JP4541143B2

JP4541143B2 - Method for producing quinoline derivative

Info

Publication number: JP4541143B2
Application number: JP2004521196A
Authority: JP
Inventors: 俊雄西塚; 寛栗原; 一美山本
Original assignee: Meiji Seika Kaisha Ltd
Current assignee: Meiji Seika Kaisha Ltd
Priority date: 2002-07-11
Filing date: 2003-07-11
Publication date: 2010-09-08
Anticipated expiration: 2023-07-11
Also published as: TWI320782B; TW200401767A; CN1668597A; JPWO2004007460A1; WO2004007460A1; CN1307160C; AU2003280976A1

Description

［発明の背景］
発明の分野
本発明は、農薬として有用な２，３，６−トリアルキル−８−フルオロ−４−キノリン誘導体または薬学的に許容されるその塩の製造法に関する。[Background of the invention]
The present invention relates to a process for the preparation of 2,3,6-trialkyl-8-fluoro-4-quinoline derivatives or pharmaceutically acceptable salts thereof useful as agricultural chemicals.

２，３，６−トリアルキル−８−フルオロ−４−キノリン誘導体は、ＷＯ０１／９２２３１号公報に記載されるように農園芸用病害に対する防除活性を有する化合物である。この化合物の製造法として、同国際公開公報には、次の反応式にしたがった方法が開示されている。

上記方法では、出発原料のｔ−ブチルアニリンのアミノ基を適当な保護基で保護した後、フッ素化試剤であるセレクトフルオロ（１−（Ｃｈｌｏｒｏｍｅｔｈｙｌ）−４−ｆｌｕｏｒｏ−１，４−ｄｉａｚｏｎｉａｂｉｃｙｃｌｏ［２．２．２］ｏｃｔａｎｅｂｉｓ（ｔｅｔｒａｆｌｕｏｒｏｂｏｒａｔｅ））を反応させアミノ基の隣接位置にフッ素原子を導入する。保護基を脱保護して中間体である４−ｔ−ブチル−２−フルオロアニリンを得て、次いでこれを２−メチルアセト酢酸エチルとのエナミン化、続く加熱による環化反応によりキノリノール体を得て、最後にキノリノール体の水酸基のアセチル化により目的とする化合物を得る。この方法におけるエナミン化−環化工程はＣｏｎｒａｄ−Ｌｉｍｐａｃｈ合成として知られている。しかしながら、この製造法は、６段階の工程を必要とするため製造工程が煩雑になる上、Ｃｏｎｒａｄ−Ｌｉｍｐａｃｈ合成収率が低く、全収率は４％程度と低い。また、この方法では、セレクトフルオロなどに代表される高価なフッ素化試剤を使用しなければならず、これは刺激性が強くかつ腐食性があることから、工業的な製造法としては経済的にも効率的にも望ましいものではない。
芳香環の目的の位置に選択的にフッ素原子を導入できる汎用性のある工業的製造法は少なく、芳香族アミノ基のジアゾ化、フッ化ホウ素ナトリウム塩との脱ジアゾフッ素化を行うＢａｌｚ−Ｓｃｈｉｅｍａｎｎ反応が知られている。しかし、これら方法にあっては、不安定で毒性の高い芳香族テトラフルオロボラート塩を経由することから、工業的には問題点が多い。ＷＯ０１／９２２３１号公報に開示されている４−アルキルアニリンの２位フルオロ化には、一般的に刺激性が強くかつ腐食性のあるセレクトフルオロに代表されるフッ素化試剤を用いる必要がある。これを大量に使用する場合には、金属またはガラスの反応器表面を腐食するため、特殊な反応装置が必要であり、工業的な取り扱いが難しいといえる。
従って、フッ素化試剤を使うことなく２，３，６−トリアルキル−８−フルオロ−４−キノリン誘導体を効率的に製造する方法の開発が望まされているといえる。
［発明の概要］
本発明らは、今般、既にフッ素が導入された安価な２−フルオロアニリンを出発原料とし、基本的に二工程からなる、安全かつ高収率で２，３，６−トリアルキル−８−フルオロ−４−キノリン誘導体を得ることができる製造方法を確立した。
従って、本発明は、２，３，６−トリアルキル−８−フルオロ−４−キノリン誘導体を収率よくかつ安全に得ることができる製造方法の提供をその目的としている。
そして、本発明による２，３，６−トリアルキル−８−フルオロ−４−キノリン誘導体の製造方法は、下記の（ｉ）および（ｉｉ）を少なくとも含んでなる、下式（Ｉ）で表される化合物またはその塩の製造法である：

［式中、
Ｒ^１は、置換基を有してもよいＣ_１〜１０アルキル基、またはＣ_３〜６シクロアルキル基を表し、
Ｒ^２は、置換基を有してもよいＣ_１〜１０アルキル基、またはＣ_３〜６シクロアルキル基を表し、
Ｒ^３は、置換基を有してもよいＣ_１〜１０アルキル基、Ｃ_２〜６アルケニル基、フェニルＣ_１〜６アルキル基、またはＣ_３〜６シクロアルキル基を表し、
Ｒ^４は水素原子または水酸基の保護基を表す。］
工程（ｉ）：式（ＩＩ）：

で表される化合物を、塩化亜鉛の存在下、加圧条件で、Ｒ^１−Ｘ（ここで、Ｒ^１は前記と同義であり、Ｘは水酸基またはハロゲン電子を表す）またはＲ^１′（ここでＲ^１′はＲ^１と同一炭素数のオレフィンを表す）によってアルキル化して式（ＩＩＩ）：

［式中、Ｒ_１は前記と同義である。］
で表される４−アルキル−２−フルオロアニリン誘導体を得る工程。
工程（ｉｉ）：式（ＩＩＩ）で表される化合物を式（ＩＶ）：

［式中、Ｒ^２およびＲ^３は前記と同義であり、Ｒ^５はＣ_１−４アルキル基を表す。］
で表されるα−アルキル−β−ケトエステルと反応させて式（Ｖ）：

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^５は前記と同様の意味を表す。］
で表されるエナミン中間体を生成させ、これを環化反応に付して式（Ｉ）で表される化合物（但し、Ｒ^４が水素原子である）を得て、さらに必要により４位の水酸基を保護基で保護する工程。
［発明の具体的説明］
定義
本発明細書において、基または基の一部としてのアルキル部は、直鎖であっても分岐鎖であってもよい。また、ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を表す。
式（Ｉ）の化合物
本発明による製造法の目的物は、上記式（Ｉ）で表される２，３，６−トリアルキル−８−フルオロ−４−キノリン誘導体である。この式（Ｉ）において、Ｒ^１およびＲ^２は独立して、Ｃ_１〜１０アルキル基（好ましくはＣ_１〜６アルキル基）、またはＣ_３−６シクロアルキル基を表す。このアルキル基は一または二以上の置換基で置換されていてもよく、置換基としては、ハロゲン原子、水酸基、およびＣ_１−４アルコキシ基が挙げられる。
また、式（Ｉ）において、Ｒ^３は、Ｃ_１−１０アルキル基（好ましくはＣ_１−６アルキル基）、Ｃ_２−６アルケニル基、フェニルＣ_１−６アルキル基、またはＣ_３−Ｃ_６シクロアルキル基を表す。上記Ｃ_１−１０アルキル基は置換されていてもよく、置換基の好ましい例としては、Ｒ^１およびＲ^２について上述したものが挙げられる。
また、式（Ｉ）で表される化合物は塩とされてもよく、その例としてはアルカリ金属塩、アルカリ土類金属塩、塩酸塩、硫酸塩、クエン酸塩、シュウ酸塩、パラトルエンスルホン酸塩、メタンスルホン酸塩などが挙げられる。
式（Ｉ）の化合物の製造
工程（ｉ）
本発明における工程（ｉ）はアルキル化反応であり、これは特開昭５８−９４４号公報の記載に準じて行うことができる。すなわち、式（ＩＩ）のフルオロアニリン塩酸塩とアルキル化剤とを、酸性触媒の存在下、好ましくは圧力容器を用いて、加圧加熱反応を行い、フリーデル−クラフト型の反応を生じさせる。
アルキル化剤は、Ｒ^１−Ｘ（ここで、Ｒ^１は式（Ｉ）で定義したものと同義であり、Ｘは水酸基またはハロゲン原子を表す）であるか、またはＲ^１と同一炭素数のオレフィンである。Ｒ^１−Ｘ（Ｘ＝ＯＨ）の場合、第二アルコールまたは第三アルコールの利用が好ましい。アルキル化剤の量は適宜決定されてよいが、式（ＩＩ）の化合物に対して１〜１０当量程度が好ましく、より好ましくは１〜５当量程度である。
フリーデル−クラフト反応の触媒として、塩酸、硫酸などに代表されるプロトン酸と、塩化亜鉛に代表されるルイス酸とを共触媒に用いて反応するのが好ましい。塩化亜鉛の利用がより好ましい。その量は適宜決定されてよいが、０．２５〜０．５当量の範囲が好ましい。
反応温度は１５０℃以上の温度が効率的な反応の進行に好ましく、１５０℃〜２００℃の温度範囲がより好ましい。
本発明の方法にあっては加圧によりアルキル化反応速度を大きくし、芳香環４位へのアルキル化の位置選択性を高める。実用的な圧力は３気圧以上であるが、４気圧〜１０気圧の範囲がより好ましい。
工程（ｉ）は、通常無溶媒で行うことが出来るが、二硫化炭素、ニトロベンジルなどの不活性な溶媒中で行うことも出来る。反応容器としては、耐圧製のガラス容器ないしステンレス容器を用いることが好ましいが、ステンレス容器の場合酸性雰囲気下で金属表面が腐食するので、ガラス容器を内封したステンレス容器ないしはタンタル張りのステンレス容器の使用が望ましい。
以上の工程（ｉ）の反応により式（ＩＩＩ）の化合物を得る。式（ＩＩＩ）の化合物の精製は、生成物と出発物質の脂溶性の違いを利用して、ヘキサンや酢酸エチルなどの適当な有機溶媒抽出にて生成物より水溶性の高い出発物質だけを選択的に水層に残したまま有機溶媒抽出することができる。また、蒸留操作によっても単離、精製することができる。
上記工程（ｉ）に続く、本発明における工程（ｉｉ）は、エナミン化工程とこれに続いて環化工程を行うものである。本発明にあっては、エナミン化工程と環化工程をワンポットで行うこともでき、また、エナミン化の後、後処理をしてエナミン体（Ｖ）を一旦取り出した後、環化反応を行い本工程を完結することもできる。
式（Ｖ）で表される化合物は互変異性体であり、下記の式（Ｖ′）で表される化合物としても存在しうることは当然である。

［式中Ｒ^１、Ｒ^２、Ｒ^３およびＲ^５は前記と同義である。］
工程（ｉｉ）
工程（ｉｉ）では、まず、式（ＩＩＩ）の化合物と式（ＩＶ）の化合物とを反応させるエナミン化工程を行う。式（ＩＶ）で表される化合物の構造はＲ^２およびＲ^３が式（Ｉ）の化合物に対応するものであることから、目的物たる式（Ｉ）の化合物の構造を勘案して適宜決定されてよい。また、Ｒ^５はＣ_１−４アルキル基を表すが、メチルまたはエチルが好ましい。式（ＩＶ）の化合物の好ましい具体例としては、２−メチルアセト酢酸メチル、２−メチルアセト酢酸エチル、２−ベンジルアセト酢酸エチル、２−エチルアセト酢酸エチル、２−イソプロピルアセト酢酸エチル、２−アリルアセト酢酸エチルが挙げられる。式（ＩＶ）で表されるα−アルキル−β−ケトエステルの量は反応条件等を勘案して適宜決定されてよいが、０．８〜２．０当量程度が好ましく、より好ましくは、１．０〜１．５当量程度であり、最も好ましくは１．２〜１．３当量程度である。
反応は、酸性触媒または塩基性触媒の存在下行うことが好ましく、酸性触媒の利用がより好ましい。酸性触媒としては、酢酸、トリフルオロ酢酸、パラトルエンスルホン酸などのプロトン酸、三フッ化ホウ素ジエチルエーテル錯体などのルイス酸が挙げられ、塩基性触媒としてはピペリジンが挙げられる。ピペリジン使用の場合にはエタノール溶媒の使用が望ましいが、反応時間は酸性触媒の時に比較して一般に長くなる傾向がある。
このエナミン化は無溶媒でも行うことが出来るが、通常はトルエン、キシレン、エタノールなどの水と共沸混合物を作る不活性溶媒中で行う。１００℃〜１４０℃に加熱して、共沸作用により生成した水を効率的に除き反応を促進させることが好ましい。また、生成する水を経時的に効率良く取り除く為に、ディーンスタークトラップ装置、モレキュラーシーブスなどの適当な脱水剤を反応装置に組み込み、水を効率的に排除するよう反応容器を工夫することが好ましい。
反応はトルエンを溶媒に用いた場合、還流条件下、２時間〜５時間撹拌しながら行う。反応の進行は、原料の４−アルキル−２−フルオロアニリン誘導体の残存率を例えば高速液体クロマトグラフィーなどにより監視することにより、知ることができる。この反応は平衡反応のため、完全に原料が消失することは無く、４−アルキル−２−フルオロアニリン誘導体の減少がほぼ止まったときには反応を停止するのが好ましい。さらに時間を延長しても、生成した式（Ｖ）のエナミン体の再分解など好ましくない反応が起こり収率の低下を招く場合があるからである。
なお、得られたエナミン化合物は不安定であり、シリカゲル中で速やかに分解するためシリカゲルクロマトグラフィーでは単離することが難しい。あえて精製、単離するときには蒸留により単離するのが好ましい。通常は単離することなく、次の環化反応に用いてよい。
本発明において留意することが好ましい事項として、原料の４−アルキル−２−フルオロアニリンが残存していると環化反応において、生成する後記式（Ｉ）（但し、Ｒ^４＝Ｈ）の互変異性体である式（ＶＩ）で表されるキノリノール体の４位ケトン部位と、４−アルキル−２−フルオロアニリンのアミノ基が反応して副成物を生じ、収率を大きく低下させるおそれがあることが挙げられる。そこで、本発明の好ましい態様によれば、エナミン化反応が終了した後、反応液の液性を、ピペリジンやトリエチルアミンなどの塩基を加えて塩基性とし安定化させた後、無水酢酸や塩化アセチルなどのアセチル化剤を加えて残存する４−アルキル−２−フルオロアニリンのアミノ基のアセチル化を行い、アミノ基の求核性を抑えて、副成物の生成を抑える。アミノ基の保護はアセチル基に限られたものではなく、一般的に用いられるピバロイル基などのアミド型保護基、ベンジルオキシカルボニル基、ｔ−ブトキシカルボニル基などのカーバメイト型保護基にて保護することもできる。
工程（ｉｉ）において、続いて行われる式（Ｖ）の化合物の環化反応は、加熱により行われる。反応は、適当な溶媒中で加熱しながら、好ましくは溶媒の還流温度で実施されてよい。溶媒の好ましい例としては、ジフェニルエーテル、キシレン、ポリリン酸、ジュレン、ビフェニル、ジメチルホルムアミド、ジメチルスルホキシド等が挙げられる。
本発明の好ましい態様によれば、前記のエナミン反応に続いて環化反応をワンポットで行う場合、エナミン反応液にジフェニルエーテルを加え、トルエンを留去しながらジフェニルエーテルの沸点の２５０℃まで加熱し反応させる。この反応は、エナミンのα，β−不飽和カルボニル部分であるジエノフィルと、ベンゼン核とが分子内で熱による多中心反応を起こしたものと見ることができ、これは一般にＣｏｎｒａｄ−Ｌｉｍｐａｃｈのキノリノール合成と称せられる反応である。この反応はキシレン溶媒で１４０℃〜還流条件においても行うこともできる。また、ＷＯ００／４７５７７号公報の記載に準じてポリリン酸を溶媒にして１６０℃に加熱すると、一気にエナミン化−環化反応が起こり、式（Ｉ）（但し、Ｒ^４＝Ｈ）のキノリノール体を得ることもできる。
式（Ｉ）（但し、Ｒ^４＝Ｈ）の化合物は互変異性体であり、下記の式（ＶＩ）としても存在しうる。

［式中、Ｒ^１、Ｒ^２、およびＲ^３は前記と同様の意味を表す。］
環化反応は、エナミン反応混合物と溶媒とを混合した後、反応系を加熱してもよく、また沸騰した溶媒の中にトルエンを留去したエナミン反応混合物を滴下してもよい。反応の進行は速やかに進み、反応液の温度が２４５℃〜２５０℃に達したとき反応は完了する。反応温度を室温に戻し通常１２時間程度ゆっくり撹拌しながら結晶化操作を行うと、ほぼ単一の式（Ｉ）の化合物（但し、Ｒ^４＝Ｈ）を得ることが出来る。
本発明にあっては、得られた式（Ｉ）の化合物（但し、Ｒ^４＝Ｈ）を、必要に応じて常法により４位水酸基において保護する。水酸基の保護基は特に限定されないが、好ましい具体例としては、Ｃ_１〜６アルキル基、Ｃ_１〜６アルキルカルボニル基、Ｃ_１〜６アルキルオキシカルボニル基、Ｃ_１〜６アルキルオキシＣ_１〜６アルキルカルボニル基、Ｃ_１〜６アルキルカルボニルオキシＣ_１〜６アルキルカルボニル基、Ｃ_３〜６シクロアルキルカルボニル基、またはＣ_３〜６シクロアルキルオキシカルボニル基が挙げられる。その導入はその保護基に慣用されている方法により行われてよい。例えば保護基がアセチル基である場合、反応はピリジンに溶解した基（Ｉ）の化合物（但し、Ｒ^４＝Ｈ）と適量の無水酢酸または塩化アセチルを加え、８０℃で１時間反応することでほぼ定量的に目的の２，３，６−トリアルキル−８−フルオロ−４−アセトキシキノリン誘導体を得ることができる。
式（Ｉ）の化合物は、反応終了後、溶剤を濃縮し、ｎ−ヘキサンから再結品することにより純粋な結晶として得ることができる。また、炭酸エステル保護型にするためには、式（Ｉ）の化合物（但し、Ｒ^４＝Ｈ）の４位水酸基を、水素化ナトリウムなどの適当な塩基にてプロトンを引き抜き、次いでクロロギ酸エチルに代表される炭酸エステル化試剤と反応させる。また、アルキルエーテル保護型にするためには、炭酸カリウムなどの塩基とともにヨウ化メチルに代表されるアルキル化剤を反応させればよい。A 2,3,6-trialkyl-8-fluoro-4-quinoline derivative is a compound having a controlling activity against agricultural and horticultural diseases as described in WO01 / 92231. As a method for producing this compound, the International Publication discloses a method according to the following reaction formula.

In the above method, the amino group of the starting t-butylaniline is protected with a suitable protecting group, and then a fluorination reagent, selectfluoro (1- (Chloromethyl) -4-fluoro-1,4-diazoniabiccyclo [2. 2.2] octane bis (tetrafluoroborate)) is reacted to introduce a fluorine atom adjacent to the amino group. The protecting group is deprotected to obtain 4-t-butyl-2-fluoroaniline as an intermediate, which is then enamined with ethyl 2-methylacetoacetate, followed by a cyclization reaction by heating to obtain a quinolinol compound. Finally, the target compound is obtained by acetylation of the hydroxyl group of the quinolinol body. The enamine-cyclization step in this method is known as Conrad-Limpach synthesis. However, since this production method requires 6 steps, the production process becomes complicated, and the Conrad-Limpach synthesis yield is low, and the overall yield is as low as about 4%. In addition, this method requires the use of an expensive fluorination reagent typified by select fluoro and the like, which is highly irritating and corrosive. Neither is efficient nor desirable.
There are few versatile industrial production methods that can selectively introduce a fluorine atom at a desired position of an aromatic ring, and Balz-Schiemann performs diazotization of an aromatic amino group and dediazofluorination with a sodium boron fluoride salt. The reaction is known. However, these methods are industrially problematic because they pass through an unstable and highly toxic aromatic tetrafluoroborate salt. In the 2-position fluorination of 4-alkylaniline disclosed in WO01 / 92231, it is necessary to use a fluorination reagent represented by select fluoro, which is generally highly irritating and corrosive. When this is used in a large amount, a metal or glass reactor surface is corroded, so that a special reaction apparatus is required, and it can be said that industrial handling is difficult.
Therefore, it can be said that development of a method for efficiently producing a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative without using a fluorination reagent is desired.
[Summary of Invention]
In the present invention, a safe, high-yield 2,3,6-trialkyl-8-fluoro is basically produced in two steps, starting from an inexpensive 2-fluoroaniline already introduced with fluorine. The manufacturing method which can obtain a -4- quinoline derivative was established.
Accordingly, an object of the present invention is to provide a production method capable of obtaining a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative with high yield and safety.
A method for producing a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative according to the present invention is represented by the following formula (I) comprising at least the following (i) and (ii): Or a salt thereof:

[Where:
R ¹ represents an optionally substituted C _1-10 alkyl group, or a C _3-6 cycloalkyl group,
R ² represents an optionally substituted C _1-10 alkyl group, or a C _3-6 cycloalkyl group,
R ³ represents an optionally substituted C _1-10 alkyl group, a C _2-6 alkenyl group, a phenyl C _1-6 alkyl group, or a C _3-6 cycloalkyl group,
R ⁴ represents a hydrogen atom or a hydroxyl-protecting group. ]
Step (i): Formula (II):

In the presence of zinc chloride under pressure, R ¹ -X (where R ¹ is as defined above, X represents a hydroxyl group or a halogen electron) or R ¹ ′ (here Wherein R ¹ ′ represents an olefin having the same carbon number as R ¹ ) to give a compound of formula (III):

[Wherein, R ₁ has the same meaning as described above. ]
A step of obtaining a 4-alkyl-2-fluoroaniline derivative represented by:
Step (ii): The compound represented by the formula (III) is converted into the formula (IV):

[Wherein, R ² and R ³ are as defined above, and R ⁵ represents a C _1-4 alkyl group. ]
Is reacted with an α-alkyl-β-ketoester represented by the formula (V):

[Wherein R ¹ , R ² , R ³ and R ⁵ represent the same meaning as described above. ]
An enamine intermediate represented by formula (I) is generated, and this is subjected to a cyclization reaction to obtain a compound represented by the formula (I) (wherein R ⁴ is a hydrogen atom). A step of protecting the hydroxyl group with a protecting group.
[Detailed Description of the Invention]
Definitions In the detailed description of the present invention, an alkyl moiety as a group or a part of the group may be linear or branched. The halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
Compound of Formula (I) The object of the production method according to the present invention is a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative represented by the above formula (I). In this formula (I), R ¹ and R ² independently represent a C _1-10 alkyl group (preferably a C _1-6 alkyl group) or a C _3-6 cycloalkyl group. This alkyl group may be substituted with one or more substituents, and examples of the substituent include a halogen atom, a hydroxyl group, and a C _1-4 alkoxy group.
In Formula (I), R ³ represents a C _1-10 alkyl group (preferably a C _1-6 alkyl group), a C _2-6 alkenyl group, a phenyl C _1-6 alkyl group, or a C ₃ -C _6. Represents a cycloalkyl group. The C _1-10 alkyl group may be substituted, and preferable examples of the substituent include those described above for R ¹ and R ² .
In addition, the compound represented by the formula (I) may be a salt, and examples thereof include alkali metal salts, alkaline earth metal salts, hydrochlorides, sulfates, citrates, oxalates, paratoluene sulfones. Acid salt, methanesulfonate, and the like.
Preparation of compounds of formula (I)
Step (i)
Step (i) in the present invention is an alkylation reaction, which can be carried out according to the description in JP-A-58-944. That is, the fluoroaniline hydrochloride of formula (II) and the alkylating agent are subjected to a pressure heating reaction in the presence of an acidic catalyst, preferably using a pressure vessel, to produce a Friedel-Craft type reaction.
The alkylating agent is R ¹ -X (wherein R ¹ has the same meaning as defined in formula (I), X represents a hydroxyl group or a halogen atom), or has the same carbon number as R ^1. Olefin. In the case of R ¹ —X (X═OH), the use of a secondary alcohol or a tertiary alcohol is preferred. The amount of the alkylating agent may be appropriately determined, but is preferably about 1 to 10 equivalents, more preferably about 1 to 5 equivalents, relative to the compound of formula (II).
As a Friedel-Craft reaction catalyst, it is preferable to use a protonic acid typified by hydrochloric acid or sulfuric acid and a Lewis acid typified by zinc chloride as a cocatalyst. The use of zinc chloride is more preferred. The amount may be appropriately determined, but is preferably in the range of 0.25 to 0.5 equivalent.
A reaction temperature of 150 ° C. or higher is preferable for efficient progress of the reaction, and a temperature range of 150 ° C. to 200 ° C. is more preferable.
In the method of the present invention, the alkylation reaction rate is increased by pressurization to enhance the regioselectivity of alkylation to the 4-position of the aromatic ring. A practical pressure is 3 atm or more, but a range of 4 to 10 atm is more preferable.
Step (i) can usually be carried out in the absence of a solvent, but can also be carried out in an inert solvent such as carbon disulfide or nitrobenzyl. As the reaction container, it is preferable to use a pressure-resistant glass container or a stainless steel container. However, in the case of a stainless steel container, the metal surface corrodes in an acidic atmosphere. Therefore, a stainless steel container enclosing a glass container or a tantalum-clad stainless steel container is used. Use is desirable.
The compound of the formula (III) is obtained by the reaction of the above step (i). For the purification of the compound of formula (III), only the starting material that is more water-soluble than the product is selected by extraction with an appropriate organic solvent such as hexane or ethyl acetate, utilizing the difference in fat solubility between the product and the starting material. Thus, the organic solvent can be extracted while remaining in the aqueous layer. It can also be isolated and purified by distillation.
Step (ii) in the present invention subsequent to the above step (i) is a step of performing an enamine step and a cyclization step subsequent thereto. In the present invention, the enaminerization step and the cyclization step can be carried out in one pot, and after the enaminerization, post-treatment is carried out to take out the enamine body (V) once, and then the cyclization reaction is carried out. This step can also be completed.
The compound represented by the formula (V) is a tautomer and can naturally exist as a compound represented by the following formula (V ′).

[Wherein R ¹ , R ² , R ³ and R ⁵ are as defined above]. ]
Step (ii)
In the step (ii), first, an enamination step of reacting the compound of the formula (III) with the compound of the formula (IV) is performed. Since the structure of the compound represented by the formula (IV) is such that R ² and R ³ correspond to the compound of the formula (I), the structure of the compound of the formula (I) as the target product is determined appropriately. May be. R ⁵ represents a C _1-4 alkyl group, preferably methyl or ethyl. Preferred specific examples of the compound of formula (IV) include methyl 2-methylacetoacetate, ethyl 2-methylacetoacetate, ethyl 2-benzylacetoacetate, ethyl 2-ethylacetoacetate, ethyl 2-isopropylacetoacetate, ethyl 2-allylacetoacetate Is mentioned. The amount of the α-alkyl-β-ketoester represented by the formula (IV) may be appropriately determined in consideration of the reaction conditions and the like, but is preferably about 0.8 to 2.0 equivalents, more preferably 1. It is about 0-1.5 equivalent, Most preferably, it is about 1.2-1.3 equivalent.
The reaction is preferably performed in the presence of an acidic catalyst or a basic catalyst, and the use of an acidic catalyst is more preferable. Examples of the acidic catalyst include proton acids such as acetic acid, trifluoroacetic acid, and paratoluenesulfonic acid, and Lewis acids such as boron trifluoride diethyl ether complex, and examples of the basic catalyst include piperidine. In the case of using piperidine, it is desirable to use an ethanol solvent, but the reaction time generally tends to be longer than when an acidic catalyst is used.
This enamination can be carried out without solvent, but is usually carried out in an inert solvent that forms an azeotrope with water, such as toluene, xylene, and ethanol. It is preferable to heat to 100 ° C. to 140 ° C. to efficiently remove water generated by azeotropic action and promote the reaction. In addition, in order to efficiently remove the generated water over time, it is preferable to devise a reaction vessel so as to efficiently remove water by incorporating an appropriate dehydrating agent such as a Dean-Stark trap device or molecular sieves into the reaction device. .
When toluene is used as a solvent, the reaction is carried out with stirring under reflux conditions for 2 hours to 5 hours. The progress of the reaction can be known by monitoring the residual rate of the starting 4-alkyl-2-fluoroaniline derivative by, for example, high performance liquid chromatography. Since this reaction is an equilibrium reaction, the raw material is not completely lost, and it is preferable to stop the reaction when the decrease of the 4-alkyl-2-fluoroaniline derivative almost stops. This is because even if the time is further extended, an undesired reaction such as re-decomposition of the generated enamine form of formula (V) may occur, leading to a decrease in yield.
In addition, since the obtained enamine compound is unstable and decomposes rapidly in silica gel, it is difficult to isolate by silica gel chromatography. When purifying and isolating, it is preferable to isolate by distillation. Usually, it may be used for the next cyclization reaction without isolation.
In the present invention, it is preferable to note that tautomerism of the following formula (I) (where R ⁴ = H) is generated in the cyclization reaction when the raw material 4-alkyl-2-fluoroaniline remains. The 4-position ketone moiety of the quinolinol compound represented by the formula (VI), which is a natural substance, reacts with the amino group of 4-alkyl-2-fluoroaniline to produce a by-product, which may greatly reduce the yield. There are some. Therefore, according to a preferred embodiment of the present invention, after the enamine reaction is completed, the liquidity of the reaction solution is made basic by adding a base such as piperidine or triethylamine and then stabilized, and then acetic anhydride, acetyl chloride, etc. The acetylating agent is added to acetylate the amino group of the remaining 4-alkyl-2-fluoroaniline to suppress the nucleophilicity of the amino group and suppress the formation of by-products. Protection of amino groups is not limited to acetyl groups, but protection with commonly used amide-type protecting groups such as pivaloyl groups, carbamate-type protecting groups such as benzyloxycarbonyl groups and t-butoxycarbonyl groups You can also.
In step (ii), the subsequent cyclization reaction of the compound of formula (V) is performed by heating. The reaction may be carried out with heating in a suitable solvent, preferably at the reflux temperature of the solvent. Preferable examples of the solvent include diphenyl ether, xylene, polyphosphoric acid, durene, biphenyl, dimethylformamide, dimethyl sulfoxide and the like.
According to a preferred embodiment of the present invention, when the cyclization reaction is carried out in one pot following the enamine reaction, diphenyl ether is added to the enamine reaction solution and heated to 250 ° C., the boiling point of diphenyl ether, while distilling off toluene. . This reaction can be seen as a heat-induced multicenter reaction between dienophile, which is the α, β-unsaturated carbonyl moiety of enamine, and the benzene nucleus, which is generally the synthesis of Conrad-Limpach's quinolinol. It is a reaction called. This reaction can also be performed in a xylene solvent at 140 ° C. to reflux conditions. In addition, when polyphosphoric acid is used as a solvent and heated to 160 ° C. according to the description of WO 00/47577, an enamine-cyclization reaction occurs at once, and a quinolinol compound of the formula (I) (where R ⁴ = H) is obtained. It can also be obtained.
Compounds of formula (I) (where R ⁴ = H) are tautomers and may also exist as formula (VI) below.

[Wherein, R ¹ , R ² , and R ³ represent the same meaning as described above. ]
In the cyclization reaction, after mixing the enamine reaction mixture and the solvent, the reaction system may be heated, or the enamine reaction mixture obtained by distilling off toluene in the boiling solvent may be added dropwise. The reaction proceeds rapidly, and the reaction is completed when the temperature of the reaction solution reaches 245 ° C to 250 ° C. When the crystallization operation is carried out while returning the reaction temperature to room temperature and usually stirring slowly for about 12 hours, almost a single compound of the formula (I) (provided that R ⁴ = H) can be obtained.
In the present invention, the obtained compound of the formula (I) (provided that R ⁴ = H) is protected at the 4-position hydroxyl group by a conventional method, if necessary. Although the hydroxyl-protecting group is not particularly limited, preferred examples thereof include C _1-6 alkyl group, C _1-6 alkylcarbonyl group, C _1-6 alkyloxycarbonyl group, C _1-6 alkyloxy C _1-6. Examples include an alkylcarbonyl group, a C _1-6 alkylcarbonyloxy C _1-6 alkylcarbonyl group, a C _3-6 cycloalkylcarbonyl group, or a C _3-6 cycloalkyloxycarbonyl group. The introduction may be performed by a method conventionally used for the protecting group. For example, when the protecting group is an acetyl group, the reaction is carried out by adding a compound (I) dissolved in pyridine (provided that R ⁴ = H) and an appropriate amount of acetic anhydride or acetyl chloride and reacting at 80 ° C. for 1 hour. The target 2,3,6-trialkyl-8-fluoro-4-acetoxyquinoline derivative can be obtained almost quantitatively.
The compound of formula (I) can be obtained as pure crystals by concentrating the solvent after completion of the reaction and recrystallizing from n-hexane. Further, in order to obtain a carbonate ester-protected type, the proton at the 4-position hydroxyl group of the compound of formula (I) (where R ⁴ = H) is extracted with a suitable base such as sodium hydride, and then ethyl chloroformate is obtained. It is made to react with a carbonic acid esterifying agent represented by In order to obtain an alkyl ether protected type, an alkylating agent represented by methyl iodide may be reacted with a base such as potassium carbonate.

以下実施例を挙げて本発明を具体的に説明する。
実施例１４−ｔ−ブチル−２−フルオロアニリン
ガラス製の反応容器の中に、撹拌子と、３６％塩酸５．５０ｍＬとを加え、塩化亜鉛（５．２４ｇ，０．０３８３ｍｏｌ）を溶解した。この溶液を撹拌しながら、２−フルオロアニリン（１０．０ｍＬ，０．１０４ｍｏｌ）およびｔ−ブタノール（９．９０ｍＬ，０．１０４ｍｏｌ）の順に加えて、このガラス容器をステンレス製の耐圧容器に格納し内部の圧力が漏れないように密封した後、１９０℃に加熱して撹拌しながら反応させた。初期の圧力は約５気圧であった。このまま反応を７２時間続けた。十分に温度の低下を確認した後、圧力容器を開封した。酢酸エチル（２００ｍＬ）を加え、攪拌して全体を均一にした後、水（２００ｍＬ）を加え、水酸化ナトリウムにて中和してｐＨ９に調整した。大量に析出した茶色の固体を濾別して、濾過液を分液し、有機層を再度水洗した。得られた有機層を濃縮して、茶褐色のオイル状物質１６．９ｇを得た。このものは標品を基準とした絶対検量線法にて定量した。その結果７９．２％の収率を算出した。
ＥＩ−ＭＳ；ｍ／ｚ１７０（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ １．２６（９Ｈ，ｓ，ｔ−Ｂｕ），３．５６（ｂｒ，ＮＨ_２），６．７４（１Ｈ，ｔ−ｌｉｋｅ，Ｊ＝９．３Ｈｚ，Ｈ_６），６．９５（１Ｈ，ｄｄｄ，Ｊ＝７．５，２．１，０．７Ｈｚ，Ｈ_５），７．９４（１Ｈ，ｄｄ，Ｊ＝１３．４，１．９Ｈｚ，Ｈ_３）．
実施例２６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール
４−ｔ−ブチル−２−フルオロアニリン（５．０６ｇ，３０．３ｍｍｏｌ）をトルエン（１２０ｍＬ）に溶解し、２−メチルアセト酢酸エチル（５．７５ｍＬ，４０．６ｍｍｏｌ）と、パラトルエンスルホン酸１水和物（５０ｍｇ）とを加え、ディーンスターク装置を完備した反応装置にて３時間加熱還流を行った。反応液を室温に戻し、ジフェニルエーテル（５０ｍＬ）、ピペリジン（２．０ｍＬ）および無水酢酸（１．０ｍＬ）を順に加え、３０分間撹拌した。再び加温を行い、溶媒のトルエンを留去した。さらに反応温度を２５０℃まで昇温し、１０分間その温度で保ち、環化反応を完結させた。反応液を室温に放冷し、一晩静置して結晶化した。析出した白色結晶を濾別し、ｎ−ヘキサンで洗浄し、得られた白色結晶を減圧下室温にて、３時間乾燥して６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール４．８２ｇを得た。収率６４．５％
ＦＡＢ−ＨＳ；ｍ／ｚ２４８（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ^３）δ １．３３（９Ｈ，ｓ，ｔ−Ｂｕ），２．１３（３Ｈ，ｓ，ＣＨ_３），２．５２（３Ｈ，ｓ，ＣＨ_３），７．３４（１Ｈ，ｄｄ，Ｊ＝１２．９，２．２Ｈｚ，Ｈ_３−ａｒｏｍａｔｉｃ），８．１０（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ，Ｈ_５−ａｒｏｍａｔｉｃ），８．９２（１Ｈ，ｂｓ，ＮＨ）．
実施例３６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール（ＥＭＡ滴下法）
４−ｔ−ブチル−２−フルオロアニリン（５．０６ｇ，３０．３ｍｍｏｌ）をトルエン（８０ｍＬ）に溶解し、パラトルエンスルホン酸１水和物（５０ｍｇ）を加え、ディーンスターク装置を完備した反応装置にて加熱還流を行った。この加熱溶液の中に、トルエン（２０ｍＬ）に溶解した２−メチルアセト酢酸エチル（５．７５ｍＬ，４０．６ｍｍｏｌ）を２時間で滴下する。滴下終了後、さらに２時間加熱還流を行った。反応液を室温に戻し、ジフェニルエーテル（５０ｍＬ）、ピペリジン（２．０ｍＬ）および無水酢酸（１．０ｍＬ）を順に加え、その後３０分間撹拌した。再び加温を行い、溶媒のトルエンを留去した。さらに反応温度を２５０℃まで昇温し、１０分間その温度で保ち環化反応を完結させた。反応液を室温に放冷し一晩静置して結晶化を行った。析出した白色結晶を濾別し、ｎ−ヘキサンで洗浄し、得られた白色結晶を減圧下室温にて３時間乾燥して、６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール５．１７ｇを得た。収率６９．０％
実施例４６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール
ポリリン酸（１０．８ｇ）を１６０℃に加熱し、その中に４−ｔ−ブチル−２−フルオロアニリン（１．８９ｇ，１１．３ｍｍｏｌ）と、２−メチルアセト酢酸エチル（１．９６ｇ，１３．５ｍｍｏｌ）との混合物を滴下し、３時間同温度で撹拌を行った。反応液を放冷後、水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で２回抽出を行った。有機層を合一し水洗を行い、有機層の溶媒を減圧下留去して、オイル状の濃縮残渣を得た。酢酸エチル−ｎ−ヘキサンから再結晶を行い、０．９７ｇの６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール白色結晶を得た。収率３４．７％
ＦＡＢ−ＭＳ；ｍ／ｚ２４８（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ １．３３（９Ｈ，ｓ，ｔ−Ｂｕ），２．１３（３Ｈ，ｓ，ＣＨ_３），２．５２（３Ｈ，ｓ，ＣＨ_３），７．３３（１Ｈ，ｄｄ，Ｊ＝１２．９，２．２Ｈｚ，Ｈ_３−ａｒｏｍａｔｉｃ），８．１０（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ，Ｈ_５−ａｒｏｍａｔｉｃ），８．９３（１Ｈ，ｂｓ，ＮＨ）．
実施例５６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール
４−ｔ−ブチル−２−フルオロアニリン（５．０６ｇ，３０．３ｍｍｏｌ）をトルエン（１２０ｍＬ）に溶解し、２−メチルアセト酢酸エチル（５．７５ｍＬ，４０．６ｍｍｏｌ）とパラトルエンスルホン酸１水和物（５０ｍｇ）とを加え、ディーンスターク装置を完備した反応装置にて３時間加熱還流を行った。放冷後、反応液を飽和重曹水中に投入し、酢酸エチル（５０ｍＬ）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、固形物を濾別した後、濾液を濃縮して５．９９ｇの茶色の油状物を得た。これをキシレン（１５５ｍＬ）に溶解して、１６０℃にて１時間加熱撹拌を行った。反応液を放冷後、溶媒を濃縮し、シリカゲルカラムクロマトグラフィー（酢酸エチル−ｎ−ヘキサン１：１）にて精製して、６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール８４５ｍｇを得た。収率１１．３％
ＦＡＢ−ＭＳ；ｍ／ｚ２４８（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ １．３３（９Ｈ，ｓ，ｔ−Ｂｕ），２．１３（３Ｈ，ｓ，ＣＨ_３），２．５２（３Ｈ，ｓ，ＣＨ_３），７．３３（１Ｈ，ｄｄ，Ｊ＝１２．９，２．１Ｈｚ，Ｈ_３−ａｒｏｍａｔｉｃ），８．１１（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ，Ｈ_５−ａｒｏｍａｔｉｃ），８．９２（１Ｈ，ｂｓ，ＮＨ）．
実施例６６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−アセトキシキノリン
実施例５で得た６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール（３．９３ｇ，１５．９ｍｍｏｌ）を、ピリジン（１３ｍＬ、１５９ｍｍｏｌ）に溶解し、無水酢酸（１５ｍＬ，１５９ｍｍｏｌ）を加え、８０℃で１時間加熱撹拌を行った。溶媒のピリジンと残存する無水酢酸とを減圧下留去して、４．９０ｇのオイル状残渣を得た。これをｎ−ヘキサン（４．５ｍＬ）に溶解し、結晶種を入れて、室温下、緩やかに１２時間撹拌を行い、白色の結晶が大量に得た。結晶を濾過し、冷ｎ−ヘキサン（４．５ｍＬ）で素早く洗浄し、得られた結晶を室温で１２時間乾燥して、２．５３ｇの６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−アセトキシキノリン白色結晶を得た。収率９０．１％
ＦＡＢ−ＭＳ；ｍ／ｚ２９０（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ １．３８（９Ｈ，ｓ，ｔ−Ｂｕ），２．２６（３Ｈ，ｓ，Ａｃｅｔｙｌ），２．５２（３Ｈ，ｓ，ＣＨ_３），２．７５（３Ｈ，ｓ，ＣＨ_３），７．３７（１Ｈ，ｄ，Ｊ＝１．９Ｈｚ，Ｈ_５−ａｒｏｍａｔｉｃ），７．４３（１Ｈ，ｄｄ，Ｊ＝１２．９，１．９Ｈｚ，Ｈ_７−ａｒｏｍａｔｉｃ）．
実施例７４−ｔ−アミル−２−フルオロアニリン
ガラス製の反応容器の中に、撹拌子と、３６％塩酸５．５０ｍＬとを加え、塩化亜鉛（５．２４ｇ，０．０３８３ｍｏｌ）を溶解した。撹拌しながら２−フルオロアニリン（１０．０ｍＬ，０．１０４ｍｏｌ）およびｔ−アミルアルコール（１１．４ｍＬ，０．１０４ｍｏｌ）を順に加え、このガラス容器をステンレス製の耐圧容器に格納し、内部の圧力が漏れないように密封した後、１９０℃に加熱して撹拌反応を行った。初期の圧力は約５気圧であった。このまま反応を７２時間続けた。十分に温度の低下を確認した後、圧力容器を開封した。酢酸エチル（２００ｍＬ）を加え、攪拌して全体を均一にして水（２００ｍＬ）を加え、水酸化ナトリウムにて中和してｐＨ９に調整した。大量に析出した茶色の固体を濾別し、濾過液を分液し、有機層を再度水洗した。得られた有機層を濃縮して、茶褐色のオイル状物質１７．５ｇを得た。このオイル状物質をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン−酢酸エチル１０：１）にて精製、分離して９．２２ｇの４−ｔ−アミル−２−フルオロアニリンを得た。収率４９．０％。なお、構造確認は一部をサンプリングしアミノ基のアセチル化を行ないアセチル体として行った。
４−ｔ−アミル−２−フルオロ−Ｎ−アセチルアニリン
ＥＩ−ＭＳ；ｍ／ｚ２２４（Ｍ＋Ｈ）^＋；１ＨＮＭＲ（ＣＤＣｌ_３）δ ０．６７（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ，ａｍｙｌ−ＣＨ_２ＣＨ _３），１．２５（６Ｈ，ｓ，ａｍｙｌ−ＣＨ_３），１．６０（２Ｈ，ｑ，Ｊ＝７．５Ｈｚ，ａｍｙｌ−ＣＨ _２ＣＨ_３），２．２１（３Ｈ，ｓ，Ａｃｅｔｙｌ−ＣＨ_３），７．０３（１Ｈ，ｄｄ，Ｊ＝１７．１，１．９Ｈｚ，Ｈ_３），７．０７（１Ｈ，ｄｄ，Ｊ＝８．３，２．０Ｈｚ，Ｈ_５），７．２９（１Ｈ，ｂｐｓ，ＮＨ），８．１６（１Ｈ，ｄｄ，Ｊ＝８．５，８．５Ｈｚ，Ｈ_６）．
実施例８６−ｔ−アミル−８−フルオロ−２，３−ジメチル−４−キノリノール
４−ｔ−アミル−２−フルオロアニリン（２．００ｇ，１１．１ｍｍｏｌ）をトルエン（１５ｍＬ）に溶解し、２−メチルアセト酢酸エチル（１．５６ｍＬ，１１．１ｍｍｏｌ）と三フッ化ホウ素ジエチルエーテル錯体（５０ｍｌ）とを加え、モレキュラーシーブスをつめた還流管をフラスコ上部に完備した反応装置にて、６時間加熱還流を行った。反応液を室温に戻し、ジフェニルエーテル（５０ｍＬ）、ピペリジン（０．７ｍＬ）および無水酢酸（０．３ｍＬ）を順に加えて、３０分間撹拌した。再び加温を行い、溶媒のトルエンを留去した。さらに反応温度を２５０℃まで昇温し、１０分間その温度で保ち、環化反応を完結させた。反応液を室温に放冷し、一晩静置して結晶化を行った。析出した褐色結晶を濾別し、ｎ−ヘキサンで洗浄し、得られた褐色結晶を減圧下室温にて３時間乾燥して、６−ｔ−アミル−８−フルオロ−２，３−ジメチル−４−キノリノール１．１８ｇを得た。収率４１．０％
ＦＡＢ−ＭＳ；ｍ／ｚ２６３（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ ０．６４（３Ｈ，ｔ，Ｊ＝７．６Ｈｚ，ａｍｙｌ−ＣＨ_２ＣＨ _３），１．３１（６Ｈ，ｓ，ａｍｙｌ−ＣＨ_３），１．６５（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ，ａｍｙｌ−ＣＨ _２ＣＨ_３），２．１４（３Ｈ，ｓ，２−ＣＨ_３），２．４８（３Ｈ，ｓ，３−ＣＨ_３），２．５２（３Ｈ，ｓ，ＣＨ_３），７．２９（１Ｈ，ｄｄ，Ｊ＝１２．９，１．９Ｈｚ，Ｈ_７−ａｒｏｍａｔｉｃ），８．０５（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ，Ｈ_５−ａｒｏｍａｔｉｃ），８．５１（１Ｈ，ｂｓ，ＮＨ）．
実施例９６−ｔ−アミル−８−フルオロ−２，３−ジメチル−４−アセトキシキノリン
実施例８で得た６−ｔ−アミル−８−フルオロ−２，３−ジメチル−４−キノリノール（１．１０ｇ５４．２１ｍｍｏｌ）をピリジン（３．４ｍＬ，４２．１ｍｍｏｌ）に溶解し、無水酢酸（６．０ｍＬ，６３．６ｍｍｏｌ）を加え、８０℃で２時間加熱撹拌を行った。溶媒のピリジンと残存する無水酢酸を減圧下留去し、酢酸エチル（１００ｍＬ）を加えた後、飽和食塩水、１０％クエン酸水および飽和食塩水の順に洗浄し、有機層を無水硫酸マグネシウムで乾燥し、固形物を濾過した後、濾液を減圧下濃縮した。得られたオイル状の濃縮残査をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン−酢酸エチル８：１）にて精製、分離して、１．２２ｇの６−ｔ−アミル−８−フルオロ−２，３−ジメチル−４−アセトキシキノリンを得た。収率９５．９％
ＦＡＢ−ＭＳ；ｍ／ｚ３０４（Ｈ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ ０．６８（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ，ａｍｙｌ−ＣＨ_２ＣＨ _３），１．３４（６Ｈ，ｓ，ａｍｙｌ−ＣＨ_３），１．６９（２Ｈ，ｑ，Ｊ＝７．６Ｈｚ，ａｍｙｌ−ＣＨ _２ＣＨ_３），２．２６（３Ｈ，ｓ，Ａｃｅｔｙｌ−ＣＨ_３），２．５２（３Ｈ，ｓ，２−ＣＨ_３），２．７５（３Ｈ，ｓ，３−ＣＨ_３），７．３２（１Ｈ，ｄ，Ｊ＝１．７Ｈｚ，Ｈ_５−ａｒｏｍａｔｉｃ），７．３７（１Ｈ，ｄｄ，Ｊ＝１２．９，２．０Ｈｚ，Ｈ_７−ａｒｏｍａｔｉｃ）．
実施例１０６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−メトキシカルボニルオキシキノリン
実施例５で得た６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール（１．００ｇ，４．０５ｍｍｏｌ）を乾燥テトラヒドロフラン（２０ｍＬ）に溶解し、氷冷下、アルゴン雰囲気下に６０％水素化ナトリウム（１６０ｍｇ）を加え、室温に戻し、ガスの発生が止むまで１時間撹拌した。再度氷冷した後、乾燥テトラヒドロフラン（５ｍＬ）に溶解したクロロギ酸メチル（３７６ｍＬ，４．８６ｍｍｏｌ）を滴下し、さらに３時間室温下で撹拌を続けた。反応液を氷水にあけ、これを酢酸エチル（５０ｍＬ）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、固形物を濾別した後、濾液を減圧下濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル−ｎ−ヘキサン３：１）にて精製して、６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−メトキシカルボニルオキシキノリン７８４ｍｇを得た。収率６３．５％
ＦＡＢ−ＭＳ；ｍ／ｚ３０６（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ １．３８（９Ｈ，ｓ，ｔ−Ｂｕ），２．３２（３Ｈ，ｓ，２−ＣＨ_３），２．７６（３Ｈ，ｓ，３−ＣＨ_３），４．００（３Ｈ，ｓ，ＯＣＨ_３），７．４２（１Ｈ，ｄ，Ｊ＝１．９Ｈｚ，Ｈ_５−ａｒｏｍａｔｉｃ），７．４５（１Ｈ，ｄｄ，Ｊ＝１２．９，１．９Ｈｚ，Ｈ_７−ａｒｏｍａｔｉｃ）．実施例１１６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−エトキシメトキシキノリン
実施例５で得た６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−キノリノール（１．００ｇ，４．０５ｍｍｏｌ）を乾燥テトラヒドロフラン（２０ｍＬ）に溶解し、氷冷下、アルゴン雰囲気下に６０％水素化ナトリウム（３２０ｍｇ）を加え、室温に戻してガスの発生が止むまで１時間撹拌した。再度氷冷した後、乾燥テトラヒドロフラン（５ｍＬ）に溶解したエトキシメチルクロリド（７６１ｍＬ，８．１０ｍｍｏｌ）を滴下し、さらに６時間室温下で撹拌を続けた。反応液を氷水にあけ、これを酢酸エチル（５０ｍＬ）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、固形物を濾別した後、濾液を減圧下濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル−ｎ−ヘキサン３：１）にて精製して、６−ｔ−ブチル−８−フルオロ−２，３−ジメチル−４−エトキシメトキシキノリン１４５ｍｇを得た。収率１１．７％
ＦＡＢ−ＭＳ；ｍ／ｚ３０６（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ １．２１（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．３６（９Ｈ，ｓ，ｔ−Ｂｕ），２．１７（３Ｈ，ｓ，２−ＣＨ_３），２．５３（３Ｈ，ｓ，３−ＣＨ_３），３．５１（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），５．５３（２Ｈ，ｓ），７．３７（１Ｈ，ｄｄ，Ｊ＝１７．３，２．４Ｈｚ，Ｈ_７−ａｒｏｍａｔｉｃ），８．２１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ，Ｈ_５−ａｒｏｍａｔｉｃ）．
実施例１２４−シクロヘキシル−２−フルオロアニリン
ガラス製の反応容器の中に、撹拌子と、３６％塩酸５．５０ｍＬとを加え、塩化亜鉛（５．２４ｇ，０．０３８３ｍｏｌ）を溶解した。撹拌しながら２−フルオロアニリン（１０．０ｍＬ，０．１０４ｍｏｌ）およびシクロヘキサノール（１０．４ｍＬ，０．１０４ｍｏｌ）を順に加え、このガラス容器をステンレス製の耐圧容器に格納し内部の圧力が漏れないように密封した後、１９０℃に加熱して撹拌反応を行った。初期の圧力は約５気圧であった。このまま反応を７２時間続けた。十分に温度の低下を確認した後圧力容器を開封した。酢酸エチル（２００ｍＬ）を加え、攪拌して全体を均一にして、水（２００ｍＬ）を加え、水酸化ナトリウムにて中和してｐＨ９に調整した。大量に析出した茶色の固体を濾別し、濾過液を分液し、有機層を再度水洗した。得られた有機層を濃縮して、茶褐色のオイル状物質１５．１ｇを得た。このものはシリカゲルカラムクロマトグラフィー（酢酸エチル−ｎ−ヘキサン１：５）にて精製して、４−シクロヘキシル−２−フルオロアニリン６．６３ｇを得た。収率３３．０％
ＥＩ−ＭＳ；ｍ／ｚ１９４（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ １．３４（６Ｈ，ｍ），１．８２（４Ｈ，ｍ），２．３９（１Ｈ，ｍ），３．５５２Ｈ，（ｂｓ，ＮＨ_２），６．７３（１Ｈ，ｄｄ，Ｊ＝１７．１，８．１Ｈｚ），６．７８（１Ｈ，ｄｄ，Ｊ＝８．０，１．９Ｈｚ），６．８４（１Ｈ，ｄｄ，Ｊ＝１２．４，１．７Ｈｚ）．
実施例１３６−シクロヘキシル−８−フルオロ−２，３−ジメチル−４−キノリノール
４−シクロヘキシル−２−フルオロアニリン（５．００ｇ，２５．９ｍｍｏｌ）をトルエン（１００ｍＬ）に溶解し、２−メチルアセト酢酸エチル（４．７７ｍＬ，３３．７ｍｍｏｌ）とパラトルエンスルホン酸１水和物（５０ｍｇ）とを加え、ディーンスターク装置を完備した反応装置にて、３時間加熱還流を行った。反応液を室温に戻し、ジフェニルエーテル（５０ｍＬ）、ピペリジン（２．０ｍＬ）および無水酢酸（１．０ｍＬ）を順に加えて３０分間撹拌した。再び加温を行い、溶媒のトルエンを留去した。さらに反応温度を２５０℃まで昇温し、１０分間その温度で保ち、環化反応を完結させる。反応液を室温に放冷し、一晩静置して結晶化を行った。析出した白色結晶を濾別し、ｎ−ヘキサンで洗浄し、得られた白色結晶を減圧下室温にて３時間乾燥して、６−シクロヘキシル−８−フルオロ−２，３−ジメチル−４−キノリノール３．５６ｇを得た。収率５０．４％
ＦＡＢ−ＭＳ；ｍ／ｚ２７４（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ｄ_６−ＤＭＳＯ）δ １．４０（６Ｈ，ｍ），１．６０（４Ｈ，ｍ），２．４１（３Ｈ，ｓ，），７．４１（１Ｈ，ｄ，Ｊ＝１２．９），７．６８（１Ｈ，ｓ），１１．２５（１Ｈ，ｓ）．
実施例１４６−シクロヘキシル−８−フルオロ−２，３−ジメチル−４−アセトキシキノリン
実施例５で得た６−シクロヘキシル−８−フルオロ−２，３−ジメチル−４−キノリノール（３．００ｇ，１１．０ｍｍｏｌ）をピリジン（８．７０ｍＬ，１１０ｍｍｏｌ）に溶解し、無水酢酸（１１．２ｍＬ，１１０ｍｍｏｌ）を加え、８０℃で２時間加熱撹拌を行った。溶媒のピリジンおよび残存する無水酢酸を減圧下留去し、酢酸エチル（１００ｍＬ）を加えた後、飽和食塩水、１０％クエン酸水および飽和食塩水を順に洗浄し、有機層を無水硫酸マグネシウムで乾燥し、固形物を濾過した後、濾液を減圧下濃縮した。得られたオイル状の濃縮残渣をシリカグルカラムクロマトグラフィー（ｎ−ヘキサン−酢酸エチル８：１）にて精製、分離して、３．１７ｇの６−シクロヘキシル−８−フルオロ−２，３−ジメチル−４−アセトキシキノリンを得た。収率９１．２％
ＦＡＢ−ＭＳ；ｍ／ｚ３１７（Ｍ＋Ｈ）^＋；^１ＨＮＭＲ（ＣＤＣｌ_３）δ １．２７（２Ｈ，ｍ），１．４５（４Ｈ，ｍ），１．９０（４Ｈ，ｍ），２．２６（３Ｈ，ｓ，Ａｃｅｔｙｌ−ＣＨ_３），２．２５（３Ｈ，ｓ），２．５２（３Ｈ，ｓ），２．７５（３Ｈ，ｓ），２．６４（１Ｈ，ｍ），７．２５（２Ｈ，ｍ）．Hereinafter, the present invention will be specifically described with reference to examples.
Example 1 4-t-butyl-2-fluoroaniline In a glass reaction vessel, a stirrer and 5.50 mL of 36% hydrochloric acid were added to dissolve zinc chloride (5.24 g, 0.0383 mol). . While stirring this solution, 2-fluoroaniline (10.0 mL, 0.104 mol) and t-butanol (9.90 mL, 0.104 mol) were added in this order, and this glass container was stored in a stainless steel pressure vessel. After sealing so that the internal pressure did not leak, it was heated to 190 ° C. and allowed to react with stirring. The initial pressure was about 5 atmospheres. The reaction was continued for 72 hours. After sufficiently confirming the temperature drop, the pressure vessel was opened. Ethyl acetate (200 mL) was added and stirred to make the whole homogeneous, and then water (200 mL) was added and neutralized with sodium hydroxide to adjust to pH 9. A large amount of the brown solid precipitated was filtered off, the filtrate was separated, and the organic layer was washed again with water. The obtained organic layer was concentrated to obtain 16.9 g of a brown oily substance. This was quantified by the absolute calibration curve method based on the standard. As a result, a yield of 79.2% was calculated.
EI-MS; m / z 170 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 1.26 (9H, s, t-Bu), 3.56 (br, NH ₂ ), 6.74 (1H, t-like, J = 9.3 Hz, H ₆ ), 6.95 (1H, ddd, J = 7.5, 2.1, 0.7 Hz, H ₅ ), 7.94 (1H, dd, J = 13.4, 1.9 Hz, H ₃ ).
Example 2 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol 4-t-butyl-2-fluoroaniline (5.06 g, 30.3 mmol) was dissolved in toluene (120 mL). Ethyl 2-methylacetoacetate (5.75 mL, 40.6 mmol) and paratoluenesulfonic acid monohydrate (50 mg) were added, and the mixture was heated to reflux for 3 hours in a reactor equipped with a Dean-Stark apparatus. The reaction solution was returned to room temperature, diphenyl ether (50 mL), piperidine (2.0 mL) and acetic anhydride (1.0 mL) were added in that order, and the mixture was stirred for 30 minutes. The mixture was heated again and the solvent toluene was distilled off. Further, the reaction temperature was raised to 250 ° C. and kept at that temperature for 10 minutes to complete the cyclization reaction. The reaction solution was allowed to cool to room temperature and allowed to stand overnight to crystallize. Precipitated white crystals were filtered off and washed with n-hexane, and the resulting white crystals were dried at room temperature under reduced pressure for 3 hours to give 6-tert-butyl-8-fluoro-2,3-dimethyl-4. -4.82 g of quinolinol was obtained. Yield 64.5%
FAB-HS; m / z 248 (M + H) ⁺ ; ¹ H NMR (CDCl ³ ) δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH ₃ ), 2.52 ( _{_{3H, s, CH 3),}} 7.34 (1H, dd, J = 12.9,2.2Hz, H 3 -aromatic), 8.10 (1H, d, J = 1.5Hz, H 5 -aromatic ), 8.92 (1H, bs, NH).
Example 3 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol (EMA dropping method)
4-t-butyl-2-fluoroaniline (5.06 g, 30.3 mmol) dissolved in toluene (80 mL), paratoluenesulfonic acid monohydrate (50 mg) was added, and a reactor equipped with a Dean-Stark apparatus The mixture was heated to reflux. To this heated solution, ethyl 2-methylacetoacetate (5.75 mL, 40.6 mmol) dissolved in toluene (20 mL) is added dropwise over 2 hours. After completion of the dropwise addition, the mixture was further heated under reflux for 2 hours. The reaction solution was returned to room temperature, diphenyl ether (50 mL), piperidine (2.0 mL) and acetic anhydride (1.0 mL) were sequentially added, and then stirred for 30 minutes. The mixture was heated again and the solvent toluene was distilled off. Further, the reaction temperature was raised to 250 ° C. and kept at that temperature for 10 minutes to complete the cyclization reaction. The reaction solution was allowed to cool to room temperature and allowed to stand overnight for crystallization. Precipitated white crystals were separated by filtration, washed with n-hexane, and the obtained white crystals were dried at room temperature under reduced pressure for 3 hours to give 6-t-butyl-8-fluoro-2,3-dimethyl-4. -5.17 g of quinolinol was obtained. Yield 69.0%
Example 4 6-t-Butyl-8-fluoro-2,3-dimethyl-4-quinolinol polyphosphoric acid (10.8 g) was heated to 160 ° C. in which 4-t-butyl-2-fluoroaniline ( A mixture of 1.89 g, 11.3 mmol) and ethyl 2-methylacetoacetate (1.96 g, 13.5 mmol) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was allowed to cool, water (50 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic layers were combined and washed with water, and the solvent of the organic layer was distilled off under reduced pressure to obtain an oily concentrated residue. Recrystallization from ethyl acetate-n-hexane gave 0.97 g of 6-tert-butyl-8-fluoro-2,3-dimethyl-4-quinolinol white crystals. Yield 34.7%
FAB-MS; m / z 248 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH ₃ ), 2.52 ( _{_{3H, s, CH 3),}} 7.33 (1H, dd, J = 12.9,2.2Hz, H 3 -aromatic), 8.10 (1H, d, J = 1.5Hz, H 5 -aromatic ), 8.93 (1H, bs, NH).
Example 5 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol 4-t-butyl-2-fluoroaniline (5.06 g, 30.3 mmol) was dissolved in toluene (120 mL). Ethyl 2-methylacetoacetate (5.75 mL, 40.6 mmol) and paratoluenesulfonic acid monohydrate (50 mg) were added, and the mixture was heated to reflux for 3 hours in a reactor equipped with a Dean-Stark apparatus. After allowing to cool, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, the solid matter was filtered off, and the filtrate was concentrated to obtain 5.99 g of a brown oil. This was dissolved in xylene (155 mL), and heated and stirred at 160 ° C. for 1 hour. After allowing the reaction solution to cool, the solvent is concentrated and purified by silica gel column chromatography (ethyl acetate-n-hexane 1: 1) to give 6-t-butyl-8-fluoro-2,3-dimethyl-4. -845 mg of quinolinol was obtained. Yield 11.3%
FAB-MS; m / z 248 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH ₃ ), 2.52 ( _{_{3H, s, CH 3),}} 7.33 (1H, dd, J = 12.9,2.1Hz, H 3 -aromatic), 8.11 (1H, d, J = 1.5Hz, H 5 -aromatic ), 8.92 (1H, bs, NH).
Example 6 6-t-butyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol (3) obtained in Example 5 .93 g, 15.9 mmol) was dissolved in pyridine (13 mL, 159 mmol), acetic anhydride (15 mL, 159 mmol) was added, and the mixture was stirred with heating at 80 ° C. for 1 hr. The solvent pyridine and the remaining acetic anhydride were distilled off under reduced pressure to obtain 4.90 g of an oily residue. This was dissolved in n-hexane (4.5 mL), a crystal seed was added, and the mixture was gently stirred at room temperature for 12 hours to obtain a large amount of white crystals. The crystals are filtered and washed quickly with cold n-hexane (4.5 mL) and the resulting crystals are dried at room temperature for 12 hours to give 2.53 g of 6-tert-butyl-8-fluoro-2,3- Dimethyl-4-acetoxyquinoline white crystals were obtained. Yield 90.1%
FAB-MS; m / z 290 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 1.38 (9H, s, t-Bu), 2.26 (3H, s, Acetyl), 2.52 (3H , S, CH ₃ ), 2.75 (3H, s, CH ₃ ), 7.37 (1H, d, J = 1.9 Hz, H ₅ -aromatic), 7.43 (1H, dd, J = 12 .9, 1.9 Hz, H ₇ -aromatic).
Example 7 4-t-amyl-2-fluoroaniline In a glass reaction vessel, a stirrer and 5.50 mL of 36% hydrochloric acid were added to dissolve zinc chloride (5.24 g, 0.0383 mol). . While stirring, 2-fluoroaniline (10.0 mL, 0.104 mol) and t-amyl alcohol (11.4 mL, 0.104 mol) were sequentially added, and this glass container was stored in a stainless steel pressure-resistant container, and the internal pressure was increased. After sealing so as not to leak, the mixture was heated to 190 ° C. to carry out a stirring reaction. The initial pressure was about 5 atmospheres. The reaction was continued for 72 hours. After sufficiently confirming the temperature drop, the pressure vessel was opened. Ethyl acetate (200 mL) was added, and the mixture was stirred to make the whole uniform, water (200 mL) was added, and the mixture was neutralized with sodium hydroxide to adjust to pH 9. A large amount of the brown solid precipitated was filtered off, the filtrate was separated, and the organic layer was washed again with water. The obtained organic layer was concentrated to obtain 17.5 g of a brown oily substance. This oily substance was purified and separated by silica gel column chromatography (n-hexane-ethyl acetate 10: 1) to obtain 9.22 g of 4-t-amyl-2-fluoroaniline. Yield 49.0%. The structure was confirmed by sampling a part and acetylating the amino group to obtain an acetylated form.
4-t-amyl-2-fluoro-N-acetylaniline EI-MS; m / z 224 (M + H) ⁺ ; 1H NMR (CDCl ₃ ) δ 0.67 (3H, t, J = 7.3 Hz, amyl- _{_{_{CH 2 CH 3), 1.25 (}}} 6H, s, amyl-CH 3), 1.60 (2H, q, J = 7.5Hz, amyl- CH 2 CH 3), 2.21 (3H, s, Acetyl-CH ₃ ), 7.03 (1H, dd, J = 17.1, 1.9 Hz, H ₃ ), 7.07 (1H, dd, J = 8.3, 2.0 Hz, H ₅ ), 7.29 (1H, bps, NH), 8.16 (1H, dd, J = 8.5, 8.5 Hz, H ₆ ).
Example 8 6-t-amyl-8-fluoro-2,3-dimethyl-4-quinolinol 4-t-amyl-2-fluoroaniline (2.00 g, 11.1 mmol) was dissolved in toluene (15 mL). Add ethyl 2-methylacetoacetate (1.56 mL, 11.1 mmol) and boron trifluoride diethyl etherate complex (50 ml) and heat for 6 hours in a reactor equipped with a reflux tube filled with molecular sieves at the top of the flask. Reflux was performed. The reaction solution was returned to room temperature, diphenyl ether (50 mL), piperidine (0.7 mL) and acetic anhydride (0.3 mL) were sequentially added, and the mixture was stirred for 30 minutes. The mixture was heated again and the solvent toluene was distilled off. Further, the reaction temperature was raised to 250 ° C. and kept at that temperature for 10 minutes to complete the cyclization reaction. The reaction solution was allowed to cool to room temperature and allowed to stand overnight for crystallization. The precipitated brown crystals were separated by filtration, washed with n-hexane, and the obtained brown crystals were dried at room temperature under reduced pressure for 3 hours to give 6-t-amyl-8-fluoro-2,3-dimethyl-4. -1.18 g of quinolinol was obtained. Yield 41.0%
FAB-MS; m / z 263 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 0.64 (3H, t, J = 7.6 Hz, amyl-CH ₂ CH ₃ ), 1.31 (6H, s , Amyl-CH ₃ ), 1.65 (2H, q, J = 7.3 Hz, amyl- CH ₂ CH ₃ ), 2.14 (3H, s, 2-CH ₃ ), 2.48 (3H, s , 3-CH ₃ ), 2.52 (3H, s, CH ₃ ), 7.29 (1H, dd, J = 12.9, 1.9 Hz, H ₇ -aromatic), 8.05 (1H, d , J = 1.2 Hz, H ₅ -aromatic), 8.51 (1H, bs, NH).
Example 9 6-t-amyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline 6-t-amyl-8-fluoro-2,3-dimethyl-4-quinolinol (1) obtained in Example 8 .10 g 54.21 mmol) was dissolved in pyridine (3.4 mL, 42.1 mmol), acetic anhydride (6.0 mL, 63.6 mmol) was added, and the mixture was stirred with heating at 80 ° C. for 2 hr. The solvent pyridine and the remaining acetic anhydride were distilled off under reduced pressure, ethyl acetate (100 mL) was added, and the mixture was washed with saturated brine, 10% citric acid and saturated brine in this order, and the organic layer was washed with anhydrous magnesium sulfate. After drying and filtering the solid, the filtrate was concentrated under reduced pressure. The resulting oily concentrated residue was purified and separated by silica gel column chromatography (n-hexane-ethyl acetate 8: 1) to obtain 1.22 g of 6-t-amyl-8-fluoro-2,3. -Dimethyl-4-acetoxyquinoline was obtained. Yield 95.9%
FAB-MS; m / z 304 (H + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 0.68 (3H, t, J = 7.3 Hz, amyl-CH ₂ CH ₃ ), 1.34 (6H, s , Amyl-CH ₃ ), 1.69 (2H, q, J = 7.6 Hz, amyl- CH ₂ CH ₃ ), 2.26 (3H, s, Acetyl-CH ₃ ), 2.52 (3H, s , 2-CH ₃ ), 2.75 (3H, s, 3-CH ₃ ), 7.32 (1H, d, J = 1.7 Hz, H ₅ -aromatic), 7.37 (1H, dd, J = 12.9, 2.0 Hz, H ₇ -aromatic).
Example 10 6-t-butyl-8-fluoro-2,3-dimethyl-4-methoxycarbonyloxyquinoline 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol obtained in Example 5 (1.00 g, 4.05 mmol) was dissolved in dry tetrahydrofuran (20 mL), 60% sodium hydride (160 mg) was added under ice cooling and argon atmosphere, returned to room temperature, and 1 hour until gas evolution ceased Stir. After ice cooling again, methyl chloroformate (376 mL, 4.86 mmol) dissolved in dry tetrahydrofuran (5 mL) was added dropwise, and stirring was continued for another 3 hours at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, the solid matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (ethyl acetate-n-hexane 3: 1) to give 784 mg of 6-t-butyl-8-fluoro-2,3-dimethyl-4-methoxycarbonyloxyquinoline. Got. Yield 63.5%
FAB-MS; m / z 306 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 1.38 (9H, s, t-Bu), 2.32 (3H, s, 2-CH ₃ ), 2. _{_{76 (3H, s, 3-}} CH 3), 4.00 (3H, s, OCH 3), 7.42 (1H, d, J = 1.9Hz, H 5 -aromatic), 7.45 (1H, dd, J = 12.9, 1.9 Hz, H ₇ -aromatic). Example 11 6-t-Butyl-8-fluoro-2,3-dimethyl-4-ethoxymethoxyquinoline 6-t-butyl-8-fluoro-2,3-dimethyl-4-quinolinol obtained in Example 5 ( 1.00 g, 4.05 mmol) was dissolved in dry tetrahydrofuran (20 mL), 60% sodium hydride (320 mg) was added under ice-cooling and argon atmosphere, and the mixture was returned to room temperature and stirred for 1 hour until gas evolution stopped. did. After ice-cooling again, ethoxymethyl chloride (761 mL, 8.10 mmol) dissolved in dry tetrahydrofuran (5 mL) was added dropwise, and stirring was further continued at room temperature for 6 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, the solid matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (ethyl acetate-n-hexane 3: 1) to give 145 mg of 6-t-butyl-8-fluoro-2,3-dimethyl-4-ethoxymethoxyquinoline. Obtained. Yield 11.7%
FAB-MS; m / z 306 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 1.21 (3H, t, J = 7.1 Hz), 1.36 (9H, s, t-Bu), 2 .17 (3H, s, 2-CH ₃ ), 2.53 (3H, s, 3-CH ₃ ), 3.51 (2H, q, J = 7.1 Hz), 5.53 (2H, s) 7.37 (1H, dd, J = 17.3, 2.4 Hz, H ₇ -aromatic), 8.21 (1 H, d, J = 2.4 Hz, H ₅ -aromatic).
Example 12 4-Cyclohexyl-2-fluoroaniline A stirrer and 5.50 mL of 36% hydrochloric acid were added to a glass reaction vessel to dissolve zinc chloride (5.24 g, 0.0383 mol). While stirring, 2-fluoroaniline (10.0 mL, 0.104 mol) and cyclohexanol (10.4 mL, 0.104 mol) are sequentially added, and this glass container is stored in a stainless steel pressure-resistant container so that the internal pressure does not leak. Then, the mixture was heated to 190 ° C. to carry out a stirring reaction. The initial pressure was about 5 atmospheres. The reaction was continued for 72 hours. After sufficiently confirming the temperature drop, the pressure vessel was opened. Ethyl acetate (200 mL) was added and stirred to make the whole homogeneous, water (200 mL) was added, and the mixture was neutralized with sodium hydroxide to adjust to pH 9. A large amount of the brown solid precipitated was filtered off, the filtrate was separated, and the organic layer was washed again with water. The obtained organic layer was concentrated to obtain 15.1 g of a brown oily substance. This was purified by silica gel column chromatography (ethyl acetate-n-hexane 1: 5) to obtain 6.63 g of 4-cyclohexyl-2-fluoroaniline. Yield 33.0%
EI-MS; m / z 194 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 1.34 (6H, m), 1.82 (4H, m), 2.39 (1H, m), 3. 55 2H, (bs, NH ₂ ), 6.73 (1H, dd, J = 17.1, 8.1 Hz), 6.78 (1H, dd, J = 8.0, 1.9 Hz), 6. 84 (1H, dd, J = 12.4, 1.7 Hz).
Example 13 6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol 4-Cyclohexyl-2-fluoroaniline (5.00 g, 25.9 mmol) was dissolved in toluene (100 mL) and 2-methylacetoacetic acid was dissolved. Ethyl (4.77 mL, 33.7 mmol) and paratoluenesulfonic acid monohydrate (50 mg) were added, and the mixture was heated to reflux for 3 hours in a reactor equipped with a Dean-Stark apparatus. The reaction solution was returned to room temperature, diphenyl ether (50 mL), piperidine (2.0 mL) and acetic anhydride (1.0 mL) were sequentially added, and the mixture was stirred for 30 minutes. The mixture was heated again and the solvent toluene was distilled off. Further, the reaction temperature is raised to 250 ° C. and maintained at that temperature for 10 minutes to complete the cyclization reaction. The reaction solution was allowed to cool to room temperature and allowed to stand overnight for crystallization. The precipitated white crystals were separated by filtration and washed with n-hexane, and the obtained white crystals were dried at room temperature under reduced pressure for 3 hours to give 6-cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol. 3.56 g was obtained. Yield 50.4%
FAB-MS; m / z 274 (M + H) ⁺ ; ¹ H NMR (d ₆ -DMSO) δ 1.40 (6H, m), 1.60 (4H, m), 2.41 (3H, s,) , 7.41 (1H, d, J = 12.9), 7.68 (1H, s), 11.25 (1H, s).
Example 14 6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-acetoxyquinoline 6-Cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol obtained in Example 5 (3.00 g, 11 0.0 mmol) was dissolved in pyridine (8.70 mL, 110 mmol), acetic anhydride (11.2 mL, 110 mmol) was added, and the mixture was heated and stirred at 80 ° C. for 2 hours. Solvent pyridine and remaining acetic anhydride were distilled off under reduced pressure, ethyl acetate (100 mL) was added, and then saturated brine, 10% aqueous citric acid and saturated brine were washed in that order, and the organic layer was washed with anhydrous magnesium sulfate. After drying and filtering the solid, the filtrate was concentrated under reduced pressure. The resulting oily concentrated residue was purified and separated by silica glu column chromatography (n-hexane-ethyl acetate 8: 1) to give 3.17 g of 6-cyclohexyl-8-fluoro-2,3-dimethyl. -4-Acetoxyquinoline was obtained. Yield 91.2%
FAB-MS; m / z 317 (M + H) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 1.27 (2H, m), 1.45 (4H, m), 1.90 (4H, m), 2. _{26 (3H, s, Acetyl-} CH 3), 2.25 (3H, s), 2.52 (3H, s), 2.75 (3H, s), 2.64 (1H, m), 7. 25 (2H, m).

Claims

A method for producing a quinoline derivative represented by the following formula (I) or a salt thereof, comprising at least the following steps (i) and (ii):

[Where:
R ¹ represents an optionally substituted C _1-10 alkyl group, or a C _3-6 cycloalkyl group,
R ² represents an optionally substituted C _1-10 alkyl group, or a C _3-6 cycloalkyl group,
R ³ represents an optionally substituted C _1-10 alkyl group, a C _2-6 alkenyl group, a phenyl C _1-6 alkyl group, or a C _3-6 cycloalkyl group,
R ⁴ represents a hydrogen atom or a hydroxyl-protecting group. ]
Step (i) Formula (II):

Or a hydrochloric acid addition salt thereof in the presence of zinc chloride under pressure, R ¹ -X (where R ¹ is as defined above, and X represents a hydroxyl group or a halogen atom ). Thus alkylating to formula (III):

[Wherein, R ¹ has the same meaning as described above. ]
In represented by 4-alkyl-2-fluoroaniline derivative obtaining step and step (ii) Formula (III) a compound represented by the formula (IV):

[Wherein R ¹ , R ² , R ³ and R ⁵ represent the same meaning as described above. ]
To produce an enamine reaction mixture (enamine reaction) , which is subjected to a cyclization reaction to obtain a compound represented by formula (I) (provided that R ⁴ is a hydrogen atom) to give certain) (cyclization reaction), further 4-position hydroxyl group step of protecting (where a protecting group if necessary, enamine reaction is carried out in toluene solvent, the cyclization reaction is diphenyl ether was added to the enamine reaction mixture The reaction is carried out by heating to 250 ° C., the boiling point of diphenyl ether, while distilling off toluene, and the enamine reaction and cyclization reaction are carried out in one pot .

The production method according to claim 1, wherein the compound represented by the formula (IV) is ethyl 2-methylacetoacetate.

The production method according to claim 1, wherein the compound represented by the formula (I) is ^{one in} which R ¹ is a t-butyl group, R ² and R ³ are methyl groups, and R ⁴ is a hydrogen atom.

The production method according to claim 1, wherein the compound represented by the formula (I) is such that R ¹ is a t-butyl group, R ² and R ³ are methyl groups, and R ⁴ is an acetyl group.

The process according to claim 1, wherein the compound of formula (II) is a hydrochloric acid addition salt.

The hydroxyl protecting group represented by R ⁴ is a C _1-6 alkyl group, a C _1-6 alkylcarbonyl group, a C _1-6 alkyloxycarbonyl group, a C _1-6 alkyloxy C _1-6 alkylcarbonyl group, C _{1. 6} alkylcarbonyloxy _{C 1 to 6} alkyl _group, a _{C 3 to 6} cycloalkyl group or a _{C 3 to 6} cycloalkyl alkyloxycarbonyl group, the process according to claim 1.

The production method according to claim 1, wherein the enamine reaction is carried out in the presence of an acidic catalyst.

The production method according to claim 7, wherein the acidic catalyst is a protonic acid.

The manufacturing method of Claim 1 with which the said process (i) and (ii) is performed by one pot.