JPH0372230B2 - - Google Patents
Info
- Publication number
- JPH0372230B2 JPH0372230B2 JP23483383A JP23483383A JPH0372230B2 JP H0372230 B2 JPH0372230 B2 JP H0372230B2 JP 23483383 A JP23483383 A JP 23483383A JP 23483383 A JP23483383 A JP 23483383A JP H0372230 B2 JPH0372230 B2 JP H0372230B2
- Authority
- JP
- Japan
- Prior art keywords
- dihydro
- methyl
- difluoro
- yield
- boron trifluoride
- 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
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 16
- 229910015900 BF3 Inorganic materials 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 150000008065 acid anhydrides Chemical class 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 10
- 239000013522 chelant Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 description 8
- 238000009835 boiling Methods 0.000 description 7
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 239000000126 substance Substances 0.000 description 6
- -1 carbocyclic carboxylic acids Chemical class 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 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 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BQHDXNZNSPVVKB-UHFFFAOYSA-N diethyl 2-methylidenepropanedioate Chemical compound CCOC(=O)C(=C)C(=O)OCC BQHDXNZNSPVVKB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-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 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical class CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical class [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
本発明はホウ素キレート化合物の製造法に関す
る。さらに詳しくは、本発明は式
（式中、R1は水素原子又は低級アルキル基を、
R2及びR3は同じ又は異なる低級アルキル基を、
X1及びX2は同じ又は異なるハロゲン原子を表わ
す）で表わされる化合物と三フツ化ホウ素又は三
フツ化ホウ素錯体とを酸無水物中で反応させるこ
とからなる式
（式中、R1，X1及びX2は前記に同じ）で表わ
される化合物の製造法に関する。
式（）の化合物は特開昭57−46986号公報に
記載された抗菌物質の合成中間体としてきわめて
重要な化合物である。
従来、式（）の化合物の製造法としては、式
（）の化合物を三フツ化ホウ素又は三フツ化ホ
ウ素錯体と反応させることからなる製造法が知ら
れている。（特開昭58−29789号公報参照）
しかしながら、この製造法では反応温度を200
〜240℃に保つた場合には目的化合物が収率良く
得られるが、反応温度をそれよりも低く保つた場
合、収率が低下している。従つて、目的化合物を
収率良く得るには反応温度を200℃以上という高
温に保たねばならず、設備面、材質面及び危険性
等から、従来の製造法は工業的製造法として満足
できるものではない。
本発明者等は、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（）の化合物と三フツ化ホ
ウ素又は三フツ化ホウ素錯体とを酸無水物中で反
応させることからなる式（）の化合物の製造法
である。
三フツ化ホウ素錯体としては三フツ化ホウ素の
テトラヒドロフラン錯体、ジエチルエーテル錯
体、ジブチルエーテル錯体、酢酸錯体及びメタノ
ール錯体等があげられる。
三フツ化ホウ素及び三フツ化ホウ素錯体は、そ
れぞれ単独又は２種以上混合して使用され、その
使用量は通常式（）の化合物に対し１〜３倍モ
ルの範囲、好ましくは１〜２倍モルの範囲であ
る。
酸無水物としては無水酢酸、無水プロピオン酸
及び無水酪酸等の脂肪族カルボン酸の無水物並び
に安息香酸等の炭素環式カルボン酸の無水物があ
げられる。これらの酸無水物は通常単独で使用さ
れるが、２種以上混合して使用してもよく、その
使用量は通常式（）の化合物１部に対して0.5
〜５部の範囲が好適である。
反応は80〜150℃、好ましくは100〜140℃で30
分〜４時間、好ましくは１〜２時間保つことによ
り実施される。
反応が進行すると、カルボン酸のアルキルエス
テル、カルボン酸並びにテトラヒドロフラン、ジ
エチルエーテル、酢酸及びメタノール等の錯体溶
媒の如き副生物が生成するが、これらを反応系外
に除去しながら、例えば低沸点のものを留去しな
がら反応を行うと目的化合物の収率が一層向上す
ることがある。
反応終了後、反応液を冷却し析出する結晶をそ
のまま濾取しメタノール等で洗浄するか、もしく
は反応液にメタノール又はエタノール等のアルコ
ール系溶媒、アセトン等のケトン系溶媒、酢酸エ
ステル等のエステル系溶媒、エチレンジクロリド
等の塩素系溶媒あるいはベンゼン等の芳香族系溶
媒を注加した後析出した結晶を濾取してメタノー
ル等で洗浄すると、目的とする式（）の化合物
を容易に得ることができる。
本発明は比較的低温で目的とする式（）の化
合物を高収率及び高純度で得ることができ、工業
的にきわめて有用な製造法である。
実施例 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5.2ｇ及
びジエチルエトキシメチレンマロネート7.4ｇの
混合物を130〜140℃で生成するエタノールを留去
しながら５時間加熱撹拌し、（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
ン酸ジエチルを生成させる。減圧下にエタノール
を留去し、残査に三フツ化ホウ素テトラヒドロフ
ラン錯体８ｇ及び無水酢酸10mlを加え、１時間撹
拌還流する。その後102〜135℃で低沸点留分を留
去しながら１時間撹拌する。冷後エチレンジクロ
リド30mlを加え析出した結晶を濾取し、メタノー
ルで洗浄して乾燥する。得られた結晶のIR，
NMR、元素分析及びTLC等は既知の９，10−ジ
フルオロ−３−メチル−７−オキソ−２，３−ジ
ヒドロ−7H−ピリド〔１，２，３−de〕〔１，
４〕ベンズオキサジン−６−カルボン酸−BF2−
キレートと一致した。収量8.01ｇ（収率85.2％）
実施例 ２
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9.33ｇ
及びジエチルエトキシメチレンマロネート13.1ｇ
の混合物を実施例１と同様に反応させて（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
チレンマロン酸ジエチルを生成させる。減圧下に
エタノールを留去し、残査を無水酢酸18mlに溶解
後100〜120℃で撹拌下に三フツ化ホウ素テトラヒ
ドロフラン錯体7.76ｇを滴下する。滴下後30分間
撹拌還流し、次いで102〜117℃で低沸点の物質を
留去しながら１時間撹拌する。冷後、エチレンジ
クロリド54mlで晶析させる。析出した結晶を濾取
しメタノール54ml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−キレートを
得る。収量13.72ｇ（収率82.8％）
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13.15ｇ
及びジエチルエトキシメチレンマロネート16.89
ｇの混合物を実施例１と同様に反応させて（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）
メチレンマロン酸ジエチルを生成させる。減圧下
にエタノールを留去し、残査を無水酢酸24mlに溶
解し、100〜120℃で撹拌下に三フツ化ホウ素テト
ラヒドロフラン錯体10.93ｇを滴下する。滴下後
30分間撹拌還流し、ついで低沸点留分を留去しな
がら２時間撹拌する。冷後アセトン30mlで晶析さ
せる。析出した結晶を濾取し、メタノール50ml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−キレートを得る。収量20.14
ｇ（収率86.2％）
実施例 ４
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2.34ｇ
及びジエチルエトキシメチレンマロネート3.29ｇ
の混合物を実施例１と同様に反応させる。減圧下
にエタノールを留去し、残査をジイソプロピルエ
ーテルで再結晶すると白色結晶の（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
マロン酸ジエチルを得る。融点68℃。
NMR（CDCl3，δ，ppm）
6.67〜6.87（2H，ｍ，芳香族プロトン）
4.0〜4.47（7H，ｍ，−ＣＨ 2−CT3，
The present invention relates to a method for producing boron chelate compounds. More specifically, the invention relates to the formula (In the formula, R 1 is a hydrogen atom or a lower alkyl group,
R 2 and R 3 are the same or different lower alkyl groups,
A formula consisting of reacting a compound represented by (X 1 and X 2 represent the same or different halogen atoms) with boron trifluoride or a boron trifluoride complex in an acid anhydride (wherein R 1 , X 1 and X 2 are the same as above). The compound of formula () is an extremely important compound as a synthetic intermediate for the antibacterial substance described in JP-A No. 57-46986. BACKGROUND ART Conventionally, as a method for producing a compound of formula (), a production method is known which involves reacting a compound of formula () with boron trifluoride or a boron trifluoride complex. (Refer to Japanese Patent Application Laid-open No. 58-29789.) However, in this production method, the reaction temperature is
When the reaction temperature is kept at ~240°C, the target compound is obtained in good yield, but when the reaction temperature is kept lower than that, the yield is reduced. Therefore, in order to obtain the target compound in good yield, the reaction temperature must be maintained at a high temperature of 200°C or higher, and the conventional manufacturing method is satisfactory as an industrial manufacturing method from the standpoint of equipment, materials, and risks. It's not a thing. The present inventors completed the present invention as a result of intensive studies to overcome these drawbacks of conventional methods. That is, the present invention is a method for producing a compound of formula (), which comprises reacting the compound of formula () with boron trifluoride or a boron trifluoride complex in an acid anhydride. Examples of boron trifluoride complexes include tetrahydrofuran complexes, diethyl ether complexes, dibutyl ether complexes, acetic acid complexes, and methanol complexes of boron trifluoride. Boron trifluoride and boron trifluoride complexes are used individually or in combination of two or more, and the amount used is usually 1 to 3 times the mole of the compound of formula (), preferably 1 to 2 times the amount of the compound of formula (). It is in the molar range. Examples of acid anhydrides include anhydrides of aliphatic carboxylic acids such as acetic anhydride, propionic anhydride, and butyric anhydride, and anhydrides of carbocyclic carboxylic acids such as benzoic acid. These acid anhydrides are usually used alone, but they may be used in combination of two or more, and the amount used is usually 0.5 to 1 part of the compound of formula ().
A range of 5 parts to 5 parts is preferred. The reaction is carried out at 80-150℃, preferably 100-140℃ for 30
This is carried out by keeping the temperature for 1 to 4 hours, preferably 1 to 2 hours. As the reaction progresses, by-products such as alkyl esters of carboxylic acids, carboxylic acids, and complex solvents such as tetrahydrofuran, diethyl ether, acetic acid, and methanol are produced. If the reaction is carried out while distilling off, the yield of the target compound may be further improved. After the reaction is complete, the reaction solution is cooled and the precipitated crystals are collected by filtration and washed with methanol, etc., or the reaction solution is mixed with an alcohol solvent such as methanol or ethanol, a ketone solvent such as acetone, or an ester solvent such as acetate. After adding a solvent, a chlorinated solvent such as ethylene dichloride, or an aromatic solvent such as benzene, the precipitated crystals are collected by filtration and washed with methanol, etc., to easily obtain the desired compound of formula (). can. The present invention is an industrially extremely useful production method that can obtain the target compound of formula () in high yield and purity at a relatively low temperature. Example 1 7,8-difluoro-2,3-dihydro-3-
A mixture of 5.2 g of methyl-4H-1,4-benzoxazine and 7.4 g of diethyl ethoxymethylene malonate was heated and stirred at 130 to 140°C for 5 hours while distilling off the ethanol produced. ,3-dihydro-3-methyl-4H-1,
Diethyl 4-benzoxazin-4-yl)methylenemalonate is produced. Ethanol was distilled off under reduced pressure, and 8 g of boron trifluoride tetrahydrofuran complex and 10 ml of acetic anhydride were added to the residue, followed by stirring and refluxing for 1 hour. Thereafter, the mixture is stirred for 1 hour at 102 to 135°C while distilling off the low boiling point fraction. After cooling, 30 ml of ethylene dichloride was added, and the precipitated crystals were collected by filtration, washed with methanol, and dried. IR of the obtained crystal,
NMR, elemental analysis, TLC, etc. were performed on the known 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,
4] Benzoxazine-6-carboxylic acid-BF 2 −
Matched with chelate. Yield 8.01g (yield 85.2%) Example 2 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 9.33g
and diethyl ethoxymethylene malonate 13.1g
(7,8) was reacted in the same manner as in Example 1.
-difluoro-2,3-dihydro-3-methyl-
Diethyl 4H-1,4-benzoxazin-4-yl)methylenemalonate is produced. Ethanol is distilled off under reduced pressure, the residue is dissolved in 18 ml of acetic anhydride, and 7.76 g of boron trifluoride tetrahydrofuran complex is added dropwise to the solution while stirring at 100-120°C. After the dropwise addition, the mixture is stirred and refluxed for 30 minutes, and then stirred for 1 hour while distilling off low-boiling substances at 102-117°C. After cooling, crystallize with 54 ml of ethylene dichloride. The precipitated crystals were collected by filtration and washed with 54 ml of methanol to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-
7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid- BF2 -chelate is obtained. Yield 13.72g (yield 82.8%) Example 3 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 13.15g
and diethyl ethoxymethylene malonate 16.89
A mixture of (7,
8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazin-4-yl)
Diethyl methylenemalonate is produced. Ethanol is distilled off under reduced pressure, the residue is dissolved in 24 ml of acetic anhydride, and 10.93 g of boron trifluoride tetrahydrofuran complex is added dropwise to the solution while stirring at 100-120°C. After dripping
Stir and reflux for 30 minutes, then stir for 2 hours while distilling off the low-boiling fraction. After cooling, crystallize with 30 ml of acetone. The precipitated crystals were collected by filtration, washed with 50 ml of methanol, and 9,10-difluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido [1,
2,3-de][1,4]benzoxazine-6-
A carboxylic acid- BF2 -chelate is obtained. Yield 20.14
g (yield 86.2%) Example 4 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 2.34g
and diethyl ethoxymethylene malonate 3.29g
The mixture is reacted in the same manner as in Example 1. Ethanol was distilled off under reduced pressure, and the residue was recrystallized from diisopropyl ether to give white crystals (7,8-difluoro-2,3-dihydro-3-methyl-4H-
Diethyl 1,4-benzoxazin-4-yl)methylenemalonate is obtained. Melting point 68℃. NMR ( CDCl3 , δ, ppm) 6.67-6.87 (2H, m, aromatic proton) 4.0-4.47 (7H, m, -CH2 - CT3 ,
【式】
7.74（1H，ｓ，−ＣＨ＝Ｃ）
1.18〜1.47（9H，−CH2−ＣＨ 3，CH−ＣＨ
３）
得られた結晶３ｇに三フツ化ホウ素テトラヒド
ロフラン錯体1.54ｇ及び無水酢酸３mlを加え、外
温150℃の低沸点の物質を留去しながら１時間撹
拌する。冷後析出した結晶を濾取し、冷メタノー
ル10ml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−キレートを得る。収
量2.31ｇ（収率83.1％）
実施例 ５
（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）メチレンマロン酸ジエチル３ｇに三フツ
化ホウ素テトラヒドロフラン錯体1.54ｇ及び無水
酢酸３mlを加え、撹拌下１時間還流する。冷後析
出した結晶を濾取し、冷メタノール10mlで洗浄す
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−BF2−キレートが得られる。収量2.18ｇ
（収率78.5％）
実施例 ６
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1.56ｇ
及びジエチルエトキシメチレンマロネート2.19ｇ
の混合物を実施例１と同様に反応させて、（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）
メチレンマロン酸ジエチルを生成させる。減圧下
にエタノールを留去し、残査を無水プロピオン酸
３ml及び三フツ化ホウ素テトラヒドロフラン錯体
1.54ｇを加え１時間撹拌還流する。次いで、外温
150℃で低沸点の物質を留去しながら１時間撹拌
する。反応後氷冷しエチレンジクロリド10mlで晶
析させる。析出した結晶を濾取し冷メタノールで
洗浄し乾燥すると、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−BF2−キレートを得る。
収量2.26ｇ（収率81.3％）
実施例 ７
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1.56ｇ
及びジエチルエトキシメチレンマロネート2.19ｇ
の混合物を実施例１と同様に反応させて、（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）
メチレンマロン酸ジエチルを生成させる。減圧下
にエタノールを留去し、残査に三フツ化ホウ素テ
トラヒドロフラン錯体1.54ｇ及び無水酪酸３mlを
加え、１時間撹拌還流する。次いで、外温150℃
で低沸点の物質を留去しながら１時間撹拌する。
反応後氷冷し、エチレンジクロリド10mlで晶析さ
せる。析出した結晶を濾取し、冷メタノールで洗
浄し、乾燥すると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−BF2−キレートを得られ
る。収量2.21ｇ（収率79.5％）
実施例 ８
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2.34ｇ
及びジエチルエトキシメチレンマロネート3.27ｇ
の混合物を実施例１と同様に反応させて（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
チレンマロン酸ジエチルを生成させる。減圧下に
エタノールを留去し、残査を三フツ化ホウ素テト
ラヒドロフラン錯体1.94ｇ及び無水安息香酸５ml
を加え、１時間撹拌還流する。次いで、外温150
℃で低沸点の物質を留去しながら１時間撹拌す
る。反応後氷冷し、エチレンジクロリド15mlで晶
析させる。析出した結晶を濾取し、メタノールで
洗浄し乾燥すると、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−BF2−キレートが得られ
る。収量3.42ｇ（収率82.4％）[Formula] 7.74 (1H, s, -CH = C) 1.18 - 1.47 (9H, -CH 2 -CH 3 , CH- CH
3 ) Add 1.54 g of boron trifluoride tetrahydrofuran complex and 3 ml of acetic anhydride to 3 g of the obtained crystals, and stir for 1 hour while distilling off low-boiling substances at an external temperature of 150°C. After cooling, the precipitated crystals were collected by filtration and washed with 10 ml of cold methanol to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrid [1,2,3-de]. 1,4] Benzoxazine-6-carboxylic acid- BF2 -chelate is obtained. Yield 2.31g (yield 83.1%) Example 5 (7,8-difluoro-2,3-dihydro-3
-Methyl-4H-1,4-benzoxazine-4
1.54 g of boron trifluoride tetrahydrofuran complex and 3 ml of acetic anhydride were added to 3 g of diethyl methylene malonate, and the mixture was refluxed for 1 hour with stirring. After cooling, the precipitated crystals were collected by filtration and washed with 10 ml of cold methanol to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrid [1,2,
3-de][1,4]benzoxazine-6-carboxylic acid- BF2 -chelate is obtained. Yield 2.18g
(Yield 78.5%) Example 6 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 1.56g
and diethyl ethoxymethylene malonate 2.19g
A mixture of (7,
8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazin-4-yl)
Diethyl methylenemalonate is produced. Ethanol was distilled off under reduced pressure, and the residue was mixed with 3 ml of propionic anhydride and boron trifluoride tetrahydrofuran complex.
Add 1.54 g and stir and reflux for 1 hour. Next, the external temperature
Stir at 150°C for 1 hour while distilling off low-boiling substances. After the reaction, cool on ice and crystallize with 10 ml of ethylene dichloride. The precipitated crystals were collected by filtration, washed with cold methanol, and dried to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1, 4] Obtain benzoxazine-6-carboxylic acid-BF 2 -chelate.
Yield 2.26g (yield 81.3%) Example 7 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 1.56g
and diethyl ethoxymethylene malonate 2.19g
A mixture of (7,
8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazin-4-yl)
Diethyl methylenemalonate is produced. Ethanol was distilled off under reduced pressure, and 1.54 g of boron trifluoride tetrahydrofuran complex and 3 ml of butyric anhydride were added to the residue, followed by stirring and refluxing for 1 hour. Next, the outside temperature is 150℃
Stir for 1 hour while distilling off low-boiling substances.
After the reaction, cool on ice and crystallize with 10 ml of ethylene dichloride. The precipitated crystals were collected by filtration, washed with cold methanol, and dried to give 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 is obtained. Yield 2.21g (yield 79.5%) Example 8 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 2.34g
and diethyl ethoxymethylene malonate 3.27g
(7,8) was reacted in the same manner as in Example 1.
-difluoro-2,3-dihydro-3-methyl-
Diethyl 4H-1,4-benzoxazin-4-yl)methylenemalonate is produced. Ethanol was distilled off under reduced pressure, and the residue was mixed with 1.94 g of boron trifluoride tetrahydrofuran complex and 5 ml of benzoic anhydride.
and stir and reflux for 1 hour. Next, external temperature 150
Stir at 1 hour while distilling off low-boiling substances. After the reaction, cool on ice and crystallize with 15 ml of ethylene dichloride. The precipitated crystals were collected by filtration, washed with methanol, and dried to give 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 is obtained. Yield 3.42g (yield 82.4%)
Claims (1)
R2及びR3は同じ又は異なる低級アルキル基を、
X1及びX2は同じ又は異なるハロゲン原子を表わ
す）で表わされる化合物と三フツ化ホウ素又は三
フツ化ホウ素錯体とを酸無水物中で反応させるこ
とを特徴とする式 （式中、R1，X1及びX2は前記に同じ）で表わ
される化合物の製造法[Claims] 1 formula (In the formula, R 1 is a hydrogen atom or a lower alkyl group,
R 2 and R 3 are the same or different lower alkyl groups,
X 1 and X 2 represent the same or different halogen atoms) is reacted with boron trifluoride or a boron trifluoride complex in an acid anhydride. Method for producing a compound represented by (wherein R 1 , X 1 and X 2 are the same as above)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23483383A JPS60126290A (en) | 1983-12-13 | 1983-12-13 | Production of boronic chelate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23483383A JPS60126290A (en) | 1983-12-13 | 1983-12-13 | Production of boronic chelate compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60126290A JPS60126290A (en) | 1985-07-05 |
| JPH0372230B2 true JPH0372230B2 (en) | 1991-11-18 |
Family
ID=16977088
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP23483383A Granted JPS60126290A (en) | 1983-12-13 | 1983-12-13 | Production of boronic chelate compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60126290A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
-
1983
- 1983-12-13 JP JP23483383A patent/JPS60126290A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60126290A (en) | 1985-07-05 |
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