JP4381220B2 - Method for producing bactericidal pyridine compound - Google Patents

Description

  The present invention relates to an industrial production method of a novel pyridine compound having bactericidal properties.

  Bis quaternary ammonium salt compounds that exhibit antibacterial activity against bacteria and fungi have been known for a long time and are still widely used as antibacterial agents. However, currently used antibacterial bis-quaternary ammonium salt compounds are usually excellent in antibacterial activity, but at the same time, the residual toxicity of biodegradation products is also high. There was a problem in the solubility and solubility in water and stability, and the application range was limited. In addition, conventional bis quaternary ammonium salt compounds have antibacterial activity antagonized by carbohydrates, proteins, lipids, etc., and the antibacterial activity decreases in the low pH (acidic) region and has no effect on cell spores. There were drawbacks.

（上記式中、Ｙはピリジン環、キノリン環、イソキノリン環またはチアゾリン環を、Ｒ¹は炭素数２〜１０のアルキレン基あるいはアルケニレン基を、Ｒ²はＹの窒素原子に結合した炭素数６〜１８のアルキル基を示し、いずれも置換基を含んでもよい。Ｘはアニオンを示す。） Therefore, bis quaternary ammonium salt compounds represented by the following general formulas (A) and (B) (see Patent Document 1),

(Wherein Y represents a pyridine ring, quinoline ring, isoquinoline ring or thiazoline ring, R ¹ represents an alkylene group or alkenylene group having 2 to 10 carbon atoms, and R ² represents 6 to 6 carbon atoms bonded to the nitrogen atom of Y. 18 represents an alkyl group, any of which may contain a substituent, and X represents an anion.)

（上記式中、Ｚはピリジン環を示し、Ｒ₁およびＲ₂は同一または異なり、各々水素原子または炭素数１〜６のアルキル基を示し、Ｒ₃は炭素数３〜１８のアルケニレン基を示し、Ｒ₄はＺの環窒素原子に結合した炭素数６〜１８のアルキル基またはアルケニル基を示し、Ｘはアニオンを示す。） Bis quaternary ammonium salt compound represented by the following general formula (C) (see Patent Document 2),

(In the above formula, Z represents a pyridine ring, R ₁ and R ₂ are the same or different, each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ₃ represents an alkenylene group having ₃ to 18 carbon atoms. R ₄ represents an alkyl or alkenyl group having 6 to 18 carbon atoms bonded to the ring nitrogen atom of Z, and X represents an anion.)

（上記式中、Ｚはピリジン環またはキノリン環を、Ｒ₃は炭素数２〜１８のアルキレン基あるいはアルケニレン基を、Ｒ₄はＺの窒素原子に結合した炭素数６〜１８のアルキル基を示し、いずれも置換基を含んでもよい。Ｒ₁およびＲ₂は同一または異なって、Ｚの窒素原子以外の原子に結合した炭素数１〜３のアルキル基、水酸基、アミノ基、炭素数１〜３のアルコキシ基あるいは水素原子を、Ｘはアニオンをそれぞれ示す。） A bis quaternary ammonium salt compound represented by the following general formula (D) (see Patent Document 3) has been reported.

(In the above formula, Z represents a pyridine ring or a quinoline ring, R ₃ represents an alkylene group or alkenylene group having 2 to 18 carbon atoms, and R ₄ represents an alkyl group having 6 to 18 carbon atoms bonded to the nitrogen atom of Z. R ₁ and R ₂ may be the same or different and each has an alkyl group having 1 to 3 carbon atoms, a hydroxyl group, an amino group, or 1 to 3 carbon atoms bonded to an atom other than the nitrogen atom of Z. And X represents an anion.)

JP-A-8-301703 Japanese Patent Laid-Open No. 10-095773 JP-A-6-321902

Development of a bis-quaternary ammonium salt compound that is extremely superior in antibacterial activity than the above-mentioned conventionally known bis-quaternary ammonium salt compounds and has little residual toxicity and is friendly to the global environment is strongly desired. ing.
Accordingly, an object of the present invention is to provide a novel bactericidal pyridine compound conveniently and inexpensively using a readily available pyridine compound as a starting material.

（但し、上記一般式（７）において、Ｒ₁およびＲ₄は、炭素数１〜４の直鎖もしくは分岐の同一または異なるアルキル基であり、Ｒ₂およびＲ₅は、水素原子、同一または異なるハロゲン原子、低級アルキル基または低級アルコキシ基であり、Ｒ₃は、炭素数２〜１２の直鎖もしくは分岐のアルキル基であり、Ｒ₆は、炭素数１〜１８の直鎖もしくは分岐のアルキル基であり、Ｚは、塩素原子、臭素原子、ヨウ素原子もしくはＯＳＯ₂Ｒ₇基（Ｒ₇は、低級アルキル基もしくは置換あるいは無置換のフェニル基である）である。）で表される殺菌性ピリジン化合物の製造方法を提供する。当該化合物は抗菌性化合物として有用である。
上記化合物を製造する場合、以下の２つの工程に大別される。なお、以下の説明においてＲ₁〜Ｒ₇およびＺは前記と同一意義を有するので、以下においてはＲ₁〜Ｒ₇およびＺの説明は省略する。 The present invention relates to the following general formula (7)

(However, in the above general formula (7), R ₁ and R ₄ is a linear or branched, identical or different alkyl groups having 1 to 4 carbon atoms, R ₂ and R ₅ are hydrogen atoms, the same or different A halogen atom, a lower alkyl group or a lower alkoxy group, R ₃ is a linear or branched alkyl group having 2 to 12 carbon atoms, and R ₆ is a linear or branched alkyl group having 1 to 18 carbon atoms. And Z is a chlorine atom, bromine atom, iodine atom or OSO ₂ R ₇ group (R ₇ is a lower alkyl group or a substituted or unsubstituted phenyl group). A method for producing a compound is provided. The compound is useful as an antibacterial compound.
When manufacturing the said compound, it divides roughly into the following two processes. In the following description, R _{1 to} R ₇ and Z have the same meaning as described above. Therefore, description of R _{1 to} R ₇ and Z is omitted in the following.

で表されるピリジン化合物の合成。 That is,
1) General formula (5)

Synthesis of a pyridine compound represented by

で表されるハロゲン化合物もしくはスルホン酸エステル化合物の反応による前記一般式（７）の殺菌性ピリジン化合物の合成。 2) Compound of general formula (5) and general formula (6)

Synthesis of the bactericidal pyridine compound of the general formula (7) by reaction of a halogen compound or a sulfonic acid ester compound represented by the formula:

（但し、式中のＡは、塩基の作用により脱離基として機能し、アルキルカチオンを生成し得る置換基であり、Ｒ₁およびＲ₂は前記の通りであり、Ｘは無機もしくは有機のプロトン酸の対アニオンであり、ｍは０〜１である）で表されるピリジン化合物（ｍ＝０）もしくはその塩（ｍ＝１）と、下記一般式（２）

で表されるジオール類の求核置換反応によるエーテル結合生成である。この場合、ジオール類は塩基によりアルコキシドを生成して活性化される必要がある。前記一般式（１）の塩を使用した場合には、該塩を中和するに足る塩基がさらに必要となる。 The present inventors first made the following plan for a method for synthesizing a novel pyridine compound represented by the general formula (5). That is, the general formula (1)

(In the formula, A is a substituent which functions as a leaving group by the action of a base and can generate an alkyl cation, R ₁ and R ₂ are as described above, and X is an inorganic or organic proton. A pyridine compound (m = 0) or a salt thereof (m = 1) represented by the following general formula (2):

It is an ether bond formation by the nucleophilic substitution reaction of diol represented by these. In this case, the diol needs to be activated by generating an alkoxide with a base. When the salt of the general formula (1) is used, a base sufficient to neutralize the salt is further required.

で表されるピリジン化合物の効率的な製造方法を見いだした。 In accordance with the plan, the inventors
1) Selection of substituents that function as leaving groups.
2) Selection of a base that enables elimination.
3) Selection of a solvent species that enables desorption.
4) Selection of highly selective reaction conditions.
As a result of diligent research for the main purpose, the following general formula (3)

The efficient manufacturing method of the pyridine compound represented by these was discovered.

（但し式中のＢは塩基の作用により脱離基として機能し、アルキルカチオンを生成し得る置換基であり、Ｙは無機もしくは有機のプロトン酸の対アニオンであり、Ｒ₄およびＲ₅は前記の通りであり、Ｂは前記Ａと同一でも異なっていてもよく、Ｙは前記Ｘと同一でも異なっていてもよく、Ｒ₄は前記Ｒ₁と同一でも異なっていてもよく、Ｒ₅は前記Ｒ₂と同一でも異なっていてもよく、ｎは０〜１であり、前記ｍと同一でも異なっていてもよい）で表されるピリジン化合物（ｎ＝０）もしくはその塩（ｎ＝１）の求核置換反応による第２のエーテル結合の生成において、
１）脱離基として機能する置換基の選択。
２）脱離を可能ならしめる塩基の選択。
３）脱離を可能ならしめる溶媒種の選択。
４）高選択的な反応条件の選択。
に着目して鋭意検討を進めた。該反応において、前記一般式（３）で表されるピリジン化合物は塩基によりアルコキシドを生成して活性化される必要がある。また、前記一般式（４）の塩を使用する場合は、該塩を中和するに足る塩基が必要になる。種々検討の結果、本発明者らは、前記一般式（５）で表されるピリジン化合物の効率的な製造方法を見いだし、本発明を完成させるに至った。なお、以下の説明においてＡ、Ｂ、Ｘ、Ｙ、ｍおよびｎは前記と同一意義を有するので、以下においてはＡ、Ｂ、Ｘ、Ｙ、ｍおよびｎの説明は省略する。 Next, the inventors have prepared a pyridine compound represented by the general formula (3) and the following general formula (4).

(In the formula, B is a substituent that functions as a leaving group by the action of a base and can generate an alkyl cation, Y is a counter anion of an inorganic or organic protonic acid, and R ₄ and R ₅ are B may be the same as or different from A, Y may be the same as or different from X, R ₄ may be the same as or different from R _1, and R ₅ may be the same as R ₂ may be the same as or different from R _2, and n is 0 to 1, and may be the same as or different from m) or a salt thereof (n = 1) In the formation of the second ether bond by the nucleophilic substitution reaction,
1) Selection of substituents that function as leaving groups.
2) Selection of a base that enables elimination.
3) Selection of a solvent species that enables desorption.
4) Selection of highly selective reaction conditions.
Focused on the study and advanced research. In the reaction, the pyridine compound represented by the general formula (3) needs to be activated by generating an alkoxide with a base. Moreover, when using the salt of the said General formula (4), the base sufficient to neutralize this salt is needed. As a result of various studies, the present inventors have found an efficient method for producing a pyridine compound represented by the general formula (5), and have completed the present invention. In the following description, A, B, X, Y, m, and n have the same meaning as described above. Therefore, description of A, B, X, Y, m, and n is omitted in the following.

で表されるピリジン化合物と、下記一般式（２）

で表されるジオール類とを、強塩基の存在下に反応させることにより、下記一般式（３）

で表されるピリジン化合物を製し、該化合物と下記一般式（４）

で表されるピリジン化合物とを強塩基の存在下に反応させることにより、下記一般式（５）

で表されるピリジン化合物を製し、該化合物と下記一般式（６）

で表されるハロゲン化合物もしくはスルホン酸エステル化合物とを反応させることを特徴とする下記一般式（７）

で表される新規な殺菌性ピリジン化合物の製造方法を提供する。 Finally, the present inventors have obtained a desired general formula (7) by the reaction of the pyridine compound represented by the general formula (5) and the alkyl halide or sulfonate ester represented by the general formula (6). As a result of intensive studies on the synthesis conditions of the bactericidal pyridine compound represented, the present invention has been completed. That is, the present invention provides the following general formula (1)

And a pyridine compound represented by the following general formula (2)

Is reacted in the presence of a strong base to give the following general formula (3):

A pyridine compound represented by the formula:

Is reacted with a pyridine compound represented by the following general formula (5):

A pyridine compound represented by the formula:

The following general formula (7), characterized by reacting with a halogen compound or a sulfonic acid ester compound represented by the formula:

A method for producing a novel bactericidal pyridine compound represented by the formula:

  According to the present invention, a novel bactericidal pyridine compound can be provided simply and inexpensively using a readily available pyridine compound as a starting material.

Next, the present invention will be described in more detail with reference to preferred embodiments.
In the pyridine compound represented by the general formula (1), a substituent that functions as a leaving group by the action of a base represented by A and can generate a carbocation includes a chlorine atom, a bromine atom, and an iodine atom. , A lower alkylsulfonyloxy group, a substituted or unsubstituted benzenesulfonyloxy group, and the like. Examples of the lower alkylsulfonyloxy group include a methanesulfonyloxy group and an ethanesulfonyloxy group, and examples of the substituted or unsubstituted benzenesulfonyloxy group include a benzenesulfonyloxy group, a 4-methylbenzenesulfonyloxy group, and a 4-methoxybenzenesulfonyloxy group. Group, 4-chlorobenzenesulfonyloxy group and the like.

In the general formula (1), as the linear or branched alkyl group having 1 to 4 carbon atoms represented by R ₁ , —CH ₂ — group, — (CH ₂ ) ₂ — group, — (CH ₂ ) ₃ - group, - (CH _{2) 4} - group, -CH ₃ CH- group, - (CH _{3) 2} C- _{group, - (CH 3 CH 2)} C (CH 3) - group and the like, R ₂ is hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, tertiary butyl group, methoxy group, ethoxy group, propoxy group, butoxy Groups and the like. The substitution positions of the substituents R ₁ and R ₂ are not particularly limited.

  Furthermore, in the general formula (1), X is a chlorine anion, a bromine anion, an iodine anion, a lower alkylsulfonyloxy anion, a substituted or unsubstituted benzenesulfonyloxy anion, a lower alkylcarboxy anion, a substituted or unsubstituted benzenecarboxy anion, etc. Is mentioned. Here, examples of the lower alkylsulfonyloxy anion include methanesulfonyloxy anion and ethanesulfonyloxy anion. Examples of the substituted or unsubstituted benzenesulfonyloxy anion include benzenesulfonyloxy anion, 4-methylbenzenesulfonyloxy anion, Examples include 4-methoxybenzenesulfonyloxy anion and 4-chlorobenzenesulfonyloxy anion. On the other hand, examples of the lower alkylcarboxy anion include an acetoxy anion and propionyloxy anion. Examples of the substituted or unsubstituted benzenecarboxy anion include benzoyloxy anion, 4-methylbenzoyloxy anion, 4-methoxybenzoyloxy anion, 4 -Chlorobenzoyloxy anion and the like.

  In the general formula (1), when m = 0, the compound of the general formula (1) is a free pyridine base, and when m = 1, the corresponding various inorganic acids or organic acid salts.

  The pyridine compound represented by the general formula (1) as a starting material can be obtained by various methods. For example, free bases such as 2-chloromethylpyridine, 3-chloromethylpyridine, 4-chloromethylpyridine and salts thereof, free bases such as 2-bromomethylpyridine, 3-bromomethylpyridine, 4-bromomethylpyridine and the like Salt, 2-iodomethylpyridine, 3-iodomethylpyridine, 4-iodomethylpyridine and salts thereof, 2- (methanesulfonyloxy) methylpyridine, 3- (methanesulfonyloxy) methylpyridine, 4- (methanesulfonyloxy) Free bases such as methylpyridine and salts thereof, free bases such as 2- (benzenesulfonyloxy) methylpyridine, 3- (benzenesulfonyloxy) methylpyridine, 4- (benzenesulfonyloxy) methylpyridine and salts thereof can be used. .

In the general formula (2), R ₃ having a linear or branched alkyl group having 2 to 12 carbon atoms can be obtained by various methods and used in the present invention. For example, ethylene glycol, propylene glycol, 1,2-propanediol, 1,4-butanediol, 1,2-butanediol, 2,3-butanediol, 1,5-pentanediol, 1,6-hexanediol, Diols such as 1,8-octanediol, 1,10-decanediol, 2-methyl-2,4-pentanediol, 2-ethyl-1,3-hexanediol, and 2-butene-1,4-diol Diols having an unsaturated bond and diols having an ether bond such as diethylene glycol and triethylene glycol can also be used.

  The amount of the pyridine compound represented by the general formula (1) or a salt thereof is preferably from 1 equivalent mole to 1.5 equivalent moles relative to the diol represented by the general formula (2). More preferred is 1 equivalent mole.

  Various reaction conditions are possible when producing the pyridine compound represented by the general formula (3) by the reaction of the pyridine compound represented by the general formula (1) and the diol represented by the general formula (2). It is. The presence of a strong base is essential for carrying out this reaction, because it is important that the diols represented by the general formula (2) produce the corresponding alkoxide. Strong bases that can be used in this reaction include metallic lithium, metallic potassium, metallic sodium and hydrides thereof, alkyllithiums such as methyllithium and butyllithium, phenyllithium, lithium tertiary riboxide, potassium tertiary riboxide, sodium Tertiary alkali metal alkoxides such as tartaribtoxide are mentioned, and sodium tartariboxide and potassium tartariboxide are preferred from the viewpoint of economy, safety and simplicity. These strong bases may be used alone or in combination of two or more.

  In this reaction, when the free base of the pyridine compound represented by the general formula (1) is used as a raw material, the strong base used is about 1 equivalent mole. Furthermore, when the pyridine compound represented by the general formula (1) forms a salt, the strong base used is about 1 equivalent mole sufficient to neutralize the salt and about 1 consumed for the desired reaction. It is about 2 equivalent moles when the equivalent moles are combined. However, when the conversion rate is low, a strong base may be added until the pyridine compound represented by the general formula (1) disappears. The strong base used for neutralizing the salt and the strong base used for the desired reaction may be the same or different. In carrying out this reaction, since the pyridine compound represented by the general formula (1) is easily changed by contact with a strong base, an alkoxide is previously obtained by reacting the diol represented by the general formula (2) with the strong base. The alkoxide and the pyridine compound represented by the general formula (1) are treated, or the pyridine compound represented by the general formula (1) and the diol represented by the general formula (2) are mixed in advance. Then, it is preferable to add a strong base to the mixture. When the pyridine compound represented by the general formula (1) forms a salt, an amount of a strong base capable of liberating the compound can be added in advance, and the treatment can be performed according to the procedure described above.

  This reaction can usually be carried out in the presence of various solvents, but as a solvent that does not adversely affect the desired reaction and gives good conversion and selectivity in the desired reaction, an aprotic polar solvent Is preferred. As the aprotic polar solvent, cyclic ether solvents such as tetrahydrofuran and dioxane, amide solvents such as dimethylformamide, N-methylpyrrolidone, and dimethylimidazolidinone are preferably used. Considering simplicity, dimethylformamide is the most suitable solvent. These solvents may be used alone or in combination of two or more. The amount of the solvent used is the solubility of the pyridine compound or its salt represented by the general formula (1) as a raw material and the solubility of the diol represented by the general formula (2) and the dispersion of the alkali metal salt generated during the reaction. Appropriate selection can be made in consideration of the mode.

  The temperature of this reaction can be selected from −20 ° C. to the boiling point of the solvent used at normal pressure. A preferable reaction temperature is −20 ° C. to room temperature, and a more preferable reaction temperature is −10 ° C. to 10 ° C. The progress of the reaction can be traced by thin layer chromatography or high performance liquid chromatography, and the completion of the reaction can be confirmed by disappearance of the raw material.

  The pyridine compound represented by the general formula (3) obtained by this reaction can be removed from the reaction mixture by a conventional method. For example, the alkali metal salt generated by solid-liquid separation of the mixture after completion of the reaction is removed, the mother liquor is concentrated under reduced pressure, the residual liquid is extracted after dispersion in water, and the extract is concentrated under reduced pressure. Higher purity compounds are produced by generating salts of inorganic or organic acids such as hydrochlorides, acetates and sulfates of pyridine compounds represented by the general formula (3), and if necessary after recrystallization thereof. It can be obtained by neutralizing the salt and treating it in a conventional manner.

  Next, the pyridine compound represented by the general formula (3) is reacted with the pyridine compound represented by the general formula (4) or a salt thereof in the presence of a strong base, thereby being represented by the general formula (5). A pyridine compound can be produced.

As the pyridine compound represented by the general formula (4) or a salt thereof, the same compound as the pyridine compound represented by the general formula (1) or a salt thereof can be selected. In this case, when R ₁ ≠ R ₄ or R ₂ ≠ R _{5 in} the pyridine compound represented by the general formula (4) or a salt thereof and the pyridine compound represented by the general formula (1) or a salt thereof, The obtained pyridine compound represented by the general formula (5) is a compound in which two pyridine rings have different pyridylalkyl groups or substituents on the ring, and R ₁ = R ₄ and R ₂ = R ₅ In the obtained pyridine compound represented by the general formula (5), a pyridylalkyl group or a substituent on the ring is the same in two pyridine rings.

Further, in the production of the pyridine compound represented by the general formula (3), when the diol represented by the general formula (2) to be used is a control type diol, the pyridine compound represented by the general formula (4) or In the case where R ₁ = R ₄ and R ₂ = R _{5 in} the salt and the pyridine compound represented by the general formula (1) or the salt thereof, the pyridine represented by the general formula (5) thus obtained The compound becomes a compound having a symmetrical structure.

The pyridine compound represented by the general formula (5) can also be produced without isolating the compound represented by the general formula (3). For example, when the pyridine compound represented by the general formula (3) is generated in the reaction system by the above-described operation, and then the pyridine compound represented by the general formula (4) is allowed to act in the presence of a strong base. Good. This method is effective when R ₁ = R ₄ and R ₂ = R _{5 in} the pyridine compound represented by the general formula (4) and the general formula (1) or a salt thereof, and A = B This is an extremely effective means when X = Y.

  The amount of the pyridine compound represented by the general formula (4) or a salt thereof is preferably 1 to 1.5 equivalents relative to the pyridine compound represented by the general formula (3). Use of 1 equivalent is preferred.

  As described above, in the reaction of the pyridine compound represented by the general formula (3) and the pyridine compound represented by the general formula (4) or a salt thereof, the pyridine compound represented by the general formula (4) or a salt thereof Since it is easy to change by contact with a strong base, after the alkoxide of the compound represented by the general formula (3) is generated in advance by the reaction of the pyridine compound represented by the general formula (3) and the strong base, Add a pyridine compound represented by formula (4), or previously mix a pyridine compound represented by formula (3) and a pyridine compound represented by formula (4), and then add a strong base It is preferable to do. When the pyridine compound represented by the general formula (4) forms a salt, an amount capable of liberating the compound, usually about 1 equivalent mole of a strong base is added in advance, and the above procedure is followed. Is possible.

  In this reaction, it is possible to use a strong base selected in the reaction of the pyridine compound represented by the general formula (1) or a salt thereof and the diol represented by the general formula (2). It may be used or two or more types may be used in combination. When the pyridine compound represented by the general formula (4) is a free base, the amount of strong base used is preferably about 1 equivalent mole. However, when the conversion rate is low, a strong base may be added until the pyridine compound represented by the general formula (3) and the pyridine compound represented by the general formula (4) disappear.

  In this reaction, it is possible to use a solvent selected in the reaction of the pyridine compound represented by the general formula (1) or a salt thereof and the diol represented by the general formula (2). Alternatively, two or more types may be used in combination. The amount of the solvent used is appropriately selected depending on the solubility of the pyridine compound represented by the general formula (3) and the pyridine compound represented by the general formula (4) and salts thereof and the dispersion state of the alkali metal salt generated during the reaction. it can.

  This reaction can be selected from −20 ° C. to the boiling point of the solvent used under normal pressure. A preferable reaction temperature is −20 ° C. to room temperature, and a more preferable reaction temperature is −10 ° C. to 10 ° C. The progress of the reaction can be traced by thin layer chromatography or high performance liquid chromatography, and the completion of the reaction can be confirmed by disappearance of the raw material. The pyridine compound represented by the general formula (5) can be taken out from the reaction mixture by a conventional method. When the compound is crystalline, a higher purity compound can be obtained by recrystallization. When the compound is non-crystalline, after forming an inorganic or organic acid salt such as monohydrochloride, dihydrochloride, monoacetate, diacetate, etc. of the compound and recrystallizing them as necessary A high-purity compound can be obtained by neutralizing the salt and removing it by a conventional method.

Next, by reacting the pyridine compound represented by the general formula (5) with the halogen compound or sulfonic acid ester compound represented by the general formula (6), a desired general formula (7) is represented. A bactericidal pyridine compound can be obtained. In the general formula (6), R ₆ can be a linear or branched alkyl group having 1 to 18 carbon atoms, and Z is represented by a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or an OSO ₂ R ₇ group. Substituted sulfonyloxy groups can be selected. In this case, R ₇ can be a lower alkyl group or a substituted or unsubstituted phenyl group. For example, examples of the halogen compound represented by the general formula (6) include alkyl chlorides having 1 to 18 carbon atoms, alkyl bromides, and alkyl iodides. Examples thereof include lower alkyl sulfonic acid esters of alcohol and substituted or unsubstituted benzene sulfonic acid esters.

  In this reaction, the amount of the halogen compound or sulfonate compound represented by the general formula (6) used relative to the pyridine compound represented by the general formula (5) is theoretically 2 equivalent moles. However, when the conversion rate is low, a larger amount of the compound of the general formula (6) can be used. If it is used in a large excess, it can be recovered and reused.

  In the reaction of the pyridine compound represented by the general formula (5) and the halogen compound or sulfonic acid ester compound represented by the general formula (6), a solvent can be used. Preferred solvents include lower aliphatic alcohols and aprotic polar solvents. Specifically, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol, acetonitrile, propionitrile, acetone, methyl ethyl ketone. , Methyl isobutyl ketone, tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone, dimethylimidazolidinone, dimethyl sulfoxide and the like can be used. Dimethylformamide is the most preferred solvent because of good conversion and selectivity of the reaction, simple post-treatment, and excellent economic efficiency.

  These solvents may be used alone or in combination of two or more. The amount of the solvent used can be appropriately selected in consideration of the solubility of the pyridine compound represented by the general formula (5), the halogen compound represented by the general formula (6) or the sulfonic acid ester compound in the solvent.

  On the other hand, this reaction can also be carried out using an excess of the halogen compound or sulfonate compound represented by the general formula (6) without using a solvent. In this case, after completion of the reaction, the unreacted compound represented by the general formula (6) can be separated from the reaction mixture, recovered, and reused, which is extremely efficient and economical.

  This reaction can be carried out from 0 ° C. at the boiling point at normal pressure of the solvent to be used or the compound represented by the general formula (6). A preferred temperature is from room temperature to 100 ° C, and a more preferred temperature is from 40 ° C to 80 ° C. The progress of the reaction can be traced by high performance liquid chromatography or the like, and the end of the reaction can be judged from the disappearance of the raw material and the amount of the bactericidal pyridine compound of the general formula (7) produced.

  Further, the reaction is represented by the general formula (6) in the reaction mixture containing the pyridine compound represented by the general formula (5) without isolating the pyridine compound represented by the general formula (5). It is also possible to carry out continuously by adding a compound. In this case, what is necessary is just to use the solvent used for manufacture of the compound of General formula (5) as it is.

  The bactericidal pyridine compound represented by the general formula (7) can be taken out by a conventional method, and a compound that is solid at room temperature can be crystallized from an appropriate solvent system. In this case, by selecting an appropriate solvent system, purification by recrystallization is possible, and a high-purity target product can be obtained.

ＤＭＦ（ジメチルホルムアミド）７５ｍｌに１，４−ブタンジオール８．２４ｇ（９１．４３ｍｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド１０．３ｇ（９１．７９ｍｍｏｌ）を添加し、室温で１．５時間撹拌した。 The following examples further illustrate the present invention.
<Example 1>
[Synthesis of Compound (3-A) represented by Structural Formula below]

To 75 ml of DMF (dimethylformamide), 8.24 g (91.43 mmol) of 1,4-butanediol was added, and 10.3 g (91.79 mmol) of potassium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1.5 hours. did.

  To this slurry solution, 1.0 g (6.10 mmol) of 3-chloromethylpyridine hydrochloride and 0.68 g (6.06 mmol) of potassium tert-butoxide were alternately added at −8 to −3 ° C., and this was repeated 15 times. In total, 15.0 g (91.45 mmol) of 3-chloromethylpyridine hydrochloride and 10.2 g (90.9 mmol) of potassium tert-butoxide were added.

  After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, a peak of 3-chloromethylpyridine was confirmed. Therefore, potassium tert-butoxide was kept at 5 ° C. or lower until the peak of 3-chloromethylpyridine disappeared. Added. The added potassium tert-butoxide was 1.13 g (10.07 mmol).

  The reaction mixture was subjected to solid-liquid separation, the cake was washed with 30 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure to obtain 17.1 g of an oily crude product (compound (3-A)). When the obtained oil was analyzed by HPLC (Condition 1), the area% of the compound (3-A) was 76.0%.

The crude product of the compound (3-A) was dissolved in 30 ml of water and washed with toluene. Thereafter, 6 g of sodium chloride was added to the aqueous layer, followed by extraction with 20 ml × 2 dichloromethane, dehydration with anhydrous magnesium sulfate, the solvent was distilled off, and 9.21 g of the oily compound (3-A) (yield (1,4 -From butanediol): 57.2%). When the obtained oil was analyzed by HPLC (Condition 1), the area% was 99.4%. _{^{(1 H-NMR (CDCl 3}} ): δ1.67-1.75 (4H, m, - (C H 2) 2 -), δ2.35 (1H, s, O H), δ3.52-3. 56 (2H, t, J = 6.0 Hz, C H ₂ ), δ 3.64-3.68 (2H, t, J = 6.0 Hz, C H ₂ ), δ 4.52 (2H, s, C H ₂ ), δ 7.27-7.31 (1H, m, arom H ), δ 7.66-7.70 (1 H, m, arom H ), δ 8.52-8.56 (2H, m, arom H × 2), MS (APCl): m / z = 182 [M + H] ⁺ )

HPLC (condition 1)
Column: Inertsil ODS-3 (GL Sciences) 4.6 mmφ × 250 mm
Column temperature: constant temperature around 15 ° C. Mobile phase: A-0.5% ammonium acetate aqueous solution, B-acetonitrile A: B = 70: 30 (constant)
・ Flow rate: 1.0ml / min
・ Detector: UV254nm
・ Injection volume: 20μL

ＤＭＦ２５ｍｌに前記化合物（３−Ａ）５．０ｇ（２７．５９ｍｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド３．１ｇ（２７．６３ｍｍｏｌ）を添加した。このスラリーに５〜６℃で３−クロロメチルピリジン塩酸塩０．５ｇ（３．０５ｍｍｏｌ）およびカリウムtert−ブトキシド０．３４ｇ（３．０３ｍｍｏｌ）を交互に添加し、これを９回繰り返し、全量で３−クロロメチルピリジン塩酸塩４．５ｇ（２７．４３ｍｍｏｌ）およびカリウムtert−ブトキシド３．０６ｇ（２７．２７ｍｍｏｌ）を添加した。 <Example 2>
[Synthesis of Compound (5-A) represented by Structural Formula below]

To 25 ml of DMF was added 5.0 g (27.59 mmol) of the compound (3-A), and 3.1 g (27.63 mmol) of potassium tert-butoxide was added under ice cooling. To this slurry, 0.5 g (3.05 mmol) of 3-chloromethylpyridine hydrochloride and 0.34 g (3.03 mmol) of potassium tert-butoxide were alternately added at 5 to 6 ° C., and this was repeated 9 times. 4.5 g (27.43 mmol) of 3-chloromethylpyridine hydrochloride and 3.06 g (27.27 mmol) of potassium tert-butoxide were added.

  After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- Potassium tert-butoxide was added at 5 ° C. or lower until the peak of A) disappeared. The added potassium tert-butoxide was 0.62 g (5.53 mmol).

The reaction mixture was separated into solid and liquid, the cake was washed with 30 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 20 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 5.8 g of an oily substance. About 0.5 g of this crude product was purified by silica gel column chromatography (developing solvent: chloroform-methanol) to obtain 0.3 g of oily compound (5-A). ( ¹ H-NMR: δ 1.70-1.74 (4H, m,-(C H ₂ ) _2- ), δ 3.50-3.54 (4H, m, C H ₂ × 2), δ 4.51 (4H, s, C H ₂ × 2), δ 7.25-7.29 (2H, dd, J = 4.9 Hz, 7.9 Hz, arom H × 2), δ 7.65-7.69 (2H, dt, J = 1.7 Hz, 7.9 Hz, arom H × 2), δ 8.52-8.57 (4H, dd, J = 1.7 Hz, 4.9 Hz, arom H × 4), MS (APCl) : M / z = 273 [M + H] ⁺ )

前記化合物（５−Ａ）５．０ｇ（１８．３６ｍｍｏｌ）にオクチルブロマイド３５．５ｇ（１８３．８ｍｍｏｌ）を加え、７０〜８０℃で２０時間反応を行った。 <Example 3>
[Synthesis of Compound (7-A) of the following Structural Formula]

35.0 g (183.8 mmol) of octyl bromide was added to 5.0 g (18.36 mmol) of the compound (5-A), and reacted at 70 to 80 ° C. for 20 hours.

  When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-A) disappeared. The upper octyl bromide layer was separated from the reaction mixture, and the lower oil layer was poured into a mixture of acetonitrile-ethyl acetate = 1: 3 (v / v). The mixture was cooled, and the precipitated crystals were filtered at 0 ° C. and dried under reduced pressure to obtain 9.7 g of grayish white crystals (crude yield (from the compound (5-A)): 85%).

2 g of the obtained crystal was recrystallized with a mixed solution of acetonitrile-ethyl acetate = 1: 3 (v / v) to obtain 1.6 g of a compound (7-A) as a fine grayish white crystal. (Mp 52-53 ° C., ¹ H-NMR (d ⁶ -DMSO): δ 0.82-0.89 (6H, t, J = 5.3 Hz, C H ₃ × 2), δ 1.25- 1.34 (20H, m, - ( C H 2) 5 - × 2), δ1.77-1.80 (4H, m, - (C H 2) 2 - × 2), δ2.04-2. 09 (4H, t, J = 7.0 Hz, C H ₂ × 2), δ 3.70-3.72 (4H, t, J = 5.9 Hz, C H ₂ × 2), δ 4.67-4. 71 (4H, t, J = 7.0 Hz, C H ₂ × 2), δ 4.84 (4H, s, C H ₂ × 2), δ 8.11-8.15 (2H, dd, J = 6. 0 Hz, 8.0 Hz, arom H × 2), δ 8.56-8.59 (2H, d, J = 8.0 Hz, arom H × 2), δ 8.69-8.92 (4H, dd, J = 6.0Hz, 13.1Hz, arom H × 4), MS (ESI): m / z = 579 [M-Br] ⁺ ).

HPLC (condition 2)
Column: Inertsil ODS-3 (GL Sciences) 4.6 mmφ × 250 mm
Column temperature: constant temperature around 15 ° C. Mobile phase: A-0.5% ammonium acetate aqueous solution, B-acetonitrile A: 70% (12 min hold) → (10 min) → A: 50% (14 min hold) → A : 70%
・ Flow rate: 1.0ml / min
・ Detector: UV254nm
・ Injection volume: 20μL

<Example 4>
[Synthesis of Compound (5-A): 3-chloromethylpyridine-DMF slurry added dropwise to 1,4-butanediol potassium salt-DMF slurry]
1,4-butanediol (1.37 g, 15.20 mmol) was added to DMF (20 ml), and potassium tert-butoxide (1.71 g, 15.24 mmol) was added under ice cooling, followed by stirring at room temperature for 1 hour.

  On the other hand, 2.5 g (15.24 mmol) of 3-chloromethylpyridine hydrochloride was added to 15 ml of DMF, and 1.71 g (15.24 mmol) of potassium tert-butoxide was added under ice cooling. To the 1,4-butanediol-DMF slurry, 3-chloromethylpyridine-DMF slurry was added dropwise at -17 to -14 ° C.

  When the reaction mixture was analyzed by HPLC (condition 1), a peak of 3-chloromethylpyridine was confirmed, and potassium tert-butoxide was added at -10 ° C. or lower until the peak of 3-chloromethylpyridine disappeared. After confirming the disappearance of the peak of 3-chloromethylpyridine, 1.71 g (15.24 mmol) of potassium tert-butoxide was added to the reaction mixture under ice-cooling, and the same amount of 3-chloromethylpyridine-DMF slurry as prepared above was added. Was added dropwise at -20 to -17 ° C. When the reaction mixture was analyzed by HPLC (condition 1), a peak of 3-chloromethylpyridine was confirmed, and potassium tert-butoxide was added at -10 ° C. or lower until the peak of 3-chloromethylpyridine disappeared. After confirming disappearance of the peak of 3-chloromethylpyridine, the reaction mixture was subjected to solid-liquid separation, the cake was washed with 25 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure.

  20 ml of dichloromethane was added to the concentrated residue, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 3.79 g of the oily compound (5-A) (crude yield (1,4-butanediol). More): 91.8%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-A) was 64.5%.

<Example 5>
[Synthesis of Compound (5-A): Potassium tert-butoxide is added in portions to a slurry of DMF-1,4-butanediol-3-chloromethylpyridine hydrochloride]
1.37 g (15.20 mmol) of 1,4-butanediol and 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride were added to 50 ml of DMF, and 6.84 g of potassium tert-butoxide at −20 to −13 ° C. 60.96 mmol) was added in 10 portions.

  When the reaction mixture was analyzed by HPLC (condition 1), the peak of 3-chloromethylpyridine and the peak of the compound (3-A) were confirmed, so the peak of 3-chloromethylpyridine and the compound (3-A) were confirmed. Until the peak disappeared, 3-chloromethylpyridine hydrochloride and potassium tert-butoxide were added at -10 ° C or lower. The added 3-chloromethylpyridine hydrochloride was 1.0 g (6.10 mmol), and potassium tert-butoxide was 8.7 g (77.53 mmol).

  The reaction mixture was separated into solid and liquid, the cake was washed with 25 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue was added 20 ml of dichloromethane, and the solution was washed with saturated brine, and then the solvent was distilled off to give 4.31 g of the oily compound (5-A) (crude yield (3-chloromethylpyridine hydrochloride). From the salt): 86.5%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-A) was 72.8%.

<Example 6>
[Synthesis of Compound (5-A): Scale-up of Example 5]
1,4-butanediol (13.73 g, 0.1524 mol) and 3-chloromethylpyridine hydrochloride (50.0 g, 0.3048 mol) were added to DMF (250 ml), and potassium tert-butoxide (68.4 g) was added at -19 to -12 ° C. 0.6096 mol) was added in 20 portions.

  When the reaction mixture was analyzed by HPLC (condition 1), the peak of 3-chloromethylpyridine and the compound (3-A) was confirmed, so the peak of 3-chloromethylpyridine and the peak of the compound (3-A) were confirmed. 3-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at −10 ° C. or lower until disappeared.

  The added 3-chloromethylpyridine hydrochloride was 8.0 g (0.0366 mol), and potassium tert-butoxide was 23.9 g (0.2130 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 125 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 200 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off. 41.0 g of the oily compound (5-A) (crude yield (1,4-butanediol) More): 98.8%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-A) was 68.8%.

<Example 7>
[Synthesis of Compound (5-A): 3-Chloromethylpyridine Hydrochloride and Potassium Tert-Butoxide Added Alternately to 1,4-Butanediol Monopotassium Salt-DMF Slurry]

  1,4-butanediol (13.73 g, 0.1524 mol) was added to DMF (250 ml), and potassium tert-butoxide (17.1 g, 0.1524 mol) was added under ice cooling, followed by stirring at room temperature for 2 hours. To this slurry, 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride and 3.42 g (30.48 mmol) of potassium tert-butoxide were alternately added at −15 to −10 ° C., and this was repeated 5 times. . Subsequent additions were carried out by alternately adding 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride and 6.84 g (60.96 mmol) of potassium tert-butoxide at −16 to −7 ° C. Repeatedly, 50.0 g (0.3048 mol) of 3-chloromethylpyridine hydrochloride and 51.3 g (0.4572 mol) of potassium tert-butoxide were added in total.

  After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- 3-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at 0 ° C. or lower until the peak of A) disappeared.

  The added 3-chloromethylpyridine hydrochloride was 2.65 g (0.0366 mol), and potassium tert-butoxide was 4.96 g (0.0442 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 125 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure.

  To this concentrated residue, 200 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 40.9 g of the oily compound (5-A) (crude yield (1,4-butanediol). More): 98.6%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-A) was 89.2%.

  2 g (7.41 mmol) of the obtained crude product was dissolved in 10 g of isopropyl alcohol, and 0.27 g (7.41 mmol) of hydrogen chloride gas was blown into the solution. The mixture was cooled to 10 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 1.1 g of monohydrochloride of the compound (5-A) (yield: 48.0%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound was 97.5%.

<Example 8>
[Synthesis of Compound (5-A): A 3-chloromethylpyridine hydrochloride-DMF solution was dropped into 1,4-butanediol-potassium tert-butoxide-DMF slurry to form the compound (3-A). The potassium tert-butoxide-DMF solution was added dropwise to the slurry obtained by adding 3-chloromethylpyridine hydrochloride to the reaction mixture.
To 100 ml of DMF, 13.73 g (0.1524 mol) of 1,4-butanediol was added, and 34.2 g (0.3048 mol) of potassium tert-butoxide was added under ice cooling, followed by stirring at 5 ° C. or lower for 30 minutes. To this slurry, a DMF (150 ml) solution of 25.0 g (0.1524 mol) of 3-chloromethylpyridine hydrochloride was added dropwise at 4 to 10 ° C. over 1.5 hours.

  Next, 25.0 g (0.1524 mol) of 3-chloromethylpyridine hydrochloride and 17.1 g (0.1524 mol) of potassium tert-butoxide were added to the reaction mixture at 0 ° C. or lower, and then 17.1 g (0 of potassium tert-butoxide). .1524 mol) in DMF (100 ml) was added dropwise at −10 to 0 ° C. over 30 minutes. After completion of the dropwise addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- 3-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at 0 ° C. or lower until the peak of A) disappeared.

  The added 3-chloromethylpyridine hydrochloride was 6.5 g (0.0396 mol), and potassium tert-butoxide was 8.89 g (0.0792 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 150 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 200 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 43.2 g of the oily compound (5-A) (crude yield (3-chloromethylpyridine hydrochloride). From the salt): 92.1%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-A) was 87.8%.

<Example 9>
[Synthesis of Compound (5-A): DMF solution of potassium tert-butoxide added dropwise to a slurry of DMF-1,4-butanediol-3-chloromethylpyridine hydrochloride]
To 200 ml of DMF, 6.87 g (0.0762 mol) of 1,4-butanediol and 25.0 g (0.1524 mol) of 3-chloromethylpyridine hydrochloride were added, and 35.9 g of potassium tert-butoxide was added at −11 to −5 ° C. 0.3199 mol) of DMF (100 ml) was added dropwise over 1.5 hours. After aging overnight at room temperature, the reaction mixture was analyzed by HPLC (condition 1). As a result, the peak of the compound (3-A) was confirmed. Therefore, until the peak of the compound (3-A) disappeared, Chloromethylpyridine hydrochloride and potassium tert-butoxide were added below 0 ° C. The added 3-chloromethylpyridine hydrochloride was 2.5 g (0.0152 mol), and potassium tert-butoxide was 3.42 g (0.0305 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 150 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue was added 100 ml of dichloromethane, and the solution was washed with saturated brine, and then the solvent was distilled off. The oily compound (5-A) 20.1 g (crude yield (1,4-butanediol) More): 96.6%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-A) was 80.3%.

<Example 10>
[Synthesis of Compound (5-A): Scale Up of Example 7]
To 750 ml of DMF, 41.2 g (0.457 mol) of 1,4-butanediol was added, and 51.3 g (0.457 mol) of potassium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, 7.5 g (45.72 mmol) of 3-chloromethylpyridine hydrochloride and 5.1 g (45.45 mmol) of potassium tert-butoxide were alternately added at −5 to 0 ° C., and this was repeated 10 times. Subsequent addition was carried out by alternately adding 7.5 g (45.72 mmol) of 3-chloromethylpyridine hydrochloride and 10.2 g (90.9 mmol) of potassium tert-butoxide at −6 to −1 ° C. Repeatedly, 150.0 g (0.9145 mol) of 3-chloromethylpyridine hydrochloride and 153.0 g (1.364 mol) of potassium tert-butoxide were added in total.

  After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- 3-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at 5 ° C. or lower until the peak of A) disappeared. There was no added 3-chloromethylpyridine hydrochloride, and potassium tert-butoxide was 10.3 g (91.79 mmol). The reaction mixture was separated into solid and liquid, the cake was washed with 300 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. Dichloromethane (500 ml) was added to the concentrated residue, the solution was washed with saturated brine, and the solvent was distilled off to give 111.9 g of the oily compound (5-A) (crude yield (1,4-butanediol). More): 89.9%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-A) was 93.9%.

<Example 11>
[Synthesis of Compound (7-A): Reaction Solvent-Methanol / Acetonitrile Mixed Solution]
10.0 g (36.72 mmol) of the compound (5-A) and 70.9 g (0.367 mol) of octyl bromide were added to 50 g of a methanol / acetonitrile = 3: 1 (v / v) mixture, and the reaction was allowed to proceed for 135 hours under reflux. went. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-A) disappeared. The upper octyl bromide layer was separated, ethyl acetate was added to the lower layer, the mixture was cooled, the precipitated crystals were filtered off at −18 ° C., the cake was washed with 10 ml of ethyl acetate, dried under reduced pressure, and the compound (7- A) 20.3 g (crude yield: 83.9%) was obtained. When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (7-A) was 91.4%.

<Example 12>
[Synthesis of Compound (7-A): Reaction Solvent-DMF]
To 25 ml of DMF, 5.0 g (18.36 mmol) of the compound (5-A) and 35.5 g (0.184 mol) of octyl bromide were added, and the reaction was carried out at 50 to 55 ° C. for 86 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-A) disappeared. From the reaction mixture, DMF and octyl bromide were distilled off under reduced pressure to obtain 12.9 g (crude yield: 106.6%) of the oily compound (7-A). When the obtained oil was analyzed by HPLC (condition 2), the peak area% of the compound (7-A) was 93.0%.

<Example 13>
[Synthesis of Compound (7-A): Reaction without Solvent, Reaction Temperature 45-55 ° C.]
70.0 g (0.3671 mol) of octyl bromide was added to 10.0 g (36.72 mmol) of the compound (5-A), and the reaction was performed at 49 to 52 ° C. for 50 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-A) disappeared. The reaction mixture was cooled, the precipitated crystals were filtered off at room temperature, washed with 20 ml of ethyl acetate, and dried under reduced pressure to obtain 21.2 g (crude yield: 87.6%) of the compound (7-A). . When the obtained crystal was analyzed by HPLC (condition 2), the area% of the peak of the compound (7-A) was 93.3%.

<Example 14>
[Synthesis of Compound (7-A): Reaction without Solvent, Crystallization with Ethanol / Ethyl Acetate Mixture, Reaction Temperature 75-80 ° C.]
70.0 g (0.3671 mol) of octyl bromide was added to 10.0 g (36.72 mmol) of the compound (5-A), and the reaction was performed at 75 to 77 ° C. for 20 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-A) disappeared. The upper octyl bromide layer was separated from the reaction mixture, 10 ml of ethanol was added to the lower layer to dissolve, and the solution was poured into 200 ml of ethyl acetate. The mixture was cooled, and the precipitated crystals were separated by filtration at -10 ° C, washed with 10 ml of ethyl acetate, and dried under reduced pressure to obtain 17.4 g (crude yield: 71.9%) of the compound (7-A). It was. When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (7-A) was 95.2%.

<Example 15>
[Synthesis of Compound (7-A): Same as Example 14 except that the ratio of ethanol / ethyl acetate mixture was changed and the reaction conditions were as follows]
70.0 g (0.3671 mol) of octyl bromide was added to 10.0 g (36.72 mmol) of the compound (5-A), and the reaction was performed at 75 to 77 ° C. for 20 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-A) disappeared. When 10 ml of ethanol was added to the reaction mixture and allowed to stand, the upper layer became an ethanol solution layer of the compound (7-A), the lower layer became an octyl bromide layer, and the lower layer was separated. The upper layer was then poured into 500 ml of ethyl acetate. The mixture was cooled, the precipitated crystals were filtered off at 5 ° C., washed with 10 ml of ethyl acetate, and dried under reduced pressure to obtain 20.8 g (crude yield: 86.0%) of the compound (7-A). When the obtained crystal was analyzed by HPLC (condition 2), the area% of the peak of the compound (7-A) was 90.8%.

<Example 16>
[Synthesis of Compound (7-A): Same as Example 14 except that the ratio of ethanol / ethyl acetate mixture was changed and the reaction conditions were as follows. Recrystallize crude product with acetonitrile / ethyl acetate mixture]
709.1 g (3.67 mol) of octyl bromide was added to 100.0 g (0.367 mol) of the compound (5-A), and the reaction was carried out at 75 to 78 ° C. for 20 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-A) disappeared. When 97 ml of ethanol was added to the reaction mixture and allowed to stand, the upper layer was an ethanol solution layer of the compound (7-A), the lower layer was an octyl bromide layer, and the lower layer was separated. The upper layer was then poured into 2900 ml of ethyl acetate. The mixture was cooled, the precipitated crystals were filtered off at 3 ° C., washed with 100 ml of ethyl acetate, and dried under reduced pressure to obtain 215.8 g (crude yield: 89.3%) of the compound (7-A). When the obtained crystal was analyzed by HPLC (condition 2), the area% of the peak of the compound (7-A) was 93.1%.

  212 g of the obtained crystals were recrystallized from a mixed liquid of 592 ml of acetonitrile and 1953 ml of ethyl acetate to obtain 192.1 g (purification yield: 90.6%) of the compound (7-A). When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (7-A) was 96.4%.

<Example 17>
[Synthesis of Compound (7-A): Compound (5-A) was synthesized from benzenesulfonate of 3-chloromethylpyridine. Synthesis of Compound (7-A) without Isolating Compound (5-A)]
To 35 g of DMF, 3.2 g (0.035 mol) of 1,4-butanediol was added, and 3.9 g (0.035 mol) of potassium tert-butoxide was added at 10 to 20 ° C. To this slurry, a DMF (55 g) solution of 20.0 g (0.07 mol) of 3-chloromethylpyridine benzenesulfonate was added dropwise at 10 to 25 ° C., and simultaneously 16.8 g (0.15 mol) of potassium tert-butoxide was added. Added in portions. After completion of the addition, the reaction mixture was analyzed by HPLC (Condition 1). Since peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed, 3-chloromethylpyridine and the compound (3-A) were confirmed. Potassium tert-butoxide was added at 20 ° C. or lower until the peak disappeared. The added potassium tert-butoxide was 1.5 g (0.01 mol).

  Inorganic salts were filtered off from the reaction mixture, and the cake was washed with 10 g of DMF. 96.0 g (0.5 mol) of octyl bromide was added to the filtrate and the reaction was carried out at 60 ° C. for 72 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-A) disappeared. The reaction mixture was subjected to solid-liquid separation, the cake was washed with 20 g of DMF, DMF and octyl bromide were distilled off from the filtrate under reduced pressure, and 41.1 g of the oily compound (7-A) was obtained (crude yield (3-chloro From methyl pyridine benzenesulfonate): 89.2%). When the obtained oil was analyzed by HPLC (condition 2), the area% of the peak of the compound (7-A) was 87.8%.

<Example 18>
[Synthesis of Compound (5-A): Same as Example 7 except that the base was replaced with sodium tert-butoxide and the reaction conditions were as follows]
1,4-butanediol (13.73 g, 0.1524 mol) was added to DMF (250 ml), and sodium tert-butoxide (14.65 g, 0.1524 mol) was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride and 2.93 g (30.48 mmol) of sodium tert-butoxide were alternately added at −15 to −10 ° C., and this was repeated 5 times. . Subsequent addition was carried out by alternately adding 5.0 g (30.48 mmol) of 3-chloromethylpyridine hydrochloride and 5.86 g (60.97 mmol) of sodium tert-butoxide at −16 to −7 ° C. Repeatedly, 50.0 g (0.3048 mol) of 3-chloromethylpyridine hydrochloride and 43.95 g (0.4573 mol) of sodium tert-butoxide were added in total.

  After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (3-A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the compound (3- 3-Chloromethylpyridine hydrochloride and sodium tert-butoxide were added at 0 ° C. or lower until the peak of A) disappeared. The added 3-chloromethylpyridine hydrochloride was 2.5 g (0.0152 mol), and sodium tert-butoxide was 2.93 g (0.0305 mol). The reaction mixture was separated into solid and liquid, the cake was washed with 125 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 200 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 39.4 g of the oily compound (5-A) (crude yield (1,4-butanediol). More): 94.9%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-A) was 88.3%.

<Example 19>
[Synthesis of Compound (5-A): Reaction Using 3-Pyridinemethanolbenzenesulfonate]
1,4-butanediol (0.9 g, 9.99 mmol) was added to 15 ml of DMF, and 1.13 g (10.07 mmol) of potassium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, a DMF (5 ml) solution of 2.5 g (10.03 mmol) of 3-pyridinemethanolbenzenesulfonate was added dropwise at -5 to 0 ° C. After stirring at −5 to 0 ° C. for 30 minutes, 1.13 g (10.07 mmol) of potassium tert-butoxide was added to the reaction mixture at −5 to 0 ° C. To this slurry, a DMF (5 ml) solution of 2.5 g (10.03 mmol) of 3-pyridinemethanolbenzenesulfonate was added dropwise at -5 to 0 ° C.

  After completion of the dropwise addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, the peak of 3-pyridinemethanolbenzenesulfonate and the peak of the compound (3-A) were confirmed. The 3-pyridinemethanolbenzenesulfonic acid ester compound and potassium tert-butoxide were added at 0 ° C. or lower until the above peak and the peak of the compound (3-A) disappeared. The added 3-pyridinemethanolbenzenesulfonic acid ester was 0.25 g (1.00 mmol), and potassium tert-butoxide was 0.22 g (1.96 mmol). The reaction mixture was separated into solid and liquid, the cake was washed with 10 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue was added 20 ml of dichloromethane, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 2.4 g of the oily compound (5-A) (crude yield (1,4-butanediol). More): 88.2%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-A) was 85.8%.

ＤＭＦ７５ｍｌに１，４−ブタンジオール８．２４ｇ（９１．４３ｍｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド１０．３ｇ（９１．７９ｍｍｏｌ）を添加し、室温で１時間撹拌した。このスラリーに−１０〜−５℃で４−クロロメチルピリジン塩酸塩１．５ｇ（９．１４ｍｍｏｌ）、カリウムtert−ブトキシド１．０３ｇ（９．１８ｍｍｏｌ）を交互に添加し、これを１０回繰り返した。 <Example 20>
[Synthesis of Compound (3-B) Represented by Structural Formula: Same as Example 1 except that 3-chloromethylpyridine hydrochloride was replaced with 4-chloromethylpyridine hydrochloride and the reaction conditions were as follows]

To 75 ml of DMF, 8.24 g (91.43 mmol) of 1,4-butanediol was added, and 10.3 g (91.79 mmol) of potassium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, 1.5 g (9.14 mmol) of 4-chloromethylpyridine hydrochloride and 1.03 g (9.18 mmol) of potassium tert-butoxide were alternately added at −10 to −5 ° C., and this was repeated 10 times. .

  After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, a peak of 4-chloromethylpyridine was confirmed, so potassium tert-butoxide was added at 10 ° C. or lower until the peak of 4-chloromethylpyridine disappeared. did. The added potassium tert-butoxide was 1.03 g (9.18 mmol). The reaction mixture was subjected to solid-liquid separation, the cake was washed with 20 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure to obtain 17.0 g of an oily crude product. When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (3-B) was 63.0%.

The crude product was dissolved in 30 ml of water and washed with toluene. Thereafter, 6 g of sodium chloride was added to the aqueous layer, followed by extraction with 20 ml of dichloromethane × 2, dehydration with anhydrous magnesium sulfate, the solvent was distilled off, and 9.21 g of the oily compound (3-B) (yield (1,4 -From butanediol): 57.2%). When the obtained oil was analyzed by HPLC (Condition 1), the area% was 99.4%. _{^{(1 H-NMR (CDCl 3}} ): δ1.65-1.80 (4H, m, - (C H 2) 2 -), δ2.4 (1H, s, O H), δ3.54-3. 58 (2H, t, J = 5.9 Hz, C H ₂ ), δ 3.66-3.70 (2H, t, J = 5.9 Hz, C H ₂ ), δ 4.53 (2H, s, C H ₂ ), δ 7.24-7.26 (2H, dd, J = 1.5 Hz, 4.5 Hz, arom H × 2), δ 8.55-8.57 (2H, dd, J = 1.5 Hz, 4 .5 Hz, arom H × 2), MS (APCl): m / z = 182 [M + H] ⁺ )

ＤＭＦ４９ｍｌに１，４−ブタンジオール２．７ｇ（３０．０ｍｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド３．４ｇ（３０．０ｍｍｏｌ）を添加し、室温で１時間撹拌した。このスラリーに−５〜−３℃で４−クロロメチルピリジン塩酸塩０．９８ｇ（６ｍｍｏｌ）、カリウムtert−ブトキシド０．６８ｇ（６ｍｍｏｌ）を交互に添加し、これを５回繰り返した。これ以降の添加は、−５〜−２℃で４−クロロメチルピリジン塩酸塩０．９８ｇ（６ｍｍｏｌ）、カリウムtert−ブトキシド１．３６ｇ（１２ｍｍｏｌ）を交互に添加し、これを５回繰り返し、全量で４−クロロメチルピリジン塩酸塩９．８ｇ（６０ｍｍｏｌ）、カリウムtert−ブトキシド１０．２ｇ（９０ｍｍｏｌ）を添加した。 <Example 21>
[Synthesis of Compound (5-B) Represented by Structural Formula below: Same as Example 7 except that 3-chloromethylpyridine hydrochloride was replaced by 4-chloromethylpyridine hydrochloride and the reaction conditions were as follows]

To 49 ml of DMF, 2.7 g (30.0 mmol) of 1,4-butanediol was added, and 3.4 g (30.0 mmol) of potassium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, 0.98 g (6 mmol) of 4-chloromethylpyridine hydrochloride and 0.68 g (6 mmol) of potassium tert-butoxide were alternately added at −5 to −3 ° C., and this was repeated 5 times. Thereafter, 0.98 g (6 mmol) of 4-chloromethylpyridine hydrochloride and 1.36 g (12 mmol) of potassium tert-butoxide were alternately added at −5 to −2 ° C., and this was repeated five times. Then, 9.8 g (60 mmol) of 4-chloromethylpyridine hydrochloride and 10.2 g (90 mmol) of potassium tert-butoxide were added.

  After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 4-chloromethylpyridine and the compound (3-B) were confirmed, and therefore the peak of 4-chloromethylpyridine and the compound (3- 4-Chloromethylpyridine hydrochloride and potassium tert-butoxide were added at 10 ° C. or lower until the peak of B) disappeared. The added 4-chloromethylpyridine hydrochloride was 2.0 g (12 mmol), and potassium tert-butoxide was 2.6 g (24 mmol). The reaction mixture was separated into solid and liquid, the cake was washed with 20 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure.

50 ml of ethyl acetate was added to the concentrated residue, and the solution was washed with water, and then the solvent was distilled off to obtain the compound (5-B) as yellow crystals. When the crystals of the compound were analyzed by HPLC (Condition 1), the area% of the compound (5-B) was 70.5%. 5 g (18 mmol) of the obtained crude product was recrystallized with 23.3 g of isopropyl alcohol to obtain 2.7 g of the compound (5-B) as white crystals. (Mp 98.6 to 100.2 ° C., ¹ H-NMR (CDCl ₃ ): δ 1.75-1.79 (4H, m, — (C H ₂ ) ₂ —), δ 3.53-3 .57 (4H, m, C H ₂ × 2), δ 4.52 (4H, s, C H ₂ × 2), δ 7.23-7.27 (4H, dd, J = 0.8 Hz, 6.0 Hz) , Arom H × 4), δ 8.55-8.57 (4H, dd, J = 1.6 Hz, 6.0 Hz, arom H × 4), MS (APCl): m / z = 273 [M + H] ⁺ )

前記化合物（５−Ｂ）２．０ｇ（７．３４ｍｍｏｌ）にオクチルブロマイド２１．３ｇ（１１０．３ｍｍｏｌ）を加え、７０〜８０℃で５３時間反応を行った。反応混合物をＨＰＬＣ（条件２）で分析すると、前記化合物（５−Ｂ）のピークは消失していた。反応混合物からオクチルブロマイドを減圧下で留去し、油状の前記化合物（７−Ｂ）５．２ｇ（粗収率：１０７．７％）を得た。得られたオイルをＨＰＬＣ（条件２）で分析すると、化合物（７−Ｂ）のピークの面積％は８１．３％であった。 <Example 22>
[Synthesis of compound (7-B) having the following structural formula: Example 3 and Example 3 except that the compound (5-B) was replaced with one derived from 4-chloromethylpyridine hydrochloride and the reaction conditions were as follows: Same]

21.3 g (110.3 mmol) of octyl bromide was added to 2.0 g (7.34 mmol) of the compound (5-B), and the reaction was performed at 70 to 80 ° C. for 53 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-B) disappeared. Octyl bromide was distilled off from the reaction mixture under reduced pressure to obtain 5.2 g (crude yield: 107.7%) of the oily compound (7-B). When the obtained oil was analyzed by HPLC (condition 2), the area% of the peak of the compound (7-B) was 81.3%.

<Example 23>
[Purification of Compound (5-B): Purification with hydrochloride. (Molar ratio of hydrochloric acid: 1.5 with respect to the compound (5-B))]
5.0 g (18.36 mmol, area ratio 90.5%) of the compound (5-B) was dissolved in 15.0 g of isopropyl alcohol, and 1.01 g (27.70 mmol) of hydrogen chloride gas was added to 20-40 in the solution. Blowed at ℃. The mixture was cooled to 10 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 4.4 g of the dihydrochloride salt of the compound (5-B) (yield: 69.8%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (5-B) was 97.9%.

<Example 24>
[Purification of Compound (5-B): Purification with hydrochloride. (Molar ratio of hydrochloric acid: 2.0 with respect to the compound (5-B))]
5.0 g (18.36 mmol, area ratio 90.5%) of the compound (5-B) was dissolved in 15.0 g of isopropyl alcohol, and 1.34 g (36.75 mmol) of hydrogen chloride gas was added to 20-40 in the solution. Blowed at ℃. The mixture was cooled to 10 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 5.7 g of the dihydrochloride salt of the compound (5-B) (yield: 90.5%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (5-B) was 96.1%.

<Example 25>
[Purification of Compound (5-B): Same as Example 23, except that the blowing temperature of hydrochloric acid was changed to 60-65 ° C. and the reaction conditions were as follows]
15.0 g (55.08 mmol, area ratio 90.5%) of the compound (5-B) was dissolved in 45.0 g of isopropyl alcohol, and 4.0 g (0.1097 mol) of hydrogen chloride gas was added to 60-65 in the solution. Blowed at ℃. The mixture was cooled to 5 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 17.2 g of the dihydrochloride salt of the compound (5-B) (yield: 90.5%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (5-B) was 97.9%.

<Example 26>
[Purification of Compound (5-B): Purification with Sulfate (Sulfuric Acid Molar Ratio: 1.0 with respect to Compound (5-B)]]
15.0 g (55.08 mmol, area ratio 90.5%) of the compound (5-B) was dissolved in 22.5 g of isopropyl alcohol, and 5.5 g (54.96 mmol) of 98% sulfuric acid was added to 70 to 75 in the solution. It was dripped at ° C. The mixture was cooled to 5 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 17.2 g of the disulfate salt of the compound (5-B) (yield: 47.5%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (5-B) was 94.6%.

<Example 27>
[Purification of Compound (5-B): Purification with Sulfate (Sulfuric Acid Molar Ratio: 1.5 with respect to Compound (5-B))]
10.0 g (36.72 mmol, area ratio 90.5%) of the compound (5-B) was dissolved in 20 ml of isopropyl alcohol, and 5.5 g (54.96 mmol) of 98% sulfuric acid was added to the solution at 45-60 ° C. It was dripped. The mixture was cooled to 5 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 10.6 g of the disulfate salt of the compound (5-B) (yield: 61.6%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (5-B) was 94.9%.

<Example 28>
[Purification of Compound (5-B): Purification with Sulfate (Sulfuric Acid Molar Ratio: 2.0 with respect to Compound (5-B))]
20.0 g (73.43 mmol, area ratio 90.5%) of the compound (5-B) was dissolved in 40 ml of isopropyl alcohol, and 14.7 g (0.1468 mol) of 98% sulfuric acid was dissolved in the solution at 60 to 80 ° C. It was dripped. The mixture was cooled to 5 ° C., and the precipitated crystals were filtered and dried under reduced pressure to obtain 27.5 g of the disulfate salt of the compound (5-B) (yield: 79.9%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (5-B) was 94.7%.

<Example 29>
[Synthesis of Compound (5-B): 4-chloromethylpyridine hydrochloride-DMF slurry and DMF solution of sodium tert-butoxide are added dropwise to 1,4-butanediol monosodium salt slurry]
To 80 ml of DMF, 8.43 g (0.0935 mol) of 1,4-butanediol was added, and 9.0 g (0.0936 mol) of sodium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1 hour. To this slurry, a solution of 34.1 g (45.72 mmol) of 4-chloromethylpyridine hydrochloride / 100 ml of DMF and a solution of 37.0 g (0.3850 mol) of sodium tert-butoxide / 60 ml of DMF were simultaneously added dropwise at 0 to 5 ° C.

  After completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour, and when the reaction mixture was analyzed by HPLC (condition 1), the peak of 4-chloromethylpyridine was not detected, and the peak of the compound (3-B) almost disappeared. The reaction mixture was subjected to solid-liquid separation, the cake was washed with 60 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To 28.3 g of the obtained residual liquid, 84.9 g of isopropyl alcohol was added and dissolved, and 6.9 g (0.1892 mol) of hydrogen chloride gas was blown into the solution at 60 to 65 ° C. The mixture was cooled to 5 ° C., the precipitated crystals were filtered, and the crystals were washed with 14.2 ml of isopropyl alcohol to obtain 36.1 g of a wet dihydrochloride salt of the compound (5-B). The obtained wet substance was dissolved in 18.1 g of water, adjusted to pH 10 to 11.5 with liquid caustic soda, extracted with 100 ml of toluene, the toluene layer was washed with 20 ml of water, and then toluene was distilled off under reduced pressure to give an oil. Of the compound (5-B) was obtained (yield (from 1,4-butanediol): 87.2%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (5-B) was 97.5%.

<Example 30>
[Synthesis of Compound (7-B): Same as Example 14 except that purified compound (5-B) was used and reaction conditions were as follows]
141.8 g (0.7343 mol) of octyl bromide was added to 20.0 g (0.0734 mol, HPLC (condition 1): 98.2 area%) of the compound (5-B), and the mixture was heated at 75 to 78 ° C. for 20.5 hours. Reaction was performed. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (5-B) disappeared. When 19.3 ml of acetonitrile was added to the reaction mixture and allowed to stand, the upper layer was an acetonitrile solution layer of the compound (7-B), the lower layer was an octyl bromide layer, and the lower layer was separated. Next, the upper layer was concentrated under reduced pressure to 80 ° C. and 10 Torr to obtain 44.9 g (crude yield: 93.0%) of the oily compound (7-B). When the obtained oily substance was analyzed by HPLC (condition 2), the area% of the peak of the compound (7-B) was 97.5%. ( ¹ H-NMR (d ⁶ -DMSO): δ0.86-0.90 (6H, t, J = 5.5 Hz, C H ₃ × 2), δ1.26-1.35 (20H, m, − (C H ₂ ) _5- × 2), δ 1.80-1.85 (4H, m,-(C H ₂ ) _2- × 2), δ 2.05-3.02 (4H, m, C H ₂ × 2), δ 3.72-3.75 (4H, m, C H ₂ × 2), δ 4.68-4.72 (4H, m, C H ₂ × 2), δ 4.85 (4H, s, C H ₂ × 2), δ 8.13 (4H, dd, J = 0.8 Hz, 6.5 Hz, arom H × 4), δ 8.85 (4H, dd, J = 1.6 Hz, 6.5 Hz, arom) H x 4)

Test Example 1 <Bacteriostatic activity against various bacteria of the compound (7-A) of the present invention>
The minimum inhibitory concentration (MIC) was measured using benzalkonium chloride as a control compound.
The minimum inhibitory concentration (MIC) was measured according to a general broth dilution method. Using a nutrient broth, a steady-state bacterial solution adjusted to a cell suspension concentration of 10 ⁶ cells / ml was serially diluted. The MIC value was determined based on the presence or absence of proliferation after mixing with the drug solution and standing culture at 37 ° C. for 24 hours.
Ten gram-negative bacteria and six gram-positive bacteria were used as test bacteria. The results are shown in Table 1.

Test Example 2 <Bactericidal activity (MBC) against various bacteria of the compound (7-A) of the present invention>
Benzalkonium iodide was used as a control compound. Using 5 kinds of gram-negative bacteria and 4 kinds of gram-positive bacteria as test bacteria, the minimum bactericidal concentration (MBC) was measured in the same manner as described above. The results are shown in Table 2.

Test Example 3 <Measurement of Minimum Growth Inhibitory Concentration (MIC) of Fungus of Compound (7-A) of the Present Invention>
TBZ (2- (4′-thiazolyl) benzimidazole) was used as a reference compound. The minimum inhibitory concentration (MIC) was measured according to a general broth dilution method, using a Sabouraud medium, and preparing a spore solution of pre-cultured test bacteria with humectant-added sterilized water. Diluted drug solution (1 ml) and spore solution (1 ml) were mixed, cultured in an incubator at 30 ° C. for 1 week, the presence or absence of growth was determined by turbidity, and the place where no turbidity occurred was defined as MIC. The results are shown in Table 3.

Test Example 4 <Bacteriostatic activity of the compound (7-B) of the present invention against various bacteria>
The results shown in Table 4 were obtained in the same manner as in Test Example 1.

Test Example 5 <bactericidal activity (MBC) against various bacteria of the compound (7-B) of the present invention>
The results shown in Table 5 were obtained in the same manner as in Test Example 2.

Test Example 6 <Measurement of Minimum Growth Inhibitory Concentration (MIC) of Fungus of Compound (7-B) of the Present Invention>
The results shown in Table 6 were obtained in the same manner as in Test Example 3.

Next, embodiments of (Claim 1) of the present invention will be enumerated.
[Claim 2]
The method for producing a bactericidal pyridine compound according to claim 1, wherein the compound represented by the general formula (1) and the compound represented by the general formula (4) are the same.
[Claim 3]
The bactericidal pyridine compound according to claim 1, wherein R ₁ and R ₄ in the general formula (1) and the general formula (4) are CH ₂ groups, and R ₂ and R ₅ are hydrogen atoms. Method.
[Claim 4]
The method for producing a bactericidal pyridine compound according to claim 1, wherein the diol represented by the general formula (2) is 1,4-butanediol.
[Claim 5]
R ₁ and R ₄ in the general formulas (1) to (7) are CH ₂ groups, R ₂ and R ₅ are hydrogen atoms, and R ₃ is a linear or branched group having 2 to 12 carbon atoms. An alkyl group, A and B are chlorine atoms, bromine atoms or iodine atoms, X and Y are chlorine anions, bromine anions, iodine anions, lower alkylsulfonyloxy anions, substituted or unsubstituted benzenesulfonyloxy anions, lower The method for producing a bactericidal pyridine compound according to claim 1, which is an alkylcarboxy anion, a substituted or unsubstituted benzenecarboxy anion or an acetoxy anion, wherein m and n are 0 to 1.
[Claim 6]
The method for producing a bactericidal pyridine compound according to claim 5, wherein A and B are chlorine atoms, and X and Y are a chlorine anion, a benzenesulfonyloxy anion or an acetoxy anion.
[Claim 7]
The method for producing a bactericidal pyridine compound according to claim 1, wherein the strong base is at least one of an alkali metal or a hydride thereof, alkyl lithium, phenyl lithium, and an alkali metal alkoxide.
[Claim 8]
The method for producing a bactericidal pyridine compound according to claim 1, wherein the strong base is sodium tertiary riboxide or potassium tertiary riboxide.
[Claim 9]
The method for producing a bactericidal pyridine compound according to claim 1, wherein the reaction is carried out in a solvent, and the solvent is an aprotic polar solvent.
[Claim 10]
The method for producing a bactericidal pyridine compound according to claim 9, wherein the solvent is dimethylformamide.
[Claim 11]
The manufacturing method of the bactericidal pyridine compound of Claim 1 made to react with the compound represented by General formula (4) continuously, without isolating the compound represented by said General formula (3).
[Claim 12]
R ₁ in the general formula (3) is a linear or branched alkyl group having 1 to 4 carbon atoms, R ₂ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and R ₃ is The method for producing a bactericidal pyridine compound according to claim 1, which is a linear or branched alkyl group having 2 to 12 carbon atoms.
[Claim 13]
The method for producing a bactericidal pyridine compound according to claim 12, wherein R ₁ is a CH ₂ group and R ₂ is a hydrogen atom.
[Claim 14]
The method for producing a bactericidal pyridine compound according to claim 12, wherein R ₁ is a CH ₂ group, R ₂ is a hydrogen atom, and R ₃ is a linear alkyl group having 4 carbon atoms.
[Claim 15]
R ₁ is a linear or branched alkyl group having 1 to 4 carbon atoms, R ₂ is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, and R ₃ is 2 to 2 carbon atoms. 12 linear or branched alkyl groups, R ₄ is a linear or branched alkyl group having 1 to ₄ carbon atoms, and R ₅ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. A method for producing a bactericidal pyridine compound according to claim 1.
[Claim 16]
The method for producing a bactericidal pyridine compound according to claim 15, wherein R ₁ and R ₄ are CH ₂ groups, and R ₂ and R ₅ are hydrogen atoms.
[Claim 17]
The method for producing a bactericidal pyridine compound according to claim 15, wherein R ₃ is a linear alkyl group having 4 carbon atoms.
[Claim 18]
The method for producing a bactericidal pyridine compound according to claim 1, wherein R ₆ is a linear or branched alkyl group having 1 to 18 carbon atoms, and Z is a chlorine atom, a bromine atom or an iodine atom.
[Claim 19]
The method for producing a bactericidal pyridine compound according to claim 18, wherein R ₆ is a linear alkyl group having 8 carbon atoms.
[Claim 20]
The method for producing a bactericidal pyridine compound according to claim 18, wherein R ₆ is a linear alkyl group having 8 carbon atoms, and Z is a bromine atom.
[Claim 21]
The solvent used for the reaction of the pyridine compound represented by the general formula (5) and the halogen compound or sulfonate compound represented by the general formula (6) is a lower aliphatic alcohol or an aprotic polar solvent. The manufacturing method of the bactericidal pyridine compound of Claim 1.
[Claim 22]
The method for producing a bactericidal pyridine compound according to claim 21, wherein the solvent is dimethylformamide.
[Claim 23]
The method for producing a bactericidal pyridine compound according to claim 1, wherein the halogen compound or sulfonic acid ester compound represented by the general formula (6) is used excessively without using the solvent.
[Claim 24]
The bactericidal pyridine compound according to claim 1, wherein the pyridine compound represented by the general formula (5) is reacted with the halogen compound or the sulfonate compound represented by the general formula (6) without isolation. Production method.

  According to the present invention, a novel bactericidal pyridine compound can be provided simply and inexpensively using a readily available pyridine compound as a starting material.

Claims (24)

The following general formula (1)

And a pyridine compound represented by the following general formula (2)

Is reacted in the presence of a strong base to give the following general formula (3):

A pyridine compound represented by the formula:

Is reacted with a pyridine compound represented by the following general formula (5):

A pyridine compound represented by the formula:

The following general formula (7), characterized by reacting with a halogen compound or a sulfonic acid ester compound represented by the formula:

(However, in the above general formulas (1) to (7), A and B are substituents capable of functioning as a leaving group by the action of a base and generating an alkyl cation, and X and Y are inorganic or organic. A counter anion of a protonic acid, m and n are 0 to ₁ , R ₁ and R ₄ are linear or branched, identical or different alkyl groups having 1 to 4 carbon atoms, and R ₂ and R ₅ are , A hydrogen atom, the same or different halogen atom, a lower alkyl group or a lower alkoxy group, R ₃ is a linear or branched alkyl group having 2 to 12 carbon atoms, and R ₆ is a C 1-18 carbon atom. A linear or branched alkyl group, and Z is a chlorine atom, bromine atom, iodine atom or OSO ₂ R ₇ group (R ₇ is a lower alkyl group or a substituted or unsubstituted phenyl group). Represented by A method for producing a bactericidal pyridine compound.   The method for producing a bactericidal pyridine compound according to claim 1, wherein the compound represented by the general formula (1) and the compound represented by the general formula (4) are the same. The bactericidal pyridine compound according to claim 1, wherein R ₁ and R ₄ in the general formula (1) and the general formula (4) are CH ₂ groups, and R ₂ and R ₅ are hydrogen atoms. Method.   The method for producing a bactericidal pyridine compound according to claim 1, wherein the diol represented by the general formula (2) is 1,4-butanediol. R ₁ and R ₄ in the general formulas (1) to (7) are CH ₂ groups, R ₂ and R ₅ are hydrogen atoms, and R ₃ is a linear or branched group having 2 to 12 carbon atoms. An alkyl group, A and B are chlorine atoms, bromine atoms or iodine atoms, X and Y are chlorine anions, bromine anions, iodine anions, lower alkylsulfonyloxy anions, substituted or unsubstituted benzenesulfonyloxy anions, lower The method for producing a bactericidal pyridine compound according to claim 1, which is an alkylcarboxy anion, a substituted or unsubstituted benzenecarboxy anion or an acetoxy anion, wherein m and n are 0 to 1.   The method for producing a bactericidal pyridine compound according to claim 5, wherein A and B are chlorine atoms, and X and Y are a chlorine anion, a benzenesulfonyloxy anion or an acetoxy anion.   The method for producing a bactericidal pyridine compound according to claim 1, wherein the strong base is at least one of an alkali metal or a hydride thereof, alkyl lithium, phenyl lithium, and an alkali metal alkoxide.   The method for producing a bactericidal pyridine compound according to claim 1, wherein the strong base is sodium tertiary riboxide or potassium tertiary riboxide.   The method for producing a bactericidal pyridine compound according to claim 1, wherein the reaction is carried out in a solvent, and the solvent is an aprotic polar solvent.   The method for producing a bactericidal pyridine compound according to claim 9, wherein the solvent is dimethylformamide.   The manufacturing method of the bactericidal pyridine compound of Claim 1 made to react with the compound represented by General formula (4) continuously, without isolating the compound represented by said General formula (3). R ₁ in the general formula (3) is a linear or branched alkyl group having 1 to 4 carbon atoms, R ₂ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and R ₃ is The method for producing a bactericidal pyridine compound according to claim 1, which is a linear or branched alkyl group having 2 to 12 carbon atoms. The method for producing a bactericidal pyridine compound according to claim 12, wherein R ₁ is a CH ₂ group and R ₂ is a hydrogen atom. The method for producing a bactericidal pyridine compound according to claim 12, wherein R ₁ is a CH ₂ group, R ₂ is a hydrogen atom, and R ₃ is a linear alkyl group having 4 carbon atoms. R ₁ is a linear or branched alkyl group having 1 to 4 carbon atoms, R ₂ is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, and R ₃ is 2 to 2 carbon atoms. 12 linear or branched alkyl groups, R ₄ is a linear or branched alkyl group having 1 to ₄ carbon atoms, and R ₅ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. A method for producing a bactericidal pyridine compound according to claim 1. The method for producing a bactericidal pyridine compound according to claim 15, wherein R ₁ and R ₄ are CH ₂ groups, and R ₂ and R ₅ are hydrogen atoms. The method for producing a bactericidal pyridine compound according to claim 15, wherein R ₃ is a linear alkyl group having 4 carbon atoms. The method for producing a bactericidal pyridine compound according to claim 1, wherein R ₆ is a linear or branched alkyl group having 1 to 18 carbon atoms, and Z is a chlorine atom, a bromine atom or an iodine atom. The method for producing a bactericidal pyridine compound according to claim 18, wherein R ₆ is a linear alkyl group having 8 carbon atoms. The method for producing a bactericidal pyridine compound according to claim 18, wherein R ₆ is a linear alkyl group having 8 carbon atoms, and Z is a bromine atom.   The solvent used for the reaction of the pyridine compound represented by the general formula (5) and the halogen compound or sulfonate compound represented by the general formula (6) is a lower aliphatic alcohol or an aprotic polar solvent. The manufacturing method of the bactericidal pyridine compound of Claim 1.   The method for producing a bactericidal pyridine compound according to claim 21, wherein the solvent is dimethylformamide.   The method for producing a bactericidal pyridine compound according to claim 1, wherein the halogen compound or sulfonic acid ester compound represented by the general formula (6) is used excessively without using the solvent.   The bactericidal pyridine compound according to claim 1, wherein the pyridine compound represented by the general formula (5) is reacted with the halogen compound or the sulfonate compound represented by the general formula (6) without isolation. Production method.