JPH0359904B2 - - Google Patents
Info
- Publication number
- JPH0359904B2 JPH0359904B2 JP8882683A JP8882683A JPH0359904B2 JP H0359904 B2 JPH0359904 B2 JP H0359904B2 JP 8882683 A JP8882683 A JP 8882683A JP 8882683 A JP8882683 A JP 8882683A JP H0359904 B2 JPH0359904 B2 JP H0359904B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- methyl
- producing
- sulfuric 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
Links
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000004820 halides Chemical class 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- -1 2,3-dihydro-4H-1,4-benzoxazin-4-yl Chemical group 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XJDDLMJULQGRLU-UHFFFAOYSA-N 1,3-dioxane-4,6-dione Chemical compound O=C1CC(=O)OCO1 XJDDLMJULQGRLU-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 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
- KLTMALVMVMGIGT-UHFFFAOYSA-N 2-methyl-4h-1,4-benzoxazine Chemical compound C1=CC=C2OC(C)=CNC2=C1 KLTMALVMVMGIGT-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
- SNTZGENQEQKPHV-UHFFFAOYSA-N O1CC=NC2=CC(C(=O)OCC)=CC=C21 Chemical compound O1CC=NC2=CC(C(=O)OCC)=CC=C21 SNTZGENQEQKPHV-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
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical class [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
本発明はピリドベンズオキサジン誘導体の製法
に関する。更に詳しくは、本発明は式
〔式中、R1は水素原子又は低級アルキル基を、
X1及びX2は同じ又は異なるハロゲン原子を意味
し、R2は式
The present invention relates to a method for producing pyridobenzoxazine derivatives. More specifically, the invention relates to the formula [In the formula, R 1 is a hydrogen atom or a lower alkyl group,
X 1 and X 2 mean the same or different halogen atoms, R 2 is of the formula
【式】又は[Formula] or
【式】
（式中、R3は低級アルキル基を、R4及びR5は
同じ又は異なる低級アルキル基を意味する。）
で表わされる基を意味する。〕で表わされる化合
物を酸ハライド及び硫酸と反応させて式
（式中、R1，X1及びX2は前記に同じであり、
R6は水素原子又は低級アルキル基を意味する。）
で表わされる化合物を製する方法に関する。
化合物（）は、医療上有用なピリドベンズオ
キサジン誘導体（特開昭57−46986号公報参照）
の中間体として重要な化合物である。
化合物（）から化合物（）への製法につい
ては、ポリリン酸エステルを用いる方法が公知で
ある（前記公報参照）。しかし、この方法は150℃
という高温を必要とすること、廃棄物として大量
のリン系化合物が生成すること、及び収率が低い
ことなど、工業的製法としては必ずしも満足でき
るものではない。
本発明者らは、化合物（）の工業的に有利な
製法について鋭意研究を重ねた結果、本発明を完
成するに至つた。
即ち、本発明は化合物（）を酸ハライド及び
硫酸と反応させることからなる化合物（）の製
法である。
原料化合物（）は公知の方法または参考例に
示した方法により製造され、結晶として単離後ま
たは反応液のままで本発明方法の原料として用い
ることができる。
本発明の反応を行なうには、化合物（）及び
酸ハライドの混合物に硫酸を添加すればよい。添
加方法は特に限定されず、室温下0.5〜60分間で
加えるのが好ましいが、冷却下または加温下に添
加してもよい。この反応は硫酸の添加終了時点で
ほとんど終了しているが、さらに室温乃至150℃
の温度範囲に５〜120分間保ち、反応の完結を図
つてもよい。
本発明において使用される酸ハライドは脂肪族
系、芳香族系など各種のものがある。具体的に
は、たとえば、塩化アセチル、塩化プロピオニ
ル、塩化ｎ−ブチリル、塩化ベンゾイルなどがあ
げられ、これらは単独または二種以上混合して使
用される。酸ハライドの使用量は化合物（）１
部に対し0.2〜20部の範囲（重量比）が好適であ
る。
硫酸は濃度90％（重量）以上が好ましく、その
使用量は化合物（）１部に対し0.1〜５部の範
囲（重量比）が好適である。
反応終了後、生成した化合物（）は、反応液
を冷却するか、もしくは冷却後難溶性の溶媒を添
加して析出させ、これを濾取することにより容易
にかつ高収率で得ることができる。
本発明の方法は、緩和な条件下で単純な操作に
より目的化合物を高収率かつ高純度で得ることが
でき、工業的にきわめて有用な製造方法である。
次に実施例及び参考例を記載する。
実施例 １
ジエチル（７，８−ジフルオロ−３−メチル−
２，３−ジヒドロ−4H−１，４−ベンズオキサ
ジン−４−イル）メチレンマロネート1000gと塩
化アセチル２mlの混液に室温下97％硫酸0.5mlを
加え、更に外温80〜90℃のオイルバス上で１時間
加熱する。反応液に氷水を加え、析出する結晶を
濾取し、水洗し、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−カルボン酸エチルエステル817mg（収率
93.9％）をえた。融点261℃。
元素分析値 C15H13NO4F2として
計算値 C58.25，H4.24，N4.53
実測値 C58.31，H4.30，N4.52
実施例 ２
ジエチル（７，８−ジフルオロ−３−メチル−
２，３−ジヒドロ−4H−１，４−ベンズオキサ
ジン−４−イル）メチレンマロネート1000gと塩
化ベンゾイル１mlの混液に室温下97％硫酸0.5ml
を加え、更に外温100〜110℃のオイルバス上で20
分間加熱する。反応液に氷水を加え、析出する結
晶を濾取し水洗する。得られた湿晶をジエチルエ
ーテル20mlに懸濁し濾取し、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−カルボン酸エチルエステル623
mg（収率71.6％）をえた。融点261℃。
実施例 ３
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1.00g、
オルトギ酸エチル0.88g及びイソプロピリデンマ
ロネート（メルドラム酸）0.78gの混液を110〜
120℃で２分間加熱する。固化した反応混合物
（イソプロピリデン（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−４−イル）メチレンマロネート）
に塩化アセチル３mlを加えて溶液として、次いで
室温下97％硫酸0.5mlを加え、さらに同温５分間
保つ。反応液と氷水を加え、析出する結晶を濾取
し、水洗し、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874mg（収率57.5％）をえた。
融点300℃以上。
参考例
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1.00gオ
ルトギ酸エチル0.88g、イソプロピリデンマロネ
ート0.36g及びトルエン10mlの混液を1.5時間還流
する。微量の粘性分解物を熱時濾取し、濾液を減
圧下濃縮する。残渣をクロロホルム−石油エーテ
ルより再結晶するとイソプロピリデン（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−４−イル）メ
チレンマロネート1.48gが得られた。融点186〜
187℃。[Formula] (In the formula, R 3 represents a lower alkyl group, and R 4 and R 5 represent the same or different lower alkyl groups.) ] is reacted with acid halide and sulfuric acid to form the formula (In the formula, R 1 , X 1 and X 2 are the same as above,
R 6 means a hydrogen atom or a lower alkyl group. ) relates to a method for producing a compound represented by Compound () is a medically useful pyridobenzoxazine derivative (see JP-A-57-46986)
It is an important compound as an intermediate for Regarding the method for producing compound () from compound (), a method using polyphosphoric acid ester is known (see the above-mentioned publication). However, this method requires 150℃
This method is not necessarily satisfactory as an industrial production method because it requires high temperatures, produces a large amount of phosphorous compounds as waste, and has a low yield. The present inventors have completed the present invention as a result of extensive research into industrially advantageous manufacturing methods for the compound (). That is, the present invention is a method for producing compound (), which comprises reacting compound () with an acid halide and sulfuric acid. The raw material compound () is produced by a known method or the method shown in Reference Examples, and can be used as a raw material for the method of the present invention after isolation as a crystal or as a reaction solution. To carry out the reaction of the present invention, sulfuric acid may be added to a mixture of compound () and acid halide. The method of addition is not particularly limited, and is preferably added at room temperature for 0.5 to 60 minutes, but may be added under cooling or heating. This reaction is almost complete at the end of the addition of sulfuric acid, but it is further
The reaction may be completed by maintaining the temperature in the range of 5 to 120 minutes. The acid halides used in the present invention include various types such as aliphatic and aromatic. Specific examples include acetyl chloride, propionyl chloride, n-butyryl chloride, and benzoyl chloride, which may be used alone or in combination of two or more. The amount of acid halide used is compound () 1
A range of 0.2 to 20 parts (weight ratio) is suitable. The concentration of sulfuric acid is preferably 90% (weight) or more, and the amount used is preferably in the range of 0.1 to 5 parts (weight ratio) per 1 part of the compound (2). After the completion of the reaction, the generated compound () can be easily obtained in high yield by cooling the reaction solution, or by adding a poorly soluble solvent after cooling to precipitate it, and then collecting it by filtration. . The method of the present invention allows the target compound to be obtained in high yield and purity through simple operations under mild conditions, and is an extremely useful production method industrially. Next, Examples and Reference Examples will be described. Example 1 Diethyl (7,8-difluoro-3-methyl-
Add 0.5 ml of 97% sulfuric acid at room temperature to a mixture of 1000 g of 2,3-dihydro-4H-1,4-benzoxazin-4-yl) methylene malonate and 2 ml of acetyl chloride, and then add 0.5 ml of 97% sulfuric acid at room temperature, and then place in an oil bath at an external temperature of 80 to 90°C. Heat on top for 1 hour. Ice water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrid [1,2,3-de] [1,4]Benzoxazine-6-carboxylic acid ethyl ester 817 mg (yield
93.9%). Melting point: 261℃. Elemental analysis value C 15 H 13 NO 4 F 2 Calculated value C58.25, H4.24, N4.53 Actual value C58.31, H4.30, N4.52 Example 2 Diethyl (7,8-difluoro-3 -Methyl-
Add 0.5 ml of 97% sulfuric acid to a mixture of 1000 g of 2,3-dihydro-4H-1,4-benzoxazin-4-yl) methylene malonate and 1 ml of benzoyl chloride at room temperature.
and further heat on an oil bath at an external temperature of 100 to 110℃ for 20 minutes.
Heat for a minute. Ice water is added to the reaction solution, and the precipitated crystals are collected by filtration and washed with water. The obtained wet crystals were suspended in 20 ml of diethyl ether and collected by filtration to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-
7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester 623
mg (yield 71.6%). Melting point: 261℃. Example 3 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 1.00g,
A mixture of 0.88g of ethyl orthoformate and 0.78g of isopropylidene malonate (Meldrum's acid)
Heat at 120℃ for 2 minutes. The solidified reaction mixture (isopropylidene (7,8-difluoro-2,
3-dihydro-3-methyl-4H-1,4-benzoxazin-4-yl)methylenemalonate)
Add 3 ml of acetyl chloride to form a solution, then add 0.5 ml of 97% sulfuric acid at room temperature, and keep at the same temperature for an additional 5 minutes. The reaction solution and ice water were added, and the precipitated crystals were collected by filtration, washed with water, and 9,10-difluoro-3-methyl-
874 mg (yield 57.5%) of 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid was obtained.
Melting point over 300℃. Reference example 7,8-difluoro-2,3-dihydro-3-
A mixture of 1.00 g of methyl-4H-1,4-benzoxazine, 0.88 g of ethyl orthoformate, 0.36 g of isopropylidene malonate, and 10 ml of toluene is refluxed for 1.5 hours. A trace amount of viscous decomposition product is filtered off while hot, and the filtrate is concentrated under reduced pressure. Recrystallization of the residue from chloroform-petroleum ether yields isopropylidene (7,8-
difluoro-2,3-dihydro-3-methyl-
1.48 g of 4H-1,4-benzoxazin-4-yl)methylene malonate were obtained. Melting point 186~
187℃.
Claims (1)
X1及びX2は同じ又は異なるハロゲン原子を意味
し、R2は式【式】又は 【式】 （式中、R3は低級アルキル基を、R4及びR5は
同じ又は異なる低級アルキル基を意味する。） で表わされる基を意味する。〕で表わされる化合
物を酸ハライド及び硫酸と反応させることを特徴
とする式 （式中、R1、X1及びX2は前記に同じであり、
R6は水素原子又は低級アルキル基を意味する。）
で表わされる化合物の製法。 ２ 特許請求の範囲第１項において、R1がメチ
ル基、R6がエチル基、X1及びX2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がメチル
基、R6が水素原子、X1及びX2がフツ素原子であ
る化合物の製法。[Claims] 1 formula [In the formula, R 1 is a hydrogen atom or a lower alkyl group,
X 1 and X 2 are the same or different halogen atoms, R 2 is the formula [ Formula] or [ Formula ] ) means a group represented by A formula characterized by reacting a compound represented by ] with an acid halide and sulfuric acid (In the formula, R 1 , X 1 and X 2 are the same as above,
R 6 means a hydrogen atom or a lower alkyl group. )
A method for producing a compound represented by 2. A method for producing a compound according to claim 1, wherein R 1 is a methyl group, R 6 is an ethyl group, and X 1 and X 2 are fluorine atoms. 3. A method for producing a compound in claim 1, wherein R 1 is a methyl group, R 6 is a hydrogen atom, and X 1 and X 2 are fluorine atoms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8882683A JPS59216890A (en) | 1983-05-20 | 1983-05-20 | Preparation of pyridobenzoxazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8882683A JPS59216890A (en) | 1983-05-20 | 1983-05-20 | Preparation of pyridobenzoxazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59216890A JPS59216890A (en) | 1984-12-06 |
| JPH0359904B2 true JPH0359904B2 (en) | 1991-09-12 |
Family
ID=13953736
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8882683A Granted JPS59216890A (en) | 1983-05-20 | 1983-05-20 | Preparation of pyridobenzoxazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59216890A (en) |
-
1983
- 1983-05-20 JP JP8882683A patent/JPS59216890A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59216890A (en) | 1984-12-06 |
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