JPH0518816B2 - - Google Patents
Info
- Publication number
- JPH0518816B2 JPH0518816B2 JP20543989A JP20543989A JPH0518816B2 JP H0518816 B2 JPH0518816 B2 JP H0518816B2 JP 20543989 A JP20543989 A JP 20543989A JP 20543989 A JP20543989 A JP 20543989A JP H0518816 B2 JPH0518816 B2 JP H0518816B2
- Authority
- JP
- Japan
- Prior art keywords
- chloroform
- residue
- difluoro
- water
- compound
- 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
- 150000001875 compounds Chemical class 0.000 claims description 14
- -1 2,3-difluoro-6-nitrophenyl Chemical group 0.000 claims description 4
- CMXSFIQKWXLYDU-UHFFFAOYSA-N 1-(2,3-difluoro-6-nitrophenoxy)-3-methoxypropan-2-ol Chemical compound COCC(O)COC1=C(F)C(F)=CC=C1[N+]([O-])=O CMXSFIQKWXLYDU-UHFFFAOYSA-N 0.000 claims description 2
- HRUQKPXEKXZHBS-UHFFFAOYSA-N 1-(2,3-difluoro-6-nitrophenoxy)-3-methoxypropan-2-one Chemical compound COCC(=O)COC1=C(F)C(F)=CC=C1[N+]([O-])=O HRUQKPXEKXZHBS-UHFFFAOYSA-N 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims 2
- 229940125782 compound 2 Drugs 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000010446 mirabilite Substances 0.000 description 5
- 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 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- 239000000843 powder Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000005457 ice water 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
- 239000002994 raw material Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 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 description 1
- PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical compound C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-UHFFFAOYSA-N 0.000 description 1
- RROQSCBOBBLOOA-UHFFFAOYSA-N C(C)OC(=O)C=1C=CC2=C(C=CNO2)C1 Chemical compound C(C)OC(=O)C=1C=CC2=C(C=CNO2)C1 RROQSCBOBBLOOA-UHFFFAOYSA-N 0.000 description 1
- BTLPSAWPCLZLCV-UHFFFAOYSA-N CCOC(=O)C1=CN2CCOc3cccc(C1)c23 Chemical compound CCOC(=O)C1=CN2CCOc3cccc(C1)c23 BTLPSAWPCLZLCV-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920000388 Polyphosphate Polymers 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- BOSBRKBHTFSORJ-UHFFFAOYSA-N diethyl 2-[[7,8-difluoro-3-(methoxymethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]methylidene]propanedioate Chemical compound C(C)OC(C(C(=O)OCC)=CN1C(COC2=C1C=CC(=C2F)F)COC)=O BOSBRKBHTFSORJ-UHFFFAOYSA-N 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 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
- 239000002244 precipitate Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Epoxy Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
産業上の利用分野
本発明は抗菌性化合物の原料として有用な化合
物に関する。
発明の構成
本発明は式
（式中Ｑは−COCH2OCH3、−CH（OH）CH2
OCH3または
INDUSTRIAL APPLICATION FIELD The present invention relates to compounds useful as raw materials for antibacterial compounds. Structure of the invention The present invention is based on the formula (In the formula, Q is −COCH 2 OCH 3 , −CH(OH)CH 2
OCH 3 or
【式】を意味する）
で表わされる化合物に関し、このものは式
（式中、Ｒは１−ピロリジニル、１−ピペリジ
ニル、１−ピペラジニル、４−モルホリニル等の
環状アミノ基を意味する）で表わされるピリド
［１，２，３−de］［１，４］ベンゾオキサジン
誘導体の製造原料として有用である。
本発明化合物の製造法の例を反応式で示し実施
例で説明する。
実施例：
２，３−ジフルオロ−６−ニトロフエノール
7.0g、エピクロルヒドリン7.0g、炭酸カリウム
15g及びヨウ化カリウム600mgをジメチルホルム
アミド150mlに加え、浴温85〜90℃で20時間攪拌
した。冷後不溶物を濾去し、濾液を減圧濃縮して
残渣をクロロホルムと水で分配した。クロロホル
ム層は水洗し、芒硝で乾燥後、溶媒を留去して残
渣をシリカゲルカラムクロマトグラフイで精製し
淡黄色油状物として２，３−ジフルオロ−６−ニ
トロフエニル・オキシラニルメチル・エーテル
6.1gを得た。
この化合物15.0gおよび第二塩化スズ0.3mlを無
水メタノール60mlに加えて２時間還流した。溶媒
を留去し残渣をクロロホルムと水で分配し、クロ
ロホルム層より、油状物として１−（２，３−ジ
フルオロ−６−ニトロフエノキシ）−３−メトキ
シ−２−プロパノール16.1gを得た。
この化合物15gをアセトン150mlにとかし、氷
冷下、攪拌しつつジヨーンズ試薬（無水クロム酸
32g、水64ml、濃硫酸16mlから調整）50mlを滴下
した。同温度で30分次いで室温で２時間攪拌し
た。不溶物を除去し、アセトン、次いでクロロホ
ルムで洗い、濾液及び洗液を合わせ溶媒を留去し
た。残渣はクロロホルムと水で分配し、クロロホ
ルム層を水洗し、芒硝で乾燥後クロロホルムを留
去した。残渣をシリカゲルカラムクロマトグラフ
イで精製し、クロロホルム溶出液から融点39〜42
℃の１−（２，３−ジフルオロ−６−ニトロフエ
ノキシ）−３−メトキシ−２−プロパノン10.6gを
得た。
元素分析値 C10H9F2NO5として
計算値 Ｃ 45.99，Ｈ 3.47，Ｎ 5.36
分析値 Ｃ 45.79，Ｈ 3.26，Ｎ 5.29
参考例
上記化合物9.5gをエタノール100mlに溶かし、
ラネー・ニツケル10mlを加えて常圧で接触還元す
る。触媒を濾去し、溶媒を減圧留去したのち、残
渣をシリカゲルカラムクロマトグラフイで精製し
て油状物3.9gを得る。この油状物3.0gにエトキシ
メチレンマロン酸ジエチル3.5gを加えて浴温105
〜115℃で２時間加熱する。冷後、反応物をシリ
カゲルカラムクロマトグラフイで精製し、融点81
℃の（７，８−ジフルオロ−３−メトキシメチル
−２，３−ジヒドロ−4H−１，４−ベンゾオキ
サジン−４−イル）メチレンマロン酸ジエチル
4.1gを得た。
元素分析値 C18H21F2NO6として
計算値 Ｃ 56.10，Ｈ 5.49，Ｎ 3.64
分析値 Ｃ 56.25，Ｈ 5.47，Ｎ 3.74
上記化合物3.0gをポリリン酸エチル20gに加え
て浴温120〜125℃で1.5時間加熱する。冷後、氷
水を加え、析出物をクロロホルムで抽出する。抽
出液は水洗し、芒硝で乾燥したのち、溶媒を留去
する。残渣をシリカゲルカラムクロマトグラフイ
で精製し、クロロホルム溶出分から得られる粉末
を、ジクロルメタンとイソプロピルエーテルの混
液から再結晶して融点238℃の微針晶として９，
10−ジフルオロ−３−エトキシメチル−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1.7gを得た。
上記化合物1.7gをジクロルメタン100mlに加え
氷冷下に臭化アルミニウム6.0gをエタンチオール
10mlに溶した溶液を滴下する。室温に戻して３時
間攪拌後溶媒を留去し、残渣に氷水を加えて不溶
物を濾取する。得た白色粉末をクロロホルムとエ
タノールの混液から再結晶し融点268〜270℃の微
針晶の９，10−ジフルオロ−３−ヒドロキシメチ
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1.1gを得た。
上記化合物400mgをクロロホルム30mlに溶かし
これに塩化チオニル３mlを加えて４時間還流し、
反応液を減圧乾固し、残渣をクロロホルムに溶か
して水、炭酸水素ナトリウム水溶液及び水で順次
洗い、芒硝で乾燥する。溶媒を留去し、残渣をク
ロロホルムとエタノールの混液から再結晶して融
点250〜251℃の微針晶として３−クロロメチル−
９，10−ジフルオロ−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220mg
を得た。
上記化合物200mgを無水ベンゼン30mlに懸濁し
１，８−ジアザビシクロ［５，４，０］−７−ウ
ンデセン（DBU）230mgを加えて１時間還流す
る。冷後反応液にクロロホルムを加えて水洗し、
芒硝で乾燥する。溶媒を留去し、残渣をシリカゲ
ルカラムクロマトグラフイで精製し、ジクロルメ
タンとイソプロピルエーテルの混液から再結晶し
融点258〜263℃の９，10−ジフルオロ−３−メチ
レン−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120mgを得た。
NMR（DMSO−d6，δppm）
３位メチレン基；5.47，5.89
（各1H，ｄ，Ｊ＝2.5Hz）
上記化合物100mgをジメチルスルホキシド３ml
に溶かし、Ｎ−メチルピペラジン100mgを加えて
浴温120〜130℃で６時間攪拌する。冷後、溶媒を
減圧乾固し、残渣をシリカゲルカラムクロマトグ
ラフイで精製する。得られた粉末100mgをエタノ
ール10mlに懸濁し、３％水酸化ナトリウム水溶液
１mlを加えて40〜50℃で30分間攪拌する。反応液
を減圧乾固し、残渣に水を加えて希塩酸で酸性と
したのち再び炭酸水素ナトリウムで塩基性とし、
クロロホルムで抽出する。抽出液は芒硝で乾燥
し、溶媒を留去する。残渣をシリカゲルカラムク
ロマトグラフイで精製し、エタノールから再結晶
して融点200〜201℃の微針晶として９−フルオロ
−10−（４−メチル−１−ピペラジニル）−３−メ
チレン−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25mgを得た。
NMR（CDCl3，δppm）
4.83（2H，ｓ，２位CH2）
5.26，5.61（各1H，ｄ，Ｊ＝3.0Hz，３位 Ｃ
＝CH2）
8.83（1H，ｓ，５位 Ｈ）
7.63（1H，ｄ，Ｊ＝12Hz，８位Ｈ）Regarding the compound represented by [formula], this compound has the formula (In the formula, R means a cyclic amino group such as 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, etc.) Pyrido[1,2,3-de][1,4]benzoxazine It is useful as a raw material for producing derivatives. An example of the method for producing the compound of the present invention will be illustrated by a reaction formula and explained in Examples. Example: 2,3-difluoro-6-nitrophenol
7.0g, epichlorohydrin 7.0g, potassium carbonate
15 g and 600 mg of potassium iodide were added to 150 ml of dimethylformamide and stirred at a bath temperature of 85 to 90°C for 20 hours. After cooling, insoluble matters were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was washed with water, dried over Glauber's salt, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 2,3-difluoro-6-nitrophenyl oxiranylmethyl ether as a pale yellow oil.
Obtained 6.1g. 15.0 g of this compound and 0.3 ml of tin(II) chloride were added to 60 ml of anhydrous methanol, and the mixture was refluxed for 2 hours. The solvent was distilled off and the residue was partitioned between chloroform and water, and 16.1 g of 1-(2,3-difluoro-6-nitrophenoxy)-3-methoxy-2-propanol was obtained as an oil from the chloroform layer. Dissolve 15 g of this compound in 150 ml of acetone, stir under ice-cooling, and use Zion's reagent (chromic anhydride).
(adjusted from 32 g, 64 ml of water, and 16 ml of concentrated sulfuric acid) was added dropwise. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. Insoluble materials were removed, washed with acetone and then with chloroform, the filtrate and washing liquid were combined, and the solvent was distilled off. The residue was partitioned between chloroform and water, the chloroform layer was washed with water, dried over sodium sulfate, and then the chloroform was distilled off. The residue was purified by silica gel column chromatography and obtained from the chloroform eluate with a melting point of 39-42.
10.6 g of 1-(2,3-difluoro-6-nitrophenoxy)-3-methoxy-2-propanone was obtained. Elemental analysis value C 10 H 9 F 2 NO 5 Calculated value C 45.99, H 3.47, N 5.36 Analysis value C 45.79, H 3.26, N 5.29 Reference example Dissolve 9.5 g of the above compound in 100 ml of ethanol,
Add 10 ml of Raney Nickel and perform catalytic reduction at normal pressure. After filtering off the catalyst and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 3.9 g of an oil. Add 3.5 g of diethyl ethoxymethylenemalonate to 3.0 g of this oil and bath temperature 105
Heat at ~115°C for 2 hours. After cooling, the reaction product was purified by silica gel column chromatography, and the melting point was 81.
Diethyl (7,8-difluoro-3-methoxymethyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methylenemalonate at °C
Obtained 4.1g. Elemental analysis value C 18 H 21 F 2 NO 6 Calculated value C 56.10, H 5.49, N 3.64 Analysis value C 56.25, H 5.47, N 3.74 Add 3.0 g of the above compound to 20 g of ethyl polyphosphate and bath temperature 120-125℃ Heat for 1.5 hours. After cooling, ice water is added and the precipitate is extracted with chloroform. The extract is washed with water, dried with Glauber's salt, and then the solvent is distilled off. The residue was purified by silica gel column chromatography, and the powder obtained from the chloroform eluate was recrystallized from a mixture of dichloromethane and isopropyl ether to give microneedles with a melting point of 238°C9.
10-difluoro-3-ethoxymethyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,
1.7 g of ethyl 3-de][1,4]benzoxazine-6-carboxylate was obtained. Add 1.7g of the above compound to 100ml of dichloromethane and add 6.0g of aluminum bromide to ethanethiol under ice cooling.
Drop the solution in 10 ml. After returning to room temperature and stirring for 3 hours, the solvent was distilled off, ice water was added to the residue, and insoluble matter was filtered off. The obtained white powder was recrystallized from a mixture of chloroform and ethanol to obtain microneedled 9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrid[1] with a melting point of 268-270°C. ,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl 1.1 g was obtained. Dissolve 400 mg of the above compound in 30 ml of chloroform, add 3 ml of thionyl chloride, and reflux for 4 hours.
The reaction solution was dried under reduced pressure, and the residue was dissolved in chloroform, washed successively with water, an aqueous sodium bicarbonate solution, and water, and dried over Glauber's salt. The solvent was distilled off, and the residue was recrystallized from a mixture of chloroform and ethanol to form 3-chloromethyl-
9,10-difluoro-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]
Ethyl benzoxazine-6-carboxylate 220mg
I got it. 200 mg of the above compound was suspended in 30 ml of anhydrous benzene, 230 mg of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) was added, and the mixture was refluxed for 1 hour. After cooling, add chloroform to the reaction solution and wash with water.
Dry with Glauber's salt. The solvent was distilled off, the residue was purified by silica gel column chromatography, and recrystallized from a mixture of dichloromethane and isopropyl ether to give 9,10-difluoro-3-methylene-7-oxo-2,3 with a melting point of 258-263°C. 120 mg of ethyl -dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate was obtained. NMR (DMSO-d 6 , δppm) Methylene group at 3-position; 5.47, 5.89 (1H, d, J = 2.5Hz each) 100mg of the above compound was dissolved in 3ml of dimethyl sulfoxide.
Add 100 mg of N-methylpiperazine and stir at a bath temperature of 120-130°C for 6 hours. After cooling, the solvent is dried under reduced pressure, and the residue is purified by silica gel column chromatography. 100 mg of the obtained powder is suspended in 10 ml of ethanol, 1 ml of 3% aqueous sodium hydroxide solution is added, and the mixture is stirred at 40 to 50°C for 30 minutes. The reaction solution was dried under reduced pressure, water was added to the residue, acidified with dilute hydrochloric acid, and then made basic again with sodium hydrogen carbonate.
Extract with chloroform. The extract was dried with Glauber's salt and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallized from ethanol to give 9-fluoro-10-(4-methyl-1-piperazinyl)-3-methylene-7-oxo as microneedles with a melting point of 200-201°C. -2,3-dihydro-7H-
25 mg of pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid was obtained. NMR (CDCl 3 , δppm) 4.83 (2H, s, 2nd place CH 2 ) 5.26, 5.61 (1H, d, J = 3.0Hz each, 3rd place C
= CH 2 ) 8.83 (1H, s, 5th H) 7.63 (1H, d, J = 12Hz, 8th H)
Claims (1)
OCH3または【式】を意味する） で表わされる化合物 ２ ２，３−ジフルオロ−６−ニトロフエニル・
オキシラニルメチル・エーテルである特許請求の
範囲第１項の化合物 ３ １−（２，３−ジフルオロ−６−ニトロフエ
ノキシ）−３−メトキシ−２−プロパノールであ
る特許請求の範囲第１項の化合物 ４ １−（２，３−ジフルオロ−６−ニトロフエ
ノキシ）−３−メトキシ−２−プロパノンである
特許請求の範囲第１項の化合物[Claims] 1 formula (In the formula, Q is −COCH 2 OCH 3 , −CH(OH)CH 2
OCH 3 or [Formula]) Compound 2 2,3-difluoro-6-nitrophenyl
Compound 3 of claim 1 which is oxiranyl methyl ether Compound 3 of claim 1 which is 1-(2,3-difluoro-6-nitrophenoxy)-3-methoxy-2-propanol 4. The compound of claim 1 which is 1-(2,3-difluoro-6-nitrophenoxy)-3-methoxy-2-propanone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20543989A JPH02152947A (en) | 1989-08-08 | 1989-08-08 | Difluorophenoxy compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20543989A JPH02152947A (en) | 1989-08-08 | 1989-08-08 | Difluorophenoxy compound |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57112040A Division JPS591489A (en) | 1982-06-29 | 1982-06-29 | Pyridobenzoxazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02152947A JPH02152947A (en) | 1990-06-12 |
| JPH0518816B2 true JPH0518816B2 (en) | 1993-03-15 |
Family
ID=16506895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20543989A Granted JPH02152947A (en) | 1989-08-08 | 1989-08-08 | Difluorophenoxy compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02152947A (en) |
-
1989
- 1989-08-08 JP JP20543989A patent/JPH02152947A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02152947A (en) | 1990-06-12 |
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