JP4392579B2 - Method for producing benzonitrile derivative - Google Patents

Description

製造例1では、対応する臭素化物から1工程でベンゾニトリル誘導体を製造することが可能であるが、この製造方法は有毒なシアン化合物を必要とし、しかも収率も高くはない。又、製造例2では、対応する安息香酸から3工程でベンゾニトリル誘導体を製造でき、各工程の収率も比較的高い。しかしながら、この製造方法は工程が長い上に各工程の化合物は単離することが必要であり、操作が非常に煩雑であった。
【０００４】
ベンズアルデヒド誘導体からオキシムを経由してベンゾニトリル誘導体を製造する方法として特開平5-286921が知られており、ここで開示されている方法はオキシム形成時に脱水剤共存下で反応を行うものである。しかし、この方法では、未反応のベンズアルデヒド誘導体が残留するため収率の面で十分ではなく、短工程で収率の良い製造方法が求められていた。
【０００５】
【発明が解決しようとする課題】
本発明が解決しようとする課題は、ベンゾニトリル誘導体を得るための、短工程で収率のよい安価な製造方法を提供することにある。
【０００６】
【課題を解決するための手段】
本発明は、上記課題を解決するために鋭意検討した結果、一般式(I)
【０００７】
【化４】

(式中、Rは炭素原子数1〜20のアルキル基、炭素原子数1〜20のアルコキシル基、炭素原子数2〜20のアルケニル基又は炭素原子数2〜20のアルケニルオキシ基を表し、これらの基は炭素原子数1〜10のアルキル基又は1個以上のフッ素原子により置換されていてもよく、X¹、X²、X³、X⁴はそれぞれ独立的に水素原子、フッ素原子又は塩素原子を表し、A¹及びA²はそれぞれ独立的に1,4-フェニレン基(この基中の1、2、3又は4個の水素原子はフッ素原子で置換されていてもよい)、1,4-シクロヘキシレン基、1,4-シクロヘキセニル基、テトラヒドロピラン-2,5-ジイル基、1,3-ジオキサン-2,5-ジイル基、テトラヒドロチオピラン-2,5-ジイル基、1,4-ビシクロ(2,2,2)オクチレン基、デカヒドロナフタレン-2,6-ジイル基、ピリジン-2,5-ジイル基、ピリミジン-2,5-ジイル基、ピラジン-2,5-ジイル基、テトラヒドロナフタレン-2,6-ジイル基(この基中の1、2又は3個の水素原子はフッ素原子で置換されていてもよい)、2,6-ナフチレン基(この基中の1、2又は3個の水素原子はフッ素原子で置換されていてもよい)、フェナントレン-2,7-ジイル基(この基中の1又は2個の水素原子はフッ素原子で置換されていてもよい)、9,10-ジヒドロフェナントレン-2,7-ジイル基(この基中の1又は2個の水素原子はフッ素原子で置換されていてもよい)、1,2,3,4,4a,9,10a-オクタヒドロフェナントレン-2,7-ジイル基(この基中の1、2又は3個の水素原子はフッ素原子で置換されていてもよい)又はフルオレン-2,7-ジイル基(この基中の1又は2個の水素原子はフッ素原子で置換されていてもよい)を表し、Z¹及びZ²はそれぞれ独立的に単結合、-COO-、-OCO-、-CH=N-、-C≡C-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH(CH₃)CH₂-、-CH₂CH(CH₃)-、-CH₂CH₂CH₂CH₂-、-CH₂O-、-OCH₂O-、-CF₂O-、-OCF₂-、-CH=N-N=CH-、-CF=CF-、-CH=CH-、-CH₂CH₂CH=CH-、-CH=CHCH₂CH₂-又は-CH₂CH=CHCH₂-を表し、m及びnはそれぞれ独立的に0、1又は2の整数を表す。)で表される化合物の製造方法であって、一般式(II)
【０００８】
【化５】

(式中、R、A¹、Z¹、A²、Z²、X¹、X²、X³、X⁴、m及びnは一般式(I)におけると同じ意味を表す。)の化合物と、ヒドロキルシアミン又はその塩を反応させオキシムを生成した後、生成したオキシムを単離することなく脱水剤を用いて脱水反応させることによる製造方法を見出し本発明を完成するに至った。
【０００９】
【発明の実施の形態】
本発明の製造方法は、以下に示すような条件下で行うことができる。
【００１０】
本発明において、一般式(II)で表されるベンズアルデヒド誘導体を、遊離のヒドロキシルアミンあるいはその塩と反応させオキシムを製造するが、ヒドロキシルアミンの塩を用いることが好ましく、ヒドロキシルアミン塩酸塩、ヒドロキシルアミンシュウ酸塩、ヒドロキシルアミン硫酸塩を用いることが特に好ましい。また、オキシム製造時には塩基の存在下で反応させることが好ましく、塩基として酢酸ナトリウム、酢酸カリウム、酢酸リチウムを用いることが特に好ましい。反応溶媒としては、酢酸、ギ酸、プロピオン酸等の有機酸を用いることが好ましいが、酢酸を用いることが特に好ましい。
【００１１】
得られたオキシムは、単離することなく脱水剤を添加することにより、一般式(I)で表されるベンゾニトリル誘導体とするが、用いる脱水剤としては酸無水物を用いることが好ましく、無水酢酸を用いることが特に好ましい。
【００１２】
本発明の製造方法において、製造できる一般式(I)で表される化合物に特に制約はないが以下の置換基を有する場合特に有用である。
【００１３】
一般式(II)において、Rは炭素原子数1〜10のアルコキシル基、炭素原子数2〜10のアルケニル基、炭素原子数2〜10のアルケニルオキシ基を表すこと好ましく、炭素原子数1〜6のアルコキシル基、炭素原子数2〜6のアルケニル基、炭素原子数2〜6のアルケニルオキシ基を表すことが特に好ましいく、X¹がフッ素原子であることが好ましく、X¹及びX⁴が共にフッ素原子を表すことが特に好ましく、A¹及びA²がそれぞれ独立的に1,4-シクロヘキシレン基、1,3-ジオキサン-2,5-ジイル基、1,4-ビシクロ(2,2,2)オクチレン基、デカヒドロナフタレン-2,6-ジイル基、ピリジン-2,5-ジイル基、ピリミジン-2,5-ジイル基、ピラジン-2,5-ジイル基、テトラヒドロナフタレン-2,6-ジイル基、2,6-ナフチレン基、フェナントレン-2,7-ジイル基、9,10-ジヒドロフェナントレン-2,7-ジイル基、1,2,3,4,4a,9,10a-オクタヒドロフェナントレン-2,7-ジイル基を表すが、特に1,4-シクロヘキシレン基、1,4-フェニレン基、1,4-ビシクロ(2,2,2)オクチレン基、ピリジン-2,5-ジイル基、ピリミジン-2,5-ジイル基を表すことが好ましく、Z¹及びZ²が単結合を表すことが好ましく、m+nが1又は2を表すことが好ましい。
【００１４】
【実施例】
以下、実施例を挙げて本発明を更に詳述するが、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1) 5-プロピル-2-(3,5-ジフルオロ-4-シアノフェニル)ピリミジンの製造
4-(5-プロピルピリミジン-2-イル)-2,6-ジフルオロベンズアルデヒド57.1gにヒドロキシルアミン塩酸塩19.3g、酢酸ナトリウム24.5g及び酢酸228mlを加え、1時間加熱還流させた後、内温を100℃まで放冷した。無水酢酸48.0gを滴下し2時間加熱還流させ、室温まで放冷し、砕いた氷に反応液を注いだ。析出した結晶を濾取し、減圧下に乾燥し、シリカゲルカラムクロマトグラフィー(溶媒：トルエン)で精製し、5-プロピル-2-(3,5-ジフルオロ-4-シアノフェニル)ピリミジン55.8g(収率98％)を得た。
【００１６】
(比較例1) 5-プロピル-2-(3,5-ジフルオロフェニル)ピリミジンの製造
4-(5-プロピルピリミジン-2-イル)-2,6-ジフルオロ安息香酸46.0gに塩化チオニル100ml及びピリジン0.1mlを加え6時間加熱還流させた。過剰の塩化チオニルを留去し、4-(5-プロピルピリミジン-2-イル)-2,6-ジフルオロ-安息香酸クロリド51.7gを得た。
【００１７】
4-(5-プロピルピリミジン-2-イル)-2,6-ジフルオロ安息香酸クロリド51.7gをジクロロメタン500mlに溶解し、氷冷下アンモニアガスが吸収されなくなるまで吹き込んだ。溶媒を留去し、テトラヒドロフラン500mlを加え不溶物を濾別し、溶媒を留去し、4-(5-プロピルピリミジン-2-イル)-2,6-ジフルオロ-安息香酸アミド46.0gを得た。
【００１８】
4-(5-プロピルピリミジン-2-イル)-2,6-ジフルオロ安息香酸アミド46.0gにトルエン300ml及びオキシ塩化リン14.0gを加え3時間加熱還流させ、室温まで放冷した。激しく撹拌している水中に反応液を注ぎ有機層を分離し、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、シリカゲルカラムクロマトグラフィー(溶媒：トルエン)で精製し、5-プロピル-2-(3,5-ジフルオロフェニル)ピリミジン41.0gを得た。(4-(5-プロピルピリミジン-2-イル)-2,6-ジフルオロ安息香酸からの収率96％)を得た。収率は本発明の製造方法よりやや劣る程度であるが、4-(5-プロピルピリミジン-2-イル)-2,6-ジフルオロ-安息香酸クロリド及び4-(5-プロピルピリミジン-2-イル)-2,6-ジフルオロ-安息香酸アミドをそれぞれ単離する必要があるため、実質的な製造工程が本発明の方法よりかなり長く、操作が煩雑であった。
【００１９】
【発明の効果】
本発明の製造方法により、液晶材料等の電子材料や機能性材料又は医農薬や香料、各種添加剤及びそれらの製造中間体として有用なベンゾニトリル誘導体を、短工程で収率良く安価に製造することが可能である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to the production of benzonitrile derivatives useful as electronic materials such as liquid crystal display materials, functional materials, medical pesticides, fragrances, various additives, and production intermediates thereof.
[0002]
[Prior art]
Benzonitrile derivatives are useful as electronic materials such as liquid crystal display materials, functional materials, medicines, agricultural chemicals, fragrances, various additives, and production intermediates thereof. Especially, liquid crystal materials having a 4-substituted benzonitrile skeleton have a driving voltage. It is important for reduction. As methods for producing benzonitrile derivatives, the following methods are generally known. (Co-edited by Mitsuji Okano and Shunsuke Kobayashi, Liquid Crystal Materials (Basics), p234-235, Double Wind Museum)
[0003]
[Chemical 3]

In Production Example 1, it is possible to produce a benzonitrile derivative from the corresponding bromide in one step, but this production method requires a toxic cyanide compound, and the yield is not high. In Production Example 2, the benzonitrile derivative can be produced from the corresponding benzoic acid in 3 steps, and the yield of each step is relatively high. However, this production method requires a long process, and it is necessary to isolate the compound in each process, and the operation is very complicated.
[0004]
Japanese Laid-Open Patent Application No. 5-86921 is known as a method for producing a benzonitrile derivative from a benzaldehyde derivative via an oxime, and the method disclosed here is a reaction in the presence of a dehydrating agent at the time of oxime formation. However, in this method, an unreacted benzaldehyde derivative remains, so that the yield is not sufficient, and a production method with a high yield in a short process has been demanded.
[0005]
[Problems to be solved by the invention]
The problem to be solved by the present invention is to provide an inexpensive production method with a good yield in a short process for obtaining a benzonitrile derivative.
[0006]
[Means for Solving the Problems]
The present invention, as a result of intensive studies to solve the above problems, general formula (I)
[0007]
[Formula 4]

Wherein R represents an alkyl group having 1 to 20 carbon atoms, an alkoxyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms or an alkenyloxy group having 2 to 20 carbon atoms, May be substituted with an alkyl group having 1 to 10 carbon atoms or one or more fluorine atoms, and X ¹ , X ² , X ³ and X ⁴ are each independently a hydrogen atom, a fluorine atom or chlorine. A ¹ and A ² each independently represents a 1,4-phenylene group (in which 1, 2, 3 or 4 hydrogen atoms may be substituted with fluorine atoms), 1, 4-cyclohexylene group, 1,4-cyclohexenyl group, tetrahydropyran-2,5-diyl group, 1,3-dioxane-2,5-diyl group, tetrahydrothiopyran-2,5-diyl group, 1, 4-bicyclo (2,2,2) octylene group, decahydronaphthalene-2,6-diyl group, pyridine-2,5-diyl group, pyrimidine-2,5-diyl group, pyra 2,5-diyl group, tetrahydronaphthalene-2,6-diyl group (1, 2 or 3 hydrogen atoms in this group may be substituted by fluorine atoms), 2,6-naphthylene group (One, two or three hydrogen atoms in this group may be substituted with fluorine atoms), phenanthrene-2,7-diyl group (one or two hydrogen atoms in this group are fluorine atoms) 9,10-dihydrophenanthrene-2,7-diyl group (one or two hydrogen atoms in this group may be substituted with fluorine atoms), 1,2,3 , 4,4a, 9,10a-octahydrophenanthrene-2,7-diyl group (one, two or three hydrogen atoms in this group may be substituted with fluorine atoms) or fluorene-2,7 -Represents a diyl group (one or two hydrogen atoms in this group may be substituted with a fluorine atom), Z ¹ and Z ² are each independently a single bond, -COO-, -OCO-, -CH = N -, - C≡C - , - CH 2 CH 2 - _{-CH 2 CH 2 CH 2 -,} - CH (CH 3) CH 2 -, - CH 2 CH (CH 3) -, - CH 2 CH 2 CH 2 CH 2 -, - CH 2 O -, - OCH 2 O -, -CF ₂ O-, -OCF _2- , -CH = NN = CH-, -CF = CF-, -CH = CH-, -CH ₂ CH ₂ CH = CH-, -CH = CHCH ₂ CH ₂ — Or —CH ₂ CH═CHCH ₂ —, and m and n each independently represent an integer of 0, 1 or 2. Is a method for producing a compound represented by the general formula (II)
[0008]
[Chemical formula 5]

Wherein R, A ¹ , Z ¹ , A ² , Z ² , X ¹ , X ² , X ³ , X ⁴ , m and n have the same meaning as in general formula (I); The present invention was completed by finding a production method by reacting hydroxylamine or a salt thereof to produce an oxime, followed by a dehydration reaction using a dehydrating agent without isolating the produced oxime.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The production method of the present invention can be carried out under the following conditions.
[0010]
In the present invention, the benzaldehyde derivative represented by the general formula (II) is reacted with free hydroxylamine or a salt thereof to produce an oxime. It is preferable to use a hydroxylamine salt, such as hydroxylamine hydrochloride, hydroxylamine. It is particularly preferable to use oxalate or hydroxylamine sulfate. Moreover, it is preferable to make it react in presence of a base at the time of oxime manufacture, and it is especially preferable to use sodium acetate, potassium acetate, and lithium acetate as a base. As the reaction solvent, an organic acid such as acetic acid, formic acid or propionic acid is preferably used, but acetic acid is particularly preferably used.
[0011]
The obtained oxime is converted to a benzonitrile derivative represented by the general formula (I) by adding a dehydrating agent without isolation, but an acid anhydride is preferably used as the dehydrating agent. It is particularly preferred to use acetic acid.
[0012]
In the production method of the present invention, the compound represented by the general formula (I) that can be produced is not particularly limited, but is particularly useful when it has the following substituents.
[0013]
In the general formula (II), R preferably represents an alkoxyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkenyloxy group having 2 to 10 carbon atoms, and 1 to 6 carbon atoms. Particularly preferably an alkoxyl group, an alkenyl group having 2 to 6 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, X ¹ is preferably a fluorine atom, and X ¹ and X ⁴ are both It is particularly preferable to represent a fluorine atom, and A ¹ and A ² are each independently 1,4-cyclohexylene group, 1,3-dioxane-2,5-diyl group, 1,4-bicyclo (2,2, 2) Octylene group, decahydronaphthalene-2,6-diyl group, pyridine-2,5-diyl group, pyrimidine-2,5-diyl group, pyrazine-2,5-diyl group, tetrahydronaphthalene-2,6- Diyl group, 2,6-naphthylene group, phenanthrene-2,7-diyl group, 9,10-dihydrophenanthrene-2,7-diyl group, 1,2,3,4,4a, 9,10a-octahydrophenanthrene-2,7-diyl group, especially 1,4-cyclohexylene group, 1,4-phenylene group, 1,4-bicyclo ( 2,2,2) preferably represents an octylene group, a pyridine-2,5-diyl group, a pyrimidine-2,5-diyl group, Z ¹ and Z ² preferably represent a single bond, and m + n represents It preferably represents 1 or 2.
[0014]
【Example】
EXAMPLES Hereinafter, although an Example is given and this invention is further explained in full detail, this invention is not limited to these Examples.
[0015]
Example 1 Production of 5-propyl-2- (3,5-difluoro-4-cyanophenyl) pyrimidine
Hydroxylamine hydrochloride (19.3 g), sodium acetate (24.5 g) and acetic acid (228 ml) were added to 4- (5-propylpyrimidin-2-yl) -2,6-difluorobenzaldehyde (57.1 g), and the mixture was heated to reflux for 1 hour. It was allowed to cool to 100 ° C. Acetic anhydride (48.0 g) was added dropwise, and the mixture was heated to reflux for 2 hours, allowed to cool to room temperature, and poured into crushed ice. The precipitated crystals were collected by filtration, dried under reduced pressure, purified by silica gel column chromatography (solvent: toluene), and 55.8 g (yield) of 5-propyl-2- (3,5-difluoro-4-cyanophenyl) pyrimidine. Rate 98%).
[0016]
(Comparative Example 1) Production of 5-propyl-2- (3,5-difluorophenyl) pyrimidine
100 ml of thionyl chloride and 0.1 ml of pyridine were added to 46.0 g of 4- (5-propylpyrimidin-2-yl) -2,6-difluorobenzoic acid, and the mixture was heated to reflux for 6 hours. Excess thionyl chloride was distilled off to obtain 51.7 g of 4- (5-propylpyrimidin-2-yl) -2,6-difluoro-benzoic acid chloride.
[0017]
4- (5-propylpyrimidin-2-yl) -2,6-difluorobenzoic acid chloride (51.7 g) was dissolved in dichloromethane (500 ml), and the solution was blown in under ice cooling until ammonia gas was not absorbed. The solvent was distilled off, 500 ml of tetrahydrofuran was added and insoluble matter was filtered off, and the solvent was distilled off to obtain 46.0 g of 4- (5-propylpyrimidin-2-yl) -2,6-difluoro-benzoic acid amide. .
[0018]
To 46.0 g of 4- (5-propylpyrimidin-2-yl) -2,6-difluorobenzoic acid amide was added 300 ml of toluene and 14.0 g of phosphorus oxychloride, and the mixture was heated to reflux for 3 hours and allowed to cool to room temperature. The reaction solution was poured into vigorously stirred water, and the organic layer was separated and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography (solvent: toluene) to obtain 41.0 g of 5-propyl-2- (3,5-difluorophenyl) pyrimidine. (Yield 96% from 4- (5-propylpyrimidin-2-yl) -2,6-difluorobenzoic acid). Although the yield is slightly inferior to the production method of the present invention, 4- (5-propylpyrimidin-2-yl) -2,6-difluoro-benzoic acid chloride and 4- (5-propylpyrimidin-2-yl) ) -2,6-difluoro-benzoic acid amide has to be isolated, so that the substantial production process is considerably longer than the method of the present invention and the operation is complicated.
[0019]
【The invention's effect】
By the production method of the present invention, electronic materials such as liquid crystal materials, functional materials, medical pesticides, fragrances, various additives, and benzonitrile derivatives useful as production intermediates thereof can be produced in a short process with good yield and low cost. It is possible.

Claims (2)

Formula (I)

Wherein R represents an alkyl group having 1 to 20 carbon atoms, an alkoxyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms or an alkenyloxy group having 2 to 20 carbon atoms, May be substituted with an alkyl group having 1 to 10 carbon atoms or one or more fluorine atoms, and X ¹ , X ² , X ³ and X ⁴ are each independently a hydrogen atom, a fluorine atom or chlorine. A ¹ and A ² each independently represents a 1,4-phenylene group (in which 1, 2, 3 or 4 hydrogen atoms may be substituted with fluorine atoms), 1, 4-cyclohexylene group, 1,4-cyclohexenyl group, tetrahydropyran-2,5-diyl group, 1,3-dioxane-2,5-diyl group, tetrahydrothiopyran-2,5-diyl group, 1, 4-bicyclo (2,2,2) octylene group, decahydronaphthalene-2,6-diyl group, pyridine-2,5-diyl group, pyrimidine-2,5-diyl group, pyra 2,5-diyl group, tetrahydronaphthalene-2,6-diyl group (1, 2 or 3 hydrogen atoms in this group may be substituted by fluorine atoms), 2,6-naphthylene group (One, two or three hydrogen atoms in this group may be substituted with fluorine atoms), phenanthrene-2,7-diyl group (one or two hydrogen atoms in this group are fluorine atoms) 9,10-dihydrophenanthrene-2,7-diyl group (one or two hydrogen atoms in this group may be substituted with fluorine atoms), 1,2,3 , 4,4a, 9,10a-octahydrophenanthrene-2,7-diyl group (one, two or three hydrogen atoms in this group may be substituted with fluorine atoms) or fluorene-2,7 -Represents a diyl group (one or two hydrogen atoms in this group may be substituted with a fluorine atom), Z ¹ and Z ² are each independently a single bond, -COO-, -OCO-, -CH = N -, - C≡C - , - CH 2 CH 2 - _{-CH 2 CH 2 CH 2 -,} - CH (CH 3) CH 2 -, - CH 2 CH (CH 3) -, - CH 2 CH 2 CH 2 CH 2 -, - CH 2 O -, - OCH 2 O -, -CF ₂ O-, -OCF _2- , -CH = NN = CH-, -CF = CF-, -CH = CH-, -CH ₂ CH ₂ CH = CH-, -CH = CHCH ₂ CH ₂ — Or —CH ₂ CH═CHCH ₂ —, and m and n each independently represent an integer of 0, 1 or 2. Is a method for producing a compound represented by the general formula (II)

Wherein R, A ¹ , Z ¹ , A ² , Z ² , X ¹ , X ² , X ³ , X ⁴ , m and n represent the same meaning as in general formula (I). In addition, after reacting with hydroxylamine or a salt thereof in the presence of a base in an organic acid solvent to produce an oxime, an acid anhydride is added as a dehydrating agent without causing isolation of the produced oxime, followed by a dehydration reaction. That method.   2. The production method according to claim 1, wherein acetic anhydride is used as a dehydrating agent in the dehydration reaction.