JP6676487B2 - Method for producing amidoxime compound as intermediate of azilsartan, and method for producing azilsartan - Google Patents

Description

  The present invention relates to a novel method for producing an amidoxime compound as an intermediate of azilsartan, and further relates to a novel method characterized by producing azilsartan using the amidoxime compound obtained by the method. .

  The following equation (4)

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

  This azilsartan is synthesized by the following production method.

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

  Subsequently, the amidoxime compound is used as it is in the cyclization reaction, or the alkyl 2-ethoxy-1-[[2 ′-(alkyloxy) represented by the above formula (5) 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”) and then cyclized The reaction is carried out, and alkyl 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl represented by the formula (3) is used. -4-yl] methyl] benzimidazole-7-carboxylate (hereinafter sometimes simply referred to as "azylsartan alkyl ester") Manufacturing.

  Finally, the azilsartan alkyl ester is hydrolyzed to produce the azilsartan represented by the formula (4) (for example, see Patent Documents 1 to 3 and Non-Patent Document 1).

  Drug substances such as azilsartan are desired to reduce impurities. However, as described above, since it is manufactured through many steps, an impurity different from the target substance may be generated in each step. Since these impurities have a similar structure to the target substance, purification and the like become extremely difficult when the amount thereof is large. 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 JP 2014-50698 A JP 2014-505097 A

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

  According to the studies by the present inventors, it has been found that there is room for improvement in the following points in the prior art when producing the amidoxime compound represented by the formula (2).

For example, in Patent Literature 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
The following equation (6)

Is a desethyl form of the nitrile compound (hereinafter, may be simply referred to as “nitrile desethyl form”), and the generation rate 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 dimethylsulfoxide reaction solvent in the presence of an organic base such as triethylamine as a base. According to the study of the present inventors, in this method, the generation ratio of the amidoxime compound increases. However, at the same time, the following formula (7)

It has been found that an amide compound represented by the formula (hereinafter sometimes simply referred to as “amide compound”) is by-produced. Furthermore, if the reaction time is extended,
The following equation (8)

And a desethyl form of an amidoxime compound represented by the following formula (hereinafter sometimes simply referred to as “amidoxime desethyl form”);

It has been found that the desethyl form of the amide form represented by the formula (hereinafter sometimes simply referred to as “amidodesethyl 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 the study by the present inventors, in this method, the amide form is reduced, and the target amidoxime compound can be increased. However, even in this method, the purity of the amidoxime compound is about 70%, and the amide compound is contained in about 10%. According to studies by the present inventors, even when the amidoxime compound is taken out of the reaction system as crystals, the purity of the adoxime compound is about 85%, and the amide form is contained in about 5%. I understood that. And it was found that the longer the reaction time, the more the amidoxime desethyl form and the above amidodesethyl form 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 high-performance liquid chromatography (HPLC) measurement conditions described in 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.

  In addition to the method described in Patent Document 3, as described above, in the methods described in Non-Patent Document 1, Patent Documents 1 and 2, dimethyl sulfoxide is mainly used as a reaction solvent. When dimethyl sulfoxide is used as a main component as a reaction solvent, according to the study of the present inventors, it has been found that the crystals of the amidoxime compound are difficult to precipitate. Therefore, in the conventional method using dimethyl sulfoxide as a reaction solvent, a method of crystallizing an amidoxime compound by adding water to a solution after the reaction is generally used. In this method, only crystals of the low-purity amidoxime compound could be obtained. Then, in order to obtain a crystal of the high-purity amidoxime compound, a purification operation such as recrystallization is separately required, and there is a problem that the operation becomes complicated.

  Accordingly, an object of the present invention is to provide a method for producing the above-mentioned amidoxime compound, which can obtain the above-mentioned amidoxime compound with high yield and high purity by a simple operation. Another object of the present invention is to provide a method for producing high-purity azilsartan using the amidoxime compound produced by the method.

  The present inventors have conducted intensive studies to solve the above problems. The reason for using an aprotic polar solvent such as dimethyl sulfoxide in the prior art when producing the amidoxime compound was presumed as follows. That is, when a protic solvent or the like is used, -OR (R; an alkyl group having 1 to 4 carbon atoms) and -OEt (Et; an ethyl group) in the nitrile compound represented by the formula (1) are subjected to transesterification. And the reaction may be further complicated.

  From this, even if a protic polar solvent is used, if the transesterification does not occur in -OR and -OEt, it may be possible to obtain the above-mentioned amidoxime compound in high yield and high purity. Advanced.

As a result, they have found that the use of a reaction solvent containing a specific alcohol enables the amidoxime compound to be obtained in high yield and high purity, and completed the present invention.
The following equation (1)

(Wherein, R 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:
A hydroxylamine, relative to the nitrile 1 mole of the compound represented by the formula (1) in the presence of 0.01 to 0.5 moles of an organic base,

(Wherein, R has the same meaning as in the above formula (1))
A method for producing an alkyl 2-ethoxy-1-[[2 '-(hydroxyiminocarboxamido) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate represented by the formula:

  Further, in the present invention, in order to be able to produce the high-purity amidoxime compound and to further improve operability, the alcohol is a linear or branched alcohol having 3 to 7 carbon atoms. But preferred. Furthermore, it is preferable to use hydroxyamine and that 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 producing the azilsartan alkyl ester represented by the formula (3) and the azilsartan represented by the formula (4).

  According to the method of the present invention, a high-purity amidoxime compound can be obtained in a high yield by a simpler operation. As a result, by producing an azilsartan alkyl ester and an azilsartan using the amidoxime compound obtained in the present invention, these can also be made to have high purity. In particular, since the purity of azilsartan finally used, which is used as a drug substance, can be increased, its industrial utility value is high.

  The present invention provides the following formula (1)

(Wherein, R is an alkyl group having 1 to 4 carbon atoms)
A nitrile compound represented by
Reacting with hydroxylamine and / or hydroxylamine,
The following equation (2)

(Wherein, R has the same meaning as in the above formula (1))
In producing an amidoxime compound represented by
The reaction is carried out in a reaction solvent containing an alcohol having 2 to 7 carbon atoms. Hereinafter, description will be made 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 solution of alkyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl) methyl] amino] benzoate in ethyl orthocarbonate described in Patent Document 1. At 80 ° C. for 1 hour with stirring (see Patent Document 1, Example 1b).

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

  The hydroxylamine and / or hydroxylamine salt used is not particularly limited, and a commercially available product can be used. Note that “and / or” means, of course, hydroxylamine alone, hydroxylamine salt alone, or a mixture of hydroxylamine and hydroxylamine 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, and hydroxylamine oxalate.
These hydroxylamine salts can be neutralized with a base and used as hydroxylamine.

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

  Among hydroxylamines and / or hydroxylamine salts, it is preferable to use hydroxylamine in order to reduce the nitrile desethyl form and the amide form and increase the purity of the obtained amidoxime compound. When hydroxylamine is used, it is preferable to use an aqueous solution of hydroxylamine, for example, an aqueous solution having a hydroxylamine concentration of 30 to 50% by mass from the viewpoint of availability. The advantages of using hydroxylamine in the present invention are not clear. However, the present inventors believe that since the reaction can proceed under appropriate pH conditions in the present reaction, the purity of the amidoxime compound can be increased. When hydroxylamine is used in the reaction as an aqueous solution, 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 resides in 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 compound and the desethyl compound can be reduced, and the high-purity amidoxime compound 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, 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 and the like. Among them, a linear or branched alcohol having 3 to 7 carbon atoms is preferable in terms of the yield, purity, and the ratio of impurities contained in the obtained amidoxime compound, and finally removing the reaction solvent. . Specifically, 1-propanol, isopropanol, 1-butanol and 2-butanol are preferred, and 1-propanol and 1-butanol are particularly preferred.

  The alcohols exemplified above can be used singly or in a mixture of two or more. When used as a mixture, the basis for the amounts used covers the entire amount of the mixture.

  In the present invention, the reaction solvent may include another solvent as long as it contains an alcohol having 2 to 7 carbon atoms. Specifically, as described above, water when an aqueous hydroxylamine solution is used, water to be newly added, and a solvent compatible with an 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 based on 100% by mass of the total amount of the reaction solvent. Preferred (naturally, the remainder of the reaction solvent is an alcohol having 2 to 7 carbon atoms). The reaction solvent may be an alcohol having a total of 2 to 7 carbon atoms. However, when an aqueous hydroxylamine solution is used for the reaction, the total amount of the reaction solvent is 100 mass%, and the reaction solvent has 2 to 7 carbon atoms. Preferably, the alcohol content is 70 to 99% by mass and the water content is 1 to 30% by mass.

  In the present invention, the amount of the reaction solvent to be used is not particularly limited, and the raw material compounds are sufficiently mixed during the reaction, and the raw material compounds and the produced amidoxime compound are sufficiently dissolved. Use as much as you can. Above all, in order to easily obtain the obtained amidoxime compound as crystals, it is preferable to use 5 to 50 ml, and more preferably 6 to 30 ml, of the reaction solvent per 1 g of the nitrile compound. The amount of the reaction solvent used is the volume at 23 ° C.

(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, in the reaction solvent, the nitrile compound and the hydroxylamine may be stirred and mixed, and the raw material compounds may be brought into contact with each other.

(base)
In the method of the present invention, the contact (reaction) between the two, which are the starting compounds, can be carried out in the 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 and the amidodesethyl 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 alone or a plurality of types can be used at the same time. When a plurality of types are used at the same time, the reference amount is based on the total amount of the plurality of types.

  Among the above bases, it is particularly preferable to use an organic base when it is desired to suppress the by-products of the amide and the amidodesethyl. The use of an organic base also facilitates the removal of the organic base. Among these organic bases, in view of industrial production, it is preferable to use triethylamine, pyridine, and diisopropylethylamine.

  The amount of the base used is not particularly limited, and may be an ordinary amount of the catalyst. In particular, when an organic base is used, the amount of the organic base used is preferably 0.01 to 0.5 mol per 1 mol of the nitrile compound represented by the formula (1). By setting the amount of the organic base to be in the above range, the amount of by-products of the amide and the amidodesethyl can be further suppressed. Furthermore, in order to suppress the by-product amount of the amide compound and the amide desethyl compound, the amount of the organic base used is 0.1 to 1 mol per 1 mol of the nitrile compound represented by the formula (1). It 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 performed under the following conditions.

  When mixing the starting compound, the reaction solvent, and the base to be blended if necessary in the reaction vessel, the procedure for introducing each component into the reaction vessel is not particularly limited. Specifically, a method can be adopted in which the raw material compound, the reaction solvent, and the base to be added as necessary are simultaneously introduced into the reaction vessel. In addition, one of the raw material compounds and the reaction solvent are introduced into the reaction vessel in advance, and then the other raw material compound (which may be diluted with the reaction solvent if necessary) and a base compounded as necessary (Which may be diluted with a reaction solvent) can be introduced into the reaction vessel. At this time, the starting compound to be added later may be introduced in several divided portions. Above all, in order to make the operation easier, first, the nitrile compound and the reaction solvent are charged into a reaction vessel. Next, a base compounded as necessary is introduced, and further, hydroxylamines are introduced. 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 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 a temperature of 50 ° C. or more and the reflux temperature of the reaction solution or less. Since the reflux temperature of the reaction solution varies depending on the type of the reaction solvent used, the concentration of the starting compound, and the like, it cannot be unconditionally limited. However, in order to suppress the decomposition of the amidoxime compound, the temperature of the reaction solution is preferably 50 to 100 ° C or lower, and more preferably 60 to 95 ° C.

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

(Post-processing step)
According to the method, the amidoxime compound can be produced. It is preferable that the amidoxime compound formed in the reaction solution is taken out by cooling the reaction solution or distilling off the reaction solvent to crystallize. Among them, when the temperature of the reaction solution is 50 ° C. or higher and the reflux temperature of the reaction solution or lower, preferably, the temperature is cooled to 30 ° C. or lower, more preferably 10 to 30 ° C. Preferably, crystals of the amidoxime compound are precipitated. Above all, in order to increase the purity of the obtained amidoxime compound, it is preferable that the cooling rate when the temperature is lowered to 30 ° C. or lower from the reaction temperature is 5 to 50 ° C./hour. In order to increase the yield, it is preferable to leave the temperature at 30 ° C. or lower for 1 hour or more, preferably 2 hours to 10 hours.

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

  According to the present invention, the obtained amidoxime compound has a purity of 90.0 to 98.0%, an amide form of 0.1 to 3.0%, and a nitrile desethyl form of 0.0 (undetected) to 0.5. %, The amidoxime desethyl compound 0.1 to 1.0%, and the amidodesethyl compound 0.05 to 1.0%. By further adjusting the conditions, the purity is preferably 94.0 to 98.0%, the amide compound 0.1 to 2.0%, and the nitriledesethyl compound 0.0 (undetected) to 0.1%. And the above-mentioned amidoxime desethyl compound of 0.1 to 1.0% and the above-mentioned amidodesethyl compound of 0.05 to 0.5% can also be used. More preferably, the purity is 94.0-98.0%, the amide compound is 0.1-1.0%, the nitriledesethyl compound is 0.0 (undetected) -0.1%, and the amidoximedesethyl compound is 0. 0.1 to 1.0%, and 0.05 to 0.5% of the above amidodesethyl compound.

  In addition, the purity of the amidoxime compound, the amide form, the nitriledesethyl form, the amidoximedesethyl form, and the amidodesethyl form ratio may include other components. Not something.

  Therefore, the obtained amidoxime compound can be suitably used as a raw 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,
The following equation (3)

(Wherein, R has the same meaning as in the above formula (1))
Can be produced.

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

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

  Further, the following method can be adopted. This is a method described in Non-Patent Document 1 and Patent Document 1. Specifically, first, the amidoxime compound and an alkyl chloroformate (an alkyl group is a protecting group for a hydroxyl group, specifically, a 2-ethylhexyl group or an ethyl group) are converted into an organic base ( By reacting in the presence of dimethylformamide and tetrahydrofuran / dichloromethane in the presence of pyridine or triethylamine), the following formula (5)

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

  The obtained azilsartan alkyl ester is not particularly limited, and is described in Org. Process. Res. Dev 2013, 17, Non-Patent Literature 1, and Patent Literature 1 may be used for purification or the like.

  Specifically, a method of recrystallizing from acetone, ethyl acetate, ethyl acetate / isopropyl ether, or chloroform / ethyl acetate can be mentioned. In order to further increase the purity of the obtained 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,
The following equation (4)

Can be produced. Conditions for the hydrolysis are not particularly limited, and a known method, for example, a method described in Patent Document 1 can be adopted. Specifically, -OMe may be converted to a hydroxyl group by performing hydrolysis in the presence of a base or an acid.

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

  Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is a specific example 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).

<HPLC measurement conditions>
Apparatus: High Performance Liquid Chromatography (HPLC).
Model: 2695-2489-2998 (Waters).
Detector: UV absorption spectrophotometer (measuring wavelength: 210 nm).
Column: Kromasil C18, inner diameter 4.6 mm, length 15 cm (particle diameter 5 μm) (manufactured by AkzoNobel).
Column temperature: constant at 30 ° C.
Sample temperature: constant at 25 ° C.
Mobile phase A: acetonitrile.
Mobile phase B: 15 mM aqueous solution of potassium dihydrogen phosphate (adjusted with pH = 2.5 phosphoric acid).
Mobile phase liquid feeding: 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: 40 minutes.

  Under the above conditions, the amidoxime desethyl form is about 1.8 minutes, the amidoxime compound is about 2.8 minutes, the amidodesethyl form is about 4.0 minutes, the amide form is about 8.5 minutes, and the nitrile is A peak is observed at about 11.2 minutes for the desethyl form, about 25.0 minutes for the nitrile compound, about 14.5 minutes for the azilsartan methyl ester, and about 7.3 minutes for the azilsartan. In the following Examples and Comparative Examples, each purity of the amidoxime compound, the azilsartan methyl ester, and the azilsartan is the sum of the area values of all peaks measured under the above conditions (excluding peaks derived from solvents). It is a ratio of the peak area value of each compound with respect to.

Reference Example 1
5 g (12.2 mmol) of the nitrile compound was weighed and placed in a 100 mL three-necked flask equipped with two stirring blades having a diameter of 2.5 cm, and 50 mL of 1-propanol, 4.0 g of a commercially available 50% by mass aqueous hydroxylamine solution (60. 8 mmol), and the mixture was heated to the reflux temperature (about 92 ° C.) and reacted at the same temperature for 12 hours. The amidoxime compound purity: 82.2%, the amide form: 9.1%, the nitrile compound: 2.2%, the amidoxime desethyl form: 6.0%, the amidodesethyl form: 0.3%, The 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. Then, the obtained slurry liquid was filtered under reduced pressure, and the precipitated crystals were collected and dried at 50 ° C., and 4.0 g of the crystals of the amidoxime compound (purity of the amidoxime compound: 94.7%, Compound: 3.0%, the nitrile compound: 0.2%, the amidoximedesethyl compound: 0.7%, the amidodesethyl compound: 0.3%, and the nitriledesethyl compound: 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 and placed in 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 50% by mass of commercially available hydroxyl After 56.2 g (850.5 mmol) of an aqueous amine solution was added and heated to a reflux temperature (about 92 ° C.), a reaction was carried out at the same temperature for 13 hours. Purity of the amidoxime compound: 83.9%, the amide compound: 2.4%, the nitrile compound: 2.4%, the amidoxime desethyl compound: 7.6%, and the amidodesethyl compound: 0.2% And the above-mentioned nitrile desethyl compound: 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. Then, the obtained slurry liquid was filtered under reduced pressure, and the precipitated crystals were collected and dried at 50 ° C. to obtain 61.0 g of crystals of the amidoxime compound (purity of the amidoxime compound: 96.9%, (0.5%), the nitrile compound: 0.1%, the amidoxime desethyl compound: 0.5%, the amidodesethyl compound: 0.1%, and the nitrile desethyl compound: undetected). (Yield: 81.0%). The results are summarized in Tables 2 and 3.

Example 3
5 g (12.2 mmol) of the nitrile compound is weighed and placed in a 100 mL three-necked flask equipped with two stirring blades having a diameter of 2.5 cm, 50 mL of 1-propanol, 0.62 g (6.1 mmol) of triethylamine, and 50% by mass of a commercially available product After adding 4.0 g (60.8 mmol) of an aqueous hydroxylamine solution and heating to a 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 form: 1.8%, the nitrile compound: 2.6%, the amidoxime desethyl form: 7.4%, and the amidodesethyl form: 0.2% And the above-mentioned nitrile desethyl compound: 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 liquid was filtered under reduced pressure, and the precipitated crystals were separated and dried at 50 ° C., and 4.1 g of the crystals of the amidoxime compound (purity of the amidoxime compound: 97.1%, Compound: 0.3%, the nitrile compound: 0.1%, the amidoxime desethyl compound: 0.5%, the amidodesethyl compound: 0.1%, and the nitrile desethyl compound: 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 the 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 above amidodesethyl derivative: 0.1% and the above nitrile desethyl derivative: not detected) were 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 used base was changed from triethylamine to pyridine, and the used amount of the base was changed from 0.62 g (6.1 mmol) to 0.37 g (3.66 mmol).

  4.3 g of the 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 above amidodesethyl derivative: 0.1% and the above nitrile desethyl derivative: not detected) were obtained (yield: 79.4%). The results are summarized in Tables 2 and 3.

Example 6
The same operation was performed as in Example 3, except that the used amount of triethylamine 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 above amidodesethyl derivative: 0.3% and the above nitrile desethyl derivative: not detected) were obtained (yield: 80.2%). The results are summarized in Tables 2 and 3.

Reference Example 7
A similar operation was performed in Example 1 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 above amidodesethyl derivative: 0.3% and the above nitrile desethyl derivative: 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 and placed in a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, 350 mL of dimethyl sulfoxide, 17.5 g of 1,1′-carbonylimidazole, and 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 and placed in a separately prepared 3 L three-necked flask, and the reaction solution was slowly dropped. The pH of the resulting solution was adjusted to about 4 by adding a 5% aqueous hydrochloric acid solution. Crystals of the precipitated azilsartan methyl ester were separated by filtration under reduced pressure, dried at 50 ° C., and 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)
20 g of the azilsartan methyl ester obtained in Example 8 was weighed into a 1 L three-necked flask equipped with two stirring blades having a diameter of 10 cm, 200 mL of a 1.25 M aqueous sodium hydroxide solution was added, and the mixture was heated to 50 ° C. The reaction was performed 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 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 5 hours. Next, the obtained slurry liquid 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)
5 g (12.2 mmol) of the nitrile compound was weighed and placed in a 500 mL three-necked flask equipped with two stirring blades having a diameter of 7.5 cm, and 50 mL of dimethyl sulfoxide, 4.2 g (60.8 mmol) of hydroxylamine hydrochloride, and triethylamine 6 After adding .15 g (60.8 mmol) and heating to 90 ° C., the reaction was carried out at the same temperature for 16 hours. The amidoxime compound purity: 42.6%, the amide form: 37.0%, the nitrile compound: 4.5%, the amidoxime desethyl form: 9.3%, the amidodesethyl form: 4.8%, The nitrile desethyl compound was 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. Then, the obtained slurry liquid was filtered under reduced pressure, and the precipitated crystals were collected and dried at 50 ° C., and 3.1 g of the crystals of the amidoxime compound (purity of the amidoxime compound: 49.9%, Isomer: 46.4%, the nitrile compound: 0.5%, the amidoximedesethyl form: 1.7%, the amidodesethyl form: 0.9%, and the nitriledesethyl form: 0.1%) Was obtained (yield: 57.1%). The results are summarized in Tables 2 and 3.

Comparative Example 2 (Production of amidoxime compound by method described in Patent Document 2)
5 g (12.2 mmol) of the nitrile compound is weighed and placed in a 500 mL three-necked flask equipped with two stirring blades having a diameter of 7.5 cm, 50 mL of dimethyl sulfoxide, and 2.0 g (30.4 mmol) of a 50% by mass aqueous hydroxylamine solution available on the market. ) Was added and the mixture was heated to 90 ° C. and reacted 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%, and the amidodesethyl form: 1.0% , The nitrile desethyl compound: 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. Then, the obtained slurry was filtered under reduced pressure, and the precipitated crystals were collected and dried at 50 ° C., and 4.2 g of the crystals of the amidoxime compound (purity of the amidoxime compound: 85.7%, the amide compound) : 5.1%, the nitrile compound: 0.5%, the amidoximedesethyl form: 5.9%, the amidodesethyl form: 0.4%, and the nitriledesethyl form: 0.1%). (Yield: 78.8%). The results are summarized in Tables 2 and 3.

Claims (6)

The following equation (1)

(Wherein, R 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:
A hydroxylamine, relative to the nitrile 1 mole of the compound represented by the formula (1) in the presence of 0.01 to 0.5 moles of an organic base,
By reacting in a reaction solvent containing an alcohol having 2 to 7 carbon atoms,
The following equation (2)

(Wherein, R has the same meaning as in the above formula (1))
A method for producing an alkyl 2-ethoxy-1-[[2 '-(hydroxyiminocarboxamido) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate represented by the formula: The method according to claim 1, wherein the alcohol is a linear or branched alcohol having 3 to 7 carbon atoms. The method according to claim 2, wherein the alcohol is at least one selected from 1-propanol, isopropanol, 1-butanol, and 2-butanol. The method according to any one of claims 1 to 3, wherein the reaction solvent One or is characterized in that it comprises water. After preparing amidoxime compound represented by the formula (2) by the method according to any one of claims 1-4, the following formula from the obtained amidoxime compound (3)

(Wherein, R has the same meaning as in the above formula (1))
Alkyl 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole represented by A method for producing -7-carboxylate. After producing the azilsartan alkyl ester represented by the formula (3) by the method according to claim 5 , by hydrolyzing the obtained azilsartan alkyl ester,
The following equation (4)

2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole represented by A method for producing 7-carboxylic acid.