JP4826863B2 - Method for producing 4-substituted cyclohexanone derivative - Google Patents

Description

(式中、Vは単結合または炭素原子数1〜4のアルキレン基を表し、Arは置換基を有していてもよいアリール基を表す。)で表される4-置換シクロヘキサノン誘導体の製造方法であって、一般式(II)
【０００６】
【化８】

(式中、Vは一般式(I)のおけると同じ意味を表す。)で表されるヒドロキシケトンを原料とし、一般式(III)
【０００７】
【化９】

(式中、V及びAr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ール誘導体を酸化する工程を含むことを特徴とする製造方法を提供する。
【０００８】
【発明の実施の形態】
上述のごとく、本発明の製造方法により得られるアリール基を有する4-置換シクロヘキサノン誘導体は一般式(I)
【化１０】

で表すことができる。
【０００９】
一般式(I)において、Vは単結合または炭素原子数1〜4のアルキレン基を表すが、単結合または-CH₂CH₂-が好ましく、単結合が最も好ましい。
【００１０】
Arは置換基を有していてもよいアリール基を表すが、アリール基としてはフェニル基、テトラヒドロナフチル基、ナフチル基、ピリミジル基、ピリジル基、ピラジル基、ビフェニリル基、フリル基、ピロリル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、イミダゾリル基、ベンゾフリル基、イソベンゾフリル基、インドリル基、イソインドリル基、キノリル基、イソキノリル基、ナフチリジル基、ベンゾイミダゾリル基、キノキサリル基、キナゾリル基等をあげることができるが、フェニル基、ナフチル基及びビフェニリル基が好ましく、フェニル基が最も好ましい。
【００１１】
これらの基が有していてもよい置換基としては、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、フッ素原子、塩素原子、アルキル基、アラルキル基、アルコキシル基、あるいは1個以上のフッ素原子により置換されたアルキル基、アラルキル基、アルコキシル基が好ましい。
【００１２】
特にArとしては一般式(IV)
【化１１】

で表される基であることがさらに好ましい。
【００１３】
一般式(IV)においてX¹、X²及びX³はそれぞれ独立的に水素原子またはフッ素原子を表すが、(X¹、X²、X³)として(H、H、H)、(F、H、H)、(F、F、H)または(F、H、F)の組み合わせが好ましい。
【００１４】
Yは水素原子、フッ素原子、塩素原子、RまたはORを表す。ここでRは直鎖状でも分岐状でもあるいは環状部を含んでいてもよい炭素原子数1〜10のアルキル基を表すが、炭素原子数1〜7のアルコキシル基または1〜5個のフッ素原子により置換されていてもよい。Yとしては水素原子、フッ素原子、トリフルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメチル基、メトキシ基、エトキシ基、メチル基またはエチル基が好ましい。
【００１５】
本発明の製造方法において、一般式(I)の化合物は一般式(III)
【化１２】

で表されるシクロヘキサノール誘導体を酸化する工程を含むことにより得ることができる。ここで一般式(III)において、V及びArは一般式(I)のおけると同じ意味を表す。
【００１６】
この酸化工程において、酸化剤としては2級アルコールをケトンに酸化しうるものであれば特に制限はないが、ハロゲン系酸化剤またはクロム酸系酸化剤が好ましく、特に塩素、臭素等のハロゲン、次亜塩素酸、次亜臭素酸等の次亜ハロゲン酸、次亜塩素酸ナトリウム、次亜臭素酸ナトリウム、さらし粉等の次亜ハロゲン酸塩、N-クロロこはく酸イミド、N-ブロモこはく酸イミド、N-ブロモアセトアミド、N-クロロイソシアヌル酸等のN-ハロカルボン酸アミドが好ましく、次亜塩素酸ナトリウム、さらし粉等の次亜塩素酸塩が最も好ましい。
【００１７】
(III)の酸化により得られた一般式(I)の化合物はさらなる精製工程を経ることなく、所望の目的に供することが可能な場合もあり、あるいは再結晶、蒸留、カラムクロマトグラフィー等の通常の精製手段により精製して用いる場合もある。
【００１８】
一般式(I)において、シクロヘキシレン基の1,4-位はトランス配置であることが好ましいが、(I)までの製造工程において、トランス体への異性化工程を含まない場合には得られた(I)は通常シス体とトランス体の混合物である。その場合には得られた(I)をいったんアセタール化し、強塩基またはルイス酸触媒等の存在下にトランス体に異性化し、その後に脱アセタール化することが好ましい。強塩基としてはN,N-ジメチルホルムアミド(DMF)等の非プロトン性極性溶媒下でのt-ブトキシカリウムが好ましく、ルイス酸としては塩化アルミニウムが好ましいが、通常はt-ブトキシカリウムが最も好ましい。
【００１９】
本発明においては原料として一般式(II)
【化１３】

で表されるヒドロキシケトンを用いることを特徴とする。一般式(II)において、Vは一般式(I)のおけると同じ意味を表す。ここで、(II)の化合物は一般式(VII)
【００２０】
【化１４】

で表されるビスフェノール誘導体を、例えば特開平12-159718号公報に記載された方法等により接触還元することで容易に得ることができる。ここで一般式(VII)においてV'は水素原子または炭素原子数1〜4のアルキレン基、アルケニレン基またはアルキニレン基を表す。)
一般式(III)のシクロヘキサノール誘導体を一般式(II)のヒドロキシケトンを原料として製造するルートはいくつか存在するが、以下に示すルートが好ましい。
【００２１】
即ち(II)のヒドロキシケトンの水酸基を保護することにより一般式(V)
【化１５】

で表される水酸基が保護されたヒドロキシケトン類が得られる。ここで一般式(V)において、Vは一般式(I)のおけると同じ意味を表す。Zは水酸基の保護基を表すが、メチル基、ベンジル基、テトラヒドロピラニル基、テトラヒドロフリル基、メトキシメチル基またはエトキシメチル基が好ましく、メチル基またはベンジル基が酸性条件や塩基性条件に安定なため特に好ましい。これらの保護基は製造の各工程において、脱保護される場合も存在するが、その場合には必要に応じ再度保護すればよい。
【００２２】
この水酸基が保護されたヒドロキシケトン類に一般式 Ar-M (VI)で表される有機金属反応剤を反応させることによりシクロヘキサノール誘導体が得られる。ここでMは金属原子または金属原子を含む基を表し、カルボニル基に求核付加する限り特に制限はないが、MgBr、MgI、MgClまたはLiが特に好ましい。前述のArの定義に従って、(VI)としてより好ましい形態は、一般式(VI')
【化１６】

で表すことができる。一般式(VI')においてMは一般式(VI)と、X¹、X²、X³及びYは一般式(IV)におけると同じ意味を表す。
【００２３】
得られたシクロヘキサノール誘導体から脱水することにより一般式(VIII)
【化１７】

で表されるシクロヘキセン誘導体を得ることができる。ここでZ、V及びArは前述の意味を表す。脱水は酸触媒存在下、あるいは塩素化や臭素化、スルホン酸エステル化した後、塩基で処理することにより行われる。酸触媒としては例えば硫酸、硫酸水素カリウム、p-トルエンスルホン酸、蟻酸等が好ましく、塩素化剤としてはオキシ塩化リン、五塩化リン、塩化チオニル等が好ましく、臭素化剤としては例えば三臭化リンが好ましく、スルホン酸エステル化剤としては塩化P-トルエンスルホニル、塩化トリフルオロメタンスルホニル、無水トリフルオロメタンスルホン酸等が好ましい。
【００２４】
(VIII)のシクロヘキセン誘導体を接触還元することにより一般式(IX)
【化１８】

で表される化合物を得ることができる。ここでZ、V及びArは前述の意味を表す。
【００２５】
還元は水素雰囲気下、遷移金属触媒存在下に行われる。
【００２６】
水素圧は常圧付近以上であれば特に制限はないが、0.1MPa〜4MPaが好ましく、0.1MPa〜1MPaがより好ましく、0.1MPa〜0.4MPaがさらに好ましい。
【００２７】
遷移金属触媒としては、通常の接触還元に用いられるものであれば特に制限はないが、パラジウム/炭素、白金/炭素、ルテニウム/炭素等の炭素に担持された金属、あるいはラネーニッケル等のラネー金属等が好ましい。
【００２８】
保護基Zとしてベンジル基を用いた場合、この工程で脱保護されることがあるので、その場合には必要に応じて再度水酸基を保護することが好ましい。
【００２９】
得られた(IX)のシクロヘキシレン基の1,4-位は通常シス及びトランス体の混合物である。目的の一般式(I)においてシクロヘキシレン基の1,4-位はトランス体であることが好ましいが、そのためにはこの工程の後でシス体をトランス体に異性化しておくことが好ましい。
【００３０】
異性化は強塩基あるいはルイス酸触媒の存在下に行われる。強塩基としてはN,N-ジメチルホルムアミド(DMF)等の非プロトン性極性溶媒下でのt-ブトキシカリウムが好ましく、ルイス酸としては塩化アルミニウムが好ましいが、保護基としてテトラヒドロピラニル基、テトラヒドロフリル基、メトキシメチル基またはエトキシメチル基を用いる場合には塩基触媒、通常はt-ブトキシカリウムが最も好ましい。
【００３１】
一般式(IX)の化合物を脱保護することにより一般式(III)のシクロヘキサノール誘導体を得ることができる。
【００３２】
脱保護は保護基がテトラヒドロピラニル基、テトラヒドロフリル基、メトキシメチル基またはエトキシメチル基の場合にはプロトン性溶媒存在下に酸で処理することにより、メチル基の場合には三臭化ホウ素、塩化アルミニウムとのルイス酸、ヨウ化トリメチルシリル、ジメチルスルフィド等のスルフィド類、あるいはこれらを組み合わせてもちいることにより脱メチル化することができる。ベンジル基の場合には接触還元により脱保護が可能である。
【００３３】
以上のようにして、一般式(II)で表されるヒドロキシケトンから、一般式(I)で表される4-置換シクロヘキサノン誘導体を製造することができる。
【００３４】
得られた(I)の化合物は液晶表示材料等の電子材料や機能性材料または医農薬や香料、各種添加剤およびそれらの合成中間体として有用であるが、本発明は一般式(I)の化合物のなかで、以下の(Ia-1)〜(Ib-21)で示される化合物の製造方法として好ましい。
【００３５】
【化１９】

【００３６】
【化２０】

【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。
【００３７】
(実施例1) トランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)の製造
1-a) 4'-ヒドロキシビシクロヘキサン-4-オン(この化合物はビフェノールから特開平12-159718号公報に準じた方法で製造でき、シス及びトランス体の混合物である。)19.6gの50mLテトラヒドロフラン(THF)溶液をTHF200mL中に懸濁させた水素化ナトリウム(50％)5.0gに滴下した。室温で1時間攪拌した後、ヨウ化メチル15gのTHF30mL溶液を30分かけて滴下した。3時間攪拌した後、水を加えて過剰の水素化ナトリウムを分解し、塩酸酸性としてトルエンで抽出した。水洗後、溶媒を溜去して4'-メトキシビシクロヘキサン-4-オン18gを得た。
1-b) 17.1gのp-ブロモトルエンと2.4gのマグネシウムから調製したグリニャール反応剤溶液中に、室温で上記4'-メトキシビシクロヘキサン-4-オンの全量のTHT溶液を滴下した。室温で3時間攪拌した後、水次いで塩酸を加えて反応を停止させ、トルエンで抽出した。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。
1-c) 濾過後、トルエンが約50mLになるまで減圧濃縮し、これに0.5gのp-トルエンスルホン酸1水和物を加え、溜出する水を除去しながら、4時間加熱還流させた。室温まで冷却し、重曹水次いで水で洗浄し、無水硫酸ナトリウムで脱水乾燥させた。濾過後減圧下に溶媒を溜去して、1-(4-メチルフェニル)-4-(4-メトキシシクロヘキシル)シクロヘキサ-1-エン19.8gを得た。
1-d) この全量をエタノール100mLに溶解し、1.0gの5％パラジウム/炭素とともにオートクレーブ中で、室温で4時間接触還元(水素圧0.4MPa)した。触媒を濾別後、減圧下に溶媒を溜去して4-(4-メチルフェニル)-4'-メトキシビシクロヘキサン19.0gを得た。
1-e) この全量を200mLのDMFに溶解し、5.6gのt-ブトキシカリウムを加え、80℃で2時間加熱攪拌した。放冷後、水を加え、塩酸水で中和した後、ヘキサンで抽出した。ヘキサン相は水で洗浄した後、無水硫酸ナトリウムで脱水乾燥させた。濾過後減圧下に溶媒を溜去して得られた粗生成物をエタノールから再結晶させて、トランス-4-(4-メチルフェニル)-4'-メトキシビシクロヘキサンの白色結晶14.5gを得た。
1-f)この全量をジクロロメタン100mLに溶解し、水冷下、ヨウ化トリメチルシラン15gを加え、室温に戻して8時間攪拌させた。水を加え、トルエンで抽出し、減圧下に溶媒を溜去して、トランス-4-(4-メチルフェニル)-4'-ヒドロキシビシクロヘキサン12.0gを得た。
1-g) この全量をジクロロメタン50mLに溶解し、酢酸50mLを加え、激しく攪拌しながら、これに8％次亜塩素酸ナトリウム水溶液(アンチホルミン)100mLを滴下した。4時間攪拌後、亜硫酸水素ナトリウム水溶液を加えて過剰の酸化剤を分解し、水を加え、トルエンで抽出した。水、飽和食塩水で洗浄後、溶媒を濃縮して得られた粗生成物をエタノールから再結晶させて、表記のトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)の白色結晶8.5gを得た。
【００３８】
(比較例1) ビシクロヘキサン-4,4'-ジオンモノエチレンアセタールを原料とする表記のトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)の製造
p-ブロモトルエン16.3gから調製したグリニャール反応剤に、ビシクロヘキサン-4,4'-ジオンモノエチレンアセタール12.0gを滴下して反応させ、シクロヘキサノール誘導体16.7gを得た。これをトルエンに溶解し、0.5gの硫酸水素ナトリウムを加えて共沸する水を除去しながら加熱還流させ、4-(4-メチルフェニル)ビシクロヘキサ-3-エン-4'-オンエチレンアセタール12.0gを得た。この全量を酢酸エチルに溶解し、ラネーニッケル0.6gを加え、オートクレーブ中水素圧0.5MPaで接触還元して、4-(4-メチルフェニル)ビシクロヘキサン-4'-オンエチレンアセタール11.5gを得た。この全量をDMFに溶解し、t-ブトキシカリウム2.2gを加え、100℃で4時間加熱還流させた。水次いで塩酸水を加えて中和し、トルエンで抽出し、溶媒を濃縮して得られた残渣をエタノールから再結晶させてトランス-4-(4-メチルフェニル)ビシクロヘキサン-4'-オンエチレンアセタール8.5gを得た。この全量をトルエンに溶解し、酢酸及び希硫酸を加え、5時間加熱攪拌させた。水を加え中和後、トルエンで抽出し、得られた粗生成物をエタノールから再結晶させて表記のトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)の白色結晶6.4gを得た。
【００３９】
従って原料としてを用いた場合でも実施例1と同様に目的のトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オンを得ることができるが、ビシクロヘキサン-4,4'-ジオンモノエチレンアセタールは4'-ヒドロキシビシクロヘキサン-4-オンと比較してはるかに高価であり、実施例1がコスト的に優れていることは明らかである。
【００４０】
(実施例2) トランス-4'-(3,4-ジフルオロフェニル)ビシクロヘキサン-4-オン(Ia-16)の製造
実施例1-b)においてp-ブロモベンゼンに換えて、3,4-ジフルオロブロモベンゼンを用い、1-d)において還元触媒としてパラジウム/炭素に換えて、高活性ラネーニッケルを用い、1-e)における異性化を室温で行った以外は同様にして、同様の収率で表記のトランス-4'-(3,4-ジフルオロフェニル)ビシクロヘキサン-4-オン(Ia-16)の白色結晶を得た。
【００４１】
(実施例3) トランス-4'-(3,4-ジフルオロフェニル)ビシクロヘキサン-4-オン(Ia-16)の製造
実施例1-f)においてヨウ化トリメチルシランに換えて、塩化トリメチルシランとヨウ化ナトリウムを用いてトランス-4-(4-メチルフェニル)-4'-ヒドロキシビシクロヘキサンを製造した以外は実施例1と同様にしてトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)を得た。
【００４２】
(実施例4) トランス-4'-(3,5-ジフルオロ-4-メトキシフェニル)ビシクロヘキサン-4-オン(Ia-12)の製造
実施例1-a)において、ヨウ化メチルに換えて塩化ベンジルを用い、1-d)における接触還元の水素圧を0.1MPaとし、1-f)の脱保護工程を水素圧0.5MPa、50℃の接触還元で実施した以外は実施例1と同様にして、トランス-4'-(3,5-ジフルオロ-4-メトキシフェニル)ビシクロヘキサン-4-オン(Ia-12)の白色結晶を得た。
【００４３】
【発明の効果】
本発明はアリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体の製造において、原料として高価なジケトン化合物のモノアセタールに換えて、安価で入手容易なヒドロキシケトンを原料とする方法を提供し、これにより所望のアリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体のより安価な製造を可能とした。得られたアリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体は、液晶表示材料等の電子材料や機能性材料または医農薬や香料、各種添加剤およびそれらの合成中間体として極めて有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to the production of 4-substituted cyclohexanone derivatives that are useful as electronic materials such as liquid crystal display materials, functional materials, medicines and agricultural chemicals, fragrances, various additives, and synthetic intermediates thereof.
[0002]
[Prior art]
4-Substituted cyclohexanone derivatives are useful as electronic materials such as liquid crystal display materials, functional materials, medical pesticides, fragrances, various additives, and synthetic intermediates thereof, and are important as production intermediates. In particular, a 4-substituted cyclohexanone derivative having an arylcyclohexyl group is very important as an intermediate of an alkenyl liquid crystal compound used for STN liquid crystal display or the like. This 4-substituted cyclohexanone derivative having an arylcyclohexyl group has heretofore been produced from a monoacetal of a diketone compound, such as bicyclohexane-4,4′-dione monoethylene acetal. Such monoacetals are usually produced by monoacetalization of diketones. However, it is not easy to selectively monoacetalize the diketone compound, and it is usually necessary to separate only the necessary monoacetal from the mixture of the raw diketone, diacetal and monoacetal, and an increase in cost can be avoided. There wasn't. Therefore, in order to obtain a 4-substituted cyclohexanone derivative having an arylcyclohexyl group, a production method using an inexpensive compound other than the diacetone monoacetal as a raw material has been desired.
[0003]
[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 cyclohexanone derivative having an arylcyclohexyl group, starting from a less expensive and easily available compound.
[0004]
[Means for Solving the Problems]
As a result of diligent studies to solve the above problems, the present invention has found that 4-substituted cyclohexanone derivatives having an arylcyclohexyl group can be easily produced from a hydroxyketone easily obtained by catalytic reduction of bisphenols or the like as a raw material. The present invention has been completed.
[0005]
That is, the present invention relates to the general formula (I)
[Chemical 7]

(Wherein V represents a single bond or an alkylene group having 1 to 4 carbon atoms, Ar represents an aryl group which may have a substituent), and a method for producing a 4-substituted cyclohexanone derivative represented by Where the general formula (II)
[0006]
[Chemical 8]

(Wherein V represents the same meaning as in general formula (I)), and the raw material is hydroxyketone represented by general formula (III)
[0007]
[Chemical 9]

(In the formula, V and Ar have the same meaning as in the general formula (I).) A production method comprising a step of oxidizing a cyclohexanol derivative represented by the formula (I) is provided.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
As described above, the 4-substituted cyclohexanone derivative having an aryl group obtained by the production method of the present invention has the general formula (I)
[Chemical Formula 10]

Can be expressed as
[0009]
In the general formula (I), V represents a single bond or an alkylene group having 1 to 4 carbon atoms, preferably a single bond or —CH ₂ CH ₂ —, and most preferably a single bond.
[0010]
Ar represents an aryl group which may have a substituent, and as the aryl group, a phenyl group, a tetrahydronaphthyl group, a naphthyl group, a pyrimidyl group, a pyridyl group, a pyrazyl group, a biphenylyl group, a furyl group, a pyrrolyl group, an oxazolyl Group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, benzofuryl group, isobenzofuryl group, indolyl group, isoindolyl group, quinolyl group, isoquinolyl group, naphthyridyl group, benzimidazolyl group, quinoxalyl group, quinazolyl group, etc. However, a phenyl group, a naphthyl group and a biphenylyl group are preferable, and a phenyl group is most preferable.
[0011]
The substituent that these groups may have is not particularly limited as long as it is an inactive group in the reaction step of production, but a fluorine atom, a chlorine atom, an alkyl group, an aralkyl group, an alkoxyl group, or Alkyl groups, aralkyl groups and alkoxyl groups substituted with one or more fluorine atoms are preferred.
[0012]
Especially as Ar, the general formula (IV)
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More preferably, it is a group represented by
[0013]
In the general formula (IV), X ¹ , X ² and X ³ each independently represent a hydrogen atom or a fluorine atom, and (X ¹ , X ² , X ³ ) are (H, H, H), (F, H, H), (F, F, H) or combinations of (F, H, F) are preferred.
[0014]
Y represents a hydrogen atom, a fluorine atom, a chlorine atom, R or OR. Here, R represents an alkyl group having 1 to 10 carbon atoms which may be linear, branched or cyclic, but is an alkoxyl group having 1 to 7 carbon atoms or 1 to 5 fluorine atoms. May be substituted. Y is preferably a hydrogen atom, a fluorine atom, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, a methoxy group, an ethoxy group, a methyl group or an ethyl group.
[0015]
In the production method of the present invention, the compound of the general formula (I) is represented by the general formula (III)
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It can obtain by including the process of oxidizing the cyclohexanol derivative represented by these. Here, in the general formula (III), V and Ar represent the same meaning as in the general formula (I).
[0016]
In this oxidation step, the oxidizing agent is not particularly limited as long as it can oxidize a secondary alcohol to a ketone, but a halogen-based oxidizing agent or a chromic acid-based oxidizing agent is preferable, and in particular, halogens such as chlorine and bromine, Hypohalous acid such as chlorous acid and hypobromous acid, sodium hypochlorite, sodium hypobromite, hypohalite such as bleaching powder, N-chlorosuccinimide, N-bromosuccinimide, N-halocarboxylic amides such as N-bromoacetamide and N-chloroisocyanuric acid are preferred, and hypochlorites such as sodium hypochlorite and bleached powder are most preferred.
[0017]
The compound of the general formula (I) obtained by oxidation of (III) may be able to be used for a desired purpose without going through further purification steps. Ordinarily, such as recrystallization, distillation, column chromatography, etc. In some cases, it is used after being purified by the purification means.
[0018]
In the general formula (I), the 1,4-position of the cyclohexylene group is preferably in the trans configuration, but it is obtained when the production steps up to (I) do not include the isomerization step into the trans isomer. (I) is usually a mixture of cis and trans isomers. In that case, it is preferable that the obtained (I) is once acetalized, isomerized to a trans isomer in the presence of a strong base or a Lewis acid catalyst, and then deacetalized. The strong base is preferably t-butoxy potassium in an aprotic polar solvent such as N, N-dimethylformamide (DMF), and the Lewis acid is preferably aluminum chloride, but usually t-butoxy potassium is most preferred.
[0019]
In the present invention, the general formula (II) is used as a raw material.
Embedded image

It is characterized by using the hydroxyketone represented by these. In general formula (II), V represents the same meaning as in general formula (I). Here, the compound of (II) is represented by the general formula (VII)
[0020]
Embedded image

Can be easily obtained by catalytic reduction, for example, by the method described in JP-A No. 12-159718. Here, in the general formula (VII), V ′ represents a hydrogen atom or an alkylene group having 1 to 4 carbon atoms, an alkenylene group or an alkynylene group. )
There are several routes for producing the cyclohexanol derivative of the general formula (III) from the hydroxyketone of the general formula (II), but the route shown below is preferable.
[0021]
That is, by protecting the hydroxyl group of the hydroxyketone of (II), the general formula (V)
Embedded image

The hydroxyketone in which the hydroxyl group represented by these is protected is obtained. Here, in the general formula (V), V represents the same meaning as in the general formula (I). Z represents a hydroxyl-protecting group, preferably a methyl group, a benzyl group, a tetrahydropyranyl group, a tetrahydrofuryl group, a methoxymethyl group or an ethoxymethyl group, and the methyl group or benzyl group is stable under acidic conditions or basic conditions. Therefore, it is particularly preferable. These protecting groups may be deprotected in each step of production, but in that case, they may be protected again if necessary.
[0022]
A cyclohexanol derivative can be obtained by reacting the hydroxyketone protected with a hydroxyl group with an organometallic reagent represented by the general formula Ar-M (VI). Here, M represents a metal atom or a group containing a metal atom, and is not particularly limited as long as nucleophilic addition is performed on a carbonyl group, but MgBr, MgI, MgCl or Li is particularly preferable. According to the above definition of Ar, a more preferable form as (VI) is represented by the general formula (VI ′)
Embedded image

Can be expressed as In general formula (VI ′), M represents the same as in general formula (VI), and X ¹ , X ² , X ³ and Y represent the same meaning as in general formula (IV).
[0023]
By dehydrating the obtained cyclohexanol derivative, the general formula (VIII)
Embedded image

Can be obtained. Here, Z, V and Ar represent the aforementioned meanings. Dehydration is performed by treatment with a base in the presence of an acid catalyst, or after chlorination, bromination or sulfonate esterification. As the acid catalyst, for example, sulfuric acid, potassium hydrogen sulfate, p-toluenesulfonic acid, formic acid and the like are preferable. As the chlorinating agent, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride and the like are preferable. As the brominating agent, for example, tribromide. Phosphorus is preferable, and as the sulfonic acid esterifying agent, P-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride and the like are preferable.
[0024]
By catalytic reduction of the cyclohexene derivative of (VIII), the general formula (IX)
Embedded image

Can be obtained. Here, Z, V and Ar represent the aforementioned meanings.
[0025]
The reduction is performed in a hydrogen atmosphere and in the presence of a transition metal catalyst.
[0026]
The hydrogen pressure is not particularly limited as long as it is near normal pressure, but is preferably 0.1 MPa to 4 MPa, more preferably 0.1 MPa to 1 MPa, and further preferably 0.1 MPa to 0.4 MPa.
[0027]
The transition metal catalyst is not particularly limited as long as it is used for ordinary catalytic reduction, but metal supported on carbon such as palladium / carbon, platinum / carbon, ruthenium / carbon, or Raney metal such as Raney nickel, etc. Is preferred.
[0028]
When a benzyl group is used as the protecting group Z, it may be deprotected in this step. In this case, it is preferable to protect the hydroxyl group again if necessary.
[0029]
The 1,4-position of the obtained (IX) cyclohexylene group is usually a mixture of cis and trans isomers. In the target general formula (I), the 1,4-position of the cyclohexylene group is preferably a trans isomer. For this purpose, it is preferable to isomerize the cis isomer to the trans isomer after this step.
[0030]
Isomerization is carried out in the presence of a strong base or Lewis acid catalyst. The strong base is preferably t-butoxy potassium in an aprotic polar solvent such as N, N-dimethylformamide (DMF), and the Lewis acid is preferably aluminum chloride, but the protective group is a tetrahydropyranyl group, tetrahydrofuryl. When a group, methoxymethyl group or ethoxymethyl group is used, a base catalyst, usually t-butoxy potassium, is most preferred.
[0031]
A cyclohexanol derivative of the general formula (III) can be obtained by deprotecting the compound of the general formula (IX).
[0032]
Deprotection is carried out by treating with an acid in the presence of a protic solvent when the protecting group is a tetrahydropyranyl group, a tetrahydrofuryl group, a methoxymethyl group or an ethoxymethyl group, and in the case of a methyl group, boron tribromide, It can be demethylated by using Lewis acid with aluminum chloride, sulfides such as trimethylsilyl iodide, dimethyl sulfide, or a combination thereof. In the case of a benzyl group, deprotection is possible by catalytic reduction.
[0033]
As described above, the 4-substituted cyclohexanone derivative represented by the general formula (I) can be produced from the hydroxyketone represented by the general formula (II).
[0034]
The obtained compound (I) is useful as an electronic material such as a liquid crystal display material, a functional material, a medical pesticide, a fragrance, various additives, and synthetic intermediates thereof. Among the compounds, it is preferable as a method for producing the compounds represented by the following (Ia-1) to (Ib-21).
[0035]
Embedded image

[0036]
Embedded image

【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.
[0037]
Example 1 Production of trans-4 ′-(4-methylphenyl) bicyclohexane-4-one (Ia-16)
1-a) 4′-hydroxybicyclohexane-4-one (This compound can be produced from biphenol by a method according to JP-A-12-159718 and is a mixture of cis and trans isomers) 19.6 g of 50 mL tetrahydrofuran The (THF) solution was added dropwise to 5.0 g of sodium hydride (50%) suspended in 200 mL of THF. After stirring for 1 hour at room temperature, a solution of 15 g of methyl iodide in 30 mL of THF was added dropwise over 30 minutes. After stirring for 3 hours, excess sodium hydride was decomposed by adding water, acidified with hydrochloric acid and extracted with toluene. After washing with water, the solvent was distilled off to obtain 18 g of 4′-methoxybicyclohexane-4-one.
1-b) The above-mentioned 4′-methoxybicyclohexane-4-one THT solution was added dropwise at room temperature to a Grignard reactant solution prepared from 17.1 g of p-bromotoluene and 2.4 g of magnesium. After stirring at room temperature for 3 hours, water and then hydrochloric acid were added to stop the reaction, and the mixture was extracted with toluene. After washing with water and saturated saline, it was dehydrated and dried over anhydrous sodium sulfate.
1-c) After filtration, the solution was concentrated under reduced pressure until toluene was about 50 mL, and 0.5 g of p-toluenesulfonic acid monohydrate was added thereto, and the mixture was heated to reflux for 4 hours while removing the distilled water. . The mixture was cooled to room temperature, washed with aqueous sodium bicarbonate and then with water, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 19.8 g of 1- (4-methylphenyl) -4- (4-methoxycyclohexyl) cyclohex-1-ene.
1-d) This whole amount was dissolved in 100 mL of ethanol and subjected to catalytic reduction (hydrogen pressure 0.4 MPa) for 4 hours at room temperature in an autoclave with 1.0 g of 5% palladium / carbon. After the catalyst was filtered off, the solvent was distilled off under reduced pressure to obtain 19.0 g of 4- (4-methylphenyl) -4′-methoxybicyclohexane.
1-e) This whole amount was dissolved in 200 mL of DMF, 5.6 g of t-butoxypotassium was added, and the mixture was heated with stirring at 80 ° C. for 2 hours. After allowing to cool, water was added, neutralized with aqueous hydrochloric acid, and extracted with hexane. The hexane phase was washed with water and then dehydrated and dried over anhydrous sodium sulfate. After filtration, the crude product obtained by distilling off the solvent under reduced pressure was recrystallized from ethanol to obtain 14.5 g of trans-4- (4-methylphenyl) -4′-methoxybicyclohexane as white crystals. .
1-f) The whole amount was dissolved in 100 mL of dichloromethane, and 15 g of trimethylsilane iodide was added under water cooling, and the mixture was returned to room temperature and stirred for 8 hours. Water was added, extraction was performed with toluene, and the solvent was distilled off under reduced pressure to obtain 12.0 g of trans-4- (4-methylphenyl) -4′-hydroxybicyclohexane.
1-g) The whole amount was dissolved in 50 mL of dichloromethane, 50 mL of acetic acid was added, and 100 mL of an 8% aqueous sodium hypochlorite solution (antiformin) was added dropwise thereto while stirring vigorously. After stirring for 4 hours, an aqueous sodium hydrogen sulfite solution was added to decompose excess oxidant, water was added, and the mixture was extracted with toluene. After washing with water and saturated brine, the crude product obtained by concentrating the solvent was recrystallized from ethanol to give the title trans-4 ′-(4-methylphenyl) bicyclohexane-4-one (Ia- 8.5 g of white crystals of 16) were obtained.
[0038]
(Comparative Example 1) Production of the indicated trans-4 '-(4-methylphenyl) bicyclohexane-4-one (Ia-16) using bicyclohexane-4,4'-dione monoethylene acetal as a raw material
Bicyclohexane-4,4′-dione monoethylene acetal (12.0 g) was added dropwise to the Grignard reactant prepared from 16.3 g of p-bromotoluene to react to obtain 16.7 g of a cyclohexanol derivative. This was dissolved in toluene, 0.5 g of sodium hydrogensulfate was added and the mixture was heated to reflux while removing azeotropic water, and 4- (4-methylphenyl) bicyclohex-3-ene-4'-one ethylene acetal 12.0 g was obtained. This total amount was dissolved in ethyl acetate, 0.6 g of Raney nickel was added, and catalytic reduction was carried out at a hydrogen pressure of 0.5 MPa in an autoclave to obtain 11.5 g of 4- (4-methylphenyl) bicyclohexane-4′-one ethylene acetal. The whole amount was dissolved in DMF, 2.2 g of potassium t-butoxy was added, and the mixture was heated to reflux at 100 ° C. for 4 hours. Water and then hydrochloric acid were added to neutralize, extracted with toluene, the solvent was concentrated, and the resulting residue was recrystallized from ethanol to obtain trans-4- (4-methylphenyl) bicyclohexane-4'-one ethylene Acetal 8.5 g was obtained. The whole amount was dissolved in toluene, acetic acid and dilute sulfuric acid were added, and the mixture was heated and stirred for 5 hours. After neutralization with water, extraction with toluene, the resulting crude product was recrystallized from ethanol to give the trans-4 '-(4-methylphenyl) bicyclohexane-4-one (Ia-16) 6.4 g of white crystals were obtained.
[0039]
Therefore, even when used as a raw material, the desired trans-4 ′-(4-methylphenyl) bicyclohexane-4-one can be obtained in the same manner as in Example 1, but bicyclohexane-4,4′-dione mono It is clear that ethylene acetal is much more expensive than 4'-hydroxybicyclohexane-4-one and that Example 1 is cost effective.
[0040]
(Example 2) Production of trans-4 '-(3,4-difluorophenyl) bicyclohexane-4-one (Ia-16) In Example 1-b), p-bromobenzene was replaced with 3,4- In the same manner, except that difluorobromobenzene was used, 1-d) was replaced with palladium / carbon as a reduction catalyst, highly active Raney nickel was used, and isomerization in 1-e) was performed at room temperature. White crystals of the indicated trans-4 ′-(3,4-difluorophenyl) bicyclohexane-4-one (Ia-16) were obtained.
[0041]
(Example 3) Production of trans-4 '-(3,4-difluorophenyl) bicyclohexane-4-one (Ia-16) In Example 1-f), instead of trimethylsilane iodide, Trans-4 '-(4-methylphenyl) bicyclohexane-4 was prepared in the same manner as in Example 1 except that trans-4- (4-methylphenyl) -4'-hydroxybicyclohexane was prepared using sodium iodide. -Obtained ON (Ia-16).
[0042]
(Example 4) Production of trans-4 '-(3,5-difluoro-4-methoxyphenyl) bicyclohexane-4-one (Ia-12) In Example 1-a), chloride was replaced with methyl iodide. Example 1 except that benzyl was used, the hydrogen pressure of catalytic reduction in 1-d) was 0.1 MPa, and the deprotection step of 1-f) was carried out by catalytic reduction at a hydrogen pressure of 0.5 MPa and 50 ° C. A white crystal of trans-4 ′-(3,5-difluoro-4-methoxyphenyl) bicyclohexane-4-one (Ia-12) was obtained.
[0043]
【The invention's effect】
The present invention provides a method using a low-cost and easily available hydroxyketone as a raw material instead of a monoacetal of an expensive diketone compound as a raw material in the production of a 4-substituted cyclohexanone derivative having an arylcyclohexyl group. A cheaper production of a 4-substituted cyclohexanone derivative having an arylcyclohexyl group was made possible. The resulting 4-substituted cyclohexanone derivative having an arylcyclohexyl group is extremely useful as an electronic material such as a liquid crystal display material, a functional material, a medical pesticide, a fragrance, various additives, and synthetic intermediates thereof.

Claims (7)

Formula (I)

(In the formula, V represents a single bond or an alkylene group having 1 to 4 carbon atoms, Ar represents a general formula (VI)

Represents. Is a method for producing a 4-substituted cyclohexanone derivative represented by the general formula (II)

(In the formula, V represents the same meaning as in general formula (I).) After protecting the hydroxyl group of the hydroxyketone represented by general formula (V),

(Wherein V represents the same meaning as in general formula (I), and Z represents a methyl group, a benzyl group, a tetrahydropyranyl group, a tetrahydrofuryl group, a methoxymethyl group or an ethoxymethyl group). Hydroxy groups with protected hydroxy groups are represented by the general formula (VI ')

(In the formula, M represents a metal atom or a group containing a metal atom of MgBr, MgI, MgCl, Li, X ¹ , X ² and X ³ each independently represent a hydrogen atom or a fluorine atom, and Y represents a hydrogen atom. Represents a fluorine atom, a chlorine atom, R or OR, and R represents a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, and 1 to 7 carbon atoms. And the resulting cyclohexanol derivative is dehydrated, and the resulting cyclohexene derivative is hydrogenated. And general formula (III) obtained by deprotecting the hydroxyl group

(In the formula, V and Ar have the same meaning as in the general formula (I).) A production method for oxidizing the cyclohexanol derivative represented by 2. The production method according to claim 1 , wherein in the general formula (I), the 1,4-position of the cyclohexylene group is in a trans configuration. 3. The production method according to claim 1 , wherein halogen, hypohalous acid, hypohalite, or N-halocarboxylic amide is used as the oxidizing agent. The production method according to any one of claims 1 to 3, wherein the hydroxyl group is protected again after dehydration of the cyclohexanol derivative. 5. The production method according to claim 1, wherein the cyclohexene derivative is hydrogenated to isomerize the cyclohexylene group. 6. The production method according to claim 1 , wherein V represents a single bond in the general formula (I). Any one of claims 1 to 6 , wherein in the general formula (IV), Y represents a hydrogen atom, a fluorine atom, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, a methoxy group, an ethoxy group, a methyl group, or an ethyl group. The manufacturing method of crab.