JP4381221B2 - Bactericidal pyridine compound - Google Patents

Description

  The present invention relates to 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.

（上記式中のＺは、塩素原子、臭素原子、ヨウ素原子もしくはＯＳＯ₂Ｒ₁基（Ｒ₁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。） The present invention provides a bactericidal pyridine compound represented by the following general formula (1) or general formula (2).

(Z in the above formula is a chlorine atom, bromine atom, iodine atom or OSO ₂ R ₁ group (R ₁ is a lower alkyl group or a substituted or unsubstituted phenyl group).)

  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.
The compound represented by the general formula (1) or the general formula (2) of the present invention can be synthesized by various methods, and one example is as follows. That is, 3-chloromethylpyridine, 4-chloromethylpyridine, 3-bromomethylpyridine, 4-bromomethylpyridine, 3-iodomethylpyridine, 4-iodomethylpyridine, 3- (methanesulfonyloxy) methylpyridine, 4- Reaction of (methanesulfonyloxy) methylpyridine, 3- (benzenesulfonyloxy) methylpyridine, 4- (benzenesulfonyloxy) methylpyridine or a salt thereof (hereinafter referred to as “raw pyridine compound”) with 1,4-butanediol By doing so, a pyridine compound of the following general formula (3) is synthesized. In the reaction, the amount of the raw material pyridine compound used relative to 1,4-butanediol is preferably 1 equivalent mole to 1.5 equivalent mole, and more preferably 1 equivalent mole to 1.1 equivalent mole.

  When producing the pyridine compound represented by General formula (3) by reaction with a raw material pyridine compound and 1, 4- butanediol, various reaction conditions are possible. The presence of a strong base is essential for carrying out this reaction because it is important to produce the corresponding alkoxide from 1,4-butanediol. 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 starting pyridine compound is used as the starting material, the strong base used is about 1 equivalent mole. Further, when the raw pyridine compound forms a salt, the strong base used is about 2 equivalents, which is about 1 equivalent moles sufficient to neutralize the salt and about 1 equivalent moles consumed for the desired reaction. Is a mole. However, if the conversion rate is low, a strong base may be added until the starting pyridine compound 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 starting pyridine compound is likely to change due to contact with a strong base, an alkoxide is generated in advance by a reaction between 1,4-butanediol and a strong base, and the alkoxide and the starting pyridine compound are treated. Alternatively, it is preferable that the raw material pyridine compound and 1,4-butanediol are mixed in advance, and then a strong base is added to the mixture. When the raw material pyridine compound forms a salt, it is possible to add in advance an amount of a strong base capable of liberating the compound, and to perform the treatment in the above-described procedure.

  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 can be appropriately selected in consideration of the solubility of the starting pyridine compound, the solubility of 1,4-butanediol, and the dispersion state of the alkali metal salt produced during the reaction.

  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 following general formula (4) can be produced by reacting the pyridine compound represented by the general formula (3) in the presence of the same raw material pyridine compound as described above with a strong base. it can.

  The pyridine compound represented by the general formula (4) can also be produced without isolating the compound represented by the general formula (3). For example, the pyridine compound represented by the general formula (3) is generated in the reaction system by the above-described operation, and then the raw material pyridine compound is allowed to act in the presence of a strong base. As for the usage-amount of the pyridine compound represented by General formula (3) or its salt, use of 1-1.5 equivalent is preferable with respect to a raw material pyridine compound, Furthermore, use of 1-1.1 equivalent is preferable.

  As described above, in the reaction of the raw material pyridine compound with the pyridine compound represented by the general formula (3) or a salt thereof, the raw material pyridine compound is easily changed by contact with a strong base. After generating alkoxide by the reaction of the base, the pyridine compound represented by the general formula (3) is added, or the pyridine compound represented by the general formula (3) and the raw material pyridine compound are mixed in advance, It is preferable to add a strong base. When the starting pyridine compound forms a salt, an amount capable of liberating the compound, usually about 1 equivalent mole of a strong base, is added in advance and can be treated by the procedure described above.

  In this reaction, the strong base selected in the reaction of the raw material pyridine compound and 1,4-butanediol can be used, and these may be used alone or in combination of two or more. When the starting pyridine compound 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 starting pyridine compound disappear.

  In this reaction, it is possible to use the solvent selected in the reaction of the raw material pyridine compound and 1,4-butanediol, which may be used alone or in combination of two or more. The amount of the solvent used can be appropriately selected depending on the solubility of the pyridine compound represented by the general formula (3) and the raw material pyridine compound and the dispersion state of the alkali metal salt produced during the reaction.

  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 (4) 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.

（上記式中のＲはオクチル基であり、Ｚは、塩素原子、臭素原子、ヨウ素原子もしくはＯＳＯ₂Ｒ₁基（Ｒ₁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。） Next, by reacting the pyridine compound represented by the general formula (4) with the compound represented by the following general formula (5), the compound represented by the general formula (1) or the general formula (2) is reacted. A bactericidal pyridine compound can be obtained.

(In the above formula, R is an octyl group, and Z is a chlorine atom, bromine atom, iodine atom or OSO ₂ R ₁ group (R ₁ is a lower alkyl group or a substituted or unsubstituted phenyl group). .)

  In this reaction, the amount of the compound represented by the general formula (5) used relative to the pyridine compound represented by the general formula (4) is theoretically 2 equivalent moles. However, when the conversion rate is low, a large amount of the compound represented by the general formula (5) may be used, and when used in a large excess, it can be recovered and reused.

  In the reaction of the pyridine compound represented by the general formula (4) and the compound represented by the general formula (5), 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 (4) and the compound represented by the general formula (5) in the solvent.

  On the other hand, this reaction can also be carried out using an excess of the compound represented by the general formula (5) without using a solvent. In this case, after completion of the reaction, the unreacted compound represented by the general formula (5) can be separated from the reaction mixture, recovered and reused, and is extremely efficient and economical.

  This reaction can be carried out from 0 ° C. at the boiling point at normal pressure of the solvent used or the compound represented by the general formula (5). 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 (1) or (2).

  Further, the reaction is represented by the general formula (5) in the reaction mixture containing the pyridine compound represented by the general formula (4) without isolating the pyridine compound represented by the general formula (4). 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 (4) as it is.

  The bactericidal pyridine compound of the present invention represented by the general formula (1) or the general formula (2) can be taken out by a conventional method, and a solid compound at room temperature is crystallized from an appropriate solvent system. Is possible. 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 (4-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 the oily compound (4-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（４−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 (1) of Structural Formula below]

35.0 g (183.8 mmol) of octyl bromide was added to 5.0 g (18.36 mmol) of the compound (4-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 (4-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 (4-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 compound (1) 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 (4-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.

  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 3.79 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 91.8%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 64.5%.

<Example 5>
[Synthesis of Compound (4-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 (4-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 (4-A) was 72.8%.

<Example 6>
[Synthesis of Compound (4-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 (4-A) (crude yield (1,4-butanediol) More): 98.8%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 68.8%.

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

  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.

  200 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 40.9 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 98.6%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-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 the monohydrochloride salt of the compound (4-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 (4-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 (4-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 (4-A) was 87.8%.

<Example 9>
[Synthesis of Compound (4-A): DMF solution of potassium tert-butoxide is 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, 100 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 20.1 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 96.6%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 80.3%.

<Example 10>
[Synthesis of Compound (4-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 (4-A) (crude yield (1,4-butanediol). More): 89.9%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 93.9%.

<Example 11>
[Synthesis of Compound (1): Reaction Solvent-Methanol / Acetonitrile Mixture]
10.0 g (36.72 mmol) of the above compound (4-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 (4-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 (1) 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 (1) was 91.4%.

<Example 12>
[Synthesis of Compound (1): Reaction Solvent-DMF]
5.0 g (18.36 mmol) of the compound (4-A) and 35.5 g (0.184 mol) of octyl bromide were added to 25 ml of DMF, and reacted at 50 to 55 ° C. for 86 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-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 (1). When the obtained oil was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 93.0%.

<Example 13>
[Synthesis of Compound (1): 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 (4-A), and reacted at 49 to 52 ° C. for 50 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-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 (1). When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 93.3%.

<Example 14>
[Synthesis of Compound (1): Reaction without Solvent, Reaction Temperature 75-80 ° C, Crystallization in Ethanol / Ethyl Acetate Mixture]
70.0 g (0.3671 mol) of octyl bromide was added to 10.0 g (36.72 mmol) of the compound (4-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 (4-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 filtered off 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 (1). When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 95.2%.

<Example 15>
[Synthesis of Compound (1): Same as Example 14 except that the ratio of ethanol / ethyl acetate mixture was changed and 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 (4-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 (4-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 (1), 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 (1). When the obtained crystal was analyzed by HPLC (Condition 2), the peak area% of the compound (1) was 90.8%.

<Example 16>
[Synthesis of Compound (1): 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 (4-A), followed by reaction at 75 to 78 ° C. for 20 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-A) disappeared. When 97 ml of ethanol was added to the reaction mixture and allowed to stand, the upper layer became an ethanol solution layer of the compound (1), the lower layer became 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 (1). When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 93.1%.

  212 g of the obtained crystals were recrystallized from a mixed solution of 592 ml of acetonitrile and 1953 ml of ethyl acetate to obtain 192.1 g of the compound (1) (purification yield: 90.6%). When the obtained crystal was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 96.4%.

<Example 17>
[Synthesis of Compound (1): Compound (4-A) is synthesized from benzenesulfonate of 3-chloromethylpyridine. Synthesis of Compound (1) without Isolating Compound (4-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 (4-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 (1) (crude yield (3-chloromethylpyridine) was obtained. -From benzenesulfonate, 89.2%) was obtained. When the obtained oil was analyzed by HPLC (condition 2), the peak area% of the compound (1) was 87.8%.

<Example 18>
[Synthesis of Compound (4-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 (4-A) (crude yield (1,4-butanediol). More): 94.9%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-A) was 88.3%.

<Example 19>
[Synthesis of Compound (4-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, 20 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to give 2.4 g of the oily compound (4-A) (crude yield (1,4-butanediol). More): 88.2%). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (4-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 (4-B) Represented by Structural Formula below: Same as Example 7 except that 3-chloromethylpyridine hydrochloride was replaced with 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 (4-B) as yellow crystals. When the crystals of the compound were analyzed by HPLC (condition 1), the area% of the compound (4-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 (4-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（４−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（４−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（２）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（２）のピークの面積％は８１．３％であった。 <Example 22>
[Synthesis of compound (2) having the following structural formula: the same as in Example 3 except that the compound (4-B) was replaced with one derived from 4-chloromethylpyridine hydrochloride and the reaction conditions were as follows]

21.3 g (110.3 mmol) of octyl bromide was added to 2.0 g (7.34 mmol) of the compound (4-B), and the reaction was carried out at 70-80 ° C. for 53 hours. When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (4-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 (2). When the obtained oil was analyzed by HPLC (condition 2), the peak area% of the compound (2) was 81.3%.

<Example 23>
[Purification of the compound (4-B): purification with hydrochloride. (Molar ratio of hydrochloric acid: 1.5 with respect to the compound (4-B))]
5.0 g (18.36 mmol, area ratio 90.5%) of the compound (4-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 (4-B) (yield: 69.8%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 97.9%.

<Example 24>
[Purification of the compound (4-B): purification with hydrochloride. (Molar ratio of hydrochloric acid: 2.0 with respect to the compound (4-B))]
5.0 g (18.36 mmol, area ratio 90.5%) of the compound (4-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 (4-B) (yield: 90.5%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 96.1%.

<Example 25>
[Purification of Compound (4-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 (4-B) was dissolved in 45.0 g of isopropyl alcohol, and 4.0 g (0.1097 mol) of hydrogen chloride gas was added to the solution at 60 to 65. 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 (4-B) (yield: 90.5%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 97.9%.

<Example 26>
[Purification of Compound (4-B): Purification with Sulfate (Sulfuric Acid Molar Ratio: 1.0 with respect to Compound (4-B))]
15.0 g (55.08 mmol, area ratio 90.5%) of the compound (4-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 (4-B) (yield: 47.5%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 94.6%.

<Example 27>
[Purification of Compound (4-B): Purification with Sulfate (Sulfuric Acid Molar Ratio: 1.5 with respect to Compound (4-B))]
10.0 g (36.72 mmol, area ratio 90.5%) of the compound (4-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 (4-B) (yield: 61.6%). When the obtained crystal was analyzed by HPLC (Condition 1), the area% of the compound (4-B) was 94.9%.

<Example 28>
[Purification of Compound (4-B): Purification with Sulfate (Sulfuric Acid Molar Ratio: 2.0 with respect to Compound (4-B))]
20.0 g (73.43 mmol, area ratio 90.5%) of the compound (4-B) was dissolved in 40 ml of isopropyl alcohol, and 14.7 g (0.1468 mol) of 98% sulfuric acid was added to 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 (4-B) (yield: 79.9%). When the obtained crystal was analyzed by HPLC (condition 1), the area% of the compound (4-B) was 94.7%.

<Example 29>
[Synthesis of Compound (4-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 (4-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 (4-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 (4-B) was 97.5%.

<Example 30>
[Synthesis of Compound (2): Same as Example 14 except that purified compound (4-B) was used and the 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 (4-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 (4-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 (2), 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 (2). When the obtained oil was analyzed by HPLC (condition 2), the area% of the peak of the compound (2) 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 (1) 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 (1) of the present invention>
Benzalkonium iodide was used as a control compound. Five gram-negative bacteria and four gram-positive bacteria were used as test bacteria, and 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 (1) 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 against various bacteria of the compound (2) of the present invention>
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 (2) 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 Inhibitory Concentration (MIC) of Fungus of Compound (2) of the Present Invention>
The results shown in Table 6 were obtained in the same manner as in Test Example 3.

  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 (1)

A bactericidal pyridine compound represented by the following general formula (1) or general formula (2).

(Z in the above formula is a chlorine atom, bromine atom, iodine atom or OSO ₂ R ₁ group (R ₁ is a lower alkyl group or a substituted or unsubstituted phenyl group).)