured using this azilsartan methyl ester as a sample, novel peaks giving characteristic peaks at 2θ = 9.8 °, 10.9 °, 13.6 °, 17.2 °, 23.2 ° are obtained. It was found to be a compound having a crystal structure.

Example 12
5 g (8.3 mmol) of the ester protecting group-containing compound B obtained in Production Example 2 was weighed into a 100 mL three-necked flask equipped with two stirring blades having a diameter of 3.5 cm, and 45 mL of 1-propanol and 0.2 g of triethylamine were measured. (1.7 mmol) was added, and the mixture was heated to the reflux temperature (about 94 ° C.), and then reacted at the same temperature for 10 hours. The purity of the azilsartan methyl ester was 91.7%, and the ester protecting group-containing compound B was 0.6%. The reaction solution after the reaction was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 12 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 3.2 g of crystals of the azilsartan methyl ester (purity of the azilsartan methyl ester: 97. 5%) was obtained (yield: 81.8%). The results are summarized in Table 4. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Moreover, the result of XRD was not different from the azilsartan methyl ester of Examples 10 and 11.

Example 13
In Example 11, the same operation was performed except that the amount of triethylamine used was changed from 0.4 g (3.9 mmol) to 1.96 g (19.4 mmol). The reaction was complete in 6 hours.

5.9 g of crystals of the azilsartan methyl ester (purity of the azilsartan methyl ester: 98.6%) were obtained (yield: 64.4%). The results are summarized in Table 4. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Moreover, the result of XRD was not different from the azilsartan methyl ester of Examples 10 and 11.

Example 14
In Example 10, the same operation was performed except that the reaction solvent was changed from 1-propanol to 1-butanol.

3.7 g of the azilsartan methyl ester crystal (purity of the azilsartan methyl ester: 97.1%) was obtained (yield: 80.9%). The results are summarized in Table 4. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Moreover, the result of XRD was not different from the azilsartan methyl ester of Examples 10 and 11.

Example 15
In Example 10, the same operation was performed except that the amount of 1-propanol used was changed from 45 mL to 125 mL.

2.3 g of crystals of the azilsartan methyl ester (purity of the azilsartan methyl ester: 98.2%) were obtained (yield: 50.9%). The results are summarized in Table 4. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Moreover, the result of XRD was not different from the azilsartan methyl ester of Examples 10 and 11.

Example 16
In Example 11, the same operation was performed except that the base used was changed from triethylamine to pyridine.

7.6 g of the azilsartan methyl ester crystal (purity of the azilsartan methyl ester: 97.7%) was obtained (yield: 83.8%). The results are summarized in Table 4. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Moreover, the result of XRD was not different from the azilsartan methyl ester of Examples 10 and 11.

[Example 17] (Synthesis of azilsartan)
After weighing 5 g of azilsartan methyl ester obtained in Example 11 into a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, adding 50 mL of a 1.25 M aqueous sodium hydroxide solution and heating to 50 ° C., The reaction was carried out at the same temperature for 3 hours. After the reaction solution was cooled to 45 ° C., 25 mL of acetone, 17 mL of acetic acid, and 17 mL of water were added at the same temperature to precipitate azilsartan crystals. The reaction solution was cooled to 20 ° C. at a rate of 20 ° C./hour, and then stirred at the same temperature for 6 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 40 ° C. to obtain 4.2 g of azilsartan crystals (purity of azilsartan: 99.0%).

[Comparative Example 3] (Production of the azilsartan methyl ester by the method described in Patent Document 1)
After weighing 5 g of the ester protective group-containing compound A obtained in Production Example 1 into a 200 mL three-necked flask equipped with two stirring blades having a diameter of 5 cm, adding 50 mL of xylene, and heating to reflux temperature (about 130 ° C.). The reaction was carried out at the same temperature for 1.5 hours. The purity of the azilsartan methyl ester was 70.1%, and the ester protecting group-containing compound A was not detected. The solution after the reaction was concentrated under reduced pressure, and 100 mL of ethyl acetate was added to the residue, but the crystals in the residue did not dissolve. Therefore, 50 mL of isopropyl ether was added and stirred at 20 ° C. for 12 hours. The obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 1.4 g of the azilsartan methyl ester crystals (purity of the azilsartan alkyl ester: 79.8% (Yield: 30.4%). Impurities having a molecular weight 10 higher than that of azilsartan methyl ester were 12.1%. The results are summarized in Table 4.

[Comparative Example 4] (Production of the azilsartan methyl ester by the method described in Non-Patent Document 1)
After weighing 5 g of the ester protective group-containing compound B obtained in Production Example 2 into a 200 mL three-necked flask equipped with two stirring blades having a diameter of 5 cm, adding 50 mL of xylene, and heating to reflux temperature (about 130 ° C.). The reaction was carried out at the same temperature for 2 hours. Purity of the azilsartan methyl ester: 72.8%, the ester protecting group-containing compound B: not detected. The solution after the reaction was concentrated under reduced pressure, 50 mL of ethyl acetate was added to the residue, the temperature was raised to reflux temperature (about 80 ° C.), and the crystals of the concentrated residue were completely dissolved. The resulting solution was cooled to 20 ° C. and stirred at 20 ° C. for 12 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 2.0 g of crystals of the azilsartan methyl ester (purity of the azilsartan methyl ester: 88. 4%) (yield: 50.2%). Impurities having a molecular weight 10 higher than that of azilsartan methyl ester were 10.8%. The results are summarized in Table 4. Further, when XRD was measured using this azilsartan methyl ester as a sample, the X-ray diffraction chart shown in FIG. 2 was obtained, and this crystal had 2θ = 8.0 °, 10.4 °, 12.0 °, 15. The compound was found to give a characteristic peak at 9 ° and 21.4 °.

 
 

 
 

C. Example and Comparative Example According to Third Invention [Production Example 3] (Synthesis of Target Azilsartan Methyl Ester)
An ester protecting group-containing compound (a compound in which R ¹ is a methyl group and R ² is an ethyl group in the above formula (3)) in a 1000 mL four-necked flask equipped with two stirring blades having a diameter of 10 cm (96. 80 mmol), 400 mL of 1-propanol and 1.96 g (19.36 mmol) of triethylamine were added, and the mixture was heated to the reflux temperature (about 95 ° C.), and then reacted at the same temperature for 14 hours. The solution after the reaction was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 14 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 38.3 g of target azilsartan methyl ester crystals (purity of azilsartan methyl ester: 97.3). %, The desethyl isomer: 0.10%, the dimer: 0.16%) (yield: 84.2%). Moreover, an impurity having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Further, when XRD is measured using this target azilsartan methyl ester as a sample, characteristic peaks are given at 2θ = 9.9 °, 10.9 °, 13.6 °, 17.2 °, 23.2 °. An X-ray diffraction chart was obtained. Further, DSC measurement confirmed that the melting points were 90.9 ° C. (heat of fusion 15.790 J / g) and 186.6 ° C. (heat of fusion 58.886 J / g).

[Example 18] (crystallization of azilsartan methyl ester)
Weigh 10 g of the target azilsartan methyl ester obtained in Production Example 3 in a 200 mL three-necked flask equipped with two stirring blades with a diameter of 5 cm, add 100 mL of acetone, and heat to reflux temperature (about 57 ° C.). Azilsartan methyl ester was dissolved. After dissolution, the mixture was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 12 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried under reduced pressure at 40 ° C. to obtain 8.7 g of azilsartan methyl ester crystals (purity of azilsartan methyl ester: 99.1% The desethyl body: not detected, and the dimer: 0.04%) was obtained (yield: 87.2%). The results are summarized in Table 5. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Further, when XRD was measured using this azilsartan methyl ester as a sample, as shown in FIG. 3, 2θ = 9.2 °, 15.8 °, 18.2 °, 22.1 °, 25.1 °, 27. It was found to be a quasicrystal of azilsartan methyl ester giving a characteristic peak at 4 °. The results are summarized in Table 6. Furthermore, when DSC measurement was performed, it was confirmed that the melting points were 160.6 ° C. (heat of fusion 9.635 J / g) and 189.9 ° C. (heat of fusion 51.766 J / g) as shown in FIG.

[Example 19] (Recrystallization of azilsartan methyl ester)
Weigh 5 g of the target azilsartan methyl ester obtained in Production Example 3 in a 100 mL three-necked flask equipped with two stirring blades with a diameter of 3.5 cm, add 30 mL of acetone and 20 mL of 1-propanol, and heat to reflux temperature. The target azilsartan methyl ester was dissolved. After dissolution, the mixture was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 12 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 4.3 g of azilsartan methyl ester crystals (purity of azilsartan methyl ester: 99.0% The desethyl body: not detected, and the dimer: 0.04%) was obtained (yield: 86.0%). The results are summarized in Table 5. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Further, when XRD is measured using this azilsartan methyl ester as a sample, it is characteristic of 2θ = 9.2 °, 15.7 °, 18.2 °, 22.1 °, 25.2 °, 27.4 °. It was found to be a quasicrystal of azilsartan methyl ester giving a peak. The results are summarized in Table 6. Furthermore, it was confirmed by DSC measurement that it has melting points at 157.2 ° C. (calorie of fusion 5.249 J / g) and 189.7 ° C. (calorie of fusion 57.266 J / g).

[Example 20] (crystallization of azilsartan methyl ester)
The same operation as in Example 19 was performed except that 1-propanol was changed to 1-butanol.

4.2 g of crystals of azilsartan methyl ester (purity of azilsartan methyl ester: 99.1%, the desethyl body: not detected, the dimer: 0.04%) were obtained (yield: 85.4). %). The results are summarized in Table 5. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Moreover, the result of XRD was the same as that of the azilsartan methyl ester of Example 19. The results are summarized in Table 6. Furthermore, when DSC measurement was performed, it was confirmed that the melting points were 158.1 ° C. (heat of fusion 4.191 J / g) and 189.5 ° C. (heat of fusion 58.734 J / g).

[Example 21] (crystallization of azilsartan methyl ester)
In a 100 mL three-necked flask equipped with two stirring blades with a diameter of 3.5 cm, weigh 4 g of the target azilsartan methyl ester produced by the method of Comparative Example 5 below, add 40 mL of acetone, and heat to reflux temperature. The subject azilsartan methyl ester was dissolved. After dissolution, the mixture was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 14 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 2.8 g of azilsartan methyl ester crystals (purity of azilsartan methyl ester: 96.6% The desethyl body: not detected, the dimer: 0.07%) was obtained (yield: 70.2%). The results are summarized in Table 5. Impurities having a molecular weight 10 higher than that of azilsartan methyl ester were 1.64%. Further, when XRD is measured using this azilsartan methyl ester as a sample, it is characteristic of 2θ = 9.2 °, 15.7 °, 18.1 °, 22.1 °, 25.3 °, 27.4 °. It was found to be a quasicrystal of azilsartan methyl ester giving a peak. The results are summarized in Table 6. Further, DSC measurement confirmed that the melting points were 159.4 ° C. (heat of fusion 7.921 J / g) and 190.2 ° C. (heat of fusion 55.015 J / g).

[Example 22] (Recrystallization of azilsartan methyl ester)
The azilsartan methyl ester produced in Example 21 was used as the target azilsartan methyl ester.

The same operation as in Example 21 was repeated using 2 g of azilsartan methyl ester produced in Example 21.

1.7 g of crystals of azilsartan methyl ester (purity of azilsartan methyl ester: 99.3%, the desethyl body: not detected, the dimer: 0.02%) were obtained (yield: 85.9). %). The results are summarized in Table 5. Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed. Moreover, the result of XRD was the same as that of the azilsartan methyl ester of Example 18. The results are summarized in Table 5. Furthermore, it was confirmed by DSC measurement that it had melting points at 160.2 ° C. (heat of fusion 6.424 J / g) and 190.1 ° C. (heat of fusion 56.971 J / g).

[Example 23] (Synthesis of azilsartan)
5 g of azilsartan methyl ester obtained in Example 19 was weighed into a 100 mL three-necked flask equipped with two stirring blades having a diameter of 3.5 cm, 50 mL of a 1.25 M aqueous sodium hydroxide solution was added, and the mixture was heated to 50 ° C. Then, reaction was performed at the same temperature for 3 hours. After the reaction solution was cooled to 45 ° C., 25 mL of acetone, 17 mL of acetic acid, and 17 mL of water were added at the same temperature to precipitate azilsartan crystals. The reaction solution was cooled to 20 ° C. at a rate of 20 ° C./hour, and then stirred at the same temperature for 6 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 40 ° C. to obtain 4.3 g of azilsartan crystals (purity of azilsartan: 99.7%).

[Comparative Example 5] (Production of the azilsartan methyl ester by the method described in Non-Patent Document 1)
10 g of an ester protecting group-containing compound (a compound in which R ¹ is a methyl group and R ² is a 2-ethylhexyl group in the formula (3)) in a 200 mL three-necked flask equipped with two stirring blades having a diameter of 5 cm Weighed out, added 100 mL of xylene, heated to reflux temperature (about 130 ° C.), and then reacted at the same temperature for 2 hours. The solution after the reaction was concentrated under reduced pressure, 100 mL of ethyl acetate was added to the residue, the temperature was raised to reflux temperature (about 80 ° C.), and the crystals of the concentrated residue were completely dissolved. The resulting solution was cooled to 20 ° C. and stirred at 20 ° C. for 12 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 4.1 g of azilsartan methyl ester crystals (purity of azilsartan methyl ester: 88.3% The desethyl body: 0.34%, the dimer: 0.27%)) (yield: 50.2%). Impurities having a molecular weight 10 higher than that of azilsartan methyl ester were 10.8%. Further, when XRD was measured using this azilsartan methyl ester as a sample, the X-ray diffraction chart shown in FIG. 4 was obtained, and this crystal had 2θ = 8.0 °, 10.4 °, 12.0 °, 15. The compound was found to give a characteristic peak at 9 ° and 21.4 °. The results are summarized in Table 6. Furthermore, when DSC measurement was carried out, as shown in FIG. 6, it was confirmed that it had a melting point at 193.6 ° C. (heat of fusion 76.619 J / g).

 

 

 

 

D. Other Examples [Production Example 4] (Production of azilsartan methyl ester)
(Ester protection reaction)
120 g (270.0 mmol) of the amidoxime compound (compound in which R ¹ is a methyl group) was weighed into a 2 L four-necked flask equipped with two stirring blades having a diameter of 15 cm, 840 mL of methylene chloride, and 33.0 g (324. 0 mmol) was added and cooled to 0 ° C. with stirring. A solution prepared by diluting 35.4 g (324.0 mmol) of ethyl chloroformate with 360 mL of methylene chloride was slowly added dropwise to the resulting solution. After the total amount was dropped, the reaction was carried out with stirring at 0 ° C. for 2 hours. The solution after the reaction was heated to 20 ° C., and 480 mL of water was added to extract the organic layer. The obtained organic layer was concentrated under reduced pressure to obtain the ester protecting group-containing compound (a compound in which R ¹ is a methyl group and R ² is an ethyl group) as a residue. The purity of the ester group-containing compound was 96.1%, and the amidoxime compound was 0.14%.

(Cyclization reaction)
960 mL of 1-propanol was added to the residue after concentration under reduced pressure, and the mixture was heated to reflux temperature (about 95 ° C.), and then reacted at the same temperature for 12 hours. The purity of the azilsartan methyl ester was 91.5%, and the ester protecting group-containing compound was 1.8%. The reaction solution after the reaction was cooled to 0 ° C. at a rate of 20 ° C./hour, and stirred at 0 ° C. for 14 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 107.6 g of the azilsartan methyl ester crystals (purity of azilsartan methyl ester: 97.3). %, The azilsartan methyl ester desethyl compound: 0.14%, and the azilsartan methyl ester dimer compound: 0.20%) (yield: 84.7%). Moreover, an impurity having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed.

[Production Example 5] (Recrystallization of azilsartan methyl ester)
Weigh 90 g of azilsartan methyl ester obtained in Production Example 4 in a 1000 mL three-necked flask equipped with two stirring blades having a diameter of 10 cm, add 900 mL of acetone, and heat to reflux temperature (about 57 ° C.). The methyl ester was dissolved. After dissolution, the mixture was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 12 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried under reduced pressure at 40 ° C. to obtain 78.9 g of azilsartan methyl ester crystals (purity of azilsartan methyl ester: 99.1% The desethyl compound: 0.02%, and the azilsartan methyl ester dimer: 0.07%) (yield: 87.7%). Moreover, an impurity having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed.

[Production Example 6] (Production of azilsartan methyl ester by the method described in Non-Patent Document 1)
(Ester protection reaction)
30 g (67.5 mmol) of the amidoxime compound (compound in which R ¹ is a methyl group) was weighed into a 500 mL four-necked flask equipped with two stirring blades having a diameter of 7.5 cm, and 120 mL of dimethylformamide and 5.9 g of pyridine ( 74.3 mmol) was added and cooled to 0 ° C. with stirring. To the resulting solution, 13.0 g (67.5 mmol) of 2-ethylhexyl chloroformate was slowly added dropwise. After the total amount was dropped, the reaction was carried out with stirring at 0 ° C. for 1 hour. The solution after the reaction was heated to 20 ° C., and 270 mL of ethyl acetate and 60 mL of water were added to extract the organic layer. The obtained organic layer was further washed with 60 mL of water, and then the organic layer was concentrated under reduced pressure. As a residue, the ester protecting group-containing compound (a compound in which R ¹ is a methyl group and R ² is a 2-ethylhexyl group) Obtained. The purity of the ester group-containing compound was 94.5%, and the amidoxime compound was 1.26%.

(Cyclization reaction)
After adding 420 mL of xylene to the residue after concentration under reduced pressure and heating to reflux temperature (about 130 ° C.), the reaction was performed at the same temperature for 2 hours. The solution after the reaction was concentrated under reduced pressure, 420 mL of ethyl acetate was added to the residue, the temperature was raised to the reflux temperature (about 80 ° C.), and the crystals of the concentrated residue were completely dissolved. The resulting solution was cooled to 20 ° C. and stirred at 20 ° C. for 12 hours. Subsequently, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried under reduced pressure at 40 ° C. to obtain 15.9 g of azilsartan methyl ester crystals (purity of azilsartan methyl ester: 88.3% The desethyl compound: 0.36%, and the azilsartan methyl ester dimer: 0.27%)) (yield: 50.1%). Impurities having a molecular weight 10 higher than that of azilsartan methyl ester were 10.8%.

[Example 24] (Production of azilsartan; with activated carbon treatment)
(Hydrolysis)
5 g of azilsartan methyl ester obtained in Production Example 5 was weighed into a 100 mL three-necked flask equipped with two stirring blades having a diameter of 3.5 cm, added with 40 mL of a 1.25 M aqueous sodium hydroxide solution, and heated to 70 ° C. Thereafter, the reaction was carried out at the same temperature for 2 hours. The crude azilsartan solution after the reaction had azilsartan purity: 99.61%, azilsartan desethyl compound: 0.06%, and azilsartan dimer: 0.08%. Table 7 shows the results of the azilsartan purity and impurity amount of the crude azilsartan solution after the reaction.

(Activated carbon treatment)
After cooling the solution after completion of the hydrolysis reaction to 30 ° C., 0.24 g of purified white birch (manufactured by Osaka Gas Chemical, specific surface area: 1430 m ² / g, cumulative pore volume: 1.17 mL / g) was added, and 20 Stirring was performed at ˜30 ° C. for 1 hour. The solution after activated carbon treatment had azilsartan purity: 99.85%, azilsartan desethyl compound: 0.05%, and azilsartan dimer: 0.01%.

(Removal and purification of activated carbon)
Subsequently, the purified white rice cake was removed by filtration under reduced pressure, and the obtained filtrate was heated to 40 ° C., and then 25 mL of acetone, 17 mL of acetic acid and 17 mL of water were added at the same temperature to precipitate crystals of azilsartan. The reaction solution was cooled to 20 ° C. at a rate of 20 ° C./hour, and then stirred at the same temperature for 6 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 40 ° C. to obtain 4.6 g of azilsartan crystals (yield: 95.6%). The purity of the azilsartan was 99.89%, the azilsartan desethyl compound was 0.03%, the azilsartan dimer was not detected, and the unknown impurity was not detected. The results are shown in Table 8.

[Examples 25 to 26]
(Hydrolysis)
A hydrolysis reaction was carried out in the same manner as in Example 24 except that the azilsartan alkyl ester of the production example shown in Table 7 was used as a raw material. Table 7 shows the purity of the crude azilsartan solution after the hydrolysis reaction and the measurement results of the amount of impurities.

((Activated carbon treatment), (removal and purification of activated carbon))
The hydrolyzed solution was subjected to (activated carbon treatment) and (removed and purified activated carbon) in the same manner as in Example 24 to obtain azilsartan crystals. The purity and the amount of impurities were similarly measured for the obtained crystals of azilsartan. The results are shown in Table 8.

[Examples 27 to 28]
(Hydrolysis)
A hydrolysis reaction was performed in the same manner as in Example 24. Table 7 shows the measurement results of the purity and impurity amount of the crude azilsartan solution after the reaction.

(Activated carbon treatment)
Moreover, as shown in Table 8, the treatment was performed in the same manner as in Example 24 except that the amount of activated carbon used during the activated carbon treatment was changed.

(Removal and purification of activated carbon)
About removal and purification of activated carbon, the same operation as in Example 24 was performed. The purity and impurity amount of the obtained azilsartan crystals were measured. The results are shown in Table 8.

[Examples 29 to 32]
(Hydrolysis)
A hydrolysis reaction was performed in the same manner as in Example 24. Table 7 shows the measurement results of the purity and impurity amount of the crude azilsartan solution after the reaction.

(Activated carbon treatment)
Moreover, as shown in Table 8, the treatment was performed in the same manner as in Example 24 except that the type and amount of the activated carbon during the activated carbon treatment were changed. Table 9 summarizes the characteristics (specific surface area, cumulative pore volume) of the activated carbon used in the examples.

(Removal and purification of activated carbon)
About removal and purification of activated carbon, the same operation as in Example 24 was performed. The purity and impurity amount of the obtained azilsartan crystals were measured. The results are shown in Table 8.

[Reference Example 1] (Manufacture of azilsartan; no activated carbon treatment)
5 g of the azilsartan methyl ester obtained in Production Example 4 was weighed into a 100 mL three-necked flask equipped with two stirring blades having a diameter of 3.5 cm, 40 mL of a 1.25 M aqueous sodium hydroxide solution was added, and the mixture was heated to 70 ° C. Thereafter, the reaction was carried out at the same temperature for 2 hours. The crude azilsartan solution after the reaction had azilsartan purity: 98.98%, azilsartan desethyl compound: 0.20%, and azilsartan dimer: 0.22%. Table 7 shows the results of the azilsartan purity and impurity amount of the crude azilsartan solution after the reaction.

Next, after the obtained reaction solution was cooled to 45 ° C., 25 mL of acetone, 17 mL of acetic acid and 17 mL of water were added at the same temperature to precipitate azilsartan crystals. The reaction solution was cooled to 20 ° C. at a rate of 20 ° C./hour, and then stirred at the same temperature for 6 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 40 ° C. to obtain 4.7 g of azilsartan crystals (yield: 96.5%). The purity of the azilsartan was 99.17%, the azilsartan desethyl compound was 0.15%, the azilsartan dimer was 0.20%, and the unknown impurity was not detected. The results are shown in Table 8.

[Reference Examples 2 to 3] (Manufacture of azilsartan; no activated carbon treatment)
A hydrolysis reaction was performed in the same manner as in Reference Example 1 except that the azilsartan alkyl ester of the production example shown in Table 7 was used as a raw material. Table 8 shows the measurement results of the purity and impurity amount of the crude azilsartan solution after the reaction.

Further, azilsartan crystals were taken out from the reaction solution obtained in the same manner as in Reference Example 1. The purity and the amount of impurities were similarly measured for the obtained crystals of azilsartan. The results are shown in Table 8.

 

 

 

 

 

 

E. Other Examples [Example 33]
(First step: Hydroxyamidination)
70 g (170.1 mmol) of the nitrile compound was weighed into a 1 L four-necked flask equipped with two stirring blades having a diameter of 10 cm, 700 mL of 1-propanol, 5.16 g (51.0 mmol) of triethylamine, and a commercially available 50% by mass hydroxyl group. After adding 56.2 g (850.5 mmol) of an aqueous amine solution and heating to the reflux temperature (about 92 ° C.), the reaction was carried out at the same temperature for 13 hours. Purity of the amidoxime compound: 83.5%, the amide compound: 2.5%, the nitrile compound: 2.4%, the amidoxime desethyl compound: 7.6%, the amido desethyl compound: 0.6% The nitrile desethyl compound was 0.01%.
The solution after the reaction was cooled to 20 ° C. at a rate of 20 ° C./hour and stirred at 20 ° C. for 13 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 50 ° C. to obtain 60.9 g of the amidoxime compound crystals (purity of the amidoxime compound: 96.6%, the amide Body: 0.6%, nitrile compound: 0.1%, amidoxime desethyl body: 0.6%, amide desethyl body: 0.1%, nitrile desethyl body: undetected) (Yield: 80.6%).

(Second step; cyclization)
The amidoxime compound 60 g (135.0 mmol) was weighed into a 1 L four-necked flask equipped with two stirring blades having a diameter of 10 cm, 420 mL of methylene chloride and 16.4 g (162.0 mmol) of triethylamine were added, and the mixture was stirred at 0 ° C. Until cooled. A solution obtained by diluting 17.6 g (162.0 mmol) of ethyl chloroformate with 180 mL of methylene chloride was slowly added dropwise to the obtained solution. After the total amount was dropped, the reaction was carried out with stirring at 0 ° C. for 2 hours. The solution after the reaction was heated to 20 ° C., and 240 mL of water was added to extract the organic layer. The obtained organic layer was washed with 240 mL of 10% brine, and then the solvent in the organic layer was concentrated under reduced pressure to obtain an ester protecting group-containing compound as a residue (ester protecting group-containing compound purity: 96.4%). ).
To the obtained residue, 1-propanol (480 mL) was added, and the mixture was heated to reflux temperature (about 92 ° C.), and then reacted at the same temperature for 12 hours. The purity of the azilsartan methyl ester was 91.7%, and the ester protecting group-containing compound was 1.7%. The reaction solution after the reaction was cooled to 4 ° C. at a rate of 20 ° C./hour and stirred at 4 ° C. for 12 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected, dried under reduced pressure at 40 ° C., and 54.0 g of crystals of the target azilsartan methyl ester (purity of the target azilsartan alkyl ester: 97. 5%, azilsartan methyl ester desethyl derivative: 0.09%, azilsartan methyl ester dimer: 0.15%) (yield: 85.0%). Impurities having a molecular weight 10 larger than that of azilsartan methyl ester could not be confirmed.

(Third step; AL-02 purification)
50 g of target azilsartan methyl ester was weighed into a 1 L four-necked flask equipped with two stirring blades having a diameter of 10 cm, 500 mL of acetone was added, and the mixture was heated to reflux temperature (about 57 ° C.) to dissolve the target azilsartan methyl ester. . After dissolution, the mixture was cooled to 0 ° C. at a rate of 20 ° C./hour and stirred at 0 ° C. for 16 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried under reduced pressure at 40 ° C. to obtain 44.0 g of azilsartan methyl ester crystals (purity of azilsartan methyl ester: 98.9% The azilsartan methyl ester desethyl body: not detected, and the azilsartan methyl ester dimer: 0.04%) was obtained (yield: 88.1%).

(Fourth step: hydrolysis)
40 g of the azilsartan methyl ester was weighed into a 1 L four-necked flask equipped with two stirring blades having a diameter of 10 cm, 260 mL of a 1.25 M aqueous sodium hydroxide solution was added, and the mixture was heated to 70 ° C. and then heated at the same temperature for 2 hours. Reaction was performed. The crude azilsartan solution after the reaction had azilsartan purity: 99.69%, azilsartan desethyl compound: 0.05%, and azilsartan dimer: 0.04%.
After cooling the solution after completion of the hydrolysis reaction to 30 ° C., 2.0 g of purified white birch (manufactured by Osaka Gas Chemical, specific surface area: 1430 m ² / g, cumulative pore volume: 1.17 mL / g) was added, and 20 Stirring was performed at ˜30 ° C. for 1 hour. The azilsartan purity of the solution after the activated carbon treatment was 99.85%, the azilsartan desethyl compound was 0.04%, and the azilsartan dimer was not detected.
Next, the filtrate was filtered under reduced pressure to remove purified white glaze, and the obtained filtrate was heated to 40 ° C., and then 260 mL of methanol and 29.2 mL of acetic acid were added at the same temperature to precipitate crystals of azilsartan. The reaction solution was cooled to 20 ° C. at a rate of 20 ° C./hour, and then stirred at the same temperature for 6 hours. Next, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 40 ° C. to obtain 38.2 g of azilsartan (purity of the azilsartan: 99.88%, azilsartane desethyl compound) : 0.02%, azilsartan dimer: not detected) crystals were obtained (yield: 95.5%).

(Fifth step: AZL purification)
35 g of the azilsartan was weighed into a 1 L four-necked flask equipped with two stirring blades having a diameter of 10 cm, and 70 mL of dimethylformamide was added and dissolved by heating at 30 ° C. After adding 350 mL of ethyl acetate to the obtained azilsartan solution, it cooled to 5 degreeC and stirred for 15 hours. Subsequently, the deposited crystals were collected by filtration under reduced pressure and dried at 50 ° C. to obtain 34.7 g of azilsartan crystals (yield: 99.2%). When XRD is measured using this azilsartan as a sample, the X-ray diffraction chart shown in FIG. 7 is obtained, and the crystal has 2θ = 9.41 °, 11.52 °, 13.33 °, 14.81 °, 26 It was found to be a compound having a novel crystal structure giving a characteristic peak at .01 °. Moreover, melting | fusing point by DSC measurement was 127 degreeC.

Claims (26)

Following formula (1)

(Wherein R ¹ is an alkyl group having 1 to 4 carbon atoms)
An alkyl 1-[(2′-cyanobiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxylate represented by the formula:
Hydroxylamine and / or hydroxylamine acid salt,
Reacting in a reaction solvent containing an alcohol having 2 to 7 carbon atoms,
Following formula (2)

(Wherein R ¹ has the same meaning as in formula (1)).
A process for producing alkyl 2-ethoxy-1-[[2 ′-(hydroxyiminocarboxamido) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate represented by the formula: The production method according to claim 1, wherein the reaction is carried out in the presence of a base. The production method according to claim 2, wherein the base comprises an organic base. The blending amount of the organic base is 1 mol of alkyl 1-[(2′-cyanobiphenyl-4-yl) methyl] -2-ethoxybenzimidazole-7-carboxylate represented by the formula (1). The production method according to claim 3, wherein the amount is 0.01 to 0.5 mol. The production method according to claim 1, wherein the alcohol is a linear or branched alcohol having 3 to 7 carbon atoms. Using the hydroxylamine,
The manufacturing method of Claim 1 with which the said reaction solvent contains water. The alkyl 2-ethoxy-1-[[2 '-(hydroxyiminocarboxamido) biphenyl-4-yl] methyl]-represented by the formula (2) by the production method according to any one of claims 1 to 6 After preparing 1H-benzimidazole-7-carboxylate,
The obtained alkyl 2-ethoxy-1-[[2 ′-(hydroxyiminocarboxamido) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate is used,
Following formula (4)

(Wherein R ¹ has the same meaning as in formula (1)).
2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole represented by A process for producing -7-carboxylate. The alkyl 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazole-) represented by the formula (4) by the production method according to claim 7 After preparing 3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate,
The resulting alkyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole -7-carboxylate is hydrolyzed,
Following formula (5)

2-Ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- A method for producing 7-carboxylic acid.
Following formula (3)

(Wherein R ¹ is an alkyl group and R ² is a protecting group for protecting the hydroxyl group)
An alkyl 2-ethoxy-1-[[2 ′-(alkyloxy-carbonyloxycarbamimidoyl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate represented by the formula: The cyclization reaction is performed in a reaction solvent containing alcohol,
Following formula (4)

(In the formula, R ¹ has the same meaning as in formula (3)).
2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole represented by A process for producing -7-carboxylate. The production method according to claim 9, wherein the cyclization reaction is performed at 50 ° C or higher and lower than a reflux temperature of the reaction solution. The production method according to claim 9, wherein the alcohol is a linear or branched alcohol having 3 to 8 carbon atoms. The production method according to claim 9, wherein the cyclization reaction is performed in the presence of a base. The amount of the base used is alkyl 2-ethoxy-1-[[2 ′-(alkyloxy-carbonyloxycarbamimidoyl) biphenyl-4-yl] methyl] -1H-benzimidazole represented by the formula (3). The process according to claim 12, wherein the amount is 0.01 to 5 mol per 1 mol of -7-carboxylate. The method according to claim 12 or 13, wherein the base is an organic base. In the reaction solvent, the alkyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) represented by the formula (4) is used. The process according to claim 9, wherein crystals of)) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate are precipitated. An alkyl 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1, represented by the formula (4) is produced by the production method according to any one of claims 9 to 15. After preparing 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate,
The resulting alkyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole -7-carboxylate is hydrolyzed,
Following formula (5)

2-Ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- A method for producing 7-carboxylic acid. In the X-ray diffraction using Cu—Kα ray, it is expressed by the above formula (4), which has at least a characteristic peak at 2θ = 9.9 ± 0.2 °, 10.9 ± 0.2 °. Alkyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7 -Carboxylate. Following formula (4)

(Wherein R ¹ is an alkyl group)
2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole represented by -7-carboxylate
Crystallization in acetone or a mixed solvent of acetone and alcohol, characterized in that alkyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4- Process for the preparation of oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate. The production method according to claim 18, wherein R ¹ in the formula (4) is a methyl group. X-ray diffraction using Cu—Kα ray shows that it has characteristic peaks at least at 2θ = 9.2 ± 0.2 °, 15.8 ± 0.2 °, 22.1 ± 0.2 °. Characterized by methyl 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benz Imidazole-7-carboxylate. Methyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo, characterized by having a melting point at least in the temperature range of 150 to 165 ° C. and in the temperature range of 185 to 195 ° C. -1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate. The production method according to claim 18, wherein the alkyl 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazole) represented by the formula (4) is used. After preparing -3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate,
The resulting alkyl 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole -7-carboxylate is hydrolyzed,
Following formula (5)

2-Ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- A method for producing 7-carboxylic acid. Methyl 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl according to claim 20 or 21 ] Hydrolyzing methyl] benzimidazole-7-carboxylate;
Following formula (5)

2-Ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- A method for producing 7-carboxylic acid.
The following formula (5) according to any one of claims 8, 16, and 22.

2-Ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- A method for producing 7-carboxylic acid, comprising:
The following formula (6) included as an impurity

2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,2, characterized in that it comprises a step of removing the azilsartan dimer represented by the following formula using activated carbon. 4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid production process. The following formula (5) according to any one of claims 8, 16, and 22.

2-Ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- A method for producing 7-carboxylic acid, comprising:
The 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7- To a solution obtained by dissolving carboxylic acid in dimethylformamide, a solvent of ketones or esters is added, and the 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1 , 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid, comprising the step of precipitating 2-ethoxy-1-[[2 ′ -(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid. By the manufacturing method according to claim 1,
Following formula (2)

(Wherein R ¹ has the same meaning as in formula (1)).
An alkyl 2-ethoxy-1-[[2 ′-(hydroxyiminocarboxamido) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate represented by the formula:
From the alkyl 2-ethoxy-1-[[2 ′-(hydroxyiminocarboxamido) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate, the following formula (3)

(Wherein R ¹ is an alkyl group and R ² is a protecting group for protecting the hydroxyl group)
An alkyl 2-ethoxy-1-[[2 ′-(alkyloxy-carbonyloxycarbamimidoyl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate represented by the formula:
10. The method according to claim 9, wherein the alkyl 2-ethoxy-1-[[2 ′-(alkyloxy-carbonyloxycarbamimidoyl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxyl From the following formula (4)

(In the formula, R ¹ has the same meaning as in formula (3)).
2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole represented by To obtain -7-carboxylate,
The production method according to claim 21, wherein the alkyl 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl- 4-yl] methyl] benzimidazole-7-carboxylate from the following formula (5)

2-Ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole- 2-Ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-, characterized by obtaining 7-carboxylic acid Process for producing 4-yl] methyl] benzimidazole-7-carboxylic acid.

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