JPH0372073B2 - - Google Patents
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- Publication number
- JPH0372073B2 JPH0372073B2 JP18813883A JP18813883A JPH0372073B2 JP H0372073 B2 JPH0372073 B2 JP H0372073B2 JP 18813883 A JP18813883 A JP 18813883A JP 18813883 A JP18813883 A JP 18813883A JP H0372073 B2 JPH0372073 B2 JP H0372073B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- methyl
- reaction
- chelate
- acid
- 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
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- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000013522 chelant Substances 0.000 claims description 21
- 238000000354 decomposition reaction Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000013078 crystal Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000004327 boric acid Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 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 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- -1 boric acid carboxylic acid anhydride Chemical class 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RVKFAZOWOXLAEC-UHFFFAOYSA-N acetyloxyboronic acid Chemical compound CC(=O)OB(O)O RVKFAZOWOXLAEC-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000006386 neutralization 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
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-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
- TZSXJUSNOOBBOP-UHFFFAOYSA-N ac1mwmhd Chemical compound CC1COC2=C(F)C(F)=CC3=C2N1C=C(C(=O)OCC)C3=O TZSXJUSNOOBBOP-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- JKWMSGQKBLHBQQ-UHFFFAOYSA-N diboron trioxide Chemical compound O=BOB=O JKWMSGQKBLHBQQ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Description
本発明は、式
（式中、X1及びX2は同じ又は異なるハロゲン
原子を、R1は水素原子又はアルキル基を、R2及
びR3は同じ又は異なつてアリール基、アルキル
基又はハロゲノアルキル基を意味する）で表わさ
れる化合物を式
（式中、Ｒは水素原子又はアルキル基を意味す
る）で表わされるピペラジン類と反応させて式
（式中、X1，R1，R2，R3及びＲは前記と同
じ）で表わされる化合物を製し、次いでこれをキ
レート分解することからなる式
（式中、X1，R1及びＲは前記に同じ）で表わ
される化合物の製法に関する。
式（）で表わされる化合物は、優れた抗菌作
用を有する物質であり（特開昭57−46986号公報
参照）、その製造法としてはBF2キレート化合物
を経由する方法（特開昭58−29789号公報及び特
開昭58−43977号公報参照）が知られている。
しかし、この方法は原料であるBF2キレート化
合物の製造過程において200℃以上という高温を
必要とすること、特殊な反応材質や装置を必要と
すること及び廃棄物として大量のフツ素系酸性化
合物が生成することなど工業的製法として必ずし
も満足すべきものではない。
本発明者は従来法のかかる欠点を克服すべく鋭
意検討した結果、本発明を完成した。
即ち、本発明は式（）の化合物にピペラジン
類を反応させて式（）の化合物を製し、次いで
これをキレート分解することからなる式（）の
化合物の製法である。
原料である式（）の化合物は式
（式中、X1，X2及びR1は前記に同じであり、
R5は水素原子又はアルキル基を意味する）で表
わされる化合物に式
（式中、R2及びR3は前記に同じであり、R4は
R2及びR3と同じ又は異なつてアリール基、アル
キル基又はハロゲノアルキル基を意味する）で表
わされるホウ酸カルボン酸無水物を反応させるこ
とにより得られる。
ホウ酸カルボン酸無水物は、三つのアシル基が
互いに異なつているものでもよいが、通常は三つ
のアシル基が同一であるものが使用される。
そのアシル基としてはアルキルカルボニル基、
ハロゲノアルキルカルボニル基及びアリールカル
ボニル基があげられる。アルキルカルボニル基の
具体例としてはアセチル基、プロピオニル基及び
ブチリル基等が、ハロゲノアルキルカルボニル基
の具体例としてはトリフルオロアセチル基等が、
更にアリールカルボニル基の具体例としてはベン
ゾイル基等があげられる。
ホウ酸カルボン酸無水物はホウ酸又は無水ホウ
酸に酸無水物を反応させるかもしくはホウ酸に酸
塩化物を反応させることにより得られるが、これ
を単離することなく反応液のままで使用すること
も可能である。
得られた式（）の化合物は、脱酸剤の存在下
式（）のピペラジン類との反応により、式
（）の化合物に導かれる。
該反応は、通常室温〜40℃の温度範囲で１〜15
時間好ましくは４〜５時間保つことにより実施さ
れる。
脱酸剤としてはトリエチルアミン及びトリブチ
ルアミン等の有機アミン並びに炭酸カリウム及び
炭酸ナトリウム等の無機塩基があげられる。脱酸
剤の使用量は式（）の化合物に対し通常１〜５
倍モルの範囲である。
使用される溶媒は極性溶媒であれば特に限定さ
れず、その例としては、アセトン、メチルエチル
ケトン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ
−ジメチルアセトアミド、ジメチルスルホキシ
ド、アセトニトリル、メタノール及びエチレンジ
クロリド等があげられる。また、脱酸剤が液体に
場合には、これを過剰に用いて溶媒として兼用す
ることも可能である。溶媒の使用量は式（）の
化合物１部に対し２〜20部（重量比）の範囲で充
分である。
生成した式（）の化合物は通常の分離手段例
えば濃縮、抽出、クロマトグラフイー及び再結晶
などにより単離精製されるが、単離することなく
反応混合物のまま次の反応に供給することも可能
である。
化合物（）は酸又は塩基で処理することによ
りキレートを分解させ、目的とする式（）の化
合物を生成させることができ、この分解反応は水
の存在下で行なうのが好ましい。
酸としては、塩酸及び硫酸等の鉱酸並びに酢酸
及びトシル酸の有機酸があげられる。又塩基とし
ては水酸化ナトリウム及び水酸化カリウム等の無
機塩基並びにトリエチルアミン等の有機塩基があ
げられる。酸及び塩基の使用量は式（）の化合
物に対し通常１〜10倍モルの範囲で充分である。
溶媒としては特に限定されず含水溶媒が好適に
使用され、その使用量は式（）の化合物１部に
対し２〜20部の範囲（重量比）で充分である。
実際に該キレート分解反応を行なうには、前工
程の反応液から脱酸剤を除去したものもしくは反
応液そのものに、酸及び水あるいは塩基及び水を
加えて実施するのが適当であり、またこれらの混
合物にアセトン等を加えて反応を行なうと後処理
の面から有利である。
反応は室温で充分進行するが、通常室温から使
用溶媒の沸点の温度範囲で１分間〜15時間保つこ
とにより実施される。
生成した式（）の化合物は、濃縮、中和及び
晶析、濾取等の手段により塩又は遊離の状態で単
離される。塩として単離されたときは、これを弱
酸又は弱塩基と処理することにより遊離の化合物
に導くことができる。
以上述べたように本発明の方法を実施すること
により、高温を要せず、反応材質に対する腐食性
もなく更にフツ素系廃棄物も少なく、目的とする
式（）の化合物を高収率及び高純度で得ること
ができ、本発明は工業的にきわめて有用な方法で
ある。
次に実施例をあげて本発明を説明する。
参考例 １
ホウ酸10ｇ及び無水酢酸50ｇの混液を60〜70℃
に加温し、均一系とした後、30分間撹拌還流す
る。反応後副生する酢酸を留去し、残渣に石油エ
ーテルを加え析出する結晶を取し乾燥する。得
られた結晶の融点、IR及び元素分析値は既知の
ホウ酸酢酸無水物のものと一致した。収量30.4ｇ
（収率100％）
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〕ベンズオキサジン−６−カルボ
ン酸2.0ｇ、ホウ酸酢酸無水物2.0ｇ及び無水酢酸
10mlの混液を15分間撹拌還流する。反応後無水酢
酸を留去し、残渣に少量のアセトン及びイソプロ
ピルエーテルを加える。冷却後析出した結晶を濾
取し、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〕ベンズオキサジン−６−カル
ボン酸−Ｂ（OCOCH3）2−キレート2.91ｇを得る
（収率100％）
融点260〜265℃（分解）
Mass 410（M+）
NMR（CDCl3 IS：TMS）：δppm
1.70（3H，ｄ，−CH3）
1.95（6H，ｄ，
The present invention is based on the formula (In the formula, X 1 and X 2 are the same or different halogen atoms, R 1 is a hydrogen atom or an alkyl group, and R 2 and R 3 are the same or different and mean an aryl group, an alkyl group, or a halogenoalkyl group) The compound represented by the formula (In the formula, R means a hydrogen atom or an alkyl group) by reacting with a piperazine represented by the formula (In the formula, X 1 , R 1 , R 2 , R 3 and R are the same as above) and then chelate decomposition of this. The present invention relates to a method for producing a compound represented by the formula (wherein X 1 , R 1 and R are the same as above). The compound represented by the formula () is a substance with excellent antibacterial activity (see Japanese Patent Application Laid-Open No. 57-46986), and the method for producing it is via a BF 2 chelate compound (Japanese Patent Application Laid-Open No. 58-29789). (see Japanese Patent Laid-Open No. 58-43977) are known. However, this method requires high temperatures of over 200℃ in the manufacturing process of the raw material BF 2 chelate compound, requires special reaction materials and equipment, and produces large amounts of fluorine-based acidic compounds as waste. This is not necessarily satisfactory as an industrial manufacturing method. The present inventor completed the present invention as a result of intensive studies to overcome these drawbacks of the conventional method. That is, the present invention is a method for producing a compound of formula (), which comprises reacting a compound of formula () with a piperazine to produce a compound of formula (), and then chelate decomposition of this. The compound of formula () which is the raw material is the formula (In the formula, X 1 , X 2 and R 1 are the same as above,
R 5 means a hydrogen atom or an alkyl group) (In the formula, R 2 and R 3 are the same as above, and R 4 is
It can be obtained by reacting boric acid carboxylic acid anhydride represented by R 2 and R 3 , which are the same or different and mean an aryl group, an alkyl group, or a halogenoalkyl group. The boric acid carboxylic acid anhydride may have three acyl groups that are different from each other, but it is usually used that has the same three acyl groups. The acyl group is an alkylcarbonyl group,
Examples include halogenoalkylcarbonyl groups and arylcarbonyl groups. Specific examples of the alkylcarbonyl group include an acetyl group, propionyl group, and butyryl group, and specific examples of the halogenoalkylcarbonyl group include a trifluoroacetyl group.
Furthermore, a specific example of the arylcarbonyl group includes a benzoyl group. Boric acid carboxylic anhydride can be obtained by reacting boric acid or boric anhydride with an acid anhydride, or by reacting boric acid with an acid chloride, but it is used as a reaction solution without isolation. It is also possible to do so. The obtained compound of formula () is reacted with a piperazine of formula () in the presence of a deoxidizing agent to lead to a compound of formula (). The reaction is usually carried out in a temperature range of room temperature to 40°C for 1 to 15
This is carried out by keeping the temperature preferably for 4 to 5 hours. Examples of deoxidizers include organic amines such as triethylamine and tributylamine, and inorganic bases such as potassium carbonate and sodium carbonate. The amount of deoxidizing agent used is usually 1 to 5 for the compound of formula ().
It is in the double molar range. The solvent used is not particularly limited as long as it is a polar solvent, and examples include acetone, methyl ethyl ketone, N,N-dimethylformamide, N,N
-Dimethylacetamide, dimethylsulfoxide, acetonitrile, methanol and ethylene dichloride. Furthermore, when the deoxidizing agent is a liquid, it can also be used as a solvent by using an excess amount of the deoxidizing agent. The amount of solvent to be used is sufficient in the range of 2 to 20 parts (weight ratio) per 1 part of the compound of formula (). The generated compound of formula () can be isolated and purified by conventional separation methods such as concentration, extraction, chromatography, and recrystallization, but it is also possible to supply it as a reaction mixture to the next reaction without isolation. It is. Compound () can be treated with an acid or base to decompose the chelate to produce the desired compound of formula (), and this decomposition reaction is preferably carried out in the presence of water. Acids include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and tosylic acid. Examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as triethylamine. The amount of acid and base to be used is generally 1 to 10 times the molar amount of the compound of formula (). The solvent is not particularly limited, and a water-containing solvent is preferably used, and the amount used is sufficient in the range of 2 to 20 parts (weight ratio) per 1 part of the compound of formula (). In order to actually perform the chelate decomposition reaction, it is appropriate to add acid and water or a base and water to the reaction solution from the previous step after removing the deoxidizing agent or to the reaction solution itself. It is advantageous in terms of post-treatment to carry out the reaction by adding acetone or the like to the mixture. Although the reaction proceeds satisfactorily at room temperature, it is usually carried out by maintaining the reaction at a temperature ranging from room temperature to the boiling point of the solvent used for 1 minute to 15 hours. The produced compound of formula () is isolated in a salt or free state by means such as concentration, neutralization, crystallization, and filtration. When isolated as a salt, it can be led to the free compound by treatment with a weak acid or base. As described above, by carrying out the method of the present invention, high temperatures are not required, there is no corrosiveness to the reaction materials, there is less fluorine-based waste, and the target compound of formula () can be produced in high yield and It can be obtained with high purity, and the present invention is an extremely useful method industrially. Next, the present invention will be explained with reference to Examples. Reference example 1 A mixture of 10 g of boric acid and 50 g of acetic anhydride was heated at 60 to 70℃.
After heating to a homogeneous system, stir and reflux for 30 minutes. After the reaction, the by-product acetic acid is distilled off, petroleum ether is added to the residue, and the precipitated crystals are collected and dried. The melting point, IR and elemental analysis values of the obtained crystals were consistent with those of known boric acid acetic anhydride. Yield 30.4g
(Yield 100%) 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de][1,4]benzoxazine-6-carboxylic acid 2.0g, boric acid acetic anhydride 2.0g and acetic anhydride
Stir and reflux 10 ml of the mixture for 15 minutes. After the reaction, acetic anhydride is distilled off, and a small amount of acetone and isopropyl ether are added to the residue. After cooling, the precipitated crystals were collected by filtration, and 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,
Obtain 2.91 g of 3-de][1,4]benzoxazine-6-carboxylic acid-B (OCOCH 3 ) 2 -chelate (yield 100%) Melting point 260-265°C (decomposition) Mass 410 (M + ) NMR (CDCl 3 IS: TMS): δppm 1.70 (3H, d, -CH 3 ) 1.95 (6H, d,
【式】）
4.60（2H，ｄ，−CH2−）
5.20（1H，ｍ，CH−CH3）
7.90（1H，ｑ，８位 ＝CH−）
9.30（1H，ｓ，５位 ＝CH−）
参考例 ２
ホウ酸0.93ｇ及び無水プロピオン酸7.0ｇの混
液を70〜90℃で１時間撹拌する。反応後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〕ベンズオキサジン−６−カルボン酸エチルエ
ステル3.09ｇを加え、還流下１時間撹拌する。反
応後、無水プロピオン酸を留去し、少量のイソプ
ロピルエーテルを加え、析出する結晶を濾取しイ
ソプロピルエーテルで洗滌すると、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〕
ベンズオキサジン−６−カルボン酸−Ｂ
〔OCOCH2CH）2−キレート4.16ｇ（収率95.2％）
を得る。
融点275〜280℃（分解）
元素分析 C10H18BF2NO8
実測値 Ｃ 51.50，Ｈ 4.25，Ｎ 3.00
計算値 Ｃ 52.20，Ｈ 4.15，Ｎ 3.20
NMR（CDCl3 IS：TS）：δppm
1.10（6H，ｑ，−CH2−CH3）
1.70（3H，ｄ，−CH3）
2.40（4H，ｑ，−CH2−CH3）
4.60（2H，ｄ，−CH2−）
5.10（1H，ｍ，CH−CH3）
7.90（1H，ｑ，８位 ＝CH−）
9.30（1H，ｓ，５位 ＝CH−）
Mass 438（M+） MW：437.162
参考例 ３
ホウ酸0.93ｇ及び無水酩酸10ｇの混液を70〜90
℃で１時間撹拌する。反応後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〕ベンズ
オキサジン−６−カルボン酸エチルエステル3.09
ｇを加え還流下１時間撹拌する。反応後無水酩酸
を留去し、少量のイソプロピルエーテルを加え析
出する結晶を濾取しイソプロピルエーテルで洗滌
すると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〕ベンズオキサジン−６−カル
ボン酸−Ｂ（OCOCH2CH2CH3）2−キレート4.65
ｇ（収率100％）を得る。
融点269〜273℃（分解）
元素分析 C21H22BF2NO8
実測値 Ｃ 53.61，Ｈ 4.71，Ｎ 2.87
計算値 Ｃ 54.21，Ｈ 4.77，Ｎ 3.01
NMR（CDCl3 IS：TMS）：δppm
0.90（6H，ｔ，−CH2−CH2−CH3）
1.65（7H，ｍ，−CH3及び
−CH2−CH2−CH3）
2.30（4H，ｍ，−CH2−CH2−CH3）
4.60（2H，ｓ，−CH2−）
5.30（1H，ｍ，CH−CH3）
7.90（1H，ｑ，８位 ＝CH−）
9.40（1H，ｓ，５位 ＝CH−）
Mass 466（M+） MW：465.214
実施例 １
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〕ベンズオキサジン−６−カルボ
ン酸−Ｂ（OCOCH3）2−キレート5.0ｇをＮ，Ｎ−
ジメチルアセトアミド10ml、４−メチルピペラジ
ン1.47ｇ及びトリエチルアミン1.24ｇと共に室温
下15時間撹拌する。反応後、減圧濃縮し、イソプ
ロピルエーテルを加え冷却する。析出した結晶を
濾取し、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〕−ベンズオキサジン−６−カルボン酸−
Ｂ（OCOCH3）2−キレート5.78ｇ（収率96.7％）
を得る。融点228〜230℃（分解）
元素分析 C22H25BFN3O8
実測値 Ｃ 53.90，Ｈ 5.15，Ｎ 8.56
計算値 Ｃ 54.00，Ｈ 5.15，Ｎ 8.59
Mass 489（M+） MW：489.264
NMR（CDCl3 IS：TMS）：δppm
1.60（3H，ｄ，−CH3）
2.00（6H，ｄ，−OCOCH3）
2.40（3H，ｓ，Ｎ−CH3）
2.55及び3.50（8H，br，[Formula]) 4.60 (2H, d, −CH 2 −) 5.20 (1H, m, CH−CH 3 ) 7.90 (1H, q, 8th position = CH−) 9.30 (1H, s, 5th position = CH−) Reference Example 2 A mixed solution of 0.93 g of boric acid and 7.0 g of propionic anhydride is stirred at 70 to 90°C for 1 hour. After reaction 9,10−
Difluoro-3-methyl-7-oxo-2,3-
Dihydro-7H-pyrido [1,2,3-de] [1,
4] Add 3.09 g of benzoxazine-6-carboxylic acid ethyl ester and stir under reflux for 1 hour. After the reaction, propionic anhydride is distilled off, a small amount of isopropyl ether is added, and the precipitated crystals are collected by filtration and washed with isopropyl ether to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro -7H-pyrido [1,2,3-de] [1,4]
Benzoxazine-6-carboxylic acid-B
[OCOCH 2 CH) 2 -chelate 4.16g (yield 95.2%)
get. Melting point 275-280℃ (decomposition) Elemental analysis C 10 H 18 BF 2 NO 8 Actual value C 51.50, H 4.25, N 3.00 Calculated value C 52.20, H 4.15, N 3.20 NMR (CDCl 3 IS: TS): δppm 1.10 ( 6H, q, -CH 2 -CH 3 ) 1.70 (3H, d, -CH 3 ) 2.40 (4H, q, -CH 2 -CH 3 ) 4.60 (2H, d, -CH 2 -) 5.10 (1H, m , CH-CH 3 ) 7.90 (1H, q, 8th position = CH-) 9.30 (1H, s, 5th position = CH-) Mass 438 (M + ) MW: 437.162 Reference example 3 Boric acid 0.93g and anhydrous acid 70~90g of mixed liquid
Stir for 1 hour at °C. After reaction, 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-
7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester 3.09
g and stirred under reflux for 1 hour. After the reaction, the acid anhydride was distilled off, a small amount of isopropyl ether was added, and the precipitated crystals were collected by filtration and washed with isopropyl ether to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H- Pyrido [1, 2,
3-de] [1,4]benzoxazine-6-carboxylic acid-B (OCOCH 2 CH 2 CH 3 ) 2 -chelate 4.65
g (yield 100%). Melting point 269-273℃ (decomposition) Elemental analysis C 21 H 22 BF 2 NO 8 Actual value C 53.61, H 4.71, N 2.87 Calculated value C 54.21, H 4.77, N 3.01 NMR (CDCl 3 IS:TMS): δppm 0.90 ( 6H, t, -CH 2 -CH 2 -CH 3 ) 1.65 (7H, m, -CH 3 and -CH 2 -CH 2 -CH 3 ) 2.30 (4H, m, -CH 2 -CH 2 -CH 3 ) 4.60 (2H, s, −CH 2 −) 5.30 (1H, m, CH−CH 3 ) 7.90 (1H, q, 8th position = CH−) 9.40 (1H, s, 5th position = CH−) Mass 466 (M + ) MW: 465.214 Example 1 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de] [1,4]benzoxazine-6-carboxylic acid-B (OCOCH 3 ) 2 - 5.0 g of chelate was added to N,N-
Stir with 10 ml of dimethylacetamide, 1.47 g of 4-methylpiperazine and 1.24 g of triethylamine at room temperature for 15 hours. After the reaction, concentrate under reduced pressure, add isopropyl ether and cool. The precipitated crystals were collected by filtration and 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-
B( OCOCH3 ) 2 -chelate 5.78g (yield 96.7%)
get. Melting point 228-230℃ (decomposition) Elemental analysis C 22 H 25 BFN 3 O 8 Actual value C 53.90, H 5.15, N 8.56 Calculated value C 54.00, H 5.15, N 8.59 Mass 489 (M + ) MW: 489.264 NMR (CDCl 3 IS:TMS): δppm 1.60 (3H, d, -CH 3 ) 2.00 (6H, d, -OCOCH 3 ) 2.40 (3H, s, N-CH 3 ) 2.55 and 3.50 (8H, br,
【式】
4.50（2H，ｓ，−CH2−）
5.10（1H，ｍ，CH−CH3）
7.80（1H，ｄ，８位 ＝CH−）
9.10（1H，ｓ，５位 ＝CH−）
得られた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〕−ベンズオキサジン−６−カルボン酸−
Ｂ（OCOCH3）2−キレート５ｇをアセトン63mlに
溶解し、撹拌下濃塩酸2.5mlを加え発熱するまま
30分間反応させる。反応後氷冷し結晶を濾取す
る。得られた結晶をトリエチルアミン1.14ｇ及び
エタノール42mlと共に１時間撹拌還流する。反応
後冷却し、結晶を濾取し、水洗する。得られた結
晶のIR，NMR、融点及びTLCは既知の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〕ベンズオ
キサジン−６−カルボン酸のものと合致した。収
量3.55ｇ（収率96％）
実施例 ２
参考例１にて得られたキレート体3.0ｇをＮ，
Ｎ−ジメチルアセトアミド６ml、４−メチルピペ
ラジン0.88ｇ及びトリエチルアミン0.74ｇと共に
室温下５時間撹拌する。反応後トリエチルアミン
を減圧下に留去し、酢酸20ml及び水４mlを加え、
５時間撹拌還流する。
反応後酢酸及び水を留去し、トリエチルアミン
を中和点まで加え少量のメタノールを加える。析
出した結晶を取しメタノールで洗滌すると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
ズオキサジン−６−カルボン酸2.41ｇを得る。
（キレート体よりの収率90.9％）
実施例 ３
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〕−ベンズオキサジン−６−カル
ボン酸−Ｂ（OCOCH2CH3）2−キレート548mgをジ
メチルスルホキシド1.1ml、トリエチルアミン128
mg及び４−メチルピペラジン150mgの混液に加え
て一夜室温で撹拌する。反応後トリエチルアミン
を減圧下に留去し、アセトン６mlを加え濃塩酸に
てPH１とし、30分間撹拌する。析出した結晶を濾
取し、エタノール10ml及びアンモニア水1.5mlの
混液に溶解する。常圧下エタノールを留去し、析
出する結晶を濾取し、水洗すると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〕ベンズオキサジ
ン−６−カルボン酸0.38ｇを得る。（キレート体
よりの収率83.9％）
実施例 ４
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〕−ベンズオキサジン−６−カル
ボン酸−Ｂ（OCOCH2CH2CH3）2−キレート1.17
ｇをジメチルスルホキシド2.3ml、トリエチルア
ミン0.26ｇ及び４−メチルピペラジン0.3ｇの混
液に加え一夜室温で撹拌する。反応後トリエチル
アミンを減圧下に留去し、アセトン12mlを加え濃
塩酸にてPH１とし、30分間撹拌する。析出した結
晶を濾取し、アンモニア水2.8ml及びエタノール
22mlの混液に溶解し、エタノールを留去する。析
出する結晶を濾取し水洗すると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〕ベンズオキサジン
−６−カルボン酸0.76ｇを得る。（キレート体よ
りの収率83.6％）
実施例 ５
実施例１で得られた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〕ベンズオキサジン−６−カル
ボン酸−Ｂ（OCOCH3）2−キレート２ｇにアセト
ン40ml及び20％水酸ナトリウム水溶液６mlを加え
て30分間撹拌還流する。反応後溶媒を留去し、酢
酸にて中和する。氷冷後、析出した結晶を濾取
し、水洗すると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〕ベンズオキサジン−６−カルボン
酸1.34ｇを得る。（収率90.7％）[Formula] 4.50 (2H, s, −CH 2 −) 5.10 (1H, m, CH−CH 3 ) 7.80 (1H, d, 8th position = CH−) 9.10 (1H, s, 5th position = CH−) Obtained 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-
Dissolve 5 g of B(OCOCH 3 ) 2 -chelate in 63 ml of acetone, add 2.5 ml of concentrated hydrochloric acid with stirring, and leave to generate heat.
Incubate for 30 minutes. After the reaction, cool on ice and collect the crystals by filtration. The obtained crystals were stirred and refluxed for 1 hour with 1.14 g of triethylamine and 42 ml of ethanol. After the reaction is cooled, the crystals are collected by filtration and washed with water. The IR, NMR, melting point and TLC of the obtained crystals were determined from the known 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. Yield 3.55g (yield 96%) Example 2 3.0g of the chelate obtained in Reference Example 1 was mixed with N,
The mixture was stirred at room temperature for 5 hours with 6 ml of N-dimethylacetamide, 0.88 g of 4-methylpiperazine and 0.74 g of triethylamine. After the reaction, triethylamine was distilled off under reduced pressure, and 20 ml of acetic acid and 4 ml of water were added.
Stir and reflux for 5 hours. After the reaction, acetic acid and water are distilled off, triethylamine is added to the neutralization point, and a small amount of methanol is added. When the precipitated crystals were taken and washed with methanol, 9-
Fluoro-3-methyl-10-(4-methyl-1-
2.41 g of benzoxazine-6-carboxylic acid are obtained.
(Yield 90.9% from chelate) Example 3 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de] [1,4]-benzoxazine-6-carboxylic acid-B (OCOCH 2 CH 3 ) 2 - 548 mg of chelate, 1.1 ml of dimethyl sulfoxide, 128 mg of triethylamine
mg and 150 mg of 4-methylpiperazine and stirred overnight at room temperature. After the reaction, triethylamine was distilled off under reduced pressure, 6 ml of acetone was added, the pH was brought to 1 with concentrated hydrochloric acid, and the mixture was stirred for 30 minutes. The precipitated crystals are collected by filtration and dissolved in a mixture of 10 ml of ethanol and 1.5 ml of aqueous ammonia. Ethanol was distilled off under normal pressure, and the precipitated crystals were collected by filtration and washed with water to give 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 Obtain 0.38g. (Yield 83.9% from chelate) Example 4 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de] [1,4]-benzoxazine-6-carboxylic acid-B (OCOCH 2 CH 2 CH 3 ) 2 -chelate 1.17
g was added to a mixture of 2.3 ml of dimethyl sulfoxide, 0.26 g of triethylamine and 0.3 g of 4-methylpiperazine, and the mixture was stirred overnight at room temperature. After the reaction, triethylamine was distilled off under reduced pressure, 12 ml of acetone was added, the pH was adjusted to 1 with concentrated hydrochloric acid, and the mixture was stirred for 30 minutes. Collect the precipitated crystals by filtration and add 2.8 ml of ammonia water and ethanol.
Dissolve in 22 ml of the mixed solution and distill off the ethanol. When the precipitated crystals are collected by filtration and washed with water, 9-fluoro-3
-Methyl-10-(4-methyl-1-piperazinyl)
0.76 g of -7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid is obtained. (Yield 83.6% from chelate) Example 5 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro- obtained in Example 1 7H-pyrido [1,2,
To 2 g of 3-de][1,4]benzoxazine-6-carboxylic acid-B (OCOCH 3 ) 2 -chelate are added 40 ml of acetone and 6 ml of a 20% aqueous sodium hydroxide solution, and the mixture is stirred and refluxed for 30 minutes. After the reaction, the solvent was distilled off and the mixture was neutralized with acetic acid. After cooling on ice, the precipitated crystals were collected by filtration and washed with water to give 9-fluoro-3-methyl-10-
(4-methyl-1-piperazinyl)-7-oxo-
2,3-dihydro-7H-pyrido [1,2,3-
1.34 g of de][1,4]benzoxazine-6-carboxylic acid is obtained. (Yield 90.7%)
Claims (1)
又はアルキル基を、R2及びR3は同じ又は異なつ
てアリール基、アルキル基又はハロゲノアルキル
基を、Ｒは水素原子又はアルキル基を意味する）
で表わされる化合物をキレート分解することを特
徴とする式 （式中、X1，R1及びＲは前記に同じ）で表わ
される化合物の製法 ２ 式 （式中、X1及びX2は同じ又は異なるハロゲン
原子を、R1は水素原子又はアルキル基を、R2及
びR3は同じ又は異なつてアリール基、アルキル
基又はハロゲノアルキル基を意味する）で表わさ
れる化合物を式 （式中、Ｒは水素原子又はアルキル基を意味す
る）で表わされる化合物と反応させて式 （式中、X1，R1，R2，R3及びＲは前記に同
じ）で表わされる化合物を製し、次いでこれをキ
レート分解することを特徴とする式 （式中、X1，R1及びＲは前記に同じ）で表わ
される化合物の製法。[Claims] 1 formula ( In the formula , means)
A formula characterized by chelate decomposition of a compound represented by (In the formula, X 1 , R 1 and R are the same as above) Method 2 for producing a compound represented by the formula (In the formula, X 1 and X 2 are the same or different halogen atoms, R 1 is a hydrogen atom or an alkyl group, and R 2 and R 3 are the same or different and mean an aryl group, an alkyl group, or a halogenoalkyl group) The compound represented by the formula (In the formula, R means a hydrogen atom or an alkyl group) by reacting with a compound represented by the formula (In the formula, X 1 , R 1 , R 2 , R 3 and R are the same as above) is prepared and then chelate decomposed. A method for producing a compound represented by the formula (wherein X 1 , R 1 and R are the same as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18813883A JPS6078986A (en) | 1983-10-07 | 1983-10-07 | Preparation of oxazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18813883A JPS6078986A (en) | 1983-10-07 | 1983-10-07 | Preparation of oxazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6078986A JPS6078986A (en) | 1985-05-04 |
| JPH0372073B2 true JPH0372073B2 (en) | 1991-11-15 |
Family
ID=16218401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18813883A Granted JPS6078986A (en) | 1983-10-07 | 1983-10-07 | Preparation of oxazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6078986A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA864518B (en) * | 1985-06-20 | 1987-03-25 | Daiichi Seiyaku Co | Optically active pyridobenzoxazine derivatives and intermediates thereof |
| CA1306750C (en) | 1985-12-09 | 1992-08-25 | Istvan Hermecz | Process for the preparation of quinoline carboxylic acide |
| HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
| NZ224150A (en) * | 1987-04-08 | 1990-11-27 | Chinoin Gyogyszer Es Vegyeszet | Preparation of piperazinyl-substituted quinoline derivatives |
| JPS6419069A (en) * | 1987-07-14 | 1989-01-23 | Dainippon Pharmaceutical Co | Production of polyhalogenoquinoline derivative |
| HU203746B (en) * | 1988-12-22 | 1991-09-30 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
-
1983
- 1983-10-07 JP JP18813883A patent/JPS6078986A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6078986A (en) | 1985-05-04 |
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| EXPY | Cancellation because of completion of term |