JP4300450B2

JP4300450B2 - Benzonitrile derivative and method for producing the same

Info

Publication number: JP4300450B2
Application number: JP2002094767A
Authority: JP
Inventors: 貞夫竹原; 政志大澤
Original assignee: DIC Corp
Current assignee: DIC Corp
Priority date: 2002-03-29
Filing date: 2002-03-29
Publication date: 2009-07-22
Anticipated expiration: 2022-03-29
Also published as: JP2003286279A

Description

【０００１】
【発明の属する技術分野】
本発明は液晶表示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合成中間体として有用な、ベンゾニトリル誘導体及びその製造方法に関する。
【０００２】
【従来の技術】
2,6-ジフルオロ-4-置換ベンゾニトリル誘導体は電子材料や機能性材料又は医農薬や香料、各種添加剤等の用途に有用であり、特にSTN型液晶表示材料用の液晶化合物として、液晶組成物の駆動電圧の低減や、応答時間の改善等に極めて有効であり、最近その需要が特に増大している。一般に4-置換ベンゾニトリル誘導体のような液晶化合物において分子の他端には鎖状基が存在するが、これまで用いられている2,6-ジフルオロ-4-置換ベンゾニトリル誘導体においては、鎖状基は直鎖状アルキル基が主に用いられてきた。液晶化合物においては鎖状基としてアルキル基に換えてアルケニル基を導入することにより、その液晶性や粘性、急峻性等の諸特性における改善が得られることが知られている(特開2001-123171)。
【０００３】
従来2,6-ジフルオロ-4-置換ベンゾニトリル誘導体である液晶化合物は、アルケニル基を導入した対応する3,5-ジフルオロベンゼン誘導体を中間体としてその4位にシアノ基を導入することによって製造されたが、この方法ではシクロヘキサン環の立体やアルケニル基の二重結合に異性化の恐れがある等、必ずしも問題がないわけではなかった。このため、アルケニル基を導入した2,6-ジフルオロ-4-置換ベンゾニトリル誘導体である液晶化合物を製造するための、より有効な中間体及びそれを用いた効率的な製造方法の開発が望まれていた。
【０００４】
【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、アルケニル基を導入した2,6-ジフルオロ-4-置換ベンゾニトリル誘導体を製造するための新しい中間体を提供し、さらにその中間体化合物の簡便な製造方法を提供することにある。
【０００５】
【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、アセタール基を有する2,6-ジフルオロ-4-置換ベンゾニトリル誘導体がアルケニル基を導入した2,6-ジフルオロ-4-置換ベンゾニトリル誘導体の製造中間体として有用であることを見出し、本発明を完成するに至った。
【０００６】
すなわち、本発明は一般式(I)
【化８】

(式中、Rは置換基を有していてもよい炭素原子数2〜4のアルキレン基を表し、M及びNはそれぞれ独立的に単結合、-CH₂CH₂-、-CH=CH-、-CF=CF-、-C≡C-、-CH₂O-、-OCH₂-、-CF₂O-、-OCF₂-、-CF₂CF₂-、-CH₂CH(CH₃)-、-CH(CH₃)CH₂-、-CH₂CH₂CH₂CH₂-、-OCH₂CH₂CH₂-、又は-CH₂CH₂CH₂O-を表し、環Aはトランス-1,4-シクロヘキシレン基、フッ素置換されていてもよい1,4-フェニレン基、又はピリミジン-2,5-ジイル基を表し、nは0又は1を表す。)で表されるベンゾニトリル誘導体を提供する。
【０００７】
また、本発明は以下に示す一般式(I)で表される化合物の製造法を提供する。
【０００８】
(製造方法1)
一般式(II)
【化９】

(式中、R、M、N、環A及びnは一般式(I)のおけると同じ意味を表す。)で表されるベンズアルデヒド誘導体をヒドロキシルアミン又はその水和物又はその塩と反応させて一般式(III)
【化１０】

(式中、R、M、N、環A及びnは一般式(I)のおけると同じ意味を表す。)で表されるオキシムとし、次いで脱水反応させることを特徴とする一般式(I)の製造方法。
【０００９】
(製造方法2)
一般式(II)の化合物を酸化剤の存在下にアンモニアと反応させることを特徴とする一般式(I)の製造方法。
【００１０】
(製造方法3)
一般式(IV)
【化１１】

(式中、R、M、N、環A及びnは一般式(I)のおけると同じ意味を表す。)で表される化合物をアルキルリチウムでリチオ化した後、ホルミル化剤と反応させることにより一般式(II)の化合物得た後、ヒドロキシルアミン又はその水和物又はその塩と反応させて一般式(III)で表されるオキシムとし、次いで脱水反応させることを特徴とする一般式(I)の製造方法。
【００１１】
(製造方法4)
一般式(V)
【化１２】

(式中、R、M、N、環A及びnは一般式(I)のおけると同じ意味を表す。)で表される安息香酸誘導体を酸アミドに導いた後、脱水することを特徴とする一般式(I)の製造方法。
【００１２】
(製造方法5)
一般式(IV)で表される化合物をアルキルリチウムでリチオ化した後、二酸化炭素と反応させることにより一般式(V)の安息香酸誘導体とし、酸アミドに導いた後、脱水することを特徴とする一般式(I)の製造方法。
【００１３】
(製造方法6)
一般式(VI)
【化１３】

(式中、R、M、N、環A及びnは一般式(I)のおけると同じ意味を表し、Xはヨウ素又は臭素原子を表す。)で表されるハロゲン化ベンゼン誘導体にシアン化銅(I)を反応させることを特徴とする一般式(I)の製造方法。
【００１４】
(製造方法7)
一般式(IV)で表される化合物をアルキルリチウムでリチオ化した後、ヨウ素又は臭素と反応させることにより一般式(VI)のハロゲン化ベンゼン誘導体とし、これにシアン化銅(I)を反応させることを特徴とする一般式(I)の製造方法。
【００１５】
(製造方法8)
一般式(VII)
【化１４】

(式中、R、M、N、環A及びnは一般式(I)のおけると同じ意味を表し、Qは炭素原子数7以下のアルキル基、パーフルオロアルキル基又はアリール基を表す。)で表されるスルホン酸エステルに触媒存在下にシアン化金属を反応させることを特徴とする一般式(I)の製造方法。
【００１６】
【発明の実施の形態】
一般式(I)において、Rは置換基を有していてもよい炭素原子数2〜4のアルキレン基を表す。置換基としては、アルケニル基を有する2,6-ジフルオロ-4-置換ベンゾニトリル誘導体製造上の反応工程で不活性な基であれば特に制限はないが、低級アルキル基又はアリール基又は無置換であることが好ましい。アルキレンの主鎖としては炭素原子数が2又は3が好ましく、Qとして-CH₂CH₂CH₂-又は-CH₂CH₂-が好ましい。
【００１７】
M及びNはそれぞれ独立的に単結合、-CH₂CH₂-、-CH=CH-、-CF=CF-、-C≡C-、-CH₂O-、-OCH₂-、-CF₂O-、-OCF₂-、-CF₂CF₂-、-CH₂CH(CH₃)-、-CH(CH₃)CH₂-、-CH₂CH₂CH₂CH₂-、-OCH₂CH₂CH₂-、又は-CH₂CH₂CH₂O-を表すが、単結合又は-CH₂CH₂-が好ましく、単結合が特に好ましい。
【００１８】
環Aはトランス-1,4-シクロヘキシレン基、フッ素置換されていてもよい1,4-フェニレン基、又はピリミジン-2、5-ジイル基を表すが、トランス-1,4-シクロヘキシレン基又はフッ素置換されていてもよい1,4-フェニレン基が好ましく、トランス-1,4-シクロヘキシレン基又はフ1,4-フェニレン基又は2-フルオロ-1,4-フェニレン基がさらに好ましく、トランス-1,4-シクロヘキシレン基が特に好ましい。
nは0又は1を表すが特にn＝0が好ましい。
【００１９】
本発明の一般式(I)の化合物は具体的には以下の(I-1)〜(I-3)で表される化合物が好ましく、(I-1)の化合物が特に好ましい。
【化１５】

【００２０】
本発明の一般式(I)で表される2,6-ジフルオロ-4-置換ベンゾニトリル誘導体の製造方法は以下に示す形態により実施することが好ましい。
【００２１】
(製造方法1)
一般式(II)で表されるベンズアルデヒド誘導体をヒドロキシルアミン又はその水和物又はその塩と反応させて一般式(III)で表されるオキシムを得る。反応は通常溶媒の存在下に実施される。溶媒はヒドロキシルアミンやアルデヒドに対する反応性がない限りにおいて特に制限はないが、ヘキサン、トルエン等の炭化水素系溶媒、テトラヒドロフラン(THF)、ジイソプロピルエーテル(IPE)、ジメトキシエタン(DME)等のエーテル系溶媒、ジクロロメタン等の塩素系溶媒、メタノール、メチルセルソルブ等のアルコール系溶媒、酢酸等のカルボン酸系溶媒あるいはこれらの混合物等が好ましく用いることができる。これらの溶媒は(II)の化合物に対し、質量比で1〜100倍、好ましくは5〜20倍使用される。反応は室温から加熱下、あるいは冷却下に実施されるが、通常は0℃〜100℃の範囲が好ましく、室温から溶媒の還流温度の範囲内がより好ましい。
【００２２】
得られた(III)の化合物を脱水反応させることにより(I)の2,6-ジフルオロ-4-置換ベンゾニトリル誘導体を製造する。
脱水剤あるいは脱水触媒としては無水酢酸、無水トリフルオロメタンスルホン酸等の酸無水物、p-トルエンスルホン酸、トリフルオロ酢酸等の酸類、ベンゼンスルホン酸クロリド、クロロ蟻酸フェニル等の酸塩化物、ピリジン、トリエチルアミン等の塩基類、蟻酸ナトリウム等の塩類、四塩化チタン等のルイス酸(通常ピリジンやトリエチルアミン等と併用される)、ジシクロヘキシルカルボジイミド(DCC)、1,1'-ジカルボニルジイミダゾール等のカルボジイミド類、トリフェニルホスフィン等のホスフィン類(通常四塩化炭素と併用される)、二酸化セレン、酸化水銀(II)等の金属酸化物、オルト蟻酸エチル等のオルトエステル類、フェニルイソシアナート等のイソシアナート類、4-アミノ-1,2,4-トリアゾール等のN-アミノ複素環類等を用いることができるが、以上の中で、無水酢酸等の酸無水物が好ましく、無水酢酸が特に好ましい。無水酢酸は(III)のオキシム調製時にあらかじめ系内に存在させておくことにより、(III)を単離することなく1バッチで(I)の2,6-ジフルオロ-4-置換ベンゾニトリル誘導体を製造することができる。
【００２３】
(製造方法2)
一般式(II)のベンズアルデヒド誘導体を酸化剤存在下にアンモニアと反応させることにより(I)の2,6-ジフルオロ-4-置換ベンゾニトリル誘導体を製造する。酸化剤としては過酸化ニッケル、二酸化マンガン等の金属酸化物、四酢酸鉛等の金属塩、酸素(通常金属塩が併用される)等を用いることができるが、二酸化マンガンが特に好ましい。反応は脱水剤を併用することも好ましい。脱水剤としては硫酸ナトリウム等の塩類の他、使用する酸化剤に対して不活性である限り特に制限はない。
上記の製法1及び製法2において、使用する反応剤あるいは反応条件によっては一般式(I)、(II)あるいは(III)の化合物における脱アセタール化が進行する場合もある。脱アセタール化が生じても次工程に支障のない場合もあるが、必要に応じて再アセタール化を実施することも好ましい。再アセタール化は一般式(I)、(II)あるいは(III)のRに応じて、即ちRが-CH₂CH₂-を表す場合には酸触媒存在下にエチレングリコールを反応させればよい。
【００２４】
(製造方法3)
一般式(IV)で表される3,5-ジフルオロベンゼン誘導体のアルキルリチウムによるリチオ化は0℃以下に冷却して実施されるが、生成するフェニルリチウム誘導体の分解を防ぐためには-30℃以下が好ましく、-80℃以下の低温では反応が遅くなるので-30〜-80℃が好ましい。
アルキルリチウムとしてはn-ブチルリチウム、s-ブチルリチウム、t-ブチルリチウム、メチルリチウム、エチルリチウム、プロピルリチウム等をあげることができるが、入手の容易さや操作性からn-ブチルリチウム、メチルリチウムが好ましく、n-ブチルリチウムがさらに好ましい。また、アルキルリチウムに換えて、リチウムジイソプロピルアミド等のリチウムアミドを使用することも可能である。
反応は溶媒中で実施されるが、反応溶媒としてはTHF、IPE、DME等のエーテル系溶媒、ヘキサン、トルエン等の炭化水素系溶媒、及びこれらの混合溶媒が好ましく、特にTHFが好ましい。
【００２５】
ホルミル化は同様に0℃以下に冷却して実施されるが、フェニルリチウム誘導体の分解を防ぐためには-30℃以下が好ましく、-80℃以下の低温では反応が遅くなるので-30〜-80℃が好ましい。
ホルミル化剤としてはN,N-ジメチルホルムアミド(DMF)等のホルムアミド類、オルト蟻酸エチル等のオルトエステル類等を用いることができるが、ホルムアミド類特にDMFが好ましい。一般式(II)で表される化合物を得た後は製造方法1と同様にして、一般式(I)で表される化合物を得る。
【００２６】
(製造方法4)
一般式(V)で表される安息香酸誘導体のアミド化は、例えばカルボン酸を塩化チオニル等の塩素化剤で酸塩化物とした後、アンモニアあるいはその塩と反応させることにより実施される。あるいは直接カルボン酸にアンモニアを反応させることも可能である。
アミドの脱水は脱水剤存在下に容易に実施できる。脱水剤としては塩化チオニル、五塩化リン、オキシ塩化リン等の無機酸の酸塩化物(ピリジン等の塩基の共存が好ましい場合もある)、塩化p-トルエンスルホニル、ホスゲン等の有機酸塩化物(ピリジン等の塩基の共存が好ましい場合もある)、五酸化リン、ポリリン酸、ポリリン酸のエステル類等のリン酸誘導体、無水酢酸等の酸無水物、DCC、1,1'-ジカルボニルジイミダゾール等のカルボジイミド類等を使用することができ、塩化チオニル、ポリリン酸あるいはそのエステル類は特に好ましい。
【００２７】
(製造方法5)
一般式(IV)で表される3,5-ジフルオロベンゼン誘導体のアルキルリチウムによるリチオ化は0℃以下に冷却して実施されるが、生成するフェニルリチウム誘導体の分解を防ぐためには-30℃以下が好ましく、-80℃以下の低温では反応が遅くなるので-30〜-80℃が好ましい。
アルキルリチウムとしてはn-ブチルリチウム、s-ブチルリチウム、t-ブチルリチウム、メチルリチウム、エチルリチウム、プロピルリチウム等をあげることができるが、入手の容易さや操作性からn-ブチルリチウム、メチルリチウムが好ましく、n-ブチルリチウムがさらに好ましい。また、アルキルリチウムに換えて、リチウムジイソプロピルアミド等のリチウムアミドを使用することも可能である。
【００２８】
反応は溶媒中で実施されるが、反応溶媒としてはTHF、IPE、DME等のエーテル系溶媒、ヘキサン、トルエン等の炭化水素系溶媒、及びこれらの混合溶媒が好ましく、特にTHFが好ましい。
得られたフェニルリチウム反応剤に二酸化炭素を反応させるが、通常は-30〜-80℃の温度範囲で二酸化炭素を吹き込むか、ドライアイスを加えることにより一般式(V)で表される化合物を得る。
一般式(V)で表される化合物を得た後は製造方法4と同様にして、一般式(I)で表される化合物を得る。
本方法においても、必要に応じて再アセタール化を実施することも好ましい。
【００２９】
(製造方法6)
本製造方法における出発物質である一般式(VI)で表されるハロゲン化ベンゼン誘導体において、Xはヨウ素又は臭素原子を表すが、ヨウ素がより好ましい。
【００３０】
(製造方法7)
一般式(IV)で表される3,5-ジフルオロベンゼン誘導体のアルキルリチウムによるリチオ化は0℃以下に冷却して実施されるが、生成するフェニルリチウム誘導体の分解を防ぐためには-30℃以下が好ましく、-80℃以下の低温では反応が遅くなるので-30〜-80℃が好ましい。
アルキルリチウムとしてはn-ブチルリチウム、s-ブチルリチウム、t-ブチルリチウム、メチルリチウム、エチルリチウム、プロピルリチウム等をあげることができるが、入手の容易さや操作性からn-ブチルリチウム、メチルリチウムが好ましく、n-ブチルリチウムがさらに好ましい。また、アルキルリチウムに換えて、リチウムジイソプロピルアミド等のリチウムアミドを使用することも可能である。
反応は溶媒中で実施されるが、反応溶媒としてはTHF、IPE、DME等のエーテル系溶媒、ヘキサン、トルエン等の炭化水素系溶媒、及びこれらの混合溶媒が好ましく、特にTHFが好ましい。
得られたフェニルリチウム反応剤にヨウ素あるいは臭素を反応させることにより一般式(VI)で表されるハロゲン化ベンゼン誘導体を得ることができる。
【００３１】
(製造方法8)
本製造方法における出発物質である一般式(VII)で表されるスルホン酸エステル誘導体において、Qは炭素原子数7以下のアルキル基、パーフルオロアルキル基又はアリール基を表すが、フェニル基、4-メチルフェニル基、メチル基、トリフルオロメチル基が好ましく、トリフルオロメチル基が特に好ましい。
反応触媒としては遷移金属の塩及び錯体を使用することが好ましく、ニッケル(II)錯体、パラジウム(II)錯体、パラジウム(II)塩、パラジウム(0)錯体がより好ましく、テトラキス(トリフェニルホスフィン)パラジウム(0)等のパラジウム(0)錯体が特に好ましい。
【００３２】
一般式(I)の化合物を中間体として一般式(A)
【化１６】

(式中、Alkenylは炭素原子数2〜20のアルケニル基を表し、M、N、環A及びnは一般式(I)におけると同じ意味を表す。)で表される、アルケニル基を導入した2,6-ジフルオロ-4-置換ベンゾニトリル誘導体を効率的に製造することができる。
【００３３】
すなわち、一般式(I)の化合物を酸で処理することにより脱アセタール化させて一般式(XI)
【化１７】

(式中、M、N、環A及びnは一般式(I)のおけると同じ意味を表す。)で表されるシクロヘキサノン誘導体を得ることができる。この(XI)に式(XIIa)
【００３４】
【化１８】

のウィッティヒ反応剤を反応させ、酸処理の後、シクロヘキサン環をトランスに異性化させて一般式(XIII-0)
【化１９】

(式中、M、N、環A及びnは一般式(I)のおけると同じ意味を表す。)で表されるシクロヘキサンカルバルデヒドを得ることができる。
【００３５】
この操作をさらにm回繰り返すことにより一般式(XIII-m)
【化２０】

(式中、M、N、環A及びnは一般式(I)のおけると同じ意味を表し、mは0以上の整数を表す。)の化合物を得ることができる。
【００３６】
この化合物に一般式(XIIb)
【化２１】

(式中、R'は水素又は炭素原子数1〜18のアルキル基を表す。)を反応させることにより一般式(B)
【００３７】
【化２２】

(式中、R'及びmは前述の意味を表す。)で表されるアルケニル基を導入することができる。ここでR'がアルキル基の場合得られたアルケニル基の二重結合は通常(Z)配置であるが、ベンゼンスルフィン酸やヨウ素等により所望の(E)体に異性化させることができる。
【００３８】
【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。
【００３９】
(実施例1) 4-(3,5-ジフルオロ-4-シアノフェニル)シクロヘキサノンエチレンアセタール(I-1)の製造(製造方法1及び製造方法3)
1-a) 4-(3,5-ジフルオロフェニル)シクロヘキサノンエチレンアセタール(この化合物は3,5-ジフルオロ-1-ブロモベンゼンから調製したグリニヤール反応剤をシクロヘキサン-1,4-ジオンモノエチレンアセタールと反応させ、酸触媒存在下の脱水後、二重結合を接触還元することにより得た。)25.8gの110mLのテトラヒドロフラン(THF)溶液を窒素雰囲気下で-55℃に冷却した。これにn-ブチルリチウム(1.57Mヘキサン溶液)67.9mLを1時間で滴下しフェニルリチウム誘導体を調製した。30分攪拌後、N,N-ジメチルホルムアミド(DMF)8.9gのTHF40mL溶液を-55℃で滴下した。-55℃で1時間攪拌後、0℃まで昇温させ、水次いで少量の10％塩酸を加え、酢酸エチルで抽出した。水、及び飽和食塩水で洗浄後、無水硫酸ナトリウムで脱水乾燥させた。溶媒を溜去して4-(3,5-ジフルオロ-4-ホルミルフェニル)シクロヘキサノンエチレンアセタール28.1gを得た。
1-b) 得られた化合物の全量を酢酸100mLに溶解し、ヒドロキシルアミン塩酸塩10.0g及び酢酸ナトリウム(無水)7.5gを加え3時間加熱還流させた。これに無水酢酸24gを加えさらに3時間攪拌させた。氷水中に反応液を加え、析出した結晶を濾取し、水で洗浄した後、トルエン100mLに溶解した。飽和食塩水で洗浄後、エチレングリコール6.3g及びp-トルエンスルホン酸1.0gを加え、共沸する水を除去しながら水の溜出がみられなくなるまで加熱還流させた。室温まで放冷後、水、飽和重曹水、水、飽和食塩水の順で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を溜去して得られた粗生成物をヘキサンから再結晶させて4-(3,5-ジフルオロ-4-シアノフェニル)シクロヘキサノンエチレンアセタールの白色結晶21.2gを得た。
【００４０】
(実施例2) 4-(3,5-ジフルオロ-4-シアノフェニル)シクロヘキサノンエチレンアセタール(I-1)の製造(製造方法4及び製造法5)
2-a) 実施例1と同様にして調製したフェニルリチウム誘導体に、DMFに換えて、粉砕したドライアイス8.8gをゆっくり加え、以下同様に反応させた。同様に後処理して2,6-ジフルオロ-4-(4,4-エチレンジオキシシクロヘキシル)安息香酸29.7gを得た。
2-b) この全量をジクロロメタン100mLに溶解し、塩化チオニル23.2g及びピリジン1mLを加え、1時間加熱還流させた。溶媒及び過剰の塩化チオニルを溜去後、再度ジクロロメタンに溶解し、30％アンモニア水を加えよく攪拌させた。有機層を水で洗浄後、溶媒を溜去して得られた粗結晶をメタノールから再結晶させて、2,6-ジフルオロ-4-(4,4-エチレンジオキシシクロヘキシル)ベンズアミド26.7gを得た。
2-c) この全量をトルエン100mLに溶解し、オキシ塩化リン20mLを加え、3時間60℃で加熱攪拌させた。室温まで放冷後、氷水にあけ、トルエン層を水、飽和重曹水、水、飽和食塩水の順で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を溜去して得られた粗生成物をヘキサンから再結晶させて4-(3,5-ジフルオロ-4-シアノフェニル)シクロヘキサノンエチレンアセタールの白色結晶19.2gを得た。
【００４１】
(実施例3) トランス-4'-(3,5-ジフルオロ-4-シアノフェニル)ビシクロヘキサン-4-オンエチレンアセタール(I-3)の製造(製造方法8)
トランス-4'-(3,5-ジフルオロ-4-トリフルオロメタンスルホニルオキシフェニル)ビシクロヘキサン-4-オンエチレンアセタール9.3gを40mLのTHFに溶解し、1.1gのシアン化ナトリウム及び400mgのテトラキス(トリフェニルホスフィン)パラジウム(0)を加え、8時間加熱還流させた。室温まで放冷後、トルエンを加え、有機層を水、飽和食塩水で洗浄した。溶媒を溜去して得られた粗生成物をヘキサンから再結晶させてトランス-4'-(3,5-ジフルオロ-4-シアノフェニル)ビシクロヘキサン-4-オンエチレンアセタールの白色結晶4.4gを得た。
【００４２】
(応用例) 4-(トランス-4-ビニルシクロヘキシル)-2,6-ジフルオロベンゾニトリルの合成
実施例1で得られた4-(3,5-ジフルオロ-4-シアノフェニル)シクロヘキサノンエチレンアセタール2.83gをトルエン10mLに溶解し、蟻酸5mLを加え、60℃で4時間加熱攪拌させた。放冷後、トルエン層を分離し、水、飽和重曹水、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水後、溶媒を溜去して4-(3,5-ジフルオロ-4-シアノフェニル)シクロヘキサノン2.03gを得た。
【００４３】
トルエン及びTHFの混合溶媒中、4.50gの塩化トリフェニルメトキシメチルホスホニウムと1.52gのt-ブトキシカリウムから調製したウィッティヒ反応剤中に、上記の4-(3,5-ジフルオロ-4-シアノフェニル)シクロヘキサノン2.03gのTHF溶液を氷冷下に滴下し、反応させた。水及びヘキサンを加え、ヘキサン層中の不溶物を濾別した後、メタノール／水の混合溶媒で洗浄した。溶媒を溜去後、THFに再度溶解し、10％塩酸を加えて室温で攪拌した。ヘキサンで抽出後、水で洗浄し、溶媒を溜去させ、メタノールに溶解した。10％水酸化ナトリウム水溶液を加え、室温で攪拌した。析出した結晶を集め、水及び冷メタノールで洗浄してトランス-4-(3,5-ジフルオロ-4-シアノフェニル)シクロヘキサンカルバルデヒド1.94gを得た。
【００４４】
トルエン及びTHFの混合溶媒中、3.25gの臭化メチルトリフェニルホスホニウムと1.05gのt-ブトキシカリウムから調製したウィッティヒ反応剤中に、上記のトランス-4-(3,5-ジフルオロ-4-シアノフェニル)シクロヘキサンカルバルデヒド1.94gのTHF溶液を氷冷下に滴下し、反応させた。室温で塩酸を加えて中和し、ヘキサンで抽出し、水洗後、無水硫酸ナトリウムで乾燥させた。溶媒を溜去した後、シリカゲルカラムクロマトグラフィー(ヘキサン)で精製し、さらにメタノールから再結晶させて、4-(トランス-4-ビニルシクロヘキシル)-2,6-ジフルオロベンゾニトリルの白色結晶1.54g(総収率68％)を得た。融点39.5℃。
【００４５】
【発明の効果】
本発明はアルケニル基を含有する2,6-ジフルオロ-4-置換ベンゾニトリル誘導体の重要な中間体である化合物を提供し、またこの化合物の効率的な製造法を提供することが可能となった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a benzonitrile derivative useful as an electronic material such as a liquid crystal display material, a functional material, a medical pesticide, a fragrance, various additives, and a synthetic intermediate thereof, and a method for producing the same.
[0002]
[Prior art]
2,6-Difluoro-4-substituted benzonitrile derivatives are useful for applications such as electronic materials, functional materials, medical pesticides, fragrances, various additives, etc., especially as liquid crystal compounds for STN type liquid crystal display materials. It is extremely effective for reducing the driving voltage of objects and improving response time, and its demand has been particularly increasing recently. Generally, in a liquid crystal compound such as a 4-substituted benzonitrile derivative, a chain group is present at the other end of the molecule. However, in a 2,6-difluoro-4-substituted benzonitrile derivative used so far, a chain group is present. As the group, a linear alkyl group has been mainly used. In liquid crystal compounds, it is known that by introducing an alkenyl group instead of an alkyl group as a chain group, improvements in various properties such as liquid crystallinity, viscosity, and steepness can be obtained (Japanese Patent Laid-Open No. 2001-123171). ).
[0003]
Conventional liquid crystal compounds that are 2,6-difluoro-4-substituted benzonitrile derivatives are produced by introducing a cyano group at the 4-position using the corresponding 3,5-difluorobenzene derivative introduced with an alkenyl group as an intermediate. However, this method is not necessarily free from problems, such as the possibility of isomerization of the steric cyclohexane ring or the double bond of the alkenyl group. Therefore, development of a more effective intermediate and an efficient production method using the same for producing a liquid crystal compound which is a 2,6-difluoro-4-substituted benzonitrile derivative having an alkenyl group introduced is desired. It was.
[0004]
[Problems to be solved by the invention]
The problem to be solved by the present invention is to provide a new intermediate for producing a 2,6-difluoro-4-substituted benzonitrile derivative having an alkenyl group introduced therein, and to provide a simple method for producing the intermediate compound. It is to provide.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present invention has resulted in 2,6-difluoro-4-substituted benzonitrile derivatives in which alkenyl groups are introduced into 2,6-difluoro-4-substituted benzonitrile derivatives having an acetal group The present invention was found to be useful as a production intermediate of the present invention.
[0006]
That is, the present invention is a general formula (I)
[Chemical 8]

(In the formula, R represents an optionally substituted alkylene group having 2 to 4 carbon atoms, M and N are each independently a single bond, —CH ₂ CH ₂ —, —CH═CH— , -CF = CF-, -C≡C-, -CH ₂ O-, -OCH _2- , -CF ₂ O-, -OCF _2- , -CF ₂ CF _2- , -CH ₂ CH (CH ₃ ) -, -CH (CH ₃ ) CH _2- , -CH ₂ CH ₂ CH ₂ CH _2- , -OCH ₂ CH ₂ CH _2- , or -CH ₂ CH ₂ CH ₂ O-, wherein ring A is trans- A benzonitrile derivative represented by 1,4-cyclohexylene group, 1,4-phenylene group optionally substituted by fluorine, or pyrimidine-2,5-diyl group, and n represents 0 or 1. I will provide a.
[0007]
The present invention also provides a method for producing a compound represented by the following general formula (I).
[0008]
(Production method 1)
Formula (II)
[Chemical 9]

(Wherein R, M, N, ring A and n represent the same meaning as in general formula (I)), and a benzaldehyde derivative represented by the formula is reacted with hydroxylamine or a hydrate or salt thereof. Formula (III)
[Chemical Formula 10]

(Wherein R, M, N, rings A and n represent the same meaning as in general formula (I)), and then the dehydration reaction is performed. Manufacturing method.
[0009]
(Production method 2)
A process for producing general formula (I), comprising reacting a compound of general formula (II) with ammonia in the presence of an oxidizing agent.
[0010]
(Manufacturing method 3)
Formula (IV)
Embedded image

(Wherein R, M, N, rings A and n have the same meaning as in general formula (I)), and lithiation with alkyllithium, followed by reaction with a formylating agent. After obtaining a compound of the general formula (II) by the following formula, it is reacted with hydroxylamine or a hydrate or salt thereof to give an oxime represented by the general formula (III), followed by a dehydration reaction. The production method of I).
[0011]
(Production method 4)
Formula (V)
Embedded image

(Wherein R, M, N, rings A and n have the same meaning as in general formula (I)), and after deriving to an acid amide, dehydration. A production method of the general formula (I).
[0012]
(Production method 5)
The compound represented by the general formula (IV) is lithiated with alkyllithium, then reacted with carbon dioxide to obtain a benzoic acid derivative of the general formula (V), led to an acid amide, and then dehydrated. A production method of the general formula (I).
[0013]
(Production method 6)
Formula (VI)
Embedded image

(Wherein R, M, N, rings A and n have the same meaning as in general formula (I), and X represents an iodine or bromine atom) copper halide cyanide represented by A process for producing general formula (I), wherein (I) is reacted.
[0014]
(Production method 7)
The compound represented by general formula (IV) is lithiated with alkyllithium and then reacted with iodine or bromine to obtain a halogenated benzene derivative of general formula (VI), which is then reacted with copper (I) cyanide. A production method of general formula (I), characterized in that
[0015]
(Production method 8)
Formula (VII)
Embedded image

(In the formula, R, M, N, rings A and n have the same meaning as in general formula (I), and Q represents an alkyl group, a perfluoroalkyl group or an aryl group having 7 or less carbon atoms.) A process for producing general formula (I), characterized in that a metal cyanide is reacted with a sulfonic acid ester represented by
[0016]
DETAILED DESCRIPTION OF THE INVENTION
In the general formula (I), R represents an alkylene group having 2 to 4 carbon atoms which may have a substituent. The substituent is not particularly limited as long as it is an inert group in the reaction process for producing the 2,6-difluoro-4-substituted benzonitrile derivative having an alkenyl group, but a lower alkyl group, an aryl group, or an unsubstituted group. Preferably there is. The alkylene main chain preferably has 2 or 3 carbon atoms, and Q is preferably —CH ₂ CH ₂ CH ₂ — or —CH ₂ CH ₂ —.
[0017]
M and N are each independently a single bond, —CH ₂ CH ₂ —, —CH═CH—, —CF═CF—, —C≡C—, —CH ₂ O—, —OCH ₂ —, —CF ₂ O-, -OCF _2- , -CF ₂ CF _2- , -CH ₂ CH (CH ₃ )-, -CH (CH ₃ ) CH _2- , -CH ₂ CH ₂ CH ₂ CH _2- , -OCH ₂ CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ O— represents a single bond or —CH ₂ CH ₂ —, and a single bond is particularly preferable.
[0018]
Ring A represents a trans-1,4-cyclohexylene group, a fluorine-substituted 1,4-phenylene group, or a pyrimidine-2,5-diyl group, but a trans-1,4-cyclohexylene group or 1,4-phenylene group optionally substituted with fluorine is preferable, trans-1,4-cyclohexylene group, or 1,4-phenylene group or 2-fluoro-1,4-phenylene group is more preferable, and trans- A 1,4-cyclohexylene group is particularly preferred.
n represents 0 or 1, but n = 0 is particularly preferable.
[0019]
Specifically, the compound of the general formula (I) of the present invention is preferably a compound represented by the following (I-1) to (I-3), and particularly preferably a compound of (I-1).
Embedded image

[0020]
The method for producing a 2,6-difluoro-4-substituted benzonitrile derivative represented by the general formula (I) of the present invention is preferably carried out in the following form.
[0021]
(Production method 1)
A benzaldehyde derivative represented by the general formula (II) is reacted with hydroxylamine or a hydrate or salt thereof to obtain an oxime represented by the general formula (III). The reaction is usually carried out in the presence of a solvent. The solvent is not particularly limited as long as it is not reactive with hydroxylamine or aldehyde, but is a hydrocarbon solvent such as hexane or toluene, or an ether solvent such as tetrahydrofuran (THF), diisopropyl ether (IPE) or dimethoxyethane (DME). A chlorinated solvent such as dichloromethane, an alcohol solvent such as methanol or methyl cellosolve, a carboxylic acid solvent such as acetic acid, or a mixture thereof can be preferably used. These solvents are used in a mass ratio of 1 to 100 times, preferably 5 to 20 times with respect to the compound (II). The reaction is carried out at room temperature under heating or under cooling, but is usually preferably in the range of 0 to 100 ° C., more preferably in the range of room temperature to the reflux temperature of the solvent.
[0022]
The resulting compound (III) is subjected to a dehydration reaction to produce a 2,6-difluoro-4-substituted benzonitrile derivative (I).
As dehydrating agents or dehydrating catalysts, acid anhydrides such as acetic anhydride and trifluoromethanesulfonic acid, acids such as p-toluenesulfonic acid and trifluoroacetic acid, acid chlorides such as benzenesulfonic acid chloride and phenyl chloroformate, pyridine, Bases such as triethylamine, salts such as sodium formate, Lewis acids such as titanium tetrachloride (usually used in combination with pyridine, triethylamine, etc.), carbodiimides such as dicyclohexylcarbodiimide (DCC), 1,1'-dicarbonyldiimidazole Phosphines such as triphenylphosphine (usually used in combination with carbon tetrachloride), metal oxides such as selenium dioxide and mercury (II) oxide, orthoesters such as ethyl orthoformate, and isocyanates such as phenyl isocyanate. N-aminoheterocycles such as 4-amino-1,2,4-triazole can be used. Of these, acid anhydrides such as acetic anhydride are preferred, and acetic anhydride is particularly preferred. Acetic anhydride is present in the system in advance when preparing the oxime of (III), so that the 2,6-difluoro-4-substituted benzonitrile derivative of (I) can be obtained in one batch without isolating (III). Can be manufactured.
[0023]
(Production method 2)
The 2,6-difluoro-4-substituted benzonitrile derivative of (I) is produced by reacting the benzaldehyde derivative of general formula (II) with ammonia in the presence of an oxidizing agent. As the oxidizing agent, metal oxides such as nickel peroxide and manganese dioxide, metal salts such as lead tetraacetate, oxygen (usually a metal salt is used in combination) and the like can be used, and manganese dioxide is particularly preferable. In the reaction, it is also preferable to use a dehydrating agent in combination. The dehydrating agent is not particularly limited as long as it is inactive to the oxidizing agent used in addition to salts such as sodium sulfate.
In the above production method 1 and production method 2, deacetalization of the compound of general formula (I), (II) or (III) may proceed depending on the reactants or reaction conditions used. Even if deacetalization occurs, there may be no problem in the next step, but it is also preferable to carry out reacetalization as necessary. The reacetalization is performed according to R in the general formula (I), (II) or (III), that is, when R represents —CH ₂ CH ₂ —, ethylene glycol may be reacted in the presence of an acid catalyst. .
[0024]
(Manufacturing method 3)
Lithiation of the 3,5-difluorobenzene derivative represented by the general formula (IV) with alkyllithium is carried out by cooling to 0 ° C or lower, but in order to prevent decomposition of the generated phenyllithium derivative, it is -30 ° C or lower. The reaction is slow at a low temperature of −80 ° C. or lower, so −30 to −80 ° C. is preferable.
Examples of alkyllithium include n-butyllithium, s-butyllithium, t-butyllithium, methyllithium, ethyllithium, propyllithium, etc., but n-butyllithium and methyllithium are preferred because of their availability and operability. Preferably, n-butyl lithium is more preferable. Further, lithium amide such as lithium diisopropylamide can be used instead of alkyllithium.
Although the reaction is carried out in a solvent, the reaction solvent is preferably an ether solvent such as THF, IPE or DME, a hydrocarbon solvent such as hexane or toluene, and a mixed solvent thereof, and THF is particularly preferable.
[0025]
The formylation is similarly carried out by cooling to 0 ° C. or lower. However, in order to prevent the decomposition of the phenyllithium derivative, it is preferably −30 ° C. or lower, and the reaction is slow at a low temperature of −80 ° C. or lower. ° C is preferred.
As the formylating agent, formamides such as N, N-dimethylformamide (DMF) and orthoesters such as ethyl orthoformate can be used, but formamides, particularly DMF, are preferred. After obtaining the compound represented by the general formula (II), the compound represented by the general formula (I) is obtained in the same manner as in Production Method 1.
[0026]
(Production method 4)
The amidation of the benzoic acid derivative represented by the general formula (V) is carried out, for example, by converting a carboxylic acid into an acid chloride with a chlorinating agent such as thionyl chloride and then reacting with ammonia or a salt thereof. Alternatively, it is also possible to react ammonia directly with a carboxylic acid.
Amide dehydration can be easily carried out in the presence of a dehydrating agent. As the dehydrating agent, acid chlorides of inorganic acids such as thionyl chloride, phosphorus pentachloride, phosphorus oxychloride (in some cases, coexistence of a base such as pyridine may be preferred), organic acid chlorides such as p-toluenesulfonyl chloride, phosgene ( Coexistence of a base such as pyridine may be preferable), phosphoric acid derivatives such as phosphorus pentoxide, polyphosphoric acid, esters of polyphosphoric acid, acid anhydrides such as acetic anhydride, DCC, 1,1′-dicarbonyldiimidazole Carbodiimides and the like can be used, and thionyl chloride, polyphosphoric acid or esters thereof are particularly preferable.
[0027]
(Production method 5)
Lithiation of the 3,5-difluorobenzene derivative represented by the general formula (IV) with alkyllithium is carried out by cooling to 0 ° C or lower, but in order to prevent decomposition of the generated phenyllithium derivative, it is -30 ° C or lower. The reaction is slow at a low temperature of −80 ° C. or lower, so −30 to −80 ° C. is preferable.
Examples of alkyllithium include n-butyllithium, s-butyllithium, t-butyllithium, methyllithium, ethyllithium, propyllithium, etc., but n-butyllithium and methyllithium are preferred because of their availability and operability. Preferably, n-butyl lithium is more preferable. Further, lithium amide such as lithium diisopropylamide can be used instead of alkyllithium.
[0028]
Although the reaction is carried out in a solvent, the reaction solvent is preferably an ether solvent such as THF, IPE or DME, a hydrocarbon solvent such as hexane or toluene, and a mixed solvent thereof, and THF is particularly preferable.
Carbon dioxide is reacted with the obtained phenyllithium reactant. Usually, the compound represented by the general formula (V) is obtained by blowing carbon dioxide in the temperature range of −30 to −80 ° C. or adding dry ice. obtain.
After obtaining the compound represented by the general formula (V), the compound represented by the general formula (I) is obtained in the same manner as in Production Method 4.
Also in this method, it is also preferable to carry out reacetalization as necessary.
[0029]
(Production method 6)
In the halogenated benzene derivative represented by the general formula (VI) which is a starting material in this production method, X represents an iodine or bromine atom, but iodine is more preferable.
[0030]
(Production method 7)
Lithiation of the 3,5-difluorobenzene derivative represented by the general formula (IV) with alkyllithium is carried out by cooling to 0 ° C or lower, but in order to prevent decomposition of the generated phenyllithium derivative, it is -30 ° C or lower. The reaction is slow at a low temperature of −80 ° C. or lower, so −30 to −80 ° C. is preferable.
Examples of alkyllithium include n-butyllithium, s-butyllithium, t-butyllithium, methyllithium, ethyllithium, propyllithium, etc., but n-butyllithium and methyllithium are preferred because of their availability and operability. Preferably, n-butyl lithium is more preferable. Further, lithium amide such as lithium diisopropylamide can be used instead of alkyllithium.
Although the reaction is carried out in a solvent, the reaction solvent is preferably an ether solvent such as THF, IPE or DME, a hydrocarbon solvent such as hexane or toluene, and a mixed solvent thereof, and THF is particularly preferable.
The halogenated benzene derivative represented by the general formula (VI) can be obtained by reacting the obtained phenyllithium reactant with iodine or bromine.
[0031]
(Production method 8)
In the sulfonic acid ester derivative represented by the general formula (VII) which is a starting material in this production method, Q represents an alkyl group, a perfluoroalkyl group or an aryl group having 7 or less carbon atoms, but a phenyl group, 4- A methylphenyl group, a methyl group and a trifluoromethyl group are preferred, and a trifluoromethyl group is particularly preferred.
As the reaction catalyst, it is preferable to use a transition metal salt and complex, more preferably a nickel (II) complex, a palladium (II) complex, a palladium (II) salt, a palladium (0) complex, tetrakis (triphenylphosphine). Palladium (0) complexes such as palladium (0) are particularly preferred.
[0032]
General formula (A) with the compound of general formula (I) as an intermediate
Embedded image

(In the formula, Alkenyl represents an alkenyl group having 2 to 20 carbon atoms, and M, N, ring A and n have the same meaning as in the general formula (I)). A 2,6-difluoro-4-substituted benzonitrile derivative can be efficiently produced.
[0033]
That is, the compound of general formula (I) is deacetalized by treatment with an acid to give a compound of general formula (XI)
Embedded image

(Wherein, M, N, rings A and n have the same meaning as in general formula (I)) can be obtained. In this (XI), the formula (XIIa)
[0034]
Embedded image

In the general formula (XIII-0), the cyclohexane ring is isomerized into trans after acid treatment.
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(Wherein, M, N, rings A and n have the same meaning as in general formula (I)) can be obtained.
[0035]
By repeating this operation m more times, the general formula (XIII-m)
Embedded image

(Wherein M, N, rings A and n have the same meaning as in general formula (I), and m represents an integer of 0 or more).
[0036]
This compound has the general formula (XIIb)
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(In the formula, R ′ represents hydrogen or an alkyl group having 1 to 18 carbon atoms).
[0037]
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An alkenyl group represented by the formula (wherein R ′ and m are as defined above) can be introduced. Here, when R ′ is an alkyl group, the double bond of the alkenyl group obtained is usually in the (Z) configuration, but it can be isomerized to the desired (E) form with benzenesulfinic acid or iodine.
[0038]
【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.
[0039]
Example 1 Production of 4- (3,5-difluoro-4-cyanophenyl) cyclohexanone ethylene acetal (I-1) (Production Method 1 and Production Method 3)
1-a) 4- (3,5-Difluorophenyl) cyclohexanone ethylene acetal (this compound is a Grignard reagent prepared from 3,5-difluoro-1-bromobenzene and reacted with cyclohexane-1,4-dione monoethylene acetal After dehydration in the presence of an acid catalyst, the double bond was obtained by catalytic reduction.) 25.8 g of 110 mL of tetrahydrofuran (THF) solution was cooled to −55 ° C. under a nitrogen atmosphere. To this was added dropwise 67.9 mL of n-butyllithium (1.57 M hexane solution) over 1 hour to prepare a phenyllithium derivative. After stirring for 30 minutes, a solution of 8.9 g of N, N-dimethylformamide (DMF) in 40 mL of THF was added dropwise at -55 ° C. After stirring at -55 ° C for 1 hour, the temperature was raised to 0 ° C, water and a small amount of 10% hydrochloric acid were added, and the mixture was extracted with ethyl acetate. After washing with water and saturated saline, it was dehydrated and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 28.1 g of 4- (3,5-difluoro-4-formylphenyl) cyclohexanone ethylene acetal.
1-b) The total amount of the obtained compound was dissolved in 100 mL of acetic acid, 10.0 g of hydroxylamine hydrochloride and 7.5 g of sodium acetate (anhydrous) were added, and the mixture was heated to reflux for 3 hours. To this was added 24 g of acetic anhydride, and the mixture was further stirred for 3 hours. The reaction solution was added to ice water, and the precipitated crystals were collected by filtration, washed with water, and dissolved in 100 mL of toluene. After washing with saturated brine, 6.3 g of ethylene glycol and 1.0 g of p-toluenesulfonic acid were added, and the mixture was heated to reflux until no water distills out while removing azeotropic water. The mixture was allowed to cool to room temperature, washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was recrystallized from hexane to obtain 21.2 g of white crystals of 4- (3,5-difluoro-4-cyanophenyl) cyclohexanone ethylene acetal.
[0040]
Example 2 Production of 4- (3,5-difluoro-4-cyanophenyl) cyclohexanone ethylene acetal (I-1) (Production Method 4 and Production Method 5)
2-a) To the phenyllithium derivative prepared in the same manner as in Example 1, 8.8 g of pulverized dry ice was slowly added instead of DMF, and the reaction was performed in the same manner. Post-treatment was conducted in the same manner to obtain 29.7 g of 2,6-difluoro-4- (4,4-ethylenedioxycyclohexyl) benzoic acid.
2-b) The total amount was dissolved in 100 mL of dichloromethane, 23.2 g of thionyl chloride and 1 mL of pyridine were added, and the mixture was heated to reflux for 1 hour. After distilling off the solvent and excess thionyl chloride, it was dissolved again in dichloromethane, and 30% aqueous ammonia was added and stirred well. After washing the organic layer with water, the solvent was distilled off and the resulting crude crystals were recrystallized from methanol to obtain 26.7 g of 2,6-difluoro-4- (4,4-ethylenedioxycyclohexyl) benzamide. It was.
2-c) The total amount was dissolved in 100 mL of toluene, 20 mL of phosphorus oxychloride was added, and the mixture was heated and stirred at 60 ° C. for 3 hours. The mixture was allowed to cool to room temperature, poured into ice water, and the toluene layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine in that order, and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent was recrystallized from hexane to obtain 19.2 g of white crystals of 4- (3,5-difluoro-4-cyanophenyl) cyclohexanone ethylene acetal.
[0041]
(Example 3) Production of trans-4 '-(3,5-difluoro-4-cyanophenyl) bicyclohexane-4-one ethylene acetal (I-3) (Production method 8)
9.3 g of trans-4 '-(3,5-difluoro-4-trifluoromethanesulfonyloxyphenyl) bicyclohexane-4-one ethylene acetal is dissolved in 40 mL of THF, 1.1 g of sodium cyanide and 400 mg of tetrakis (tri Phenylphosphine) palladium (0) was added and heated to reflux for 8 hours. After cooling to room temperature, toluene was added, and the organic layer was washed with water and saturated brine. The crude product obtained by distilling off the solvent was recrystallized from hexane to obtain 4.4 g of trans-4 ′-(3,5-difluoro-4-cyanophenyl) bicyclohexane-4-one ethylene acetal as white crystals. Obtained.
[0042]
(Application Example) Synthesis of 4- (trans-4-vinylcyclohexyl) -2,6-difluorobenzonitrile 2.83 g of 4- (3,5-difluoro-4-cyanophenyl) cyclohexanone ethylene acetal obtained in Example 1 Was dissolved in 10 mL of toluene, 5 mL of formic acid was added, and the mixture was heated and stirred at 60 ° C. for 4 hours. After standing to cool, the toluene layer was separated, washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dehydrated with anhydrous sodium sulfate, and the solvent was distilled off to remove 4- (3,5-difluoro-4-cyano. 2.03 g of phenyl) cyclohexanone was obtained.
[0043]
In a Wittig reagent prepared from 4.50 g of triphenylmethoxymethylphosphonium chloride and 1.52 g of t-butoxy potassium in a mixed solvent of toluene and THF, the above 4- (3,5-difluoro-4-cyanophenyl) was added. A THF solution of 2.03 g of cyclohexanone was added dropwise under ice cooling to cause a reaction. Water and hexane were added, insolubles in the hexane layer were filtered off, and washed with a mixed solvent of methanol / water. After distilling off the solvent, it was dissolved again in THF, 10% hydrochloric acid was added, and the mixture was stirred at room temperature. After extraction with hexane, the mixture was washed with water, the solvent was distilled off, and the residue was dissolved in methanol. A 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature. The precipitated crystals were collected and washed with water and cold methanol to obtain 1.94 g of trans-4- (3,5-difluoro-4-cyanophenyl) cyclohexanecarbaldehyde.
[0044]
In a Wittig reagent prepared from 3.25 g methyltriphenylphosphonium bromide and 1.05 g potassium t-butoxy in a mixed solvent of toluene and THF, the above trans-4- (3,5-difluoro-4-cyano was added. A THF solution of 1.94 g of (phenyl) cyclohexanecarbaldehyde was added dropwise under ice cooling to cause a reaction. The mixture was neutralized by adding hydrochloric acid at room temperature, extracted with hexane, washed with water, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane) and recrystallized from methanol to give 1.54 g of 4- (trans-4-vinylcyclohexyl) -2,6-difluorobenzonitrile as white crystals ( Total yield 68%) was obtained. Melting point 39.5 ° C.
[0045]
【The invention's effect】
The present invention provides a compound that is an important intermediate of a 2,6-difluoro-4-substituted benzonitrile derivative containing an alkenyl group, and has made it possible to provide an efficient process for producing this compound. .

Claims

Formula (I)

(Wherein, R represents an alkylene group having 2 to 4 carbon atoms which may have a substituent, M and N represents a single bond, ring A is trans-1,4-cyclohexylene group or fluorine Represents an optionally substituted 1,4-phenylene group , and n represents 0 or 1.).

The benzonitrile derivative according to claim 1, wherein n represents 0 in the general formula (I).

Benzonitrile derivative according to any one of claims 1-2 that represents the - or -CH _{_₂} CH ₂ CH ₂ - R is -CH ₂ CH ₂ in the general formula (I).

A process for producing a benzonitrile derivative represented by the general formula (I), comprising the general formula (II)

(Wherein R, M, N, ring A and n represent the same meaning as in general formula (I)), and a benzaldehyde derivative represented by the formula is reacted with hydroxylamine or a hydrate or salt thereof. Formula (III)

(Wherein R, M, N, rings A and n represent the same meaning as in general formula (I)), followed by a dehydration reaction.

5. The production method according to claim 4 , wherein the dehydration of the general formula (III) is carried out in the presence of acetic anhydride.

A method for producing a benzonitrile derivative represented by the general formula (I), which comprises reacting a benzaldehyde derivative of the general formula (II) with ammonia in the presence of an oxidizing agent.

7. The production method according to claim 6 , wherein the oxidizing agent is manganese dioxide.

The production method according to any one of claims 4 to 7 , comprising a reacetalization step.

A process for producing a benzonitrile derivative represented by the general formula (I), comprising the general formula (IV)

(Wherein R, M, N, rings A and n have the same meaning as in general formula (I)), and lithiation with alkyllithium, followed by reaction with a formylating agent. A benzaldehyde derivative represented by the general formula (II), which is reacted with hydroxylamine or a hydrate or salt thereof to give an oxime represented by the general formula (III), followed by a dehydration reaction. That way.

11. The production method according to claim 10 , wherein the dehydration of the general formula (III) is performed in the presence of acetic anhydride.

A method for producing a benzonitrile derivative represented by the general formula (I), the general formula (V)

(Wherein R, M, N, rings A and n have the same meaning as in general formula (I)), and after deriving to an acid amide, dehydration. That way.

12. The production method according to claim 11 , comprising a reacetalization step.

A method for producing a benzonitrile derivative represented by the general formula (I), wherein the compound represented by the general formula (IV) is lithiated with alkyllithium and then reacted with carbon dioxide to thereby produce the general formula (V). A benzoic acid derivative of the above, led to acid amide, and then dehydrated.

A process for producing a benzonitrile derivative represented by the general formula (I), comprising the general formula (VI)

(Wherein R, M, N, rings A and n have the same meaning as in general formula (I), and X represents an iodine or bromine atom) copper halide cyanide represented by The said method characterized by making (I) react.

A method for producing a benzonitrile derivative represented by the general formula (I), wherein the compound represented by the general formula (IV) is lithiated with alkyllithium and then reacted with iodine or bromine to give a general formula (VI ) And a halogenated benzene derivative, and this is reacted with copper (I) cyanide.

A process for producing a benzonitrile derivative represented by the general formula (I), comprising the general formula (VII)

(In the formula, R, M, N, rings A and n have the same meaning as in general formula (I), and Q represents an alkyl group, a perfluoroalkyl group or an aryl group having 7 or less carbon atoms.) And a metal cyanide in the presence of a catalyst.

17. The production method according to claim 16, wherein Q in the general formula (VII) represents a trifluoromethyl group.

18. The production method according to claim 17 , wherein the catalyst is a salt or complex of palladium or nickel.