JP2008037761A - 2-trifluromethylquinoline and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide 2-trifluoromethylquinolines and an efficient method for producing them. <P>SOLUTION: The 4-amino-2-trifluoromethylquinolines are expressed by general formula (1) [wherein, R<SP>1</SP>to R<SP>4</SP>are each H, an alkyl or the like: and R<SP>5</SP>, R<SP>6</SP>are each H or form 1,1,1-trifluoro-2-propilidene group by joining the R<SP>5</SP>, R<SP>6</SP>as one unit], and a method for producing them is also provided. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to 2-trifluoromethylquinolines and a method for producing the same.

  Quinolines are compounds that have a specific physiological activity and are included in the skeletons of various medical and agricultural chemicals. In particular, quinolines having a trifluoromethyl group, such as 4-amino-2-trifluoromethylquinolines, have been conventionally used as leading compounds for antimalarial drugs (for example, Non-Patent Document 1). Recently, it has attracted attention as a pharmaceutical intermediate for gastric ulcer, hypertension, congestive heart failure, acute type or chronic type neurodegeneration (for example, Patent Document 1). The following two methods are known as methods for producing 4-amino-2-trifluoromethylquinolines. In the first method, aniline and ethyl trifluoroacetoacetate were cyclized to give 4-hydroxy-2-trifluoromethylquinoline, which was further converted to 4-chloro-2-trifluoromethylquinoline with phosphorus oxychloride. Then, it is a method of amination with ammonia, amine or the like (Non-patent Document 2, Patent Document 2). In the second method, aniline and 2-phenylimino-1,1,1,4,4,4-hexafluorobutane are reacted in the presence of potassium hydroxide to give 4- (N-phenylamino) -2. -Obtaining trifluoromethylquinoline (Non-patent Document 3). Any of these reactions is a process that is difficult to use industrially because it is multistage, the raw materials are special, the reaction time is long, and the like.

Australian Journal of Chemistry, 1993, 46, 21-29 US Patent Application Publication No. 2005/0070573 Journal of Heterocyclic Chemistry, 1965, Volume 2, pages 113-119 Japanese Patent Application Laid-Open No. 5-213884 Tetrahedron, 1998, 54, 4949-4964

  An object of the present invention is to provide 2-trifluoromethylquinolines and a method for producing the same.

  As a result of intensive studies in view of the above problems, the present inventors have found that 2- [N- (1,1,1-trimethyl) represented by the general formula (2) is present in the presence of a palladium catalyst and a base. Fluoro-2-propylidene)] aminobenzonitriles and 2-bromo-3,3,3-trifluoropropene are reacted to form quinolines having a trifluoromethyl group at the 2-position and an amino group at the 4-position. It has been found that a good yield can be obtained in one stage. The amino group at the 4-position further reacts with another molecule of 2-bromo-3,3,3-trifluoropropene in the presence of a palladium catalyst and a base, and [N- (1,1,1- Trifluoro-2-propylidene)]] It was found that it could be easily converted into an amino group, and the present invention was completed.

  That is, the present invention relates to the general formula (1)

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、各々独立に水素原子、炭素数１〜４のアルキル基、炭素数２〜４のアルケニル基、炭素数２〜４のアルキニル基、炭素数１〜４のアルコキシ基、炭素数２〜５のアシル基、（炭素数１〜４のアルコキシ）カルボニル基、（炭素数１〜４のアルキル）アミノ基、ジ（炭素数１〜４のアルキル）アミノ基、シアノ基、水酸基またはハロゲン原子を示す。Ｒ_５およびＲ_６は、水素原子またはＲ_５とＲ_６が一体となって１，１，１−トリフルオロ−２−プロピリデン基を示す。］であらわされることを特徴とする４−アミノ−２−トリフルオロメチルキノリン類（但し、４−アミノ−２−トリフルオロメチルキノリン、４−アミノ−６，８−ジクロロ−２−トリフルオロメチルキノリン、４−アミノ−８−ヨード−２−トリフルオロメチルキノリン、４−アミノ−８−ブロモ−２−トリフルオロメチルキノリン、４−アミノ−８−クロロ−２−トリフルオロメチルキノリン、４−アミノ−８−フルオロ−２−トリフルオロメチルキノリン、４−アミノ−６−ヨード−２−トリフルオロメチルキノリン、４−アミノ−６−クロロ−２−トリフルオロメチルキノリン、４−アミノ−６−フルオロ−２−トリフルオロメチルキノリン、４−アミノ−６−ブロモ−２−トリフルオロメチルキノリンおよび４−アミノ−６−メチル−２−トリフルオロメチルキノリンを除く）である。

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, C1-C4 alkoxy group, C2-C5 acyl group, (C1-C4 alkoxy) carbonyl group, (C1-C4 alkyl) amino group, Di (C1-C4) Alkyl) amino group, cyano group, hydroxyl group or halogen atom. R ₅ and R ₆ represent a hydrogen atom or a 1,1,1-trifluoro-2-propylidene group in which R ₅ and R ₆ are combined. 4-amino-2-trifluoromethylquinoline (provided that 4-amino-2-trifluoromethylquinoline, 4-amino-6,8-dichloro-2-trifluoromethylquinoline) 4-amino-8-iodo-2-trifluoromethylquinoline, 4-amino-8-bromo-2-trifluoromethylquinoline, 4-amino-8-chloro-2-trifluoromethylquinoline, 4-amino- 8-fluoro-2-trifluoromethylquinoline, 4-amino-6-iodo-2-trifluoromethylquinoline, 4-amino-6-chloro-2-trifluoromethylquinoline, 4-amino-6-fluoro-2 -Trifluoromethylquinoline, 4-amino-6-bromo-2-trifluoromethylquinoline and 4-amino-6-methyl -2 excluding trifluoromethyl quinoline).

  The present invention also provides a compound represented by the general formula (1a)

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、前記と同じ内容を示す。］で表される４−アミノ−２−トリフルオロメチルキノリン類と２−ブロモ−３，３，３−トリフルオロプロペンをパラジウム触媒および塩基の存在下に反応させることを特徴とする、一般式（１ｂ）

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. Wherein 2-amino-2-trifluoromethylquinolines and 2-bromo-3,3,3-trifluoropropene are reacted in the presence of a palladium catalyst and a base, 1b)

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、前記と同じ内容を示す。］で表される２−トリフルオロメチル−４−［Ｎ−（１，１，１−トリフルオロ−２−プロピリデン）］アミノキノリン類の製造方法である。

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ] 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by these.

  Furthermore, the present invention relates to a general formula (2)

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、前記と同じ内容を示す。］で表される２−［Ｎ−（１，１，１−トリフルオロ−２−プロピリデン）］アミノベンゾニトリル類と２−ブロモ−３，３，３−トリフルオロプロペンをパラジウム触媒および塩基の存在下に反応させることを特徴とする、一般式（１ｂ）で表される２−トリフルオロメチル−４−［Ｎ−（１，１，１−トリフルオロ−２−プロピリデン）］アミノキノリン類および／または一般式（１ａ）で表される４−アミノ−２−トリフルオロメチルキノリン類の製造方法である。

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile and 2-bromo-3,3,3-trifluoropropene represented by a palladium catalyst and a base 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by the general formula (1b) and / or Or it is a manufacturing method of 4-amino-2- trifluoromethyl quinoline represented by General formula (1a).

  The present invention also provides a general formula (3)

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、前記と同じ内容を示す。］で表される２−アミノベンゾニトリル類と２−ブロモ−３，３，３−トリフルオロプロペンをパラジウム触媒および塩基の存在下に反応させることを特徴とする、一般式（１ｂ）で表される２−トリフルオロメチル−４−［Ｎ−（１，１，１−トリフルオロ−２−プロピリデン）］アミノキノリン類および／または一般式（１ａ）で表される４−アミノ−２−トリフルオロメチルキノリン類および／または一般式（２）で表される２−［Ｎ−（１，１，１−トリフルオロ−２−プロピリデン）］アミノベンゾニトリル類の製造方法である。

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. Represented by the general formula (1b), wherein the 2-aminobenzonitrile and 2-bromo-3,3,3-trifluoropropene represented by the formula are reacted in the presence of a palladium catalyst and a base. 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines and / or 4-amino-2-trifluoro represented by the general formula (1a) This is a process for producing methylquinolines and / or 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitriles represented by the general formula (2).

  The present invention further comprises reacting 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile represented by the general formula (2) in the presence of a palladium catalyst and a base. Is a process for producing 4-amino-2-trifluoromethylquinolines represented by the general formula (1a). Hereinafter, the present invention will be described in more detail.

  Specific examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group or A cyclopropylmethyl group etc. can be illustrated.

  In addition, one or more of these alkyl groups may be substituted with a halogen atom. Specifically, a chloromethyl group, a 2-chloroethyl group, a 3-chloropropyl group, a difluoromethyl group, a 3-fluoropropyl group, a trimethyl group, Examples thereof include a fluoromethyl group, a 2-fluoroethyl group, a 2,2,2-trifluoroethyl group, and a 2,2,2-trichloroethyl group.

  Specific examples of the alkenyl group having 2 to 4 carbon atoms include vinyl group, 1-methylvinyl group, 1-propenyl group, 2-propenyl group, 3-butenyl group, 2-methyl-2-propenyl group, 1- Examples thereof include an ethyl vinyl group, a 2-butenyl group, and a 1,3-butanedienyl group.

  In addition, one or more of these alkenyl groups may be substituted with a halogen atom. Specifically, 1- (difluoromethyl) vinyl group, 1- (trifluoromethyl) vinyl group, 2-chloromethyl-2- Propenyl group, 2-difluoromethyl-propenyl group, 2-trifluoromethyl-2-propenyl group, 1- (2-chloroethyl) vinyl group, 1- (2-fluoroethyl) vinyl group, 1- (2,2, Examples thereof include 2-trifluoroethyl) vinyl group and 1- (2,2,2-trichloroethyl) vinyl group.

  Specific examples of the alkynyl group having 2 to 4 carbon atoms include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group and 3-butynyl group.

  One or more of these alkynyl groups may be substituted with a halogen atom, specifically, 3-chloro-1-propenyl group, 3,3-difluoro-1-propenyl group, 3,3,3-tri Fluoro-1-propenyl group, 4-chloro-1-butynyl group, 4-fluoro-1-butynyl group, 4,4-difluoro-1-butynyl group, 4,4,4-trifluoro-1-butynyl group, Examples include 4-chloro-2-butynyl group, 4,4-difluoro-2-butynyl group, 4,4,4-trifluoro-2-butynyl group and the like.

  Specific examples of the alkoxy group having 1 to 4 carbon atoms include methoxy group, ethoxy group, propoxy group, isopropyloxy group, cyclopropyloxy group, butoxy group, isobutyloxy group, sec-butyloxy group, tert-butyloxy group, Examples include a cyclobutyloxy group or a cyclopropylmethyloxy group.

  In addition, one or more of these alkoxy groups may be substituted with a halogen atom, specifically, a chloromethoxy group, a 2-chloroethoxy group, a 3-chloropropoxy group, a difluoromethoxy group, a 3-fluoropropoxy group, Examples thereof include a trifluoromethoxy group, a 2-fluoroethoxy group, a 2,2,2-trifluoroethoxy group, and a 2,2,2-trichloroethoxy group.

  Specific examples of the acyl group having 2 to 5 carbon atoms include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, sec-butylcarbonyl group and pivaloyl group.

  In these acyl groups, one or more alkyl groups may be substituted with halogen atoms. Specifically, 2-chloroethylcarbonyl group, 3-chloropropylcarbonyl group, difluoromethylcarbonyl group, 3-fluoro Examples include propylcarbonyl group, trifluoromethylcarbonyl group, 2-fluoroethylcarbonyl group, 2,2,2-trifluoroethylcarbonyl group, 2,2,2-trichloroethylcarbonyl group, and the like.

  Specific examples of (C1-C4 alkoxy) carbonyl groups include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropyloxycarbonyl group, butyloxycarbonyl group, isobutyloxycarbonyl group, sec-butyloxycarbonyl. Group or tert-butyloxycarbonyl group.

  In these alkoxycarbonyl groups, one or more alkyl groups may be substituted with halogen atoms. Specifically, 2-chloroethoxycarbonyl group, 3-chloropropyloxycarbonyl group, difluoromethoxycarbonyl group, 3 -Fluoropropyloxycarbonyl group, trifluoromethoxycarbonyl group, 2-fluoroethoxycarbonyl group, 2,2,2-trifluoroethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and the like can be exemplified.

  Specific examples of the (amino group having 1 to 4 carbon atoms) amino group include methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, and tert- A butylamino group etc. can be illustrated.

  Further, one or more of these alkyl groups may be substituted with a halogen atom. Specifically, a chloromethylamino group, a 2-chloroethylamino group, a 3-chloropropylamino group, a difluoromethylamino group, 3- Examples thereof include a fluoropropylamino group, a trifluoromethylamino group, a 2-fluoroethylamino group, a 2,2,2-trifluoroethylamino group, and a 2,2,2-trichloroethylamino group.

  Specific examples of the di (C 1-4 alkyl) amino group include a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group, a diisobutylamino group, and a di (sec-butyl) amino group. Group, methylethylamino group, methylpropylamino group, methylisopropylamino group, methylbutylamino group, methylisobutylamino group, methyl (sec-butyl) amino group, ethylpropylamino group, ethylbutylamino group or propylbutylamino group Etc. can be illustrated.

  In addition, one or more of these alkyl groups may be substituted with a halogen atom, specifically, a di (chloromethyl) amino group, a di (2-chloroethyl) amino group, or a di (3-chloropropyl) amino group. Bis (difluoromethyl) amino group, di (3-fluoropropyl) amino group, bis (trifluoromethyl) amino group, di (2-fluoroethyl) amino group, di (2,2,2-trifluoroethyl) Examples thereof include an amino group and a di (2,2,2-trichloroethyl) amino group.

  Specific examples of the halogen atom include fluorine, chlorine, bromine and iodine.

Next, the production method of the present invention will be described in detail. Step A is a method for producing 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by the general formula (1b).
[Step A]

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、前記と同じ内容を示す。］
工程Ａで用いることのできるパラジウム触媒としては、パラジウム黒、パラジウムスポンジ等のパラジウム金属、パラジウム／アルミナ、パラジウム／炭素、パラジウム／シリカ、パラジウム／Ｙ型ゼオライト、パラジウム／Ａ型ゼオライト、パラジウム／Ｘ型ゼオライト、パラジウム／モルデナイト、パラジウム／ＺＳＭ−５等の担持パラジウム金属が例示できる。また、塩化パラジウム、臭化パラジウム、ヨウ化パラジウム、酢酸パラジウム、トリフルオロ酢酸パラジウム、硝酸パラジウム、酸化パラジウム、硫酸パラジウム、シアン化パラジウム、ヘキサクロロパラジウム酸四ナトリウム、ヘキサクロロパラジウム酸四カリウム、テトラクロロパラジウム酸二ナトリウム、テトラクロロパラジウム酸二カリウム等の金属塩を例示できる。

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ]
Examples of the palladium catalyst that can be used in Step A include palladium metal such as palladium black and palladium sponge, palladium / alumina, palladium / carbon, palladium / silica, palladium / Y-type zeolite, palladium / A-type zeolite, palladium / X-type. Illustrative are supported palladium metals such as zeolite, palladium / mordenite, palladium / ZSM-5. Also, palladium chloride, palladium bromide, palladium iodide, palladium acetate, palladium trifluoroacetate, palladium nitrate, palladium oxide, palladium sulfate, palladium cyanide, tetrasodium hexachloropalladate, tetrapotassium hexachloropalladate, tetrachloropalladium acid Examples thereof include metal salts such as disodium and dipotassium tetrachloropalladate.

  Furthermore, π-allyl palladium chloride dimer, palladium acetylacetonate, tetrafluoro (acetonitrile) palladium borofluoride, dichlorobis (acetonitrile) palladium, dichlorobis (benzonitrile) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) di Palladium, dichlorodiammine palladium, tetraamminepalladium nitrate, dichlorodipyridinepalladium, dichloro (2,2'-bipyridyl) palladium, dichloro (phenanthroline) palladium, nitrate (tetramethylphenanthroline) palladium, diphenanthrolinepalladium nitrate, bis (tetramethylmethylnitrate) Phenanthroline) palladium, dichlorobis (triphenylphosphine) palladium, dichlorobis ( Licyclohexylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichloro [1,2-bis (diphenylphosphino) ethane] palladium, dichloro [1,3-bis (diphenylphosphino) propane] palladium, dichloro [1, Examples include complex compounds such as 4-bis (diphenylphosphino) butane] palladium and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium.

  The palladium catalyst may be any of these metals, supported metals, metal salts, and complex compounds, but in terms of high yield, palladium chloride, palladium acetate, π-allyl palladium chloride dimer, bis (dibenzylideneacetone) palladium, Tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichloro [1,2-bis (diphenylphosphino) ethane] palladium, dichloro [1,3-bis (diphenyl) Phosphino) propane] palladium, dichloro [1,4-bis (diphenylphosphino) butane] palladium, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium, palladium / alumina and palladium / charcoal Is desirable, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium is further desirable.

  The palladium catalyst is desirably 0.01 equivalent or more with respect to the 4-amino-2-trifluoromethylquinoline represented by the general formula (1a). It is desirable in that it can be obtained well.

  Examples of the palladium catalyst that can be used in Step A include a catalyst system composed of a palladium compound and a tertiary phosphine. Examples of the tertiary phosphine at this time include triphenylphosphine, trimethylphosphine, triethylphosphine, Tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tri-tert-butylphosphine, trineopentylphosphine, tricyclohexylphosphine, trioctylphosphine, tris (hydroxymethyl) phosphine, tris (2-hydroxyethyl) phosphine , Tris (3-hydroxypropyl) phosphine, tris (2-cyanoethyl) phosphine, (+)-1,2-bis [(2R, 5R) -2,5-diethyl Suhorano] ethane, triallyl phosphine, triamyl phosphine, cyclohexyl diphenylphosphine, may be mentioned methyl diphenyl phosphine.

  Also, ethyl diphenylphosphine, propyldiphenylphosphine, isopropyldiphenylphosphine, butyldiphenylphosphine, isobutyldiphenylphosphine, tert-butyldiphenylphosphine, 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene, 2- (diphenyl) (Phosphino) -2 '-(N, N-dimethylamino) biphenyl, (R)-(+)-2- (diphenylphosphino) -2'-methoxy-1,1'-binaphthyl, (-)-1 , 2-bis [(2R, 5R) -2,5-dimethylphosphorano] benzene, (+)-1,2-bis [(2S, 5S) -2,5-dimethylphosphorano] benzene, (−) -1,2-bis ((2R, 5R) -2,5-diethylphosphorano) benzene, (+)-1,2-bi [(2S, 5S)-2,5-diethyl phosphoramidite Roh] benzene, 1,1'-bis can be mentioned (diisopropylphosphino) ferrocene.

  (-)-1,1'-bis [(2S, 4S) -2,4-diethylphosphorano] ferrocene, (R)-(-)-1-[(S) -2- (dicyclohexylphosphino ) Ferrocenyl] ethyldicyclohexylphosphine, (+)-1,2-bis [(2R, 5R) -2,5-di-isopropylphosphorano] benzene, (−)-1,2-bis [(2S, 5S) -2,5-di-isopropylphosphorano] benzene, (±) -2- (di-tert-butylphosphino) -1,1'-binaphthyl, 2- (di-tert-butylphosphino) biphenyl, 2 -(Dicyclohexylphosphino) biphenyl, 2- (dicyclohexylphosphino) -2'-methylbiphenyl, bis (diphenylphosphino) methane, 1,2-bis (diphenylphosphino) Emissions, 1,2-bis (di-pentafluorophenyl phosphino) ethane, 1,3-bis can be mentioned (diphenylphosphino) propane.

  Also, 1,4-bis (diphenylphosphino) butane, 1,4-bis (diphenylphosphino) pentane, 1,1′-bis (diphenylphosphino) ferrocene, (2R, 3R)-(−)-2 , 3-bis (diphenylphosphino) -bicyclo [2.2.1] hept-5-ene, (2S, 3S)-(+)-2,3-bis (diphenylphosphino) -bicyclo [2.2 .1] Hept-5-ene, (2S, 3S)-(−)-bis (diphenylphosphino) butane, cis-1,2-bis (diphenylphosphino) ethylene, bis (2-diphenylphosphinoethyl) Phenylphosphine, (2S, 4S)-(−)-2,4-1,4-bis (diphenylphosphino) pentane, (2R, 4R)-(−)-2,4-1,4-bis (diphenyl) Phosphino Pentane, R - (+) - 1,2- bis (diphenylphosphino) can be mentioned propane.

  In addition, (2S, 3S)-(+)-1,4-bis (diphenylphosphino) -2,3-O-isopropylidene-2,3-butanediol, tri (2-furyl) phosphine, tri (1 -Naphthyl) phosphine, tris [3,5-bis (trifluoromethyl) phenyl] phosphine, tris (3-chlorophenyl) phosphine, tris (4-chlorophenyl) phosphine, tris (3,5-dimethylphenyl) phosphine, tris ( 3-fluorophenyl) phosphine, tris (4-fluorophenyl) phosphine, tris (2-methoxyphenyl) phosphine, tris (3-methoxyphenyl) phosphine, tris (4-methoxyphenyl) phosphine, tris (2,4,6 -Trimethoxyphenyl) phosphine, tris (pentafluoropheny ) Phosphine, tris [4- (hexyl perfluoro) phenyl] phosphine, may be mentioned tris (2-thienyl) phosphine and the like.

  Also, tris (m-tolyl) phosphine, tris (o-tolyl) phosphine, tris (p-tolyl) phosphine, tris (4-trifluoromethylphenyl) phosphine, tri (2,5-xylyl) phosphine, tri (3 , 5-Xylyl) phosphine, 1,2-bis (diphenylphosphino) benzene, (R)-(+)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, (S) — (−)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2,2 ′ -Bis (diphenylphosphino) -1,1'-biphenyl, (S)-(+)-4,12-bis (diphenylphosphino)-[2.2] -paracyclophane, (R)-(- ) -4, 2-bis (diphenylphosphino)-[2.2] -paracyclophane, (R)-(+)-2,2′-bis (di-p-tolylphosphino) -1,1′-binaphthyl and the like. be able to.

  (S)-(−)-2,2′-bis (di-p-tolylphosphino) -1,1′-binaphthyl, bis (2-methoxyphenyl) phenylphosphine, 1,2-bis (diphenylphosphino) ) Benzene, (1R, 2R)-(+)-N, N′-bis (2′-diphenylphosphinobenzoyl) -1,2-diaminocyclohexane, (1S, 2S)-(+)-N, N ′ -Bis (2'-diphenylphosphinobenzoyl) -1,2-diaminocyclohexane, (±) -N, N'-bis (2'-diphenylphosphinobenzoyl) -1,2-diaminocyclohexane, (1S, 2S )-(−)-N, N′-bis (2-diphenylphosphino-1-naphthoyl) -1,2-diaminocyclohexane, (1R, 2R)-(+)-N, N′-bis (2- Gif Niruhosufino-1-naphthoyl) -1,2-diaminocyclohexane, can be cited (±) -N, N'-bis (2-diphenylphosphino-1-naphthoyl) diaminocyclohexane, and the like.

  Also, tris (diethylamino) phosphine, bis (diphenylphosphino) acetylene, bis (2-diphenylphosphinophenyl) ether, (R)-(−)-1-[(S) -2- (dicyclohexylphosphino) ferrocenyl ] Ethyl diphenylphosphine, (R)-(-)-1-[(S) -2- (diphenylphosphino) ferrocenyl] ethyldi-tert-butylphosphine, bis (p-sulfonatophenyl) phenylphosphine dipotassium salt, 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, (S)-(−)-1- (2-diphenylphosphino-1-naphthyl) isoquinoline, tris (trimethylsilyl) phosphine, 2- Di-tert-butylphosphino-2 ′-(N, N-dimethylamino Biphenyl, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl and 2- (Dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl and the like can be exemplified.

  The tertiary phosphine may be any of the above-mentioned tertiary phosphines, but is triphenylphosphine, trimethylphosphine, triethylphosphine, tributylphosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, trioctyl in terms of good yield. Phosphine, 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 1,2-bis (diphenylphosphine) Fino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1′-bis (diphenylphosphino) ferrocene, (R)-(+)-2 , 2'-bis (diphenylphosphino) -1,1'- Naphthyl, (S)-(−)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl and (±) -2,2′-bis (diphenylphosphino) -1,1′- Binaphthyl is preferred.

  In particular, tri (tert-butyl) phosphine, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 1,2-bis (diphenylphosphino) ethane, 1,3-bis ( Diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1′-bis (diphenylphosphino) ferrocene, (R)-(+)-2,2′-bis (diphenylphosphino) -1,1'-binaphthyl, (S)-(-)-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 2-di-tert-butylphosphino-2 '-(N, N-dimethylamino) biphenyl, 2-di-tert-butylphosphino-2 -Methylbiphenyl, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl and 2- (dicyclohexylphosphino) -2', 4 ', 6' More preferred is triisopropyl-1,1′-biphenyl.

  The amount of the tertiary phosphine used is desirably 0.1 equivalent or more with respect to the palladium compound, and preferably 1 equivalent or more is desirable in that the target product can be obtained in good yield.

  Examples of the base that can be used in the step A include organic bases such as trimethylamine, triethylamine, tripropylamine, tributylamine, pyridine, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium-tert- Mention may be made of inorganic bases such as butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride. An inorganic base is desirable in terms of a good yield, and cesium carbonate, potassium phosphate, and sodium-tert-butoxide are more desirable.

  The amount of the base used is desirable in that the target product can be obtained in good yield when used in an amount of 1 equivalent or more with respect to the 4-amino-2-trifluoromethylquinolines represented by the general formula (1a).

  In Step A, 2-bromo-3,3,3-trifluoropropene itself may be used, but 1,2-dibromo-3,3,3-trifluoropropane is added to trimethylamine, triethylamine, diethylamine, tripropylamine. Alternatively, an organic base such as tributylamine, dibutylamine, piperidine or pyridine may be allowed to act to generate 2-bromo-3,3,3-trifluoropropene in the reaction system, which may be used. The amount of the organic base used is preferably 1 equivalent or more with respect to 1,2-dibromo-3,3,3-trifluoropropane, and 2 equivalents or more is 2-bromo-3,3,3- It is desirable in that trifluoropropene can be generated with good yield.

  The amount of 2-bromo-3,3,3-trifluoropropene to be used is that when 1 equivalent or more of 4-amino-2-trifluoromethylquinoline represented by the general formula (1a) is used, the target product is used. It is desirable in that it can be obtained with good yield.

  This reaction can be carried out in a solvent. For example, tetrahydrofuran, diethyl ether, benzene, toluene, o-xylene, m-xylene, p-xylene, dichloromethane, tetrachloroethane, acetonitrile, ethyl acetate and the like can be used. . Of these, tetrahydrofuran, toluene, dichloromethane, and ethyl acetate are desirable from the viewpoint of good yield, and toluene is more desirable.

  Although there is no restriction | limiting in particular in reaction temperature, It is preferable to carry out at the temperature suitably selected from the range of -10 degreeC to solvent reflux temperature. The reaction time is 10 minutes to 48 hours depending on the reaction temperature.

  In the method for isolating 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by the general formula (1b) from the solution after the reaction There is no restriction | limiting in particular, It can carry out by the general purpose method suitable for products, such as distillation, solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization, or sublimation.

  Some compounds of 4-amino-2-trifluoromethylquinoline represented by the general formula (1a) as a raw material can be produced by the method described in Non-Patent Document 2 or Patent Document 2, It is desirable to manufacture by the process B, the process C, or the process D shown in the above in terms of a good yield and a simple process.

Step B is represented by 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinoline represented by the general formula (1b) and the general formula (1a). To produce a mixture of 4-amino-2-trifluoromethylquinolines.
[Step B]

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、前記と同じ内容を示す。］
工程Ｂで用いることのできるパラジウム触媒は、工程Ａの説明で記載の塩化パラジウム、酢酸パラジウム、π−アリルパラジウムクロリドダイマー、ビス（ジベンジリデンアセトン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロ［１，２−ビス（ジフェニルホスフィノ）エタン］パラジウム、ジクロロ［１，３−ビス（ジフェニルホスフィノ）プロパン］パラジウム、ジクロロ［１，４−ビス（ジフェニルホスフィノ）ブタン］パラジウム、ジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム、パラジウム／アルミナおよびパラジウム／炭素等を用いることができる。

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ]
The palladium catalyst that can be used in Step B is palladium chloride, palladium acetate, π-allyl palladium chloride dimer, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis ( Triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichloro [1,2-bis (diphenylphosphino) ethane] palladium, dichloro [1,3-bis (diphenylphosphino) propane] palladium, dichloro [1, 4-bis (diphenylphosphino) butane] palladium, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium, palladium / alumina, palladium / carbon, and the like can be used.

  The amount of the palladium catalyst used is 0.01 equivalent or more with respect to the 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile represented by the general formula (2). Desirably, preferably 0.5 equivalent or more is desirable in that the desired product can be obtained in good yield.

  Examples of the palladium catalyst that can be used in Step B include a catalyst system composed of a palladium compound and a tertiary phosphine. The tertiary phosphine at this time is triphenylphosphine described in the description of Step A, Trimethylphosphine, tributylphosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, trioctylphosphine, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 1,2-bis ( Diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1'-bis (diphenylphosphino) ferrocene, (R)-(+) -2,2'-bis (diphenylphosphino -1,1'-binaphthyl, (S)-(-)-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, (±) -2,2'-bis (diphenylphosphino) -1,1′-binaphthyl, 2-di-tert-butylphosphino-2 ′-(N, N-dimethylamino) biphenyl, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2- ( Dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl and 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1,1 '-Biphenyl and the like can be used.

  The amount of the tertiary phosphine used is desirably 0.1 equivalent or more with respect to the palladium compound, and preferably 1 equivalent or more is desirable in that the target product can be obtained in good yield.

  The base that can be used in the step B is preferably an inorganic base described in the description of the step A, and more preferably cesium carbonate, potassium phosphate, or sodium-tert-butoxide.

  When the base is used in an amount of 1 equivalent or more based on 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile represented by the general formula (2), the desired product is used. Is desirable in that it can be obtained in good yield.

  In Step B, 2-bromo-3,3,3-trifluoropropene itself may be used, but 1,2-dibromo-3,3,3-trifluoropropane is added to trimethylamine, triethylamine, tripropylamine, An organic base such as butylamine or pyridine may be allowed to act to generate 2-bromo-3,3,3-trifluoropropene in the reaction system, which may be used. The amount of the organic base used is preferably 1 equivalent or more with respect to 1,2-dibromo-3,3,3-trifluoropropane, and 2 equivalents or more is 2-bromo-3,3,3- It is desirable in that trifluoropropene can be generated with good yield.

  The amount of 2-bromo-3,3,3-trifluoropropene used is 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile represented by the general formula (2). It is desirable that 1 equivalent or more is used in terms of the yield of the desired product in good yield. In order to obtain 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by the general formula (1b) with good yield, 2 It is desirable to use more than equivalent amount.

  This reaction can be carried out in a solvent. For example, tetrahydrofuran, diethyl ether, benzene, toluene, o-xylene, m-xylene, p-xylene, dichloromethane, tetrachloroethane, acetonitrile, ethyl acetate and the like can be used. . Of these, tetrahydrofuran, toluene, dichloromethane, and ethyl acetate are desirable from the viewpoint of good yield, and toluene is more desirable.

  Although there is no restriction | limiting in particular in reaction temperature, It is preferable to carry out at the temperature suitably selected from the range of -10 degreeC to solvent reflux temperature. The reaction time is 10 minutes to 48 hours depending on the reaction temperature.

  From the solution after the reaction, 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by the general formula (1b) and the general formula (1a) The 4-amino-2-trifluoromethylquinolines represented by the above can be separated and isolated from each other. The method is not particularly limited, and can be performed by a general-purpose method suitable for a target product such as distillation, solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. . Moreover, only (1b) or (1a) may be obtained depending on the kind of substrate and reaction conditions.

  Some compounds of 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitriles represented by the general formula (2) used as the raw material of Step B are, for example, Izvestiya Akademii Nauk. USSR, Seriya Kimicheskaya, 1965, Vol. 3, pages 450-456 can also be used to produce from anilines and 1,1,1-trifluoroacetone. It is desirable because of its good rate and simple process.

Step C includes 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by the general formula (1b) and / or the general formula (1a). 4-amino-2-trifluoromethylquinoline and / or 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile represented by the general formula (2) It is a method of manufacturing a kind.
[Step C]

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、前記と同じ内容を示す。］
工程Ｃで用いることのできるパラジウム触媒は、工程Ａの説明で記載の塩化パラジウム、酢酸パラジウム、π−アリルパラジウムクロリドダイマー、ビス（ジベンジリデンアセトン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロ［１，２−ビス（ジフェニルホスフィノ）エタン］パラジウム、ジクロロ［１，３−ビス（ジフェニルホスフィノ）プロパン］パラジウム、ジクロロ［１，４−ビス（ジフェニルホスフィノ）ブタン］パラジウム、ジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム、パラジウム／アルミナおよびパラジウム／炭素等を用いることができる。

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ]
The palladium catalyst that can be used in Step C is palladium chloride, palladium acetate, π-allyl palladium chloride dimer, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis ( Triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichloro [1,2-bis (diphenylphosphino) ethane] palladium, dichloro [1,3-bis (diphenylphosphino) propane] palladium, dichloro [1, 4-bis (diphenylphosphino) butane] palladium, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium, palladium / alumina, palladium / carbon, and the like can be used.

  The amount of the palladium catalyst used is desirably 0.01 equivalents or more with respect to the 2-aminobenzonitriles represented by the general formula (3), and preferably 0.5 equivalents or more provides the desired product in good yield. It is desirable in that it can.

  Examples of the palladium catalyst that can be used in Step C include a catalyst system composed of a palladium compound and a tertiary phosphine. The tertiary phosphine at this time is triphenylphosphine described in the description of Step A. , Trimethylphosphine, tributylphosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, trioctylphosphine, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 1,2-bis (Diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1'-bis (diphenylphosphino) ferrocene, (R)-(+ ) -2,2′-bis (diphenylphosphite) ) -1,1′-binaphthyl, (S)-(−)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, (±) -2,2′-bis (diphenylphosphino) ) -1,1′-binaphthyl, 2-di-tert-butylphosphino-2 ′-(N, N-dimethylamino) biphenyl, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2- (Dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl and 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1, 1′-biphenyl and the like can be used.

The amount of the tertiary phosphine used is desirably 0.1 equivalent or more with respect to the palladium compound, and preferably 1 equivalent or more is desirable in that the target product can be obtained in good yield.
The base that can be used in Step C is preferably the inorganic base described in the description of Step A, and more preferably cesium carbonate, potassium phosphate, and sodium tert-butoxide.

  The amount of the base used is desirable in that the target product can be obtained in good yield when used in an amount of 1 equivalent or more with respect to the 2-aminobenzonitriles represented by the general formula (3).

  In Step C, 2-bromo-3,3,3-trifluoropropene itself may be used, but 1,2-dibromo-3,3,3-trifluoropropane is added to trimethylamine, triethylamine, diethylamine, tripropylamine. Alternatively, an organic base such as tributylamine, dibutylamine, piperidine or pyridine may be allowed to act to generate 2-bromo-3,3,3-trifluoropropene in the reaction system, which may be used. The amount of the organic base used is preferably 1 equivalent or more with respect to 1,2-dibromo-3,3,3-trifluoropropane, and 2 equivalents or more is 2-bromo-3,3,3- It is desirable in that trifluoropropene can be generated with good yield.

  When the amount of 2-bromo-3,3,3-trifluoropropene used is 1 equivalent or more with respect to the 2-aminobenzonitriles represented by the general formula (3), the target product can be obtained in good yield. It is desirable in that it can. In order to obtain 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by the general formula (1b) with good yield, 2 It is desirable to use an equivalent amount or more.

  This reaction can be carried out in a solvent. For example, tetrahydrofuran, diethyl ether, benzene, toluene, o-xylene, m-xylene, p-xylene, dichloromethane, tetrachloroethane, acetonitrile, ethyl acetate and the like can be used. . Of these, toluene is desirable because of its good yield.

  Although there is no restriction | limiting in particular in reaction temperature, It is preferable to carry out at the temperature suitably selected from the range of -10 degreeC to solvent reflux temperature. The reaction time is 10 minutes to 48 hours depending on the reaction temperature.

  From the solution after the reaction, 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by general formula (1b), general formula (1a) 4-amino-2-trifluoromethylquinolines represented by the formula: 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitriles represented by the general formula (2): Separate and each can be isolated. The method is not particularly limited, and can be performed by a general-purpose method suitable for a target product such as distillation, solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. . Depending on the type of substrate and the reaction conditions, only (1b) and (1a) or (1a) and (2) or (1b), (1a), or (2) may be obtained.

  Step D is a method for producing 4-amino-2-trifluoromethylquinolines represented by the general formula (1a).

  [Process D]

［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、前記と同じ内容を示す。］
工程Ｄで用いることのできるパラジウム触媒は、工程Ａの説明で記載の塩化パラジウム、酢酸パラジウム、π−アリルパラジウムクロリドダイマー、ビス（ジベンジリデンアセトン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロ［１，２−ビス（ジフェニルホスフィノ）エタン］パラジウム、ジクロロ［１，３−ビス（ジフェニルホスフィノ）プロパン］パラジウム、ジクロロ［１，４−ビス（ジフェニルホスフィノ）ブタン］パラジウム、ジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム、パラジウム／アルミナおよびパラジウム／炭素等を用いることができる。

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ]
The palladium catalyst that can be used in Step D is palladium chloride, palladium acetate, π-allyl palladium chloride dimer, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis ( Triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichloro [1,2-bis (diphenylphosphino) ethane] palladium, dichloro [1,3-bis (diphenylphosphino) propane] palladium, dichloro [1, 4-bis (diphenylphosphino) butane] palladium, dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium, palladium / alumina, palladium / carbon, and the like can be used.

  The amount of the palladium catalyst used is 0.01 equivalent or more with respect to the 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile represented by the general formula (2). Desirably, preferably 0.5 equivalent or more is desirable in that the desired product can be obtained in good yield.

  Examples of the palladium catalyst that can be used in the step D include a catalyst system composed of a palladium compound and a tertiary phosphine. The tertiary phosphine at this time includes, for example, triphenylphosphine described in the description of the step A, Trimethylphosphine, tributylphosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, trioctylphosphine, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 1,2-bis ( Diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1'-bis (diphenylphosphino) ferrocene, (R)-(+) -2,2'-bis (diphenylphosphite ) -1,1′-binaphthyl, (S)-(−)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, (±) -2,2′-bis (diphenylphosphino) ) -1,1′-binaphthyl, 2-di-tert-butylphosphino-2 ′-(N, N-dimethylamino) biphenyl, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2- (Dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl and 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropyl-1, 1′-biphenyl and the like can be used.

  The amount of the tertiary phosphine used is desirably 0.1 equivalent or more with respect to the palladium compound, and preferably 1 equivalent or more is desirable in that the target product can be obtained in good yield.

  The base that can be used in the step D is preferably an inorganic base described in the description of the step A, and more preferably cesium carbonate, potassium phosphate, or sodium-tert-butoxide.

  When the base is used in an amount of 1 equivalent or more based on 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile represented by the general formula (2), the desired product is used. Is desirable in that it can be obtained in good yield.

  This reaction can be carried out in a solvent. For example, tetrahydrofuran, diethyl ether, benzene, toluene, o-xylene, m-xylene, p-xylene, dichloromethane, tetrachloroethane, acetonitrile, ethyl acetate and the like can be used. . Of these, toluene is desirable because of its good yield.

  Although there is no restriction | limiting in particular in reaction temperature, It is preferable to carry out at the temperature suitably selected from the range of -10 degreeC to solvent reflux temperature. The reaction time is 10 minutes to 48 hours depending on the reaction temperature.

  There is no particular limitation on the method for isolating the 4-amino-2-trifluoromethylquinoline represented by the general formula (1a) from the solution after the reaction, and distillation, solvent extraction, column chromatography, preparative thin layer It can be performed by a general-purpose method suitable for a target product such as chromatography, preparative liquid chromatography, recrystallization or sublimation.

  The present invention provides 2-trifluoromethylquinolines which are expected as useful intermediates for medicines, agricultural chemicals, electronic materials and the like, and an efficient production method thereof.

  Next, although a reference example and an Example demonstrate this invention in detail, this invention is not limited to these.

(Reference Example 1)
2-Aminobenzonitrile (118.0 mg, 1.0 mmol) and 1,1,1-trifluoroacetone (110 μL, 1.23 mmol) were dissolved in benzene (0.5 mL), and the mixture was heated and stirred at 110 ° C. for 15 hours. 2,2,2-trifluoroethanol was added as an internal standard, and 2- [N- (1,1,1-trifluoro-2-propylidene) amino] benzonitrile was produced at a yield of 6% by ¹⁹ F-NMR. It was confirmed that it was generated.

(Reference Example 2)
2-aminobenzonitrile (118.0 mg, 1.0 mmol), 1,1,1-trifluoroacetone (110 μL, 1.23 mmol) and cesium carbonate (391 mg, 1.2 mmol) were dissolved in benzene (0.5 mL), and the mixture was dissolved at room temperature. Stir with heating for hours. 2,2,2-trifluoroethanol was added as an internal standard, and 2- [N- (1,1,1-trifluoro-2-propylidene) amino] benzonitrile was produced at a yield of 42% by ¹⁹ F-NMR. I confirmed that

(Example 1)
In a 10 mL test tube with a screw cap, 57.5 mg (0.10 mmol) of bis (dibenzylideneacetone) palladium, 391 mg (1.2 mmol) of cesium carbonate, 83.2 mg of 1,1′-bis (diphenylphosphino) ferrocene ( 0.15 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While the test tube was cooled in an ice bath, 118.0 mg (1.0 mmol) of 2-aminobenzonitrile and 250 μL (2.4 mmol) of 2-bromo-3,3,3-trifluoropropene were added. This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 2- [N- (1,1,1-trifluoro-2-propylidene) was analyzed by ¹⁹ F-NMR. Amino] benzonitrile was produced at a rate of 3%, 4-amino-2-trifluoromethylquinoline was produced at a rate of 41%, and 4- [N- (1,1,1-trifluoro-2-propylidene) amino]- It was confirmed that 2-trifluoromethylquinoline was produced at a production rate of 17%. The filtrate was concentrated and separated and purified with a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) to give 4-amino-2-trifluoromethylquinoline (brown solid, yield 35%). 74.3 mg) and 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline (brown oil, 11% yield, 33.7 mg) each Obtained by isolation.

2- [N- (1,1,1-trifluoro-2-propylidene) amino] benzonitrile
¹⁹ F-NMR (CDCl ₃ , ppm): −75.0.

4-amino-2-trifluoromethylquinoline
¹ H-NMR (CDCl ₃ , ppm): 5.17 (s, 2H), 6.89 (s, 1H), 7.52 (ddd, J _HH = 8.4 Hz, J _HH = 7.0 Hz, J _{HH = 1.2Hz, 1H), 7.71} (ddd, J HH = 8.5Hz, J HH = 7.0Hz, J HH = 1.4Hz, 1H), 7.79 (d, J HH = 8. 4 Hz, 1 H), 8.09 (d, J _HH = 8.5 Hz, 1 H).
¹³ C-NMR (CDCl ₃ , ppm): 99.1 (q, J _CF = 2.4 Hz), 118.7, 120.2, 121.8 (q, J _CF = 275.3 Hz), 126.6 , 130.4, 130.6, 148.0, 148.6 (q, J _CF = 33.6 Hz), 151.4.
¹⁹ F-NMR (CDCl ₃ , ppm): −68.2.

2-Trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline
¹ H-NMR (CDCl ₃ , ppm): 2.04 (s, 3H), 7.06 (s, 1H), 7.66-7.67 (m, 2H), 7.86 (ddd, J _{HH = 8.5Hz, J HH = 5.7Hz,} J HH = 2.7Hz, 1H), 8.25 (d, J HH = 8.5Hz, 1H).
_{^{13 C-NMR (CDCl 3,}} ppm): 15.5,103.7,119.8 (q, J CF = 279.0Hz), 120.9,122.1 (q, J CF = 275.4Hz) , 123.2, 129.7, 131.3, 132.3, 148.9, 149.2 (q, J _CF = 34.9 Hz), 154.5, 162.0 (q, J _CF = 35. 0 Hz).
¹⁹ F-NMR (CDCl ₃ , ppm): −68.0, −74.7.

(Example 2)
In a 10 mL test tube with a screw cap, 57.5 mg (0.10 mmol) of bis (dibenzylideneacetone) palladium, 391 mg (1.2 mmol) of cesium carbonate, 83.2 mg of 1,1′-bis (diphenylphosphino) ferrocene ( 0.15 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While cooling the test tube in an ice bath, 132.2 mg (1.0 mmol) of 2-amino-6-methylbenzonitrile and 250 μL (2.4 mmol) of 2-bromo-3,3,3-trifluoropropene were added. . This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 6-methyl-2- [N- (1,1,1-trifluoro-) was analyzed by ¹⁹ F-NMR. 2-propylidene) amino] benzonitrile is 43% yield, 4-amino-5-methyl-2-trifluoromethylquinoline is 7% yield, 5-methyl-2-trifluoromethyl-4- [N It was confirmed that-(1,1,1-trifluoro-2-propylidene) amino] quinoline was produced at a production rate of 13%. The filtrate is concentrated and then separated and purified with a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) to give 6-methyl-2- [N- (1,1,1-trifluoro). -2-propylidene) amino] benzonitrile (yellow oil, 33% yield, 74.6 mg) and 5-methyl-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2) -Propyridene) amino] quinoline (brown oil, 72% yield, 230.1 mg) each isolated.

6-Methyl-2- [N- (1,1,1-trifluoro-2-propylidene) amino] benzonitrile
¹ H-NMR (CDCl ₃ , ppm): 2.07 (s, 3H), 2.57 (s, 3H), 6.70 (d, J _HH = 7.9 Hz, 1H), 7.12 (d , J _HH = 7.8 Hz, 1 H), 7.47 (dd, J _HH = 7.9 Hz, J _HH = 7.8 Hz, 1 H).
¹³ C-NMR (CDCl ₃ , ppm): 15.2, 20.7, 103.1, 115.0, 116.0, 119.2 (q, J _CF = 278.7 Hz), 126.4, 133 2, 143.4, 150.6, 160.4 (q, J _CF = 35.0 Hz).
¹⁹ F-NMR (CDCl ₃ , ppm): −74.9.
4-Amino-5-methyl-2-trifluoromethylquinoline
¹⁹ F-NMR (CDCl ₃ , ppm): −68.7.

5-Methyl-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline
¹ H-NMR (CDCl ₃ , ppm): 2.06 (s, 3H), 2.61 (s, 3H), 6.83 (s, 1H), 7.41 (d, J _HH = 7.1 Hz) _{, 1H), 7.69 (dd,} J HH = 8.5Hz, J HH = 7.1Hz, 1H), 8.08 (d, J HH = 8.5Hz, 1H).
¹³ C-NMR (CDCl ₃ , ppm): 15.5, 24.3, 103.9, 119.2 (q, J _CF = 276.7), 120.8, 122.4 (q, J _CF = 275.3 Hz), 129.0, 130.9, 131.2, 135.0, 147.6 (q, J _CF = 35.0 Hz), 149.8, 154.9, 157.9 (q, J _CF = 35.2 Hz).
¹⁹ F-NMR (CDCl ₃ , ppm): −68.1, −75.3.

(Example 3)
The reaction was conducted in the same manner as in Example 2 except that cesium carbonate in Example 2 was changed to 782 mg. By ¹⁹ F-NMR, 6-methyl-2- [N- (1,1,1-trifluoro-2-phenyl) was used. Propyridene) amino] benzonitrile was produced at a rate of 21%, 4-amino-5-methyl-2-trifluoromethylquinoline was produced at a rate of 6%, and 5-methyl-2-trifluoromethyl-4- [N- ( It was confirmed that 1,1,1-trifluoro-2-propylidene) amino] quinoline was produced at a production rate of 73%. The filtrate was concentrated and then separated and purified with a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) to give 5-methyl-2-trifluoromethyl-4- [N- (1, 1,1-trifluoro-2-propylidene) amino] quinoline (brown oil, 72% yield, 230.1 mg) was obtained by isolation.

Example 4
In a 10 mL test tube with a screw cap, bis (dibenzylideneacetone) palladium 57.5 mg (0.10 mmol), cesium carbonate 782 mg (2.4 mmol), 1,1′-bis (diphenylphosphino) ferrocene 83.2 mg ( 0.15 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While the test tube was cooled in an ice bath, 132.0 mg (1.0 mmol) of 2-amino-4-methylbenzonitrile and 250 μL (2.4 mmol) of 2-bromo-3,3,3-trifluoropropene were added. . This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 4-methyl-2- [N- (1,1,1-trifluoro-) was analyzed by ¹⁹ F-NMR. 2-propylidene) amino] benzonitrile was produced at a rate of 4%, 4-amino-7-methyl-2-trifluoromethylquinoline was produced at a rate of 26%, and 7-methyl-2-trifluoromethyl-4- [N It was confirmed that-(1,1,1-trifluoro-2-propylidene) amino] quinoline was produced at a production rate of 44%. The filtrate was concentrated and then separated and purified with a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) to give 4-amino-7-methyl-2-trifluoromethylquinoline (brown solid, Yield 17%, 39.2 mg) was isolated and obtained.

4-Methyl-2- [N- (1,1,1-trifluoro-2-propylidene) amino] benzonitrile
¹⁹ F-NMR (CDCl ₃ , ppm): −75.0.
4-Amino-7-methyl-2-trifluoromethylquinoline
¹ H-NMR (CDCl ₃ , ppm): 2.54 (s, 3H), 4.94 (s, 2H), 6.86 (s, 1H), 7.38 (dd, J _HH = 8.6 Hz) , J _HH = 1.6 Hz, 1H), 7.68 (d, J _HH = 8.6 Hz, 1H), 7.90 (s, 1H).
_{^{13 C-NMR (CDCl 3,}} ppm): 21.6,99.4 (q, J CF = 2.4Hz), 116.6,119.7,122.5 (q, J CF = 275.2Hz) , 128.8, 129.7, 141.0, 148.3, 149.5 (q, J _CF = 33.5 Hz), 151.0.
¹⁹ F-NMR (CDCl ₃ , ppm): −68.4.
7-Methyl-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline
¹⁹ F-NMR (CDCl ₃ , ppm): −68.2, −74.8.

(Example 5)
In a 10 mL test tube with a screw cap, bis (dibenzylideneacetone) palladium 57.5 mg (0.10 mmol), cesium carbonate 782 mg (2.4 mmol), 1,1′-bis (diphenylphosphino) ferrocene 83.2 mg ( 0.15 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While the test tube was cooled in an ice bath, 152.4 mg (1.0 mmol) of 2-amino-5-chlorobenzonitrile and 250 μL (2.4 mmol) of 2-bromo-3,3,3-trifluoropropene were added. . This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 4-amino-6-chloro-2-trifluoromethylquinoline was produced at a rate of 66% by ¹⁹ F-NMR. Thus, it was confirmed that 6-chloro-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline was produced at a production rate of 5%. After concentrating the filtrate, separation and purification with a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) gave 4-amino-6-chloro-2-trifluoromethylquinoline (yellow solid, Yield 39%, 95.7 mg) was isolated and obtained.

4-amino-6-chloro-2-trifluoromethylquinoline
¹ H-NMR (CDCl ₃ , ppm): 4.96 (s, 2H), 6.94 (s, 1H), 7.68 (dd, J _HH = 9.0 Hz, J _HH = 2.2 Hz, 1H ), 7.78 (d, J _HH = 2.2 Hz, 1 H), 8.05 (d, J _HH = 9.0 Hz, 1 H).
¹³ C-NMR (CDCl ₃ , ppm): 99.9 (q, J _CF = 2.3 Hz), 120.1, 120.2, 122.3 (q, J _CF = 275.5 Hz), 132.2 , 133.1, 133.4, 147.4, 149.7 (q, J _CF = 33.9 Hz), 151.2.
¹⁹ F-NMR (CDCl ₃ , ppm): −68.6.
6-Chloro-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline
¹⁹ F-NMR (CDCl ₃ , ppm): −68.1, −75.0.

(Example 6)
In a 10 mL test tube with a screw cap, bis (dibenzylideneacetone) palladium 57.5 mg (0.10 mmol), cesium carbonate 782 mg (2.4 mmol), 1,1′-bis (diphenylphosphino) ferrocene 83.2 mg ( 0.15 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While the test tube was cooled in an ice bath, 153.0 mg (1.0 mmol) of 2-amino-4-chlorobenzonitrile and 250 μL (2.4 mmol) of 2-bromo-3,3,3-trifluoropropene were added. . This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 4-amino-7-chloro-2-trifluoromethylquinoline was produced at a rate of 35% by ¹⁹ F-NMR. It was confirmed that it was generated by. The filtrate was concentrated and purified by a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) to give 4-amino-7-chloro-2-trifluoromethylquinoline (brown solid, yield). 10%, 25.3 mg) was obtained isolated.

4-Amino-7-chloro-2-trifluoromethylquinoline
¹ H-NMR (CDCl ₃ , ppm): 5.01 (s, 2H), 6.90 (s, 1H), 7.50 (dd, J _HH = 9.0 Hz, J _HH = 2.1 Hz, 1H ), 7.72 (d, J _HH = 9.0 Hz, 1 H), 8.11 (d, J _HH = 2.1 Hz, 1 H).
¹³ C-NMR (CDCl ₃ , ppm): 99.6 (q, J _CF = 2.4 Hz), 117.0, 121.5, 121.5 (q, J _CF = 275.4 Hz), 127.5 , 129.6, 136.6, 148.7, 149.7 (q, J _CF = 34.0 Hz), 151.2.
¹⁹ F-NMR (CDCl ₃ , ppm): −68.6.

(Example 7)
In a 10 mL test tube with a screw cap, bis (dibenzylideneacetone) palladium 57.5 mg (0.10 mmol), cesium carbonate 782 mg (2.4 mmol), 1,1′-bis (diphenylphosphino) ferrocene 83.2 mg ( 0.15 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While cooling the test tube in an ice bath, 179.0 mg (1.0 mmol) of 2-amino-4,5-dimethoxybenzonitrile and 250 μL (2.4 mmol) of 2-bromo-3,3,3-trifluoropropene were added. added. This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through celite, 2,2,2-trifluoroethanol was added as an internal standard, and 4,5-dimethoxy-2- [N- (1,1,1-trimethyl) was analyzed by ¹⁹ F-NMR. Fluoro-2-propylidene) amino] benzonitrile at a yield of 19%, 4-amino-6,7-dimethoxy-2-trifluoromethylquinoline at a yield of 23%, and 6,7-dimethoxy-2-trifluoro It was confirmed that methyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline was produced at a production rate of 33%. The filtrate was concentrated and separated and purified with a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) to give 4,5-dimethoxy-2- [N- (1,1,1- Trifluoro-2-propylidene) amino] benzonitrile (yellow liquid, 11% yield, 29.9 mg), 4-amino-6,7-dimethoxy-2-trifluoromethylquinoline (brown solid, 20% yield) 54.4 mg) and 6,7-dimethoxy-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline (white pink solid, yield 23%, 83 .9 mg) were obtained by isolation.

4,5-Dimethoxy-2- [N- (1,1,1-trifluoro-2-propylidene) amino] benzonitrile
¹ H-NMR (CDCl ₃ , ppm): 2.12 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 6.40 (s, 1H), 7.03 (S, 1H).
¹³ C-NMR (CDCl ₃ , ppm): 15.3, 56.4, 92.7, 103.0, 113.7, 116.4, 119.2 (q, J _CF = 278.7 Hz), 145 .5, 146.6, 153.7, 161.0 (q, J _CF = 34.8 Hz).
¹⁹ F-NMR (CDCl ₃ , ppm): −74.8.

4-Amino-6,7-dimethoxy-2-trifluoromethylquinoline
¹ H-NMR (CDCl ₃ , ppm): 3.94 (s, 3H), 3.96 (s, 3H), 5.00 (s, 2H), 6.84 (s, 1H), 6.98 (S, 1H), 7.39 (s, 1H).
¹³ C-NMR (CDCl ₃ , ppm): 56.0, 56.2, 98.6, 99.0 (q, J _CF = 2.5 Hz), 109.0, 113.5, 122.0 (q , J _CF = 274.7 Hz), 145.2, 146.6 (q, J _CF = 33.6 Hz), 149.9, 153.1, 171.3.
¹⁹ F-NMR (CDCl ₃ , ppm): −67.9.

6,7-Dimethoxy-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline
¹ H-NMR (CDCl ₃ , ppm): 2.06 (s, 3H), 3.99 (s, 3H), 4.06 (s, 3H), 6.79 (s, 1H), 6.94 (S, 1H), 7.54 (s, 1H).
¹³ C-NMR (CDCl ₃ , ppm): 15.3, 56.1, 56.4, 99.4, 102.8, 108.8, 115.9, 119.2 (q, J _CF = 278. 6 Hz), 121.6 (q, J _CF = 274.8 Hz), 145.5, 146.1 (q, J _CF = 34.7 Hz), 151.3, 151.6, 154.1, 160.6 (Q, J _CF = 35.2 Hz).
¹⁹ F-NMR (CDCl ₃ , ppm): −67.6, −74.6.

(Example 8)
In a 10 mL test tube with a screw cap, 57.5 mg (0.10 mmol) of bis (dibenzylideneacetone) palladium, 782 mg (2.4 mmol) of cesium carbonate, 83.2 mg of 1,1′-bis (diphenylphosphino) ferrocene ( 0.15 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While cooling the test tube in an ice bath, 136.0 mg (1.0 mmol) of 2-amino-6-fluorobenzonitrile and 250 μL (2.4 mmol) of 2-bromo-3,3,3-trifluoropropene were added. . This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 4-amino-5-fluoro-2-trifluoromethylquinoline was produced by 48% by ¹⁹ F-NMR. Thus, it was confirmed that 5-fluoro-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline was produced at a production rate of 20%. After concentrating the filtrate, separation and purification with a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) gave 4-amino-5-fluoro-2-trifluoromethylquinoline (brown solid, 48% yield, 110.9 mg) was isolated and obtained. In addition, a crude product of 5-fluoro-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline (brown oily substance) was also obtained.

4-amino-5-fluoro-2-trifluoromethylquinoline
¹ H-NMR (CDCl ₃ , ppm): 5.61 (s, 2H), 6.81 (s, 1H), 7.14 (ddd, J _HF = 13.7 Hz, J _HH = 7.8 Hz, J _{HH = 0.8Hz, 1H), 7.61} (ddd, J HH = 8.4Hz, J HF = 8.1Hz, J HH = 7.8Hz, 1H), 7.87 (d, J HH = 8. 4 Hz, 1 H).
¹³ C-NMR (CDCl ₃ , ppm): 99.8 (q, J _CF = 2.1 Hz), 109.6 (d, J _CF = 9.0 Hz), 111.4 (d, J _CF = 23. 0 Hz), 122.2 (q, J _CF = 275.3 Hz), 127.3 (d, J _CF = 3.8 Hz), 130.7 (d, J _CF = 11.0 Hz), 150.4 (q , J _CF = 35.4 Hz), 151.2, 152.4 (d, J _CF = 2.7 Hz), 160.4 (d, J _CF = 250.7 Hz).
¹⁹ F-NMR (CDCl ₃ , ppm): −68.7, −115.1 (ddd, J _FH = 13.7 Hz, J _FH = 8.1 Hz, J _FH = 4.0 Hz).

5-Fluoro-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline
¹ H-NMR (CDCl ₃ , ppm): 2.06 (s, 3H), 7.02 (s, 1H), 7.30 (ddd, J _HF = 11.5 Hz, J _HH = 8.0 Hz, J _{HH = 0.6Hz, 1H), 7.78} (ddd, J HH = 8.4Hz, J HH = 8.0Hz, J HF = 5.6Hz, 1H), 8.06 (d, J HH = 8. 4 Hz, 1 H).
¹³ C-NMR (CDCl ₃ , ppm): 15.7, 105.4, 111.7 (d, J _CF = 10.8 Hz), 114.2 (d, J _CF = 20.9 Hz), 119.7 (Q, J _CF = 278.7 Hz), 121.8 (q, J _CF = 275.6 Hz), 127.4 (d, J _CF = 4.5 Hz), 131.9 (d, J _CF = 15. 8 Hz), 144.1 (q, J _CF = 34.7 Hz), 150.2 (q, J _CF = 35.2 Hz), 150.4, 153.6 (d, J _CF = 3.6 Hz), 158 .6 (d, J _CF = 259.4 Hz).
¹⁹ F-NMR (CDCl ₃ , ppm): −68.3, −72.1, −111.8 (dd, J _FH = 11.5 Hz, J _FH = 5.6 Hz).

Example 9
In a 10 mL test tube with a screw cap, 28.8 mg (0.05 mmol) of bis (dibenzylideneacetone) palladium, 391 mg (1.2 mmol) of cesium carbonate, 41.6 mg of 1,1′-bis (diphenylphosphino) ferrocene ( 0.075 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While the test tube was cooled in an ice bath, 63.1-methyl-2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile 113.1 mg (0. 5 mmol) was added. This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 4-amino-5-methyl-2-trifluoromethylquinoline was produced at a yield of 33% by ¹⁹ F-NMR. And confirmed that it was generated.

(Example 10)
In a 10 mL test tube with a screw cap, 28.8 mg (0.05 mmol) of bis (dibenzylideneacetone) palladium, 196 mg (0.6 mmol) of cesium carbonate, 41.6 mg of 1,1′-bis (diphenylphosphino) ferrocene ( 0.075 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 1 mL of toluene was added and stirred at room temperature for 5 minutes. While the test tube was cooled in an ice bath, 63.1-methyl-2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile 113.1 mg (0. 5 mmol) and 70 μL (0.67 mmol) of 2-bromo-3,3,3-trifluoropropene. This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, as an internal standard 2,2,2-trifluoroethanol was ^added, 19 F-NMR with 4-amino-5-methyl-2-trifluoromethyl quinoline product 9% Thus, it was confirmed that 5-methyl-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline was produced at a production rate of 22%. The filtrate was concentrated and then separated and purified with a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) to give 5-methyl-2-trifluoromethyl-4- [N- (1, 1,1-trifluoro-2-propylidene) amino] quinoline (brown oil, 14% yield, 22.4 mg) was isolated.

¹ H-NMR (CDCl ₃ , ppm): 2.06 (s, 3H), 2.61 (s, 3H), 6.83 (s, 1H), 7.41 (d, J _HH = 7.1 Hz) _{, 1H), 7.69 (dd,} J HH = 8.5Hz, J HH = 7.1Hz, 1H), 8.08 (d, J HH = 8.5Hz, 1H).
_{^{13 C-NMR (CDCl 3,}} ppm): 15.5,24.3,103.9,119.2 (q, J CF = 276.7Hz), 120.8,122.4 (q, J CF = 275.3 Hz), 129.0, 130.9, 131.2, 135.0, 147.6 (q, J _CF = 35.0 Hz), 149.8, 154.9, 157.9 (q, J _CF = 35.2 Hz).
¹⁹ F-NMR (CDCl ₃ , ppm): −68.1, −75.3.

(Reference Example 3)
Cesium carbonate (391 mg, 1.2 mmol) was placed in a 10 mL test tube with a screw cap, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While the test tube was cooled in an ice bath, 63.1-methyl-2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile 113.1 mg (0. 5 mmol) was added. This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 4-amino-5-methyl-2-trifluoromethylquinoline and 5-methyl- were added by ¹⁹ F-NMR. It was confirmed that 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline was not produced.

(Reference Example 4)
Sodium-tert-butoxide (23.1 mg, 0.24 mmol) was placed in a 10 mL test tube with a screw cap, and the inside of the test tube was replaced with argon gas. Next, 0.5 mL of toluene was added and stirred at room temperature for 5 minutes. While the test tube was cooled in an ice bath, 22.6 mg (0.2 mg) of 6-methyl-2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile obtained in Example 2 was obtained. 1 mmol) was added. This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 4-amino-5-methyl-2-trifluoromethylquinoline and 5-methyl- were added by ¹⁹ F-NMR. It was confirmed that 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline was not produced.

(Reference Example 5)
In Reference Example 4, instead of sodium-tert-butoxide, 151.4 mg (3.8 mmol) of sodium hydroxide was added, and the reaction was carried out in the same manner as in Reference Example 4. As a result of ¹⁹ F-NMR, 4-amino-5-methyl It was confirmed that 2-trifluoromethylquinoline and 5-methyl-2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene) amino] quinoline were not formed.

(Example 11)
In a 10 mL test tube with a screw cap, bis (dibenzylideneacetone) palladium 11.5 mg (0.02 mmol), cesium carbonate 78.2 mg (0.24 mmol), 1,1′-bis (diphenylphosphino) ferrocene 16. 6 mg (0.03 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 0.5 mL of toluene was added and stirred at room temperature for 5 minutes. While cooling the test tube in an ice bath, 42.4 mg (0.20 mmol) of 4-amino-2-trifluoromethylquinoline obtained in Example 1 and 30 μL of 2-bromo-3,3,3-trifluoropropene were obtained. (0.29 mmol) was added. This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 2-trifluoromethyl-4- [N- (1,1,1-trimethyl) was analyzed by ¹⁹ F-NMR. It was confirmed that fluoro-2-propylidene) amino] quinoline was produced at a production rate of 19%.

Example 12
In a 10 mL test tube with a screw cap, 13.6 mg (0.024 mmol) of bis (dibenzylideneacetone) palladium, 92.9 mg (0.28 mmol) of cesium carbonate, 1,1′-bis (diphenylphosphino) ferrocene. 5 mg (0.037 mmol) was added, and the inside of the test tube was replaced with argon gas. Next, 2 mL of toluene was added and stirred at room temperature for 5 minutes. While cooling the test tube in an ice bath, 54.0 mg (0.23 mmol) of 4-amino-5-fluoro-2-trifluoromethylquinoline obtained in Example 8 and 2-bromo-3,3,3- Trifluoropropene 250 μL (2.4 mmol) was added. This was heated at 110 ° C. for 15 hours and stirred. After completion of the reaction, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 5-fluoro-2-trifluoromethyl-4- [N- (1,1) was detected by ¹⁹ F-NMR. , 1-trifluoro-2-propylidene) amino] quinoline was confirmed to be produced at a production rate of 90%. The filtrate is concentrated and then separated and purified by a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) to give 5-fluoro-2-trifluoromethyl-4- [N- (1, 1,1-trifluoro-2-propylidene) amino] quinoline (brown oil, 80% yield, 59.6 mg) was obtained by isolation.

¹ H-NMR (CDCl ₃ , ppm): 2.06 (s, 3H), 7.02 (s, 1H), 7.30 (ddd, J _HF = 11.5 Hz, J _HH = 8.0 Hz, J _{HH = 0.6Hz, 1H), 7.78} (ddd, J HH = 8.4Hz, J HH = 8.0Hz, J HH = 5.6Hz, 1H), 8.06 (d, J HH = 8. 4 Hz, 1 H).
¹³ C-NMR (CDCl ₃ , ppm): 15.7, 105.4, 111.7 (d, J _CF = 10.8 Hz), 114.2 (d, J _CF = 20.9 Hz), 119.7 (Q, J _CF = 278.7 Hz), 121.8 (q, J _CF = 275.6 Hz), 127.4 (d, J _CF = 4.5 Hz), 131.9 (d, J _CF = 15. 8 Hz), 144.1 (q, J _CF = 34.7 Hz), 150.2 (q, J _CF = 35.2 Hz), 150.4, 153.6 (d, J _CF = 3.6 Hz), 158 .6 (d, J _CF = 259.4 Hz).
¹⁹ F-NMR (CDCl ₃ , ppm): −68.3, −72.1, −111.8 (dd, J _FH = 11.5 Hz, J _FH = 5.6 Hz).

(Reference Example 6)
In a 20 mL two-necked eggplant flask, 37 mg (0.97 mmol) of lithium aluminum hydride was placed, and the inside of the reaction vessel was replaced with argon gas. Next, 1 mL of dehydrated diethyl ether was added and stirred at room temperature for 5 minutes. To this was added 2 mL of dehydrated ether in which 336.5 mg (1.10 mmol) of 4- [N- (1,1,1-trifluoro-2-propylidene) amino] -2-trifluoromethylquinoline was dissolved. Stir for 24 hours. After completion of the reaction, ethyl acetate was added, the solid was filtered through Celite, 2,2,2-trifluoroethanol was added as an internal standard, and 4- [N- (1,1,1-trifluoro) was detected by ¹⁹ F-NMR. -2-propyl) amino] -2-trifluoromethylquinoline was confirmed to be produced at a production rate of 92%. The filtrate was concentrated and purified by a silica gel column (eluent hexane: ethyl acetate = 8: 1 to 1: 1) to obtain a pale yellow solid (yield 83%, 282.5 mg).

¹ H-NMR (CDCl ₃ , ppm): 1.60 (d, J _HH = 6.8 Hz, 3H), 4.36-4.44 (m, 1H), 5.12 (brd, J _HH = 8 .7 Hz, 1 H), 6.87 (s, 1 H), 7.59 (ddd, J _HH = 8.1 Hz, J _HH = 7.3 Hz, J _HH = 1.0 Hz, 1 H), 7.76 (ddd , J _HH = 8.4 Hz, J _HH = 7.3 Hz, J _HH = 1.2 Hz, 1 H), 7.79 (d, J _HH = 8.1 Hz, 1 H), 8.14 (d, J _HH = 8.4 Hz, 1 H).
¹³ C-NMR (CDCl ₃ , ppm): 14.9 (q, J _CF = 2.2 Hz), 50.5 (q, J _CF = 31.5 Hz), 95.3, 118.4, 118.9 , 121.7 (q, J _CF = 275.5 Hz), 125.6 (q, J _CF = 282.5 Hz), 127.1, 130.5, 131.0, 147.7, 148.8 (q , J _CF = 33.7 Hz), 149.5.
¹⁹ F-NMR (CDCl ₃ , ppm): −77.2 (d, J _FH = 6.3 Hz), −68.4.

Claims (6)

General formula (1)

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, C1-C4 alkoxy group, C2-C5 acyl group, (C1-C4 alkoxy) carbonyl group, (C1-C4 alkyl) amino group, Di (C1-C4) Alkyl) amino group, cyano group, hydroxyl group or halogen atom. R ₅ and R ₆ represent a hydrogen atom or a 1,1,1-trifluoro-2-propylidene group in which R ₅ and R ₆ are combined. 4-amino-2-trifluoromethylquinoline (provided that 4-amino-2-trifluoromethylquinoline, 4-amino-6,8-dichloro-2-trifluoromethylquinoline) 4-amino-8-iodo-2-trifluoromethylquinoline, 4-amino-8-bromo-2-trifluoromethylquinoline, 4-amino-8-chloro-2-trifluoromethylquinoline, 4-amino- 8-fluoro-2-trifluoromethylquinoline, 4-amino-6-iodo-2-trifluoromethylquinoline, 4-amino-6-chloro-2-trifluoromethylquinoline, 4-amino-6-fluoro-2 -Trifluoromethylquinoline, 4-amino-6-bromo-2-trifluoromethylquinoline and 4-amino-6-methyl Except 2-trifluoromethyl quinoline). General formula (1a)

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, C1-C4 alkoxy group, C2-C5 acyl group, (C1-C4 alkoxy) carbonyl group, (C1-C4 alkyl) amino group, Di (C1-C4) Alkyl) amino group, cyano group, hydroxyl group or halogen atom. Wherein 2-amino-2-trifluoromethylquinolines and 2-bromo-3,3,3-trifluoropropene are reacted in the presence of a palladium catalyst and a base, 1b)

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ] The manufacturing method of 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinoline represented by this. General formula (2)

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, C1-C4 alkoxy group, C2-C5 acyl group, (C1-C4 alkoxy) carbonyl group, (C1-C4 alkyl) amino group, Di (C1-C4) Alkyl) amino group, cyano group, hydroxyl group or halogen atom. 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile and 2-bromo-3,3,3-trifluoropropene represented by a palladium catalyst and a base General formula (1b), characterized by reacting below

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by the general formula (1a)

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ] The manufacturing method of 4-amino- 2-trifluoromethyl quinoline represented by this. General formula (3)

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, C1-C4 alkoxy group, C2-C5 acyl group, (C1-C4 alkoxy) carbonyl group, (C1-C4 alkyl) amino group, Di (C1-C4) Alkyl) amino group, cyano group, hydroxyl group or halogen atom. A 2-aminobenzonitrile represented by the general formula (1b) is reacted with 2-bromo-3,3,3-trifluoropropene in the presence of a palladium catalyst and a base.

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. 2-trifluoromethyl-4- [N- (1,1,1-trifluoro-2-propylidene)] aminoquinolines represented by the general formula (1a)

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ] 4-amino-2-trifluoromethylquinolines represented by the general formula (2)

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ] 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitrile represented by this. General formula (2)

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, C1-C4 alkoxy group, C2-C5 acyl group, (C1-C4 alkoxy) carbonyl group, (C1-C4 alkyl) amino group, Di (C1-C4) Alkyl) amino group, cyano group, hydroxyl group or halogen atom. Wherein 2- [N- (1,1,1-trifluoro-2-propylidene)] aminobenzonitriles are reacted in the presence of a palladium catalyst and a base. )

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same contents as described above. ] The manufacturing method of 4-amino- 2-trifluoromethyl quinoline represented by this. The production method according to any one of claims 2 to 5, wherein the palladium catalyst is a catalyst system comprising a palladium compound and a tertiary phosphine.