JP4258590B2 - Method for producing halogen-substituted quinoline derivative - Google Patents
Method for producing halogen-substituted quinoline derivative Download PDFInfo
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- JP4258590B2 JP4258590B2 JP31903599A JP31903599A JP4258590B2 JP 4258590 B2 JP4258590 B2 JP 4258590B2 JP 31903599 A JP31903599 A JP 31903599A JP 31903599 A JP31903599 A JP 31903599A JP 4258590 B2 JP4258590 B2 JP 4258590B2
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- general formula
- derivative represented
- halogen
- reaction
- substituted quinoline
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- 0 *c(cc1*)c(*)cc1N Chemical compound *c(cc1*)c(*)cc1N 0.000 description 1
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- Quinoline Compounds (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、ハロゲン置換キノリン誘導体の製造方法に関する。
【０００２】
【従来の技術】
一般式
【０００３】
【化３】
〔式中、Ｘ1、Ｘ2及びＸ3は、各々ハロゲン原子を示す。Ｒ1は水素原子又は低級アルキル基を示す。〕
で表されるハロゲン置換キノリン誘導体は、例えば抗菌剤等の医薬品を合成するための中間体として有用な化合物である。
【０００５】
従来、デーブナー・ミラー（Doebner-Miller）反応は、２−アルキルキノリンを合成するための方法として広く利用されている。ところが、この反応を適用して、上記一般式（１）のハロゲン置換キノリン誘導体を製造する場合、反応後の反応混合物がコールタール状のものとなり、目的とする一般式（１）のハロゲン置換キノリン誘導体と反応副生物との沸点が近いこと等の理由から、目的化合物を低収率、低純度でしか製造し得なかった。
【０００６】
このような欠点を解消するために、一般式（２）で表されるアニリン誘導体と一般式（３）で表されるアルデヒド誘導体との反応を、ｍ−ニトロベンゼンスルホン酸のアルカリ金属塩、硫酸鉄及びホウ酸の存在下に行う方法が開発されている（特開平２−１８８５７０号公報）。この方法に従えば、目的とする一般式（１）のハロゲン置換キノリン誘導体を比較的高い収率で得られるようになったものの、反応混合物がタール状となって目的化合物が着色する等の不都合があり、純度の高い目的化合物を得ようとすれば煩雑な精製工程が必要となり、その場合には収率が低下するのが避けられない。このため、特開平２−１８８５７０号公報に記載の方法は目的化合物の収率及び純度の点で尚不充分であった。更に特開平２−１８８５７０号公報に記載の方法では、一般式（３）で表されるアルデヒド誘導体を反応系内に徐々に添加する必要があり、しかもその滴下条件により目的化合物の収率が左右され、目的化合物を再現性よく同レベルの収率で製造するのが困難であった。
【０００７】
【発明が解決しようとする課題】
本発明は、反応混合物がタール状となって目的化合物が着色するという不都合がなく、そのため煩雑な精製工程を経ることなく、簡便な操作で、目的とする一般式（１）のハロゲン置換キノリン誘導体を高収率且つ高純度で製造する方法を提供することを課題とする。
【０００８】
本発明は、目的とする一般式（１）のハロゲン置換キノリン誘導体を再現性よく高収率で製造する方法を提供することを課題とする。
【０００９】
本発明は、目的とする一般式（１）のハロゲン置換キノリン誘導体の工業的に有利に製造する方法を提供することを課題とする。
【００１０】
【課題を解決するための手段】
本発明者は、上記課題を達成するために鋭意研究を重ねた結果、溶媒として水と非水系溶媒との二相系溶媒を使用した場合に上記課題が解決できることを見い出した。本発明は、斯かる知見に基づき完成されたものである。
【００１１】
即ち、本発明は、一般式
【００１２】
【化４】
〔式中、Ｘ1、Ｘ2及びＸ3は、各々ハロゲン原子を示す。〕
で表されるアニリン誘導体に一般式
Ｒ1ＣＨ＝ＣＨＣＨＯ （３）
〔式中、Ｒ1は水素原子又は低級アルキル基を示す。〕
で表されるアルデヒド誘導体を反応させて一般式（１）で表されるハロゲン置換キノリン誘導体を製造する方法において、一般式（２）で表されるアニリン誘導体と一般式（３）で表されるアルデヒド誘導体との反応を、酸の存在下、水と非水系溶媒と界面で行うことを特徴とする一般式（１）で表されるハロゲン置換キノリン誘導体の製造方法に係る。
【００１４】
本発明の方法によれば、反応混合物がタール状となって目的化合物が着色するという不都合がなく、そのため煩雑な精製工程を経ることなく、簡便な操作で、目的とする一般式（１）のハロゲン置換キノリン誘導体を高収率且つ高純度で製造し得る。
【００１５】
また、本発明の方法によれば、一般式（３）で表されるアルデヒド誘導体の反応系内への滴下条件により目的化合物の収率が左右されることはなく、目的とする一般式（１）のハロゲン置換キノリン誘導体を再現性よく高収率で製造し得る。
【００１６】
更に、本発明の方法によれば、ｍ−ニトロベンゼンスルホン酸のアルカリ金属塩や硫酸鉄を反応系内に添加する必要はなく、経済的な面からも有利な方法である。
【００１７】
【発明の実施の形態】
本明細書において示される各基は、より具体的には次の通りである。
【００１８】
Ｒ1で示される低級アルキル基としては、例えばメチル、エチル、プロピル、イソプロピル、ブチル、tert−ブチル、ペンチル、ヘキシル基等の炭素数１〜６の直鎖又は分枝鎖状アルキル基を例示できる。Ｒ1で示される低級アルキル基としては、メチル基が好ましい。
【００１９】
Ｘ1、Ｘ2及びＸ3で示されるハロゲン原子としては、弗素原子、塩素原子、臭素原子、沃素原子等を例示できる。Ｘ1及びＸ2で示されるハロゲン原子としては弗素原子が好ましく、Ｘ3で示されるハロゲン原子としては臭素原子が好ましい。
【００２０】
本発明においては、一般式（２）で表されるアニリン誘導体と一般式（３）で表されるアルデヒド誘導体との反応は、酸の存在下、水と非水系溶媒との二相系溶媒中にて行われる。
【００２１】
酸としては、従来公知の鉱酸を広く使用でき、例えば塩酸、硫酸、臭化水素酸等を挙げることができる。これらの中でも、塩酸が特に好ましい。
【００２２】
非水系溶媒としては、反応に悪影響を及ぼさず、水と混じり合わずに二相になるものである限り、従来公知のものを広く使用でき、例えばジエチルエーテル、ジイソプロピルエーテル等のエーテル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジクロロメタン、ジクロロエタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類、酢酸メチル、酢酸エチル、酢酸ブチル等のエステル類等を挙げることができる。これらの中でも、ベンゼン、トルエン、キシレン等の芳香族炭化水素類が好ましく、トルエンが特に好ましい。
【００２３】
非水系溶媒の使用量としては、特に制限されるものではないが、通常一般式（２）で表されるアニリン誘導体に対して少なくとも３倍体積量（Ｖ／Ｖ）、好ましくは３〜５倍体積量（Ｖ／Ｖ）とするのがよい。また、水の使用量としても、特に制限されるものではないが、通常一般式（２）で表されるアニリン誘導体に対して少なくとも１３倍体積量（Ｖ／Ｖ）、好ましくは１３〜２０倍体積量（Ｖ／Ｖ）とするのがよい。
【００２４】
また、本発明においては、一般式（３）で表されるアルデヒド誘導体は、非水系溶媒に溶解させるのがよい。
【００２５】
本発明では、水と非水系溶媒との界面で、一般式（２）で表されるアニリン誘導体と一般式（３）で表されるアルデヒド誘導体との反応が進行する。
【００２６】
本発明の方法においては、反応系内にホウ酸を存在させてもよい。反応系内にホウ酸を存在させることにより、一般式（２）で表されるアニリン誘導体と一般式（３）で表されるアルデヒド誘導体との反応がより一層有利に進行し、収率が一段と向上する場合がある。ホウ酸の使用量としては、通常一般式（２）で表されるアニリン誘導体に対して少なくとも等モル量、好ましくは等モル〜２倍モル量とするのがよい。ホウ酸は、水及び非水系溶媒のどちらの系に存在させておいてもよい。
【００２７】
一般式（２）で表されるアニリン誘導体と一般式（３）で表されるアルデヒド誘導体との反応において、両者の使用割合としては、特に制限されるものではなく、広い範囲内から適宜選択され得るが、通常前者に対して後者を少なくとも等モル量、好ましくは等モル〜３倍モル量とするのがよい。
【００２８】
本発明の反応は、室温下及び加温下のいずれでも進行するが、通常室温〜１５０℃程度、好ましくは８０〜１２０℃程度で反応を行うのがよく、一般に１〜３時間程度で該反応は完結する。
【００２９】
斯くして得られる本発明の一般式（１）で表されるハロゲン置換キノリン誘導体は、通常の分離手段により反応混合物から容易に単離精製される。該分離手段としては、例えば溶媒抽出法、希釈法、再結晶法、カラムクロマトグラフィー、プレパラティブ薄層クロマトグラフィー等を挙げることができる。
【００３０】
本発明において出発原料として用いられる一般式（２）で表されるアニリン誘導体は、従来公知の各種の方法により製造される。例えば一般式（２）で表されるアニリン誘導体は、一般式（４）
【００３１】
【化５】
〔式中、Ｘ1、Ｘ2及びＸ3は、前記に同じ。Ｒ2は低級アルカノイル基を示す。〕で表されるアニリド誘導体を酸により加水分解することにより製造される。
【００３３】
一般式（４）において、Ｒ2で示される低級アルカノイル基としては、例えばアセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、tert−ブチルカルボニル、へキサノイル基等の炭素数２〜６の直鎖又は分枝鎖状アルカノイル基を例示できる。
【００３４】
【実施例】
以下に実施例を掲げて、本発明をより一層明らかにする。
【００３５】
実施例１
５，６−ジフルオロ−８−ブロモキナルジンの製造
２−ブロモ−４，５−ジフルオロアセトアニリド４．０２ｇを懸濁させた６Ｎ塩酸水溶液６４．３ｍｌを３０分間還流し、２−ブロモ−４，５−ジフルオロアニリンを得た後、トルエン１６．１ｍｌを反応液に加え、クロトンアルデヒド２．６６ｍｌを約１０分かけて滴下した。滴下後、更に２時間還流下に攪拌し、次いで反応混合物を室温まで冷却し、水層を２５％水酸化ナトリウム水溶液及び５０％酢酸ナトリウム水溶液にて中和した後、結晶を濾取し、５，６−ジフルオロ−８−ブロモキナルジンを３．２４ｇ（収率：７８．２％）得た。
融点：１０７〜１０８℃、白色結晶。
【００３６】
実施例２
５，６−ジフルオロ−８−ブロモキナルジンの製造
２−ブロモ−４，５−ジフルオロアセトアニリド５．６０ｇ及び無水ホウ酸１．３８ｇを懸濁させた６Ｎ塩酸水溶液１１２ｍｌを３０分間還流し、２−ブロモ−４，５−ジフルオロアニリンを得た後、トルエン２８ｍｌを反応液に加え、クロトンアルデヒド３．７１ｍｌを約１０分かけて滴下した。滴下後、更に２時間還流下に攪拌し、次いで反応混合物を室温まで冷却し、水層を２５％水酸化ナトリウム水溶液にて中和した後、結晶を濾取し、５，６−ジフルオロ−８−ブロモキナルジンを４．６７ｇ（収率：８１．４％）得た。
融点：１０７〜１０８℃、白色結晶。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a halogen-substituted quinoline derivative.
[0002]
[Prior art]
General formula
[Chemical 3]
[Wherein, X 1 , X 2 and X 3 each represent a halogen atom. R 1 represents a hydrogen atom or a lower alkyl group. ]
Is a compound useful as an intermediate for synthesizing pharmaceuticals such as antibacterial agents.
[0005]
Conventionally, the Doebner-Miller reaction is widely used as a method for synthesizing 2-alkylquinolines. However, when this reaction is applied to produce a halogen-substituted quinoline derivative of the above general formula (1), the reaction mixture after the reaction becomes coal tar-like, and the desired halogen-substituted quinoline of the general formula (1) For the reason that the boiling point of the derivative and the reaction by-product is close, the target compound could be produced only in low yield and low purity.
[0006]
In order to eliminate such drawbacks, the reaction between the aniline derivative represented by the general formula (2) and the aldehyde derivative represented by the general formula (3) is carried out by reacting an alkali metal salt of m-nitrobenzenesulfonic acid, iron sulfate. And a method in the presence of boric acid has been developed (Japanese Patent Laid-Open No. 2-188570). According to this method, the desired halogen-substituted quinoline derivative of the general formula (1) can be obtained in a relatively high yield, but the reaction mixture becomes tar and the target compound is colored. In order to obtain a target compound with high purity, a complicated purification step is required, and in this case, the yield is inevitably lowered. For this reason, the method described in JP-A-2-188570 is still insufficient in terms of the yield and purity of the target compound. Furthermore, in the method described in JP-A-2-188570, it is necessary to gradually add the aldehyde derivative represented by the general formula (3) into the reaction system, and the yield of the target compound depends on the dropping conditions. Therefore, it was difficult to produce the target compound with the same level of yield with good reproducibility.
[0007]
[Problems to be solved by the invention]
The present invention does not have the disadvantage that the reaction mixture becomes tar and the target compound is colored, and therefore, the target halogen-substituted quinoline derivative of the general formula (1) can be obtained by a simple operation without going through complicated purification steps. It is an object of the present invention to provide a method for producing a compound with high yield and high purity.
[0008]
An object of the present invention is to provide a method for producing a target halogen-substituted quinoline derivative of the general formula (1) with high reproducibility and high yield.
[0009]
An object of the present invention is to provide a method for industrially advantageously producing a target halogen-substituted quinoline derivative of the general formula (1).
[0010]
[Means for Solving the Problems]
As a result of intensive studies to achieve the above-mentioned problems, the present inventor has found that the above problems can be solved when a two-phase solvent of water and a non-aqueous solvent is used as a solvent. The present invention has been completed based on such findings.
[0011]
That is, the present invention has the general formula
[Formula 4]
[Wherein, X 1 , X 2 and X 3 each represent a halogen atom. ]
An aniline derivative represented by the general formula R 1 CH═CHCHO (3)
[Wherein, R 1 represents a hydrogen atom or a lower alkyl group. ]
In the method for producing the halogen-substituted quinoline derivative represented by the general formula (1) by reacting the aldehyde derivative represented by the general formula (1), the aniline derivative represented by the general formula (2) and the general formula (3) The present invention relates to a method for producing a halogen-substituted quinoline derivative represented by the general formula (1), wherein the reaction with an aldehyde derivative is carried out at the interface between water and a non-aqueous solvent in the presence of an acid.
[0014]
According to the method of the present invention, there is no inconvenience that the reaction mixture becomes tar and the target compound is colored, and therefore, without the complicated purification step, the target of the general formula (1) can be obtained by a simple operation. Halogen-substituted quinoline derivatives can be produced in high yield and purity.
[0015]
Further, according to the method of the present invention, the yield of the target compound is not affected by the dropping conditions of the aldehyde derivative represented by the general formula (3) into the reaction system, and the target general formula (1 Can be produced with high reproducibility and high yield.
[0016]
Furthermore, according to the method of the present invention, there is no need to add an alkali metal salt of m-nitrobenzenesulfonic acid or iron sulfate to the reaction system, which is advantageous from the economical viewpoint.
[0017]
DETAILED DESCRIPTION OF THE INVENTION
More specifically, each group shown in the present specification is as follows.
[0018]
Examples of the lower alkyl group represented by R 1 include linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups. . The lower alkyl group represented by R 1 is preferably a methyl group.
[0019]
Examples of the halogen atom represented by X 1 , X 2 and X 3 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The halogen atom represented by X 1 and X 2 is preferably a fluorine atom, and the halogen atom represented by X 3 is preferably a bromine atom.
[0020]
In the present invention, the reaction between the aniline derivative represented by the general formula (2) and the aldehyde derivative represented by the general formula (3) is carried out in a two-phase solvent of water and a non-aqueous solvent in the presence of an acid. It is done at.
[0021]
As the acid, conventionally known mineral acids can be widely used, and examples thereof include hydrochloric acid, sulfuric acid, hydrobromic acid and the like. Among these, hydrochloric acid is particularly preferable.
[0022]
As the non-aqueous solvent, conventionally known ones can be widely used as long as they do not adversely affect the reaction and become two-phase without being mixed with water, for example, ethers such as diethyl ether and diisopropyl ether, benzene, Aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, esters such as methyl acetate, ethyl acetate and butyl acetate can be used. Among these, aromatic hydrocarbons such as benzene, toluene and xylene are preferable, and toluene is particularly preferable.
[0023]
The amount of the non-aqueous solvent used is not particularly limited, but is usually at least 3 times volume (V / V), preferably 3 to 5 times that of the aniline derivative represented by the general formula (2). The volume (V / V) is preferable. Also, the amount of water used is not particularly limited, but is usually at least 13 times volume (V / V), preferably 13 to 20 times that of the aniline derivative represented by the general formula (2). The volume (V / V) is preferable.
[0024]
In the present invention, the aldehyde derivative represented by the general formula (3) is preferably dissolved in a non-aqueous solvent.
[0025]
In the present invention, the reaction between the aniline derivative represented by the general formula (2) and the aldehyde derivative represented by the general formula (3) proceeds at the interface between water and the non-aqueous solvent.
[0026]
In the method of the present invention, boric acid may be present in the reaction system. By making boric acid present in the reaction system, the reaction between the aniline derivative represented by the general formula (2) and the aldehyde derivative represented by the general formula (3) proceeds more advantageously, and the yield is further improved. May improve. The amount of boric acid used is usually at least an equimolar amount, preferably an equimolar to double molar amount with respect to the aniline derivative represented by the general formula (2). Boric acid may be present in either water or non-aqueous solvent.
[0027]
In the reaction of the aniline derivative represented by the general formula (2) and the aldehyde derivative represented by the general formula (3), the use ratio of both is not particularly limited and is appropriately selected from a wide range. Usually, the latter should be at least equimolar, preferably equimolar to 3-fold molar relative to the former.
[0028]
The reaction of the present invention proceeds at both room temperature and under heating, but the reaction is usually carried out at room temperature to about 150 ° C, preferably about 80 to 120 ° C, and generally the reaction takes about 1 to 3 hours. Is completed.
[0029]
The halogen-substituted quinoline derivative represented by the general formula (1) of the present invention thus obtained is easily isolated and purified from the reaction mixture by a usual separation means. Examples of the separation means include a solvent extraction method, a dilution method, a recrystallization method, column chromatography, and preparative thin layer chromatography.
[0030]
The aniline derivative represented by the general formula (2) used as a starting material in the present invention is produced by various conventionally known methods. For example, the aniline derivative represented by the general formula (2) is represented by the general formula (4)
[0031]
[Chemical formula 5]
[Wherein, X 1 , X 2 and X 3 are the same as above. R 2 represents a lower alkanoyl group. It is manufactured by hydrolyzing the anilide derivative represented by this with an acid.
[0033]
In the general formula (4), the lower alkanoyl group represented by R 2 is, for example, a straight chain or branched chain having 2 to 6 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl group, etc. A chain alkanoyl group can be exemplified.
[0034]
【Example】
The present invention will be further clarified by the following examples.
[0035]
Example 1
Preparation of 5,6-difluoro-8-bromoquinaldine 64.3 ml of 6N aqueous hydrochloric acid in which 4.02 g of 2-bromo-4,5-difluoroacetanilide was suspended was refluxed for 30 minutes, and 2-bromo-4,5-difluoro After obtaining aniline, 16.1 ml of toluene was added to the reaction solution, and 2.66 ml of crotonaldehyde was added dropwise over about 10 minutes. After the dropwise addition, the mixture was further stirred for 2 hours under reflux, then the reaction mixture was cooled to room temperature, the aqueous layer was neutralized with 25% aqueous sodium hydroxide and 50% aqueous sodium acetate, and the crystals were collected by filtration. , 6-difluoro-8-bromoquinaldine was obtained (yield: 78.2%).
Melting point: 107-108 ° C., white crystals.
[0036]
Example 2
Preparation of 5,6-difluoro-8-bromoquinaldine 112 ml of 6N aqueous hydrochloric acid suspension of 5.60 g of 2-bromo-4,5-difluoroacetanilide and 1.38 g of boric anhydride was refluxed for 30 minutes. After obtaining 4,5-difluoroaniline, 28 ml of toluene was added to the reaction solution, and 3.71 ml of crotonaldehyde was added dropwise over about 10 minutes. After the dropwise addition, the mixture was further stirred under reflux for 2 hours, and then the reaction mixture was cooled to room temperature. The aqueous layer was neutralized with 25% aqueous sodium hydroxide solution, and then the crystals were collected by filtration to give 5,6-difluoro-8. -4.67 g (yield: 81.4%) of bromoquinaldine was obtained.
Melting point: 107-108 ° C., white crystals.
Claims (2)
Ｒ１ＣＨ＝ＣＨＣＨＯ （３）
〔式中、Ｒ１は水素原子又は低級アルキル基を示す。〕で表されるアルデヒド誘導体を反応させて一般式
[Wherein, R 1 represents a hydrogen atom or a lower alkyl group. ] Is reacted with an aldehyde derivative represented by the general formula
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