JPS642108B2 - - Google Patents
Info
- Publication number
- JPS642108B2 JPS642108B2 JP55032368A JP3236880A JPS642108B2 JP S642108 B2 JPS642108 B2 JP S642108B2 JP 55032368 A JP55032368 A JP 55032368A JP 3236880 A JP3236880 A JP 3236880A JP S642108 B2 JPS642108 B2 JP S642108B2
- Authority
- JP
- Japan
- Prior art keywords
- lower alkyl
- alkyl group
- formula
- general formula
- malonic 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
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- -1 Methylene malonic acid ester Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000002690 malonic acid derivatives Chemical class 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Description
【発明の詳細な説明】
本発明は、抗菌剤として有用なキノロンカルボ
ン酸誘導体の合成中間体として有用であるアニリ
ノメチレンマロン酸エステル誘導体およびその製
法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anilinomethylene malonic acid ester derivative useful as a synthetic intermediate for quinolone carboxylic acid derivatives useful as antibacterial agents, and a method for producing the same.
本発明者らは、先に下記の一般式（）で表わ
されるキノロンカルボン酸誘導体が顕著な抗菌活
性を有することを見い出した。 The present inventors previously discovered that a quinolone carboxylic acid derivative represented by the following general formula () has significant antibacterial activity.
〔式中R4は低級アルキル基（該基はヒドロキ
シ基、ハロゲン原子、フエニル基で置換されてい
てもよい。また不飽和結合を有していてもよい）
を示し、R5は水素、低級アルキル基、アシル基
を示す。Ｘ，X1は水素又はハロゲン原子を示す
が、同時に水素を表わすことはない〕
本発明の一般式（）で表わされるアニリノメ
チレンマロン酸エステル誘導体は
（式中R1低級アルキル基を示し、R2は低級ア
ルキル基、アシル基を示しＸ，X1は前述と同様
の意味を有する）
一般式（）で表わされるキノロンカルボン酸
誘導体の有用な合成中間体であり、下記式に従つ
て一般式（）の化合物へ導くことができる。 [In the formula, R 4 is a lower alkyl group (the group may be substituted with a hydroxy group, a halogen atom, or a phenyl group. It may also have an unsaturated bond)
and R 5 represents hydrogen, a lower alkyl group, or an acyl group. X and X 1 represent hydrogen or halogen atoms, but do not represent hydrogen at the same time.] The anilinomethylene malonic acid ester derivative represented by the general formula () of the present invention is (In the formula, R 1 represents a lower alkyl group, R 2 represents a lower alkyl group or an acyl group, and X and X 1 have the same meanings as above.) Useful synthesis of quinolone carboxylic acid derivatives represented by the general formula () It is an intermediate and can be led to the compound of general formula () according to the following formula.
（式中R1，R2，R4，R5，Ｘ，X1は前記と同様
の意味を有する。X2は脱離基を示す）
本発明の一般式（）の化合物は、一般式
（）
（式中R2，Ｘ，X1は前記と同様の意味を有す
る）
で表わされるアニリン誘導体と、一般式（）
R3OCH＝Ｃ（COOR1）2 （）
（式中R1は前述と同様の意味を有する。R3は
低級アルキル基を示す。）
で表わされるマロン酸誘導体とを反応させること
によつて合成される。本反応は無溶媒下、または
不活性溶媒の存在下（本発明に於ける不活性溶媒
とは、エタノール等のアルコール類、ベンゼン、
トルエンのような芳香族炭化水素、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素、
テトラヒドロフラン、ジオキサンのようなエーテ
ル類、アセトニトリル、ジメチルホルムアミドの
ような非プロトン性、極性溶媒、あるいはこれら
の混合溶媒を意味する）室温〜180℃の範囲内で
行なう方が望ましい。 (In the formula, R 1 , R 2 , R 4 , R 5 , X, and X 1 have the same meanings as above. X 2 represents a leaving group) () (In the formula, R 2 , X, and X 1 have the same meanings as above.) An aniline derivative represented by the general formula ( ) It has the same meaning. R 3 represents a lower alkyl group.) It is synthesized by reacting with a malonic acid derivative represented by: This reaction is carried out without solvent or in the presence of an inert solvent (in the present invention, inert solvents include alcohols such as ethanol, benzene,
Aromatic hydrocarbons such as toluene, halogenated hydrocarbons such as dichloroethane, chloroform,
It is preferable to carry out the reaction at a temperature ranging from room temperature to 180°C (meaning an ether such as tetrahydrofuran or dioxane, an aprotic or polar solvent such as acetonitrile or dimethylformamide, or a mixed solvent thereof).
以下、実施例を挙げて具体的に説明するが、本
発明に使用する原料が新規物質であるので、その
製法を含めて記載する。 Hereinafter, the present invention will be specifically explained with reference to examples, but since the raw material used in the present invention is a new substance, the method for producing it will also be described.
実施例
Ｏ―フルオロフエニルピペラジン11.4g、無水
酢酸12.9g及びＮ，Ｎ―ジメチルホルムアミド10
mlの混合物を80〜90℃で１時間撹拌した。溶媒留
去後、氷水を加え、炭酸カリウムで塩基性にし、
ジクロロメタンで抽出し、乾燥後、溶媒を留去し
た。残油を減圧蒸留し、12.3gのＮ―アセチル―
Ｏ―フルオロフエニルピペラジンを得た。bp：
185℃／６mmHg
元素分析値 （C12H15ON2Fとして）
Ｃ Ｈ Ｎ
計算値(%) 64.85 6.80 12.60
実測値(%) 64.47 6.83 12.54
以上で得られたＮ―アセチル―Ｏ―フルオロフ
エニルピペラジン12gを25℃以下で濃硫酸40mlに
とかし、５〜10℃に冷却しながら60％硝酸4.2ml
及び濃硫酸５mlの混合液を滴下した。10℃以下で
２時間撹拌後、氷中に加え、濃アンモニア水でPH
４にした。ベンゼンで抽出し乾燥後溶媒を留去し
た。酸渣をエタノールから再結晶し、黄色結晶と
して6.3gの１―アセチル―４―（２―フルオロ―
５―ニトロフエニル）ピペラジンを得た。mp：
132〜134℃
元素分析値 （C12H14O3N3Fとして）
Ｃ Ｈ Ｎ
計算値(%) 53.93 5.28 15.72
実測値(%) 53.91 5.26 15.69
以上で得られた１―アセチル―４―（２―フル
オロ―５―ニトロフエニル）ピペラジン6.0gを
100mlのエタノールに溶かし、10％pd／Ｃ 2gを
加え撹拌しながら水素を1.6吸収させた。触媒
を去し、エタノールを留去した。残渣をベンゼ
ンから再結晶し、無色結晶として5.3gの４―フル
オロ―３―（４―アセチル―１―ピペラジニル）
アニリンを得た。Example 11.4 g O-fluorophenylpiperazine, 12.9 g acetic anhydride and 10 N,N-dimethylformamide
ml of the mixture was stirred at 80-90°C for 1 hour. After evaporating the solvent, add ice water and make basic with potassium carbonate.
After extraction with dichloromethane and drying, the solvent was distilled off. Distill the residual oil under reduced pressure to obtain 12.3g of N-acetyl-
O-fluorophenylpiperazine was obtained. bp：
185℃/6mmHg Elemental analysis value (as C 12 H 15 ON 2 F) C H N Calculated value (%) 64.85 6.80 12.60 Actual value (%) 64.47 6.83 12.54 N-acetyl-O-fluorophenyl obtained above Dissolve 12g of piperazine in 40ml of concentrated sulfuric acid at below 25°C, and then cool to 5-10°C with 4.2ml of 60% nitric acid.
A mixed solution of 5 ml of concentrated sulfuric acid and 5 ml of concentrated sulfuric acid was added dropwise. After stirring at 10℃ or less for 2 hours, add to ice and PH with concentrated ammonia water.
I gave it a 4. After extraction with benzene and drying, the solvent was distilled off. The acid residue was recrystallized from ethanol to give 6.3 g of 1-acetyl-4-(2-fluoro-
5-nitrophenyl)piperazine was obtained. mp:
132-134℃ Elemental analysis value (as C 12 H 14 O 3 N 3 F) C H N Calculated value (%) 53.93 5.28 15.72 Actual value (%) 53.91 5.26 15.69 1-Acetyl-4-( 6.0g of 2-fluoro-5-nitrophenyl)piperazine
It was dissolved in 100ml of ethanol, 2g of 10% PD/C was added, and 1.6% of hydrogen was absorbed with stirring. The catalyst was removed and ethanol was distilled off. The residue was recrystallized from benzene to give 5.3 g of 4-fluoro-3-(4-acetyl-1-piperazinyl) as colorless crystals.
Obtained aniline.
mp：132℃
元素分析値 （C12H16ON3Fとして）
Ｃ Ｈ Ｎ
計算値(%) 60.74 6.80 17.71
実測値(%) 60.62 6.86 17.73
以上で得られた４―フルオロ―３―（４―アセ
チル―１―ピペラジニル）アニリン4.8g及びエト
キシメチレンマロン酸ジエチルエステル4.3gの混
合物を120〜130℃で２時間反応させた。生成した
油状物をアルミナカラムクロマイトグラフイーで
ジクロロメタンを展開液として精製し、無色非晶
性固体として7.7gのＮ―（２，２―ジエトキシカ
ルボニルビニル）―４―フルオロ―３―（４―ア
セチル―１―ピペラジニル）アニリンを得た。mp: 132℃ Elemental analysis value (as C 12 H 16 ON 3 F) C H N Calculated value (%) 60.74 6.80 17.71 Actual value (%) 60.62 6.86 17.73 4-Fluoro-3-(4- A mixture of 4.8 g of acetyl-1-piperazinyl)aniline and 4.3 g of ethoxymethylene malonic acid diethyl ester was reacted at 120 to 130°C for 2 hours. The resulting oil was purified by alumina column chromatography using dichloromethane as a developing solution to obtain 7.7 g of N-(2,2-diethoxycarbonylvinyl)-4-fluoro-3-(4-) as a colorless amorphous solid. Acetyl-1-piperazinyl)aniline was obtained.
元素分析値 （C20H26O5N3Fとして） Ｃ Ｈ Ｎ 計算値(%) 58.96 6.43 10.31 実測値(%) 58.75 6.55 10.23Elemental analysis value (as C 20 H 26 O 5 N 3 F) C H N Calculated value (%) 58.96 6.43 10.31 Actual value (%) 58.75 6.55 10.23
Claims (1)
アルキル基、アシル基を示す。Ｘ，X1は水素又
はハロゲン原子を示すが、同時に水素を表わすこ
とはない） で表わされるアニリノメチレンマロン酸エステル
誘導体。 ２ 一般式 （式中R2は低級アルキル基、アシル基を示し、
Ｘ，X1は水素又はハロゲン原子を示すが、同時
に水素を表わすことはない。） で表わされるアニリン誘導体と 一般式 R3OCH＝Ｃ（COOR1）2 （式中R1は低級アルキル基を示し、R3も低級
アルキル基を示す。） で表わされるマロン酸誘導体とを反応させること
を特徴とする一般式 で表わされるアニリノメチレンマロン酸エステル
誘導体の製法。[Claims] 1. General formula (In the formula, R 1 represents a lower alkyl group, R 2 represents a lower alkyl group or an acyl group. Methylene malonic acid ester derivative. 2 General formula (In the formula, R 2 represents a lower alkyl group or an acyl group,
X and X 1 represent hydrogen or halogen atoms, but do not represent hydrogen at the same time. ) and a malonic acid derivative represented by the general formula R 3 OCH=C(COOR 1 ) 2 (in the formula, R 1 represents a lower alkyl group, and R 3 also represents a lower alkyl group). A general formula characterized by A method for producing an anilinomethylene malonic acid ester derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3236880A JPS56128773A (en) | 1980-03-14 | 1980-03-14 | Anilinomethylenemalonic ester derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3236880A JPS56128773A (en) | 1980-03-14 | 1980-03-14 | Anilinomethylenemalonic ester derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS56128773A JPS56128773A (en) | 1981-10-08 |
| JPS642108B2 true JPS642108B2 (en) | 1989-01-13 |
Family
ID=12356997
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3236880A Granted JPS56128773A (en) | 1980-03-14 | 1980-03-14 | Anilinomethylenemalonic ester derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS56128773A (en) |
-
1980
- 1980-03-14 JP JP3236880A patent/JPS56128773A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56128773A (en) | 1981-10-08 |
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