JPH0153861B2 - - Google Patents
Info
- Publication number
- JPH0153861B2 JPH0153861B2 JP18763585A JP18763585A JPH0153861B2 JP H0153861 B2 JPH0153861 B2 JP H0153861B2 JP 18763585 A JP18763585 A JP 18763585A JP 18763585 A JP18763585 A JP 18763585A JP H0153861 B2 JPH0153861 B2 JP H0153861B2
- Authority
- JP
- Japan
- Prior art keywords
- difluoro
- methyl
- dihydro
- compound
- benzoxazine
- 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
- KEGOHDCHURMFKX-UHFFFAOYSA-N 2,3-difluoro-6-nitrophenol Chemical compound OC1=C(F)C(F)=CC=C1[N+]([O-])=O KEGOHDCHURMFKX-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- -1 inorganic acid salt Chemical class 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- ARCACZWMYGILNI-UHFFFAOYSA-N 1,2,3-trifluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1F ARCACZWMYGILNI-UHFFFAOYSA-N 0.000 description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical group N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- BVHSAZFNVBBGNX-UHFFFAOYSA-N 7,8-difluoro-3-methyl-3,4-dihydro-2h-1,4-benzoxazine Chemical compound C1=CC(F)=C(F)C2=C1NC(C)CO2 BVHSAZFNVBBGNX-UHFFFAOYSA-N 0.000 description 1
- NVKWWNNJFKZNJO-UHFFFAOYSA-N 82419-35-0 Chemical compound O1CC(C)N2C=C(C(O)=O)C(=O)C3=C2C1=C(F)C(F)=C3 NVKWWNNJFKZNJO-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は、オフロキサシン（９−フルオロ−３
−メチル−10−（４−メチル−１−ピペラジニル）
−７−オキソ−２，３−ジヒドロ−7H−ピリド
［１，２，３−de］−１，４−ベンゾオキサジン
−６−カルボン酸）の製造に有用な２，３−ジフ
ルオロ−６−ニトロフエノールに関するものであ
る。DETAILED DESCRIPTION OF THE INVENTION The present invention provides ofloxacin (9-fluoro-3
-Methyl-10-(4-methyl-1-piperazinyl)
-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid) It concerns phenols.
本発明の化合物は、２，３，４−トリフルオロ
ニトロベンゼンをジメチルスルホキシド、スルホ
ラン等の溶媒中で、水酸化カリウム、水酸化ナト
リウムの如き強塩基の存在下に室温で撹拌する
と、ニトロ基のオルト位の弗素原子が選択的に加
水分解されて収率よく生成する。 The compound of the present invention is produced by stirring 2,3,4-trifluoronitrobenzene in a solvent such as dimethyl sulfoxide or sulfolane at room temperature in the presence of a strong base such as potassium hydroxide or sodium hydroxide. The fluorine atom in the position is selectively hydrolyzed and produced in good yield.
この化合物を用いてオフロサキシンを製造する
には、例えば次の如く反応をおこなう。 In order to produce oflosaxin using this compound, the following reaction is carried out, for example.
脱酸剤として炭酸カリウムまたは炭酸ナトリウ
ムを用い、触媒量の沃化カリウムの存在下に、
２，３−ジフルオロ−６−ニトロフエノールをモ
ノクロルアセトンと反応させ、得られる中間体を
ラネー・ニツケル、パラジウム炭等の触媒の存在
下常圧で接触還元するとオキサジン環が形成さ
れ、７，８−ジフルオロ−３−メチル−２，３−
ジヒドロ−4H−１，４−ベンゾオキサジンを収
率よく得ることができる。この化合物は遊離塩基
のまま、または無機酸塩、例えば塩酸塩として、
ジメチルアミノメチレンマロン酸エステルと加熱
すると高収率で７，８−ジフルオロ−３−メチル
−２，３−ジヒドロ−4H−１，４−ベンゾオキ
サジン−４−イル）メチレンマロン酸エステルに
導くことができる。これを、ポリリン酸またはそ
のエステル中で加熱すると、ピリジン環閉環反応
が起り、ついで、酸または塩基中で処理するとカ
ルボン酸のエステルが加水分解されて９，10−ジ
フルオロ−３−メチル−７−オキソ−２，３−ジ
ヒドロ−7H−ピリド［１，２，３−de］−１，４
−ベンゾオキサジン−６−カルボン酸が生成す
る。本化合物をＮ−メチルピペラジンと加熱反応
させるとオフロサキシンが高収率で得られる。オ
フロサキシンは極めてすぐれた抗菌剤である（特
開昭57−46986号公報参照）。 using potassium carbonate or sodium carbonate as a deoxidizing agent and in the presence of a catalytic amount of potassium iodide.
When 2,3-difluoro-6-nitrophenol is reacted with monochloroacetone and the resulting intermediate is catalytically reduced in the presence of a catalyst such as Raney-nickel or palladium on charcoal at normal pressure, an oxazine ring is formed, and a 7,8- difluoro-3-methyl-2,3-
Dihydro-4H-1,4-benzoxazine can be obtained in good yield. The compound can be used as a free base or as an inorganic acid salt, e.g. hydrochloride.
When heated with dimethylaminomethylene malonic acid ester, it can lead to 7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methylene malonic acid ester in high yield. can. When this is heated in polyphosphoric acid or its ester, a pyridine ring closure reaction occurs, and then when it is treated in an acid or base, the carboxylic acid ester is hydrolyzed and 9,10-difluoro-3-methyl-7- Oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4
-benzoxazine-6-carboxylic acid is produced. When this compound is reacted with N-methylpiperazine under heating, oflosaxine can be obtained in high yield. Oflosaxin is an extremely excellent antibacterial agent (see JP-A-57-46986).
実施例
２，３，４−トリフルオロニトロベンゼン20ｇ
をジメチルスルホキシド100mlに溶かし、18〜20
℃で20％水酸化カリウム水溶液65mlを滴下し、同
温度で５時間撹拌する。反応液に水500mlを加え
てクロロホルムと振盪する。水層を分取し、塩酸
で酸性としたのちクロロホルムで抽出する。抽出
液は水洗し、茫硝で乾燥したのち、クロロホルム
を留去すると融点61℃の２，３−ジフルオロ−６
−ニトロフエノール16.9ｇ（85.5％）が得られ
た。Example 2,3,4-trifluoronitrobenzene 20g
Dissolve in 100ml of dimethyl sulfoxide and add 18 to 20
65 ml of 20% potassium hydroxide aqueous solution was added dropwise at °C, and the mixture was stirred at the same temperature for 5 hours. Add 500 ml of water to the reaction solution and shake with chloroform. The aqueous layer is separated, acidified with hydrochloric acid, and extracted with chloroform. The extract was washed with water, dried over sulfur, and the chloroform was distilled off to produce 2,3-difluoro-6 with a melting point of 61°C.
- 16.9 g (85.5%) of nitrophenol were obtained.
元素分析値 C6H3F2NO3として 計算値 Ｃ 41.16、Ｈ 1.73、Ｎ 8.00 分析値 Ｃ 40.95、Ｈ 1.75、Ｎ 8.22Elemental analysis value C 6 H 3 F 2 NO 3 Calculated value C 41.16, H 1.73, N 8.00 Analysis value C 40.95, H 1.75, N 8.22
Claims (1)
ル。1 2,3-difluoro-6-nitrophenol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18763585A JPS61246150A (en) | 1985-08-27 | 1985-08-27 | 2,3-dilfluoro-6-nitrophenol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18763585A JPS61246150A (en) | 1985-08-27 | 1985-08-27 | 2,3-dilfluoro-6-nitrophenol |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17162181A Division JPS5872588A (en) | 1981-10-27 | 1981-10-27 | Production of pyrido(1,2,3-de)-1,4-benzoxazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61246150A JPS61246150A (en) | 1986-11-01 |
| JPH0153861B2 true JPH0153861B2 (en) | 1989-11-15 |
Family
ID=16209559
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18763585A Granted JPS61246150A (en) | 1985-08-27 | 1985-08-27 | 2,3-dilfluoro-6-nitrophenol |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61246150A (en) |
-
1985
- 1985-08-27 JP JP18763585A patent/JPS61246150A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61246150A (en) | 1986-11-01 |
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