JP2688712B2 - Method for producing halogen-substituted quinoline derivative - Google Patents
Method for producing halogen-substituted quinoline derivativeInfo
- Publication number
- JP2688712B2 JP2688712B2 JP923589A JP923589A JP2688712B2 JP 2688712 B2 JP2688712 B2 JP 2688712B2 JP 923589 A JP923589 A JP 923589A JP 923589 A JP923589 A JP 923589A JP 2688712 B2 JP2688712 B2 JP 2688712B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- substituted quinoline
- halogen
- derivative represented
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- Quinoline Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は、ハロゲン置換キノリン誘導体の製造法、更
に詳しくは一般式 〔式中R1はハロゲン原子を示す。R3は水素原子又は低級
アルキル基を示す。ｍは１〜４の整数を示す。〕 で表わされるハロゲン置換キノリン誘導体の製造法に関
する。TECHNICAL FIELD The present invention relates to a method for producing a halogen-substituted quinoline derivative, more specifically a general formula [In the formula, R 1 represents a halogen atom. R 3 represents a hydrogen atom or a lower alkyl group. m shows the integer of 1-4. ] It is related with the manufacturing method of the halogen-substituted quinoline derivative represented by these.
従来の技術及びその問題点 従来、上記一般式（１）のハロゲン置換キノリン誘導
体は、一般式 〔式中、R1及びｍは前記に同じ。R2は水素原子又は低級
アルカノイル基を示す。〕 で表わされるアニリン誘導体と一般式 R3CH＝CHCHO （３） 〔式中R3は前記に同じ。〕 で表わされるアルデヒド誘導体とを、塩酸、硫酸、臭化
水素酸等の鉱酸の存在下に反応させることにより製造さ
れている。2. Description of the Related Art Conventionally, the halogen-substituted quinoline derivative represented by the general formula (1) has been represented by the general formula: [In the formula, R 1 and m are the same as defined above. R 2 represents a hydrogen atom or a lower alkanoyl group. ] And an aniline derivative represented by the general formula R 3 CH = CHCHO (3) [wherein R 3 is the same as defined above]. ] It is manufactured by reacting an aldehyde derivative represented by the following in the presence of a mineral acid such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like.
しかしながら、上記の鉱酸のみを用いる方法によれ
ば、多量の重合物が生成し、そのため目的物が低収率、
低純度でしか得られず、その上目的物を単離、精製する
ことが非常に困難であり、大量合成を行ない得ないとい
う欠点を有している。However, according to the method using only the above-mentioned mineral acid, a large amount of polymer is produced, and thus the target product is produced in a low yield,
It has a drawback that it can be obtained only in low purity, and that it is very difficult to isolate and purify the desired product and mass synthesis cannot be performed.
問題点を解決するための手段 本発明は、上記欠点を有しない一般式（１）のハロゲ
ン置換キノリン誘導体の製造法を提供するものである。Means for Solving the Problems The present invention provides a method for producing a halogen-substituted quinoline derivative of the general formula (1) which does not have the above-mentioned drawbacks.
即ち、本発明は、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、一般式
（２）で表わされるアニリン誘導体と一般式（３）で表
わされるアルデヒド誘導体とを反応させることを特徴と
する一般式（１）で表わされるハロゲン置換キノリン誘
導体の製造法に係る。That is, in the present invention, an aniline derivative represented by the general formula (2) and an aldehyde derivative represented by the general formula (3) are reacted in the presence of an alkali metal salt of m-nitrobenzenesulfonic acid, iron sulfate and boric acid. The present invention relates to a method for producing a halogen-substituted quinoline derivative represented by the general formula (1).
本発明で得ら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。The halogen-substituted quinoline derivative obtained in the present invention is a compound useful as an intermediate for synthesizing pharmaceuticals such as antibacterial agents.
本明細書において、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。In the present specification, examples of the halogen atom include fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
低級アルキル基としては、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の直鎖又は分岐鎖状アルキ
ル基を例示できる。Lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl,
A linear or branched alkyl group having 1 to 6 carbon atoms such as a hexyl group can be exemplified.
低級アルカノイル基としては、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、ヘキサノイル基等の炭素数２〜６の直
鎖又は分岐鎖状アルカノイル基を例示できる。Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 2 to 6 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl groups.
本発明においては、反応系内にｍ−ニトロベンゼンス
ルホン酸のアルカリ金属塩、硫酸鉄及びホウ酸を存在さ
せることを必須とする。これらのうちのいずれか一つを
欠いても本発明の所期の目的を達成することは不可能で
ある。In the present invention, it is essential that the alkali metal salt of m-nitrobenzenesulfonic acid, iron sulfate and boric acid be present in the reaction system. Without any one of these, it is impossible to achieve the intended purpose of the invention.
ｍ−ニトロベンゼンスルホン酸のアルカリ金属塩とし
ては、例えばｍ−ニトロベンゼンスルホン酸ナトリウ
ム、ｍ−ニトロベンゼンスルホン酸カリウム等が挙げら
れ、これらは１種単独で又は２種以上混合して用いられ
る。Examples of the alkali metal salt of m-nitrobenzene sulfonic acid include sodium m-nitrobenzene sulfonate and potassium m-nitrobenzene sulfonate, and these may be used alone or in combination of two or more.
反応系内に存在させるべきｍ−ニトロベンゼンスルホ
ン酸のアルカリ金属塩の量は、一般式（２）のアニリン
誘導体に対して通常少なくとも等モル量程度、好ましく
は等モル〜1.5倍モル量程度である。また硫酸鉄の量
は、一般式（２）のアニリン誘導体に対して通常少なく
とも0.01〜0.2倍モル量程度、好ましくは0.05〜0.15倍
モル量程度である。更にホウ酸の量は、一般式（２）の
アニリン誘導体に対して通常等モル〜７倍モル量程度、
好ましくは等モル〜５倍モル量程度である。The amount of the alkali metal salt of m-nitrobenzenesulfonic acid to be present in the reaction system is usually at least about equimolar amount, preferably about equimolar to 1.5-fold molar amount with respect to the aniline derivative of the general formula (2). . The amount of iron sulfate is usually at least about 0.01 to 0.2 times, and preferably about 0.05 to 0.15 times the molar amount of the aniline derivative of the general formula (2). Further, the amount of boric acid is usually equimolar to 7 times the molar amount of the aniline derivative of the general formula (2),
The amount is preferably equimolar to 5 times the molar amount.
本発明では、一般式（２）のアニリン誘導体と一般式
（３）のアルデヒド誘導体との配合割合は、前者に対し
て後者を通常少なくとも等モル量程度、好ましくは等モ
ル〜２倍モル量程度とするのがよい。In the present invention, the compounding ratio of the aniline derivative of the general formula (2) and the aldehyde derivative of the general formula (3) is such that the latter is usually at least an equimolar amount, preferably an equimolar to 2-fold molar amount with respect to the former. It is good to say
本発明の反応は、水等の溶媒中、塩酸、硫酸、臭化水
素酸等の鉱酸の存在下に行なわれる。該反応は、通常室
温〜150℃程度、好ましくは室温〜120℃付近にて好適に
進行し、一般に１〜３時間程度で該反応は完結する。The reaction of the present invention is carried out in a solvent such as water in the presence of a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid. The reaction generally proceeds suitably at room temperature to about 150 ° C., preferably at room temperature to about 120 ° C., and generally the reaction is completed in about 1 to 3 hours.
斯くして得られる本発明の目的化合物は、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が挙げられる。The object compound of the present invention thus obtained is easily isolated and purified from the reaction mixture by a conventional 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.
発明の効果 本発明による製造法は、従来の方法に比し、目的物が
高収率且つ高純度で得られ、また反応時間が短く、反応
操作及び目的物の単離・精製が極めて簡便であり、その
ため大量合成も容易であり、従って工業的に極めて有利
な方法である。EFFECTS OF THE INVENTION The production method according to the present invention, compared with the conventional method, can obtain the target product in high yield and high purity, the reaction time is short, and the reaction operation and the isolation / purification of the target product are extremely simple. Therefore, large-scale synthesis is easy, and therefore, it is an industrially extremely advantageous method.
実施例 以下に参考例及び実施例を掲げて本発明をより一層明
らかにする。Examples The present invention will be further clarified with reference to Reference Examples and Examples below.
参考例１ ２−ブロモ−4,5−ジフルオロアセトアニリド50g、メ
タノール200ml及び40％水酸化カリウム40mlを室温で撹
拌後、加熱還流下で３〜４時間反応させる。反応終了後
1,2−ジクロロエタン300mlで抽出し、次いで濃硫酸11g
を滴下分散させ、氷冷後取して２−ブロモ−4,5−ジ
フルオロアニリン・1/2硫酸塩46.9gを得る。Reference Example 1 2-Bromo-4,5-difluoroacetanilide (50 g), methanol (200 ml) and 40% potassium hydroxide (40 ml) were stirred at room temperature and then reacted under heating under reflux for 3 to 4 hours. After the reaction
Extracted with 1,2-dichloroethane (300 ml), then concentrated sulfuric acid (11 g)
Was dropped and dispersed, and after cooling with ice, it was collected to obtain 46.9 g of 2-bromo-4,5-difluoroaniline.1 / 2 sulfate.
融点:205〜209℃、白色結晶 実施例１ ２−ブロモ−4,5−ジフルオロアニリン・1/2硫酸塩10
g、ｍ−ニトロベンゼンスルホン酸ナトリウム8.76g、硫
酸鉄・７水和物1.1g、ホウ酸10.4g、濃硫酸35ml及び水3
5mlを同時に仕込み、加熱還流下まで加熱する。次にク
ロトンアルデヒド4.1gを２時間要して徐々に滴下する。
滴下終了後、30分間撹拌する。反応終了後不溶物を去
する。その後液を25％水酸化ナトリウムで中和後、析
出晶を取する。50％メタノールで洗浄後、5,6−ジフ
ルオロ−８−ブロモキナルジン7gを得る（収率:70
％）。Melting point: 205-209 ° C, white crystal Example 1 2-Bromo-4,5-difluoroaniline 1/2 sulfate 10
g, sodium m-nitrobenzenesulfonate 8.76 g, iron sulfate heptahydrate 1.1 g, boric acid 10.4 g, concentrated sulfuric acid 35 ml and water 3
Charge 5 ml at the same time and heat to reflux. Next, 4.1 g of crotonaldehyde is gradually added dropwise over 2 hours.
After completion of dropping, stir for 30 minutes. After the reaction is completed, the insoluble matter is removed. After that, the solution is neutralized with 25% sodium hydroxide and the precipitated crystals are collected. After washing with 50% methanol, 7 g of 5,6-difluoro-8-bromoquinaldine was obtained (yield: 70
%).
融点:107〜108℃、白色結晶 実施例２ ２−ブロモ−4,5−ジフルオロアセトアニリド2000g、
ｍ−ニトロベンゼンスルホン酸ナトリウム1801g、硫酸
鉄・７水和物222g、ホウ酸2176g及び6N−塩酸14を同
時に仕込み、加熱還流下まで加熱する。次にクロトンア
ルデヒド841gを２時間要して徐々に滴下する。滴下終了
後、30分間撹拌する。反応終了後不溶物を去する。そ
の後液を25％水酸化ナトリウムで中和後、析出晶を
取する。50％メタノールで洗浄後、5,6−ジフルオロ−
８−ブロモキナルジン3395gを得る（収率:71.9％）。Melting point: 107-108 ° C., white crystal Example 2 2000 g of 2-bromo-4,5-difluoroacetanilide,
1801 g of sodium m-nitrobenzenesulfonate, 222 g of iron sulfate heptahydrate, 2176 g of boric acid and 14N of 6N-hydrochloric acid are charged at the same time and heated to reflux. Next, 841 g of crotonaldehyde is gradually added dropwise over 2 hours. After completion of dropping, stir for 30 minutes. After the reaction is completed, the insoluble matter is removed. After that, the solution is neutralized with 25% sodium hydroxide and the precipitated crystals are collected. After washing with 50% methanol, 5,6-difluoro-
3395 g of 8-bromoquinaldine is obtained (yield: 71.9%).
融点:107〜108℃、白色結晶Melting point: 107-108 ° C, white crystals
Claims (1)
金属塩、硫酸鉄及びホウ酸の存在下に、一般式 〔式中、R1はハロゲン原子を示す。R2は水素原子又は低
級アルカノイル基を示す。ｍは１〜４の整数を示す。〕 で表わされるアニリン誘導体と一般式 R3CH＝CHCHO 〔式中R3は水素原子又は低級アルキル基を示す。〕 で表わされるアルデヒド誘導体とを反応させることを特
徴とする一般式 〔式中R1、R3及びｍは前記に同じ。〕 で表わされるハロゲン置換キノリン誘導体の製造法。1. In the presence of an alkali metal salt of m-nitrobenzenesulfonic acid, iron sulfate and boric acid, a compound of the general formula [In the formula, R 1 represents a halogen atom. R 2 represents a hydrogen atom or a lower alkanoyl group. m shows the integer of 1-4. ] And an aniline derivative represented by the general formula R 3 CH = CHCHO [wherein R 3 represents a hydrogen atom or a lower alkyl group]. ] The general formula characterized by reacting with an aldehyde derivative represented by [In the formula, R 1 , R 3 and m are the same as defined above. ] The manufacturing method of the halogen-substituted quinoline derivative represented by these.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP923589A JP2688712B2 (en) | 1989-01-17 | 1989-01-17 | Method for producing halogen-substituted quinoline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP923589A JP2688712B2 (en) | 1989-01-17 | 1989-01-17 | Method for producing halogen-substituted quinoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02188570A JPH02188570A (en) | 1990-07-24 |
| JP2688712B2 true JP2688712B2 (en) | 1997-12-10 |
Family
ID=11714740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP923589A Expired - Lifetime JP2688712B2 (en) | 1989-01-17 | 1989-01-17 | Method for producing halogen-substituted quinoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2688712B2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60040979D1 (en) | 1999-05-07 | 2009-01-15 | Wockhardt Ltd | (S) -BENZOCHINOLICIN CARBOXYLIC ACIDS AND THEIR USE AS ANTIBACTERIAL AGENTS |
| US6514986B2 (en) | 2000-11-22 | 2003-02-04 | Wockhardt Limited | Chiral fluoroquinolone arginine salt forms |
| US6608078B2 (en) | 2000-05-08 | 2003-08-19 | Wockhardt Limited | Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment |
| US7098219B2 (en) | 2000-08-01 | 2006-08-29 | Wockhart Limited | Inhibitors of cellular efflux pumps of microbes |
| US6878713B2 (en) | 2001-04-25 | 2005-04-12 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
| US6964966B2 (en) | 2001-04-25 | 2005-11-15 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
| WO2003099815A1 (en) | 2002-05-28 | 2003-12-04 | Wockhardt Limited | Crystalline fluoroquinolone arginine salt form |
| CA2537066C (en) | 2003-09-04 | 2011-05-24 | Wockhardt Limited | Benzoquinolizine-2-carboxylic acid arginine salt tetrahydrate |
| CN114890945B (en) * | 2022-04-06 | 2023-09-05 | 大连万福制药有限公司 | Method for synthesizing nadifloxacin intermediate |
-
1989
- 1989-01-17 JP JP923589A patent/JP2688712B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02188570A (en) | 1990-07-24 |
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