JP2825641B2 - Method for producing quinoline carboxylic acid derivative - Google Patents
Method for producing quinoline carboxylic acid derivativeInfo
- Publication number
- JP2825641B2 JP2825641B2 JP2500847A JP50084789A JP2825641B2 JP 2825641 B2 JP2825641 B2 JP 2825641B2 JP 2500847 A JP2500847 A JP 2500847A JP 50084789 A JP50084789 A JP 50084789A JP 2825641 B2 JP2825641 B2 JP 2825641B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- general formula
- acid
- formula
- halogen
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
Description
【発明の詳細な説明】 この発明は次の一般式Ｉ を有する１−（任意的にハロ−置換）−エチル−７−
（3,4,5−置換ピペラジン）−6,8−ジフルオロ−４−オ
キソ−1,4−ジヒドロ−キノリン−３−カルボン酸の誘
導体および薬学的に許容しうるそれらの塩の新規な製造
方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention has the following general formula I 1- (optionally halo-substituted) -ethyl-7- having
Novel process for the preparation of (3,4,5-substituted piperazine) -6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid derivatives and pharmaceutically acceptable salts thereof About.
一般式Ｉにおいて、R1およびR3は水素またはC1-4のア
ルキルを示し、R2はC1-4のアルキルを示し、R4，R5およ
びR6は水素またはハロゲンを示す。In the general formula I, R 1 and R 3 represent hydrogen or C 1-4 alkyl, R 2 represents C 1-4 alkyl, and R 4 , R 5 and R 6 represent hydrogen or halogen.
一般式１で示される一群の７−（3,4,5−置換−ピペ
ラジン）−キノリン−３−カルボン酸誘導体が高い抗バ
クテリア活性を示すことが知られている（Antimicrob.A
gents Chemother.1987,31,854;Drugs of Fut.1986,11 5
78;26th Intersci.Conf.Antimicrob.Agents Chemother.
1986,Abst.430−431;25th Intersci.Conf.Antimicrob.A
gents Chemother.1985,567）。これらの化合物は6,7,8
−トリフルオロ−４−オキソ−1,4−ジヒドロ−キノリ
ン−３−カルボン酸と環状アミンとを反応させることに
よって製造し得る（独国特許明細書3 433 924,日本特許
明細書60−142980,61−85381,61−65882）。It is known that a group of 7- (3,4,5-substituted-piperazine) -quinoline-3-carboxylic acid derivatives represented by the general formula 1 exhibit high antibacterial activity (Antimicrob.A.
gents Chemother. 1987, 31 , 854; Drugs of Fut. 1986, 11 5
78; 26th Intersci.Conf.Antimicrob.Agents Chemother.
1986, Abst. 430-431; 25th Intersci. Conf. Antimicrob.A
gents Chemother. 1985, 567). These compounds are 6,7,8
-Trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with a cyclic amine (German Patent Specification 3 433 924, Japanese Patent Specification 60-142980, 61-85381, 61-65882).
本発明によれば、一般式Ｉ（式中R1およびR3は水素ま
たはC1-4のアルキルを示し、R2はC1-4のアルキルを示
し、R4，R5およびR6は水素またはハロゲンを示す）で表
わされるキノリン−３−カルボン酸誘導体およびそれら
の薬学的に許容しうる塩の新規な製造方法を提供するも
のであり、一般式II （式中、Ｒはハロゲン、炭素数２〜６の脂肪族アシルオ
キシ基、または炭素数７〜11の芳香族アシルオキシ基を
示し、R4，R5，R6は上記で規定した意味を有する） で表わされる化合物と一般式III （式中、R1，R2およびR3は上記で規定した意味を有す
る）で表わされるアミンまたはその塩とを反応させ、得
られた一般式IV （式中、R,R1，R2，R3，R4，R5およびR6は上記の通りで
ある） で表わされる化合物を単離後または単離することなく加
水分解し、次いでこのようにして得られた一般式Ｉの化
合物を必要に応じてその塩に変えるかまたはその塩から
上記化合物を遊離させることを特徴とする。According to the present invention, R 1 and R 3 represent hydrogen or C 1-4 alkyl, R 2 represents C 1-4 alkyl, and R 4 , R 5 and R 6 represent A novel process for producing quinoline-3-carboxylic acid derivatives represented by hydrogen or halogen) and their pharmaceutically acceptable salts. (In the formula, R represents a halogen, an aliphatic acyloxy group having 2 to 6 carbon atoms, or an aromatic acyloxy group having 7 to 11 carbon atoms, and R 4 , R 5 , and R 6 have the meanings defined above.) And a compound of the general formula III (Wherein R 1 , R 2 and R 3 have the meanings defined above) or a salt thereof, and the resulting compound of the general formula IV Wherein R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described above, after or without isolation, hydrolyzing the compound The compound of the general formula I thus obtained is converted into a salt thereof as required or the compound is liberated from the salt.
本発明の方法の利点は、簡単な方法かつ短い反応時間
で、極めて高収率で一般式Ｉの化合物を製造しうるとい
うことである。An advantage of the process according to the invention is that the compounds of general formula I can be prepared in very simple manner and in short reaction times in very high yields.
一般式IVの硼素誘導体は新規化合物である。 The boron derivative of the general formula IV is a novel compound.
本発明の方法を実施するための好ましい態様によれ
ば、一般式IVの硼素誘導体は、単離することなく必要と
する一般式Ｉのキノリン−３−カルボン酸に変換され
る。According to a preferred embodiment for carrying out the process according to the invention, the boron derivative of the general formula IV is converted without isolation into the required quinoline-3-carboxylic acid of the general formula I.
一般式IIの硼素誘導体は、必要に応じて不活性有機溶
媒および酸結合剤の存在下で、一般式IIIのアミンと反
応させる。The boron derivative of general formula II is reacted with an amine of general formula III, optionally in the presence of an inert organic solvent and an acid binder.
不活性有機溶媒として、好ましくは酸アミド（例えば
ジメチルホルムアミド、ジメチルアセトアミド）、ケト
ン（例えばアセトン、メチルエチルケトン）、エーテル
（例えばジオキサン、テトラヒドロフラン、ジエチルエ
ーテル）、エステル（例えば酢酸エチル、酢酸メチル、
プロピオン酸エチル）、スルホキシド（例えばジメチル
スルホキシド）、アルコール（例えばメタノール、エタ
ノール、１−デカノール、ブタノール）、ニトリル（例
えばアセトニトリル）、ハロゲン化有機溶媒（例えばク
ロロホルム、ジクロロメタン）が使用される。As the inert organic solvent, preferably, acid amide (eg, dimethylformamide, dimethylacetamide), ketone (eg, acetone, methyl ethyl ketone), ether (eg, dioxane, tetrahydrofuran, diethyl ether), ester (eg, ethyl acetate, methyl acetate,
Ethyl propionate), sulfoxides (eg, dimethylsulfoxide), alcohols (eg, methanol, ethanol, 1-decanol, butanol), nitriles (eg, acetonitrile), and halogenated organic solvents (eg, chloroform, dichloromethane) are used.
酸結合剤としては、有機または無機の塩基が使用され
る。有機の塩基のグループとしては、トリアルキルアミ
ン（例えばトリエチルアミン、トリブチルアミン）、環
状アミン（例えばピリジン、1,5−ジアザビシクロ/5,4,
0/ウンデカ−５−エン、1,5−ジアザビシクロ/4,3,0/−
ノナ−５−エン、1,4−ジアザビシクロ/2,2,2/オクタ
ン）があげられ、一方無機の塩基として好ましくは、ア
ルカリもしくはアルカリ土類金属の水酸化物または炭酸
塩が用いられる。このような酸結合剤として、有利に
は、炭酸カリウム、炭酸水素カリウム、水酸化ナトリウ
ム、水酸化カルシウムなどのほか、過剰量の一般式III
のアミンを使用することができる。As the acid binder, an organic or inorganic base is used. Groups of organic bases include trialkylamines (eg, triethylamine, tributylamine), cyclic amines (eg, pyridine, 1,5-diazabicyclo / 5,4,
0 / undec-5-ene, 1,5-diazabicyclo / 4,3,0 /-
Nona-5-ene and 1,4-diazabicyclo / 2,2,2 / octane). On the other hand, as the inorganic base, an alkali or alkaline earth metal hydroxide or carbonate is preferably used. As such an acid binder, advantageously, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide and the like, as well as an excess amount of the general formula III
Amines can be used.
一般式IIの硼素誘導体および一般式IIIのアミンは、
使用溶媒に応じて、10〜200℃の間の温度で反応させる
ことができる。反応時間は0.1〜10時間の間で変えられ
る。また、反応時間は、反応温度によっても変化する。
もし反応が高温で行なわれるときには、反応時間は短く
てよい。上記の反応条件は好ましい値であり、他の条件
も同様に使用しうる。The boron derivative of the general formula II and the amine of the general formula III
The reaction can be carried out at a temperature between 10 and 200 ° C., depending on the solvent used. The reaction time can be varied between 0.1 and 10 hours. Further, the reaction time varies depending on the reaction temperature.
If the reaction is carried out at an elevated temperature, the reaction time may be short. The above reaction conditions are preferred values and other conditions can be used as well.
一般式IVの化合物は単離後または単離することなく、
酸性もしくは塩基性の条件下で目的の一般式Ｉのキノリ
ン−３−カルボン酸に加水分解される。一般式IVの化合
物は、例えば冷却して反応混合物から析出させ、必要に
応じて例えば過または遠心分離によって分離される。The compound of general formula IV can be isolated or without isolation,
Hydrolysis to the desired quinoline-3-carboxylic acid of general formula I under acidic or basic conditions. The compound of general formula IV is precipitated, for example, from the reaction mixture by cooling, and is separated if necessary, for example, by filtration or centrifugation.
塩基による加水分解は、好ましくはアルカリ金属の水
酸化物もしくは炭酸塩またはアルカリ土類金属の水酸化
物を水溶液として用い、加熱することによって行われ
る。水酸化ナトリウム、水酸化カリウム、炭酸ナトリウ
ム、炭酸カリウム、水酸化カルシウムの水溶液を用いる
のも好ましい方法である。しかしながら、有機アミン
（例えばトリエチルアミン）を加水分解工程で用いるこ
ともできる。The hydrolysis with a base is preferably carried out by using a hydroxide or carbonate of an alkali metal or a hydroxide of an alkaline earth metal as an aqueous solution and heating. It is also a preferable method to use an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and calcium hydroxide. However, organic amines (eg, triethylamine) can also be used in the hydrolysis step.
酸による加水分解は、好ましくは鉱酸の水溶液を用い
ることによって達成される。好ましい方法として、一般
式IVの化合物を塩酸、臭化水素、硫酸または燐酸の水溶
液と共に加熱することによって加水分解する方法があ
る。加水分解は、また有機の酸（例えば酢酸、プロピオ
ン酸など）を用いて達成し得る。Acid hydrolysis is preferably achieved by using an aqueous solution of a mineral acid. A preferred method is to hydrolyze the compound of general formula IV by heating with an aqueous solution of hydrochloric acid, hydrogen bromide, sulfuric acid or phosphoric acid. Hydrolysis can also be accomplished with organic acids (eg, acetic acid, propionic acid, etc.).
一般式IVの化合物の加水分解はまた、水混和性の有機
溶媒の存在下、水性媒体中で行われる。この目的のため
に、例えばアルコール（例えばメタノール、エタノー
ル）、ケトン（例えばアセトン）、エーテル（例えばジ
オキサン）、酸アミド（例えばジメチルホルムアミ
ド）、スルホキシド（例えばジメチルスルホキシド）、
またはピリジンが使用される。The hydrolysis of the compound of general formula IV is also carried out in an aqueous medium in the presence of a water-miscible organic solvent. For this purpose, for example, alcohols (eg, methanol, ethanol), ketones (eg, acetone), ethers (eg, dioxane), acid amides (eg, dimethylformamide), sulfoxides (eg, dimethylsulfoxide),
Or pyridine is used.
このようにして得られた一般式Ｉのキノリン−３−カ
ルボン酸は、水溶液のpH値を適当な値に調整し、沈殿し
た結晶を例えば過または遠心分離するか、または水性
反応混合物を凍結乾燥すること（liophylizing）によっ
て分離して単離することができる。The quinoline-3-carboxylic acids of the general formula I thus obtained can be prepared by adjusting the pH value of the aqueous solution to a suitable value and filtering out the precipitated crystals, for example, by filtration or centrifugation, or by freeze-drying the aqueous reaction mixture. Can be separated and isolated by liophylizing.
一般式Ｉの化合物は公知の方法によって薬学的に許容
しうるその塩に変えることができる。このような酸の付
加塩として、好ましくは例えばハロゲン化水素、スルホ
ン酸、硫酸または有機の酸とから生成される塩がある。
好ましいものとしては、クロライド、ブロマイド、アリ
ールスルホネート、メタンスルホネート、マレエート、
フマレート、ベンゾエートなどの形かある。一般式Ｉの
化合物はアルカリもしくはアルカリ土類金属とまたは同
様に他の金属イオンと塩を形成する。よって、ナトリウ
ム、カリウム、マグネシウム、銀、銅の塩などが製造さ
れる。Compounds of general formula I can be converted into pharmaceutically acceptable salts thereof by known methods. Such acid addition salts preferably include, for example, those formed from hydrogen halides, sulfonic acids, sulfuric acids or organic acids.
Preferred are chloride, bromide, arylsulfonate, methanesulfonate, maleate,
There are forms such as fumarate and benzoate. The compounds of the general formula I form salts with alkali or alkaline earth metals or likewise with other metal ions. Thus, sodium, potassium, magnesium, silver, copper salts and the like are produced.
一般式Ｉの化合物および薬学的に許容されるその塩
は、それ自体公知の方法によって水和物（例えばヘミ水
和物、トリ水和物など）に変えられる。Compounds of general formula I and pharmaceutically acceptable salts thereof can be converted into hydrates (eg, hemihydrate, trihydrate, etc.) by methods known per se.
本発明のもう一つの態様に従って、一般式IV（式中、
R,R1，R2，R3，R4，R5およびR6は上記の通りである）の
新規な化合物が提供される。According to another embodiment of the present invention, there is provided a compound of general formula IV wherein
R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above).
一般式IIの出発物質は、１−エチル−6,7,8−トリフ
ルオロ−４−オキソ−1,4−ジヒドロ−キノリン−３−
カルボン酸（GB特許明細書2,057,440）と硼素誘導体
［例えば次の一般式Ｖ （式中、Ｒはハロゲンまたは炭素数２〜６の脂肪族アシ
ルオキシ基または炭素数７〜11の芳香族アシルオキシ基
を示す）で表わされる化合物］またはフルオロボレート
とを水性媒体もしくは有機溶媒中で反応させることによ
って製造される。The starting material of general formula II is 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-
Carboxylic acid (GB Patent Specification 2,057,440) and boron derivative [for example, the following general formula V (Wherein, R represents a halogen or an aliphatic acyloxy group having 2 to 6 carbon atoms or an aromatic acyloxy group having 7 to 11 carbon atoms)] or a fluoroborate in an aqueous medium or an organic solvent. Manufactured by letting
次の実施例によって本発明を更に詳細に説明するが、
以下の実施例に本発明の範囲を限定するものではない。The invention is described in more detail by the following examples,
The following examples do not limit the scope of the present invention.
実施例１ （１−エチル−6,7,8−トリフルオロ−1,4−ジヒドロ
−４−オキソ−キノリン−３−カルボキシレート−O 3，
O 4）−ジフルオロ−ボロン31.9gと2,6−ジメチル−ピペ
ラジン57.1gとをジメチルスルホキシド150ml中100℃で
３時間反応させた。水酸化ナトリウム400mlの３重量／
容量％水溶液を加え、２時間加熱して加水分解を行っ
た。反応混合物を過し、96重量／容量％酢酸でpH値を
７に調整した。結晶性の反応混合物を一晩冷却し、析出
した結晶を過、水洗、乾燥した。このようにして７−
/3,5−ジメチル−ピペラジノ/1−エチル−6,8−ジフル
オロ−1,4−ジヒドロ−４−オキソ−キノリン−３−カ
ルボン酸29.9gを得た。融点232〜234℃。Example 1 (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo - quinoline-3-carboxylate - O 3,
31.9 g of O 4 ) -difluoro-boron and 57.1 g of 2,6-dimethyl-piperazine were reacted in 150 ml of dimethyl sulfoxide at 100 ° C. for 3 hours. 3 weight of 400 ml of sodium hydroxide /
A volume% aqueous solution was added, and the mixture was heated for 2 hours to carry out hydrolysis. The reaction mixture was filtered and the pH was adjusted to 7 with 96% w / v acetic acid. The crystalline reaction mixture was cooled overnight, and the precipitated crystals were filtered, washed with water and dried. In this way 7-
29.9 g of / 3,5-dimethyl-piperazino / 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid were obtained. 232-234 ° C.
式 C18H21F2N3O3の分析結果： 計算値 Ｃ＝59.17％ H＝5.80％ N＝11.49％ 実測値 Ｃ＝59.05％ H＝5.91％ N＝11.45％ 実施例２ 実施例１に従い、（１−エチル−6,7,8−トリフルオ
ロ−1,4−ジヒドロ−４−オキソ−キノリン−３−カル
ボキシレート−O 3，O 4）−ジフルオロ−ボロン31.9gを
ジメチルスルホキシド150ml中で２−メチル−ピペラジ
ン50.1gと反応させた。このようにして１−エチル−6,8
ジ−フルオロ−1,4−ジヒドロ−４−オキソ−７−（３
−メチル−ピペラジノ）−キノリン−３−カルボン酸3
0.6gを得た。融点238〜240℃。Formula C 18 H 21 F 2 N 3 O 3 Analysis Results: Calculated C = 59.17% H = 5.80% N = 11.49% Found C = 59.05% H = 5.91% N = 11.45% Example 2 According to Example 1 31.9 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate- O 3 , O 4 ) -difluoro-boron in 150 ml of dimethyl sulfoxide It was reacted with 50.1 g of 2-methyl-piperazine. Thus, 1-ethyl-6,8
Di-fluoro-1,4-dihydro-4-oxo-7- (3
-Methyl-piperazino) -quinoline-3-carboxylic acid 3
0.6 g was obtained. 238-240 ° C.
式 C17H19F2N3O3の分析結果： 計算値 Ｃ＝58.11％ H＝5.45％ N＝11.96％ 実測値 Ｃ＝58.01％ H＝5.55％ N＝12.07％ 実施例３ 実施例１に従い、（１−エチル−6,7,8−トリフルオ
ロ−1,4−ジヒドロ−４−オキソ−キノリン−３−カル
ボキシレート−O 3，O 4）−ビス−（アセタト−O）−ボ
ロン39.9gを２−メチル−ピペラジン50.1gとジメチルス
ルホキシド150ml中で反応させた。このようにして１−
エチル−6,8−ジフルオロ−1,4−ジヒドロ−４−オキソ
−７−（３−メチル−ペピラジノ）−キノリン−３−カ
ルボン酸30.2gを得た。融点237〜239℃。Formula C 17 H 19 F 2 N 3 O 3 Analysis Results: Calculated C = 58.11% H = 5.45% N = 11.96% Observed C = 58.01% H = 5.55% N = 12.77% Example 3 According to Example 1 , (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo - quinoline-3-carboxylate - O 3, O 4) - bis - (acetato - O) - boron 39.9g Was reacted with 50.1 g of 2-methyl-piperazine in 150 ml of dimethyl sulfoxide. Thus, 1-
30.2 g of ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-methyl-pepyrazino) -quinoline-3-carboxylic acid were obtained. 237-239 ° C.
式 C17H19F2N3O3の分析結果： 計算値 Ｃ＝58.11％ H＝5.45％ N＝11.96％ 実測値 Ｃ＝57.97％ H＝5.53％ N＝11.90％ 実施例４ 実施例１に従い、（１−エチル−6,7,8−トリフルオ
ロ−1,4−ジヒドロ−４−オキソ−キノリン−３−カル
ボキシレート−O 3，O 4）−ビス−（プロピオナト−O）
−ボロン42.7gを２−メチル−ピペラジン50.1gと反応さ
せた。このようにして１−エチル−6,8−ジフルオロ−
1,4−ジヒドロ−４−オキソ−７−（３−メチル−ピペ
ラジノ）−キノリン−３−カルボン酸28.7gを得た。融
点237〜239℃。Formula C 17 H 19 F 2 N 3 O 3 Analysis Results: Calculated C = 58.11% H = 5.45% N = 11.96% Observed C = 57.97% H = 5.53% N = 11.90% Example 4 According to Example 1 , (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo - quinoline-3-carboxylate - O 3, O 4) - bis - (Puropionato - O)
42.7 g of boron were reacted with 50.1 g of 2-methyl-piperazine. Thus, 1-ethyl-6,8-difluoro-
28.7 g of 1,4-dihydro-4-oxo-7- (3-methyl-piperazino) -quinoline-3-carboxylic acid were obtained. 237-239 ° C.
式 C17H19F2N3O3の分析結果： 計算値 Ｃ＝58.11％ H＝5.45％ N＝11.96％ 実測値 Ｃ＝57.99％ H＝5.52％ N＝12.10％Formula C 17 H 19 F 2 N 3 O 3 Analysis Results: Calculated C = 58.11% H = 5.45% N = 11.96% Observed C = 57.99% H = 5.52% N = 12.10%
───────────────────────────────────────────────────── フロントページの続き (72)発明者 バシユバーリ，レツレ ハンガリー国、ハー‐1122、ブダペシユ ト、ゴルドマルク・カー・ウツツア、33 (72)発明者 ホルバート，アーグネシユ ハンガリー国、ハー‐1021、ブダペシユ ト、ブデンズ・ウツツア、30／ア (72)発明者 バログ，マーリア ハンガリー国、ハー‐2120、ドウナケ シ、バラーチヤーグ・ウツツア、20 (72)発明者 リトリ，ペーテル ハンガリー国、ハー‐1066、ブダペシユ ト、オー・ウツツア、43 (72)発明者 シポシユ，ユデイツト ハンガリー国、ハー‐1116、ブダペシユ ト、シヤーフラーニ・ウツツア、10 (72)発明者 パヨル，アニコー ハンガリー国、ハー‐1092、ブダペシユ ト、フエレンツ・ケルート、36 (56)参考文献 特開 昭61−85381（ＪＰ，Ａ) 特開 昭64−19069（ＪＰ，Ａ) 特開 昭61−65882（ＪＰ，Ａ) 国際公開88／7998（ＷＯ，Ａ１) 国際公開87／3587（ＷＯ，Ａ１) (58)調査した分野(Int.Cl.6，ＤＢ名) C07D 401/04 C07F 5/02 ＣＡ，ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Bash ユ bari, Let ツ le, Hungary, Har-1122, Budapest, Gordmark Ka ・ u ツ t ユ a, 33 (72) Inventor Holbert, Agnécille, Hungary, Har-1021, Budapéciut, Budden's Utsua, 30 / A (72) Inventor Balog, Maria, Hungary, Har-2120, Dhunakesh, Barachiag Utua, 20 (72) Inventor Litri, Peter Hungary, Har-1066, Budapeshut, Oh Utua, 43 (72) Inventor Siposiyu, Juditto Hungary, Har-1116, Budapest, Shafrani Utua, 10 (72) Inventor Payol, Anikou Hungary, Har-1092, Budapeciut, Ellenz Kelut, 36 (56) References JP-A-61-85381 (JP, A) JP-A-64-19069 (JP, A) JP-A-61-65882 (JP, A) WO 88/7998 (WO , A1) WO 87/3587 (WO, A1) (58) Fields investigated (Int. Cl. 6 , DB name) C07D 401/04 C07F 5/02 CA, REGISTRY (STN)
Claims (10)
し、R2はC1-4のアルキルを示し、R4，R5およびR6は水素
またはハロゲンを示す） で表わされる化合物および薬学的に許容し得るそれらの
塩の製造方法であって、 一般式II （式中、Ｒはハロゲンまたは炭素数２〜６の脂肪族アシ
ルオキシ基または炭素数７〜11の芳香族アシルオキシ基
を示し、R4，R5，R6は上記に規定した通りである） で表わされる化合物と、一般式III （式中、R1，R2およびR3は上記に規定した意味を有す
る）で表わされるピペラジン誘導体またはその塩とを反
応させ、得られた一般式IV （式中、R,R1，R2，R3，R4，R5およびR6は上記の通りで
ある） で表わされる化合物を単離後または単離することなく加
水分解し、このようにして得られた一般式Ｉの化合物を
必要に応じてその塩に変えるか、またはその塩から上記
の化合物を遊離させることを特徴とする方法。1. A compound of the general formula I Wherein R 1 and R 3 represent hydrogen or C 1-4 alkyl, R 2 represents C 1-4 alkyl, and R 4 , R 5 and R 6 represent hydrogen or halogen. A process for the preparation of a compound of the formula (In the formula, R represents a halogen or an aliphatic acyloxy group having 2 to 6 carbon atoms or an aromatic acyloxy group having 7 to 11 carbon atoms, and R 4 , R 5 , and R 6 are as defined above.) A compound of general formula III (Wherein R 1 , R 2 and R 3 have the meanings defined above), and a reaction with a piperazine derivative represented by the formula (Wherein R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above) after isolation or without isolation. Converting the compound of the general formula I obtained as described above into a salt thereof as required, or releasing the compound from the salt.
を有機溶媒、好ましくは酸アミド、スルホキシド、ケト
ン、アルコール、エーテル、エステルまたはニトリルの
存在下で反応させることを特徴とする請求の範囲１に記
載の方法。2. The method according to claim 1, wherein the compound of formula II is reacted with an amine of formula III in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether, ester or nitrile. The method of range 1.
いることを特徴とする請求の範囲２に記載の方法。3. The method according to claim 2, wherein dimethyl sulfoxide is used as the organic solvent.
の反応を酸結合剤の存在下で行うことを特徴とする請求
の範囲１に記載の方法。4. The process according to claim 1, wherein the reaction of the compound of the general formula II with the compound of the general formula III is carried out in the presence of an acid binder.
式IIIの化合物を用いることを特徴とする請求の範囲４
に記載の方法。5. The method according to claim 4, wherein the acid binder is an amine or an excess of a compound of the formula III.
The method described in.
する請求の範囲１に記載の方法。6. The method according to claim 1, wherein the hydrolysis is carried out in an acidic medium.
酸または酢酸を用いて反応を行うことを特徴とする請求
の範囲６に記載の方法。7. The process according to claim 6, wherein the reaction is carried out using an organic or inorganic acid, preferably hydrochloric acid, sulfuric acid or acetic acid.
特徴とする請求の範囲１に記載の方法。8. The method according to claim 1, wherein the hydrolysis is performed in an alkaline medium.
水酸化物または有機塩基、好ましくはトリエチルアミン
水溶液を用いることを特徴とする請求の範囲８に記載の
方法。9. The method according to claim 8, wherein an alkali metal hydroxide, an alkaline earth metal hydroxide or an organic base, preferably an aqueous triethylamine solution, is used.
ルオキシ基または炭素数７〜11の芳香族アシルオキシ基
を示し、R1およびR3は水素またはC1-4のアルキルを示
し、R2はC1-4のアルキルを示し、R4，R5およびR6は水素
またはハロゲンを示す） で表わされる化合物。10. A compound of the general formula IV (Wherein, R represents a halogen or an aliphatic acyloxy group having 2 to 6 carbon atoms or an aromatic acyloxy group having 7 to 11 carbon atoms, R 1 and R 3 represent hydrogen or C 1-4 alkyl; 2 represents C 1-4 alkyl, and R 4 , R 5 and R 6 represent hydrogen or halogen).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU6560/88 | 1988-12-22 | ||
| HU886560A HU203746B (en) | 1988-12-22 | 1988-12-22 | Process for producing quinoline-carboxylic acid derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03502803A JPH03502803A (en) | 1991-06-27 |
| JP2825641B2 true JP2825641B2 (en) | 1998-11-18 |
Family
ID=10971814
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2500847A Expired - Lifetime JP2825641B2 (en) | 1988-12-22 | 1989-12-15 | Method for producing quinoline carboxylic acid derivative |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JP2825641B2 (en) |
| KR (1) | KR0146335B1 (en) |
| CN (1) | CN1031190C (en) |
| AT (1) | AT397385B (en) |
| AU (1) | AU622256B2 (en) |
| FR (1) | FR2640974B1 (en) |
| GB (1) | GB2245562B (en) |
| HU (1) | HU203746B (en) |
| IL (1) | IL92821A0 (en) |
| WO (1) | WO1990006922A1 (en) |
| YU (1) | YU47215B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2077490B1 (en) * | 1992-11-18 | 1996-10-16 | Marga Investigacion | TRIMETILSILILIC ESTERS AND SOLVATES OF CHELATES OF QUINOLIN-3-CARBOXYL ACIDS. PREPARATION AND APPLICATION TO THE QUINOLON PROCESS. |
| NZ260530A (en) * | 1994-05-16 | 1997-06-24 | Nigel Paul Maynard | Organoborate complexes of divalent metal; use as timber treament agents |
| ES2092963B1 (en) * | 1995-04-12 | 1997-12-16 | Sint Quimica Sa | PROCEDURE FOR THE PREPARATION OF ACID 1-CICLOPROPIL-6-FLUORO-1, 4-DIHIDRO-7- (1S, 4S) -5-METHYL-2,5-DIAZABICICLO (2.2.1) HEPT-2-IL) -4 -OXO-3-QUINOLINCARBOXILICO AND ITS SALTS. |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59122470A (en) * | 1982-12-27 | 1984-07-14 | Dai Ichi Seiyaku Co Ltd | Preparation of quinoline-3-carboxylic acid derivative |
| US4550167A (en) * | 1983-05-23 | 1985-10-29 | Ethyl Corporation | Preparation of 1-alkyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3-quinoline carboxylic acid |
| JPS6078986A (en) * | 1983-10-07 | 1985-05-04 | Dai Ichi Seiyaku Co Ltd | Preparation of oxazine derivative |
| JPS6165882A (en) * | 1984-09-06 | 1986-04-04 | Hokuriku Seiyaku Co Ltd | 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazinyquinoline-3-carboxylic ester derivative and its preparation |
| JPS6185381A (en) * | 1984-10-04 | 1986-04-30 | Hokuriku Seiyaku Co Ltd | Preparation of 1-ethyl-6, 8-difluoro-1, 4-dihydro-4-oxo-7-piperazinylquinoline-3-carboxylic acid derivative |
| HU196782B (en) * | 1985-12-09 | 1989-01-30 | Chinoin Gyogyszer Es Vegyeszet | Process for production of quinoline carbonic acid |
| CA1306750C (en) * | 1985-12-09 | 1992-08-25 | Istvan Hermecz | Process for the preparation of quinoline carboxylic acide |
| US4738800A (en) * | 1986-03-26 | 1988-04-19 | Ciba-Geigy Corporation | Process for the preparation of 1,4-diamino-2,3-dicyanoanthraquinones |
| HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
| JPS6419069A (en) * | 1987-07-14 | 1989-01-23 | Dainippon Pharmaceutical Co | Production of polyhalogenoquinoline derivative |
-
1988
- 1988-12-22 HU HU886560A patent/HU203746B/en not_active IP Right Cessation
-
1989
- 1989-12-15 AT AT0902489A patent/AT397385B/en not_active IP Right Cessation
- 1989-12-15 WO PCT/HU1989/000063 patent/WO1990006922A1/en unknown
- 1989-12-15 JP JP2500847A patent/JP2825641B2/en not_active Expired - Lifetime
- 1989-12-15 KR KR1019900701858A patent/KR0146335B1/en not_active IP Right Cessation
- 1989-12-15 AU AU47480/90A patent/AU622256B2/en not_active Ceased
- 1989-12-15 GB GB9018360A patent/GB2245562B/en not_active Expired - Lifetime
- 1989-12-20 IL IL92821A patent/IL92821A0/en not_active IP Right Cessation
- 1989-12-22 YU YU243789A patent/YU47215B/en unknown
- 1989-12-22 CN CN89109448A patent/CN1031190C/en not_active Expired - Fee Related
- 1989-12-22 FR FR8917102A patent/FR2640974B1/fr not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| AT397385B (en) | 1994-03-25 |
| KR0146335B1 (en) | 1998-08-17 |
| HU203746B (en) | 1991-09-30 |
| YU47215B (en) | 1995-01-31 |
| CN1031190C (en) | 1996-03-06 |
| FR2640974B1 (en) | 1994-02-18 |
| WO1990006922A1 (en) | 1990-06-28 |
| HUT52086A (en) | 1990-06-28 |
| YU243789A (en) | 1991-02-28 |
| GB2245562B (en) | 1992-12-23 |
| KR910700245A (en) | 1991-03-14 |
| JPH03502803A (en) | 1991-06-27 |
| FR2640974A1 (en) | 1990-06-29 |
| GB9018360D0 (en) | 1990-10-24 |
| ATA902489A (en) | 1993-08-15 |
| AU4748090A (en) | 1990-07-10 |
| CN1043712A (en) | 1990-07-11 |
| GB2245562A (en) | 1992-01-08 |
| IL92821A0 (en) | 1990-09-17 |
| AU622256B2 (en) | 1992-04-02 |
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