JPH0148910B2 - - Google Patents
Info
- Publication number
- JPH0148910B2 JPH0148910B2 JP14191981A JP14191981A JPH0148910B2 JP H0148910 B2 JPH0148910 B2 JP H0148910B2 JP 14191981 A JP14191981 A JP 14191981A JP 14191981 A JP14191981 A JP 14191981A JP H0148910 B2 JPH0148910 B2 JP H0148910B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- benzoxazine
- dihydro
- pyrido
- oxo
- 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
- 150000001875 compounds Chemical class 0.000 claims description 22
- 238000000354 decomposition reaction Methods 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 4
- QDEJGQKJMKXYLM-UHFFFAOYSA-N 2h-pyrido[2,3-h][1,2]benzoxazine Chemical class C1=CC2=NC=CC=C2C2=C1C=CNO2 QDEJGQKJMKXYLM-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 150000004885 piperazines Chemical class 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000013522 chelant Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000013078 crystal Substances 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 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 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 229940113088 dimethylacetamide Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- DUGFZRFLUQJFOO-UHFFFAOYSA-N 4-oxa-1-azatricyclo[7.3.1.05,13]trideca-2,5,7,9(13),11-pentaene-11-carboxylic acid Chemical compound C1=COC2=CC=CC3=C2N1C=C(C(=O)O)C3 DUGFZRFLUQJFOO-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- SIHHLZPXQLFPMC-UHFFFAOYSA-N chloroform;methanol;hydrate Chemical compound O.OC.ClC(Cl)Cl SIHHLZPXQLFPMC-UHFFFAOYSA-N 0.000 description 2
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- YILGXIZRZUDENO-UHFFFAOYSA-N 10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5,7,9(13),11-tetraene-11-carboxylic acid Chemical compound C1COC2=CC=CC3=C2N1C=C(C(=O)O)C3=O YILGXIZRZUDENO-UHFFFAOYSA-N 0.000 description 1
- CFLBIADORGSMCX-UHFFFAOYSA-N 2h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC=NC2=CC(C(=O)O)=CC=C21 CFLBIADORGSMCX-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
- WKRSSAPQZDHYRV-UHFFFAOYSA-N 82419-52-1 Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCNCC1 WKRSSAPQZDHYRV-UHFFFAOYSA-N 0.000 description 1
- OYHNLEGFMGVEHA-UHFFFAOYSA-N 9-chloro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid Chemical compound ClC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 OYHNLEGFMGVEHA-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical class F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- -1 etc. Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
本発明はピリドベンズオキサジン誘導体の製造
法に関する。さらに詳しくは、本発明は一般式
（）
（式中、R1は水素原子または低級アルキル基
を、X1およびX2は同じまたは異なるハロゲン原
子を示す）で表わされる化合物に一般式（）
（式中、R2は水素原子または低級アルキル基
を示す）で表わされるピペラジン類を反応させ一
般式（）
（式中、R1，R2およびX1は前記と同じ）で表
わされる化合物を製し、次いでこれを分解して一
般式（）の化合物を製する方法である。
原料として用いる一般式（）で表わされるキ
レート化合物は次式に示すごとく化合物(A)をジエ
チルエトキシメチレンマロネートと縮合し、次い
で生成したＮ―ジエチルメチレンマロネート置換
体を三フツ化ホウ素および（または）三フツ化ホ
ウ素錯体と加熱環化することにより合成される。
一般式（）で表わされる化合物と一般式
（）で表わされるピペラジン類との反応は無溶
媒または溶媒中、脱酸剤の存在下に行なわれる
が、ピペラジン類あるいは脱酸剤が液体の場合
は、これを過剰に用いて溶媒を兼ねさせてもよ
い。
斯かる溶媒としては、ケトン類、例えばアセト
ン、メチルエチルケトン等、あるいは極性非プロ
トン系溶媒、例えばジメチルホルムアミド、ジメ
チルスルホキシド等が好適であり、通常一般式
（）で表わされる化合物１部に対し２〜20部の
範囲で使用される。
脱酸剤としては、種々のアルカリ金属の水酸化
物、炭酸塩または重炭酸塩等、あるいはトリエチ
ルアミン、トリブチルアミン、ピリジン等の有機
の三級アミン類が用いられるが、反応に関与する
ピペラジン類を過剰に用いて脱酸剤として兼用す
ることも可能である。斯かる脱酸剤の添加量は、
一般式（）で表わされる化合物に対して通常１
〜３倍モルが好ましい。
該反応は通常100℃以下の温度で行なわれるが、
具体的にはケトン系の溶媒ではその沸点付近、ま
た極性非プロトン性の溶媒では室温あるいはそれ
以下の温度で反応を行なえば通常0.5〜５時間で
一般式（）で表わされる化合物が生成する。ま
た、ジメチルスルホキシド、ジメチルアセトアミ
ド等の非プロトン性極性溶媒中で脱酸剤の存在下
50〜180℃の温度で反応させれば一挙に一般式
（）で表わされる化合物が生成する。一般式
（）で表わされる化合物は、要すれば他の溶媒、
例えば水、アセトン、メタノール等を加えた後濾
取すれば容易にかつ高収率に収得される。このも
のを単離し、次いで分解反応を行なう方法を採用
することにより一挙に反応を行なうよりも最終目
的物（）の純度と収率が向上することがある。
このキレート化合物（）より一般式（）で
表わされる化合物への分解は脱酸剤の存在下、プ
ロトン性の化合物で処理することにより行なわれ
るが、本反応は単にプロトン性の化合物で処理す
るだけでも可能であり、その場合一般式（）で
表わされる化合物のフツ化水素酸塩、あるいはそ
の塩類として収得される。該処理におけるプロト
ン性の化合物としては、具体的には水、メタノー
ル、エタノール等のヒドロキシル系の化合物等が
例示できる。
この工程において使用される溶媒は不活性であ
れば、特に限定されないが、通常水および（また
は）アルコールが好適であり、一般式（）で表
わされる化合物１部に対し５〜30部使用するのが
好ましい。
脱酸剤としては、例えばアルカリ金属の水酸化
物、炭酸塩または重炭酸塩等の無機塩、あるいは
トリエチルアミン、ピリジン等の有機塩基が用い
られる。
該反応は室温でも進行するが、反応時間の面か
ら反応温度は溶媒の沸点付近が好ましく、反応は
通常0.5〜10時間で終了する。斯くして生成した
一般式（）で表わされる化合物は反応後冷却
し、濾取することにより容易にかつ高収率で収得
することができる。
以上述べたごとく、本発明の方法を実施するこ
とにより、高収率、高純度、かつ能率良く、一般
式（）で表わされる医薬上きわめて有用な抗菌
剤であるピリドベンズオキサジン誘導体、及びそ
の塩類を得ることができるので本発明は工業的に
きわめて有意義な方法である。
本発明で得られる化合物（）は、試験管内抗
菌試験において次表に示すように優れた抗菌活性
を示した。
最小発育阻止濃度（MIC，μg／ml）
平板希釈法（ミユラー・ヒントン・ブイヨン）
接種菌量 106／ml
培養条件 37℃，18時間
The present invention relates to a method for producing pyridobenzoxazine derivatives. More specifically, the present invention relates to the general formula () (In the formula, R 1 is a hydrogen atom or a lower alkyl group, and X 1 and X 2 are the same or different halogen atoms.) (In the formula, R 2 represents a hydrogen atom or a lower alkyl group) is reacted with the general formula () In this method, a compound represented by the formula (wherein R 1 , R 2 and X 1 are the same as above) is prepared, and then this is decomposed to produce a compound of the general formula (). The chelate compound represented by the general formula () used as a raw material is obtained by condensing compound (A) with diethyl ethoxymethylene malonate as shown in the following formula, and then condensing the resulting N-diethyl methylene malonate substituted product with boron trifluoride and ( or) synthesized by heating cyclization with a boron trifluoride complex. The reaction between the compound represented by the general formula () and the piperazine represented by the general formula () is carried out without a solvent or in a solvent in the presence of a deoxidizing agent. However, when the piperazine or the deoxidizing agent is liquid, , this may be used in excess to also serve as a solvent. As such a solvent, ketones such as acetone, methyl ethyl ketone, etc., or polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, etc. are suitable, and usually 2 to 20 Used within the scope of the section. As deoxidizing agents, various alkali metal hydroxides, carbonates, bicarbonates, etc., or organic tertiary amines such as triethylamine, tributylamine, pyridine, etc. are used. It is also possible to use it in excess so that it also serves as a deoxidizing agent. The amount of such deoxidizing agent added is
Usually 1 for the compound represented by the general formula ()
~3 times the mole is preferred. The reaction is usually carried out at a temperature of 100°C or lower,
Specifically, if the reaction is carried out near the boiling point of a ketone solvent, or at room temperature or lower in a polar aprotic solvent, the compound represented by the general formula () is usually produced in 0.5 to 5 hours. In addition, in the presence of a deoxidizing agent in an aprotic polar solvent such as dimethyl sulfoxide or dimethyl acetamide.
If the reaction is carried out at a temperature of 50 to 180°C, the compound represented by the general formula () will be produced all at once. The compound represented by the general formula () can be prepared using other solvents, if necessary.
For example, it can be easily obtained in a high yield by adding water, acetone, methanol, etc. and then collecting it by filtration. By employing a method in which this product is isolated and then subjected to a decomposition reaction, the purity and yield of the final target product () may be improved compared to performing the reaction all at once. The decomposition of this chelate compound () into the compound represented by the general formula () is carried out by treatment with a protic compound in the presence of a deoxidizer. In that case, it is obtained as a hydrofluoride salt of the compound represented by the general formula () or its salts. Specific examples of protic compounds in this treatment include water, hydroxyl compounds such as methanol, and ethanol. The solvent used in this step is not particularly limited as long as it is inert, but usually water and/or alcohol are suitable, and 5 to 30 parts are used per 1 part of the compound represented by the general formula (). is preferred. As the deoxidizing agent, for example, an alkali metal hydroxide, an inorganic salt such as carbonate or bicarbonate, or an organic base such as triethylamine or pyridine is used. The reaction proceeds at room temperature, but from the viewpoint of reaction time, the reaction temperature is preferably around the boiling point of the solvent, and the reaction is usually completed in 0.5 to 10 hours. The compound represented by the general formula () thus produced can be easily obtained in high yield by cooling after the reaction and collecting it by filtration. As described above, by carrying out the method of the present invention, it is possible to produce the pyridobenzoxazine derivative represented by the general formula ( Since salts can be obtained, the present invention is an extremely meaningful method industrially. The compound () obtained according to the present invention showed excellent antibacterial activity in an in vitro antibacterial test as shown in the following table. Minimum inhibitory concentration (MIC, μg/ml) Plate dilution method (Muller-Hinton broth) Inoculum amount 10 6 /ml Culture conditions 37℃, 18 hours
【表】
次に参考例および実施例を記載する。
参考例 １
７，８―ジフルオロ―２，３―ジヒドロ―３―
メチル―4H―１，４―ベンズオキサジン2.00ｇ
およびジエチルエトキシメチレンマロネート2.57
ｇの混合物を120〜130℃で５時間加熱させた。反
応で生成するエタノールを減圧下に留去したの
ち、残渣油状物をダウサーム（ダウケミカル社
製）10mlに溶解させ、この溶液に室温下三フツ化
ホウ素テトラヒドロフラン錯体2.0ｇを加えた。
これをあらかじめ250℃に加熱したダウサーム10
ml中に220〜240℃で30分間かけて滴下し、更に同
温度に１時間保つた。冷却後、反応液にジクロル
エタン５mlを加え、結晶を濾取し、ジクロルエタ
ンとメタノールで洗浄し、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―BF2―キレート
3.38ｇ（収率94.2％）をえた。
融点300℃以上。
元素分析値 C13H8BF4NO4として
計算値 Ｃ 47.45，Ｈ 2.45，Ｎ 4.26
実測値 Ｃ 47.69，Ｈ 2.46，Ｎ 4.21
Ｈ―NMR（DMSO―d6，IS：TMS）
δ（ppm）：1.59（3H，ｄ，―ＣＨ 3）
4.73（2H，ｑ，―ＣＨ 2―）
5.35（1H，ｍ，＞ＣＨ―CH3）
8.18（1H，ｍ，８位＝ＣＨ―）
9.68（1H，Ｓ，５位＝ＣＨ―）
Mass：M+329
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―BF2―キレート1.00ｇ、Ｎ―メチルピペ
ラジン0.46ｇ、トリエチルアミン0.62ｇ及びジメ
チルスルホキシド５mlの混液を室温下３時間反応
させた。反応後、析出晶を水５mlを注加し濾取
し、結晶を水で洗い、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―BF2―キレート1.23ｇ（収率98.9
％）をえた。融点252〜255℃（分解）
元素分析値 C18H19BF4N3O4として
計算値 Ｃ 52.84，Ｈ 4.68，Ｎ 10.27
実測値 Ｃ 52.94，Ｈ 4.67，Ｎ 10.01
Ｈ―NMR（DMSO―d6，IS：TMS）
δ（ppm）：1.54（3H，ｄ，Ｃ―ＣＨ 3）
2.24（3H，ｓ，Ｎ―ＣＨ 3）
3.4（8H，br，[Table] Next, reference examples and examples are described. Reference example 1 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 2.00g
and diethyl ethoxymethylene malonate 2.57
The mixture of g was heated at 120-130°C for 5 hours. After ethanol produced in the reaction was distilled off under reduced pressure, the residual oil was dissolved in 10 ml of Dowtherm (manufactured by Dow Chemical Company), and 2.0 g of boron trifluoride tetrahydrofuran complex was added to this solution at room temperature.
Dowtherm 10 heated to 250℃ in advance
ml over 30 minutes at 220 to 240°C, and further kept at the same temperature for 1 hour. After cooling, 5 ml of dichloroethane was added to the reaction solution, the crystals were collected by filtration, washed with dichloroethane and methanol, and 9,10-difluoro-
3-methyl-7-oxo-2,3-dihydro-
7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate
3.38g (yield 94.2%) was obtained. Melting point over 300℃. Elemental analysis value C 13 H 8 BF 4 NO 4 Calculated value C 47.45, H 2.45, N 4.26 Actual value C 47.69, H 2.46, N 4.21 H-NMR (DMSO-d 6 , IS:TMS) δ (ppm): 1.59 (3H, d, -C H 3 ) 4.73 (2H, q, -C H 2 -) 5.35 (1H, m, > C H - CH 3 ) 8.18 (1H, m, 8th position = C H -) 9.68 (1H, S, 5th position = C H -) Mass: M + 329 Example 1 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
A mixture of 1.00 g of -de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate, 0.46 g of N-methylpiperazine, 0.62 g of triethylamine and 5 ml of dimethyl sulfoxide was reacted at room temperature for 3 hours. After the reaction, add 5 ml of water and collect the precipitated crystals by filtration, wash the crystals with water, and 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-BF 2 -chelate 1.23g (yield 98.9
%) was obtained. Melting point 252-255℃ (decomposition) Elemental analysis value C 18 H 19 BF 4 N 3 O 4 Calculated value C 52.84, H 4.68, N 10.27 Actual value C 52.94, H 4.67, N 10.01 H-NMR (DMSO-d 6 , IS: TMS) δ (ppm): 1.54 (3H, d, C-C H 3 ) 2.24 (3H, s, N-C H 3 ) 3.4 (8H, br,
【式】）
4.58（2H，ｑ，―ＣＨ 2―）
5.21（1H，ｍ，ＣＨ―CH3）
7.83（1H，ｄ，８位＝CH―）
9.46（1H，ｄ，５位＝CH―）
Mass：M+409
実施例 ２
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―BF2―キレート5.00ｇ、Ｎ―メチルピペ
ラジン4.57ｇ及びジメチルアセトアミド25mlの混
液を室温下２時間反応させた。反応液に水25mlを
加え、結晶を濾取し、水洗し、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―BF2―キレート6.04ｇ
（収率97.1％）をえた。融点250〜254℃（分解）。
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―BF2―キレート0.61ｇ，Ｎ―メチルピペ
ラジン0.58ｇ及びアセトン12mlの混液を3.5時間
還流した。反応液を冷却し、析出晶を濾取し、ア
セトンで洗浄し、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―BF2―キレート0.43ｇ（収率57％）を
えた。融点250〜255℃（分解）。
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―BF2―キレート3.00ｇ、無水ピペラジン
2.44ｇ及びジメチルアセトアミド15mlの混液を室
温下２時間反応させた。反応後、アセトン30mlを
注加し、冷却し、析出晶を濾取し、アセトンで洗
い、９―フルオロ―３―メチル―10―（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―BF2―キレート
２・97ｇ（収率82.4％）をえた。融点235℃（分
解）。
元素分析値 C17H17BF4N3O4として
計算値 Ｃ 51.67，Ｈ 4.34，Ｎ 10.63
実測値 Ｃ 51.15，Ｈ 4.44，Ｎ 10.32
Ｈ―NMR（CF3COOH，IS：TMS）
δ（ppm）：1.73（3H，ｄ，―ＣＨ 3）
3.7（8H，br，[Formula]) 4.58 (2H, q, -C H 2 -) 5.21 (1H, m, C H -CH 3 ) 7.83 (1H, d, 8th position = CH -) 9.46 (1H, d, 5th position = CH --) Mass: M + 409 Example 2 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
A mixture of 5.00 g of -de](1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate, 4.57 g of N-methylpiperazine, and 25 ml of dimethylacetamide was reacted at room temperature for 2 hours. 25 ml of water was added to the reaction solution. was added, the crystals were collected by filtration, washed with water, 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 -BF 2 -Chelate 6.04g
(yield 97.1%). Melting point 250-254℃ (decomposition). Example 3 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3
A mixture of 0.61 g of -de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate, 0.58 g of N-methylpiperazine, and 12 ml of acetone was refluxed for 3.5 hours. The reaction solution was cooled, the precipitated crystals were collected by filtration, washed with acetone, and 9-fluoro-3-methyl-10
-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido [1,2,
0.43 g (yield 57%) of 3-de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate was obtained. Melting point 250-255℃ (decomposition). Example 4 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate 3.00g, anhydrous piperazine
A mixture of 2.44 g and 15 ml of dimethylacetamide was reacted at room temperature for 2 hours. After the reaction, 30 ml of acetone was added, cooled, and the precipitated crystals were collected by filtration and washed with acetone to give 9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo-2,3-dihydro-
2.97 g (yield: 82.4%) of 7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate was obtained. Melting point 235℃ (decomposition). Elemental analysis value C 17 H 17 BF 4 N 3 O 4 Calculated value C 51.67, H 4.34, N 10.63 Actual value C 51.15, H 4.44, N 10.32 H-NMR (CF 3 COOH, IS: TMS) δ (ppm) :1.73(3H,d, -CH3 ) 3.7(8H,br ,
【式】）
4.63（2H，br，―ＣＨ 2―）
5.1（1H，ｍ，＞ＣＨ―CH3）
7.90（1H，ｄ，８位＝ＣＨ―）
9.20（1H，ｓ，５位＝ＣＨ―）
実施例 ５
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―BF2―キレート1.00ｇ、無水ピペラジン
0.81ｇ及びジメチルホルムアミド５mlの混液を室
温下１時間反応させた。反応後水10mlを注加し、
冷却後析出晶を濾取し結晶を水で洗い、９―フル
オロ―３―メチル―10―（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―BF2―キレート1.16ｇ（収
率96.6％）をえた。融点230℃（分解）。
実施例 ６
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―BF2―
キレート1.00ｇ、トリエチルアミン0.50ｇ及び95
％エタノール20mlの混液を６時間還流した。反応
後析出晶を冷却し、濾取し、冷含水メタノールで
洗浄し、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
0.76（収率86％）をえた。クロロホルム・メタノ
ール（10：１）の混液で再結晶したのち減圧乾燥
（100〜110℃、5hr）した。融点254〜256℃（分
解）。
元素分析値 C18H20FN3O4として
計算値 Ｃ 59.82，Ｈ 5.58，Ｎ 11.63
実測値 Ｃ 59.61，Ｈ 5.63，Ｎ 11.51
Ｈ―NMR（DMSO―d6，IS：TMS）
δ（ppm）：1.45（3H，ｄ，CH―ＣＨ 3）
2.22（3H，Ｓ，Ｎ―ＣＨ 3）
3.4（8H，br，[Formula]) 4.63 (2H, br, -C H 2 -) 5.1 (1H, m, > C H - CH 3 ) 7.90 (1H, d, 8th position = C H -) 9.20 (1H, s, 5th position =C H -) Example 5 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate 1.00g, anhydrous piperazine
A mixture of 0.81 g and 5 ml of dimethylformamide was reacted at room temperature for 1 hour. After the reaction, add 10ml of water,
After cooling, the precipitated crystals were collected by filtration, the crystals were washed with water, and 9-fluoro-3-methyl-10-(1-piperazinyl)-
1.16 g (yield 96.6%) of 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate was obtained. . Melting point: 230℃ (decomposition). Example 6 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-BF 2 -
Chelate 1.00g, triethylamine 0.50g and 95
% ethanol was refluxed for 6 hours. After the reaction, the precipitated crystals were cooled, collected by filtration, and washed with cold aqueous methanol 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
0.76 (yield 86%). After recrystallizing with a mixture of chloroform and methanol (10:1), it was dried under reduced pressure (100-110°C, 5 hours). Melting point 254-256°C (decomposition). Elemental analysis value C 18 H 20 FN 3 O 4 Calculated value C 59.82, H 5.58, N 11.63 Actual value C 59.61, H 5.63, N 11.51 H-NMR (DMSO-d 6 , IS:TMS) δ (ppm): 1.45 (3H, d, CH-C H 3 ) 2.22 (3H, S, N-C H 3 ) 3.4 (8H, br,
【式】）
4.49（2H，ｑ，―ＣＨ 2―）
4.93（1H，ｍ，＝ＣＨ―CH3）
7.59（1H，ｄ，８位＝ＣＨ―）
8.98（1H，ｄ，５位＝CH―）
実施例 ７
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―BF2
―キレート1.00ｇ、トリエチルアミン0.50ｇ及び
メタノール20mlの混液を４時間還流した。反応
後、析出晶を冷却濾取し、メタノールで洗い、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0.69ｇ（収率
78％）を得た。これをシメチルホルムアミドで再
結晶した。融点253〜255℃（分解）。
実施例 ８
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―BF2
―キレート1.00ｇ、トリエチルアミン0.50ｇ及び
水20mlの混液を２時間還流した。水を減圧留去
し、残渣にメタノール20mlを注加して濾取し、メ
タノールで洗い、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0.66ｇ（収率75％）を得た。これを濃ア
ンモニア水２mlとエタノール20mlの混液に室温下
溶解し、活性炭で処理後過剰のアンモニアをエタ
ノールと共に加熱留去して精製晶0.62ｇを得た。
融点254〜255℃（分解）。
実施例 ９
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―BF2
―キレート1.00ｇとエタノール20mlの混液を４時
間還流した。冷後析出物を濾取、エタノールで洗
浄し、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
0.88ｇ（収率84％）を得た。融点253〜255℃（分
解）。
元素分析値 C18H20FN3O4.HF.BOFとして
計算値 Ｃ 50.61，Ｈ 4.95，Ｎ 9.84
実測値 Ｃ 50.52，Ｈ 5.05，Ｎ 9.79
実施例 10
９―フルオロ―３―メチル―10―（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―BF2―キレート
1.00ｇ、トリエチルアミン0.62ｇ及びジメチルス
ルホキシド５mlの混液を120〜130℃に３時間加熱
した。冷後析出晶を濾取し、メタノールで洗い、
クロロホルム―メタノール―水の混液で再結晶し
て９―フルオロ―３―メチル―10―（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0.67ｇ（収率72％）
を得た。融点258〜260℃（分解）。
元素分析値 C17H18FN3O4・３／２H2Oとして
計算値 Ｃ 54.69，Ｈ 5.40，Ｎ 11.25
実測値 Ｃ 54.82，Ｈ 5.06，Ｎ 11.13
実施例 11
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―BF2―キレート、5.21ｇ、Ｎ―メチルピ
ペラジン4.76ｇおよびジメチルスルホキシド26ml
の混液を110〜120℃に２時間加熱した。析出晶を
冷却後濾取し、冷エタノールで洗浄し、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4.25ｇ（収率74.3
％）をえた。濃アンモニア―メタノール（１：
20）に室温下溶解し過剰のアンモニアを加熱留去
し精晶をえた。融点254〜255℃（分解）。
実施例 12
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―BF2―キレート2.00ｇ、Ｎ―メチルピペ
ラジン0.73ｇ、トリエチルアミン1.23ｇおよびジ
メチルスルホキシド10mlの混液を120〜130℃に５
時間加熱した。析出晶を冷却し、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1.69ｇ（収率76.9
％）をえた。これを濃アンモニア水―エタノール
（１：20）で再結晶した。融点254〜256℃（分
解）。
実施例 13
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―BF2―キレート0.70ｇ、Ｎ―メチルピペ
ラジン0.66ｇ及びピリジン７mlの混液を２時間還
流した。反応液を減圧濃縮し、残渣にメタノール
を加え、析出晶を濾取し、メタノールで洗浄し、
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0.60ｇ（収
率78％）をえた。融点253〜256℃（分解）。
実施例 14
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―BF2―キレート0.77ｇ、Ｎ―メチルピペ
ラジン0.73ｇ及びジメチルアセトアミド４mlの混
液を110〜120℃で５時間加熱した。析出晶を冷却
後濾取し、エタノールで洗浄し、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0.65ｇ（収率77％）をえ
た。これをジメチルホルムアミドから再結晶し
た。融点254〜256℃。
（分解）
実施例 15
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―BF2―キレート2.00ｇ、無水ピペラジン
1.57ｇ及びジメチルアセトアミド10mlの混液を
110〜120℃で２時間加熱した。冷後、析出晶を濾
取し、冷メタノールで洗浄し、９―フルオロ―３
―メチル―10―（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1.66ｇ（収率73.4％）を得、これをクロ
ロホルム―メタノール―水の混合溶媒で再結晶し
た。融点260℃（分解）。
元素分析値 C17H18FN3O4・３／２H2Oとして
計算値 Ｃ 54.69，Ｈ 5.40，Ｎ 11.25
実測値 Ｃ 54.74，Ｈ 5.19，Ｎ 11.33
実施例 16
９―クロロ―10―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―BF2―キレート0.50ｇ、Ｎ―メチ
ルピペラジン0.44ｇ及びジメチルスルホキシド
2.5mlの混液を110〜130℃で５時間加熱した。析
出晶をメタノールを加えて濾取し、メタノールで
洗い、９―クロロ―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0.43ｇ
（収率78％）をえた。これをクロロホルム―メタ
ノールの混合溶媒で再結晶した。融点280℃（分
解）。
元素分析値 C18H20ClN3O4として
計算値 Ｃ 57.22，Ｈ 5.34，Ｎ 11.12
実測値 Ｃ 56.78，Ｈ 5.34，Ｎ 11.07[Formula]) 4.49 (2H, q, -C H 2 -) 4.93 (1H, m, = C H - CH 3 ) 7.59 (1H, d, 8th position = C H -) 8.98 (1H, d, 5th position =CH-) Example 7 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-BF 2
-A mixture of 1.00 g of chelate, 0.50 g of triethylamine and 20 ml of methanol was refluxed for 4 hours. After the reaction, the precipitated crystals were collected by cooling filtration, washed with methanol,
-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 0.69g (yield
78%). This was recrystallized from dimethylformamide. Melting point 253-255°C (decomposition). Example 8 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-BF 2
-A mixture of 1.00 g of chelate, 0.50 g of triethylamine and 20 ml of water was refluxed for 2 hours. Water was distilled off under reduced pressure, 20 ml of methanol was added to the residue, collected by filtration, washed with methanol, and the 9-fluoro-3-methyl-10
-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido [1,2,
0.66 g (yield 75%) of 3-de][1,4]-benzoxazine-6-carboxylic acid was obtained. This was dissolved in a mixture of 2 ml of concentrated aqueous ammonia and 20 ml of ethanol at room temperature, treated with activated carbon, and the excess ammonia was distilled off by heating together with ethanol to obtain 0.62 g of purified crystals.
Melting point 254-255°C (decomposition). Example 9 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-BF 2
-A mixture of 1.00 g of chelate and 20 ml of ethanol was refluxed for 4 hours. After cooling, the precipitate was collected by filtration and washed with ethanol 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
0.88g (yield 84%) was obtained. Melting point 253-255°C (decomposition). Elemental analysis value C 18 H 20 FN 3 O 4 .HF.BOF Calculated value C 50.61, H 4.95, N 9.84 Actual value C 50.52, H 5.05, N 9.79 Example 10 9-fluoro-3-methyl-10-( 1-Piperazinyl)-7-oxo-2,3-dihydro-7H
-Pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate
A mixture of 1.00g of triethylamine, 0.62g of triethylamine, and 5ml of dimethyl sulfoxide was heated to 120-130°C for 3 hours. After cooling, the precipitated crystals were collected by filtration, washed with methanol,
Recrystallize from a chloroform-methanol-water mixture to obtain 9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo-2,3-dihydro-7H.
-Pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid 0.67g (yield 72%)
I got it. Melting point 258-260℃ (decomposition). Elemental analysis value C 17 H 18 FN 3 O 4・3/2H 2 O Calculated value C 54.69, H 5.40, N 11.25 Actual value C 54.82, H 5.06, N 11.13 Example 11 9,10-difluoro-3-methyl -7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de] [1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate, 5.21 g, N-methylpiperazine 4.76 g and dimethyl sulfoxide 26 ml
The mixture was heated to 110-120°C for 2 hours. After cooling, the precipitated crystals were collected by filtration, washed with cold ethanol, and 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-
4.25 g of 7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid (yield 74.3
%) was obtained. Concentrated ammonia-methanol (1:
20) at room temperature, excess ammonia was distilled off under heating to obtain fine crystals. Melting point 254-255°C (decomposition). Example 12 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -A mixture of 2.00 g of chelate, 0.73 g of N-methylpiperazine, 1.23 g of triethylamine, and 10 ml of dimethyl sulfoxide was heated to 120-130°C for 5 minutes.
heated for an hour. The precipitated crystals were cooled and collected by filtration 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 1.69g (yield 76.9
%) was obtained. This was recrystallized from concentrated ammonia water-ethanol (1:20). Melting point 254-256°C (decomposition). Example 13 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
A mixture of 0.70 g of -de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate, 0.66 g of N-methylpiperazine and 7 ml of pyridine was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, methanol was added to the residue, the precipitated crystals were collected by filtration, and washed with methanol.
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 0.60g (yield 78%) was obtained. Melting point 253-256°C (decomposition). Example 14 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
A mixture of 0.77 g of -de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate, 0.73 g of N-methylpiperazine, and 4 ml of dimethylacetamide was heated at 110 to 120°C for 5 hours. After cooling, the precipitated crystals were collected by filtration, washed with ethanol, 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-carvone 0.65 g (yield 77%) of acid was obtained. This was recrystallized from dimethylformamide. Melting point 254-256℃. (Decomposition) Example 15 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
-de][1,4]-benzoxazine-6-carboxylic acid-BF 2 -chelate 2.00g, anhydrous piperazine
Mixture of 1.57g and 10ml of dimethylacetamide
Heated at 110-120°C for 2 hours. After cooling, the precipitated crystals were collected by filtration, washed with cold methanol, and 9-fluoro-3
-Methyl-10-(1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido [1,2,
1.66 g (yield 73.4%) of 3-de][1,4]-benzoxazine-6-carboxylic acid was obtained, which was recrystallized from a mixed solvent of chloroform-methanol-water. Melting point: 260℃ (decomposition). Elemental analysis value C 17 H 18 FN 3 O 4・3/2H 2 O Calculated value C 54.69, H 5.40, N 11.25 Actual value C 54.74, H 5.19, N 11.33 Example 16 9-chloro-10-fluoro-3 -Methyl-7-
Oxo-2,3-dihydro-7H-pyrido [1,
2,3-de〕[1,4]-benzoxazine-6
- Carboxylic acid - BF 2 - Chelate 0.50g, N-methylpiperazine 0.44g and dimethyl sulfoxide
2.5 ml of the mixture was heated at 110-130°C for 5 hours. Add methanol to the precipitated crystals, collect by filtration, wash with methanol, and give 9-chloro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-
Dihydro-7H-pyrido [1,2,3-de] [1,
4]-Benzoxazine-6-carboxylic acid 0.43g
(yield 78%). This was recrystallized from a mixed solvent of chloroform and methanol. Melting point: 280℃ (decomposition). Elemental analysis value C 18 H 20 ClN 3 O 4 Calculated value C 57.22, H 5.34, N 11.12 Actual value C 56.78, H 5.34, N 11.07
Claims (1)
して一般式 で表わされる化合物を製することを特徴とするピ
リドベンズオキサジン誘導体およびその塩類の製
法。上記式中R1およびR2は同じまたは異なり、
水素原子または低級アルキル基を意味し、X1お
よびX2は同じまたは異なるハロゲン原子を意味
する。 ２ 特許請求の範囲第１項においてR1およびR2
がメチル基、X1がフツ素原子である化合物の製
法。 ３ 特許請求の範囲第１項においてR1およびR2
がメチル基、X1が塩素原子である化合物の製法。[Claims] 1. General formula The general formula for the compound represented by By reacting piperazines represented by the general formula A compound represented by is prepared and subjected to a decomposition reaction to obtain the general formula 1. A method for producing a pyridobenzoxazine derivative and its salts, which comprises producing a compound represented by: In the above formula, R 1 and R 2 are the same or different,
It means a hydrogen atom or a lower alkyl group, and X 1 and X 2 mean the same or different halogen atoms. 2 R 1 and R 2 in claim 1
A method for producing a compound in which is a methyl group and X 1 is a fluorine atom. 3 R 1 and R 2 in claim 1
A method for producing a compound in which is a methyl group and X 1 is a chlorine atom.
Priority Applications (16)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14191981A JPS5843977A (en) | 1981-09-09 | 1981-09-09 | Preparation of pyridobenzoxazine derivative |
| AR29051082A AR230451A1 (en) | 1981-09-09 | 1982-09-01 | PROCEDURE FOR PREPARING DERIVATIVES OF PIRIDO ACID (1,3-DE) 1,4-BENZOXACIN-6-CARBOXILICO |
| FI823024A FI76345C (en) | 1981-09-09 | 1982-09-01 | FOERFARANDE FOER FRAMSTAELLNING AV PYRIDOBENSOXAZINDERIVAT. |
| DK399782A DK158268C (en) | 1981-09-09 | 1982-09-07 | PROCEDURE FOR PREPARING PYRIDOBENZOXAZINE DERIVATIVES |
| YU202182A YU43922B (en) | 1981-09-09 | 1982-09-07 | Process for preparing pyrido (1,2,3-de)(1,4)-benzoxazine-6-carboxylic acid derivatives |
| SI8212021A SI8212021A8 (en) | 1981-09-09 | 1982-09-07 | Process for preparing pyrido /1,2,3-de/ /1,4/-benzoxazine-6-carboxylic acid derivatives |
| PT7552382A PT75523B (en) | 1981-09-09 | 1982-09-07 | Process for preparing pyridobenzoxazine derivatives |
| PL23817782A PL130881B1 (en) | 1981-09-09 | 1982-09-08 | Process for preparing novel derivatives of pyrido /1,2,3-de/-/1,4/-benzoxazin-6-carboxylic acid |
| DD24311682A DD203719A5 (en) | 1981-09-09 | 1982-09-08 | PROCESS FOR PREPARING NEW ANTIBACTERIAL PYRIDO (1,2,3-DE) (1,4) BENZOXAZINE-5-CARBOXYLIC ACID DERIVATIVES |
| MX787982A MX155044A (en) | 1981-09-09 | 1982-09-08 | PROCEDURE TO PREPARE PIRIDOBENZO-XAZINA DERIVATIVES |
| ES515608A ES8400432A1 (en) | 1981-09-09 | 1982-09-09 | Preparation of pyridobenzoxazine derivative |
| FI881403A FI80463C (en) | 1981-09-09 | 1988-03-24 | PYRIDO / 1,2,3-DE // 1,4 / BENZOXAZIN-6-CARBOXYLSYRA-BF2-CHELATED DIVIDED FOR FRAMSTAELLNING. |
| DK173588A DK173588D0 (en) | 1981-09-09 | 1988-03-29 | METHOD FOR PREPARING PYRIDO (1,2,3-DE) (1,4) BENZOXAZINE-6-CARBOXYLIC ACID-BF2-CHELATE COMPOUNDS |
| SI8810746A SI8810746A8 (en) | 1981-09-09 | 1988-04-14 | Process for preparation of BF2-chelate compound of pyrido /1,2,3-de//1,4/ benzoxazine-6-carboxylic acid |
| YU74688A YU46542B (en) | 1981-09-09 | 1988-04-14 | PROCESS FOR PREPARATION OF BF2-CHELATE COMPOUND PIRIDO / 1,2,3-DE // 1,4 / BENZOXAZINE-6-CARBOXYLIC ACIDS |
| HR930085A HRP930085B1 (en) | 1981-09-09 | 1993-02-01 | PROCESS FOR THE PREPARATION OF BF2-KETONIC COMPOUND PYRIDOL (1,2,3-de)(1,4) BENZOXAZYNE-6-CARBOXYLIC ACID |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14191981A JPS5843977A (en) | 1981-09-09 | 1981-09-09 | Preparation of pyridobenzoxazine derivative |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62234466A Division JPS63119487A (en) | 1987-09-18 | 1987-09-18 | Production of pyridobenzoxazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5843977A JPS5843977A (en) | 1983-03-14 |
| JPH0148910B2 true JPH0148910B2 (en) | 1989-10-20 |
Family
ID=15303207
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14191981A Granted JPS5843977A (en) | 1981-09-09 | 1981-09-09 | Preparation of pyridobenzoxazine derivative |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5843977A (en) |
| AR (1) | AR230451A1 (en) |
| DD (1) | DD203719A5 (en) |
| DK (2) | DK158268C (en) |
| ES (1) | ES8400432A1 (en) |
| FI (1) | FI76345C (en) |
| PL (1) | PL130881B1 (en) |
| PT (1) | PT75523B (en) |
| YU (2) | YU43922B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0160284B1 (en) * | 1984-04-26 | 1990-10-24 | Abbott Laboratories | Quino-benoxazine antibacterial compounds |
| CA1306750C (en) | 1985-12-09 | 1992-08-25 | Istvan Hermecz | Process for the preparation of quinoline carboxylic acide |
| TW208013B (en) * | 1990-03-01 | 1993-06-21 | Daiichi Co Ltd |
-
1981
- 1981-09-09 JP JP14191981A patent/JPS5843977A/en active Granted
-
1982
- 1982-09-01 AR AR29051082A patent/AR230451A1/en active
- 1982-09-01 FI FI823024A patent/FI76345C/en not_active IP Right Cessation
- 1982-09-07 DK DK399782A patent/DK158268C/en not_active IP Right Cessation
- 1982-09-07 YU YU202182A patent/YU43922B/en unknown
- 1982-09-07 PT PT7552382A patent/PT75523B/en unknown
- 1982-09-08 PL PL23817782A patent/PL130881B1/en unknown
- 1982-09-08 DD DD24311682A patent/DD203719A5/en unknown
- 1982-09-09 ES ES515608A patent/ES8400432A1/en not_active Expired
-
1988
- 1988-03-29 DK DK173588A patent/DK173588D0/en active IP Right Grant
- 1988-04-14 YU YU74688A patent/YU46542B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR230451A1 (en) | 1984-04-30 |
| FI823024L (en) | 1983-03-10 |
| JPS5843977A (en) | 1983-03-14 |
| YU74688A (en) | 1989-12-31 |
| DD203719A5 (en) | 1983-11-02 |
| PT75523A (en) | 1982-10-01 |
| FI823024A0 (en) | 1982-09-01 |
| FI76345B (en) | 1988-06-30 |
| DK158268B (en) | 1990-04-23 |
| PL130881B1 (en) | 1984-09-29 |
| PT75523B (en) | 1984-12-12 |
| DK173588A (en) | 1988-03-29 |
| YU46542B (en) | 1993-11-16 |
| YU43922B (en) | 1989-12-31 |
| DK158268C (en) | 1990-10-15 |
| DK173588D0 (en) | 1988-03-29 |
| FI76345C (en) | 1988-10-10 |
| PL238177A1 (en) | 1983-05-09 |
| YU202182A (en) | 1984-12-31 |
| ES515608A0 (en) | 1983-11-01 |
| ES8400432A1 (en) | 1983-11-01 |
| DK399782A (en) | 1983-03-10 |
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| EXPY | Cancellation because of completion of term |