WO2017209035A1 - Method for producing biphenyl benzimidazole derivative - Google Patents

Abstract

[Problem] To provide a production method capable of inhibiting production of byproducts, etc., and improving the yield of a biphenyl benzimidazole derivative which is the intended product. [Solution] A method for producing a biphenyl benzimidazole derivative represented by by reacting, in the presence of a base, a benzimidazole derivative represented by (R¹ represents a C1-6 alkyl group, and R² represents a C1-6 alkyl group, a cilexetil group, or a medoxomil group) with a biphenyl compound represented by (R^A represents a cyano group or a 1-trityl-1H-tetrazole-5-yl group, and X represents a halogen atom), wherein the reaction is carried out in a reaction solvent containing a branched alcohol represented by (R³, R⁴, and R⁵ each represent a hydrogen atom, a C1-6 alkyl group, or the like. However, two or more groups among R³-R⁵ would not simultaneously be a hydrogen atom).

Description

Method for producing biphenylbenzimidazole derivative

The present invention relates to a novel method for producing biphenylbenzimidazole derivatives useful as pharmaceutical intermediates.

Sultan based drug substances such as candesartan and azilsartan are used as antihypertensive agents, and their utility value is extremely high. These sultan based drug substances have a structure represented by the following formula.

　式中、Ｒ、Ｒ’、Ｒ’’、およびｚは、それぞれ該当する原薬によって異なる。例えば、Ｒがテトラゾール－５－イル基であり、Ｒ’がエトキシ基であり、Ｒ’’が７－（シレキセチルオキシカルボニル）基である場合には、前記原薬はカンデサルタンシレキセチルである。また、Ｒが５－オキソ－２，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル基であり、Ｒ’がエトキシ基であり、Ｒ’’がカルボキシル基である場合には、前記原薬はアジルサルタンである。さらには、Ｒが５－オキソ－２，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル基であり、Ｒ’がエトキシ基であり、Ｒ’’がメドキソミルオキシカルボニル基である場合には、前記原薬はアジルサルタンメドキソミルである。

In the formula, R, R ′, R ″, and z differ depending on the corresponding drug substance. For example, when R is a tetrazol-5-yl group, R ′ is an ethoxy group, and R ″ is a 7- (cilexetyloxycarbonyl) group, the drug substance is candesartan cilexetil. is there. When R is a 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl group, R ′ is an ethoxy group, and R ″ is a carboxyl group The drug substance is azilsartan. Furthermore, R is a 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl group, R ′ is an ethoxy group, and R ″ is a medoxomiloxycarbonyl group. In some cases, the drug substance is azilsartan medoxomil.

These drug substances have a complicated structure and are synthesized through many processes. For example, candesartan cilexetil is produced by a method represented by the following reaction formula (see Patent Document 1, etc.).

　このような原薬を製造する工程においては、その中間体を製造する工程も重要となる。すなわち、最終的に得られる原薬は、数多くの工程を経て得られるため、各中間体の収率、純度等が原薬の品質、又は製造コストに大きく影響する。そのため、該中間体の製造方法についても様々な検討がなされている。

In the process for producing such a drug substance, the process for producing the intermediate is also important. That is, since the drug substance finally obtained is obtained through many steps, the yield and purity of each intermediate greatly affect the quality of the drug substance or the manufacturing cost. For this reason, various investigations have been made on the method for producing the intermediate.

For example, the following formula, which is an intermediate of sultan based drug substance

で示される一種のシアノビフェニルベンズイミダゾール誘導体は、カンデサルタンシレキセチル、アジルサルタン、アジルサルタンメドキソミルの中間体として使用できる、非常に有用な化合物である（例えば、特許文献２参照）。

Is a very useful compound that can be used as an intermediate of candesartan cilexetil, azilsartan, and azilsartan medoxomil (see, for example, Patent Document 2).

Many production methods are known for the cyanobiphenylbenzimidazole derivative represented by the above formula (see, for example, Non-Patent Document 1). Specifically, Patent Document 2 and Non-Patent Document 1 describe processes for carrying out reactions of nitration, Curtius rearrangement, cyanobiphenylation, reduction, and cyclization from o-phthalic acid. . In this method, each reaction is performed on the compound obtained in the previous step, and there are problems such as a decrease in total yield and an increase in cost due to an increase in the basic unit of expensive reagents. Therefore, it has been desired to develop an inexpensive manufacturing method that reduces the number of continuous steps.

Therefore, the compounds as raw materials are synthesized separately, and the resulting compounds (raw materials compounds) react with each other. As a reaction with few steps, a benzimidazole derivative and a biphenyl compound (cyanobiphenyl bromide) represented by the following reaction formula are used. Has been proposed (see, for example, Patent Documents 3 and 4).

　具体的には、特許文献３、および４には、前記ベンズイミダゾール誘導体と前記シアノビフェニルブロマイドとを、塩基存在下、メタノール、又はエタノール中で反応させて前記シアノビフェニルベンズイミダゾール誘導体を製造する方法が示されている。

Specifically, Patent Documents 3 and 4 include a method for producing the cyanobiphenylbenzimidazole derivative by reacting the benzimidazole derivative and the cyanobiphenyl bromide in the presence of a base in methanol or ethanol. It is shown.

In order to further reduce the number of steps, there is also known a method of reacting a compound in which a cyano group is replaced with a tetrazolyl group protected with a triphenyl group in the biphenyl compound and the benzimidazole derivative (Patent Document). 5, see Non-Patent Document 1). Specifically, a method is described in which this reaction is carried out in dimethylformamide in the presence of a base.

Further, in the biphenyl compound, a compound in which a cyano group is replaced with a tetrazolyl group protected with a benzyl group and the benzimidazole derivative are mixed with an alcohol (for example, methanol or isopropyl alcohol), dimethylformamide, dimethyl in the presence of a base. A method of reacting in a solvent such as acetamide is also known (see Non-Patent Document 2, Patent Documents 6 and 7). In Patent Document 6, a trityl group is also mentioned as a protective group.

Patent No. 2514282 International Publication No. 2013/114305 Chinese Patent Application No. 1027616638 International Publication No. 2006/015134 Chinese Patent Application No. 1013223610 International Publication No. 2014/034868 International Publication No. 2014/051008

Journal of Medicinal Chemistry, 1993, Vol. 36, No. 15 ACS Catalysis 2014, 4 (11) 4047-4050

As described above, by using a biphenyl compound, the biphenylbenzimidazole derivative can be produced with fewer steps.

However, the conventional method has a problem that the yield of the biphenylbenzimidazole derivative is low.

When the present inventors examined the problem, the following factors were considered. That is, in the methods described in Patent Documents 3 and 4, the reaction is carried out in a reaction solvent of methanol or ethanol. However, by reacting the cyanobiphenyl bromide with these reaction solvents, a byproduct (hereinafter referred to as a by-product) , Which is sometimes referred to as “ether by-product”). That is, in the said method etc., since it is necessary to remove this ether by-product, it was thought that the yield of the target cyano biphenyl benzimidazole derivative falls. For the above reasons, the method and the like require a large amount of cyanobiphenyl bromide, and the method and the like have room for improvement in this respect.

In addition, in the above method or the like, a cyanobiphenyl compound is bonded to a nitrogen atom which is not a nitrogen atom to be reacted with a cyanobiphenyl compound among the two nitrogen atoms of the benzimidazole derivative.

で示される異性体の生成割合が多くなる場合があることが確認された。この異性体は、目的物と類似の化合物であるため、この異性体を含むまま次の反応に進むと、さらに目的物とは異なる不純物が副生されることになる。そのため、このような異性体は、中間体であってもその副生量が少ないことが望まれる。

It was confirmed that the production rate of the isomer represented by may increase. Since this isomer is a compound similar to the target product, when the next reaction is carried out with the isomer included, impurities different from the target product are further generated as a by-product. Therefore, it is desired that such an isomer has a small amount of by-product even if it is an intermediate.

Patent Documents 3 and 4 do not describe that the obtained cyanobiphenylbenzimidazole derivative contains the ether by-product. Patent Document 3 also does not describe that the obtained cyanobiphenylbenzimidazole derivative contains the isomer. However, according to the study by the present inventors, in the above method and the like, the ether by-product is often present in the reaction solution before taking out the cyanobiphenylbenzimidazole derivative from the reaction system, that is, after completion of the reaction. It was confirmed that the isomer was also contained. In the above method and the like, it is considered that a crystallization method in which the loss of the cyanobiphenylbenzimidazole derivative is increased in order to remove this ether by-product and isomers.

The above-mentioned problem of isomers also occurred in the methods described in Patent Document 5 and Non-Patent Document 1 described above, and there was room for improvement as well.

Also, in the methods described in Non-Patent Document 2, Patent Documents 6 and 7, the above-mentioned problem of ether by-products and the problem of isomers may occur. In addition, in these methods, since a raw material compound having a benzyl group is used as a protecting group, a hydrogen source such as hydrogen gas or formic acid is used in the deprotection reaction performed in the final step of the drug substance production. It was necessary to use ammonium / palladium metal or the like. For this reason, when industrial production of candesartan cilexetil is carried out, it is possible to prevent the explosion of hydrogen gas and enhance safety, or to prevent the introduction of harmful metals into the final product (the drug substance). Therefore, there is room for improvement in that strict control is required.

Therefore, an object of the present invention is to provide a production method capable of suppressing the production of the ether by-product and improving the yield of the target biphenylbenzimidazole derivative.

The inventors of the present invention made extensive studies to solve the above problems. First, in order to facilitate a deprotection reaction or reaction in a post-process (ie, a process after manufacturing the biphenylbenzimidazole in the manufacture of the drug substance), the biphenyl compound is converted to a cyano group or 1-trityl- Various studies were conducted focusing on compounds having a 1H-tetrazol-5-yl group. Various studies were conducted to suppress the production of the ether by-product and isomer. In particular, a reaction solvent that hardly reacts with the biphenyl bromide (halide) and that can increase the yield of the biphenylbenzimidazole derivative was examined. As a result, it has been found that the production of ether by-products can be suppressed by using a reaction solvent containing at least a secondary or tertiary branched alcohol having a specific structure. In addition, it has been found that if the conditions are adjusted, the selectivity of the target product (that is, the ratio of the target product to the target product and the isomer) can be improved, and the reaction time can be shortened, thereby completing the present invention. It was.

That is, the first aspect of the present invention is
(1) in the presence of a base,
Following formula (1)

（式中、Ｒ¹は、炭素数１～６のアルキル基であり、
　Ｒ²は、炭素数１～６のアルキル基、シレキセチル基、又はメドキソミル基である。）
で示されるベンズイミダゾール誘導体と、
　下記式（２）

(Wherein R ¹ is an alkyl group having 1 to 6 carbon atoms,
R ² is an alkyl group having 1 to 6 carbon atoms, a cilexetil group, or a medoxomil group. )
A benzimidazole derivative represented by
Following formula (2)

（式中、Ｒ^Aは、シアノ基、又は１－トリチル－１Ｈ－テトラゾール－５－イル基であり、
　Ｘは、ハロゲン原子である。）
で示されるビフェニル化合物とを反応させて、
　下記式（３）

(Wherein R ^A is a cyano group or a 1-trityl-1H-tetrazol-5-yl group;
X is a halogen atom. )
Is reacted with a biphenyl compound represented by
Following formula (3)

（式中、Ｒ¹、およびＲ²は、前記式（１）におけるものと同義であり、
　Ｒ^Aは、前記式（２）におけるものと同義である。）
で示されるビフェニルベンズイミダゾール誘導体を製造する方法であって、
　前記の反応が、下記式（４）

(Wherein R ¹ and R ² have the same meanings as in formula (1),
R ^A has the same meaning as in formula (2). )
A method for producing a biphenylbenzimidazole derivative represented by
Said reaction is represented by the following formula (4):

（式中、Ｒ³、Ｒ⁴、およびＲ⁵は、それぞれ、水素原子、炭素数１～６のアルキル基、炭素数７～１２のアラルキル基、又は炭素数２～１２のアルキルオキシアルキル基である。ただし、Ｒ³、Ｒ⁴、およびＲ⁵の内、２つ以上の基が同時に水素原子となることはない。）
で示される分岐アルコールを含む反応溶媒中で行われるビフェニルベンズイミダゾール誘導体の製造方法である。

(Wherein R ³ , R ⁴ , and R ⁵ are each a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an alkyloxyalkyl group having 2 to 12 carbon atoms) (However, two or more of R ³ , R ⁴ , and R ⁵ are not hydrogen atoms at the same time.)
The manufacturing method of the biphenyl benzimidazole derivative performed in the reaction solvent containing the branched alcohol shown by these.

The first aspect of the present invention can take the following aspects.

(2) The branched alcohol is at least one selected from the group consisting of isopropyl alcohol, 2-butanol, t-butanol, 2-pentanol, and 3-pentanol.

(3) The branched alcohol is a secondary alcohol.

(4) The reaction solvent further contains a polar solvent (excluding the branched alcohol represented by the formula (4)).

(5) The reaction is represented by the following formula (5)

（式中、Ｒ⁶は、炭素数１～１２のアルキル基であり、複数のＲ⁶は、互いに同一の基であっても、異なる基であってもよい。）
で示されるヨウ素触媒の存在下で行われる。

(Wherein R ⁶ is an alkyl group having 1 to 12 carbon atoms, and the plurality of R ⁶ may be the same group or different groups.)
Is carried out in the presence of an iodine catalyst.

The second aspect of the present invention is
(6) A step of producing the biphenylbenzimidazole derivative by the production method of any one of (1) to (5),
The benzimidazole derivative is represented by the following formula (1 ′)

（式中、Ｅｔはエチル基であり、Ｒ²は炭素数１～６のアルキル基である。）
で示されるベンズイミダゾール誘導体であり、
　前記ビフェニル化合物が下記式（２’）

(In the formula, Et is an ethyl group, and R ² is an alkyl group having 1 to 6 carbon atoms.)
A benzimidazole derivative represented by
The biphenyl compound is represented by the following formula (2 ′)

（式中、Ｔｒはトリフェニルメチル基（「トリチル基」とも記載する。）であり、Ｘは前記式（２）におけるものと同義である。）
で示されるビフェニル化合物であり、
　前記ビフェニルベンズイミダゾール誘導体が下記式（３’）

(In the formula, Tr is a triphenylmethyl group (also referred to as “trityl group”), and X has the same meaning as in formula (2).)
A biphenyl compound represented by
The biphenylbenzimidazole derivative is represented by the following formula (3 ′)

（式中、Ｅｔはエチル基であり、Ｔｒはトリフェニルメチル基であり、Ｒ²は炭素数１～６のアルキル基である。）
で示されるカンデサルタン中間体である工程、
　前記カンデサルタン中間体のエステル基を加水分解することにより、下記式（６）

(In the formula, Et is an ethyl group, Tr is a triphenylmethyl group, and R ² is an alkyl group having 1 to 6 carbon atoms.)
A process which is a candesartan intermediate represented by
By hydrolyzing the ester group of the candesartan intermediate, the following formula (6)

（式中、Ｅｔはエチル基であり、Ｔｒはトリフェニルメチル基である。）
で示されるトリチルカンデサルタン（以下、単に「トリチルカンデサルタン」と記載する場合もある。）を製造する工程、ならびに
　前記トリチルカンデサルタンにシレキセチル基を導入することにより、下記式（７）

(In the formula, Et is an ethyl group, and Tr is a triphenylmethyl group.)
A process for producing trityl candesartan represented by the formula (hereinafter sometimes simply referred to as “trityl candesartan”), and by introducing a cilexetil group into the trityl candesartan, the following formula (7):

（式中、Ｅｔはエチル基であり、Ｔｒはトリフェニルメチル基である。）
で示されるトリチルカンデサルタンシレキセチルを製造する工程
を含むトリチルカンデサルタンシレキセチルの製造方法
である。

(In the formula, Et is an ethyl group, and Tr is a triphenylmethyl group.)
It is a manufacturing method of a trityl candesartan cilexetil including the process of manufacturing the trityl candesartan cilexetil shown by these.

The third aspect of the present invention is
(7) The step of producing the trityl candesartan cilexetil by the production method of (6), and detritylating the trityl candesartan cilexetil, the following formula (8)

で示されるカンデサルタンシレキセチルを製造する工程
を含むカンデサルタンシレキセチルの製造方法である。

It is a manufacturing method of candesartan cilexetil including the process of manufacturing the candesartan cilexetil shown by these.

The fourth aspect of the present invention is
(8) A step of producing the biphenylbenzimidazole derivative by the production method of any one of (1) to (5),
The benzimidazole derivative is represented by the following formula (1 ′)

（式中、Ｅｔはエチル基であり、Ｒ²はシレキセチル基である。）
で示されるベンズイミダゾール誘導体であり、
　前記ビフェニル化合物が下記式（２’）

(In the formula, Et is an ethyl group, and R ² is a cilexetil group.)
A benzimidazole derivative represented by
The biphenyl compound is represented by the following formula (2 ′)

（式中、Ｔｒはトリフェニルメチル基であり、Ｘは前記式（２）におけるものと同義である。）
で示されるビフェニル化合物であり、
　前記ビフェニルベンズイミダゾール誘導体が下記式（７）

(In the formula, Tr is a triphenylmethyl group, and X has the same meaning as in formula (2).)
A biphenyl compound represented by
The biphenylbenzimidazole derivative is represented by the following formula (7)

（式中、Ｅｔはエチル基であり、Ｔｒはトリフェニルメチル基である。）
で示されるトリチルカンデサルタンシレキセチルである工程、および
　前記トリチルカンデサルタンシレキセチルを脱トリチル化することにより、下記式（８）

(In the formula, Et is an ethyl group, and Tr is a triphenylmethyl group.)
And a step of detritylating the trityl candesartan cilexetil represented by the following formula (8):

で示されるカンデサルタンシレキセチルを製造する工程
を含むカンデサルタンシレキセチルの製造方法である。

It is a manufacturing method of candesartan cilexetil including the process of manufacturing the candesartan cilexetil shown by these.

According to the method of the present invention, a biphenylbenzimidazole derivative, which is an intermediate of a sultan based drug substance such as candesartan or azilsartan, can be obtained in a state where the conversion rate of the benzimidazole derivative is high and the ether by-product is small. Can do. That is, a biphenylbenzimidazole derivative can be obtained with a high yield. As a result, by producing the sultan based drug substance from the biphenylbenzimidazole derivative obtained by the method of the present invention, it is possible to efficiently increase the yield and purity of the drug substance and reduce the cost.

Further, when a biphenyl compound having a 1-trityl-1H-tetrazol-5-yl group is used as the biphenyl compound represented by the formula (2), candesartan cilexetil can be produced in a shorter process. According to the fourth aspect of the present invention, candesartan cilexetil can be produced in a particularly short process.

In the present invention, in the presence of a base, a benzimidazole derivative represented by the above formula (1) (hereinafter sometimes simply referred to as “benzimidazole derivative”) and a biphenyl compound represented by the above formula (2) ( Hereinafter, it may be simply referred to as “biphenyl compound”) and may be described as a biphenylbenzimidazole derivative represented by the above formula (3) (hereinafter simply referred to as “biphenylbenzimidazole derivative”). In the reaction solvent containing a branched alcohol having a specific structure (hereinafter, this reaction is also referred to as “the reaction of the present invention”). It is characterized by doing. Hereinafter, the present invention will be described in order.

(Raw compound: benzimidazole derivative)
The starting compound benzimidazole derivative used in the present invention has the following formula (1):

で示される。

Indicated by

In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms. Among these, an ethyl group is preferable in consideration of the usefulness and ease of use of the obtained biphenylbenzimidazole derivative.

In the formula, R ² is an alkyl group having 1 to 6 carbon atoms, a cilexetil group, or a medoxomil group. Among these, considering the usefulness of the obtained biphenylbenzimidazole derivative, ease of use, and productivity of the benzimidazole derivative itself, R ² is preferably an alkyl group having 1 to 6 carbon atoms, A methyl group or an ethyl group is particularly preferable.

In the present invention, the “silexetyl group”

（右端の直線は、隣接する原子への結合を示す。）
で表される基をいう。なお、他の化学式においては、メチル基を－ＣＨ₃と表記せず、単に－と表記している。

(The straight line at the right end indicates a bond to an adjacent atom.)
The group represented by these. In other chemical formulas, the methyl group is not represented as —CH ₃ but simply represented as —.

The benzimidazole derivative represented by the formula (1) is a known compound and can be produced according to a known method.

(Raw compound; Biphenyl compound)
The other raw material biphenyl compound used in the present invention has the following formula (2):

（式中、Ｒ^Aは、シアノ基、又は１－トリチル－１Ｈ－テトラゾール－５－イル基であり、
　Ｘは、ハロゲン原子である。）
で示されるビフェニル化合物である。

(Wherein R ^A is a cyano group or a 1-trityl-1H-tetrazol-5-yl group;
X is a halogen atom. )
It is a biphenyl compound shown by these.

In the case where R ^A is a cyano group, the biphenyl compound has the following formula (2 ″)

（式中、Ｘはハロゲン原子である。）
で示される化合物（以下「シアノビフェニル化合物」と記載する場合もある。）である。

(In the formula, X is a halogen atom.)
(Hereinafter also referred to as “cyanobiphenyl compound”).

The biphenyl compound has the following formula (2 ′) when R ^A is a 1-trityl-1H-tetrazol-5-yl group:

（式中、Ｘはハロゲン原子であり、Ｔｒはトリフェニルメチル基（すなわち、トリチル基）である。）
で示される化合物（以下「テトラゾリルビフェニル化合物」と記載する場合もある。）である。

(In the formula, X is a halogen atom, and Tr is a triphenylmethyl group (that is, a trityl group).)
(Hereinafter also referred to as “tetrazolylbiphenyl compound”).

Considering the productivity of the biphenyl compound itself and the reactivity of the reaction of the present invention, the halogen atom X in the formula (2) is preferably a bromine atom or a chlorine atom, more preferably a bromine atom.

The biphenyl compound (2) is a known compound and can be produced according to a known method.

In the present invention, the amount of the biphenyl compound used is not particularly limited, but is preferably 0.8 to 5 moles, preferably 0.9 to 2.0 moles per mole of the benzimidazole derivative. More preferably, the molar amount is 1.0 to 1.5 mol. According to the present invention, since the reaction between the reaction solvent and the biphenyl compound can be suppressed, the amount of the biphenyl compound used can be reduced.

(Biphenyl compound: Cyanobiphenyl compound)
In the present invention, advantages of using the cyanobiphenyl compound are as follows.

When the cyanobiphenyl compound is used, the resulting product is a cyanobiphenylbenzimidazole derivative having a cyano group. As will be described in detail below, the cyanobiphenylbenzimidazole derivative is an intermediate of various sultan based drug substances, and once this intermediate is manufactured, this intermediate is manufactured with various sultan based drug substances. be able to. Therefore, its usefulness is high.

Further, according to the method of the present invention, since the cyano group in the cyanobiphenyl compound usually does not react, there is no increase in by-products or impurities due to the reaction of the cyano group.

(Biphenyl compound: tetrazolyl biphenyl compound)
In the present invention, the advantages of using the tetrazolylbiphenyl compound are as follows.

When the tetrazolylbiphenyl compound is used, the product obtained is a biphenylbenzimidazole derivative having a tetrazolyl group protected with a trityl group. In the reaction of the present invention, since the reaction of the detrityl group of the tetrazolylbiphenyl compound is difficult to occur, it will be described in detail below, but according to the second invention, or the third or fourth invention, side reaction Trityl candesartan cilexetil or candesartan cilexetil can be produced in a small number of steps and in a small number of steps.

(base)
In the present invention, the reaction between the raw material compounds is carried out in the presence of a base. Making the reaction system in the presence of a base can be achieved by adding a base to the reaction system.

As the base used in the present invention, an inorganic base, for example, an inorganic base containing an alkali metal, an organic base, or the like can be used without any limitation. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium carbonate, calcium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, Bases containing alkali metals such as cesium hydroxide, lithium hydride, sodium hydride, potassium hydride, sodium t-butoxide, potassium t-butoxide,
Examples include organic bases such as pyridine, N, N-dimethylaminopyridine, triethylamine, diisopropylethylamine, N, N-dimethylaniline, quinoline, tetrabutylammonium hydroxide, and benzyldimethylammonium hydroxide. These bases can be used individually by 1 type, and can also use multiple types.

Of these, alkali metal carbonates such as potassium carbonate and sodium carbonate are preferred in consideration of reactivity, availability, and ease of subsequent processing. Among these, potassium carbonate is preferable in order to obtain the target biphenylbenzimidazole derivative with high yield.

The amount of the base used is not particularly limited, but considering the reactivity, ease of treatment in the subsequent steps, etc., it is 0.5 to 10 mol with respect to 1 mol of the benzimidazole derivative. Preferably, the amount is 1.0 to 5.0 mol. In addition, the usage-amount of the said base is based on the total number of moles, when multiple types of base are used.

(Other catalysts)
In the present invention, in order to shorten the reaction time, in addition to the base, the following formula (5)

で示されるヨウ素触媒を反応系内に存在させることが好ましい。

It is preferable that the iodine catalyst shown by these is present in the reaction system.

In the formula (5), I represents an iodine atom, and N represents a nitrogen atom.

R ⁶ is an alkyl group having 1 to 12 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms, and the plurality of R ⁶ may be the same group or different groups.

Among such iodine catalysts, in view of availability, tetramethylammonium iodide, tetraethylammonium iodide, tetra-n-butylammonium iodide, benzyltrimethylammonium iodide, or the like can be used. preferable. These iodine catalysts can be used alone or in a plurality of types. Among these, it is preferable to use tetra-n-butylammonium iodide in consideration of reactivity, ease of processing in the subsequent process, cost, and the like.

In the present invention, when the iodine catalyst is used, the amount of the iodine catalyst used is 0.1% with respect to 1 mol of the benzimidazole derivative in consideration of reactivity, ease of treatment in the subsequent step, and the like. The amount is preferably 001 to 1.0 mol, more preferably 0.01 to 0.1 mol. In addition, the usage-amount of the said iodine catalyst is based on the total number of moles, when multiple types of iodine catalysts are used.

(Reaction solvent)
(Branched alcohol)
A feature of the present invention is that the reaction between the two raw material compounds is represented by the following formula (4) in the presence of the base and the iodine catalyst used as necessary.

で示される分岐アルコールを含む反応溶媒中で実施することにある。

It carries out in the reaction solvent containing the branched alcohol shown by these.

In the formula, each of R ³ , R ⁴ , and R ⁵ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an alkyloxyalkyl group having 2 to 12 carbon atoms. However, R ³ , R ⁴ , and R ⁵ are groups in which two or more groups are not hydrogen atoms at the same time. In other words, the branched alcohol represented by the formula (4) includes at least a group selected from an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, and an alkyloxyalkyl group having 2 to 12 carbon atoms. A secondary or tertiary alcohol having one. These branched alcohols can be used singly or as a mixture of plural kinds.

In consideration of the yield of the obtained biphenylbenzimidazole derivative, ease of post-treatment, etc., groups other than hydrogen atoms in R ³ , R ⁴ and R ⁵ include methyl group, ethyl group, n-propyl group, An isopropyl group, n-butyl group, methoxymethyl group, ethoxymethyl group, n-butoxymethyl group and the like are preferable.

As the alcohol (4), from the viewpoint of increasing the production rate of the biphenylbenzimidazole derivative, if the tetrazolylbiphenyl compound is used, from the viewpoint of further suppressing detritylation, the number of carbon atoms of 3 to 6 Secondary alcohols or tertiary alcohols are preferable, and secondary alcohols having 3 to 6 carbon atoms are particularly preferable.

Among the above branched alcohols, specifically, isopropyl alcohol (2-propanol), 2-butanol, t-butanol, 2-pentanol, 3-pentanol, 1-methoxy-2-propanol, 1-ethoxy- 2-Propanol, 1-butoxy-2-propanol is preferably used. Among these, isopropyl alcohol, 2-butanol, t-butanol, 2-pentanol, or 3-pentanol is more preferable, and 2-butanol is a yield of biphenylbenzimidazole derivative and easy handling (easy to remove). In particular, it is preferable in terms of versatility and safety.

In addition, it is particularly preferable to use the following branched alcohol depending on the type of biphenyl compound. For example, when a cyanobiphenyl compound is used, it is more preferable to use isopropyl alcohol, 2-butanol, t-butanol, 2-pentanol, or 3-pentanol. Among them, it is particularly preferable to use isopropyl alcohol or 2-butanol in consideration of the yield and the effect of suppressing isomers. By using isopropyl alcohol, the conversion of the benzimidazole derivative can be increased and the production of ether by-products can be suppressed. Furthermore, since the production | generation of an isomer can also be suppressed comparatively, the yield of a biphenyl benzimidazole derivative can be improved. This effect is considered to be related to the reactivity between the branched alcohol and the cyano group. Further, by using 2-butanol, it is possible to suppress the formation of isomers while achieving a relatively high yield.

On the other hand, when a tetrazolylbiphenyl compound is used, it is more preferable to use isopropyl alcohol, 2-butanol, t-butanol, 2-pentanol, or 3-pentanol. Among these, it is particularly preferable to use 2-butanol, 3-pentanol, or t-butanol in consideration of the high conversion rate of the benzimidazole derivative, the ether by-product, and the effect of suppressing isomers. In addition to the above effects, the use of 2-butanol, 3-pentanol, or t-butanol is considered to suppress the elimination reaction of the trityl group. Among 2-butanol, 3-pentanol, and t-butanol, 2-butanol is used in consideration of the yield of biphenylbenzimidazole derivatives, ease of handling (easy to remove), versatility, safety, etc. It is preferable to do.

If the reaction solvent is a branched alcohol as described above, the amount of ether by-product that is a reaction product of the biphenyl compound and the reaction solvent can be suppressed. This is considered to be because the reactivity between the biphenyl compound and the branched alcohol is low and the production of ether by-products can be suppressed.

In the present invention in which a reaction solvent containing the branched alcohol is used, if the reaction conditions are adjusted, for example, the reaction temperature is set to a relatively low value (near room temperature, for example, 10 to 30 ° C.), Can be remarkably suppressed. The reason for this is not clear, but is estimated as follows. That is, the branched alcohol acts on one nitrogen atom to be reacted in the benzimidazole derivative (the 1st-position nitrogen atom in the following formula) by a hydrogen bond or the like, and as a result, a base easily acts on the nitrogen atom. The biphenylbenzimidazole derivative which is aimed at with high selectivity (“high selectivity” means a high proportion of the biphenylbenzimidazole derivative produced and the biphenylbenzimidazole derivative in the isomer). Is estimated to be obtained. Although it depends on the type of branched alcohol used, it is presumed that the reason why the selectivity may be higher than that of linear alcohol is as follows. That is, it is considered that the oxygen atom of the branched alcohol having an electron density higher than the oxygen atom of the linear alcohol (the oxygen atom of the hydroxyl group) acts strongly on the hydrogen atom bonded to the nitrogen atom. This is presumed to be the cause of high selectivity. In particular, when the reaction temperature is relatively low, it is considered that the above-described action is remarkably exhibited. Such an effect becomes remarkable when a cyanobiphenyl compound is used.

　さらには、前記テトラゾリルビフェニル化合物を使用した場合に、本発明の反応における脱トリチル基の反応を抑制することができる。

Furthermore, when the said tetrazolyl biphenyl compound is used, reaction of the detrityl group in reaction of this invention can be suppressed.

(Other polar solvents)
In the present invention, the entire amount of the reaction solvent may be the branched alcohol, except for a solvent inevitably mixed in the reaction system. However, in order to shorten the reaction time in the reaction of the present invention, the reaction solvent can also contain a polar solvent (excluding the branched alcohol).

In the present invention, the polar solvent used in combination with the branched alcohol is preferably a polar solvent having a relative dielectric constant of preferably 20 or more, more preferably 30 or more. The upper limit of the relative dielectric constant is not particularly limited, but is 100. The polar solvent may be an aprotic polar solvent or a polar solvent containing a hetero atom. Among them, it is preferable to use a polar solvent containing a hetero atom such as a nitrogen atom, a sulfur atom, or an oxygen atom. Specific examples of suitable polar solvents include acetonitrile (dielectric constant 37), N, N-dimethylformamide (dielectric constant 38), N, N-dimethylacetamide (dielectric constant 38), N-methyl- Examples include 2-pyrrolidone (relative permittivity: 32.2) and dimethyl sulfoxide (relative permittivity: 47). Furthermore, in the case of using a polar solvent, in order to suppress the generation of ether by-products, achieve high selectivity, shorten the reaction time, and facilitate post-treatment, among the polar solvents, N, N-dimethylformamide, N, N-dimethylacetamide is preferably used.

These polar solvents can be used singly or as a mixture of plural kinds.

(Combination ratio of branched alcohol and polar solvent)
In the present invention, when a polar solvent is used, in order to suppress the generation of ether by-products and achieve high selectivity, when the branched alcohol is 1 ml, the polar solvent is 0.01 to 1 ml. It is preferably 0.05 to 0.5 ml, more preferably 0.1 to 0.3 ml. In addition, when using multiple types of polar solvent, the total amount of this multiple types of polar solvent should just satisfy the said range.

(Amount of reaction solvent used)
In the present invention, the amount of the reaction solvent used is not particularly limited, and an amount that can sufficiently contact the benzimidazole derivative and the biphenyl compound in the reaction system may be used. Specifically, the reaction solvent is preferably used in an amount such that the reaction solvent is 0.5 to 100 ml with respect to 1 g of the benzimidazole derivative, and more preferably 1 to 20 ml. This amount is the amount of the reaction solvent at 23 ° C. Moreover, when the reaction solvent contains the polar solvent, the amount of the reaction solvent may be such that the total amount of the branched alcohol and the polar solvent satisfies the above range. In addition, when multiple types of branched alcohol and multiple types of polar solvents are used, the total amount of them should just satisfy the said range.

(Other reaction conditions)
In order to carry out the present invention, the benzimidazole derivative and the biphenyl compound may be contacted in the reaction solvent in the presence of a base. Therefore, it is preferable to stir and mix the base, the benzimidazole derivative, and the cyanobiphenyl compound in the reaction solvent.

In the present invention, the procedure for introducing each component into the reaction system is not particularly limited. For example, the base diluted with the reaction solvent as necessary, the iodine catalyst used as necessary, the benzimidazole derivative, and the biphenyl compound can be mixed with stirring while being simultaneously introduced into the reaction system. In addition, if necessary, one raw material compound diluted with a reaction solvent is first introduced into the reaction system and stirred and mixed, and if necessary, the other raw material compound diluted with a reaction solvent is added to the reaction system. The method of adding can also be employ | adopted. In the case of adding the other raw material compound into the reaction system, the base and the iodine catalyst used as necessary can be introduced into the reaction system together with the one raw material compound in advance. The raw material compound can be added to the reaction system simultaneously with the addition of the other raw material compound, or can be added separately to the reaction system after the other raw material compound is added.

In the present invention, the reaction temperature is not particularly limited. In order to suppress the generation of ether by-products, achieve high selectivity, and obtain a biphenylbenzimidazole derivative in a high yield, −30 to 150 It is preferable to set it as ° C. Among them, the reaction temperature is preferably 0 to 100 ° C., more preferably 5 to 70 ° C., in order to further suppress the generation of ether by-products and to achieve higher selectivity and higher yield. More preferably, the temperature is 10 to 60 ° C. Further, the reaction temperature is preferably 25 to 60 ° C. Further, in order to suppress the generation of ether by-products, achieve high selectivity, shorten the reaction time, and increase the yield, it is particularly preferably 40 to 60 ° C. The reaction time is not particularly limited, and may be appropriately determined while confirming the consumption state of the raw material compound or the amount of the biphenylbenzimidazole derivative to be generated. Specifically, 0.5 to 72 hours is sufficient, and may be about 1 to 24 hours.

In addition, the atmosphere in the reaction system is not particularly limited, and the reaction can be performed in any atmosphere such as an air atmosphere or an inert gas atmosphere. Further, the pressure in the reaction system is not particularly limited, and the reaction of the present invention may be carried out in any state under atmospheric pressure, reduced pressure, or increased pressure.

(Removal and purification of target product)
In the present invention, the target biphenylbenzimidazole derivative can be produced by carrying out the reaction according to the above method. The method for taking out the biphenylbenzimidazole derivative from the reaction system is not particularly limited, and a known method can be adopted. For example, a method of crystallizing the biphenylbenzimidazole derivative by adding water as a poor solvent into the system, extraction with a solvent, washing, or distillation of the reaction solvent, and then recrystallization of the obtained solid content A method etc. can be adopted. Further, the purity of the obtained biphenylbenzimidazole derivative can be increased by slurry purification, recrystallization, column purification, or the like.

According to the method of the present invention, the following formula (3)

（式中、Ｒ¹、およびＲ²は、前記式（１）におけるものと同義であり、
　Ｒ^Aは、前記式（２）におけるものと同義である。）
で示されるビフェニルベンズイミダゾール誘導体の収率を高めることができる。以下、前記ビフェニルベンズイミダゾール誘導体を、Ｒ^Aがシアノ基の場合には「シアノビフェニルベンズイミダゾール誘導体」と記載する場合もあり、Ｒ^Aが１－トリチル－１Ｈ－テトラゾール－５－イル基の場合には「カンデサルタン中間体」と記載する場合もある。

(Wherein R ¹ and R ² have the same meanings as in formula (1),
R ^A has the same meaning as in formula (2). )
The yield of the biphenylbenzimidazole derivative represented by can be increased. Hereinafter, the biphenylbenzimidazole derivative may be referred to as “cyanobiphenylbenzimidazole derivative” when R ^A is a cyano group, and when R ^A is a 1-trityl-1H-tetrazol-5-yl group. May be described as “candesartan intermediate”.

According to the study by the present inventors, when the branched alcohol is not used, specifically, when a linear alcohol such as methanol or ethanol is used as a reaction solvent, the linear alcohol and the biphenyl compound It was found that a large amount of ether by-product was produced. Since the branched alcohol used in the present invention is bulkier than the straight chain alcohol, it is considered that the reaction with the biphenyl compound is difficult to proceed.

In addition, when the linear alcohol is used, a large amount of ether by-products is considered to be a factor, but the conversion rate of the benzimidazole derivative is low. Depending on the raw materials used, reaction conditions, etc., the following formula (B)

（式中、Ｒ¹、Ｒ²、およびＲ^Aは、前記式（３）におけるものと同義である。）
で示される異性体の生成割合が高くなる場合があった。このように該直鎖アルコールを使用した場合、転化率が低く、異性体も生成することから、結果的に目的物の収率が低下する。

(In the formula, R ¹ , R ² and R ^A have the same meanings as those in the formula (3).)
In some cases, the production ratio of the isomer represented by Thus, when this linear alcohol is used, since the conversion rate is low and an isomer is also produced | generated, the yield of a target object falls as a result.

In contrast, in the present invention, by using a reaction solvent containing a branched alcohol, the production of the ether by-product can be reduced and the production rate of the isomer can be suppressed. The rate can be improved.

Furthermore, when the cyanobiphenyl compound is used as the biphenyl compound and the sultan drug substance such as candesartan or azilsartan is produced from the obtained cyanobiphenylbenzimidazole derivative, impurities can be efficiently reduced.

When the cyanobiphenyl compound is used, R ^A in the biphenylbenzimidazole derivative becomes a cyano group, and the cyano group can be substituted with various groups depending on the target drug substance. Therefore, when the obtained compound is a cyanobiphenylbenzimidazole derivative, the obtained compound can be used as an intermediate of candesartan or azilsartan, so that the usefulness is increased.

When a tetrazolyl biphenyl compound is used as the biphenyl compound, the biphenylbenzimidazole derivative is represented by the following formula (3 ′)

（式中、Ｅｔはエチル基であり、Ｔｒはトリフェニルメチル基である。）
で示されるカンデサルタン中間体が製造される。

(In the formula, Et is an ethyl group, and Tr is a triphenylmethyl group.)
A candesartan intermediate is produced as shown below.

In the formula (3 ′), when R ² is an alkyl group having 1 to 6 carbon atoms, a candesartan intermediate is prepared by the method for producing a biphenylbenzimidazole derivative of the present invention, and then the obtained candesartan intermediate By hydrolyzing the ester group, the following formula (6)

（式中、Ｅｔはエチル基であり、Ｔｒはトリフェニルメチル基である。）
で示されるトリチルカンデサルタンを製造することができる。加水分解は公知の方法で実施することができる。

(In the formula, Et is an ethyl group, and Tr is a triphenylmethyl group.)
The trityl candesartan shown by this can be manufactured. Hydrolysis can be carried out by a known method.

Further, subsequently, a cilexetil group was introduced into the obtained trityl candesartan, and the following formula (7)

（式中、Ｅｔはエチル基であり、Ｔｒトリフェニルメチル基である。）
で示されるトリチルカンデサルタンシレキセチルを製造することができる。シレキセチル基の導入は公知の方法で実施することができる。

(In the formula, Et is an ethyl group and a Tr triphenylmethyl group.)
The trityl candesartan cilexetil shown by can be manufactured. Introduction of a cilexetil group can be carried out by a known method.

Alternatively, in the formula (3 ′), when R ² is a cilexetil group, the biphenylbenzimidazole derivative or the candesartan intermediate may be used as the biphenylbenzimidazole derivative or the candesartan intermediate by the method for producing a biphenylbenzimidazole derivative of the present invention. The represented trityl candesartan cilexetil can be produced.

Furthermore, after producing the trityl candesartan cilexetil by any of the methods described above, a candesartan cilexetil represented by the following formula (8) is produced from the trityl candesartan cilexetil by a detritylation reaction. Can do.

　前記脱トリチル化反応（すなわち脱保護反応）は、公知の方法で実施でき、水、酸、アルコール、又はアルカリを使用することにより、特に、安全な水、及び／又はアルコールを使用することにより、実施することができる。

The detritylation reaction (i.e. deprotection reaction) can be carried out in a known manner, by using water, acid, alcohol or alkali, in particular by using safe water and / or alcohol. Can be implemented.

When the biphenyl compound is the tetrazolyl biphenyl compound, according to the present invention, a candesartan intermediate that is easy to perform a deprotection reaction is produced, and finally candesartan cilexetil is also an easy method. Can be manufactured.

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

(Example of using a cyanobiphenyl compound as a raw material compound)
[Example 1]
2-Ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (1.00 g, 4.541 mmol, “benzimidazole derivative”), potassium carbonate (1.26 g, 9.08 mmol, “base”), and 2- Butanol (10 mL, “reaction solvent”) was introduced into the reaction vessel and stirred at room temperature (23 ° C.) for 5 minutes.

Furthermore, 4′-bromomethyl-2-cyano-1,1′-biphenyl (1.30 g, 4.80 mmol, “cyanobiphenyl compound”) and tetra-n-butylammonium iodide (0.084 g, 0.23 mmol, “ Iodine catalyst ") was added and the reaction was carried out in a reaction solvent containing 2-butanol with stirring for 24 hours at room temperature.

Water (10 mL), ethyl acetate (20 mL), and chloroform (30 mL) were added to the resulting reaction solution and stirred, and the organic layer was measured by high performance liquid chromatography (hereinafter referred to as “HPLC”). Conversion of benzimidazole derivative: 17.2% (area%), by-product (4 ′-(2-butoxy) methyl-2-cyano-1,1′-biphenyl, “ether by-product”) 0% (area) %) And the desired product (1-[(2′-cyano [1,1′-biphenyl] -4-yl) methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester): isomer = 93% (area%): 7% (area%).

[Example 2]
2-Ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (1.00 g, 4.541 mmol, “benzimidazole derivative”), potassium carbonate (1.26 g, 9.08 mmol, “base”), and 2- Butanol (10 mL “reaction solvent”) was introduced into the reaction vessel and stirred at room temperature for 5 minutes.

Furthermore, 4′-bromomethyl-2-cyano-1,1′-biphenyl (1.30 g, 4.80 mmol, “cyanobiphenyl compound”) and tetra-n-butylammonium iodide (0.084 g, 0.23 mmol, “ Iodine catalyst ") was added, and the reaction was carried out in a reaction solvent containing 2-butanol by stirring at 50 ° C for 11 hours.

Water (350 mL) was added to the obtained reaction solution, stirred and filtered to obtain a white solid. This solid was blown and dried at 55 ° C. for 19 hours to give the desired product (1-[(2′-cyano [1,1′-biphenyl] -4-yl) methyl] -2-ethoxy-1H-benzimidazole-7). A crude product (1.83 g) of -carboxylic acid methyl ester) was obtained. The crude product was dissolved in acetonitrile and measured by HPLC. As a result, the conversion of the benzimidazole derivative was 84.9% (area%), the ether by-product was 0% (area%), and the target product: isomer = 90% (area). %): 10% (area%).

[Example 3]
The same operation as in Example 1 was performed except that the reaction temperature was 40 ° C.

[Example 4]
2-Ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (1.00 g, 4.541 mmol, “benzimidazole derivative”), potassium carbonate (1.26 g, 9.08 mmol, “base”), and 1- Methoxy-2-propanol (10 mL, “Reaction solvent”) was introduced into the reaction vessel and stirred at room temperature for 5 minutes.

Furthermore, 4′-bromomethyl-2-cyano-1,1′-biphenyl (1.30 g, 4.80 mmol, “cyanobiphenyl compound”) and tetra-n-butylammonium iodide (0.084 g, 0.23 mmol, “ Iodine catalyst ") was added and the reaction was carried out in a reaction solvent containing 1-methoxy-2-propanol at room temperature for 24 hours.

Water (10 mL), ethyl acetate (20 mL), and chloroform (30 mL) were added to the obtained reaction solution and stirred, and the organic layer was measured by HPLC. The conversion of benzimidazole derivative was 73.0% (area). %), Ether by-product 0% (area%), target product: isomer = 81% (area%): 19% (area%).

[Example 5]
2-Ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (5.00 g, 22.7 mmol, “benzimidazole derivative”), potassium carbonate (6.3 g, 45.4 mmol, “base”), 2-butanol (40 mL, “reaction solvent”) and N, N-dimethylacetamide (10 mL, “reaction solvent (polar solvent)”) were introduced into a reaction vessel and stirred at room temperature for 5 minutes.

Furthermore, 4′-bromomethyl-2-cyano-1,1′-biphenyl (6.5 g, 24 mmol, “cyanobiphenyl compound”) and tetra-n-butylammonium iodide (0.42 g, 1.15 mmol, “iodine catalyst”) )) Was added, and the reaction was carried out with stirring for 24 hours at room temperature in a reaction solvent containing 2-butanol and N, N-dimethylacetamide (polar solvent).

Water (400 mL) was added to the obtained reaction liquid and stirred, and the precipitated crystals were filtered and dried to obtain the target product (1-[(2′-cyano [1,1′-biphenyl] -4- Yl) methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester) (9.28 g). The crude product was dissolved in acetonitrile and measured by HPLC. As a result, the conversion of the benzimidazole derivative was 84.0% (area%), the ether by-product was 0% (area%), and the target product: isomer = 87% (area%). ): 13% (area%).

Ethyl acetate was added to this crude product, and after heating and stirring, it was filtered. The obtained solid was dried to obtain a pure product (7.5 g, 80%). The analysis result of the obtained pure product was as follows.
Mp; 167 ° C.
IR (KBr); 3444, 2953, 2227, 1721, 1550, 1269, 1035, 746 cm ⁻¹ .
¹ H-NMR (CDCl ₃ ); δ 1.49 (t, J = 7.1 Hz, 3H), δ 3.75 (s, 3H), δ 4.67 (q, J = 7.0 Hz, 2H), δ5. 69 (s, 2H), δ 7.09-7.75 (m, 11H).

[Example 6]
The same operation as in Example 1 was carried out except that isopropyl alcohol (10 mL) was used instead of 2-butanol as the reaction solvent and the reaction temperature was 40 ° C.

[Example 7]
The same operation as in Example 1 was performed except that 1-ethoxy-2-propanol (10 mL) was used instead of 2-butanol as a reaction solvent.

[Example 8]
The same operation as in Example 1 was carried out except that 1-butoxy-2-propanol (10 mL) was used instead of 2-butanol as the reaction solvent.

[Example 9]
The same operation as in Example 1 was performed except that 2-pentanol (10 mL) was used instead of 2-butanol as a reaction solvent and the reaction temperature was 40 ° C.

[Example 10]
The reaction was conducted in the same manner as in Example 1 except that 3-pentanol (10 mL) was used instead of 2-butanol as the reaction solvent and the reaction temperature was 40 ° C.

[Example 11]
The reaction was conducted in the same manner as in Example 1 except that t-butanol (10 mL) was used instead of 2-butanol as a reaction solvent and the reaction temperature was 40 ° C.

[Comparative Example 1]
The same operation as in Example 1 was performed except that methanol (10 mL) was used instead of 2-butanol as a reaction solvent.

As a result of HPLC analysis, the conversion of the benzimidazole derivative was 52.0% (area%), the by-product (4′-methoxymethyl-2-cyano-1,1′-biphenyl; ether by-product) 28.8% ( area%), target product: isomer = 90% (area%): 10% (area%).

[Comparative Example 2]
The same operation as in Example 1 was performed, except that ethanol (10 mL) was used instead of 2-butanol as a reaction solvent.

The analysis results by HPLC were as follows: conversion of benzimidazole derivative: 22.8% (area%), by-product (4′-ethoxymethyl-2-cyano-1,1′-biphenyl; ether by-product) 16.2% ( area%), target product: isomer = 89% (area%): 11% (area%).

[Comparative Example 3]
The same operation as in Example 1 was carried out except that N, N-dimethylformamide (10 mL) was used instead of 2-butanol as the reaction solvent.

[Comparative Example 4]
The same operation as in Comparative Example 3 was performed except that the reaction temperature was 40 ° C.

[Comparative Example 5]
The same operation as in Comparative Example 4 was performed except that N, N-dimethylacetamide was used in place of N, N-dimethylformamide as the reaction solvent.

Table 1 shows the results of Examples 1 to 11 and Comparative Examples 1 to 5 described above.

　以上の通り、前記分岐アルコール含む反応溶媒を使用することにより、前記エーテル副生物の生成を抑制できた。また、前記分岐アルコール含む反応溶媒を使用し、反応温度を１０～３０℃とすることにより、前記異性体の生成割合を抑制することもできた（実施例１）。さらに、反応温度を４０～６０℃とするか、さらに極性溶媒を含む反応溶媒を使用することにより、前記異性体の副生を抑制しつつ、ベンズイミダゾール誘導体の転化率を高くすることができるため、目的物の収率を高くすることができた（実施例２、４）。

As described above, the use of the reaction solvent containing the branched alcohol could suppress the formation of the ether by-product. In addition, by using the reaction solvent containing the branched alcohol and setting the reaction temperature to 10 to 30 ° C., the production ratio of the isomer could be suppressed (Example 1). Furthermore, since the reaction temperature is set to 40 to 60 ° C. or a reaction solvent containing a polar solvent is used, the conversion of the benzimidazole derivative can be increased while suppressing the by-production of the isomer. The yield of the target product could be increased (Examples 2 and 4).

[Comparative Reference Example 1]
(Synthesis of ether by-product of Comparative Example 1 (confirmation))
The same operation as in Comparative Example 1 was performed, except that 2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester was not charged, the reaction temperature was 50 ° C., and the reaction time was 5 hours. After the reaction, the obtained reaction solution was filtered, the filtrate was treated with activated carbon, and further filtered through Celite. The solid obtained by concentrating the filtrate under reduced pressure was crystallized by adding ethyl acetate to give 4′-methoxymethyl-2-cyano-1,1′-biphenyl (770 mg, yield 72.2%). Got. The HPLC retention time of this product coincided with the retention time of the HPLC impurity peak of Comparative Example 1.
Mp: 79 ° C.
IR (KBr); 3437, 2888, 2224, 1595, 1481, 1381, 1197, 1093, 960, 824, 770 cm- ¹ .
¹ H-NMR (CDCl ₃ ); δ 3.44 (s, 3H), δ 4.53 (s, 2H), δ 7.42-7.78 (m, 8H).

(Example using tetrazolylbiphenyl compound as raw material compound)
[Example 12]
2-Ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (1.0 g, 4.54 mmol, “benzimidazole derivative”), potassium carbonate (1.25 g, 9.05 mmol, “base”), 5- [ 4 ′-(bromomethyl)-[1,1′-biphenyl] -2-yl] -1- (triphenylmethyl) -1H-tetrazole (3.04 g, 5.45 mmol, “tetrazolylbiphenyl compound”), And 20 ml of isopropyl alcohol was mixed at 25 degreeC as a reaction solvent, and it stirred at 40 degreeC (reaction temperature) for 24 hours. After cooling the reaction solution, about 15 ml of isopropyl alcohol was distilled off, 20 ml of water was added, and the mixture was extracted with chloroform. When the obtained organic phase was measured by HPLC, the conversion of the benzimidazole derivative was 31%.

There was no ether by-product (4 '-(2-propoxy) methyl-2-triphenylmethyltetrazol-1,1'-biphenyl) (0% (0 area%)). Target product: isomer = 91% (area%): 9% (area%).

[Example 13]
The same operation as in Example 12 was performed, except that 2-butanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.

[Example 14]
The same operation as in Example 12 was performed, except that 2-butanol (16 mL) and N, N-dimethylacetamide (4 mL) were used in place of isopropyl alcohol as the reaction solvent.

[Example 15]
The same operation as in Example 12 was performed, except that 2-pentanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.

[Example 16]
The same operation as in Example 12 was performed, except that 3-pentanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.

[Example 17]
The same operation as in Example 12 was performed, except that t-butanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.

[Example 18]
The same operation as in Example 12 was performed, except that 1-methoxy-2-propanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.

[Example 19]
The same operation as in Example 12 was performed, except that 1-ethoxy-2-propanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.

[Example 20]
The same operation as in Example 12 was performed, except that 1-butoxy-2-propanol (20 mL) was used instead of isopropyl alcohol as a reaction solvent.

[Comparative Example 6]
The reaction was performed in the same manner as in Example 12 except that methanol (20 mL) was used as the reaction solvent instead of isopropyl alcohol. As a result, 1.26 g (yield 40%) of the target product was obtained. Target product: isomer = 92%: 8%.

[Comparative Example 7]
The same operation as in Comparative Example 6 was performed except that ethanol (20 mL) was used instead of methanol as the reaction solvent. (20 mL)
[Comparative Example 8]
The same operation as in Comparative Example 6 was performed, except that N, N-dimethylformamide (20 mL) was used as the reaction solvent instead of methanol.

[Comparative Example 9]
The same operation as in Comparative Example 6 was performed, except that N, N-dimethylacetamide (20 mL) was used instead of methanol as the reaction solvent.

Table 2 shows the results of Examples 12 to 20 and Comparative Examples 6 to 9 described above.

　［実施例２１］
　実施例１３で得られた２－エトキシ－１－［２’－［１－トリフェニルメチル－１Ｈ－テトラゾール－５－イル］ビフェニル－４－イル］－１Ｈ－ベンズイミダゾール－７－カルボン酸メチルエステル（カンデサルタン中間体）１ｇ（１．４３ｍｍｏｌ）を１Ｎ ＮａＯＨ水溶液 ６ｍｌとエタノール ２０ｍｌとの混合溶媒中、７０℃で３時間撹拌した。反応液を冷却後、反応液に、１Ｎ ＨＣｌ ６ｍｌを入れた氷水を徐々に加えた。塩化メチレンで抽出を行い、乾燥、ろ過後、濃縮を行い、トリチルカンデサルタン（式（６）で示される化合物）の粗体を固形物として０．８９ｇ（１．３０ｍｍｏｌ）得た。

[Example 21]
2-Ethoxy-1- [2 ′-[1-triphenylmethyl-1H-tetrazol-5-yl] biphenyl-4-yl] -1H-benzimidazole-7-carboxylic acid methyl ester obtained in Example 13 (Candesartan intermediate) 1 g (1.43 mmol) was stirred at 70 ° C. for 3 hours in a mixed solvent of 6 ml of 1N NaOH aqueous solution and 20 ml of ethanol. After cooling the reaction solution, ice water containing 6 ml of 1N HCl was gradually added to the reaction solution. Extraction with methylene chloride, drying, filtration and concentration were performed to obtain 0.89 g (1.30 mmol) of a crude product of trityl candesartan (compound represented by formula (6)) as a solid.

0.8 g (0.12 mmol) of the crude product of trityl candesartan obtained was dissolved in 8 ml of dimethylformamide, and further 0.19 g (0.14 mmol) of potassium carbonate and 0.46 g (0.22 mmol) of cyclohexyl 1-iodoethyl carbonate. ) And stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and dried, and then the solvent was distilled off to obtain a crude product of trityl candesartan cilexetil (compound represented by formula (7)) as a residue.

The obtained residue was dissolved in 20 ml of methanol, 4 ml of 1N HCl was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with water and dried. Thereafter, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography to obtain 0.35 g (0.057 mmol, yield 49%) of candesartan cilexetil as a white solid.

Claims (8)

In the presence of a base,
Following formula (1)

(Wherein R ¹ is an alkyl group having 1 to 6 carbon atoms,
R ² is an alkyl group having 1 to 6 carbon atoms, a cilexetil group, or a medoxomil group. )
A benzimidazole derivative represented by
Following formula (2)

(Wherein R ^A is a cyano group or a 1-trityl-1H-tetrazol-5-yl group;
X is a halogen atom. )
Is reacted with a biphenyl compound represented by the following formula (3):

(Wherein R ¹ and R ² have the same meanings as in formula (1),
R ^A has the same meaning as in formula (2). )
A method for producing a biphenylbenzimidazole derivative represented by
Said reaction is represented by the following formula (4):

(Wherein R ³ , R ⁴ , and R ⁵ are each a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an alkyloxyalkyl group having 2 to 12 carbon atoms) (However, two or more of R ³ , R ⁴ , and R ⁵ are not hydrogen atoms at the same time.)
The manufacturing method of the biphenyl benzimidazole derivative performed in the reaction solvent containing the branched alcohol shown by these. The method for producing a biphenylbenzimidazole derivative according to claim 1, wherein the branched alcohol is at least one selected from the group consisting of isopropyl alcohol, 2-butanol, t-butanol, 2-pentanol, and 3-pentanol. . The method for producing a biphenylbenzimidazole derivative according to claim 1 or 2, wherein the branched alcohol is a secondary alcohol. The method for producing a biphenylbenzimidazole derivative according to any one of claims 1 to 3, wherein the reaction solvent further contains a polar solvent (excluding the branched alcohol). The reaction is represented by the following formula (5):

(Wherein R ⁶ is an alkyl group having 1 to 12 carbon atoms, and the plurality of R ⁶ may be the same group or different groups.)
The method for producing a biphenylbenzimidazole derivative according to any one of claims 1 to 4, which is carried out in the presence of an iodine catalyst represented by the formula: A step of producing the biphenylbenzimidazole derivative by the production method according to any one of claims 1 to 5,
The benzimidazole derivative is represented by the following formula (1 ′)

(In the formula, Et is an ethyl group, and R ² is an alkyl group having 1 to 6 carbon atoms.)
A benzimidazole derivative represented by
The biphenyl compound is represented by the following formula (2 ′)

(In the formula, Tr is a triphenylmethyl group, and X has the same meaning as in formula (2).)
A biphenyl compound represented by
The biphenylbenzimidazole derivative is represented by the following formula (3 ′)

(In the formula, Et is an ethyl group, Tr is a triphenylmethyl group, and R ² is an alkyl group having 1 to 6 carbon atoms.)
A process which is a candesartan intermediate represented by
By hydrolyzing the ester group of the candesartan intermediate, the following formula (6)

(In the formula, Et is an ethyl group, and Tr is a triphenylmethyl group.)
A process for producing trityl candesartan represented by formula (7), and by introducing a cilexetil group into the trityl candesartan,

(In the formula, Et is an ethyl group, and Tr is a triphenylmethyl group.)
The manufacturing method of a trityl candesartan cilexetil including the process of manufacturing the trityl candesartan cilexetil shown by these. The step of producing the trityl candesartan cilexetil by the production method according to claim 6, and detritylating the trityl candesartan cilexetil, the following formula (8)

The manufacturing method of candesartan cilexetil including the process of manufacturing the candesartan cilexetil shown by these. A step of producing the biphenylbenzimidazole derivative by the production method according to any one of claims 1 to 5,
The benzimidazole derivative is represented by the following formula (1 ′)

(In the formula, Et is an ethyl group, and R ² is a cilexetil group.)
A benzimidazole derivative represented by
The biphenyl compound is represented by the following formula (2 ′)

(In the formula, Tr is a triphenylmethyl group, and X has the same meaning as in formula (2).)
A biphenyl compound represented by
The biphenylbenzimidazole derivative is represented by the following formula (7)

(In the formula, Et is an ethyl group, and Tr is a triphenylmethyl group.)
And a step of detritylating the trityl candesartan cilexetil represented by the following formula (8):

The manufacturing method of candesartan cilexetil including the process of manufacturing the candesartan cilexetil shown by these.