JPH03127755A - Production of 2,4,5-trifluoro-3-hydroxybenzoic acid - Google Patents
Production of 2,4,5-trifluoro-3-hydroxybenzoic acidInfo
- Publication number
- JPH03127755A JPH03127755A JP26495689A JP26495689A JPH03127755A JP H03127755 A JPH03127755 A JP H03127755A JP 26495689 A JP26495689 A JP 26495689A JP 26495689 A JP26495689 A JP 26495689A JP H03127755 A JPH03127755 A JP H03127755A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- trifluoro
- reaction
- compound
- water
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- YYAFUGSJSHXYNK-UHFFFAOYSA-N 2,4,5-trifluoro-3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(O)=C1F YYAFUGSJSHXYNK-UHFFFAOYSA-N 0.000 title description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- YJLVXRPNNDKMMO-UHFFFAOYSA-N 3,4,5,6-tetrafluorophthalic acid Chemical compound OC(=O)C1=C(F)C(F)=C(F)C(F)=C1C(O)=O YJLVXRPNNDKMMO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 239000003125 aqueous solvent Substances 0.000 claims abstract description 5
- BJDDKZDZTHIIJB-UHFFFAOYSA-N 4,5,6,7-tetrafluoro-2-benzofuran-1,3-dione Chemical compound FC1=C(F)C(F)=C2C(=O)OC(=O)C2=C1F BJDDKZDZTHIIJB-UHFFFAOYSA-N 0.000 claims abstract description 4
- MNUOZFHYBCRUOD-UHFFFAOYSA-N hydroxyphthalic acid Natural products OC(=O)C1=CC=CC(O)=C1C(O)=O MNUOZFHYBCRUOD-UHFFFAOYSA-N 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 14
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 6
- BYXIMXYJZPMWAX-UHFFFAOYSA-N 3,4,6-trifluoro-5-hydroxyphthalic acid Chemical compound OC(=O)C1=C(F)C(O)=C(F)C(F)=C1C(O)=O BYXIMXYJZPMWAX-UHFFFAOYSA-N 0.000 abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 4
- 150000007513 acids Chemical class 0.000 abstract description 4
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 abstract description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract 3
- 239000004599 antimicrobial Substances 0.000 abstract 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IJFXRHURBJZNAO-UHFFFAOYSA-N 3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- ZOCSBJTWWJARJQ-UHFFFAOYSA-N 8-methoxy-2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=C(C(O)=O)C(=O)NC2=C1C=CC=C2OC ZOCSBJTWWJARJQ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- XLHBKVBAAVKFFG-UHFFFAOYSA-N [Cl-].[NH4+].C=C.C=C.C=C.C=C Chemical compound [Cl-].[NH4+].C=C.C=C.C=C.C=C XLHBKVBAAVKFFG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、２，４．５− トリフルオロ−３−ヒドロキ
シ安息香酸の製造法に関するものであり、本発明によっ
て提供される２、４．Ｓ−トリフルオロ−３−ヒドロキ
シ安息香酸は農薬、医薬、特にキノロンカルボン酸系抗
菌剤の製造原料として有用である。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing 2,4,5-trifluoro-3-hydroxybenzoic acid, and relates to a method for producing 2,4,5-trifluoro-3-hydroxybenzoic acid provided by the present invention. S-trifluoro-3-hydroxybenzoic acid is useful as a raw material for producing agricultural chemicals and medicines, especially quinolone carboxylic acid antibacterial agents.
本発明者らは、先にキノロンカルボン酸系抗菌剤の新し
い有用な中間体として、２，４．５− ）リフルオロ−
３−ヒドロキシ安息香酸を見出し、これを３．５゜６−
ドリフルオｏ−４−ヒドロキシフタルフタル酸から製造
する方法、及びこの３，５．６− トリフルオロ−４ヒ
ドロキシフタル酸を容易に入手可能なテトラフルオロフ
タル酸から製造する方法を確立した（特開昭６３−２６
４４３９号、特開昭６３−２６４４４０号参照）。The present inventors previously discovered that 2,4.5-)refluoro-
Found 3-hydroxybenzoic acid and converted it to 3.5゜6-
We have established a method for producing 3,5,6-trifluoro-4-hydroxyphthalic acid from trifluoro-4-hydroxyphthalic acid and a method for producing 3,5,6-trifluoro-4-hydroxyphthalic acid from easily available tetrafluorophthalic acid (Japanese Patent Application Laid-open No. 63-26
No. 4439, JP-A No. 63-264440).
一般にいくつかの反応を経て、ある目的化合物を製造す
る場合、途中に生成する中間体を単離精製することなく
次工程の反応が実施できるならば、産業上有用である。Generally, when a certain target compound is produced through several reactions, it is industrially useful if the next step reaction can be carried out without isolating and purifying intermediates produced during the process.
本発明者らは、この様な観点から、テトラフルオロフタ
ル酸またはその無水物から、中間体３，５゜ロートリフ
ルオロ−４−ヒドロキシフタル酸を単離することなく、
いわゆるワンポットで２．４．５−トリフルオロ−３−
ヒドロキシ安息香酸を製造する方法を鋭意検討し、本発
明を完成するに至った。From this point of view, the present inventors did not isolate the intermediate 3,5゜rotrifluoro-4-hydroxyphthalic acid from tetrafluorophthalic acid or its anhydride.
2.4.5-trifluoro-3- in so-called one-pot
The present invention has been completed after intensive study on a method for producing hydroxybenzoic acid.
本発明の２．４．５−１−リフルオロ−３−ヒドロキシ
安息香酸の製造法は、３，４，５．６−テトラフルオロ
フタル酸無水物または３，４，５．６−テトラフルオロ
フタル酸とアルカリ性化合物とを、水または水性溶媒中
において加熱下に反応させ、生成する３、５．６− ）
リフルオロ−４−ヒドロキシフタル酸を、加熱すること
を特徴とするものである。The method for producing 2.4.5-1-lifluoro-3-hydroxybenzoic acid of the present invention includes 3,4,5,6-tetrafluorophthalic anhydride or 3,4,5,6-tetrafluorophthalic acid. and an alkaline compound in water or an aqueous solvent under heating to produce 3,5.6-)
This method is characterized by heating refluoro-4-hydroxyphthalic acid.
本発明で用いられるアルカリ性化合物としては、アルカ
リ金属の水酸化物、炭酸水素塩、炭酸塩を挙げることが
できる。Examples of the alkaline compound used in the present invention include alkali metal hydroxides, hydrogen carbonates, and carbonates.
アルカリ金属の水酸化物の具体例としては、水酸化リチ
ウム、水酸化ナトリウム、水酸化カリウム、水酸化セシ
ウムを挙げることができる。Specific examples of alkali metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide.
また、炭酸水素塩の具体例としては、炭酸水素カリウム
、炭酸水素すＩ・リウムを挙げることができる。Specific examples of hydrogen carbonates include potassium hydrogen carbonate and lium hydrogen carbonate.
さらに、炭酸塩の具体例としては、炭酸カリウム、炭酸
ナトリウムを挙げることができる。Furthermore, specific examples of carbonates include potassium carbonate and sodium carbonate.
これらのなかでも、水酸化ナトリウムまたは水酸化カリ
ウムが好ましく用いられる。Among these, sodium hydroxide or potassium hydroxide is preferably used.
アルカリ性化合物の使用量は、テトラフルオロフタル酸
１モルに対して４当量使用するのが好ましい。The alkaline compound is preferably used in an amount of 4 equivalents per mole of tetrafluorophthalic acid.
また、アルカリ性化合物の反応液中の濃度は、５〜４０
重量％の範囲であることが好ましい。In addition, the concentration of the alkaline compound in the reaction solution is 5 to 40
A range of % by weight is preferred.
本反応は、水または水性溶媒中で行われ、溶媒の量はテ
トラフルオロフタル酸に対して、３〜１００重量部の範
囲であることが好ましい。水性溶媒としては、水と任意
の割合で溶解し、酸性およびアルカリ性条件下において
、反応しない溶媒と水との混合ものが使用できる。This reaction is carried out in water or an aqueous solvent, and the amount of the solvent is preferably in the range of 3 to 100 parts by weight based on tetrafluorophthalic acid. As the aqueous solvent, a mixture of water and a solvent that dissolves in any proportion with water and does not react under acidic or alkaline conditions can be used.
その具体例としては、メタノール、エタノール等のアル
コール類、ジオキサン、テトラヒドロフラン等のエーテ
ル類と水の混合溶媒を挙げることができる。その場合の
水の含有量はｌ０％以上が好ましい。Specific examples thereof include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and water mixed solvents. In that case, the water content is preferably 10% or more.
加熱下における反応は、５０〜１５０°Ｃ１好ましくは
８０〜９５°Ｃである。The reaction under heating is carried out at a temperature of 50 to 150°C, preferably 80 to 95°C.
反応時間は反応温度に依存するが、通常０．５〜２０時
間で完結する。The reaction time depends on the reaction temperature, but is usually completed in 0.5 to 20 hours.
このようにして得られた反応混合物はそのままか、ある
いは酸性化合物を添加して中和または酸性化後、脱炭酸
反応に供される。反応の選択性を上げるためには、酸性
化合物を添加してＰＩ（１〜４に調整した後に、脱炭酸
反応を行う方が好ましい。The reaction mixture thus obtained is subjected to a decarboxylation reaction either as it is or after being neutralized or acidified by adding an acidic compound. In order to increase the selectivity of the reaction, it is preferable to add an acidic compound to adjust the PI (PI to 1 to 4) and then perform the decarboxylation reaction.
この場合、添加する酸性化合物としては、アルカリ性を
中和できるものならいかなるものでも良いが、例えば、
硫酸、塩酸、リン酸またはその水溶液が好適に用いられ
る。In this case, any acidic compound can be added as long as it can neutralize alkalinity, but for example,
Sulfuric acid, hydrochloric acid, phosphoric acid or an aqueous solution thereof is preferably used.
前述の反応混合物について脱炭酸反応を実施する際の反
応温度は５０〜２５０°Ｃ１好ましくは１００〜２００
°Ｃの範囲である。The reaction temperature when carrying out the decarboxylation reaction on the above reaction mixture is 50 to 250°C, preferably 100 to 200°C.
°C range.
反応時間は、反応温度に依存するが、通常０．５〜２０
時間で完結する。本反応は、不活性ガス、例えば窒素、
アルゴンの雰囲気下で行うこともできる。The reaction time depends on the reaction temperature, but is usually 0.5 to 20
It will be completed in time. This reaction is performed using an inert gas, such as nitrogen,
It can also be carried out under an argon atmosphere.
反応後反応液のＰＨを３以下に調整し、濃縮すると目的
化合物２，４．５−トリフルオロ−３−ヒドロキシ安息
香酸が無色結晶または粉末として析出するのでこれを濾
過、抽出等の通常の方法で単離することができる。After the reaction, adjust the pH of the reaction solution to 3 or less and concentrate. The target compound, 2,4.5-trifluoro-3-hydroxybenzoic acid, will precipitate as colorless crystals or powder. can be isolated.
以下、本発明を実施例により具体的に説明するが本発明
はこれらに限定されるものではない。EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.
実施例１
２００ｍのガラスオートクレーブ中で８６％水酸化カリ
ウム１８．１６ｇ（０，２８モル）を水５０ｍ１に溶解
し８０°Ｃに加熱した後、テトラフルオロフタル酸１０
．０ ｇ （０，０４２モル）を反応温度が８５〜９０
°Ｃに維持されるように分割添加した。Example 1 In a 200 m glass autoclave, 18.16 g (0.28 mol) of 86% potassium hydroxide was dissolved in 50 ml of water and heated to 80 °C, and then 10 g of tetrafluorophthalic acid was dissolved.
．． 0 g (0,042 mol) at a reaction temperature of 85-90
It was added in portions to maintain the temperature at °C.
添加終了後９０〜９５°Ｃで３時間攪拌し、濃塩酸２０
ｍ（０，２４モル）を添加して１４０°Ｃで３時間攪拌
した。この間、発生する炭酸ガスによって反応器内の圧
力が上昇するため、時々ガスを抜いて圧力を３ ｋｇ
／ ｃｒＭｌになるように調整した。反応終了後、反応
液を室温まで冷却し濃塩酸ｉｏ＃１ｉ！を加えてＰＨ２
以下とし、酢酸エチルで抽出した。有機層を水洗、乾燥
後、減圧濃縮して、２，４．５− ）リフルオロ−３−
ヒドロキシ安息香酸６．９３ｇを無色粉末として得た。After the addition was complete, stir at 90-95°C for 3 hours and add 20% concentrated hydrochloric acid.
m (0.24 mol) was added and stirred at 140°C for 3 hours. During this time, the pressure inside the reactor increases due to the carbon dioxide gas generated, so the gas is removed from time to time to reduce the pressure to 3 kg.
/crMl. After the reaction is completed, the reaction solution is cooled to room temperature and added with concentrated hydrochloric acid io#1i! Add PH2
The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to give 2,4.5-)refluoro-3-
6.93 g of hydroxybenzoic acid was obtained as a colorless powder.
融点１４２〜１４５°Ｃ０マススベクトル＝ ｍ／ｚ
１９２ （Ｍ” ）。Melting point 142-145°C0 mass vector = m/z
192 (M”).
（参考例）
実施例で得た、２，４．５− ）リフルオロ−３−ヒ
ドロキシ安息香酸から、優れた抗菌剤である８−メトキ
シキノロンカルボン酸類の重要な中間体２．４．５トリ
フルオロ−３−メトキシ安息香酸（特開昭６３−１９８
６６４号）を下記の方法で合成した。(Reference Example) From the 2,4.5-)trifluoro-3-hydroxybenzoic acid obtained in the example, 2.4.5-trifluoro, an important intermediate of 8-methoxyquinolonecarboxylic acids, which is an excellent antibacterial agent. -3-Methoxybenzoic acid (JP-A-63-198
No. 664) was synthesized by the following method.
合成例１
２．４．５− ）リフルオロ−３−ヒドロキシ安息香酸
５．７６ｇ（０，０３モル）をメタノール５０１ｄに溶
解後、炭酸カリウム９．１１ｇ（０，０６６モル）とジ
メチル硫酸８．３２ ｇ （０，０６６モル）を加え、
６時間加熱還流した。反応液にＩＮ−水酸化ナトリウム
水溶液５０ｍを加え、２時間加熱還流した後、メタノー
ルを減圧留去した。残置に濃塩酸を加えて、ＰＲを２以
下とし、酢酸エチルで抽出した。Synthesis Example 1 2.4.5-) After dissolving 5.76 g (0.03 mol) of refluoro-3-hydroxybenzoic acid in 501d of methanol, 9.11 g (0.066 mol) of potassium carbonate and 8.32 g (0.066 mol) of dimethyl sulfate were added. g (0,066 mol) was added,
The mixture was heated under reflux for 6 hours. After adding 50 ml of IN-sodium hydroxide aqueous solution to the reaction solution and heating under reflux for 2 hours, methanol was distilled off under reduced pressure. Concentrated hydrochloric acid was added to the residue to bring the PR to 2 or less, and the mixture was extracted with ethyl acetate.
有機層を水洗乾燥後、減圧濃縮し、残置をシリカゲルカ
ラムクロマトグラフィー（溶媒：トルエンと酢酸エチル
のｌ：ｌ混合液）に付し、２．４．５− ）リフルオロ
−３−メトキシ安息香４．３０ ｇを無色粉末として得
た。融点１１３〜１１６℃。マススペクトル： ｍ／
ｚ ２０６ （Ｍ”″）。The organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: 1:1 mixture of toluene and ethyl acetate) to extract 2.4.5-)lifluoro-3-methoxybenzoate4. 30 g were obtained as a colorless powder. Melting point 113-116°C. Mass spectrum: m/
z 206 (M"").
合成例２
２．４．５− ）リフルオロ−３−ヒドロキシ安息香酸
５．７６ｇ（０，０３モル）をアセトン５０−に溶解し
、炭酸カリウム９．１１ｇ（０，０６６モル）とジメチ
ル硫酸８．３２ ｇ （０，０６６モル）を加え、２時
間加熱還流した。反応液にＩＮ−塩酸水溶液３０１ｄ（
０，０５モル）を加えてアセトンを減圧留去した後クロ
ロホルムで抽出した。抽出したクロロホルム層を乾燥後
濃縮し、残置を減圧蒸留して、２．４．５−１−リフル
オロ−３−メトキシ安息香酸メチルを６．０Ｗ得た。沸
点９５〜ｂ
９１％。マススペクトル＝ ｍ／ｚ ２２０ （Ｍ”
）プロトンＮＭＲスペクトル（ＣＤＲ１３、δｐｐｍ）
７．４８ （ｍ、 Ｉ Ｈ１３ＪＨＦＩ０．２５Ｈ２
，４ＪＨＦ ８．４３Ｈｚ、４ＪＨＦ ６．１１Ｈ
ｚ、芳香族プロトン） 、４．０５ （ｍ、フッ素との
小さな認められる、３Ｈ，０ＣＨｓ） 、３．９４
（ｓ、３Ｈ，ＣＯ、Ｃ０Ｗ）
上記の２．４．５− ）リフルオロ−３−メトキシ安息
香メチル６．０ｇ（０，０２７モル）にメタノール３〇
−を加え６時間室温で攪拌した。この溶液に濃塩酸６ｄ
を加え、析出した結晶を濾過し、水洗後減圧乾燥して２
．４．５−トリフルオロ−３−メトキシ安息香酸５．３
ｇを無色粉末として得た。Synthesis Example 2 2.4.5-) 5.76 g (0.03 mol) of refluoro-3-hydroxybenzoic acid was dissolved in 50-mL of acetone, and 9.11 g (0.066 mol) of potassium carbonate and 8.0 g (0.066 mol) of dimethyl sulfuric acid were dissolved. 32 g (0,066 mol) was added and heated under reflux for 2 hours. IN-hydrochloric acid aqueous solution 301d (
After the acetone was distilled off under reduced pressure, the mixture was extracted with chloroform. The extracted chloroform layer was dried and concentrated, and the residue was distilled under reduced pressure to obtain 6.0W of methyl 2.4.5-1-refluoro-3-methoxybenzoate. Boiling point 95-b 91%. Mass spectrum = m/z 220 (M”
) Proton NMR spectrum (CDR13, δppm)
7.48 (m, I H13JHFI0.25H2
, 4JHF 8.43Hz, 4JHF 6.11H
z, aromatic proton), 4.05 (m, small observed with fluorine, 3H,0CHs), 3.94
(s, 3H, CO, C0W) 30-methanol was added to 6.0 g (0,027 mol) of the above 2.4.5-)rifluoro-3-methoxybenzomethyl and stirred at room temperature for 6 hours. Add 6 d of concentrated hydrochloric acid to this solution.
was added, the precipitated crystals were filtered, washed with water and dried under reduced pressure.
．． 4.5-Trifluoro-3-methoxybenzoic acid 5.3
g was obtained as a colorless powder.
５１点１１３〜１１６℃、収率９５％。マススペクトル
＝ ｍ ／ ｚ ２０６ （Ｍ” ） ＊プロトｙＮ
ＭＲスペクトル（ＣＤＣ１３、δｐｐｍ）７．５０（ｍ
、３ＪＨＦ １０．２Ｈｚ、ＡＪＨＦ ８．５Ｈｚ
、ａＪＨＦ ６．１Ｈｚ、ＩＨ，芳香族プロトン）
、５．００ （ｂｒ、ＩＨ，ＣＯｘ Ｈ） 、４．０３
（ｍ、３Ｈ，０ＣＲ３）
合成例３
実施例１で得られた脱炭酸反応後の溶液に濃塩酸を加え
中和した。この２．４．５− ）リフルオロ−３ヒドロ
キシ安息香酸を含む混合物に炭酸カリウム１７．５ｇ（
０，１２６モル）、トルエン５０１１およびテトラエチ
Ｊレアンモニウムクロライド０．３ｇを添加した。混合
物を７５℃で３時間激しく攪拌した、その後、エタノー
ル１１０ｄ、水酸化ナトリウム２．８ｇ（０，０７２モ
ル）を溶解した水３〇−を加えて７５℃で３時間攪拌し
た。この固体を濾過、水洗後減圧乾燥して２，４．５−
）リフルオロ−３メトキシ安息香酸６．８ｇ（０，０
３３モル）を得た。51 points 113-116°C, yield 95%. Mass spectrum = m/z 206 (M”) *ProtoyN
MR spectrum (CDC13, δppm) 7.50 (m
, 3JHF 10.2Hz, AJHF 8.5Hz
, aJHF 6.1Hz, IH, aromatic proton)
, 5.00 (br, IH, COx H) , 4.03
(m, 3H, 0CR3) Synthesis Example 3 Concentrated hydrochloric acid was added to the solution obtained in Example 1 after the decarboxylation reaction to neutralize it. Add 17.5 g of potassium carbonate (2.4.5-) to the mixture containing
0.126 mol), 5011 toluene and 0.3 g of tetraethylene ammonium chloride were added. The mixture was vigorously stirred at 75°C for 3 hours, and then 110d of ethanol and 30ml of water in which 2.8g (0,072 mol) of sodium hydroxide had been dissolved were added, and the mixture was stirred at 75°C for 3 hours. This solid was filtered, washed with water, and dried under reduced pressure to obtain 2,4.5-
) 6.8 g (0,0
33 mol) was obtained.
収率７８％（テトラフルオロフタル酸基準）。融点ｌ１
３〜１１６℃。マススペクトル ｍ／ ｚ２０６（Ｍ”
）。Yield 78% (based on tetrafluorophthalic acid). Melting point l1
3-116℃. Mass spectrum m/z206(M”
).
本発明によれば、抗菌剤として有用なキノロンカルボン
酸誘導体の合成中間体として有用な２．４゜５−トリフ
ルオロ−３−ヒドロキシ安息香酸を、途中に生成する中
間体を単離精製することなく、簡便に得ることができる
。According to the present invention, 2.4゜5-trifluoro-3-hydroxybenzoic acid, which is useful as an intermediate for the synthesis of quinolone carboxylic acid derivatives useful as antibacterial agents, is purified by isolating the intermediate produced during the process. It can be easily obtained.
Claims (1)
または３，４，５，６−テトラフルオロフタル酸とアル
カリ性化合物とを、水または水性溶媒中において加熱下
に反応させ、生成する３，５，６−トリフルオロ−４−
ヒドロキシフタル酸を、加熱することを特徴とする２，
４，５−トリフルオロ−３−ヒドロキシ安息香酸の製造
法。(1) Produced by reacting 3,4,5,6-tetrafluorophthalic anhydride or 3,4,5,6-tetrafluorophthalic acid with an alkaline compound under heating in water or an aqueous solvent. 3,5,6-trifluoro-4-
2, characterized by heating hydroxyphthalic acid;
A method for producing 4,5-trifluoro-3-hydroxybenzoic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1264956A JP2547100B2 (en) | 1989-10-13 | 1989-10-13 | Process for producing 2,4,5-trifluoro-3-alkoxybenzoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1264956A JP2547100B2 (en) | 1989-10-13 | 1989-10-13 | Process for producing 2,4,5-trifluoro-3-alkoxybenzoic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03127755A true JPH03127755A (en) | 1991-05-30 |
| JP2547100B2 JP2547100B2 (en) | 1996-10-23 |
Family
ID=17410540
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1264956A Expired - Lifetime JP2547100B2 (en) | 1989-10-13 | 1989-10-13 | Process for producing 2,4,5-trifluoro-3-alkoxybenzoic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2547100B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5233082A (en) * | 1982-11-16 | 1993-08-03 | Occidental Chemical Corporation | Method of making 3-hydroxy-2,4,5-trifluorobenzoic acid |
| WO2008093837A1 (en) | 2007-02-02 | 2008-08-07 | Ube Industries, Ltd. | Ester compound, and non-aqueous electrolyte solution and lithium secondary battery each using the ester compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63264439A (en) * | 1986-12-08 | 1988-11-01 | Ube Ind Ltd | Production of 3,5,6-trifluoro-4-hydroxyphthalic acid |
| JPH01268662A (en) * | 1988-04-21 | 1989-10-26 | Nippon Carbide Ind Co Inc | Production of 2,4,5-trifluoro-3-hydroxybenzoic acid and production of 2,4,5-trifluoro-3-alkoxybenzoic acid |
-
1989
- 1989-10-13 JP JP1264956A patent/JP2547100B2/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63264439A (en) * | 1986-12-08 | 1988-11-01 | Ube Ind Ltd | Production of 3,5,6-trifluoro-4-hydroxyphthalic acid |
| JPH01268662A (en) * | 1988-04-21 | 1989-10-26 | Nippon Carbide Ind Co Inc | Production of 2,4,5-trifluoro-3-hydroxybenzoic acid and production of 2,4,5-trifluoro-3-alkoxybenzoic acid |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5233082A (en) * | 1982-11-16 | 1993-08-03 | Occidental Chemical Corporation | Method of making 3-hydroxy-2,4,5-trifluorobenzoic acid |
| WO2008093837A1 (en) | 2007-02-02 | 2008-08-07 | Ube Industries, Ltd. | Ester compound, and non-aqueous electrolyte solution and lithium secondary battery each using the ester compound |
| US8263268B2 (en) | 2007-02-02 | 2012-09-11 | Ube Industries, Ltd. | Ester compound, and non-aqueous electrolyte solution and lithium secondary battery each using the ester compound |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2547100B2 (en) | 1996-10-23 |
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