JPS59122470A - Preparation of quinoline-3-carboxylic acid derivative - Google Patents
Preparation of quinoline-3-carboxylic acid derivativeInfo
- Publication number
- JPS59122470A JPS59122470A JP23368482A JP23368482A JPS59122470A JP S59122470 A JPS59122470 A JP S59122470A JP 23368482 A JP23368482 A JP 23368482A JP 23368482 A JP23368482 A JP 23368482A JP S59122470 A JPS59122470 A JP S59122470A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- carboxylic acid
- ethyl
- formula
- dihydroquinoline
- 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.)
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Links
Abstract
Description
【発明の詳細な説明】
本発明はキノリン−３−カルボン酸誘導体の製造法に関
する。更に詳しくは１本発明は式（式中、 Ｒ１は低級
アルキル基を、 ｘｌ及びｋは同じ又は異なるハロゲン
原子を意味する。）で表わされる化合物を式
（式中、Ｒ２は水素原子又は低級アルキル基を意味する
。）で表わされる化合物と反応させて式％式％
（）
×１
（式中、Ｒ１，Ｒ１２及び海は前記に同じである。）で
表わされる化合物を製する方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing quinoline-3-carboxylic acid derivatives. More specifically, the present invention provides a compound represented by the formula (wherein R1 represents a lower alkyl group, and xl and k represent the same or different halogen atoms), a compound represented by the formula (wherein R2 represents a hydrogen atom or a lower alkyl The present invention relates to a method for producing a compound represented by the formula % formula % ( ) × 1 (wherein R1, R12 and sea are the same as above) by reacting the compound with a compound represented by the formula %.
化合物（１）は医療上有用な抗菌物質として知られてお
り（特開昭５８−１４１２８６号及び特開昭５４−１３
８５８２号公報参照）、その製造法としては前記公報及
び特開昭５７−６２２５９号公報に記載されている製造
法がある。Compound (1) is known as a medically useful antibacterial substance (JP-A-58-141286 and JP-A-54-13).
(Refer to Japanese Patent No. 8582), and its manufacturing method includes the manufacturing method described in the aforementioned publication and Japanese Patent Application Laid-open No. 57-62259.
しかし、これらの製造法を用いた場合、ピペラジン類（
１）がキノリン誘導体の６位に置換した式
（式中、Ｒ１，Ｒ２及びｘ２は前記に同じであり、 Ｒ
３は水素原子又は低級アルキル基を意味する。）で表わ
される化合物が少なからず副生ずるという欠点がある。However, when these production methods are used, piperazines (
1) is substituted at the 6-position of a quinoline derivative (wherein R1, R2 and x2 are the same as above, R
3 means a hydrogen atom or a lower alkyl group. ) has the disadvantage that a considerable amount of the compound represented by is produced as a by-product.
前記特開昭５７−６２２５９号公報には化合物（酌のよ
うな副生物は全く見られないとの記載があるが９本発明
者らが本公報記載の製造法を追試したところ、得られた
生成物中には約２５％の副生物（ト）が存在することが
判明した。Although the above-mentioned Japanese Patent Application Laid-open No. 57-62259 states that no by-products such as cup are observed at all, the inventors of the present invention reexamined the production method described in this publication and obtained Approximately 25% by-products were found to be present in the product.
本発明者らは従来法のかかる欠点を克服すべく鋭意検討
した結果１本発明を完成した。The present inventors have completed the present invention as a result of intensive studies to overcome these drawbacks of conventional methods.
即ち１本発明は化合物（１）をピペラジン類（Ｉｆ）と
反応させることからなる化合物（１）の製造法である。That is, the present invention is a method for producing compound (1), which comprises reacting compound (1) with piperazine (If).
原料として用いられる化合物（Ｉ）は次の方法に（式中
＊ Ｘ＋＋ Ｘ２及び昭ま前記に同じであり、Ｒ４は水
素原子又は低級アルキル基を意味する。）即ち、化合物
（Ｖ）に三７ツ化ホウ素、三７．化ホｆｙ素ｆａ体又は
ホウフッ化水素酸を反応させることにより原料化合物（
Ｉ）を得ることができる。Compound (I) used as a raw material is prepared by the following method (in the formula *X++ is the same as above, and R4 means a hydrogen atom or a lower alkyl group). Boron tsunide, 37. The raw material compound (
I) can be obtained.
三フッ化ホウ素錯体としては各種のものが使用可能であ
るが、三７．化ホウ素のテトラヒドロフラン錯体及びジ
エチルエーテル錯体などが具体例としてあげられる。ま
たホウフッ化水素酸は通常水溶液として使用される。Various types of boron trifluoride complexes can be used, including 37. Specific examples include tetrahydrofuran complexes and diethyl ether complexes of boron chloride. Further, fluoroboric acid is usually used as an aqueous solution.
三７７化ホウ素、三フッ化ホウ素錯体又はホウフッ化水
素酸の使用量は化合物（Ｖ） １モルに対し１モル以上
存在すれば良いが通常１〜５０モルの範囲が使用される
。The amount of boron tri77ide, boron trifluoride complex or fluoroboric acid to be used may be 1 mol or more per 1 mol of compound (V), but it is usually in the range of 1 to 50 mol.
溶媒としてはアセトンなどのケトン系のもの。The solvent is a ketone type such as acetone.
ジエチルエーテルなどのエーテル系のもの、ベンゼン又
はトルエン等各種のものが使用でき。Various types of ethers such as diethyl ether, benzene or toluene can be used.
また三フッ化ホウ素錯体もしくはホウフッ化水素酸を溶
媒と兼ねさせても良い。溶媒の使用量は通常化合物（Ｖ
）１部に対し２−５０部の範囲が好適である。Further, a boron trifluoride complex or fluoroboric acid may also be used as a solvent. The amount of solvent used is usually determined by the amount of the compound (V
) is preferably in the range of 2-50 parts.
反応温度は室温でもよいが１反応時間の短縮ということ
から更に高温でもよく９通常室温〜１５０°Ｃの温度範
囲が好適である。The reaction temperature may be at room temperature, but may be at a higher temperature in order to shorten the reaction time.9 Usually, a temperature range of room temperature to 150°C is preferred.
生成した化合物（Ｉ）は反応液を冷却すれば結晶として
析出するので、これを濾取することにより容易に得るこ
とができる。The produced compound (I) precipitates as crystals when the reaction solution is cooled, and can be easily obtained by filtering the crystals.
このようにして得られた原料化合物（１）を用いて本発
明方法を行うには、化合物（Ｉ）に対し一乃 ５−
全数倍モルの化合物（１）を無溶媒で又は溶媒中。In order to carry out the method of the present invention using the raw material compound (1) thus obtained, compound (1) is added in an amount of 1 to 5 times the total number of moles of compound (I) without a solvent or in a solvent.
脱酸剤の存在下反応させればよい。The reaction may be carried out in the presence of a deoxidizing agent.
脱酸剤は、副生ずるハロゲン水素及びＢＦ２−キレート
分解物の除去に使用され、その具体例としてはトリエチ
ルアミン、トリブチルアミンもしくはピリジンの如き有
機三級アミン又は炭酸カリウムの如き無機塩基があげら
れるが、を委吻徊看過剰の化合物（Ｉ［）が脱酸剤とし
て働くこともある。脱酸剤の使用量は化合物（Ｉ）１モ
ルに対し通常１〜８モルが好ましい。A deoxidizer is used to remove by-produced halogen hydrogen and BF2-chelate decomposition products, and specific examples include organic tertiary amines such as triethylamine, tributylamine, or pyridine, or inorganic bases such as potassium carbonate. Excess amount of compound (I[) may act as a deoxidizing agent. The amount of the deoxidizing agent used is usually preferably 1 to 8 mol per 1 mol of compound (I).
また、この反応ではＢＦ２−キレート部分がカルボキシ
ル基となるためにプロトンが必要とされるが、これは過
剰の原料又は混在する微量の水分等により供給されるこ
とが考えられる。Further, in this reaction, a proton is required because the BF2-chelate moiety becomes a carboxyl group, but it is thought that this is supplied by an excess raw material or a small amount of water present.
溶媒としては、ジメチルスルホキシド、ジメチルホルム
アミドもしくはジメチルアセトアミド等の非プロトン性
極性溶媒、アセトンもしくはメチルエチルケトン等のケ
トン系溶媒、ジエ ６−
メタノールモジくハエタノール等のアルコール系溶媒等
が使用できる。溶媒の使用量は化合物（１） １部に対
し２〜８０部（重散比）の範囲で使用される。As the solvent, aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide or dimethylacetamide, ketone solvents such as acetone or methyl ethyl ketone, alcohol solvents such as ethanol, etc. can be used. The amount of solvent to be used is in the range of 2 to 80 parts (polydispersity ratio) per 1 part of compound (1).
反応は室温〜２００°Ｃの範囲で２〜ｌＯ時間行なえば
よい。The reaction may be carried out at room temperature to 200°C for 2 to 10 hours.
尚、該反応においては溶媒の種類を選択し、脱酸剤の使
用量１反応温度及び反応時間等を調節することにより、
ピペラジン類（Ｉ）の置換反応のく式中＊ ”Ｉ＋ Ｒ
２及びｘｌは前記に同じである。）で表わされる中間体
を得ることも可能である。In addition, in this reaction, by selecting the type of solvent, adjusting the amount of deoxidizing agent used, reaction temperature, reaction time, etc.
In the substitution reaction of piperazine (I) * “I+ R
2 and xl are the same as above. ) It is also possible to obtain intermediates of the form
例えば、ジメチルスルホキシド中室温で反応を行なった
場合、中間体側）が収率よく得られる。For example, when the reaction is carried out in dimethyl sulfoxide at room temperature, the intermediate) can be obtained in good yield.
中間体側）は１反応液を冷却するか２反応液に水等の難
溶性の溶媒を加えることにより析出するので、これを濾
取することにより容易に単離できる。Since the intermediate (intermediate side) is precipitated by cooling the first reaction solution or adding a poorly soluble solvent such as water to the second reaction solution, it can be easily isolated by filtering it.
中間体（９）は単離してもよいが、単離せずに次のキレ
ート分解反応を行なっても良い。Intermediate (9) may be isolated, but may also be subjected to the next chelate decomposition reaction without being isolated.
中間体（Ｗ）より目的化合物（１）を得るには、中間体
（ｖ）を脱酸剤の存在下無溶媒もしくは溶媒中プロトン
性の化合物と処理すればよい。In order to obtain the target compound (1) from the intermediate (W), the intermediate (v) may be treated with a protic compound in the presence of a deoxidizer or without a solvent.
プロトン性化合物としては水、アルコール類。Protic compounds include water and alcohols.
チオール類、−級アミン類、二級アミン類又は無機水酸
化物等が使用される。Thiols, -class amines, secondary amines, inorganic hydroxides, etc. are used.
脱酸剤としては水酸化ナトリウム、炭酸ナトリウムもし
くは炭酸水素ナトリウム等の無機塩基又は−級アミン、
二級アミンもしくは三級アミン等の有機塩基があげられ
、中間体ＣＭ）に対し等モル以上使用される。As a deoxidizing agent, an inorganic base such as sodium hydroxide, sodium carbonate or sodium bicarbonate, or a -class amine;
Organic bases such as secondary amines or tertiary amines are mentioned, and are used in an amount equal to or more than the same mole relative to the intermediate CM).
溶媒としては非プロトン性極性溶媒、ケトン系溶媒、ア
ルコール系溶媒、エステル系溶媒又はエーテル系溶媒等
があげられるが特にアルコール系溶媒、エステル系溶媒
又はエーテル系溶媒が好ましい。Examples of the solvent include aprotic polar solvents, ketone solvents, alcohol solvents, ester solvents, and ether solvents, with alcohol solvents, ester solvents, and ether solvents being particularly preferred.
反応は、室温〜１５０℃までの範囲で行なえばよい。The reaction may be carried out at a temperature ranging from room temperature to 150°C.
生成した化合物（１）は１反応液を中和するが又は冷却
すれば結晶として析出するので、これを濾取することに
より容易に得ることができる。The produced compound (1) precipitates as crystals when the reaction solution is neutralized or cooled, and can be easily obtained by filtering the crystals.
以上のように本発明方法により選択的、高収率、高純度
及び能率よく、医療上有用な抗菌剤である化合物偵）を
得ることができ９本発明は工業的に有利な製造法である
。As described above, by the method of the present invention, it is possible to selectively, in high yield, with high purity, and efficiently obtain a compound which is a medically useful antibacterial agent.9 The present invention is an industrially advantageous production method. .
次に参考例及び実施例を説明する。Next, reference examples and examples will be explained.
参考例１
７−クロロ−１−エチル−６−フルオロ−４−オキソ−
１，４−ジヒドロキノリン−３−カルボン酸エチルエス
テル２．９３９及びホウ７ツ化水素酸４２％水溶液１５
ｍ／の混液を８０〜９０’Ｃで３時間加熱する。冷後析
出晶を濾取し、水及びメタノールで洗浄し、？−クロロ
ー１−エチル−６−フルオロ−４−オキソ−１，４−ジ
ヒドロキノリン−８−カルボン酸−ＢＦｚ−キレート８
．１０ｇ（収率９９％）をえた。融点ａｏｏ”（：以上
。Reference example 1 7-chloro-1-ethyl-6-fluoro-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid ethyl ester 2.939 and 42% aqueous borosilicate 15
Heat the m/mixture at 80-90'C for 3 hours. After cooling, the precipitated crystals were filtered and washed with water and methanol. -chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-8-carboxylic acid-BFz-chelate 8
．． 10 g (yield 99%) was obtained. Melting point aoo" (: or higher.
−〇 −
元素分析値 Ｏｓ ２ ）１８Ｎ ＯｓＢ ＣＩ Ｆ３
として計算値 Ｇ ４５．４０． Ｈｇ、５４．
Ｎ ４．４１実測値 Ｃ４５，２１，Ｈ２，６１，Ｎ
４．４２’Ｈ−ＮＭＲ（ＤＭＳＯ−ａｓ、ＩＳ：Ｔ
ＭＳ）δ（ｐｐｍ）：１．４９ （：３ Ｈ，ｔ、 −
ＣＨ５・）４．９５ （２Ｈ，Ｑ、 −ＣＨ２−）８．
５８ （ＩＨ，ｄ、 Ｊ−１０Ｈ２，５位−〇Ｈ−）８
．８８ （ＩＨ，ｄ、 Ｊ−６）１２．８位−ＣＨ−）
９．６４ （ＩＨ，ｓ、 ２位−〇Ｈ−）Ｍａｓｓ ：
８１７ （Ｍ” ）
参考例２
７−クロロ−１−エチル−６−フルオロ−４−オキソ−
１，４−ジヒドロキノリン−８−カルボン酸エチルエス
テル５，８５９．三フフ化ホウ素テトラヒドロ７ラン錯
体１２．７り及びダウサム２１−の混液を１２０〜１３
０”Ｃで２時間加熱する。今後、析出晶を濾取し、クロ
ロポルム及びメタノールで洗浄し、７−クロ＊−１−エ
チル−６−フルオロ−４−オキソ−１，４−ジヒドロキ
ノリン−３−カルボン酸−ＢＦ２−キレー）４．６７９
（収率８２％〕をえた。融点３００°Ｃ以上。-〇- Elemental analysis value Os2)18N OsB CI F3
Calculated value as G 45.40. Hg, 54.
N 4.41 actual measurement value C45, 21, H2, 61, N
4.42'H-NMR (DMSO-as, IS:T
MS) δ (ppm): 1.49 (:3 H, t, -
CH5・)4.95 (2H,Q, -CH2-)8.
58 (IH, d, J-10H2, 5th position-〇H-)8
．． 88 (IH, d, J-6) 12.8-position -CH-)
9.64 (IH,s, 2nd place-〇H-)Mass:
817 (M”) Reference example 2 7-chloro-1-ethyl-6-fluoro-4-oxo-
1,4-dihydroquinoline-8-carboxylic acid ethyl ester 5,859. A mixture of boron trifluoride tetrahydro 7 run complex 12.7 and Dowsum 21 was added to 120 to 13
Heat at 0"C for 2 hours. Then, the precipitated crystals are collected by filtration, washed with chloroporm and methanol, and 7-chloro*-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3 -Carboxylic acid-BF2-Kyle) 4.679
(Yield: 82%). Melting point: 300°C or higher.
参考例３
７−クロロ−１−エチル−６−フルオロ−４−オキソ−
１，４−ジヒドロキノリン−３−カルボン１１４．８０
９及びホウフッ化水素酸４２％水溶液２１−の混液を８
０〜９０’Ｃで２時間加熱する。冷後、析出晶を濾取し
、水及びメタノールで洗浄し、７−クロロ−１−エチル
−６−フルオロ−４−オキソ−１，４−ジヒドロキノリ
ン−８−カルボン酸−ＢＦ２−キレ−）５．１０９（収
率１００％）をえた。融点８００°Ｃ以上。Reference example 3 7-chloro-1-ethyl-6-fluoro-4-oxo-
1,4-dihydroquinoline-3-carvone 114.80
9 and a 42% aqueous solution of borohydrofluoric acid 21-
Heat at 0-90'C for 2 hours. After cooling, the precipitated crystals were collected by filtration and washed with water and methanol to give 7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-8-carboxylic acid-BF2-chelate). 5.109 (yield 100%) was obtained. Melting point over 800°C.
参考例４
７−クロロ−１−エチル−６−フルオロ−４オキソ−１
，４−ジヒドロキノリン−８−カルボン酸１．６６９及
び三ツ、化ホウ素テトラヒドロ７ラン錯体１７ｍ／の混
液を８０〜９０°Ｃで８時間加熱する。冷後、析出晶を
濾取し、クロロホルムで洗浄し、７−クロロ−１−エチ
ル−６−フルオロ−４−オキソ−１，４−ジヒドロキノ
リンー３−カルボン酸−ＢＦ２−キレート１．６８ｇ（
収率８６％）をえた。融点ａｏｏ’ｃ以上。Reference example 4 7-chloro-1-ethyl-6-fluoro-4oxo-1
, 1.669 m/4-dihydroquinoline-8-carboxylic acid and 17 m/m of tri-borohydride tetrahydro-7-rane complex is heated at 80-90°C for 8 hours. After cooling, the precipitated crystals were collected by filtration and washed with chloroform to give 1.68 g of 7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid-BF2-chelate (
A yield of 86% was obtained. Melting point aoo'c or higher.
′実施例１
７−クロロ−１−エチル−６−フルオロ−４−オキソ−
１，４−ジヒドロキノリン−８−カルボン酸−ＢＦ２−
キレート１．０００ｇ、無水ピペラジン０．８１４ｇ及
びジメチルスルホキシド５−の混液を室温下６時間攪拌
する。反応液はいったん溶液となるが１時間程経過する
と結晶が析出する。反応後、冷水５−を加え結晶を濾取
し、水洗し、９０°Ｃで５時間減圧乾燥し、１−エチル
−６−フルオロ−４−オキソ−７−（ｌ−ピペラジニル
）−１，４−ジヒドロキノリン−３−カルボン酸−ＢＦ
２−キレート１．１１８９（収率９６％）をえた。融点
２５３〜２５５℃。'Example 1 7-chloro-1-ethyl-6-fluoro-4-oxo-
1,4-dihydroquinoline-8-carboxylic acid-BF2-
A mixture of 1.000 g of chelate, 0.814 g of anhydrous piperazine, and 5-dimethyl sulfoxide is stirred at room temperature for 6 hours. The reaction solution becomes a solution once, but crystals precipitate out after about 1 hour. After the reaction, cold water was added and the crystals were collected by filtration, washed with water, and dried under reduced pressure at 90°C for 5 hours to give 1-ethyl-6-fluoro-4-oxo-7-(l-piperazinyl)-1,4. -dihydroquinoline-3-carboxylic acid-BF
1.1189 2-chelate (yield 96%) was obtained. Melting point: 253-255°C.
元素分析値 ０１６Ｈ１７Ｎ３０３８Ｆ３として計算値
Ｇ ５２．８４． Ｈ４，６７、Ｎ １１．４
５実測値 ０ ５２．４６． Ｈ４，５６，Ｎ １
１．８２’Ｈ−ＮＭＲ（ＤＭＳＯ−ｄｓ、Ｉｓ：ＴＭ８
）δ（ｐｐｍ）：１．４９ （８Ｈ，ｔ、 −ａＨ３）
４−８７ （２Ｊ ｑ＋ ＣＨ２０Ｈ３）７．８５
（ＬＨ，ｄ、 Ｊ−８Ｈｚ、 ８位−ＣＨ−）８．０９
（ＬＨ，ｄ、 Ｊ−１４Ｈ２，５位−〇Ｈ−）９．０
４ （ＩＨ，８，２位−〇Ｈ−）Ｍａｓｓ ： ８
６７ （Ｍ”）
上記化合物１．１１８９及び６％水酸化す） ＩＪウム
水溶液８．９−の混液を１時間還流した。反応液を酢酸
で中和して、 ｐＨ７〜７．５に調整する。今後、析出
する結晶を濾取し、水及びメタノールで洗浄する。これ
をクロロホルムとエタノールの混合溶液から再結晶し、
９０°Ｃで５時Ｍ減圧乾燥し、１−エチル−６−フルオ
ロ−４−オキソ−７−（１−ピペラジニル）−１，４−
ジヒドロキノリン−３−カルボン１０．９０４ｇ（収率
９３％ンをえた。融点２２１〜２２２℃。Elemental analysis value Calculated value as 016H17N3038F3 G 52.84. H4, 67, N 11.4
5 Actual value 0 52.46. H4, 56, N 1
1.82'H-NMR (DMSO-ds, Is:TM8
) δ (ppm): 1.49 (8H, t, -aH3) 4-87 (2J q+ CH20H3) 7.85
(LH, d, J-8Hz, 8th position -CH-)8.09
(LH, d, J-14H2, 5th position-〇H-)9.0
4 (IH, 8, 2nd position-〇H-)Mass: 8
67 (M") A mixture of the above compound 1.1189 and 6% hydroxylated IJium aqueous solution 8.9- was refluxed for 1 hour. The reaction solution was neutralized with acetic acid and adjusted to pH 7 to 7.5. .Then, the precipitated crystals are collected by filtration and washed with water and methanol.This is recrystallized from a mixed solution of chloroform and ethanol.
Dry at 90°C for 5 hours under reduced pressure to obtain 1-ethyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-
10.904 g of dihydroquinoline-3-carvone (yield 93%) was obtained. Melting point: 221-222°C.
元素分析値 Ｇ）ｓＨＩＢ０３Ｎ３Ｆとして計算値 Ｃ
６０，１８，Ｈ５，６８，Ｎ １３．１６実測値 Ｃ
６０，１５，Ｈ５，７４，Ｎ １８．２７本品は前記
公報（特開昭５ａ−０＋ｉ２ｓ／致した。Elemental analysis value G) Calculated value as sHIB03N3F C
60,18,H5,68,N 13.16 Actual value C
60, 15, H5, 74, N 18.27 This product was published in the above-mentioned publication (JP-A-5A-0+I2S/).
実施例２
７−クロロ−１−エチル−６−フルオロ−４−オキソ−
１，４−ジヒドロキノリン−８−カルボン酸−ＢＦ２−
キレート１．ｏｏｏｇ、無水ピペラジン０．８１４ｇ及
びジメチルスルホキシド５ａ／（７）混液を１００℃で
３時間加熱する。次いで６％水酸化す） ＩＪウム水溶
液８−を加え。Example 2 7-chloro-1-ethyl-6-fluoro-4-oxo-
1,4-dihydroquinoline-8-carboxylic acid-BF2-
Chelate 1. ooog, 0.814 g of anhydrous piperazine and dimethyl sulfoxide 5a/(7) mixture are heated at 100° C. for 3 hours. Then, a 6% aqueous solution of hydroxide was added.
１２０°Ｃで２時間加熱した。反応液に酢酸を加え、ｐ
Ｈ７〜７．５に調整し、析出する結晶を濾取し、水及び
メタノールで洗浄する。クロロホルムとエタノールの混
合溶液で再結晶し、９０″Ｃで５時間減圧乾燥し、１−
エチル−６−フルオロ−４−オキソ−７−（ｌ−ヒ°ペ
ラジニル）−１，４−ジヒドロキノリン−３−カルボン
酸０．８６１９（収率８６％ンをえた。融点２２０〜２
２１℃。Heated at 120°C for 2 hours. Add acetic acid to the reaction solution,
The temperature is adjusted to 7 to 7.5, and the precipitated crystals are collected by filtration and washed with water and methanol. The 1-
Ethyl-6-fluoro-4-oxo-7-(l-hyperazinyl)-1,4-dihydroquinoline-3-carboxylic acid 0.8619% (yield 86%) was obtained. Melting point 220-2
21℃.
実施例３
７−クロロ−１−エチル−６−フルオロ−４−オキソ−
１，４−ジヒドロキノリン−８−カルボン酸−ＢＦ２−
キレート５６７■、無水ピペラジン６３０■及びジメチ
ルスルホキシド２．８−の混液を１１０℃で８時間加熱
した。反応液に水１０−を加え、さらに酢酸を加え、
ｐＨ７，５に調整する。冷後、析出晶を濾取し水洗する
。Example 3 7-chloro-1-ethyl-6-fluoro-4-oxo-
1,4-dihydroquinoline-8-carboxylic acid-BF2-
A mixture of 567 ml of chelate, 630 ml of anhydrous piperazine and 2.8 ml of dimethyl sulfoxide was heated at 110 DEG C. for 8 hours. Add water 10- to the reaction solution, further add acetic acid,
Adjust the pH to 7.5. After cooling, the precipitated crystals are collected by filtration and washed with water.
これをクロロホルムとエタノールの混合溶液で再結晶し
、９０’Ｃで５時間減圧乾燥し、■−エチルー６−フル
オロー４−オキソ−７−（１−ス や
ピプラシル）−１，４−ジヒドロキノリン−８−カルボ
ン酸４１９■（収率７３％）をえた。融点２２０〜２２
１″Ｃ０
実施例４
７−クロロ−１−エチル−６−フルオロ−４−オキソ−
１，４−ジヒドロキノリン−８−カルホン酸−ＢＦ２−
キレ−）７２ｆｌ１９，４−メチルビペラジン６８７１
Ｌ９及びジメチルスルホキシド８．６−の混液を１１０
℃で３時間加熱した。反１５一
応液に６％水酸化す） ＩＪウム水溶液５．８ｄを加え
、１１０℃で２時間加熱した。反応終了後。This was recrystallized from a mixed solution of chloroform and ethanol, dried under reduced pressure at 90'C for 5 hours, and 1-ethyl-6-fluoro-4-oxo-7-(1-su or pipracil)-1,4-dihydroquinoline- 419 ml of 8-carboxylic acid (yield 73%) was obtained. Melting point 220-22
1″C0 Example 4 7-chloro-1-ethyl-6-fluoro-4-oxo-
1,4-dihydroquinoline-8-carphonic acid-BF2-
72fl19,4-methylbiperazine 6871
A mixture of L9 and dimethyl sulfoxide 8.6-110
Heated at ℃ for 3 hours. 5.8 d of an aqueous IJ solution (6% hydroxide) was added to the anti-15 solution and heated at 110° C. for 2 hours. After the reaction is complete.
酢酸を反応液に加え、ｐＨ７〜７．５に調整する。Add acetic acid to the reaction solution and adjust the pH to 7-7.5.
冷後、析出する結晶を濾取する。メタノールで洗浄し、
９０°Ｃで５詩間減圧乾燥し、ｌ−エチル−６−フルオ
ロ−７−（４−メチル−１−ピペラジニル）−４−オキ
ソ−１，４−ジヒドロキノリン−８−カルボン酸６５３
■（収率８６％）をえた。融点２６８〜２７０℃。After cooling, precipitated crystals are collected by filtration. Wash with methanol,
Dry under reduced pressure at 90°C for 5 cycles to obtain l-ethyl-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-8-carboxylic acid 653
(yield 86%) was obtained. Melting point: 268-270°C.
元素分析値 ０１７Ｈ２ＯＮ３０３Ｆとして計算値 Ｇ
６１．２５． Ｈ６，０５，Ｎ １２．６０実
測値 ０ ６１．１０． Ｈ５，９１，Ｎ １２．
２７１６−Elemental analysis value Calculated value as 017H2ON303F G
61.25. H6,05,N 12.60 Actual value 0 61.10. H5,91,N 12.
2716-
Claims (1)
＋ ”Ｉは低級アルキル基を意味する。）で表わされる
化合物を１式 （式中、Ｒ２は水素原子又は低級アルキル基を意味する
。）で表わされるピペラジン類と反応させることを特徴
とする式 （式中＋ ｘＩ＋ Ｆｌｌ及び−は前記に同じである。 ）１− で表わされる化合物の製造法 ２、特許請求の範囲第１項においてＲ１がエチル基、
Ｒ２が水素原子、Ｘｌがフッ素原子である化金物の製造
法[Scope of Claims] ■) A compound represented by the formula (wherein xl and 0 are the same or different halogen atoms + ``I means a lower alkyl group) (wherein, R2 is a hydrogen atom) or a lower alkyl group) (in the formula, + In claim 1, R1 is an ethyl group,
A method for producing a chemical compound in which R2 is a hydrogen atom and Xl is a fluorine atom
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23368482A JPS59122470A (en) | 1982-12-27 | 1982-12-27 | Preparation of quinoline-3-carboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23368482A JPS59122470A (en) | 1982-12-27 | 1982-12-27 | Preparation of quinoline-3-carboxylic acid derivative |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13400487A Division JPS62294689A (en) | 1987-05-29 | 1987-05-29 | Quinoline-3-carboxylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59122470A true JPS59122470A (en) | 1984-07-14 |
| JPH0240066B2 JPH0240066B2 (en) | 1990-09-10 |
Family
ID=16958915
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP23368482A Granted JPS59122470A (en) | 1982-12-27 | 1982-12-27 | Preparation of quinoline-3-carboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59122470A (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987003595A1 (en) | 1985-12-09 | 1987-06-18 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Norfloxacin intermediate |
| WO1987003587A1 (en) | 1985-12-09 | 1987-06-18 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Process for the preparation of quinoline carboxylic acids |
| WO1988007998A1 (en) * | 1987-04-08 | 1988-10-20 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Quinoline carboxylic acid boric acid anhydrides and process for the preparation thereof |
| JPS6419069A (en) * | 1987-07-14 | 1989-01-23 | Dainippon Pharmaceutical Co | Production of polyhalogenoquinoline derivative |
| GR880100231A (en) * | 1987-04-08 | 1989-01-31 | Chinoin Gyogyszer Es Vegyeszet | Preparation method of quinoline carboxylic acids |
| JPH01503301A (en) * | 1987-04-08 | 1989-11-09 | キノイン ギオギスゼル エス ベギエスゼチ テルメケク ギヤラ アール．ティー | Method for producing quinoline carboxylic acid |
| JPH02500366A (en) * | 1987-06-24 | 1990-02-08 | キノイン ギオギスゼル エス ベギエスゼチ テルメケク ギヤラ アールティー． | Method for producing quinoline carboxylic acid derivatives |
| JPH02501839A (en) * | 1986-12-04 | 1990-06-21 | アウディ アクチェンゲゼルシャフト | Exhaust gas system for internal combustion engines with two cylinder supports |
| FR2640974A1 (en) * | 1988-12-22 | 1990-06-29 | Chinoin Gyogyszer Es Vegyeszet | |
| WO1993002055A1 (en) * | 1991-07-16 | 1993-02-04 | Chugai Seiyaku Kabushiki Kaisha | Process for producing quinolonecarboxylic acid derivative |
| US5284950A (en) * | 1985-12-09 | 1994-02-08 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | Process for the preparation of quinoline carboxyolic acids |
| US5294712A (en) * | 1985-12-09 | 1994-03-15 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | Process for the preparation of quinoline carboxylic acids |
| US5869661A (en) * | 1991-07-16 | 1999-02-09 | Chugai Seiyaku Kabushiki Kaisha | Method of producing a quinolonecarboxylic acid derivative |
| US7361780B2 (en) | 2003-01-31 | 2008-04-22 | Mitsubishi Rayon Co., Ltd. | Apparatus for producing hydroxyalkyl(meth)acrylate and process for producing the same |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| JPS54138582A (en) * | 1978-04-19 | 1979-10-27 | Kyorin Seiyaku Kk | Substituted quinolinecarboxylic acid |
| JPS5547658A (en) * | 1978-09-29 | 1980-04-04 | Kyorin Pharmaceut Co Ltd | Substituted quinolinecarboxylic acid derivative |
| JPS5762259A (en) * | 1980-09-05 | 1982-04-15 | Kyorin Pharmaceut Co Ltd | Preparation of substituted quinolinecarboxylic acid derivative |
-
1982
- 1982-12-27 JP JP23368482A patent/JPS59122470A/en active Granted
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| JPS54138582A (en) * | 1978-04-19 | 1979-10-27 | Kyorin Seiyaku Kk | Substituted quinolinecarboxylic acid |
| JPS5547658A (en) * | 1978-09-29 | 1980-04-04 | Kyorin Pharmaceut Co Ltd | Substituted quinolinecarboxylic acid derivative |
| JPS5762259A (en) * | 1980-09-05 | 1982-04-15 | Kyorin Pharmaceut Co Ltd | Preparation of substituted quinolinecarboxylic acid derivative |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0351889A1 (en) | 1985-12-09 | 1990-01-24 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | Process for the preparation of a quinoline carboxylic acid |
| WO1987003587A1 (en) | 1985-12-09 | 1987-06-18 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Process for the preparation of quinoline carboxylic acids |
| US5294712A (en) * | 1985-12-09 | 1994-03-15 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | Process for the preparation of quinoline carboxylic acids |
| US5284950A (en) * | 1985-12-09 | 1994-02-08 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | Process for the preparation of quinoline carboxyolic acids |
| WO1987003595A1 (en) | 1985-12-09 | 1987-06-18 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Norfloxacin intermediate |
| JPH02501839A (en) * | 1986-12-04 | 1990-06-21 | アウディ アクチェンゲゼルシャフト | Exhaust gas system for internal combustion engines with two cylinder supports |
| GR880100231A (en) * | 1987-04-08 | 1989-01-31 | Chinoin Gyogyszer Es Vegyeszet | Preparation method of quinoline carboxylic acids |
| JPH01503301A (en) * | 1987-04-08 | 1989-11-09 | キノイン ギオギスゼル エス ベギエスゼチ テルメケク ギヤラ アール．ティー | Method for producing quinoline carboxylic acid |
| JPH01503300A (en) * | 1987-04-08 | 1989-11-09 | キノイン ギオギスゼル エス ベギエスゼチ テルメケク ギヤラ アール．ティー | Quinoline carboxylic acid boric anhydride and its production method |
| GR880100232A (en) * | 1987-04-08 | 1989-01-31 | Chinoin Gyogyszer Es Vegyeszet | Quinoline carboxylic acid boric acid anhydrides and process for the preparation therefor |
| AU612648B2 (en) * | 1987-04-08 | 1991-07-18 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara | Process for the preparation of quinoline carboxylic acids |
| AU613035B2 (en) * | 1987-04-08 | 1991-07-25 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara | Quinoline carboxylic acid boric acid anhydrides and process for the preparation thereof |
| WO1988007998A1 (en) * | 1987-04-08 | 1988-10-20 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Quinoline carboxylic acid boric acid anhydrides and process for the preparation thereof |
| JPH02500366A (en) * | 1987-06-24 | 1990-02-08 | キノイン ギオギスゼル エス ベギエスゼチ テルメケク ギヤラ アールティー． | Method for producing quinoline carboxylic acid derivatives |
| JPS6419069A (en) * | 1987-07-14 | 1989-01-23 | Dainippon Pharmaceutical Co | Production of polyhalogenoquinoline derivative |
| FR2640974A1 (en) * | 1988-12-22 | 1990-06-29 | Chinoin Gyogyszer Es Vegyeszet | |
| WO1993002055A1 (en) * | 1991-07-16 | 1993-02-04 | Chugai Seiyaku Kabushiki Kaisha | Process for producing quinolonecarboxylic acid derivative |
| US5869661A (en) * | 1991-07-16 | 1999-02-09 | Chugai Seiyaku Kabushiki Kaisha | Method of producing a quinolonecarboxylic acid derivative |
| US7361780B2 (en) | 2003-01-31 | 2008-04-22 | Mitsubishi Rayon Co., Ltd. | Apparatus for producing hydroxyalkyl(meth)acrylate and process for producing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0240066B2 (en) | 1990-09-10 |
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