JPWO2007021001A1 - 2,3,4-Trifluoro-5-substituted benzoic acid compound and process for producing the same - Google Patents
2,3,4-Trifluoro-5-substituted benzoic acid compound and process for producing the same Download PDFInfo
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Abstract
本発明は、一般式（１）： 式中、Ｙはヨウ素原子、ホルミル基又は求電子種を表し、Ｍは水素原子又は金属原子を表す、で示される２，３，４−トリフルオロ−５−置換安息香酸化合物及びその製法並びに一般式（３ａ）又は（３ｂ）： 式中、Ｍ１は金属原子を表す、で示される２，３，４−トリフルオロ−５−リチオ安息香酸及びその製法を提供する。In the present invention, 2,3,4-trifluoro-5 represented by the general formula (1): wherein Y represents an iodine atom, a formyl group or an electrophilic species, and M represents a hydrogen atom or a metal atom -Substituted benzoic acid compound and production method thereof, and general formula (3a) or (3b): wherein M1 represents a metal atom, 2,3,4-trifluoro-5-lithiobenzoic acid represented by provide.
Description
本発明は、新規な２，３，４−トリフルオロ−５−置換安息香酸化合物及びその新規な製法に関する。２，３，４−トリフルオロ−５−置換安息香酸化合物は、医薬・農薬等の原料や合成中間体として有用な化合物である（例えば、特許文献１及び２参照）。 The present invention relates to a novel 2,3,4-trifluoro-5-substituted benzoic acid compound and a novel production method thereof. 2,3,4-Trifluoro-5-substituted benzoic acid compounds are useful compounds as raw materials and synthetic intermediates for pharmaceuticals and agricultural chemicals (see, for example, Patent Documents 1 and 2).
２，３，４−トリフルオロ−５−置換安息香酸化合物としては、例えば、２，３，４−トリフルオロ−５−ヨード安息香酸化合物等が知られている。
従来、２，３，４−トリフルオロ−５−ヨード安息香酸化合物を製造する方法としては、例えば、２，３，４−トリフルオロ安息香酸を濃硫酸中で発煙硝酸と反応させて２，３，４−トリフルオロ−５−ニトロ安息香酸とし、次いで、これを水素還元して２，３，４−トリフルオロ−５−アミノ安息香酸を得、更に、これに、ヨウ化銅（Ｉ）及び亜硝酸ナトリウムの存在下、５７％ヨウ化水素酸水溶液を反応させて、合計収率５８％で２，３，４−トリフルオロ−５−ヨード安息香酸を合成する方法が開示されている（例えば、特許文献３参照）。しかしながら、この方法では、反応工程数が多い上に、収率が低いという問題があった。
一方、本発明の２，３，４−トリフルオロ−５−ホルミル安息香酸化合物及び２，３，４−トリフルオロ−５−リチオ安息香酸化合物の存在及びその製法については、全く知られていない。
Conventionally, as a method for producing 2,3,4-trifluoro-5-iodobenzoic acid compound, for example, 2,3,4-trifluorobenzoic acid is reacted with fuming nitric acid in concentrated sulfuric acid. , 4-trifluoro-5-nitrobenzoic acid, which is then reduced with hydrogen to give 2,3,4-trifluoro-5-aminobenzoic acid, further containing copper (I) iodide and A method of synthesizing 2,3,4-trifluoro-5-iodobenzoic acid in a total yield of 58% by reacting 57% aqueous hydroiodic acid in the presence of sodium nitrite is disclosed (for example, And Patent Document 3). However, this method has a problem that the number of reaction steps is large and the yield is low.
On the other hand, the presence of 2,3,4-trifluoro-5-formylbenzoic acid compound and 2,3,4-trifluoro-5-lithiobenzoic acid compound of the present invention and the production method thereof are not known at all.
本発明の課題は、新規な２，３，４−トリフルオロ−５−置換安息香酸化合物及び、簡便な方法にて、高収率で目的化合物を合成可能であり、工業的に好適な２，３，４−トリフルオロ−５−置換安息香酸化合物の製法を提供することにある。 An object of the present invention is to provide a novel 2,3,4-trifluoro-5-substituted benzoic acid compound and a simple method to synthesize the target compound in high yield, The object is to provide a method for producing a 3,4-trifluoro-5-substituted benzoic acid compound.
本発明の第１の発明は、一般式（１）：
で示される２，３，４−トリフルオロ−５−置換安息香酸化合物に関する。
本発明の第２の発明は、塩基の存在下、有機溶媒中にて、一般式（２）：The first invention of the present invention is represented by the general formula (1):
And 2,3,4-trifluoro-5-substituted benzoic acid compounds represented by
In a second aspect of the present invention, the general formula (2):
式中、Ｍは、前記と同義である、
で示される２，３，４−トリフルオロ安息香酸化合物とヨウ素化剤又はホルミル化剤とを反応させることを特徴とする、一般式（１ａ）：
で示される２，３，４−トリフルオロ−５−置換安息香酸化合物の製法に関する。In the formula, M is as defined above.
A general formula (1a) characterized by reacting a 2,3,4-trifluorobenzoic acid compound represented by the following formula with an iodinating agent or a formylating agent:
It is related with the manufacturing method of the 2,3,4-trifluoro-5-substituted benzoic acid compound shown by these.
本発明の第３の発明は、一般式（３ａ）又は（３ｂ）：
で示される２，３，４−トリフルオロ−５−リチオ安息香酸に関する。A third invention of the present invention is represented by the general formula (3a) or (3b):
And 2,3,4-trifluoro-5-lithiobenzoic acid.
本発明の第４の発明は、一般式（４ａ）又は（４ｂ）：
で示される２，３，４−トリフルオロ安息香酸化合物とリチウム化合物とを反応させることを特徴とする前記一般式（３ａ）又は（３ｂ）で示される２，３，４−トリフルオロ−５−リチオ安息香酸の製造方法に関する。A fourth invention of the present invention is represented by the general formula (4a) or (4b):
2,3,4-trifluorobenzoic acid compound represented by the formula (3a) or (3b) is reacted with a 2,3,4-trifluorobenzoic acid compound represented by general formula (3a) or (3b) The present invention relates to a method for producing lithiobenzoic acid.
本発明の第５の発明は、前記一般式（３ａ）又は（３ｂ）で示される２，３，４−トリフルオロ−５−リチオ安息香酸と、求電子種を発生させ得る化合物とを反応させることを特徴とする、一般式（１ｂ）：
で示される２，３，４−トリフルオロ−５−置換安息香酸化合物の製法に関する。In a fifth aspect of the present invention, the 2,3,4-trifluoro-5-lithiobenzoic acid represented by the general formula (3a) or (3b) is reacted with a compound capable of generating an electrophilic species. General formula (1b):
It is related with the manufacturing method of the 2,3,4-trifluoro-5-substituted benzoic acid compound shown by these.
本発明により、新規な２，３，４−トリフルオロ−５−置換安息香酸化合物、及び簡便な方法にて、高収率で２，３，４−トリフルオロ−５−置換安息香酸化合物を合成出来る、工業的に好適な２，３，４−トリフルオロ−５−置換安息香酸の製法を提供することが出来る。
また、本発明により、新規な２，３，４−トリフルオロ−５−リチオ安息香酸化合物及びその製法を提供することが出来る。According to the present invention, a novel 2,3,4-trifluoro-5-substituted benzoic acid compound and a 2,3,4-trifluoro-5-substituted benzoic acid compound are synthesized in a high yield by a simple method. An industrially suitable production method of 2,3,4-trifluoro-5-substituted benzoic acid can be provided.
Further, according to the present invention, a novel 2,3,4-trifluoro-5-lithiobenzoic acid compound and a production method thereof can be provided.
本発明の新規な２，３，４−トリフルオロ−５−置換安息香酸化合物は、前記一般式（１）で示される。式（１）において、Ｍは、水素原子又は金属原子を表す。金属原子としては、例えば、リチウム原子、ナトリウム原子、カリウム原子、セシウム原子等のアルカリ金属原子、マグネシウム原子、カルシウム原子、ストロンチウム原子、バリウム原子等のアルカリ土類金属原子、及び銅原子等が挙げられる。本発明においては、これらの中でも、リチウム原子、ナトリウム原子、カリウム原子、セシウム原子及び銅原子が好ましく、更に好ましくは、リチウム原子又はナトリウム原子である。 The novel 2,3,4-trifluoro-5-substituted benzoic acid compound of the present invention is represented by the general formula (1). In formula (1), M represents a hydrogen atom or a metal atom. Examples of the metal atom include alkali metal atoms such as lithium atom, sodium atom, potassium atom and cesium atom, alkaline earth metal atoms such as magnesium atom, calcium atom, strontium atom and barium atom, and copper atom. . In the present invention, among these, a lithium atom, a sodium atom, a potassium atom, a cesium atom and a copper atom are preferable, and a lithium atom or a sodium atom is more preferable.
式（１）において、Ｙはヨウ素原子、ホルミル基又は求電子種を表す。式（１）で示される化合物としては、具体的には、下記一般式（１ａ−１）、（１ａ−２）又は（１ｂ−１）：
で示される２，３，４−トリフルオロ−５−ヨード安息香酸化合物、２，３，４−トリフルオロ−５−ホルミル安息香酸化合物又は２，３，４−トリフルオロ−５−置換安息香酸が挙げられる。In the formula (1), Y represents an iodine atom, a formyl group or an electrophilic species. Specifically as a compound shown by Formula (1), following general formula (1a-1), (1a-2) or (1b-1):
2,3,4-trifluoro-5-iodobenzoic acid compound, 2,3,4-trifluoro-5-formylbenzoic acid compound or 2,3,4-trifluoro-5-substituted benzoic acid represented by the formula: Can be mentioned.
また、求電子種（Ｘ＋）としては、例えば、ジューテリオイオン；クロロカチオン、ブロモカチオン、ヨードカチオン等のハロゲンカチオン；メチルカチオン等のアルキルカチオン；ホルミルカチオン、アセチルカチオン等のアシルカチオン；トリメチルシリルカチオン、トリエチルシリルカチオン、ｔｅｒｔ−ブチルジメチルシリルカチオン等のアルキルシリルカチオン；ジメトキシボロニウムカチオン、ジエトキシボロニウムカチオン、ジイソプロポキシボロニウムカチオン等のアルコキシボロニウムカチオン；トリメチルスタニウムカチオン、トリｎ−ブチルスタニウムカチオン、トリｎ−ブチルスタニウムカチオン等のトリアルキルスタニウムカチオン等が挙げられる。これらの中でも、本発明においては、ジューテリオイオン及びトリメチルシリルカチオンが好ましい。Examples of the electrophilic species (X + ) include deuterio ion; halogen cation such as chloro cation, bromo cation and iodo cation; alkyl cation such as methyl cation; acyl cation such as formyl cation and acetyl cation; Alkylsilyl cations such as triethylsilyl cation and tert-butyldimethylsilyl cation; alkoxyboronium cations such as dimethoxyboronium cation, diethoxyboronium cation and diisopropoxyboronium cation; trimethylstannium cation and tri-n-butyl And trialkyl stannium cations such as stannium cation and tri-n-butyl stannium cation. Of these, deuterio ions and trimethylsilyl cations are preferred in the present invention.
本発明の前記一般式（１ａ）で示される２，３，４−トリフルオロ−５−置換安息香酸化合物の製法において使用する２，３，４−トリフルオロ安息香酸化合物は、前記の一般式（２）で示される。その一般式（２）において、Ｍは前記と同義であり、Ｙ１はヨウ素原子又はホルミル基を表す。The 2,3,4-trifluorobenzoic acid compound used in the process for producing the 2,3,4-trifluoro-5-substituted benzoic acid compound represented by the general formula (1a) of the present invention is the above general formula ( 2). In the general formula (2), M is as defined above, and Y 1 represents an iodine atom or a formyl group.
本発明の製法において使用する塩基としては、例えば、リチウムアミド化合物が挙げられ、具体的には、リチウム２，２，６，６−テトラメチルピペリジド、リチウムジイソプロピルアミド等が好適に使用される。なお、これらの塩基は、単独又は二種以上を混合して使用しても良く、又、予め別途合成したものでも、反応前に系内で調整したものでも構わない。 Examples of the base used in the production method of the present invention include lithium amide compounds, and specifically, lithium 2,2,6,6-tetramethylpiperidide, lithium diisopropylamide and the like are preferably used. . These bases may be used alone or in admixture of two or more, and may be synthesized separately in advance or prepared in the system before the reaction.
前記塩基の使用量は、２，３，４−トリフルオロ安息香酸化合物１モルに対して、Ｍが水素原子の場合には、好ましくは２．０〜５．０モル、更に好ましくは２．１〜３．０モルであり、一方、Ｍが、金属原子の場合には、好ましくは１．０〜３．０モル、更に好ましくは１．１〜２．０モルである。 The amount of the base used is preferably 2.0 to 5.0 moles, more preferably 2.1 moles when M is a hydrogen atom with respect to 1 mole of the 2,3,4-trifluorobenzoic acid compound. On the other hand, when M is a metal atom, it is preferably 1.0 to 3.0 mol, and more preferably 1.1 to 2.0 mol.
本発明の反応において使用するヨウ素化剤としては、一般のヨウ素化剤ならば特に限定されないが、例えば、一塩化ヨウ素、一臭化ヨウ素、ヨウ素、Ｎ−ヨードコハク酸イミドが挙げられるが、好ましくは一塩化ヨウ素、一臭化ヨウ素、ヨウ素が使用される。なお、これらのヨウ素化剤は、単独又は二種以上を混合して使用しても良い。 The iodinating agent used in the reaction of the present invention is not particularly limited as long as it is a general iodinating agent, and examples thereof include iodine monochloride, iodine monobromide, iodine, and N-iodosuccinimide. Iodine monochloride, iodine monobromide, iodine are used. In addition, you may use these iodinating agents individually or in mixture of 2 or more types.
前記ヨウ素化剤の使用量は、２，３，４−トリフルオロ安息香酸化合物１モルに対して、好ましくは０．５〜５．０モル、更に好ましくは１．０〜２．０モルである。 The amount of the iodinating agent used is preferably 0.5 to 5.0 mol, more preferably 1.0 to 2.0 mol, with respect to 1 mol of the 2,3,4-trifluorobenzoic acid compound. .
本発明の反応において使用するホルミル化剤としては、一般のホルミル化剤ならば特に限定されないが、例えば、一酸化炭素；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ−メチルホルムアニリド等のホルムアミド類；ギ酸メチル、ギ酸エチル、ギ酸イソプロピル等のギ酸エステル類等が挙げられるが、好ましくはホルムアミド類、更に好ましくはＮ，Ｎ−ジメチルホルムアミドが使用される。なお、これらのホルミル化剤は、単独又は二種以上を混合して使用しても良い。 The formylating agent used in the reaction of the present invention is not particularly limited as long as it is a general formylating agent. Examples thereof include carbon monoxide; formamides such as N, N-dimethylformamide and N-methylformanilide; methyl formate Formic acid esters such as ethyl formate and isopropyl formate are preferred, and formamides are preferred, and N, N-dimethylformamide is more preferred. In addition, you may use these formylation agents individually or in mixture of 2 or more types.
前記ホルミル化剤の使用量は、２，３，４−トリフルオロ安息香酸化合物１モルに対して、好ましくは０．５〜５．０モル、更に好ましくは１．０〜２．０モルである。 The amount of the formylating agent used is preferably 0.5 to 5.0 mol, more preferably 1.0 to 2.0 mol, with respect to 1 mol of the 2,3,4-trifluorobenzoic acid compound. .
本発明の反応において使用する有機溶媒としては、反応を阻害しないものならば特に限定されないが、例えば、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン等のエーテル類；ヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類が挙げられるが、好ましくはエーテル類、脂肪族炭化水素類、芳香族炭化水素類、更に好ましくはエーテル類、脂肪族炭化水素類が使用される。なお、これらの有機溶媒は、単独又は二種以上を混合して使用しても良い。 The organic solvent used in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aliphatic carbonization such as hexane, heptane and cyclohexane Hydrogen; aromatic hydrocarbons such as benzene, toluene, xylene, etc. are mentioned, preferably ethers, aliphatic hydrocarbons, aromatic hydrocarbons, more preferably ethers, aliphatic hydrocarbons are used. Is done. In addition, you may use these organic solvents individually or in mixture of 2 or more types.
前記有機溶媒の使用量は、反応液の均一性や攪拌性等により適宜調節するが、２，３，４−トリフルオロ安息香酸化合物１ｇに対して、好ましくは５〜１００ｍｌ、更に好ましくは１０〜５０ｍｌである。 The amount of the organic solvent used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 5 to 100 ml, more preferably 10 to 1 g of 2,3,4-trifluorobenzoic acid compound. 50 ml.
本発明の反応は、例えば、塩基の存在下、有機溶媒中にて、２，３，４−トリフルオロ安息香酸とヨウ素化剤又はホルミル化剤とを、攪拌しながら反応させる等の方法によって行われる。その際の反応温度は、好ましくは−１００〜０℃、更に好ましくは−８０〜−１０℃であり、反応圧力は特に制限されない。なお、本発明の反応は、水の非存在下で行うことが望ましい。 The reaction of the present invention is performed, for example, by a method of reacting 2,3,4-trifluorobenzoic acid with an iodinating agent or a formylating agent in the presence of a base in an organic solvent while stirring. Is called. The reaction temperature at that time is preferably −100 to 0 ° C., more preferably −80 to −10 ° C., and the reaction pressure is not particularly limited. The reaction of the present invention is desirably performed in the absence of water.
本発明の新規な２，３，４−トリフルオロ−５−リチオ安息香酸化合物は、前記の式（３ａ）又は（３ｂ）で示される。その式（３ｂ）において、Ｍ１は、金属原子であり、例えば、ナトリウム原子、カリウム原子、セシウム原子等のアルカリ金属、マグネシウム原子、カルシウム原子、ストロンチウム原子、バリウム原子等のアルカリ土類金属原子、及び銅原子等が挙げられる。本発明においては、これらの中でも、リチウム原子、ナトリウム原子、カリウム原子、セシウム原子及び銅原子が好ましく、更に好ましくは、リチウム原子又はナトリウム原子である。The novel 2,3,4-trifluoro-5-lithiobenzoic acid compound of the present invention is represented by the above formula (3a) or (3b). In the formula (3b), M 1 is a metal atom, for example, an alkali metal such as a sodium atom, a potassium atom or a cesium atom, an alkaline earth metal atom such as a magnesium atom, a calcium atom, a strontium atom or a barium atom, And a copper atom. In the present invention, among these, a lithium atom, a sodium atom, a potassium atom, a cesium atom and a copper atom are preferable, and a lithium atom or a sodium atom is more preferable.
前記２，３，４−トリフルオロ−５−リチオ安息香酸化合物は、２，３，４−トリフルオロ安息香酸化合物とリチウム化合物とを反応させることによって得られる。２，３，４−トリフルオロ安息香酸化合物は、前記の式（４ａ）又は（４ｂ）で示されるが、その式（４ｂ）において、Ｍ１は、前記と同義である。その際の反応温度は、好ましくは−１００〜０℃、更に好ましくは−８０〜−１０℃であり、反応圧力は特に制限されない。なお、該反応は、水の非存在下で行うことが望ましい。The 2,3,4-trifluoro-5-lithiobenzoic acid compound is obtained by reacting a 2,3,4-trifluorobenzoic acid compound with a lithium compound. The 2,3,4-trifluorobenzoic acid compound is represented by the above formula (4a) or (4b), and in the formula (4b), M 1 is as defined above. The reaction temperature at that time is preferably −100 to 0 ° C., more preferably −80 to −10 ° C., and the reaction pressure is not particularly limited. The reaction is desirably performed in the absence of water.
前記リチウム化合物としては、例えば、リチウム２，２，６，６−テトラメチルピペリジド、リチウムジイソプロピルアミド等が好適に使用される。なお、これらのリチウム化合物は、単独又は二種以上を混合して使用しても良く、又、予め別途合成したものでも、反応前に系内で調製したものでも構わない。 As the lithium compound, for example, lithium 2,2,6,6-tetramethylpiperidide, lithium diisopropylamide and the like are preferably used. These lithium compounds may be used alone or in combination of two or more, and may be separately synthesized in advance or prepared in the system before the reaction.
前記リチウム化合物の使用量は、２，３，４−トリフルオロ安息香酸化合物（４ａ）１モルに対して、好ましくは２．０〜５．０モル、更に好ましくは２．１〜３．０モルであり、一方、２，３，４−トリフルオロ安息香酸化合物（４ｂ）１モルに対して、好ましくは１．０〜３．０モル、更に好ましくは１．１〜２．０モルである。 The amount of the lithium compound used is preferably 2.0 to 5.0 mol, more preferably 2.1 to 3.0 mol, per 1 mol of the 2,3,4-trifluorobenzoic acid compound (4a). On the other hand, it is preferably 1.0 to 3.0 mol, more preferably 1.1 to 2.0 mol, per 1 mol of 2,3,4-trifluorobenzoic acid compound (4b).
前記２，３，４−トリフルオロ安息香酸化合物とリチウム化合物との反応は、有機溶媒の存在下で行うのが望ましく、使用する有機溶媒としては、反応を阻害しないものならば特に限定されないが、例えば、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン等のエーテル類；ヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類が挙げられるが、好ましくはエーテル類、脂肪族炭化水素類、芳香族炭化水素類、更に好ましくはエーテル類、脂肪族炭化水素類が使用される。なお、これらの有機溶媒は、単独又は二種以上を混合して使用しても良い。 The reaction between the 2,3,4-trifluorobenzoic acid compound and the lithium compound is desirably performed in the presence of an organic solvent, and the organic solvent used is not particularly limited as long as it does not inhibit the reaction, Examples include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aliphatic hydrocarbons such as hexane, heptane, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene, preferably ethers. , Aliphatic hydrocarbons and aromatic hydrocarbons, more preferably ethers and aliphatic hydrocarbons. In addition, you may use these organic solvents individually or in mixture of 2 or more types.
前記有機溶媒の使用量は、反応液の均一性や攪拌性等により適宜調節するが、２，３，４−トリフルオロ安息香酸化合物１ｇに対して、好ましくは５〜１００ｍｌ、更に好ましくは１０〜５０ｍｌである。 The amount of the organic solvent used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 5 to 100 ml, more preferably 10 to 1 g of 2,3,4-trifluorobenzoic acid compound. 50 ml.
本発明の新規な２，３，４−トリフルオロ−５−リチオ安息香酸化合物は、これに求電子種（Ｘ＋）を発生させ得る化合物を反応させることによって、一般式（１ｂ）で示される２，３，４−トリフルオロ−５−置換安息香酸化合物を生成させることが出来る。The novel 2,3,4-trifluoro-5-lithiobenzoic acid compound of the present invention is represented by the general formula (1b) by reacting it with a compound capable of generating an electrophilic species (X + ). 2,3,4-Trifluoro-5-substituted benzoic acid compounds can be produced.
前記求電子種（Ｘ＋）を発生させ得る化合物としては、例えば、重水（求電子種：ジューテリオイオン）；塩素（求電子種：クロロカチオン）、臭素（求電子種：ブロモカチオン）、ヨウ素（求電子種：ヨードカチオン）等のハロゲン原子；メチルメシラート（求電子種：メチルカチオン）、メチルトシラート（求電子種：メチルカチオン）、メチルトリフラート（求電子種：メチルカチオン）等のスルホナート類；Ｎ，Ｎ−ジメチルホルムアミド（求電子種：ホルミルカチオン）、Ｎ，Ｎ−ジメチルアセトアミド（求電子種：アセチルカチオン）等のアミド類；クロロトリメチルシラン（求電子種：トリメチルシリルカチオン）、クロロトリエチルシラン（求電子種：トリエチルシリルカチオン）、ｔｅｒｔ−ブチルクロロジメチルシラン（求電子種：ｔｅｒｔ−ブチルジメチルシリルカチオン）等のクロロシラン類；ホウ酸トリメチル（求電子種：ジメトキシボロニウムカチオン）、ホウ酸トリエチル（求電子種：ジエトキシボロニウムカチオン）、ホウ酸トリイソプロピル（求電子種：ジイソプロポキシボロニウムカチオン）等のホウ酸エステル類；塩化トリメチルスズ（求電子種：トリメチルスタニウムカチオン）、塩化トリｎ−ブチルスズ（求電子種：トリｎ−ブチルスタニウムカチオン）、トリｎ−ブチルスズトリフラート（求電子種：トリｎ−ブチルスタニウムカチオン）等のトリアルキルスズ塩類が挙げられる。Examples of the compound capable of generating the electrophilic species (X + ) include heavy water (electrophilic species: deuterio ion); chlorine (electrophilic species: chlorocation), bromine (electrophilic species: bromocation), iodine. Halogen atoms such as (electrophilic species: iodo cation); sulfonates such as methyl mesylate (electrophilic species: methyl cation), methyl tosylate (electrophilic species: methyl cation), methyl triflate (electrophilic species: methyl cation) Amides such as N, N-dimethylformamide (electrophilic species: formyl cation), N, N-dimethylacetamide (electrophilic species: acetyl cation); chlorotrimethylsilane (electrophilic species: trimethylsilyl cation), chlorotriethyl Silane (electrophilic species: triethylsilyl cation), tert-butylchlorodimethylsila Chlorosilanes such as (electrophilic species: tert-butyldimethylsilyl cation); trimethyl borate (electrophilic species: dimethoxyboronium cation), triethyl borate (electrophilic species: diethoxyboronium cation), triisopropyl borate Boric acid esters such as (electrophilic species: diisopropoxyboronium cation); trimethyltin chloride (electrophilic species: trimethylstannium cation), tri-n-butyltin chloride (electrophilic species: tri-n-butylstannium cation) ), Trialkyltin salts such as tri-n-butyltin triflate (electrophilic species: tri-n-butylstannium cation).
前記式（１ｂ）で示される化合物の中でも、本発明においては、下記式（１ｂ−１）及び（１ｂ−２）：
で示される２，３，４−トリフルオロ−５−ジューテリオ安息香酸又は２，３，４−トリフルオロ−５−トリメチルシリル安息香酸が好ましい。Among the compounds represented by the formula (1b), in the present invention, the following formulas (1b-1) and (1b-2):
2,3,4-trifluoro-5-deuteriobenzoic acid or 2,3,4-trifluoro-5-trimethylsilylbenzoic acid represented by
前記一般式（３ａ）又は（３ｂ）で示される２，３，４−トリフルオロ−５−リチオ安息香酸と、求電子種を発生させ得る化合物との反応は、例えば、２，３，４−トリフルオロ−５−リチオ安息香酸を含む溶液に求電子種を発生させ得る化合物を有機溶媒の存在下又は非存在下において、ゆるやかに添加し、攪拌しながら反応させることができる。その際の反応温度は、好ましくは−１００〜０℃、更に好ましくは−８０〜−１０℃であり、反応圧力は特に制限されない。 The reaction of 2,3,4-trifluoro-5-lithiobenzoic acid represented by the general formula (3a) or (3b) with a compound capable of generating an electrophilic species is, for example, 2,3,4- A compound capable of generating an electrophilic species in a solution containing trifluoro-5-lithiobenzoic acid can be slowly added in the presence or absence of an organic solvent and allowed to react with stirring. The reaction temperature at that time is preferably −100 to 0 ° C., more preferably −80 to −10 ° C., and the reaction pressure is not particularly limited.
使用する有機溶媒としては、反応を阻害しないものならば特に限定されないが、例えば、Ｎ，Ｎ’−ジメチルイミダゾリジノン等の尿素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン等のエーテル類；ヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類が挙げられるが、好ましくはエーテル類、脂肪族炭化水素類、芳香族炭化水素類、更に好ましくはエーテル類、脂肪族炭化水素類が使用される。なお、これらの有機溶媒は、単独又は二種以上を混合して使用しても良い。 The organic solvent to be used is not particularly limited as long as it does not inhibit the reaction. For example, ureas such as N, N′-dimethylimidazolidinone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; hexane Aliphatic hydrocarbons such as benzene, toluene, xylene, etc., preferably ethers, aliphatic hydrocarbons, aromatic hydrocarbons, more preferably ethers Aliphatic hydrocarbons are used. In addition, you may use these organic solvents individually or in mixture of 2 or more types.
前記有機溶媒の使用量は、反応液の均一性や攪拌性等により適宜調節するが、２，３，４−トリフルオロ−５−リチオ安息香酸１ｇに対して、好ましくは５〜１００ｍｌ、更に好ましくは１０〜５０ｍｌである。 The amount of the organic solvent used is appropriately adjusted depending on the uniformity of the reaction solution, the stirring ability, etc., but is preferably 5 to 100 ml, more preferably 1 g of 2,3,4-trifluoro-5-lithiobenzoic acid. Is 10-50 ml.
本発明の反応によって２，３，４−トリフルオロ−５−置換安息香酸化合物が得られるが、目的物が２，３，４−トリフルオロ−５−置換安息香酸化合物の場合には、反応終了後、例えば、中和、抽出、濾過、濃縮、蒸留、再結晶、晶析、カラムクロマトグラフィー等の一般的な製法によって単離・精製され、一方、目的物が２，３，４−トリフルオロ−５−置換安息香酸の金属塩の場合には、反応終了後、例えば、抽出、濾過、濃縮、蒸留、再結晶、晶析、カラムクロマトグラフィー等の一般的な製法によって単離・精製される。 A 2,3,4-trifluoro-5-substituted benzoic acid compound is obtained by the reaction of the present invention. When the target product is a 2,3,4-trifluoro-5-substituted benzoic acid compound, the reaction is completed. Then, for example, it is isolated and purified by a general production method such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography, etc., while the target product is 2,3,4-trifluoro. In the case of a metal salt of -5-substituted benzoic acid, it is isolated and purified by a general production method such as extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after completion of the reaction. .
次に、実施例を挙げて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。 Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
実施例１（２，３，４−トリフルオロ−５−ヨード安息香酸の合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、２，２，６，６−テトラメチルピペリジン２０．０ｇ（０．１４２ｍｏｌ）及びテトラヒドロフラン７０ｍｌを加え、液温を−１５℃以下に保ちながら、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液８９．９ｍｌ（０．１４２ｍｏｌ）をゆるやかに滴下し、−１５℃で３０分間攪拌させてリチウム２，２，６，６−テトラメチルピペリジドを含む溶液を調製した。
次いで、該溶液の液温を−１５℃以下に保ちながら、２，３，４−トリフルオロ安息香酸１０．０ｇ（０．０５７ｍｏｌ）をテトラヒドロフラン１００ｍｌに溶かした溶液をゆるやかに加えた後、−１５℃で３０分間攪拌させた。その後、この溶液を、ヨウ素２１．７ｇ（０．０８６ｍｏｌ）をテトラヒドロフラン４０ｍｌに溶解させて０℃に冷却した溶液に、液温を１０℃以下に保ちながらゆるやかに滴下し、攪拌しながら１０℃で３０分間反応させた。
反応終了後、反応液に１０％亜硫酸ナトリウム水溶液６０ｇ（０．０４８ｍｏｌ）を加えた後、濃塩酸を加えて酸性化した。次いで、反応液を濾過し、濾液から有機層を分液した後、有機層を減圧下で濃縮した。濃縮物をシリカゲルカラムクロマトグラフィー（展開溶媒：酢酸エチル）で精製し、淡黄色結晶として、２，３，４−トリフルオロ−５−ヨード安息香酸１０．３ｇを得た（単離収率；６０％）。
なお、２，３，４−トリフルオロ−５−ヨード安息香酸の物性値は以下の通りであった。Example 1 (Synthesis of 2,3,4-trifluoro-5-iodobenzoic acid)
To a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel, 20.0 g (0.142 mol) of 2,2,6,6-tetramethylpiperidine and 70 ml of tetrahydrofuran were added under an argon atmosphere. While maintaining the temperature at -15 ° C. or lower, 89.9 ml (0.142 mol) of a hexane solution of 1.58 mol / ln-butyllithium was slowly dropped and stirred at −15 ° C. for 30 minutes to obtain lithium 2,2,6. A solution containing 1,6-tetramethylpiperidide was prepared.
Next, while keeping the solution temperature at −15 ° C. or lower, a solution in which 10.0 g (0.057 mol) of 2,3,4-trifluorobenzoic acid was dissolved in 100 ml of tetrahydrofuran was slowly added, and then −15 Stir at 30 ° C. for 30 minutes. Thereafter, 21.7 g (0.086 mol) of iodine was dissolved in 40 ml of tetrahydrofuran and the solution was cooled slowly to 0 ° C. while slowly dropping the solution at a temperature of 10 ° C. or lower. The reaction was allowed for 30 minutes.
After completion of the reaction, 60 g (0.048 mol) of a 10% aqueous sodium sulfite solution was added to the reaction solution, and then acidified by adding concentrated hydrochloric acid. Next, the reaction solution was filtered, and the organic layer was separated from the filtrate, and then the organic layer was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 10.3 g of 2,3,4-trifluoro-5-iodobenzoic acid as pale yellow crystals (isolated yield; 60 %).
The physical properties of 2,3,4-trifluoro-5-iodobenzoic acid were as follows.
融点；１６０〜１６１℃
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；８．２２〜８．２７（１Ｈ，ｔｄ，Ｊ＝７．０８，２．４４Ｈｚ）、９．７０（１Ｈ，ｂｒ）
ＣＩ−ＭＳ（ｍ／ｅ）；３０３（Ｍ＋１）Melting point: 160-161 ° C
1 H-NMR (DMSO-d 6 , δ (ppm)); 8.22 to 8.27 (1H, td, J = 7.08, 2.44 Hz), 9.70 (1H, br)
CI-MS (m / e); 303 (M + 1)
実施例２（２，３，４−トリフルオロ−５−ヨード安息香酸の合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、２，２，６，６−テトラメチルピペリジン２０．０ｇ（０．１４２ｍｏｌ）及びテトラヒドロフラン７０ｍｌを加え、液温を−１５℃以下に保ちながら、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液８９．９ｍｌ（０．１４２ｍｏｌ）をゆるやかに滴下し、−１５℃で３０分間攪拌させてリチウム２，２，６，６−テトラメチルピペリジドを含む溶液を調製した。
次いで、該溶液の液温を−１５℃以下に保ちながら、２，３，４−トリフルオロ安息香酸１０．０ｇ（０．０５７ｍｏｌ）をテトラヒドロフラン１００ｍｌに溶かした溶液をゆるやかに加えた後、−１５℃で３０分間攪拌させた。その後、この溶液を、一塩化ヨウ素１４．０ｇ（０．０８６ｍｏｌ）をテトラヒドロフラン４０ｍｌに溶解させて０℃に冷却した溶液に、液温を１０℃以下に保ちながらゆるやかに滴下し、攪拌しながら１０℃で３０分間反応させた。
反応終了後、反応液に１０％亜硫酸ナトリウム水溶液６０ｇ（０．０４８ｍｏｌ）を加えた後、濃塩酸を加えて酸性化した。次いで、反応液を濾過し、濾液から有機層を分液した後、有機層を減圧下で濃縮した。濃縮物をシリカゲルカラムクロマトグラフィー（展開溶媒：酢酸エチル）で精製し、淡黄色結晶として、２，３，４−トリフルオロ−５−ヨード安息香酸１１．２ｇを得た（単離収率；６５％）。Example 2 (Synthesis of 2,3,4-trifluoro-5-iodobenzoic acid)
To a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel, 20.0 g (0.142 mol) of 2,2,6,6-tetramethylpiperidine and 70 ml of tetrahydrofuran were added under an argon atmosphere. While maintaining the temperature at -15 ° C. or lower, 89.9 ml (0.142 mol) of a hexane solution of 1.58 mol / ln-butyllithium was slowly dropped and stirred at −15 ° C. for 30 minutes to obtain lithium 2,2,6. A solution containing 1,6-tetramethylpiperidide was prepared.
Next, while keeping the solution temperature at −15 ° C. or lower, a solution in which 10.0 g (0.057 mol) of 2,3,4-trifluorobenzoic acid was dissolved in 100 ml of tetrahydrofuran was slowly added, and then −15 Stir at 30 ° C. for 30 minutes. Thereafter, 14.0 g (0.086 mol) of iodine monochloride was dissolved in 40 ml of tetrahydrofuran and cooled to 0 ° C., and this solution was slowly dropped while maintaining the liquid temperature at 10 ° C. or lower. The reaction was carried out at 30 ° C. for 30 minutes.
After completion of the reaction, 60 g (0.048 mol) of 10% aqueous sodium sulfite solution was added to the reaction solution, and then acidified by adding concentrated hydrochloric acid. Next, the reaction solution was filtered, and the organic layer was separated from the filtrate, and then the organic layer was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 11.2 g of 2,3,4-trifluoro-5-iodobenzoic acid as a pale yellow crystal (isolated yield; 65 %).
実施例３（２，３，４−トリフルオロ−５−ヨード安息香酸の合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、ジイソプロピルアミン１４．３ｇ（０．１４２ｍｏｌ）及びテトラヒドロフラン７０ｍｌを加え、液温を−１５℃以下に保ちながら、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液８９．９ｍｌ（０．１４２ｍｏｌ）をゆるやかに滴下し、−７０℃で３０分間攪拌させてリチウムジイソプロピルアミドを含む溶液を調製した。
次いで、該溶液の液温を−６０℃以下に保ちながら、２，３，４−トリフルオロ安息香酸１０．０ｇ（０．０５７ｍｏｌ）をテトラヒドロフラン１００ｍｌに溶かした溶液をゆるやかに加えた後、−７０℃で３０分間攪拌させた。その後、この溶液を、ヨウ素２１．７ｇ（０．０８６ｍｏｌ）をテトラヒドロフラン４０ｍｌに溶解させて−７０℃に冷却した溶液に、液温を−６０℃以下に保ちながらゆるやかに滴下し、攪拌しながら−６０℃で３０分間反応させた。
反応終了後、反応液に１０％亜硫酸ナトリウム水溶液６０ｇ（０．０４８ｍｏｌ）を加えた後、濃塩酸を加えて酸性化した。次いで、反応液を濾過し、濾液から有機層を分液した後、有機層を減圧下で濃縮した。濃縮物をシリカゲルカラムクロマトグラフィー（展開溶媒：酢酸エチル）で精製し、淡黄色結晶として、２，３，４−トリフルオロ−５−ヨード安息香酸１５．３ｇを得た（単離収率；８９％）。Example 3 (Synthesis of 2,3,4-trifluoro-5-iodobenzoic acid)
To a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel, 14.3 g (0.142 mol) of diisopropylamine and 70 ml of tetrahydrofuran are added under an argon atmosphere, and the liquid temperature is kept at −15 ° C. or lower. Then, 89.9 ml (0.142 mol) of a hexane solution of 1.58 mol / ln-butyllithium was slowly added dropwise and stirred at −70 ° C. for 30 minutes to prepare a solution containing lithium diisopropylamide.
Next, while keeping the liquid temperature of the solution at −60 ° C. or lower, a solution obtained by dissolving 10.0 g (0.057 mol) of 2,3,4-trifluorobenzoic acid in 100 ml of tetrahydrofuran was slowly added, and then −70 Stir at 30 ° C. for 30 minutes. Thereafter, 21.7 g (0.086 mol) of iodine was dissolved in 40 ml of tetrahydrofuran and the solution was cooled to −70 ° C. while slowly dropping the solution at −60 ° C. or lower and stirring. The reaction was performed at 60 ° C. for 30 minutes.
After completion of the reaction, 60 g (0.048 mol) of 10% aqueous sodium sulfite solution was added to the reaction solution, and then acidified by adding concentrated hydrochloric acid. Next, the reaction solution was filtered, and the organic layer was separated from the filtrate, and then the organic layer was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 15.3 g of 2,3,4-trifluoro-5-iodobenzoic acid as pale yellow crystals (isolated yield; 89 %).
実施例４（２，３，４−トリフルオロ−５−ヨード安息香酸の合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、２，２，６，６−テトラメチルピペリジン９．６４ｇ（０．０６８ｍｏｌ）及びテトラヒドロフラン３５ｍｌを加え、液温を−１５℃以下に保ちながら、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液４３．３ｍｌ（０．０６８ｍｏｌ）をゆるやかに滴下し、−１５℃で３０分間攪拌させてリチウム２，２，６，６−テトラメチルピペリジドを含む溶液を調製した。
次いで、該溶液の液温を−１５℃以下に保ちながら、２，３，４−トリフルオロ安息香酸ナトリウム１１．３ｇ（０．０５７ｍｏｌ）をテトラヒドロフラン１００ｍｌに懸濁した溶液をゆるやかに加えた後、−１５℃で３０分間攪拌させた。その後、この溶液を、ヨウ素２１．７ｇ（０．０８６ｍｏｌ）をテトラヒドロフラン４０ｍｌに溶解させて０℃に冷却した溶液に、液温を１０℃以下に保ちながらゆるやかに滴下し、攪拌しながら１０℃で３０分間反応させた。
反応終了後、反応液に１０％亜硫酸ナトリウム水溶液６０ｇ（０．０４８ｍｏｌ）を加えた後、濃塩酸を加えて酸性化した。次いで、反応液を濾過し、濾液から有機層を分液した後、有機層を高速液体クロマトグラフィーで分析（絶対定量法）したところ、２，３，４−トリフルオロ−５−ヨード安息香酸が１０．３ｇ生成していた（反応収率；６０％）。Example 4 (Synthesis of 2,3,4-trifluoro-5-iodobenzoic acid)
Under an argon atmosphere, 9.64 g (0.068 mol) of 2,2,6,6-tetramethylpiperidine and 35 ml of tetrahydrofuran were added to a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel. While maintaining the temperature at −15 ° C. or lower, 43.3 ml (0.068 mol) of a hexane solution of 1.58 mol / ln-butyllithium was slowly dropped and stirred at −15 ° C. for 30 minutes to obtain lithium 2,2,6 A solution containing 1,6-tetramethylpiperidide was prepared.
Subsequently, while keeping the liquid temperature of the solution at −15 ° C. or lower, a solution in which 11.3 g (0.057 mol) of sodium 2,3,4-trifluorobenzoate was suspended in 100 ml of tetrahydrofuran was slowly added, The mixture was stirred at -15 ° C for 30 minutes. Thereafter, 21.7 g (0.086 mol) of iodine was dissolved in 40 ml of tetrahydrofuran and the solution was cooled slowly to 0 ° C. while slowly dropping the solution at a temperature of 10 ° C. or lower. The reaction was allowed for 30 minutes.
After completion of the reaction, 60 g (0.048 mol) of 10% aqueous sodium sulfite solution was added to the reaction solution, and then acidified by adding concentrated hydrochloric acid. Next, the reaction solution was filtered, and the organic layer was separated from the filtrate, and then the organic layer was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 2,3,4-trifluoro-5-iodobenzoic acid was 10.3 g was produced (reaction yield; 60%).
実施例５（２，３，４−トリフルオロ−５−ヨード安息香酸リチウムの合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、２，２，６，６−テトラメチルピペリジン２０．０ｇ（０．１４２ｍｏｌ）及びテトラヒドロフラン７０ｍｌを加え、液温を−１５℃以下に保ちながら、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液８９．９ｍｌ（０．１４２ｍｏｌ）をゆるやかに滴下し、−１５℃で３０分間攪拌させてリチウム２，２，６，６−テトラメチルピペリジドを含む溶液を調製した。
次いで、該溶液の液温を−１５℃以下に保ちながら、２，３，４−トリフルオロ安息香酸１０．０ｇ（０．０５７ｍｏｌ）をテトラヒドロフラン１００ｍｌに溶かした溶液をゆるやかに加えた後、−１５℃で３０分間攪拌させた。その後、この溶液を、ヨウ素２１．７ｇ（０．０８６ｍｏｌ）をテトラヒドロフラン４０ｍｌに溶解させて０℃に冷却した溶液に、液温を１０℃以下に保ちながらゆるやかに滴下し、攪拌しながら１０℃で３０分間反応させた。
反応終了後、反応液に水３０ｍｌを加えた後、減圧下で濃縮した。得られた濃縮物をトルエン３０ｍｌで２回洗浄した後に乾燥させ、淡橙色結晶として、２，３，４−トリフルオロ−５−ヨード安息香酸リチウム９．９８ｇを得た（単離収率；５７％）。
なお、２，３，４−トリフルオロ−５−ヨード安息香酸リチウムは、以下の物性値で示される新規な化合物である。Example 5 (Synthesis of lithium 2,3,4-trifluoro-5-iodobenzoate)
To a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel, 20.0 g (0.142 mol) of 2,2,6,6-tetramethylpiperidine and 70 ml of tetrahydrofuran were added under an argon atmosphere. While maintaining the temperature at -15 ° C. or lower, 89.9 ml (0.142 mol) of a hexane solution of 1.58 mol / ln-butyllithium was slowly dropped and stirred at −15 ° C. for 30 minutes to obtain lithium 2,2,6. A solution containing 1,6-tetramethylpiperidide was prepared.
Next, while keeping the solution temperature at −15 ° C. or lower, a solution in which 10.0 g (0.057 mol) of 2,3,4-trifluorobenzoic acid was dissolved in 100 ml of tetrahydrofuran was slowly added, and then −15 Stir at 30 ° C. for 30 minutes. Thereafter, 21.7 g (0.086 mol) of iodine was dissolved in 40 ml of tetrahydrofuran and the solution was cooled slowly to 0 ° C. while slowly dropping the solution at a temperature of 10 ° C. or lower. The reaction was allowed for 30 minutes.
After completion of the reaction, 30 ml of water was added to the reaction solution, followed by concentration under reduced pressure. The obtained concentrate was washed twice with 30 ml of toluene and then dried to obtain 9.98 g of lithium 2,3,4-trifluoro-5-iodobenzoate as pale orange crystals (isolation yield; 57 %).
Note that lithium 2,3,4-trifluoro-5-iodobenzoate is a novel compound represented by the following physical property values.
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；７．８４〜７．９０（１Ｈ，ｄｄｄ，Ｊ＝７．３１，４．６３，２．６８Ｈｚ） 1 H-NMR (DMSO-d 6 , δ (ppm)); 7.84 to 7.90 (1H, ddd, J = 7.31, 4.63, 2.68 Hz)
実施例６（２，３，４−トリフルオロ−５−ホルミル安息香酸の合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、２，２，６，６−テトラメチルピペリジン２０．０ｇ（０．１４２ｍｏｌ）及びテトラヒドロフラン７０ｍｌを加え、液温を−６０℃以下に保ちながら、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液８９．９ｍｌ（０．１４２ｍｏｌ）をゆるやかに滴下し、−７０℃で３０分間攪拌させてリチウム２，２，６，６−テトラメチルピペリジドを含む溶液を調製した。
次いで、該溶液の液温を−６０℃以下に保ちながら、２，３，４−トリフルオロ安息香酸１０．０ｇ（０．０５７ｍｏｌ）をテトラヒドロフラン１００ｍｌに溶かした溶液をゆるやかに加えた後、−７０℃で３０分間攪拌させた。その後、この溶液に、Ｎ，Ｎ−ジメチルホルムアミド６．２８ｇ（０．０８６ｍｏｌ）をテトラヒドロフラン４０ｍｌに溶解させて−６０℃に冷却した溶液を、液温を−６０℃以下に保ちながらゆるやかに滴下し、攪拌しながら−６０℃で３０分間反応させた。
反応終了後、反応液に２ｍｏｌ／ｌ塩酸を加えて酸性化し、有機層を分液した後、水層を酢酸エチル５０ｍｌで２回抽出した。次いで、有機層と抽出液を合わせて無水硫酸マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃縮した後、濃縮物をジイソプロピルエーテルを用いて再結晶させ、無色結晶として、２，３，４−トリフルオロ−５−ホルミル安息香酸１０．２ｇを得た（単離収率；８８％）。
なお、２，３，４−トリフルオロ−５−ホルミル安息香酸は以下の物性値で示される新規な化合物である。Example 6 (Synthesis of 2,3,4-trifluoro-5-formylbenzoic acid)
To a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel, 20.0 g (0.142 mol) of 2,2,6,6-tetramethylpiperidine and 70 ml of tetrahydrofuran were added under an argon atmosphere. While maintaining the temperature at −60 ° C. or lower, 89.9 ml (0.142 mol) of a hexane solution of 1.58 mol / ln-butyllithium was slowly added dropwise and stirred at −70 ° C. for 30 minutes to give lithium 2,2,6 A solution containing 1,6-tetramethylpiperidide was prepared.
Next, while keeping the liquid temperature of the solution at −60 ° C. or lower, a solution obtained by dissolving 10.0 g (0.057 mol) of 2,3,4-trifluorobenzoic acid in 100 ml of tetrahydrofuran was slowly added, and then −70 Stir at 30 ° C. for 30 minutes. Thereafter, a solution obtained by dissolving 6.28 g (0.086 mol) of N, N-dimethylformamide in 40 ml of tetrahydrofuran and cooling to −60 ° C. was slowly dropped into this solution while keeping the liquid temperature at −60 ° C. or lower. The mixture was reacted at −60 ° C. for 30 minutes with stirring.
After completion of the reaction, the reaction solution was acidified by adding 2 mol / l hydrochloric acid, the organic layer was separated, and the aqueous layer was extracted twice with 50 ml of ethyl acetate. Next, the organic layer and the extract were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrate was recrystallized using diisopropyl ether to obtain 10.3 g of 2,3,4-trifluoro-5-formylbenzoic acid as colorless crystals (single (Separation yield; 88%).
2,3,4-Trifluoro-5-formylbenzoic acid is a novel compound represented by the following physical property values.
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；８．３５〜８．４１（１Ｈ，ｄｄｄ，Ｊ＝７．３１，４．８７，２．４４Ｈｚ）、１０．２７（１Ｈ，ｓ）、１２．０（１Ｈ，ｂｒ）
ＣＩ−ＭＳ（ｍ／ｅ）；２０５（Ｍ＋１） 1 H-NMR (DMSO-d 6 , δ (ppm)); 8.35 to 8.41 (1H, ddd, J = 7.31, 4.87, 2.44 Hz), 10.27 (1H, s ) 12.0 (1H, br)
CI-MS (m / e); 205 (M + 1)
実施例７（２，３，４−トリフルオロ−５−リチオ安息香酸リチウムの合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、２，２，６，６−テトラメチルピペリジン２０．０ｇ（０．１４２ｍｏｌ）及びテトラヒドロフラン７０ｍｌを加え、液温を−５０℃以下に保ちながら、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液８９．９ｍｌ（０．１４２ｍｏｌ）をゆるやかに滴下し、−６０℃で３０分間攪拌させてリチウム２，２，６，６−テトラメチルピペリジドを含む溶液を調製した。次いで、該溶液の液温を−５０℃以下に保ちながら、２，３，４−トリフルオロ安息香酸１０．０ｇ（０．０５７ｍｏｌ）をテトラヒドロフラン１００ｍｌに溶かした溶液をゆるやかに加えた後、−６０℃で３０分間攪拌させて、２，３，４−トリフルオロ−５−リチオ安息香酸リチウムを含む溶液を生成させた。
次いで、この２，３，４−トリフルオロ−５−リチオ安息香酸リチウムを含む溶液に、重水１．７２ｇ（０．０８６ｍｏｌ）（求電子種；ジューテリオイオン）をゆるやかに添加して、攪拌しながら−５０℃で３０分間反応させた。反応終了後、反応液に濃塩酸を加えて酸性化し、有機層を分液した後に減圧下で濃縮した。得られた濃縮物をシリカゲルカラムクロマトグラフィーで精製（展開溶媒；酢酸エチル）し、淡黄色結晶として、２，３，４−トリフルオロ−５−ジューテリオ安息香酸７．２６ｇを得た（単離収率；７２％）。
なお、２，３，４−トリフルオロ−５−ジューテリオ安息香酸は、以下の物性値で示される新規な化合物である。Example 7 (Synthesis of lithium 2,3,4-trifluoro-5-lithiobenzoate)
To a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel, 20.0 g (0.142 mol) of 2,2,6,6-tetramethylpiperidine and 70 ml of tetrahydrofuran were added under an argon atmosphere. While maintaining the temperature at -50 ° C. or lower, 89.9 ml (0.142 mol) of a hexane solution of 1.58 mol / ln-butyllithium was slowly dropped and stirred at −60 ° C. for 30 minutes to obtain lithium 2,2,6. A solution containing 1,6-tetramethylpiperidide was prepared. Next, while keeping the liquid temperature of the solution at −50 ° C. or lower, a solution obtained by dissolving 10.0 g (0.057 mol) of 2,3,4-trifluorobenzoic acid in 100 ml of tetrahydrofuran was slowly added, and then −60 The solution was stirred at 30 ° C. for 30 minutes to produce a solution containing lithium 2,3,4-trifluoro-5-lithiobenzoate.
Next, 1.72 g (0.086 mol) of heavy water (electrophilic species; deuterio ion) was slowly added to the solution containing lithium 2,3,4-trifluoro-5-lithiobenzoate and stirred. The reaction was carried out at -50 ° C for 30 minutes. After completion of the reaction, the reaction solution was acidified by adding concentrated hydrochloric acid, and the organic layer was separated and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (developing solvent; ethyl acetate) to obtain 7.26 g of 2,3,4-trifluoro-5-deuteriobenzoic acid as a pale yellow crystal (isolated product). Rate; 72%).
In addition, 2,3,4-trifluoro-5-deuteriobenzoic acid is a novel compound represented by the following physical property values.
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ（ｐｐｍ））；７．７９〜７．８８（１Ｈ，ｄｄｄ，Ｊ＝４．３９，２．４４，１．９５Ｈｚ）、１２．０（１Ｈ，ｓ）
ＣＩ−ＭＳ（ｍ／ｅ）；１７８（Ｍ＋１） 1 H-NMR (CDCl 3 , δ (ppm)); 7.79 to 7.88 (1H, ddd, J = 4.39, 2.44, 1.95 Hz), 12.0 (1H, s)
CI-MS (m / e); 178 (M + 1)
実施例８（２，３，４−トリフルオロ−５−リチオ安息香酸ナトリウムの合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、２，２，６，６−テトラメチルピペリジン９．６４ｇ（０．０６８ｍｏｌ）及びテトラヒドロフラン３５ｍｌを加え、液温を−１５℃以下に保ちながら、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液４３．３ｍｌ（０．０６８ｍｏｌ）をゆるやかに滴下し、−１５℃で３０分間攪拌させてリチウム２，２，６，６−テトラメチルピペリジドを含む溶液を調製した。次いで、該溶液の液温を−１５℃以下に保ちながら、２，３，４−トリフルオロ安息香酸ナトリウム１１．３ｇ（０．０５７ｍｏｌ）をテトラヒドロフラン１００ｍｌに懸濁した溶液をゆるやかに加えた後、−１５℃で３０分間攪拌させて、２，３，４−トリフルオロ−５−リチオ安息香酸ナトリウムを含む溶液を生成させた。
次いで、この２，３，４−トリフルオロ−５−リチオ安息香酸ナトリウムを含む溶液に、重水１．７２ｇ（０．０８６ｍｏｌ）（求電子種；ジューテリオイオン）をゆるやかに添加して、攪拌しながら−１５℃で３０分間反応させた。反応終了後、反応液に濃塩酸を加えて酸性化し、有機層を分液した後に減圧下で濃縮した。得られた濃縮物をシリカゲルカラムクロマトグラフィーで精製（展開溶媒；酢酸エチル）し、淡黄色結晶として、２，３，４−トリフルオロ−５−ジューテリオ安息香酸６．９６ｇを得た（単離収率；６９％）。Example 8 (Synthesis of sodium 2,3,4-trifluoro-5-lithiobenzoate)
Under an argon atmosphere, 9.64 g (0.068 mol) of 2,2,6,6-tetramethylpiperidine and 35 ml of tetrahydrofuran were added to a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel. While maintaining the temperature at −15 ° C. or lower, 43.3 ml (0.068 mol) of a hexane solution of 1.58 mol / ln-butyllithium was slowly dropped and stirred at −15 ° C. for 30 minutes to obtain lithium 2,2,6 A solution containing 1,6-tetramethylpiperidide was prepared. Subsequently, while keeping the liquid temperature of the solution at −15 ° C. or lower, a solution in which 11.3 g (0.057 mol) of sodium 2,3,4-trifluorobenzoate was suspended in 100 ml of tetrahydrofuran was slowly added, Stir at -15 ° C for 30 minutes to produce a solution containing sodium 2,3,4-trifluoro-5-lithiobenzoate.
Next, 1.72 g (0.086 mol) of heavy water (electrophilic species; deuterio ion) was gently added to the solution containing sodium 2,3,4-trifluoro-5-lithiobenzoate and stirred. The reaction was carried out at -15 ° C for 30 minutes. After completion of the reaction, the reaction solution was acidified by adding concentrated hydrochloric acid, and the organic layer was separated and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (developing solvent; ethyl acetate) to obtain 6.96 g of 2,3,4-trifluoro-5-deuteriobenzoic acid as a pale yellow crystal (isolated product). Rate; 69%).
実施例９（２，３，４−トリフルオロ−５−リチオ安息香酸リチウムの合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、２，２，６，６−テトラメチルピペリジン２０．０ｇ（０．１４２ｍｏｌ）及びテトラヒドロフラン７０ｍｌを加え、液温を−５０℃以下に保ちながら、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液８９．９ｍｌ（０．１４２ｍｏｌ）をゆるやかに滴下し、−６０℃で３０分間攪拌させてリチウム２，２，６，６−テトラメチルピペリジドを含む溶液を調製した。次いで、該溶液の液温を−５０℃以下に保ちながら、２，３，４−トリフルオロ安息香酸１０．０ｇ（０．０５７ｍｏｌ）をテトラヒドロフラン１００ｍｌに溶かした溶液をゆるやかに加えた後、−６０℃で３０分間攪拌させて、２，３，４−トリフルオロ−５−リチオ安息香酸リチウムを含む溶液を生成させた。
次いで、この２，３，４−トリフルオロ−５−リチオ安息香酸リチウムを含む溶液に、クロロトリメチルシラン１４．６ｇ（０．１３４ｍｏｌ）（求電子種；トリメチルシリルカチオン）をゆるやかに添加して、攪拌しながら−５０℃で３０分間反応させた。反応終了後、反応液に濃塩酸を加えて酸性化し、有機層を分液した後に減圧下で濃縮した。得られた濃縮物をシリカゲルカラムクロマトグラフィーで精製（展開溶媒；酢酸エチル）し、淡黄色結晶として、２，３，４−トリフルオロ−５−トリメチルシリル安息香酸７．０７ｇを得た（単離収率；５０％）。
なお、２，３，４−トリフルオロ−５−トリメチルシリル安息香酸は、以下の物性値で示される新規な化合物である。Example 9 (Synthesis of lithium 2,3,4-trifluoro-5-lithiobenzoate)
To a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel, 20.0 g (0.142 mol) of 2,2,6,6-tetramethylpiperidine and 70 ml of tetrahydrofuran were added under an argon atmosphere. While maintaining the temperature at -50 ° C. or lower, 89.9 ml (0.142 mol) of a hexane solution of 1.58 mol / ln-butyllithium was slowly dropped and stirred at −60 ° C. for 30 minutes to obtain lithium 2,2,6. A solution containing 1,6-tetramethylpiperidide was prepared. Next, while keeping the liquid temperature of the solution at −50 ° C. or lower, a solution obtained by dissolving 10.0 g (0.057 mol) of 2,3,4-trifluorobenzoic acid in 100 ml of tetrahydrofuran was slowly added, and then −60 The solution was stirred at 30 ° C. for 30 minutes to produce a solution containing lithium 2,3,4-trifluoro-5-lithiobenzoate.
Next, 14.6 g (0.134 mol) of chlorotrimethylsilane (electrophilic species; trimethylsilyl cation) is slowly added to the solution containing lithium 2,3,4-trifluoro-5-lithiobenzoate and stirred. The reaction was carried out at −50 ° C. for 30 minutes. After completion of the reaction, the reaction solution was acidified by adding concentrated hydrochloric acid, and the organic layer was separated and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (developing solvent; ethyl acetate) to obtain 7.07 g of 2,3,4-trifluoro-5-trimethylsilylbenzoic acid as a pale yellow crystal (isolated product). Rate; 50%).
2,3,4-trifluoro-5-trimethylsilylbenzoic acid is a novel compound represented by the following physical property values.
１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ（ｐｐｍ））；０．３７（９Ｈ，ｓ）、７．６５〜７．７３（１Ｈ，ｄｄｄ，Ｊ＝８．０６，５．６２，２．４４Ｈｚ）、１２．０（１Ｈ，ｂｒｓ）
ＣＩ−ＭＳ（ｍ／ｅ）；２４９（Ｍ＋１） 1 H-NMR (CDCl 3 , δ (ppm)); 0.37 (9H, s), 7.65 to 7.73 (1H, ddd, J = 8.06, 5.62, 2.44 Hz), 12.0 (1H, brs)
CI-MS (m / e); 249 (M + 1)
実施例１０（２，３，４−トリフルオロ−５−リチオ安息香酸リチウムの合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５００ｍｌのガラス製フラスコに、アルゴン雰囲気下、１．５８ｍｏｌ／ｌｎ−ブチルリチウムのヘキサン溶液６４．０ｍｌ（０．１０１ｍｏｌ）及びテトラヒドロフラン１００ｍｌを加え、液温を−５０℃以下に保ちながら、２，２，６，６−テトラメチルピペリジン１２．３ｇ（０．１０１ｍｏｌ）をゆるやかに滴下し、−６０℃で３０分間攪拌させてリチウム２，２，６，６−テトラメチルピペリジドを含む溶液を調製した。次いで、該溶液の液温を−５０℃以下に保ちながら、２，３，４−トリフルオロ安息香酸８．２０ｇ（０．０４７ｍｏｌ）をテトラヒドロフラン１００ｍｌに溶かした溶液をゆるやかに加えた後、−７０℃で３０分間攪拌させて、２，３，４−トリフルオロ−５−リチオ安息香酸リチウムを含む溶液を生成させた。
次いで、この２，３，４−トリフルオロ−５−リチオ安息香酸リチウムを含む溶液に、二酸化炭素（求電子種：カルボキシルカチオン）をゆるやかに添加して、攪拌しながら−７０℃で３０分間反応させた。反応終了後、反応液に濃塩酸を加えて酸性化し、有機層を分液した後に減圧下で濃縮した。得られた濃縮物を酢酸エチルでリパルプし、白色結晶として、４，５，６−トリフルオロイソフタル酸４．６７ｇを得た（単離収率；４６％）。
なお、４，５，６−トリフルオロイソフタル酸の物性値は以下の通りであった。Example 10 (Synthesis of lithium 2,3,4-trifluoro-5-lithiobenzoate)
To a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a dropping funnel, 64.0 ml (0.101 mol) of a hexane solution of 1.58 mol / ln-butyllithium and 100 ml of tetrahydrofuran were added under an argon atmosphere. While maintaining the temperature at −50 ° C. or lower, 12.3 g (0.101 mol) of 2,2,6,6-tetramethylpiperidine was slowly added dropwise and stirred at −60 ° C. for 30 minutes to obtain lithium 2,2,6. A solution containing 1,6-tetramethylpiperidide was prepared. Next, while keeping the liquid temperature of the solution at −50 ° C. or lower, a solution in which 8.20 g (0.047 mol) of 2,3,4-trifluorobenzoic acid was dissolved in 100 ml of tetrahydrofuran was slowly added, and then −70 The solution was stirred at 30 ° C. for 30 minutes to produce a solution containing lithium 2,3,4-trifluoro-5-lithiobenzoate.
Next, carbon dioxide (electrophilic species: carboxyl cation) is slowly added to the solution containing lithium 2,3,4-trifluoro-5-lithiobenzoate, and the reaction is performed at −70 ° C. for 30 minutes with stirring. I let you. After completion of the reaction, the reaction solution was acidified by adding concentrated hydrochloric acid, and the organic layer was separated and concentrated under reduced pressure. The obtained concentrate was repulped with ethyl acetate to obtain 4.67 g of 4,5,6-trifluoroisophthalic acid as white crystals (isolation yield; 46%).
The physical properties of 4,5,6-trifluoroisophthalic acid were as follows.
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６，δ（ｐｐｍ））；８．２１（２Ｈ，ｔｄ，Ｊ＝８．０６，２．４４Ｈｚ）、１３．０（１Ｈ，ｂｒｓ）
ＣＩ−ＭＳ（ｍ／ｅ）；２２１（Ｍ＋１） 1 H-NMR (DMSO-d 6 , δ (ppm)); 8.21 (2H, td, J = 8.06, 2.44 Hz), 13.0 (1H, brs)
CI-MS (m / e); 221 (M + 1)
本発明は、新規な２，３，４−トリフルオロ−５−置換安息香酸化合物及び、２，３，４−トリフルオロ−５−置換安息香酸化合物の新規な製法に関する。２，３，４−トリフルオロ−５−置換安息香酸化合物は、医薬・農薬等の原料や合成中間体として有用な化合物である。 The present invention relates to a novel 2,3,4-trifluoro-5-substituted benzoic acid compound and a novel process for producing a 2,3,4-trifluoro-5-substituted benzoic acid compound. 2,3,4-trifluoro-5-substituted benzoic acid compounds are useful compounds as raw materials and synthetic intermediates for pharmaceuticals and agricultural chemicals.
Claims (25)
で示される２，３，４−トリフルオロ−５−置換安息香酸化合物。General formula (1):
A 2,3,4-trifluoro-5-substituted benzoic acid compound represented by the formula:
で示される２，３，４−トリフルオロ安息香酸化合物とヨウ素化剤又はホルミル化剤とを反応させることを特徴とする、式（１ａ）：
で示される２，３，４−トリフルオロ−５−置換安息香酸化合物の製法。In the presence of a base, in an organic solvent, the general formula (2):
Wherein the 2,3,4-trifluorobenzoic acid compound represented by formula (1a) is reacted with an iodinating agent or a formylating agent:
The manufacturing method of the 2,3,4-trifluoro-5-substituted benzoic acid compound shown by these.
で示される２，３，４−トリフルオロ−５−リチオ安息香酸。General formula (3a) or (3b):
2,3,4-trifluoro-5-lithiobenzoic acid represented by
で示される２，３，４−トリフルオロ安息香酸化合物とリチウム化合物とを反応させることを特徴とする、一般式（３ａ）又は（３ｂ）：
で示される２，３，４−トリフルオロ−５−リチオ安息香酸の製造方法。General formula (4a) or (4b):
A general formula (3a) or (3b) characterized by reacting a 2,3,4-trifluorobenzoic acid compound represented by the formula (I) with a lithium compound:
The manufacturing method of 2,3,4-trifluoro-5-lithiobenzoic acid shown by these.
で示される２，３，４−トリフルオロ−５−リチオ安息香酸と、求電子種を発生させ得る化合物とを反応させることを特徴とする、一般式（１ｂ）：
で示される２，３，４−トリフルオロ−５−置換安息香酸化合物の製法。General formula (3a) or (3b):
2,3,4-trifluoro-5-lithiobenzoic acid represented by the following general formula (1b), characterized by reacting a compound capable of generating an electrophilic species:
The manufacturing method of the 2,3,4-trifluoro-5-substituted benzoic acid compound shown by these.
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| JP2005237134 | 2005-08-18 | ||
| PCT/JP2006/316238 WO2007021001A1 (en) | 2005-08-18 | 2006-08-18 | 2,3,4-trifluoro-5-substituent-benzoic acid compound and process for producing the same |
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| JPH1180076A (en) * | 1997-07-08 | 1999-03-23 | Ube Ind Ltd | 2,3,4-trifluoro-5-trifluoromethylbenzoic acid, its esters and their production |
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