JPH02131447A - 2-chloro-4,5-difluorobenzoic acid derivative - Google Patents
2-chloro-4,5-difluorobenzoic acid derivativeInfo
- Publication number
- JPH02131447A JPH02131447A JP1089822A JP8982289A JPH02131447A JP H02131447 A JPH02131447 A JP H02131447A JP 1089822 A JP1089822 A JP 1089822A JP 8982289 A JP8982289 A JP 8982289A JP H02131447 A JPH02131447 A JP H02131447A
- Authority
- JP
- Japan
- Prior art keywords
- chloro
- formula
- difluorobenzoyl
- reaction
- 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.)
- Granted
Links
- CGFMLBSNHNWJAW-UHFFFAOYSA-N 2-chloro-4,5-difluorobenzoic acid Chemical class OC(=O)C1=CC(F)=C(F)C=C1Cl CGFMLBSNHNWJAW-UHFFFAOYSA-N 0.000 title abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims description 9
- 239000011737 fluorine Chemical group 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- DDXCBYLLYRMHRJ-UHFFFAOYSA-N C(C)(=O)OC(C1=C(C(=CC=C1)F)F)=O Chemical compound C(C)(=O)OC(C1=C(C(=CC=C1)F)F)=O DDXCBYLLYRMHRJ-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- -1 2-chloro-4,5-difluorobenzoyl halide compound Chemical class 0.000 abstract description 16
- 150000001875 compounds Chemical class 0.000 abstract description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 abstract description 10
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000012320 chlorinating reagent Substances 0.000 abstract description 3
- 238000007796 conventional method Methods 0.000 abstract description 3
- 239000002798 polar solvent Substances 0.000 abstract description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 abstract description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000009257 reactivity Effects 0.000 abstract description 2
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 2
- 239000004599 antimicrobial Substances 0.000 abstract 2
- WVGSPMZLNNRZRH-UHFFFAOYSA-N 2-chloro-4,5-difluorobenzoyl chloride Chemical compound FC1=CC(Cl)=C(C(Cl)=O)C=C1F WVGSPMZLNNRZRH-UHFFFAOYSA-N 0.000 abstract 1
- 229910006124 SOCl2 Inorganic materials 0.000 abstract 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000003242 anti bacterial agent Substances 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- QMQGGCRCCRHQNF-UHFFFAOYSA-N ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(F)=C(F)C=C1Cl QMQGGCRCCRHQNF-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 150000002085 enols Chemical group 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- ICWHQONNTRXCIJ-UHFFFAOYSA-N diethyl 2-(2-chloro-4,5-difluorobenzoyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C(=O)C1=CC(F)=C(F)C=C1Cl ICWHQONNTRXCIJ-UHFFFAOYSA-N 0.000 description 3
- 125000000468 ketone group Chemical group 0.000 description 3
- XDKQUSKHRIUJEO-UHFFFAOYSA-N magnesium;ethanolate Chemical compound [Mg+2].CC[O-].CC[O-] XDKQUSKHRIUJEO-UHFFFAOYSA-N 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XEBNBRGYFQUIJV-UHFFFAOYSA-N 2-chloro-4,5-difluorobenzoyl fluoride Chemical compound FC(=O)C1=CC(F)=C(F)C=C1Cl XEBNBRGYFQUIJV-UHFFFAOYSA-N 0.000 description 2
- PISLHDVOCMRDSD-UHFFFAOYSA-N 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoic acid Chemical compound OC(=O)CC(=O)C1=CC(F)=C(F)C=C1Cl PISLHDVOCMRDSD-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001495 ethyl group Chemical class [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RPZXUSJCSDQNTE-UHFFFAOYSA-N 2,4-dichloro-5-fluorobenzoyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(Cl)C=C1Cl RPZXUSJCSDQNTE-UHFFFAOYSA-N 0.000 description 1
- SYVNVEGIRVXRQH-UHFFFAOYSA-N 3-fluorobenzoyl chloride Chemical compound FC1=CC=CC(C(Cl)=O)=C1 SYVNVEGIRVXRQH-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000003323 beak Anatomy 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
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ITQFPVUDTFABDH-AATRIKPKSA-N ethyl (e)-3-ethoxyprop-2-enoate Chemical compound CCO\C=C\C(=O)OCC ITQFPVUDTFABDH-AATRIKPKSA-N 0.000 description 1
- WXMSGMOIAQWILS-UHFFFAOYSA-N ethyl 2-ethoxyprop-2-enoate Chemical compound CCOC(=C)C(=O)OCC WXMSGMOIAQWILS-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、キノロンカルボン酸系合成抗菌剤用中間体と
して有用な２−クロロ−４．５−ジフルオ口安息香酸誘
導体に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to 2-chloro-4,5-difluorobenzoic acid derivatives useful as intermediates for quinolone carboxylic acid-based synthetic antibacterial agents.
［従来の技術及び発明が解決しようとする課題］本発明
の２−クロロ−４．５−ジフルオ口安息香酸誘導体は、
新規物質であり、キノロンカルボン酸系合成抗菌剤用中
間体として有用なものである。[Prior art and problems to be solved by the invention] The 2-chloro-4,5-difluorobenzoic acid derivative of the present invention is
It is a new substance and is useful as an intermediate for quinolone carboxylic acid-based synthetic antibacterial agents.
キノロンカルボン酸系合成抗菌剤用中間体として、２．
４−ジクロロー５−フル才ロベンゾイルクロライドが知
られている（特開昭５８−７４６３８号参照）が、キノ
ロンカルボン酸系合成抗菌剤へ導く反応条件が、本発明
の化合物に比べて不利である。すなわち、本発明の化合
物の方が、反応温度を低くでき、又収率が良い等である
。2. As an intermediate for quinolone carboxylic acid-based synthetic antibacterial agents.
4-Dichloro-5-fluorobenzoyl chloride is known (see JP-A-58-74638), but the reaction conditions leading to a quinolone carboxylic acid-based synthetic antibacterial agent are disadvantageous compared to the compounds of the present invention. . That is, the compounds of the present invention allow for lower reaction temperatures and higher yields.
さらに本発明の化合物を出発原料とすることにより、２
，４−ジクロロー５−フル才ロベンゾイルクロライドで
は得ることができない種類の合成抗菌剤へと導くことが
できる。Furthermore, by using the compound of the present invention as a starting material, 2
, 4-dichloro-5-fluorobenzoyl chloride can lead to a type of synthetic antibacterial agent that cannot be obtained with 5-fluorobenzoyl chloride.
［課題を解決するための手段］
本発明の２−クロロ−４．５−ジフル才口安息香酸誘導
体は次式（ｒ）．（ＩＩ）， （ｍ）で示される。[Means for Solving the Problems] The 2-chloro-4,5-difulbenzoic acid derivative of the present invention has the following formula (r). (II), (m).
Ｆ
しｌ
（式中、Ｘは塩素または弗素を示す）
Ｆ
しｌ
（式中、Ｒ′は低級アルキル基を示す）ＯＲ”
（式中、Ｒ”，Ｒ”は低級アルキル基を示す）具体的に
は（ｒ）に関しては、
２−クロロ−４．５−ジフルオ口ペンゾイルクロライド
（Ｘ＝ＣＩ）
２−クロロ−４．５−ジフルオ口ペンゾイルフルオライ
ド（Ｘ＝Ｆ）
の化合物を表わし、（ｎ）に関しては、２−クロロ−４
．５−ジフルオ口ベンゾイル酢酸メチル（Ｒ＝ＣＨ．）
２−クロロ−４．５−ジフルオ口ベンゾイル酢酸エチル
（トＣＪｓ）
２−クロロ−４，５−ジフルオロベンゾイル酢酸プロビ
ル（Ｒ＝Ｃ．Ｉ｛，）
２−クロロ−４，５−ジフルオ口ベンゾイル酢酸ブチル
（Ｒ＝Ｃ４Ｈ．）
等の化合物を表わし、（Ｉ［［）に関しては２−（２−
クロロー４．５−ジフロオ口ベンゾイル）−３・メト
キシアクリル酸メチル
２−（２−クロロ−４．５−ジフロオ口ベンゾイル）−
３・エトキシアクリル酸エチル
２− （２−クロロ−４．５−ジフロオ口ベンゾイル）
−３・ブロボキシアクリル酸プロビル
２−（２−クロロ−４．５−ジフロオ口ベンゾイル）＝
３・ブトキシアクリル酸ブチル
などの化合物を表わすものである。F Shil (In the formula, X represents chlorine or fluorine) F Shil (In the formula, R' represents a lower alkyl group) OR" (In the formula, R" and R" represent a lower alkyl group) Specific Specifically, (r) represents the compound 2-chloro-4,5-difluoropenzoyl chloride (X=CI) 2-chloro-4,5-difluoropenzoyl fluoride (X=F), Regarding n), 2-chloro-4
．． Methyl 5-difluorobenzoylacetate (R=CH.) Ethyl 2-chloro-4,5-difluorobenzoylacetate (CJs) Probyl 2-chloro-4,5-difluorobenzoylacetate (R=C.I{, ) represents a compound such as 2-chloro-4,5-difluorobenzoylacetate (R=C4H.), and for (I[[), 2-(2-
Chloro-4,5-difluorobenzoyl)-3-methoxymethyl acrylate 2-(2-chloro-4,5-difluorobenzoyl)-
3.Ethyl 2-ethoxyacrylate (2-chloro-4,5-difluorobenzoyl)
-3.probyl broboxyacrylate 2-(2-chloro-4.5-difluorobenzoyl)=
3-Butoxy represents a compound such as butyl acrylate.
（Ｉ）のペンゾイルハライド化合物は既知の２−クロロ
−４．５−ジフル才口安息香酸から反応式（１）および
（２）に従い容易に製造できる．は下記に示す様な方
法により容易に製造できる。The penzoyl halide compound (I) can be easily produced from the known 2-chloro-4,5-difulbenzoic acid according to reaction formulas (1) and (2). can be easily produced by the method shown below.
一方（ＩＩ）のベンゾイル酢酸エステル化合物しｌ
前記式中， ｒＥｔＪとしては、このエチル基以外の低
級アルキル基であってもよい。On the other hand, in the benzoyl acetate compound of (II), in the above formula, rEtJ may be a lower alkyl group other than this ethyl group.
（ＩＩＩ）のベンゾイルアルコキシアクリル酸エステル
化合物の製法としては、（ＩＩ）のベンゾイル酢酸エス
テル化合物を無水酢酸等の反応溶媒の存在下、オルトギ
酸エチル等のオルトギ酸アルキルと １００℃〜１５０
℃の反応温度で反応させる。反応終了後、蒸留により反
応溶媒及び未反応のオルトギ酸アルキルを除くと、（Ｉ
ＩＩ）のベンゾイルアルコキシアクリル酸エステル化合
物が残渣として得られる．通常その残渣をそのまま次工
程で使用し得る。As a method for producing the benzoyl alkoxy acrylate compound (III), the benzoyl acetate compound (II) is mixed with an alkyl orthoformate such as ethyl orthoformate in the presence of a reaction solvent such as acetic anhydride at 100°C to 150°C.
The reaction is carried out at a reaction temperature of °C. After the reaction is completed, the reaction solvent and unreacted alkyl orthoformate are removed by distillation, resulting in (I
The benzoyl alkoxy acrylate compound II) is obtained as a residue. Usually, the residue can be used as is in the next step.
（ｍ）のベンゾイルアルコキシアクリル酸エステル化合
物から数ステップの既知の反応を応用することにより、
合成抗菌剤として有用なキノロンカルボン酸に誘導する
ことができる。By applying a known reaction of several steps from the benzoyl alkoxy acrylate compound of (m),
It can be derived into quinolone carboxylic acids, which are useful as synthetic antibacterial agents.
ＮＨＲ’
Ｒ４
式中、Ｒ４はシクロプ口ビル基、２，４−ジフルオロフ
ェニル基、４−フル才ロフェニル基等の置換アリール基
等
Ｕｈ
等を示す。NHR' R4 In the formula, R4 represents a substituted aryl group such as a cyclopylophenyl group, a 2,4-difluorophenyl group, or a 4-difluorophenyl group, or the like.
反応式（１）の塩素化において、塩素化剤としてチオニ
ルクロライド、塩化スルフリル、五塩化リン、オキシ塩
化リン等を用いることができ、中でもチオニルクロライ
ドが好ましい。塩素化はＤＭＦ， ＤＭＳＯ，ジオキサ
ン等の非プロトン性極性溶媒中もしくは無溶媒下、反応
温度５０〜８０℃にて、２−クロロ−４．５−ジフル才
口安息香酸と塩素化剤を反応させ、蒸留等の通常の方法
で単離することにより、２−クロロ−４．５−ジフルオ
口ペンゾイルクロライドを得ることができる。In the chlorination of reaction formula (1), thionyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus oxychloride, etc. can be used as the chlorinating agent, and among them, thionyl chloride is preferred. Chlorination is carried out by reacting 2-chloro-4,5-difulbenzoic acid with a chlorinating agent in an aprotic polar solvent such as DMF, DMSO, dioxane or in the absence of a solvent at a reaction temperature of 50 to 80°C. , 2-chloro-4,5-difluoropenzoyl chloride can be obtained by isolation by a conventional method such as distillation.
反応式（２）のフッ素化においては、フッ素化剤として
通常フッ化カリウムが用いられ、スルホラン等の非プロ
トン性極性溶媒の存在下、８０〜１５０℃の反応温度条
件下、実施され、反応終了後蒸留等の通例の反応で単離
し、２−クロロ−４．５−ジフルオ口ペンゾイルフルオ
ライドを得ることができる。In the fluorination of reaction formula (2), potassium fluoride is usually used as the fluorination agent, and the reaction is carried out in the presence of an aprotic polar solvent such as sulfolane at a reaction temperature of 80 to 150°C, and the reaction is completed. It can be isolated by customary reactions such as post-distillation to give 2-chloro-4,5-difluoropenzoyl fluoride.
反応式（３）のβケト酸エステルは二段反応により得ら
れる。即ち、２−クロロ−４．５−ジフル才口ペンゾイ
ルハライドとマロン酸ジエチルとをマグネシウムエチラ
ートの存在下、反応させることにより、２−クロロ−４
．５−ジフルオ口ベンゾイルマロン酸ジエチルを得たの
ち、それを水性媒体中、触媒量のｐ−トルエンスルホン
酸を用いて、８０〜１００℃の反応温度で、部分加水分
解および脱カルボキシル化によって、目的とする２−ク
ロロ−４．５−ジフルオロベンゾイル酢酸エチルのβケ
ト酸エステルが得られる。The β-keto acid ester of reaction formula (3) is obtained by a two-stage reaction. That is, by reacting 2-chloro-4,5-difulpenzoyl halide with diethyl malonate in the presence of magnesium ethylate, 2-chloro-4.
．． After obtaining diethyl 5-difluorobenzoylmalonate, it was purified by partial hydrolysis and decarboxylation with a catalytic amount of p-toluenesulfonic acid in an aqueous medium at a reaction temperature of 80-100°C. A β-keto acid ester of ethyl 2-chloro-4,5-difluorobenzoylacetate is obtained.
反応式（３）の前段反応をさらに詳しく説明すると、通
常、まず、エタノールとマグネシウム金属との反応によ
り、マグネシウムエチラートを得、さらにジエチルエー
テル，トルエン等の非プロトン性溶媒の存在下、マロン
酸ジェチルとマグネシウムエチラートを３０〜６０℃の
反応温度で、反応させることにより、マロン酸ジェチル
のマグネシウム塩を系中で得る。その後、それと２−ク
ロロ−４．５−ジフルオ口ペンゾイルハライドとの反応
を、−１０〜−５℃の反応温度で行い、酸処理，溶媒抽
出，二層分離，溶媒留去等の操作後、目的とする２−ク
ロロ−４．５−ジフルオ口ベンゾイルマロン酸ジエチル
が得られる。To explain the first stage reaction of reaction formula (3) in more detail, first, magnesium ethylate is obtained by the reaction of ethanol and magnesium metal, and then malonic acid is obtained in the presence of an aprotic solvent such as diethyl ether or toluene. A magnesium salt of jetyl malonate is obtained in the system by reacting jetyl and magnesium ethylate at a reaction temperature of 30 to 60°C. Thereafter, a reaction between it and 2-chloro-4,5-difluoropenzoyl halide was carried out at a reaction temperature of -10 to -5°C, and after operations such as acid treatment, solvent extraction, two-layer separation, and solvent distillation, The desired diethyl 2-chloro-4,5-difluorobenzoylmalonate is obtained.
反応式（４）のエステル交換は、触媒量の硫酸やｐ−１
ルエンスルホン酸の酸触媒存在下、５０〜８０℃の反応
温度でβ−ケト酸エチルエステルとブロバノール，ブタ
ノール等のアルコールと反応させることにより容易に実
施可能である。The transesterification of reaction formula (4) is carried out using a catalytic amount of sulfuric acid or p-1
This can be easily carried out by reacting β-keto acid ethyl ester with an alcohol such as brobanol or butanol at a reaction temperature of 50 to 80° C. in the presence of an acid catalyst of luenesulfonic acid.
またβ−ケト酸エチルエステルを水酸化ナトリウム等の
アルカリにより加水分解後、硫酸，塩酸等の酸存在化、
プロノール，ブタノール等によりエステル化することに
よっても実施可能である。In addition, after hydrolyzing β-keto acid ethyl ester with an alkali such as sodium hydroxide, it is converted into the presence of an acid such as sulfuric acid or hydrochloric acid,
It can also be carried out by esterification with pronol, butanol, etc.
［実施例］
実施例１
「２−クロロ−４．５−ジフルオ口ペンゾイルクロライ
ドの合成」
３００ｃｃのガラス製反応器に２−クロロ−４．５一ジ
フル才口安息香酸１００ｇとチオニルクロライド２００
ｇを入れ約６０〜７０℃で３時間撹拌した。未反応のチ
オニルク口ライドを留去後、減圧蒸留することにより、
２−クロロ−４．５−ジフルオ口ペンゾイルクロライド
を１０１．８ｇ得た。得られた２−クロロ−４．５−ジ
フル才口ペンゾイルクロライドの物性値は以下の通りで
あった。[Example] Example 1 "Synthesis of 2-chloro-4.5-difluoropenzoyl chloride" 100 g of 2-chloro-4.5-difluorbenzoic acid and 200 g of thionyl chloride were placed in a 300 cc glass reactor.
g and stirred at about 60 to 70°C for 3 hours. After distilling off unreacted thionyl chloride, by distilling under reduced pressure,
101.8 g of 2-chloro-4.5-difluoropenzoyl chloride was obtained. The physical properties of the obtained 2-chloro-4,5-diful penzoyl chloride were as follows.
・沸点 ９３〜９６℃／ １２ 〜１３ｍｍＨｇ・Ｎ
ＭＲ分析
＜ ”Ｆ−ＮＭＲ ＞ δｐｐｍ ｆｒｏｍ Ｃ
ＦＣＩｓ６ １２５．１ｐｐｍ（ｄ．ｄ．ｄ．，Ｊｒ−
ｒ＝２２．９Ｈｚ，ＪＨ−ｒ ＝ ９． ４ＨＺ，
Ｊ｝ｌ−Ｆ ＝ ８． １Ｈｚ ）δ １３６．
１ｐｐｍ（ｄ．ｄ．ｄ．，Ｊｔ−ｒ＝ ２２．９Ｈｚ，
ＪＨ−ｒ ＝ ７． ＯＨＺ， Ｊ｝ｌ−ｒ ＝
１０． ０Ｈｚ）＜ ’Ｈ−ＮＭＲ＞ δｐｐｍ
ｆｒｏｍ ＴＭＳ６ ７．３７ ｐｐｍ ，
δ ８、０３ｐｐｍ＜ＩＲ分析〉
１７７８ｃｍ−ｌ（Ｃ＝０）
実施例２
「２−クロロ−４．５−ジフル才口ペンゾイルフル才ラ
イドの合成」
還流器付き２００ｃｃのガラス製反応器に２−クロロ−
４．５−ジフル才口ペンゾイルクロライド５０ｇとスプ
レー乾燥フッ化カリウム１３．７ｇおよびスルホラン１
００ｇを仕込み、撹拌しながら１３５℃で４時間反応さ
せた。冷却後、無機塩を濾別し、減圧蒸留により、２−
クロロ−４．５−ジフルオ口ペンゾイルフルオライドを
４２ｇ得た。得られた２−クロロ−４．５−ジフルオロ
ベンゾイルフルオライドの物性値は以下の通りであった
。・Boiling point 93-96℃/ 12-13mmHg・N
MR analysis <”F-NMR> δppm from C
FCIs6 125.1ppm (d.d.d., Jr-
r=22.9Hz, JH-r=9. 4Hz,
J}l−F=8. 1Hz) δ 136.
1 ppm (d.d.d., Jt-r=22.9Hz,
JH-r=7. OHZ, J}l−r =
10. 0Hz) <'H-NMR> δppm
from TMS6 7.37 ppm,
δ 8,03 ppm <IR analysis> 1778 cm-l (C=0) Example 2 "Synthesis of 2-chloro-4,5-difulpenzoylfuride" Chloro
4. 50 g of 5-difulpenzoyl chloride, 13.7 g of spray-dried potassium fluoride and 1 sulfolane.
00g was charged and reacted at 135°C for 4 hours with stirring. After cooling, inorganic salts were filtered off and 2-
42 g of chloro-4,5-difluoropenzoyl fluoride was obtained. The physical properties of the obtained 2-chloro-4,5-difluorobenzoyl fluoride were as follows.
・沸点 ７２〜７５℃／１５ｍｍＨｇ・ＮＭＲ分析
＜ ”Ｆ−ＮＭＲ ＞ δｐｐｍ ｆｒｏｍ Ｃ
ＦＣｌａδ −３２．１ｐｐｍ（ｓ）， ６１３６．
９ｐｐｍ（ｄ．ｄ．ｄ．，ＪＦ−Ｆ ＝ ２３．４Ｈ
ｚ， ＪＨ−ｒ ＝ ９．６Ｈｚ，ＪＨ−Ｆ
＝９．０ＨＺ ），
δ １２４．１ｐｐｍ（ｄ．ｄ．ｄ．，Ｊｒ−ｒ＝２３
．４Ｈｚ，ＪＭ−Ｆ ＝ ８．１ＨＺ，ＪＨ−Ｆ
＝ ８．７Ｈｚ ）＜ ’Ｈ−ＮＭＲ＞ δｐｐｍ
ｆｒｏｍ ＴＭＳ７．１ ｐｐｍ（ｍ）
実施例３
「２−クロロ−４．５〜ジフルオ口ベンゾイルマロン酸
ジエチルの合成」
削り状のマグネシウム６、３４ｇに無水エタノール１３
ｃｃおよび四塩化炭素１．２ｎ＋βを加え、撹拌を行い
、反応開始後、これにマロン酸ジエチル３９．９ｇ ，
無水エタノール２２ｃｃおよびトルエン７５ｃｃの溶液
を５０〜７０℃で滴下し、滴下終了後２時間撹拌した。・Boiling point 72-75℃/15mmHg・NMR analysis <"F-NMR> δppm from C
FClaδ -32.1ppm(s), 6136.
9ppm (d.d.d., JF-F = 23.4H
z, JH-r = 9.6Hz, JH-F
=9.0HZ), δ 124.1ppm (d.d.d., Jr-r=23
．． 4Hz, JM-F = 8.1Hz, JH-F
= 8.7Hz) <'H-NMR> δppm
from TMS7.1 ppm (m) Example 3 "Synthesis of diethyl 2-chloro-4.5-difluorobenzoylmalonate" 6.34 g of magnesium shavings and 13 g of absolute ethanol
cc and 1.2n+β of carbon tetrachloride were added, stirred, and after the reaction started, 39.9g of diethyl malonate,
A solution of 22 cc of absolute ethanol and 75 cc of toluene was added dropwise at 50 to 70°C, and stirred for 2 hours after the addition was completed.
その後、−１０〜−５℃に反応液を冷却し、そこに２−
クロロ−４．５−ジフル才口ペンゾイルクロライド５０
ｇとトルエン１５ ｍＩ２の溶液を３０分間で滴下し、
次いで２時間撹拌した。これに水冷希硫酸水溶液を加え
、内容物を溶かして層分離を行い、トルエン６０ｃｃで
３回抽出した。有機層を水洗し、無水硫酸マグネシウム
で乾燥後濃縮して淡黄色油状の目的物を７９．２ｇ得た
。Thereafter, the reaction solution was cooled to -10 to -5°C, and 2-
Chloro-4,5-difur penzoyl chloride 50
A solution of g and toluene 15 mI2 was added dropwise over 30 minutes,
The mixture was then stirred for 2 hours. A water-cooled dilute sulfuric acid aqueous solution was added to this, the contents were dissolved, the layers were separated, and the mixture was extracted three times with 60 cc of toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain 79.2 g of the target product as a pale yellow oil.
実施例４
「２−クロロ−４．５−ジフルオ口ベンゾイルマロン酸
ジエチルの合成」
原料として、２−クロロ−４．５−ジフルオ口ペンゾイ
ルフルオライドを用いた以外、実施例３と同様の方法で
、２−クロロ−４．５−ジフルオ口ペンゾイルマロン酸
ジエチルの合成を行った。その結果、２−クロロ−４．
５−ジフル才口ペンゾイルフルオライド５０ｇから目的
化合物が８３． ５ｇ得られた。Example 4 "Synthesis of diethyl 2-chloro-4,5-difluorobenzoylmalonate" Produced in the same manner as in Example 3 except that 2-chloro-4,5-difluorobenzoyl fluoride was used as the raw material. , 2-chloro-4,5-difluoropenzoyl diethylmalonate was synthesized. As a result, 2-chloro-4.
The target compound was obtained from 50 g of 5-difur-penzoyl fluoride at 83%. 5g was obtained.
実施例５
「２−クロロ−４．５−ジフルオ口ベンゾイル酢酸エチ
ルの合成」
２−クロロ−４−５−ジフノレオロペンゾイＪレマロン
酸ジエテル７０ｇに水９０ｃｃを加えて乳濁させ、これ
にバラトルエンスルホン酸０．２ｇを加えて激しく撹拌
しながら、３時間還流させた。冷却後、塩化メチレン１
５０ｃｃで３回抽出し、飽和食塩水で洗浄し、無水芒
硝で乾燥して濃縮後、塩化メチレン／ｎ−ヘキサンから
再結晶して目的化合物を３２ｇ得た。得られた２−クロ
ロ−４．５−ジフルオ口ベンゾイル酢酸エチルの物性値
は以下の通りであるが、重クロロホルム中のＮＭＲ分析
の結果、本化合物はケト体とエノール体の混合物である
ことが判った。Example 5 "Synthesis of ethyl 2-chloro-4,5-difluorobenzoylacetate" 90 cc of water was added to 70 g of 2-chloro-4-5-difluoropenzoi J remalonic acid diether to emulsify it. 0.2 g of balatoluenesulfonic acid was added, and the mixture was refluxed for 3 hours with vigorous stirring. After cooling, methylene chloride 1
The extract was extracted three times with 50 cc, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then recrystallized from methylene chloride/n-hexane to obtain 32 g of the target compound. The physical properties of the obtained ethyl 2-chloro-4.5-difluorobenzoylacetate are as follows, but as a result of NMR analysis in deuterated chloroform, this compound was found to be a mixture of a keto form and an enol form. understood.
ｒ
（ケト体）
ｒ
（エノール体）
・融点 ４８〜５０℃
・マススペクトル ペアレントビーク ２６２・ＩＲ
３０６０ 〜３１２０ｃｍ−’， ２８５０〜２９９
０ｃｍ−’１７１４ 〜１７３９ｃｍ−’， １４５０
〜１５００ｃｍ−’１１３０ 〜１１２０ｃｍ−’
・ＮＭＲ分析
＜ ”Ｆ−ＮＭＲ ＞δｐｐｍ ｆｒｏｍ ＣＦＣ
Ｉｓケト体 δ１２９．Ｏｐｐｍ ，６１３２． ３ｐ
ｐｍエノール体 δ １３７．５ｐｐｍ ，
６ １３８．５ｐｐｍ＜ ’Ｈ−ＮＭＲ＞ δｐｐ
ｍ ｆｒｏｍ ＴＭＳケト体 δ７． ３ｐｐｎ＋
（ＪＨ−ｒ”９−４ＨＺ＋ Ｊｏ−ｒ＝６．７ＨＺ）
δ ７．６ｐｐｍ
（ＪＨ−Ｆ＝８．３ＨＺ，Ｊｌ４−Ｆ＝ＩＯ．ＯＨＺ）
δ ４． Ｏｐｐｍ （ｓ）
エノール体
δ ４．２ｐｐｍ
（Ｊｃｏ −ｃｏ ” ７．０８ｐｐｍ）δ ｌ
．２６ｐｐｍ
ＣＪｃ，ｌ −ｃｓ ” ７．０８ｐｐｍ）δ
７．３ｐｐｍ
（Ｊｌ４−Ｆ＝９．４ＨＺ， ＪＨ−Ｆ”６．７ＨＺ
）δ ７．５ｐｐｍ
（ＪＨ−Ｆ”８．３ＨＺ， Ｊｌ４−Ｆ”ｌ０．８Ｈ
Ｚ）６ ５． ６２ｐｐｍ （ｓ）
δ ４．３ｐｐｍ
（ＪＣＨ −ｃＨ ” ７．１Ｈｚ）δ １．
３５ｐｐｍ
（Ｊｃｎ −ａｎ ” ７．１Ｈｚ）δ １２
．５ｐｐｍ（ＯＨ）
実施例６
ｒ２−（２−クロロ−４．５−ジフルオ口ベンゾイル）
３−エトキシアクリル酸エチルの合成」攪拌器付きの２
００ｃｃ容量のガラス製反応器に２−クロロ−４．５−
ジフルオ口ベンゾイル酢酸エチル２６．３ｇ ，オルト
ギ酸エチル２３．７ｇ及び無水酢酸４０ｍｌを入れ、反
応温度１２０〜１３５℃で反応させた。反応終了後、減
圧蒸留を行ない濃縮して目的化合物を残渣として３１．
５ｇ得た。得られた目的化合物２−（２−クロロ−４．
５−ジフルオロベンゾイル）−３−エトキシーアクリル
酸エチルの分析値は以下の通りであった。r (keto form) r (enol form) ・Melting point 48-50℃ ・Mass spectrum Parent beak 262・IR
3060~3120cm-', 2850~299
0cm-'1714 ~1739cm-', 1450
~1500cm-'1130 ~1120cm-' ・NMR analysis <"F-NMR> δppm from CFC
Is keto form δ129. Oppm, 6132. 3p
pm enol form δ 137.5ppm,
6 138.5ppm<'H-NMR> δpp
m from TMS keto body δ7. 3ppn+ (JH-r”9-4HZ+ Jo-r=6.7HZ)
δ 7.6ppm (JH-F=8.3HZ, Jl4-F=IO.OHZ)
δ 4. Oppm (s) Enol body δ 4.2ppm (Jco -co ” 7.08ppm) δ l
．． 26ppm CJc, l -cs ” 7.08ppm) δ
7.3ppm (Jl4-F=9.4HZ, JH-F”6.7HZ
) δ 7.5ppm (JH-F"8.3HZ, Jl4-F"l0.8H
Z)6 5. 62ppm (s) δ 4.3ppm (JCH −cH ” 7.1Hz) δ 1.
35ppm (Jcn-an” 7.1Hz) δ 12
．． 5ppm (OH) Example 6 r2-(2-chloro-4.5-difluorobenzoyl)
“Synthesis of ethyl 3-ethoxyacrylate” 2 with a stirrer
2-chloro-4.5- in a glass reactor with a capacity of 00 cc.
26.3 g of ethyl difluorobenzoyl acetate, 23.7 g of ethyl orthoformate, and 40 ml of acetic anhydride were added, and the mixture was reacted at a reaction temperature of 120 to 135°C. After the reaction is completed, vacuum distillation is performed to concentrate the target compound as a residue.31.
I got 5g. The obtained target compound 2-(2-chloro-4.
The analytical values of ethyl 5-difluorobenzoyl)-3-ethoxyacrylate were as follows.
なお、ＮＭＲ分析の結果、本化合物はＥ体とＺ体との混
合物であることがわかった。As a result of NMR analysis, it was found that this compound was a mixture of E-form and Z-form.
・マススペクトル Ｍ／Ｚ ： １４７，１７５，２２
７，２５５，２８３， ３１８
・ＮＭＲ分析（重クロロホルム溶媒）
＜ ”Ｆ−ＮＭＲ ＞δｐｐｍ ｆｒｏｍ ＣＦＣ
Ｌａδ １３１．１ｐｐｍ（ｍ） ， １３９，Ｏｐｐ
ｍ（Ｈ）＜ ’Ｈ−ＮＭＲ＞ δｐｐｍ ｆｒｏｍ
ＴＭＳδ ｌ．１１ｐｐｍ（ｔ） Ｊ ＣＭ −
ｃｏ ＝７．２０Ｈｚδ ｌ．１５ｐｐｍ（ｔ） Ｊ
ｃｓ−ｃＨ＝”ｌ、０８Ｈｚ６ １．３２ｐｐｍ（ｔ
） Ｊ ｃｓ−ｃＨ＝７．０８Ｈｚδ １．４５ｐｐ
ｍ（ｔ） Ｊ ｃ，Ｉ−ａｎ ”７、２０Ｈｚδ ４
．１３ｐｐｍ（ｑ）
６ ４．１４ｐｐｍ（ｑ）
δ ４．２１ｐｐｍ（ｑ）
６ ４．３３ｐｐｍ（ｑ）
６ ７．６８ｐｐｍ（ｓ）
６ ７．８１ｐｐｍ（ｓ）
・ＩＲ分析
Ｊ ｃＭ −ｃｏ ”７．０８ＨｚＪ ＣＭ
−ｃｏ ＝７．２０ＨｚＪ ＣＨ −ＣＭ ＝
７．０８ＨＺＪ ＣＭ −ｃｓ ＝７．２０Ｈｚ
１７１３ｃｍ−’ （ −Ｃ＝０ ，−ＧＯ
− ）１６６５ｃｍ−’ （−Ｃ＝ＣＯ−）［
発明の効果］
本発明の新規物質である２−クロロ−４．５−ジフルオ
口安息香酸誘導体は、医農薬中間体として、特に含フッ
素ビリドン力ルバオン酸系の合成抗菌剤用中間体として
有用である。しかも、本発明の中間体は、７位に反応性
の高いフッ素があるキノロン化合物へ導くことができる
ため、従来７位に塩素があるキノロン化合物に比べ、合
成抗菌剤へさらに導《ために必要とされる例えば環状ア
ミンとの反応性が高く、高収率で目的の合成抗菌剤へと
導《ことができる。さらに、この反応性の高いフッ素の
ために、従来法では得られない種類の合成抗菌剤へと導
くことができる。・Mass spectrum M/Z: 147,175,22
7,255,283, 318 ・NMR analysis (deuterated chloroform solvent) <”F-NMR>δppm from CFC
Laδ 131.1ppm (m), 139, Opp
m(H)<'H-NMR> δppm from
TMSδ l. 11ppm(t) J CM −
co =7.20Hzδ l. 15ppm (t) J
cs-cH=”l, 08Hz6 1.32ppm(t
) J cs-cH=7.08Hzδ 1.45pp
m(t) J c, I-an ”7, 20Hz δ 4
．． 13ppm(q) 6 4.14ppm(q) δ 4.21ppm(q) 6 4.33ppm(q) 6 7.68ppm(s) 6 7.81ppm(s) ・IR analysis J cM -co "7.08HzJ CM
-co =7.20HzJ CH -CM =
7.08HzJCM-cs =7.20Hz
1713cm-' (-C=0,-GO
-)1665cm-' (-C=CO-)[
Effects of the Invention] The 2-chloro-4,5-difluorobenzoic acid derivative, which is a novel substance of the present invention, is useful as a pharmaceutical and agricultural intermediate, particularly as an intermediate for fluorine-containing pyridone-rubaonic acid-based synthetic antibacterial agents. be. Moreover, since the intermediate of the present invention can lead to a quinolone compound with highly reactive fluorine at the 7-position, it is necessary to further lead to a synthetic antibacterial agent, compared to conventional quinolone compounds that have chlorine at the 7-position. It has high reactivity with, for example, cyclic amines, and can be used to produce the desired synthetic antibacterial agent in high yield. Moreover, this highly reactive fluorine can lead to a class of synthetic antibacterial agents that cannot be obtained by conventional methods.
Claims (3)
−ジフロオロベンゾイルハライド化合物。 ▲数式、化学式、表等があります▼（ I ） （式中、Ｘは塩素または弗素を示す）(1) 2-chloro-4,5 represented by general formula (I)
-Difluorobenzoyl halide compound. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents chlorine or fluorine)
ジフルオロベンゾイル酢酸エステル。 ▲数式、化学式、表等があります▼（II） （式中、Ｒ＾１は低級アルキル基を示す）(2) 2-chloro-4,5- represented by general formula (II)
Difluorobenzoyl acetate. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 represents a lower alkyl group)
４，５−ジフルオロベンゾイル）−３・アルコキシアク
リル酸エステル。 ▲数式、化学式、表等があります▼（III） （式中、Ｒ＾２、Ｒ＾３は低級アルキル基を示す）(3) 2-(2-chloro-
4,5-difluorobenzoyl)-3-alkoxyacrylic acid ester. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R^2 and R^3 represent lower alkyl groups)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-91609 | 1988-04-15 | ||
| JP9160988 | 1988-04-15 | ||
| JP21080288 | 1988-08-26 | ||
| JP63-210802 | 1988-08-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02131447A true JPH02131447A (en) | 1990-05-21 |
| JPH072679B2 JPH072679B2 (en) | 1995-01-18 |
Family
ID=26433056
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1089822A Expired - Lifetime JPH072679B2 (en) | 1988-04-15 | 1989-04-11 | 2-chloro-4,5-difluorobenzoic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH072679B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0608714A1 (en) * | 1993-01-29 | 1994-08-03 | Hoechst Aktiengesellschaft | Process for preparing chlorinated 4,5-difluorobenzoic acids, -benzoic acid derivatives and -benzaldehyde |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5874638A (en) * | 1981-10-29 | 1983-05-06 | バイエル・アクチエンゲゼルシヤフト | Manufacture of 2,4-dichloro-5-fluorobenzoylchloride |
| JPS6072885A (en) * | 1983-09-28 | 1985-04-24 | Dai Ichi Seiyaku Co Ltd | Quinoline derivative |
| JPS617220A (en) * | 1984-06-04 | 1986-01-13 | バイエル・アクチエンゲゼルシヤフト | 2,4,5-trihalogeno- and 2,3,4,5-tetrahalogenobenzene derivative |
| JPS62148484A (en) * | 1985-12-20 | 1987-07-02 | Otsuka Pharmaceut Co Ltd | Quinolinecarboxylic acid derivative |
| JPS6322580A (en) * | 1986-07-04 | 1988-01-30 | ヘミ−・リンツ・アクチエンゲゼルシヤフト | Novel 4-pyridone, its production and pharmacological composition containing said derivative |
-
1989
- 1989-04-11 JP JP1089822A patent/JPH072679B2/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5874638A (en) * | 1981-10-29 | 1983-05-06 | バイエル・アクチエンゲゼルシヤフト | Manufacture of 2,4-dichloro-5-fluorobenzoylchloride |
| JPS6072885A (en) * | 1983-09-28 | 1985-04-24 | Dai Ichi Seiyaku Co Ltd | Quinoline derivative |
| JPS617220A (en) * | 1984-06-04 | 1986-01-13 | バイエル・アクチエンゲゼルシヤフト | 2,4,5-trihalogeno- and 2,3,4,5-tetrahalogenobenzene derivative |
| JPS62148484A (en) * | 1985-12-20 | 1987-07-02 | Otsuka Pharmaceut Co Ltd | Quinolinecarboxylic acid derivative |
| JPS6322580A (en) * | 1986-07-04 | 1988-01-30 | ヘミ−・リンツ・アクチエンゲゼルシヤフト | Novel 4-pyridone, its production and pharmacological composition containing said derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0608714A1 (en) * | 1993-01-29 | 1994-08-03 | Hoechst Aktiengesellschaft | Process for preparing chlorinated 4,5-difluorobenzoic acids, -benzoic acid derivatives and -benzaldehyde |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH072679B2 (en) | 1995-01-18 |
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