JPS6256154B2 - - Google Patents
Info
- Publication number
- JPS6256154B2 JPS6256154B2 JP1225487A JP1225487A JPS6256154B2 JP S6256154 B2 JPS6256154 B2 JP S6256154B2 JP 1225487 A JP1225487 A JP 1225487A JP 1225487 A JP1225487 A JP 1225487A JP S6256154 B2 JPS6256154 B2 JP S6256154B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- chloroform
- water
- benzoxazine
- dihydro
- 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
- 150000003839 salts Chemical class 0.000 claims description 5
- XNIVKSPSCYJKBL-UHFFFAOYSA-N 2h-1,2-benzoxazine-6-carboxylic acid Chemical compound O1NC=CC2=CC(C(=O)O)=CC=C21 XNIVKSPSCYJKBL-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 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 1
- JSEVUBOYVADSHX-UHFFFAOYSA-N 1,3-dichloro-2-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(F)=C1Cl JSEVUBOYVADSHX-UHFFFAOYSA-N 0.000 description 1
- ZJVPAAJHCJMGGL-UHFFFAOYSA-N 1-(2,3-difluoro-6-nitrophenoxy)propan-2-one Chemical compound CC(=O)COC1=C(F)C(F)=CC=C1[N+]([O-])=O ZJVPAAJHCJMGGL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 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
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical group C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-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
- 229920001817 Agar Polymers 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 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
- 238000003113 dilution method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、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
酸およびその塩に関する。
ピリド［１・２・３−de］［１・４］ベンゾオ
キサジン骨格を有する化合物は特開昭50−108298
号公報に、またベンゾキノリジン骨格を有する化
合物は特開昭51−127099号および特開昭55−
76875号公報に記載があるが、本発明化合物はそ
の何れよりも優れた活性を示す。
本発明化合物は、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−カルボン酸をジメチルスルホキシド、
スルホラン、ジメチルホルムアミド、ジメチルア
セトアミド、水の如き極性溶媒中で、Ｎ−メチル
ピペラジンと室温ないし200℃、好ましくは70〜
150℃で１時間ないし48時間加熱することによつ
て得られる。
塩としては、塩酸、硫酸、メタンスルホン酸の
如き無機もしくは有機酸との塩、あるいはカルボ
ン酸のナトリウム塩やカリウム塩が具体例として
挙げられる。
本発明の化合物およびその塩は、緑膿菌を含む
グラム陰性菌およびグラム陽性菌に対して強い抗
菌作用を示し、医薬品としての使用が期待でき
る。例えば、医薬品として使用されているピペミ
ド酸を対照とした試験管内抗菌試験において、最
小発育阻止濃度を測定した結果は次表に示すよう
に優れた抗菌活性を示す。
最小発育阻止濃度（MIC、μｇ／ml）
平板希釈法（ハートインフユージヨン寒天培地）
接種菌量 106／ml
培養条件 37℃、18時間
The present invention provides 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 and salts thereof. Compounds having a pyrido[1,2,3-de][1,4]benzoxazine skeleton are disclosed in JP-A-50-108298.
In addition, compounds having a benzoquinolidine skeleton are described in JP-A-51-127099 and JP-A-55-
Although it is described in Japanese Patent No. 76875, the compound of the present invention exhibits superior activity to any of them. The compound of the present invention contains 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. dimethyl sulfoxide,
N-methylpiperazine in a polar solvent such as sulfolane, dimethylformamide, dimethylacetamide, or water at room temperature to 200°C, preferably 70°C to
Obtained by heating at 150°C for 1 to 48 hours. Specific examples of the salt include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, and methanesulfonic acid, and sodium and potassium salts of carboxylic acids. The compounds of the present invention and their salts exhibit strong antibacterial activity against Gram-negative bacteria and Gram-positive bacteria, including Pseudomonas aeruginosa, and can be expected to be used as pharmaceuticals. For example, in an in vitro antibacterial test using pipemic acid, which is used as a pharmaceutical, as a control, the minimum inhibitory concentration was measured, and the results show excellent antibacterial activity as shown in the table below. Minimum inhibitory concentration (MIC, μg/ml) Plate dilution method (heart infusion agar medium) Inoculum amount 10 6 /ml Culture conditions 37℃, 18 hours
【表】【table】
【表】
次に参考例および実施例を記載する。
参考例
２・４−ジクロロ−３−フルオロニトロベンゼ
ン5.0ｇおよび粉末フツ化カリウム5.8ｇをジメチ
ルスルホキシド５mlに加えて140〜155℃で4.5時
間撹拌する。減圧下に溶媒を留去し、残渣を水と
クロロホルムで分配する。クロロホルム層は水洗
し、乾燥後、クロロホルムを留去して油状物の
２・３・４−トリフルオロニトロベンゼン3.8ｇ
を得る。
このものの20ｇをジメチルスルホキシド150ml
にとかし、18〜20℃で10％水酸化カリウム水溶液
50mlを滴下する。更に室温で２時間撹拌し、水１
を加えてクロロホルムと振とうする。水層は塩
酸々性としてクロロホルムで抽出し、抽出液は水
洗し、乾燥したのちクロロホルムを濃縮する。残
渣をシリカゲルカラムクロマトグラフイーで精製
し、黄色油状物として２・３−ジフルオロ−６−
ニトロフエノール5.8ｇを得る。
このものの5.8ｇをモノクロロアセトン5.0ｇ、
炭酸カリウム8.0ｇおよびヨウ化カリウム0.8ｇと
アセトン100mlに加えて４時間還流する。不溶物
を濾去し、溶媒を留去して、残渣をクロロホルム
と水で分配する。クロロホルム層は水洗し、乾燥
したのち、溶媒を留去して残渣をｎ−ヘキサンで
処理し、淡黄白色結晶として２−アセトニルオキ
シ−３・４−ジフルオロニトロベンゼン5.0ｇを
得る。
このものの7.1ｇをエタノール200mlにとかし、
ラネーニツケル14mlを加えて常圧接触還元する。
触媒を濾去し、溶媒を留去したのち、残渣をシリ
カゲルの層を通じて脱色すると、７・８−ジフル
オロ−２・３−ジヒドロ−３−メチル−4H−
［１・４］ベンゾオキサジンを淡黄色油状物とし
て5.1ｇ得ることが出来る。
このものの4.8ｇおよびエトキシメチレンマロ
ン酸ジエチル5.3ｇの混合物を140〜145℃で１時
間加熱する。原料消失後少量のエタノールを減圧
留去し、得られる油状物にポリリン酸エチル35ｇ
を加え、浴温140〜145℃で１時間撹拌する。冷後
氷水に注ぎ、析出沈殿をクロロホルム600ml（200
×３）で抽出する。クロロホルム層を５％炭酸カ
リウム水溶液、ついで水で分配後、芒硝で乾燥
し、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
ボン酸エチルの白色粉末5.1ｇを得る。融点261
℃。
このものの4.0ｇを濃塩酸−酢酸（１：４）50
mlに溶解し、油浴にて、３時間還流する。冷後析
出晶を濾取し、充分水洗後、エタノール−エーテ
ル（１：４）の混液で洗い、減圧乾燥して透明板
状晶の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3.7ｇを得る。融点＞300℃。
NMR（CF3COOH）δppm：
1.88（3H、ｄ、C3−CH3）
4.72（2H、b.s、C2−H2）
4.8〜5.1（1H、ｍ、C3−Ｈ）
7.9〜8.2（1H、ｑ、C8−Ｈ）
9.42（1H、ｓ、C5−Ｈ）
実施例
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1.0ｇおよびＮ−メチルピペラジン2.85ｇを
ジメチルスルホキシド15mlに加え、100〜110℃で
12時間撹拌する。反応混合物を減圧乾固し、残渣
に水40mlを加えてクロロホルムで抽出する。抽出
液を乾燥後、減圧乾固し、残渣をエタノールから
再結晶すると融点250〜257℃（分解）の無色針状
晶として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550
mgが得られる。
元素分析値 C18H20FN3O4として
計算値 Ｃ 59.82、Ｈ 5.58、Ｎ 11.63
分析値 Ｃ 59.62、Ｈ 5.59、Ｎ 11.65
1H−NMR（CDCl3）δppm：
1.63（3H、ｄ、Ｊ＝７Hz、C3−ＣＨ ３）
2.38（3H、ｓ、Ｎ−ＣＨ ３）
2.54〜2.60（4H、ｍ、[Table] Next, reference examples and examples are described. Reference Example 5.0 g of 2,4-dichloro-3-fluoronitrobenzene and 5.8 g of powdered potassium fluoride are added to 5 ml of dimethyl sulfoxide and stirred at 140-155°C for 4.5 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and chloroform. The chloroform layer was washed with water, dried, and the chloroform was distilled off to obtain 3.8 g of 2,3,4-trifluoronitrobenzene as an oil.
get. 20g of this and 150ml of dimethyl sulfoxide
Mix with 10% potassium hydroxide aqueous solution at 18-20℃
Drop 50ml. Stir further at room temperature for 2 hours, then add 1 liter of water.
Add chloroform and shake. The aqueous layer is diluted with hydrochloric acid and extracted with chloroform. The extract is washed with water, dried, and the chloroform is concentrated. The residue was purified by silica gel column chromatography to give 2,3-difluoro-6- as a yellow oil.
5.8 g of nitrophenol is obtained. 5.8g of this stuff, 5.0g of monochloroacetone,
Add 8.0 g of potassium carbonate, 0.8 g of potassium iodide and 100 ml of acetone and reflux for 4 hours. Insoluble materials are filtered off, the solvent is distilled off, and the residue is partitioned between chloroform and water. The chloroform layer is washed with water, dried, and then the solvent is distilled off and the residue is treated with n-hexane to obtain 5.0 g of 2-acetonyloxy-3,4-difluoronitrobenzene as pale yellow-white crystals. Dissolve 7.1g of this substance in 200ml of ethanol,
Add 14 ml of Raney nickel and perform atmospheric pressure catalytic reduction.
After filtering off the catalyst and distilling off the solvent, the residue was decolorized through a layer of silica gel to give 7,8-difluoro-2,3-dihydro-3-methyl-4H-
5.1 g of [1.4] benzoxazine can be obtained as a pale yellow oil. A mixture of 4.8 g of this and 5.3 g of diethyl ethoxymethylenemalonate is heated at 140-145°C for 1 hour. After the raw materials disappeared, a small amount of ethanol was distilled off under reduced pressure, and 35 g of ethyl polyphosphate was added to the resulting oil.
and stir for 1 hour at a bath temperature of 140-145°C. After cooling, pour into ice water and dissolve the precipitate in chloroform 600ml (200ml).
×3) Extract. The chloroform layer was partitioned with a 5% aqueous potassium carbonate solution and then with water, dried over Glauber's salt, and 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrid [1,2,
5.1 g of white powder of ethyl 3-de][1.4]benzoxazine-6-carboxylate is obtained. melting point 261
℃. Add 4.0g of this to concentrated hydrochloric acid-acetic acid (1:4)50
ml and reflux for 3 hours in an oil bath. After cooling, the precipitated crystals were collected by filtration, thoroughly washed with water, washed with a mixture of ethanol and ether (1:4), and dried under reduced pressure to obtain transparent plate-like crystals of 9,10-difluoro-3-methyl-7-oxo-2.・3-dihydro-7H-pyrido [1.
2,3-de][1,4]benzoxazine-6-
3.7 g of carboxylic acid are obtained. Melting point >300℃. NMR ( CF3COOH ) δppm: 1.88 (3H, d, C3 - CH3 ) 4.72 (2H, bs, C2 - H2 ) 4.8-5.1 (1H, m, C3 - H) 7.9-8.2 (1H , q, C 8 -H) 9.42 (1H, s, C 5 -H) Example 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de] [1,4] 1.0 g of benzoxazine-6-carboxylic acid and 2.85 g of N-methylpiperazine were added to 15 ml of dimethyl sulfoxide and heated at 100 to 110°C.
Stir for 12 hours. The reaction mixture was dried under reduced pressure, 40 ml of water was added to the residue, and the mixture was extracted with chloroform. After drying the extract, the residue was recrystallized from ethanol to give 9-fluoro-3-methyl-10-(4-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 550
mg is obtained. Elemental analysis value C 18 H 20 FN 3 O 4 Calculated value C 59.82, H 5.58, N 11.63 Analysis value C 59.62, H 5.59, N 11.65 1 H-NMR (CDCl 3 ) δppm: 1.63 (3H, d, J= 7Hz, C3 - CH3 ) 2.38 ( 3H, s, N- CH3 ) 2.54-2.60 (4H, m,
【式】） 3.40〜3.44（4H、ｍ、【formula】) 3.40~3.44 (4H, m,
【式】）
4.35〜4.51（3H、ｍ、C3−ＨおよびC2−Ｈ
２）
7.75（1H、ｄ、Ｊ＝12Hz、C8−Ｈ）
8.64（1H、ｓ、C5−Ｈ） [Formula]) 4.35-4.51 (3H, m, C3 - H and C2 - H
2 ) 7.75 (1H, d, J=12Hz, C8 - H ) 8.64 (1H, s, C5 - H )
Claims (1)
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−カルボン酸およびそ
の塩。1 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 and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1225487A JPS62187473A (en) | 1987-01-23 | 1987-01-23 | Pyridobenzoxazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1225487A JPS62187473A (en) | 1987-01-23 | 1987-01-23 | Pyridobenzoxazine derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13447084A Division JPS6034968A (en) | 1984-06-29 | 1984-06-29 | Pyrido(1,2,3-de)(1,4)benzoxazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62187473A JPS62187473A (en) | 1987-08-15 |
| JPS6256154B2 true JPS6256154B2 (en) | 1987-11-24 |
Family
ID=11800229
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1225487A Granted JPS62187473A (en) | 1987-01-23 | 1987-01-23 | Pyridobenzoxazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62187473A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0629986Y2 (en) * | 1989-07-18 | 1994-08-17 | 富士ロビン株式会社 | Fuel tank mounting structure for backpack type power sprayer |
-
1987
- 1987-01-23 JP JP1225487A patent/JPS62187473A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0629986Y2 (en) * | 1989-07-18 | 1994-08-17 | 富士ロビン株式会社 | Fuel tank mounting structure for backpack type power sprayer |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62187473A (en) | 1987-08-15 |
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| EXPY | Cancellation because of completion of term | ||
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