JPH024222B2 - - Google Patents
Info
- Publication number
- JPH024222B2 JPH024222B2 JP18763885A JP18763885A JPH024222B2 JP H024222 B2 JPH024222 B2 JP H024222B2 JP 18763885 A JP18763885 A JP 18763885A JP 18763885 A JP18763885 A JP 18763885A JP H024222 B2 JPH024222 B2 JP H024222B2
- Authority
- JP
- Japan
- Prior art keywords
- difluoro
- methyl
- dihydro
- solvent
- distilled
- 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
- -1 (7,8-difluoro-3-methyl-2,3 -dihydro-4H-1,4-benzoxazine- 4-yl) methylene malonic acid Chemical compound 0.000 claims description 6
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000010446 mirabilite Substances 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 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
- 239000000243 solution Substances 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
- 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 2
- 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 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 2
- XNSXXTKUKYWLAH-UHFFFAOYSA-N diethyl 2-(dimethylaminomethylidene)propanedioate Chemical compound CCOC(=O)C(=CN(C)C)C(=O)OCC XNSXXTKUKYWLAH-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000003756 stirring Methods 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
- ZADJRGYAXJDFGT-UHFFFAOYSA-N 7,8-difluoro-3-methyl-3,4-dihydro-2h-1,2-benzoxazine Chemical compound C1=C(F)C(F)=C2ONC(C)CC2=C1 ZADJRGYAXJDFGT-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
- XBMWHBCGUKOIGL-UHFFFAOYSA-N 7,8-difluoro-3-methyl-3,4-dihydro-2h-1,4-benzoxazine;hydrochloride Chemical compound Cl.FC1=CC=C2NC(C)COC2=C1F XBMWHBCGUKOIGL-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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- ASGJEMPQQVNTGO-UHFFFAOYSA-N benzene chloroform Chemical compound C(Cl)(Cl)Cl.C1=CC=CC=C1.C1=CC=CC=C1 ASGJEMPQQVNTGO-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- BQHDXNZNSPVVKB-UHFFFAOYSA-N diethyl 2-methylidenepropanedioate Chemical compound CCOC(=O)C(=C)C(=O)OCC BQHDXNZNSPVVKB-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
本発明は(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)メチレンマロン酸ジ低級アルキ
ルエステルに関する。
このものは、極めて優れた抗菌薬として知られ
るオフロキサシン(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)の製造に有用である。
本発明化合物の製造法は次のごとくである。
すなわち、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、2,3−ジフルオロ−6−ニトロフエノー
ルが収率よく得られる。次いで脱酸剤として炭酸
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−・ニツケル、パラ
ジウム炭等の触媒の存在下常圧で接触覇還元する
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
−ベンゾオキサジンが収率よく生成する。
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反応させると、高収率で目
的物の(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が得られ
る。
この化合物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、酸または塩基と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−カルボン酸が得られ、このものを
N−メチルピペラジンと加熱反応させるとオフロ
キサシンが高収率で得られる。
(特開昭57−46986号および特開昭58−72588号
公報参照)。
実施例 1
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〓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
液を水洗し、芒硝で乾燥後、クロロホルムを留去
し、融点61℃の2,3−ジフルオロ−6−ニトロ
フエノール16.9g(85.5%)を得た。
元素分析値C6H3F2NO3として
計算値C41.16,H1.73,N8.00
分析値C40.95,H1.75,N3.22
上記化合物5.8g、モノクロルアセトン5.0g、
炭酸カリウム8.0gおよび沃化カリウム0.8gをア
セトン100mlに加えて4時間還流する。冷後、不
溶物を濾去し、溶媒を留去して残渣をベンゼンに
溶かし、水洗後、芒硝で乾燥する。溶媒を留去し
て油状物の2−アセトニルオキシ−3,4−ジフ
ルオロニトロベンゼン6.2g(18.0%)を得た。
元素分析値C9H7F2NO4として
計算値C46.76,H3.05,N6.06
分析値C46.49,H2.96,N5.95
上記化合物5.0gをエタノール50mlに溶かし、
ラネー・ニツケル5mlを加えて常圧で接触還元す
る。理論量の水素を吸収させたのち、触媒を濾去
し溶媒を留去する。残渣をベンゼンに溶かし、6
%塩酸と振盪すると7,8−ジフルオロ−3−メ
チル−2,3−ジヒドロ−4H−1,4−ベンゾ
オキサジン塩酸塩が析出するのでこれを濾取し
た。融点182〜185℃、3.5g(73.2%)。
上記塩酸塩2.0gおよびジメチルアミノメチレ
ンマロン酸ジエチル2.5gを氷酢酸20mlに加え、
80〜90℃で5時間撹拌する。溶媒を減圧留去し、
残渣をシリカゲルクロマトグラフイーで精製し、
ベンゼン−クロロホルム(3:2)で溶出する部
分から油状物として(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)メチレンマロン酸ジエ
チル2.4g(74.8%)を得た。
元素分析値C17H19F2NO5として
計算値C57.46,H5.39,N3.94
分析値C57.15,H5.35,N3.91
NMRδ6ppm(CDCl3):1.25および1.35(各々3H,
t,j=7.5Hz,2X−CH2CH 3)
1.32(3H,d,j=7.5Hz,
The present invention provides (7,8-difluoro-3-methyl-
2,3-dihydro-4H-1,4-benzoxazin-4-yl)methylenemalonic acid di-lower alkyl ester. 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). The method for producing the compound of the present invention is as follows. That is, when 2,3,4-trifluoronitrobenzene is stirred at room temperature in a solvent such as dimethyl sulfoxide or sulfolane in the presence of a strong base such as potassium hydroxide or sodium hydroxide, fluorine at the ortho position of the nitro group is dissolved. Atoms are selectively hydrolyzed to obtain 2,3-difluoro-6-nitrophenol in good yield. Then, 2,3-difluoro-6
- When nitrophenol is reacted with monochloroacetone and the resulting intermediate is catalytically reduced at normal pressure in the presence of a catalyst such as Raney-nickel or palladium on charcoal, an oxazine ring is formed, and 7,8-difluoro-3-methyl -2,3-dihydro-4H-1,4
- Benzoxazine is produced in good yield. When this compound is heated as a free base or as an inorganic acid salt such as hydrochloride and reacted with dimethylaminomethylene malonic acid ester, the desired product (7,8-difluoro-3-methyl-2,
3-dihydro-4H-1,4-benzoxazin-4-yl)methylene malonic acid ester is obtained. Heating this compound in polyphosphoric acid or its ester results in a pyridine ring closure reaction, which is then treated with an acid or base to hydrolyze the ester of the carboxylic acid, resulting in 9,10-difluoro-3
-Methyl-7-oxo-2,3-dihydro-7H
-Pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid is obtained, and when this is heated and reacted with N-methylpiperazine, ofloxacin is obtained in high yield. (Refer to JP-A-57-46986 and JP-A-58-72588). Example 1 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 Glauber's salt, and then chloroform was distilled off to obtain 16.9 g (85.5%) of 2,3-difluoro-6-nitrophenol with a melting point of 61°C. Elemental analysis value C 6 H 3 F 2 NO 3 Calculated value C41.16, H1.73, N8.00 Analysis value C40.95, H1.75, N3.22 5.8 g of the above compound, 5.0 g of monochloroacetone,
8.0 g of potassium carbonate and 0.8 g of potassium iodide are added to 100 ml of acetone and refluxed for 4 hours. After cooling, insoluble materials are filtered off, the solvent is distilled off, and the residue is dissolved in benzene, washed with water, and dried over Glauber's salt. The solvent was distilled off to obtain 6.2 g (18.0%) of 2-acetonyloxy-3,4-difluoronitrobenzene as an oil. Elemental analysis value C 9 H 7 F 2 NO 4 Calculated value C46.76, H3.05, N6.06 Analysis value C46.49, H2.96, N5.95 Dissolve 5.0 g of the above compound in 50 ml of ethanol,
Add 5 ml of Raney Nickel and perform catalytic reduction at normal pressure. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is distilled off. Dissolve the residue in benzene, 6
% hydrochloric acid to precipitate 7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazine hydrochloride, which was collected by filtration. Melting point 182-185°C, 3.5g (73.2%). Add 2.0 g of the above hydrochloride and 2.5 g of diethyl dimethylaminomethylenemalonate to 20 ml of glacial acetic acid,
Stir at 80-90°C for 5 hours. Remove the solvent under reduced pressure,
The residue was purified by silica gel chromatography,
(7,8-difluoro-3-
2.4 g (74.8%) of diethyl methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methylenemalonate was obtained. Elemental analysis value C 17 H 19 F 2 NO 5 Calculated value C57.46, H5.39, N3.94 Analysis value C57.15, H5.35, N3.91 NMRδ6ppm (CDCl 3 ): 1.25 and 1.35 (respectively ,
t, j = 7.5Hz, 2X-CH 2 C H 3 ) 1.32 (3H, d, j = 7.5Hz,
【式】) 3.90〜4.44(7H,m,【formula】) 3.90~4.44 (7H, m,
【式】およ
び2XCH 2CH3)
6.68〜6.90(2H,m,芳香核プロトン)
7.76(1H,s,−N−CH=C(COO)2)
実施例 2
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をエタノール5mlに溶かし、
ラネー・ニツケル5mlを加えて常圧で接触還元す
る。理論量の水素を吸収させたのち、触媒を濾去
し、溶媒を留去する。残渣をベンゼンに溶かし、
10%塩酸と振とうする。析出物を生じたら10%塩
酸を追加する。水層は10%水酸化ナトリウム水溶
液でアルカリ性とし、ベンゼンで抽出する。ベン
ゼン層は水洗し芒硝で乾燥したのち溶媒を留去す
ると油状物として7,8−ジフルオロ−3−メチ
ル−2,3−ジヒドロ−4H−ベンゾオキサジン
2.56g(64%)が得られる。
上記化合物0.60gおよびジメチルアミノメチレ
ンマロン酸ジエチル0.80gを氷酢酸5mlに加え、
80〜90℃で6時間撹拌する。溶媒を留去し、残渣
をシリカゲルクロマトグラフイーで精製し、ベン
ゼン−クロロホルム(3:2)で溶出する部分か
ら、油状物として(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)メチレンマロン酸ジエチ
ル0.78g(67.7%)を得た。
参考例
(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)メチレンマロン酸ジエチル2.0gをポリ
リン酸エチル20gに加えて140〜145℃で1.5時間
撹拌する。反応液を氷水にあけ、析出物をクロロ
ホルムで抽出する。抽出液は5%炭酸カリウム水
溶液、ついで水で洗浄し、芒硝乾燥後溶媒を留去
して融点261℃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−カルボン酸エチル1.30g(74.6%)を得
た。
元素分析値C15H13F2NO4として
計算値C58.25,H4.24,N4.53
分析値C58.16,H4.33、N4.38[Formula] and 2XC H 2 CH 3 ) 6.68-6.90 (2H, m, aromatic nucleus proton) 7.76 (1H, s, -N-C H = C(COO) 2 ) Example 2 Dissolve 5.0 g of 2-acetonyloxy-3,4-difluoronitrobenzene in 5 ml of ethanol,
Add 5 ml of Raney Nickel and perform catalytic reduction at normal pressure. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is distilled off. Dissolve the residue in benzene,
Shake with 10% hydrochloric acid. If a precipitate appears, add 10% hydrochloric acid. The aqueous layer is made alkaline with a 10% aqueous sodium hydroxide solution and extracted with benzene. The benzene layer was washed with water, dried with Glauber's salt, and the solvent was distilled off, leaving 7,8-difluoro-3-methyl-2,3-dihydro-4H-benzoxazine as an oil.
2.56 g (64%) is obtained. Add 0.60 g of the above compound and 0.80 g of diethyl dimethylaminomethylenemalonate to 5 ml of glacial acetic acid,
Stir at 80-90°C for 6 hours. The solvent was distilled off, the residue was purified by silica gel chromatography, and the fraction eluted with benzene-chloroform (3:2) was extracted as an oil (7,8-difluoro-3-methyl-2,3-dihydro- 0.78 g (67.7%) of diethyl 4H-1,4-benzoxazin-4-yl)methylenemalonate was obtained. Reference example (7,8-difluoro-3-methyl-2,3-
Dihydro-4H-1,4-benzoxazine-4
2.0 g of diethyl methylene malonate is added to 20 g of ethyl polyphosphate and stirred at 140-145°C for 1.5 hours. Pour the reaction solution into ice water and extract the precipitate with chloroform. The extract was washed with a 5% aqueous potassium carbonate solution and then with water, dried with mirabilite, and the solvent was distilled off to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H- with a melting point of 261°C. 1.30 g (74.6%) of ethyl pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate was obtained. Elemental analysis value C 15 H 13 F 2 NO 4 Calculated value C58.25, H4.24, N4.53 Analysis value C58.16, H4.33, N4.38
Claims (1)
−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低級アルキルエス
テル。1 (7,8-difluoro-3-methyl-2,3
-dihydro-4H-1,4-benzoxazine-
4-yl) methylene malonic acid di-lower alkyl ester.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP18763885A JPS61246172A (en) | 1985-08-27 | 1985-08-27 | Benzoxazinylmalonic acid derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP18763885A JPS61246172A (en) | 1985-08-27 | 1985-08-27 | Benzoxazinylmalonic acid derivative |
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 |
---|---|
JPS61246172A JPS61246172A (en) | 1986-11-01 |
JPH024222B2 true JPH024222B2 (en) | 1990-01-26 |
Family
ID=16209614
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP18763885A Granted JPS61246172A (en) | 1985-08-27 | 1985-08-27 | Benzoxazinylmalonic acid derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS61246172A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2573269B2 (en) * | 1986-12-25 | 1997-01-22 | 第一製薬株式会社 | Optically active benzoxazine |
-
1985
- 1985-08-27 JP JP18763885A patent/JPS61246172A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS61246172A (en) | 1986-11-01 |
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