JPH02138268A - Benzoxazine compound - Google Patents
Benzoxazine compoundInfo
- Publication number
- JPH02138268A JPH02138268A JP20544089A JP20544089A JPH02138268A JP H02138268 A JPH02138268 A JP H02138268A JP 20544089 A JP20544089 A JP 20544089A JP 20544089 A JP20544089 A JP 20544089A JP H02138268 A JPH02138268 A JP H02138268A
- Authority
- JP
- Japan
- Prior art keywords
- difluoro
- chloroform
- benzoxazine
- residue
- water
- 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.)
- Granted
Links
- -1 Benzoxazine compound Chemical class 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 12
- 239000007868 Raney catalyst Substances 0.000 abstract description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract description 2
- 229910000564 Raney nickel Inorganic materials 0.000 abstract 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 abstract 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 abstract 1
- PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical class C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-UHFFFAOYSA-N 0.000 abstract 1
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 238000004587 chromatography analysis Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 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 13
- 239000002904 solvent Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 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
- 239000000243 solution Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000010446 mirabilite Substances 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 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 3
- 235000011152 sodium sulphate Nutrition 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000013078 crystal Substances 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
- 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
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 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 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
- 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
- 239000003810 Jones reagent Substances 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000005130 benzoxazines Chemical class 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
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000001914 filtration Methods 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
- 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 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
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
【発明の詳細な説明】
産業 の
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。DETAILED DESCRIPTION OF THE INVENTION This invention relates to compounds useful as raw materials for antimicrobial compounds.
一見豆立盗五一
本発明はく７．８−ジフルオロ−３−メトキシメチル−
２，３−ジヒドロ−４）１−１．４−ベンゾオキサジン
−４−イル）メチレンマロン酸ジ低級アルキルエステル
に関し、このものはピリド［１，２，３−ｄｅｌ ［１
，４１ベンゾオキサジン誘導体の製造原料として有用で
ある。At first glance, the present invention is 7.8-difluoro-3-methoxymethyl-
2,3-dihydro-4)1-1.4-benzoxazin-4-yl)methylene malonic acid di-lower alkyl ester, which is a pyrido[1,2,3-del[1
, 41 is useful as a raw material for producing benzoxazine derivatives.
本発明化合物の製造法を実施例で説明する。The method for producing the compound of the present invention will be explained in Examples.
実施例
１− （２，３−ジフルオロ−６−二トロフエノキシ）
−３−メトキシ−２−プロパノン９．５ｇをエタノール
１００ｍ１に溶かし、ラネー・ニッケル１０＋ｓｌを加
えて常圧で接触還元した。触媒を濾去し、溶媒を減圧留
去後残渣をシリカゲルカラムクロマトグラフィで精製し
て油状物３．９８を得た。この油状物３．０８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１０
５〜１１５℃で２時間加熱した。冷後、反応物をシリカ
ゲルカラムクロマトグラフィで精製し融点８１℃の（７
，８−ジフルオロ−３−メトキシメチル−２，３−ジヒ
ドロ−４８−１，４−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。Example 1- (2,3-difluoro-6-nitrophenoxy)
9.5 g of -3-methoxy-2-propanone was dissolved in 100 ml of ethanol, 10+ sl of Raney nickel was added, and catalytic reduction was carried out at normal pressure. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.98% of an oil. Add 3.5 g of diethyl ethoxymethylenemalonate to 3.08 g of this oil, and add the bath temperature to 10 g.
Heated at 5-115°C for 2 hours. After cooling, the reaction product was purified by silica gel column chromatography to obtain a solution with a melting point of 81°C (7
, 8-difluoro-3-methoxymethyl-2,3-dihydro-48-1,4-benzoxazin-4-yl)methylenemalonate (4.1 g) was obtained.
元素分析値 Ｃ５ａ）１２＋ＦｚＮＯｓとして計算値
Ｃ５６，１Ｇ、 Ｈ５，４９，Ｎ ３．６４分析値 Ｃ
５６，２５，Ｈ５，４フ、 Ｎ ３．７４参考例１
２．３−ジフルオロ−６−二トロフエノール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
１５０ｍ１に加え、浴温８５〜９０℃で２０時間攪拌す
る。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する。クロロホルム層は水洗し
、芒硝で乾燥後、溶媒を留去して残漬をシリカゲルカラ
ムクロマトグラフィで精製し淡黄色油状物として２．３
−ジフルオロ−６−二トロフエニル・オキシラニルメチ
ル・エーテル６．１ｇを得た。Elemental analysis value C5a) Calculated value as 12+FzNOs
C56,1G, H5,49,N 3.64 analysis value C
56,25,H5,4 ph, N 3.74 Reference example 1 2.3-difluoro-6-nitrophenol 7.0 g,
7.0 g of epichlorohydrin, 15 g of potassium carbonate, and 600 mg of potassium iodide were dissolved in dimethylformamide.
150ml and stirred for 20 hours at a bath temperature of 85-90°C. 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 with Glauber's salt, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give a pale yellow oil (2.3).
6.1 g of -difluoro-6-nitrophenyl oxiranylmethyl ether was obtained.
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８０ｍ１に加えて２時間還流する。溶媒
を留去し残漬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！−（２，３−ジフルオロ−６
−ニトロフェノキシ）−３−メトキシ−２−プロパツー
ル１１ｉ、１ｇを得た。15.0 g of this compound and 0.3 ml of stannic chloride were added to 80 ml of anhydrous methanol, and the mixture was refluxed for 2 hours. The solvent is distilled off and the residue is distributed between chloroform and water, and from the chloroform layer, an oil is obtained! -(2,3-difluoro-6
-Nitrophenoxy)-3-methoxy-2-propatool 11i, 1 g was obtained.
この化合物１５ｇをアセトン１５０ｍ１にとかし、水冷
下、攪拌しつつジョーンズ試薬（無水クロム酸３２ｇ、
水６４ｍ１、濃硫酸１６ｍ１から調製） ５０ｍ１を滴
下し同温度で３０分、次いで室温で２時間攪拌する。不
溶物を除去し、アセトン、次いでクロロホルムで洗って
、濾液及び洗液を合わせ溶媒を留去する。15 g of this compound was dissolved in 150 ml of acetone, and while stirring under water cooling, Jones reagent (chromic anhydride 32 g,
50 ml (prepared from 64 ml of water and 16 ml of concentrated sulfuric acid) was added dropwise and stirred at the same temperature for 30 minutes, then at room temperature for 2 hours. Insoluble matters were removed, washed with acetone and then with chloroform, the filtrate and washing liquid were combined, and the solvent was distilled off.
残漬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する。残漬をシ
リカゲルカラムクロマトグラフィで精製し、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−ニトロフェノキシ）−３−メトキシ−２−
プロパノン１０．６ｇを得た。The remaining residue is divided between chloroform and water, the chloroform layer is washed with water, dried over sodium sulfate, and the chloroform is distilled off. The residue was purified by silica gel column chromatography, and 1-(2,3-difluoro-6-nitrophenoxy)-3-methoxy-2- with a melting point of 39-42°C was obtained from the chloroform eluate.
10.6 g of propanone was obtained.
参考例２
（７，８−ジフルオロ−３−メトキシメチル−２，３−
ジヒドロ−４８−１，４−ベンゾオキサジン−４−イル
）メチレンマロン酸ジエチル３．０ｇをポリリン酸エチ
ル２０８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、芒硝乾燥後溶媒を留去する。Reference example 2 (7,8-difluoro-3-methoxymethyl-2,3-
3.0 g of diethyl dihydro-48-1,4-benzoxazin-4-yl)methylenemalonate is added to ethyl polyphosphate 208 and heated at a bath temperature of 120 to 125°C for 1.5 hours. After cooling, ice water is added and the precipitate is extracted with chloroform. The extract is washed with water, dried over sodium sulfate, and then the solvent is distilled off.
残漬をシリカゲルカラムクロマトグラフィで精製し、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２３
８℃の徴針晶とじて９．１０−ジフルオロ−３−メトキ
シメチル−７−オキソ−２，３−ジヒドロ−７Ｈ−とリ
ド［１、２、３−ｄｅｌ ［１、４］ ベンゾオキサジ
ン−６−カルボン酸エチル１．７ｇを得た。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 a melting point of 23.
9.10-difluoro-3-methoxymethyl-7-oxo-2,3-dihydro-7H- and lido[1,2,3-del[1,4]benzoxazine-6 at 8°C. -1.7 g of ethyl carboxylate was obtained.
上記化合物１．７ｇをジクロルメタン１００ｍ１に加え
て水冷下に臭化アルミニウム６．０ｇをエタンチオール
１０ｍ１に溶かした溶液を滴下する。室温にもどして３
時間攪拌したのち、溶媒を留去し、残漬に氷水を加えて
不溶物を濾取する。得られ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て融点２６８〜２７０℃
の徴針晶として９．ｌＱ−ジフルオロ−３−ヒドロキシ
メチル−７−オキソ−２，３−ジヒド０−７Ｈ−ピリド
［１，２，３−ｄｅｌ ［１，４］ ベンゾオキサジン
−６−カルボン酸エチル１．１８を得た。1.7 g of the above compound was added to 100 ml of dichloromethane, and a solution of 6.0 g of aluminum bromide dissolved in 10 ml of ethanethiol was added dropwise while cooling with water. Return to room temperature 3
After stirring for an hour, the solvent is distilled off, ice water is added to the residue, and insoluble matter is filtered off. The obtained white powder was recrystallized from a mixture of chloroform and ethanol to a melting point of 268-270°C.
9. As a needle crystal. lQ-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro0-7H-pyrido[1,2,3-del[1,4] ethyl benzoxazine-6-carboxylate 1.18 was obtained .
上記化合物４００ｍｇをクロロホルム３０ｍ１に溶かし
これに塩化チオニル３ｍｌを加えて４時間遠流し、反応
液を減圧乾固し、残漬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’Ｃの徴針晶
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−７）１−ピリド［１，２，
３−ｄｅｌ ［１，４］ベンゾオキサジン−６−カルボ
ン酸エチル２２０ｍｇを得た。Dissolve 400 mg of the above compound in 30 ml of chloroform, add 3 ml of thionyl chloride, and centrifuge for 4 hours. The reaction solution is dried under reduced pressure. The residue is dissolved in chloroform, washed sequentially with water, an aqueous sodium bicarbonate solution, and water, and washed with sodium sulfate. dry. The solvent was distilled off, and the residue was recrystallized from a mixture of chloroform and ethanol to give 3-chloromethyl-9,10-difluoro-7- as needle crystals with a melting point of 250-251'C.
oxo-2,3-dihydro-7)1-pyrido[1,2,
220 mg of ethyl 3-del[1,4]benzoxazine-6-carboxylate was obtained.
上記化合物２００ｍｇを無水ベンゼン３０ｍ１に懸濁さ
せ、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時間遠流する
。冷後反応液にクロロホルムを加えて水洗し、芒硝乾燥
後溶媒を留去し、残渣をシリカゲルカラムクロマトグラ
フィで精製し、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て融点２５８〜２６３℃の９．１０
−ジフルオロ−３−メチレン−ツーオキソ−２，３−ジ
ヒドロ−７Ｈ−ピリド［１，２，３−ｄｅｌ ［１，４
］−ベンゾオキサジン−６−カルボン酸エチル１２０１
１１ｇを得た。200 mg of the above compound is suspended in 30 ml of anhydrous benzene, 230 mg of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) is added, and the suspension is centrifuged for 1 hour. After cooling, chloroform was added to the reaction solution and washed with water. After drying 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 obtain a 9.10% solution with a melting point of 258-263°C.
-difluoro-3-methylene-twooxo-2,3-dihydro-7H-pyrido [1,2,3-del [1,4
]-ethyl benzoxazine-6-carboxylate 1201
11 g was obtained.
ＮＭＲ（ＤＭＳＯ−ｄａ 、δｐｐｍ）３位メチレン基
； ５．４７．５．８９（各ＩＨ，ｄ、 Ｊ−２，５）
１２）
上記化合物１００＋ｏｇをジメチルスルホキシド３１Ｉ
ｌｌに溶かし、Ｎ−メチルビペラジン １００ｍｇをカ
ロえてン谷温１２０〜１３０℃で６時間攪拌する。冷後
、溶媒を減圧乾固し、残漬をシリカゲルカラムクロマト
グラフィで精製する。得られた粉末１００ｍｇをエタノ
ール１００１１に懸濁し、濾水酸化ナトリウム水溶液１
ＩＩｌｌを加えて４０〜５０℃で３０分間攪拌する０反
応液を減圧乾固し、残漬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ィで精製し
、エタノールから再結晶して融点２００〜２０１ｔ：の
徴針晶として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 (DMSO-da, δppm) 3-position methylene group; 5.47.5.89 (each IH, d, J-2, 5)
12) Add 100+og of the above compound to dimethyl sulfoxide 31I
Add 100 mg of N-methylbiperazine and stir at a temperature of 120 to 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 was suspended in ethanol 10011, and a filtered sodium hydroxide aqueous solution 1
The reaction mixture is stirred at 40 to 50° C. for 30 minutes and dried to dryness under reduced pressure. Water is added to the residue, made acidic with dilute hydrochloric acid, made basic again with sodium bicarbonate, and extracted 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-2,3-
Dihydro-7H-pyrido [1,2,3-de] [1,
4] 25 mg of benzoxazine-6-carboxylic acid was obtained.
ＮＭＲ（ＣＤＣＩｓ、δｐｐｍ）
４．８３（２８，ｓ、 ２位Ｃ１，）５．２６．５．
６１ （各ｌＨ，ｄ、 Ｊ−３，０）１ｚ、３位Ｃ−Ｃ
Ｈ２）８．８３ （ＩＨ，ｓ、５位Ｈ）NMR (CDCIs, δppm) 4.83 (28,s, 2nd place C1,) 5.26.5.
61 (each lH, d, J-3, 0) 1z, 3rd position C-C
H2) 8.83 (IH, s, 5th position H)
Claims (2)
る化合物(1) Compounds represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 means a lower alkyl group)
，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である特許請求の範
囲第１項の化合物(2) (7,8-difluoro-3-methoxymethyl-2
,3-dihydro-4H-1,4-benzoxazine-4
The compound of claim 1 which is diethyl-yl)methylenemalonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20544089A JPH02138268A (en) | 1989-08-08 | 1989-08-08 | Benzoxazine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20544089A JPH02138268A (en) | 1989-08-08 | 1989-08-08 | Benzoxazine 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 |
|---|---|
| JPH02138268A true JPH02138268A (en) | 1990-05-28 |
| JPH0331710B2 JPH0331710B2 (en) | 1991-05-08 |
Family
ID=16506912
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20544089A Granted JPH02138268A (en) | 1989-08-08 | 1989-08-08 | Benzoxazine compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02138268A (en) |
-
1989
- 1989-08-08 JP JP20544089A patent/JPH02138268A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0331710B2 (en) | 1991-05-08 |
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