JP4047040B2 - Method for producing 2-fluorobenzoic acid derivative - Google Patents

Description

(式中、Rは炭素原子数20以下の直鎖状、分岐状または環状のアルキル基、アルケニル基、アルコキシル基、アルケニルオキシ基を表すが、これらの基は炭素原子数1〜10のアルコキシル基で置換されていてもよい。)で表される2-フルオロ安息香酸誘導体の製造方法であって一般式(II)
【０００６】
【化４】

(式中、Rは一般式(I)におけると同じ意味を表す。)で表されるフルオロベンゼン誘導体にs-ブチルリチウムを反応させ、次いで二酸化炭素を反応させることを特徴とする製造方法を提供するものである。
【０００７】
【発明の実施の形態】
本発明の製造方法において、反応は溶媒中で実施されるが、溶媒としてはテトラヒドロフラン(THF)、1,4-ジオキサン等の環状エーテル類、ジエチルエーテル、ジブチルエーテル、ジイソプロピルエーテル(IPE)、ジメトキシエタン(DME)等の鎖状エーテル類、ヘキサン、ペンタン、ヘプタン、石油エーテル等の飽和炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類が用いることができ、これらは単独でもあるいは混合しても用いることができるが、THF等の環状エーテル類が好ましい。
【０００８】
反応は通常、室温以下に冷却して実施されるが、s-ブチルリチウムとの反応時には、0〜-100℃が好ましく、-30℃〜-80℃がさらに好ましい。次いで二酸化炭素との反応時には0〜-100℃が好ましく、-20℃〜-80℃がさらに好ましい。
【０００９】
本発明の製造方法においては一般式(II)のフルオロベンゼン誘導体にs-ブチルリチウムを反応させ、次いで二酸化炭素を反応させることを特徴としているが、得られた安息香酸がリチウム塩として存在している場合には、必要に応じて酸で処理することが好ましい。
【００１０】
本発明の製造方法において、一般式(I)の2-フルオロ安息香酸誘導体は、Rがアルキル基を表す化合物の製造に好ましく、炭素原子数1〜10の直鎖状アルキル基の化合物の製造が特に好ましい。
【００１１】
原料として使用される一般式(II)のフルオロベンゼン誘導体は、安価で入手容易な3-フルオロブロモベンゼンから容易に製造入手が可能である。例えば、3-フルオロ-1-アルキルベンゼンの場合、3-フルオロブロモベンゼンから調製したグリニャール反応剤をN,N-ジメチルホルムアミド(DMF)と反応させ、得られた3-フルオロベンズアルデヒドにアルキルウィッティヒ反応剤を反応させ、次いで接触還元することにより得ることができる。あるいは3-フルオロブロモベンゼンと1-アルキン類を遷移金属触媒存在下に反応させ、次いで接触還元することによっても得ることができる。一般式(II)で表される他のフルオロベンゼン誘導体も同様または類似の製造方法により容易に得ることができる。
【００１２】
かくして得られた一般式(I)の安息香酸誘導体を中間体として、種々の有用な液晶化合物が製造することができる。例えば、(I)を塩化チオニルやシュウ酸ジクロリドと反応させて酸クロリドとした後に、あるいは(I)をジシクロヘキシルカルボジイミド等の縮合剤存在下に直接、4-置換フェノール類と反応させることにより、各種2-フルオロ安息香酸フェニル誘導体である液晶性エステル化合物を得ることができるが、これらは液晶組成物の構成材料として非常に有用である。
【００１３】
例えば、一般式(I)においてRがプロピル基である化合物を中間体として、4-置換フェノールとして3、5-ジフルオロ-4-シアノフェノールと反応させて得られる4-プロピル-2-フルオロ安息香酸3、5-ジフルオロ-4-シアノフェニル(A)
【化５】

は融点が69℃で、液晶組成物、特にSTN用液晶組成物に添加することにより、その駆動電圧を大幅に低減するなど、種々の特性改良が可能な有用な化合物である。
【００１４】
【実施例】
以下に本発明の実施例を示し、本発明を更に説明する。しかし、本発明はこれらの実施例に限定されるものではない。
【００１５】
(実施例) 2-フルオロ-4-プロピル安息香酸の製造
24.1gの3-フルオロプロピルベンゼン(0.174mol)を乾燥したTHF240mLに溶解し、-78℃に冷却した。アルゴン雰囲気下、攪拌下しながらs-ブチルリチウム(0.96M シクロヘキサン溶液)200mL(0.192mol)を内温が-60℃以下に保たれる速度で滴下した。滴下終了後、同温度で1時間攪拌した後、二酸化炭素を-60℃以下で吹き込んだ。二酸化炭素の吸収と発熱が確認されなくなった後、10％塩酸を滴下し、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで脱水乾燥後、減圧下に溶媒を溜去して得られた粗結晶をn-ヘキサンで洗浄し、さらに減圧下に乾燥させて融点124〜125℃の2-フルオロ-4-プロピル安息香酸の白色結晶22.8gを得た。(収率72％)
【００１６】
(比較例)
実施例において、s-ブチルリチウムに換えて、n-ブチルリチウム(1.6M n-ヘキサン溶液)120mL(0.192mol)を用いた他は全く同様にして、2-フルオロ-4-プロピル安息香酸の白色結晶(融点124〜125℃)を得たが、収量は8.0gであった。(収率23％)
【００１７】
【発明の効果】
本発明の提供する製造方法により、安価で入手容易な化合物を原料として2-フルオロ安息香酸誘導体を従来よりも高い収率で容易に製造することができる。得られた2-フルオロ安息香酸誘導体は液晶表示用に使用される液晶化合物の製造中間体として極めて有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for producing a 2-fluorobenzoic acid derivative useful as an intermediate for the synthesis of electronic materials, medical pesticides, and particularly liquid crystal materials for electro-optical display.
[0002]
[Prior art]
2-Fluorobenzoic acid derivatives, especially 2-fluorobenzoic acid substituted at the 4-position with an alkyl group, etc. are useful as intermediates for the production of various electronic materials, pharmaceuticals, agricultural chemicals, etc. No. -503637 discloses a production intermediate for liquid crystal compounds. In this publication, alkynes are coupled to 2-fluoro-4-bromobenzonitrile, and then the alkynyl group is converted to an alkyl group by catalytic reduction, and the cyano group is hydrolyzed to give 4-alkyl-2-fluorobenzoic acid. A method of obtaining is disclosed. However, this method has many problems such as the expensive raw material 2-fluoro-4-bromobenzonitrile, the yield in the coupling process is low, and the availability of alkyne is difficult. It was hard to say.
[0003]
In addition, German Published Patent No. 3939116 discloses that 4-fluoro-2-benzoic acid is obtained by reacting n-butyllithium with a 3-fluorobenzene derivative having a liquid crystal skeleton to lithiate the 4-position and reacting with dry ice. There is a description that an acid is obtained as a synthetic intermediate. However, in this method, the selectivity and yield of the reaction are extremely low and the practicality is poor. Therefore, development of a method for producing 4-substituted-2-fluorobenzoic acid derivatives such as 4-alkyl-2-fluorobenzoic acid at a high yield and at low cost has been desired.
[0004]
[Problems to be solved by the invention]
The problem to be solved by the present invention is to provide a method for producing a 4-substituted-2-fluorobenzoic acid derivative with high yield and low cost.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have found that the general formula (I)
[Chemical 3]

(In the formula, R represents a linear, branched or cyclic alkyl group having 20 or less carbon atoms, an alkenyl group, an alkoxyl group or an alkenyloxy group. These groups are alkoxyl groups having 1 to 10 carbon atoms. In which 2-fluorobenzoic acid derivatives are represented by the general formula (II):
[0006]
[Formula 4]

(Wherein R represents the same meaning as in general formula (I).) Provided is a production method characterized by reacting s-butyllithium with a fluorobenzene derivative represented by formula (I) and then reacting with carbon dioxide To do.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
In the production method of the present invention, the reaction is carried out in a solvent. Examples of the solvent include cyclic ethers such as tetrahydrofuran (THF) and 1,4-dioxane, diethyl ether, dibutyl ether, diisopropyl ether (IPE), dimethoxyethane. Chain ethers such as (DME), saturated hydrocarbons such as hexane, pentane, heptane and petroleum ether, and aromatic hydrocarbons such as benzene, toluene and xylene can be used alone or in combination. Can be used, but cyclic ethers such as THF are preferred.
[0008]
The reaction is usually carried out by cooling to room temperature or lower, but preferably 0 to -100 ° C, more preferably -30 to -80 ° C when reacting with s-butyllithium. Next, at the time of reaction with carbon dioxide, 0 to -100 ° C is preferable, and -20 ° C to -80 ° C is more preferable.
[0009]
The production method of the present invention is characterized by reacting the fluorobenzene derivative of the general formula (II) with s-butyllithium and then with carbon dioxide, but the obtained benzoic acid is present as a lithium salt. If necessary, it is preferable to treat with an acid if necessary.
[0010]
In the production method of the present invention, the 2-fluorobenzoic acid derivative of the general formula (I) is preferably used for the production of a compound in which R represents an alkyl group, and the production of a linear alkyl group having 1 to 10 carbon atoms is preferred. Particularly preferred.
[0011]
The fluorobenzene derivative of the general formula (II) used as a raw material can be easily produced and obtained from 3-fluorobromobenzene which is inexpensive and readily available. For example, in the case of 3-fluoro-1-alkylbenzene, a Grignard reactant prepared from 3-fluorobromobenzene is reacted with N, N-dimethylformamide (DMF), and the resulting 3-fluorobenzaldehyde is reacted with an alkyl Wittig reactant. Can be reacted and then catalytically reduced. Alternatively, it can also be obtained by reacting 3-fluorobromobenzene and 1-alkynes in the presence of a transition metal catalyst and then catalytic reduction. Other fluorobenzene derivatives represented by the general formula (II) can be easily obtained by the same or similar production method.
[0012]
Various useful liquid crystal compounds can be produced using the benzoic acid derivative of the general formula (I) thus obtained as an intermediate. For example, by reacting (I) with thionyl chloride or oxalic acid dichloride to give an acid chloride, or by directly reacting (I) with a 4-substituted phenol in the presence of a condensing agent such as dicyclohexylcarbodiimide, Although liquid crystalline ester compounds that are phenyl derivatives of 2-fluorobenzoic acid can be obtained, these are very useful as constituent materials for liquid crystal compositions.
[0013]
For example, 4-propyl-2-fluorobenzoic acid obtained by reacting a compound in which R is a propyl group in general formula (I) with 3,5-difluoro-4-cyanophenol as a 4-substituted phenol 3,5-difluoro-4-cyanophenyl (A)
[Chemical formula 5]

Has a melting point of 69 ° C. and is a useful compound that can be improved in various properties, for example, by drastically reducing its driving voltage when added to a liquid crystal composition, particularly a liquid crystal composition for STN.
[0014]
【Example】
The following examples further illustrate the present invention. However, the present invention is not limited to these examples.
[0015]
(Example) Production of 2-fluoro-4-propylbenzoic acid
24.1 g of 3-fluoropropylbenzene (0.174 mol) was dissolved in 240 mL of dry THF and cooled to -78 ° C. Under an argon atmosphere, 200 mL (0.192 mol) of s-butyllithium (0.96M cyclohexane solution) was added dropwise with stirring at such a rate that the internal temperature was kept at -60 ° C or lower. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and then carbon dioxide was blown at −60 ° C. or lower. After absorption of carbon dioxide and exotherm were no longer confirmed, 10% hydrochloric acid was added dropwise and extracted with ethyl acetate. The organic layer was washed with water, dehydrated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude crystals were washed with n-hexane and further dried under reduced pressure to obtain a melting point of 124 to 125 ° C. 22.8 g of 2-fluoro-4-propylbenzoic acid white crystals was obtained. (Yield 72%)
[0016]
(Comparative example)
In the examples, 2-fluoro-4-propylbenzoic acid white was used in exactly the same manner except that 120 mL (0.192 mol) of n-butyllithium (1.6M n-hexane solution) was used instead of s-butyllithium. Crystals (melting point 124-125 ° C.) were obtained, and the yield was 8.0 g. (Yield 23%)
[0017]
【The invention's effect】
According to the production method provided by the present invention, a 2-fluorobenzoic acid derivative can be easily produced in a higher yield than before using a cheap and readily available compound as a raw material. The obtained 2-fluorobenzoic acid derivative is extremely useful as an intermediate for producing a liquid crystal compound used for liquid crystal display.

Claims (2)

Formula (I)

(In the formula, R represents a linear, branched or cyclic alkyl group having 20 or less carbon atoms, an alkenyl group, an alkoxyl group or an alkenyloxy group. These groups are alkoxyl groups having 1 to 10 carbon atoms. In which 2-fluorobenzoic acid derivatives are represented by the general formula (II):

(Wherein R represents the same meaning as in the general formula (I)), and reacting s-butyllithium with a 3-fluorobenzene derivative represented by the following formula, followed by reacting with carbon dioxide . 2. The production method according to claim 1, wherein R represents a linear alkyl group having 1 to 10 carbon atoms.