JP2012067060A - Method for producing aniline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently and economically producing aniline derivatives which are intermediates of pyrazole carboxylic acid anilide derivatives, being acaricides, on an industrial scale.SOLUTION: The method for producing an aniline derivative represented by formula (I) or a salt thereof includes making a compound of formula (III) and a compound of formula (II) react with each other in the presence of a Lewis acid (in formulae, each of Rand Ris an alkyl, an aryl or the like, Ris H, an alkyl or the like, M is an alkali metal, X is O or S, and R is an alkyl or the like).

Description

  The present invention relates to a method for producing aniline derivatives or salts thereof which are intermediates of pyrazole carboxylic acid anilide derivatives which are acaricides.

  Certain alkoxyalkylaniline derivatives are known to be useful as intermediates for pharmaceuticals, agricultural chemicals and the like, particularly as agricultural and horticultural insecticides and acaricides (for example, Patent Documents 1 and 2). reference.). The aniline derivatives are produced by reacting perfluoroalkylaniline with sodium methoxide.

JP 2004-189738 A JP 2007-308470 A

  However, the disclosed production method takes a long reaction time and is not an industrially advantageous production method with a low yield. An object of the present invention is to provide an industrially advantageous method for producing alkoxyalkylaniline derivatives useful as intermediates for pharmaceuticals and agricultural chemicals.

  As a result of intensive studies conducted by the present inventors to solve the above-mentioned problems, various Lewis acids can be used in the reaction system of the fluoroalkylaniline derivative represented by the general formula (III) or a salt thereof and an alkali metal alkoxide. As a result, it was found that the aniline derivatives represented by the general formula (I) or salts thereof can be efficiently produced, and the present invention has been completed.

{式中、Ｒ^１及びＲ^２は、同一又は異なっても良く、(a1) （Ｃ_１-Ｃ_６）アルキル基；(a2) （Ｃ_２-Ｃ_６）アルケニル基；(a3) （Ｃ_２-Ｃ_６）アルキニル基；(a4) （Ｃ_３-Ｃ_６）シクロアルキル基；(a5) ハロ（Ｃ_１-Ｃ_６）アルキル基；(a6) ハロ（Ｃ_２-Ｃ_６）アルケニル基；(a7) ハロ（Ｃ_２-Ｃ_６）アルキニル基；(a8) ハロ（Ｃ_３-Ｃ_６）シクロアルキル基；(a9) （Ｃ_３-Ｃ_６）シクロアルキル（Ｃ_１-Ｃ_６）アルキル基；(a10)（Ｃ_３-Ｃ_６）シクロアルキル（Ｃ_１-Ｃ_６）ハロアルキル基；(a11) （Ｃ₁-Ｃ_６）アルキル（Ｃ_３-Ｃ_６）シクロアルキル基；(a12) （Ｃ₁-Ｃ_６）アルキル（Ｃ_３-Ｃ_６）シクロハロアルキル基；
(a13) アリール基；(a14) 同一又は異なっても良く、(a)ハロゲン原子、(b)シアノ基、(c)ニトロ基、(d)（Ｃ_１-Ｃ_６）アルキル基、(e)ハロ（Ｃ_１-Ｃ_６）アルキル基、(f)（Ｃ_１-Ｃ_６）アルコキシ基、(g)ハロ（Ｃ_１-Ｃ_６）アルコキシ基、(h)（Ｃ_２-Ｃ_６）アルケニ
ルオキシ基、(i)ハロ（Ｃ_２-Ｃ_６）アルケニルオキシ基、(j)（Ｃ_２-Ｃ_６）アルキニルオキシ基、(k)ハロ（Ｃ_２-Ｃ_６）アルキニルオキシ基、(l)（Ｃ_３-Ｃ_６）シクロアルコキシ基、又は(m)ハロ（Ｃ_３-Ｃ_６）シクロアルコキシ基）から選択される１〜５の置換基を環上に有するアリール基； That is, the present invention
General formula (III):

{In the formula, R ¹ and R ² may be the same or different, and (a1) (C ₁ -C ₆ ) alkyl group; (a2) (C ₂ -C ₆ ) alkenyl group; (a3) (C ₂ -C ₆₎ alkynyl group; (a4) _{(C 3} -C ₆₎ cycloalkyl group; (a5) halo _{(C 1} -C ₆₎ alkyl group; (a6) halo _{(C 2} -C ₆₎ alkenyl group; ( a7) a halo (C ₂ -C ₆ ) alkynyl group; (a8) a halo (C ₃ -C ₆ ) cycloalkyl group; (a9) a (C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₆ ) alkyl group; (a10) _{(C 3} -C ₆₎ cycloalkyl _{(C 1} -C ₆₎ haloalkyl group; (a11) (C ₁ -C ₆₎ alkyl _{(C 3} -C ₆₎ cycloalkyl group; (a12) (C ₁ -C ₆₎ alkyl _{(C 3} -C ₆₎ cycloalkyl haloalkyl group;
(a13) aryl group; (a14) may be the same or different, (a) halogen atom, (b) cyano group, (c) nitro group, (d) (C ₁ -C ₆ ) alkyl group, (e) Halo (C ₁ -C ₆ ) alkyl group, (f) (C ₁ -C ₆ ) alkoxy group, (g) halo (C ₁ -C ₆ ) alkoxy group, (h) (C ₂ -C ₆ ) alkenyloxy Group, (i) halo (C ₂ -C ₆ ) alkenyloxy group, (j) (C ₂ -C ₆ ) alkynyloxy group, (k) halo (C ₂ -C ₆ ) alkynyloxy group, (l) ( An aryl group having 1 to 5 substituents on the ring selected from C ₃ -C ₆ ) cycloalkoxy group or (m) halo (C ₃ -C ₆ ) cycloalkoxy group;

(a15) aryl (C ₁ -C ₆ ) alkyl group; (a16) which may be the same or different, (a) halogen atom, (b) cyano group, (c) nitro group, (d) (C ₁ -C ₆ ) alkyl group, (e) halo (C ₁ -C ₆ ) alkyl group, (f) (C ₁ -C ₆ ) alkoxy group, (g) halo (C ₁ -C ₆ ) alkoxy group, (h) ( C ₂ -C ₆ ) alkenyloxy group, (i) halo (C ₂ -C ₆ ) alkenyloxy group, (j) (C ₂ -C ₆ ) alkynyloxy group, (k) halo (C ₂ -C ₆ ) An aryl having 1 to 5 substituents on the ring selected from an alkynyloxy group, (l) (C ₃ -C ₆ ) cycloalkoxy group, or (m) halo (C ₃ -C ₆ ) cycloalkoxy group ( C ₁ -C ₆₎ alkyl group;
(a17) heterocyclic group; or (a18) which may be the same or different, (a) halogen atom, (b) cyano group, (c) nitro group, (d) formyl group, (e) (C ₁ -C ₆ ) alkyl group, (f) halo (C ₁ -C ₆ ) alkyl group, (g) (C ₁ -C ₆ ) alkoxy group, (h) halo (C ₁ -C ₆ ) alkoxy group, (i) ( C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₈ ) alkoxy group, (j) (C ₁ -C ₆ ) alkylthio group, (k) halo (C ₁ -C ₆ ) alkylthio group, (l) (C _1- C ₈ ) alkylsulfinyl group, (m) halo (C ₁ -C ₆ ) alkylsulfinyl group, (n) (C ₁ -C ₆ ) alkylsulfonyl group, (o) halo (C ₁ -C ₆ ) alkyl ₁ to 5 substituents selected from a sulfonyl group, (p) (C ₁ -C ₆ ) alkylcarbonyl group, (q) carboxyl group, or (r) (C ₁ -C ₆ ) alkoxycarbonyl group on the ring And represents a heterocyclic group.
R ¹ may be combined with R ² to form a (a19) C ₁ -C ₆ cyclo ring, which may be the same or different; (a) a halogen atom, (b ) (C ₁ -C ₆ ) alkyl group, (c) halo (C ₁ -C ₆ ) alkyl group, (d) (C ₁ -C ₆ ) alkoxy group, or (e) halo (C ₁ -C ₆ ) It may have one or more substituents selected from alkoxy groups.

R ³ is (b1) a hydrogen atom; (b2) a halogen atom; (b3) a nitro group; (b4) a cyano group; (b5) a formyl group; (b6) a (C ₁ -C ₆ ) alkyl group; (b7) (C ₃ -C ₆ ) cycloalkyl group; (b8) (C ₂ -C ₆ ) alkenyl group; (b9) (C ₂ -C ₆ ) alkynyl group; (b10) halo (C ₁ -C ₆ ) alkyl group ;
(b11) halo (C ₃ -C ₆ ) cycloalkyl group; (b12) halo (C ₂ -C ₆ ) alkenyl group; (b13) halo (C ₂ -C ₆ ) alkynyl group; (b14) (C _1- C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl group; (b15) (C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₆ ) alkyl group; (b16) (C ₁ -C ₆ ) alkylthio (C ₁ -C ₆ ) alkyl group; (b17) (C ₁ -C ₆ ) alkylsulfinyl (C ₁ -C ₆ ) alkyl group; (b18) (C ₁ -C ₆ ) alkylsulfonyl (C ₁ -C ₆ ) alkyl group (B19) halo (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl group; (b20) halo (C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₆ ) alkyl group; (b21) halo _{(C 1} -C ₆₎ alkylthio _{(C 1} -C ₆₎ alkyl group; (b22) halo _{(C 1} -C ₆₎ alkylsulfinyl _{(C 1} -C ) Alkyl group; (b23) halo _{(C 1} -C ₆₎ alkylsulfonyl _{(C 1} -C ₆₎ alkyl group; (b24) _{(C 1} -C ₆₎ Arukokishiharo _{(C 1} -C ₆₎ alkyl group; ( b25) Halo (C ₁ -C ₆ ) alkoxyhalo (C ₁ -C ₆ ) alkyl groups:
(b26) aryl group; (b27) may be the same or different, (a) halogen atom, (b) cyano group, (c) nitro group, (d) (C ₁ -C ₆ ) alkyl group, (e) Halo (C ₁ -C ₆ ) alkyl group, (f) (C ₁ -C ₆ ) alkoxy group, (g) halo (C ₁ -C ₆ ) alkoxy group, (h) (C ₂ -C ₆ ) alkenyloxy Group, (i) halo (C ₂ -C ₆ ) alkenyloxy group, (j) (C ₂ -C ₆ ) alkynyloxy group, (k) halo (C ₂ -C ₆ ) alkynyloxy group, (l) ( C ₃ -C ₆₎ cycloalkoxy group, or (m) halo _{(C 3} -C ₆₎ aryl groups having from 1 to 5 substituents selected from the cycloalkoxy group on the ring;
(b28) a heterocyclic group; or (b29) which may be the same or different, (a) a halogen atom, (b) a cyano group, (c) a nitro group, (d) a formyl group, (e) (C ₁ -C ₆ ) alkyl group, (f) halo (C ₁ -C ₆ ) alkyl group, (g) (C ₁ -C ₆ ) alkoxy group, (h) halo (C ₁ -C ₆ ) alkoxy group, (i) ( C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₈ ) alkoxy group, (j) (C ₁ -C ₆ ) alkylthio group, (k) halo (C ₁ -C ₆ ) alkylthio group, (l) (C _1- C ₈ ) alkylsulfinyl group, (m) halo (C ₁ -C ₆ ) alkylsulfinyl group, (n) (C ₁ -C ₆ ) alkylsulfonyl group, (o) halo (C ₁ -C ₆ ) alkyl ₁ to 5 substituents selected from a sulfonyl group, (p) (C ₁ -C ₆ ) alkylcarbonyl group, (q) carboxyl group or (r) (C ₁ -C ₆ ) alkoxycarbonyl group on the ring The heterocyclic group which has is shown.

R ⁴ represents (c1) a hydrogen atom; (c2) (C ₁ -C ₆ ) alkyl group; (c3) (C ₃ -C ₆ ) cycloalkyl group; (c4) (C ₂ -C ₆ ) alkenyl group; (c5) (C ₂ -C ₆ ) alkynyl group; (c6) halo (C ₁ -C ₆ ) alkyl group; (c7) halo (C ₃ -C ₆ ) cycloalkyl group; (c8) halo (C _2- C ₆ ) an alkenyl group; or (c9) a halo (C ₂ -C ₆ ) alkynyl group. }
A fluoroalkylaniline derivative represented by the formula:

｛式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ、及びＸは、前記に同じ。｝
で示されるアニリン誘導体又はその塩の製造方法に関する。 General formula (II):
MXR (II)
{Wherein M represents an alkali metal atom, X represents an oxygen atom or a sulfur atom,
R represents (d1) (C ₁ -C ₆ ) alkyl group; (d2) halo (C ₁ -C ₆ ) alkyl group; (d3) (C ₃ -C ₆ ) cycloalkyl group; or (d4) halo ( C ₃ -C ₆ ) represents a cycloalkyl group. }
Is reacted with an alkali metal alcoholate represented by the following in the presence of a Lewis acid:
Formula (I):

{Wherein R ¹ , R ² , R ³ , R ⁴ , R, and X are the same as above. }
The manufacturing method of the aniline derivative shown by these, or its salt.

  According to the present invention, an objective compound can be produced efficiently and economically on an industrial scale in a short time using an easily available reagent.

In the definitions of general formulas (I) to (III) of the aniline derivatives of the present invention,
“Halo” means “halogen atom” and represents chlorine atom, bromine atom, iodine atom or fluorine atom,
“(C ₁ -C ₆ ) alkyl group” means, for example, methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, tertiary butyl group, normal pentyl group, isopentyl group, neopentyl group, A linear or branched alkyl group having 1 to 6 carbon atoms such as a normal hexyl group,
“(C ₂ -C ₆ ) alkenyl group” means, for example, vinyl group, allyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 1-methyl-2-propenyl group, pentenyl group, 1-hexenyl. A linear or branched alkenyl group having 2 to 6 carbon atoms such as a group,
“(C ₂ -C ₆ ) alkynyl group” means, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group, 1-hexynyl group A straight chain or branched chain alkynyl group having 2 to 6 carbon atoms such as

“(C ₃ -C ₆ ) cycloalkyl” means a cyclic alkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
Examples of the “(C ₁ -C ₆ ) alkoxy group” include a methoxy group, an ethoxy group, a normal propoxy group, an isopropoxy group, a normal butoxy group, a secondary butoxy group, a tertiary butoxy group, a normal pentyloxy group, and isopentyl. A linear or branched alkoxy group having 1 to 6 carbon atoms such as an oxy group, a neopentyloxy group, and a normal hexyloxy group is shown.

As the “(C ₂ -C ₆ ) alkenyloxy group”, for example, a linear or branched alkenyloxy group having 2 to 6 carbon atoms such as a propenyloxy group, a butenyloxy group, a pentenyloxy group, and the like is shown.
Examples of the “(C ₂ -C ₆ ) alkynyloxy group” include linear or branched alkynyloxy having 2 to 6 carbon atoms such as propynyloxy group, butynyloxy group, pentynyloxy group, hexynyloxy group and the like. Indicates a group.
The “(C ₃ -C ₆ ) cycloalkoxy group” refers to a cyclic alkyloxy group having 3 to 6 carbon atoms such as cyclopropyloxy group, cyclobutoxy group, cyclohexyloxy group and the like.

Examples of the “(C ₁ -C ₆ ) alkylthio group” include methylthio group, ethylthio group, normal propylthio group, isopropylthio group, normal butylthio group, secondary butylthio group, tertiary butylthio group, and normal pentylthio group. A linear or branched alkylthio group having 1 to 6 carbon atoms such as a group, an isopentylthio group, and a normal hexylthio group;
Examples of the “(C ₁ -C ₆ ) alkylsulfinyl group” include, for example, methylsulfinyl group, ethylsulfinyl group, normal propylsulfinyl group, isopropylsulfinyl group, normal butylsulfinyl group, secondary butylsulfinyl group, tertiary butylsulfinyl group, A normal or branched alkyl sulfinyl group having 1 to 6 carbon atoms such as a normal pentylsulfinyl group, an isopentylsulfinyl group, and a normal hexylsulfinyl group,
As the “(C ₁ -C ₆ ) alkylsulfonyl group”, for example, a methylsulfonyl group, an ethylsulfonyl group, a normalpropylsulfonyl group, an isopropylsulfonyl group, a normalbutylsulfonyl group, a secondary butylsulfonyl group, a tertiary butylsulfonyl group, A linear or branched alkylsulfonyl group having 1 to 6 carbon atoms such as a normal pentylsulfonyl group, an isopentylsulfonyl group, a neopentylsulfonyl group, and a normal hexylsulfonyl group is shown.

The “aryl group” refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms such as a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
“Heterocyclic group” and “heterocycle” are 5- or 6-membered monocyclic aromatics containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms as ring-constituting atoms. Group heterocyclic group. Examples thereof include heterocyclic groups such as furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like.

The above “(C ₁ -C ₆ ) alkyl group”, “(C ₂ -C ₆ ) alkenyl group”, “(C ₂ -C ₆ ) alkynyl group”, “(C ₃ -C ₆ ) cycloalkyl group”, “(C ₃ -C ₆ ) cycloalkyloxy group”, “(C ₁ -C ₆ ) alkoxy group”, “(C ₂ -C ₆ ) alkenyloxy group”, “(C ₂ -C ₆ ) alkynyloxy group Or “(C ₃ -C ₆ ) cycloalkyloxy group” may be substituted with one or more halogen atoms at the substitutable position, and when two or more halogen atoms are substituted, The halogen atoms may be the same or different.
“Halo (C ₁ -C ₆ ) alkyl”, “Halo (C ₂ -C ₆ ) alkenyl”, “Halo (C ₂ -C ₆ ) alkynyl”, “Halo (C ₃ -C ₆ )” “Cycloalkyl group”, “halo (C ₃ -C ₆ ) cycloalkyloxy group”, “halo (C ₁ -C ₆ ) alkoxy group”, “halo (C ₂ -C ₆ ) alkenyloxy group”, “halo ( C ₂ -C ₆₎ alkynyloxy group ", or indicate" halo _(C 3 -C ₆₎ cycloalkyl group ".

In addition, expressions such as “(C ₁ -C ₆ )”, “(C ₂ -C ₆ )”, and “(C ₃ -C ₆ )” indicate the range of the number of carbon atoms of various substituents. Further, the above definition can be shown for a group to which the above substituent is linked. For example, in the case of “(C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₆ ) alkyl group”, a cyclic carbon number of 1 to It shows that 6 cycloalkyl groups are bonded to a linear or branched alkyl group having 1 to 6 carbon atoms.

In a preferred embodiment of the invention, R ¹ and R ² are halo (C ₁ -C ₆ ) alkyl groups, preferably halo (C ₁ -C ₃ ) alkyl groups, more preferably fluoro (C ₁ -C). ₃ ) an alkyl group, most preferably a trifluoromethyl group, R ³ is preferably a (C ₁ -C ₆ ) alkyl group, R ⁴ is a hydrogen atom, and a (C ₁ -C ₆ ) alkyl group, preferably It is a hydrogen atom, R is preferably a (C ₁ -C ₆ ) alkyl group, X is an oxygen atom or a sulfur atom, preferably an oxygen atom. M is an alkali metal atom, preferably a sodium atom.
As the Lewis acid, zinc chloride, zinc bromide, zinc hydroxide, triisopropoxyaluminum, and ytterbium (III) triflate are preferable.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ、Ｍ及びＸは前記に同じ。）
一般式（III）で表されるフルオロアルキルアニリン誘導体類又はその塩類と一般式（II）で表されるアルカリ金属アルコレート類、及びルイス酸を不活性溶媒の存在下、反応させることにより、一般式（Ｉ)で表されるアニリン誘導体類又はその塩類を製造することができる。 The present invention is illustrated as follows.
Manufacturing method 1.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R, M and X are the same as above)
By reacting a fluoroalkylaniline derivative represented by the general formula (III) or a salt thereof with an alkali metal alcoholate represented by the general formula (II) and a Lewis acid in the presence of an inert solvent, An aniline derivative represented by the formula (I) or a salt thereof can be produced.

The amount of the Lewis acid used is in the range of 0.05 to 3 molar equivalents relative to the fluoroalkylaniline derivative represented by the general formula (III) or a salt thereof. Preferably, the range of 0.1-1 molar equivalent is good. As used herein, “Lewis acid” means a substance that can accept an electron pair, as defined by GN Lewis. Examples of Lewis acids used in this reaction include boric acid, iron halides such as iron chloride, magnesium halides such as magnesium chloride and magnesium bromide, zinc halides such as zinc chloride and zinc bromide, zinc hydroxide, Examples thereof include triisopropoxyaluminum or lanthanoid metal salts of trifluoromethanesulfonic acid.
Here, the lanthanoid metal is lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb). ), Dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), and lutetium (Lu). Examples of the Lewis acid of the metal include Halogenated salts, triflates of the metal (ie, trifluoromethanesulfonate) [(OTf) ₃ ]. Specific examples include cerium (III) chloride, cerium (III) triflate, ytterbium chloride (III), ytterbium (III) triflate, and the like.

The inert solvent that can be used in this reaction is not particularly limited as long as it does not significantly inhibit this reaction. Examples thereof include alcohols such as methanol, ethanol, propanol, butanol, and 2-propanol; diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. Linear or cyclic ethers such as (DME); aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; halogenated aroma such as chlorobenzene and dichlorobenzene Aromatic hydrocarbons; Nitriles such as acetonitrile; Esters such as ethyl acetate; Polarity such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, water Solvents can be mentioned Inert solvent al may be used singly or as mixtures of two or more.
The reaction temperature in this reaction may usually be in the range of about 20 ° C. to the boiling point of the solvent used, and the reaction time is not constant depending on the reaction scale, reaction temperature, etc., but may be appropriately selected within the range of several minutes to 48 hours. .
The alkali metal alcoholates represented by the general formula (II) are used in the range of 1.0 to 20 molar equivalents relative to the fluoroalkylaniline derivative represented by the general formula (III). Preferably, it is the range of 3.0-10 molar equivalent.
In addition, this reaction is preferably performed in an atmosphere of an inert gas such as nitrogen gas or argon gas.
After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary.

  The fluoroalkylaniline derivative represented by the general formula (III) or a salt thereof, which is a raw material compound for this reaction, can be produced according to the method described in JP-A-2004-189738.

  Although the manufacturing method of this invention is illustrated below, this invention is not limited to these.

Example 1. Preparation of 3-isobutyl-4- [1-methoxy-2,2,2-trifluoro-1- (trifluoromethyl) ethyl] aniline 3-isobutyl-4- [1,2,2,2-tetrafluoro- 1- (Trifluoromethyl) ethyl] aniline 0.317 g (1 mmol), 28% sodium methoxide methanol solution 0.965 g (5 mmol), and the additives shown in Table 1 were added and stirred for 5 hours under reflux. After completion of the reaction, the reaction solution was cooled to room temperature, and 10 mL of methanol and 2 mL of 5% aqueous acetic acid were added to obtain a homogeneous solution. The resulting solution was analyzed by HPLC to determine the yield of the title compound, and the results are shown in Table 1.

Analysis conditions Column: INERTSIL ODS-2, φ4.6 mm × 150 mm, 5 μm, GL
Sciences Inc.
Mobile layer: CH ₃ CN: H ₂ O = 60: 40 (v / v)
Column temperature: 40 ° C
Flow rate: 1.0 mL / min.
Detection wavelength: 240 nm
Analysis time: 40 min.
Internal standard: Dipentyl phthalate

The comparative data was performed without adding any additives under the above reaction conditions.

Example 2 Preparation of 3-n-propyl-4- [1-methoxy-2,2,2-trifluoro-1- (trifluoromethyl) ethyl] aniline 3-n-propyl-4- [1,2,2,2 -Tetrafluoro-1- (trifluoromethyl) ethyl] aniline 4.97 g (16.4 mmol), 28% sodium methoxide methanol solution 15.82 g (82.0 mmol), zinc chloride 2.24 g (16.4 mmol) Sequentially added and stirred under reflux for 3 hours. After cooling with ice water, the reaction was stopped by adding a mixture of 35% hydrochloric acid 5.13 g (49.2 mmol), acetic acid 4.92 g (82.0 mmol) and water 33 mL, followed by extraction with 30 mL of ethyl acetate twice. . The organic phases were combined, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 4.76 g of the desired product.
Yield: 92%
Physical properties:
1) ¹ H-NMR [CDCl ₃ / TMS, δ value (ppm)]
7.23 (d, 1H), 6.68 (d, 1H), 6.54 (dd, 1H), 3.78 (br.s, 2H), 3.42 (s, 3H), 2.86 (M, 2H), 1.64 (m, 2H), 1.01 (t, 3H)
2) ¹⁹ F-NMR [CDCl ₃ / CFCl ₃ , δ value (ppm)] −70.1 (s)

Example 3 Preparation of 2- [1-methoxy-2,2,2-trifluoro-1- (trifluoromethyl) ethyl] -5- (2-methylbutyl) aniline 2- [1,2,2,2-tetrafluoro- 1.99 g (6 mmol) of 1- (trifluoromethyl) ethyl] -5- (2-methylbutyl) aniline, 5.79 g (30 mmol) of 28% sodium methoxide methanol solution, 0.82 g (6 mmol) of zinc chloride were sequentially added. The mixture was stirred for 2 hours under reflux. Thereafter, the same treatment as in Example 2 was performed to obtain 2.02 g of the desired product.
Yield: 98%
Physical properties:
1) ¹ H-NMR [CDCl ₃ / TMS, δ value (ppm)]
7.16 (d, 1H), 6.55 (dd, 1H), 6.46 (d, 1H), 4.47 (br.s, 2H), 3.55 (s, 3H), 2.53 (Dd, 1H), 2.25 (dd, 1H), 1.63 (m, 1H), 1.40 (m, 1H), 1.19 (m, 1H) 0.91 (t, 3H), 0.86 (d, 3H)
2) ¹⁹ F-NMR [CDCl ₃ / CFCl ₃ , δ value (ppm)] −70.5 (s)

Example 4 Preparation of 3- (2-methyl-1-propen-1-yl) -4- [1-methoxy-2,2,2-trifluoro-1- (trifluoromethyl) ethyl] aniline 3- (2-Methyl -1-propen-1-yl) -4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline 5.15 g (16.3 mmol), 28% sodium methoxide methanol solution 15.76 g (81.7 mmol) and zinc chloride 2.22 g (16.3 mmol) were sequentially added, and the mixture was stirred for 4 hours under reflux. Thereafter, the same treatment as in Example 2 was performed to obtain 5.14 g of the desired product.
Yield: 96%
Physical properties:
1) ¹ H-NMR [CDCl ₃ / TMS, δ value (ppm)]
7.28 (d, 1H), 6.58 (dd, 1H), 6.48 (s, 1H), 6.47 (s, 1H), 3.80 (br.s, 2H), 3.24 (S, 3H), 1.86 (d, 3H), 1.71 (d, 3H)
2) ¹⁹ F-NMR [CDCl ₃ / CFCl ₃ , δ value (ppm)]-70.5 (s)

Reference Example 1 Of N- {3-isobutyl-4- [1-methoxy-2,2,2-trifluoro-1- (trifluoromethyl) ethyl] phenyl} -1,3,5-trimethylpyrazole-4-carboxylic acid amide Preparation 1,3,5-trimethylpyrazole-4-carboxylic acid chloride (3.93 g, 22.8 mmol), 3-isobutyl-4- [1-methoxy-2,2,2-trifluoro-1- (trifluoro Methyl) ethyl] aniline (5.0 g, 15.2 mmol) and triethylamine (3.07 g, 30.4 mmol) were dissolved in tetrahydrofuran (100 ml) and heated to reflux for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude crystals were washed with ether to obtain 5.62 g of the desired product.
Yield: 80%
Physical properties: melting point 189-190 ° C

Claims (6)

General formula (III):

{Wherein R ¹ and R ² may be the same or different, and are a (C ₁ -C ₆ ) alkyl group; a (C ₂ -C ₆ ) alkenyl group; a (C ₂ -C ₆ ) alkynyl group; ₃ -C ₆ ) cycloalkyl group; halo (C ₁ -C ₆ ) alkyl group; halo (C ₂ -C ₆ ) alkenyl group; halo (C ₂ -C ₆ ) alkynyl group; halo (C ₃ -C ₆ ) (C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₆ ) alkyl group; (C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₆ ) haloalkyl group; (C ₁ -C ₆ ) alkyl (C ₃ -C ₆ ) cycloalkyl group; (C ₁ -C ₆ ) alkyl (C ₃ -C ₆ ) cyclohaloalkyl group; aryl group; may be the same or different, and may be a halogen atom, cyano group, nitro group, ( A C ₁ -C ₆ ) alkyl group, a halo (C ₁ -C ₆ ) alkyl group, (C ₁ -C ₆ ) alkoxy group, halo (C ₁ -C ₆ ) alkoxy group, (C ₂ -C ₆ ) alkenyloxy group, halo (C ₂ -C ₆ ) alkenyloxy group, (C ₂ -C ₆ ) alkynyloxy group, a halo _{(C 2} -C ₆₎ alkynyloxy group, _{(C 3} -C ₆₎ cycloalkoxy group, or halo _{(C 3} -C ₆₎ substituted 1-5 selected from cycloalkoxy group) Aryl group having a group on the ring; aryl (C ₁ -C ₆ ) alkyl group; may be the same or different, and may be a halogen atom, cyano group, nitro group, (C ₁ -C ₆ ) alkyl group, halo (C ₁ -C ₆ ) alkyl group, (C ₁ -C ₆ ) alkoxy group, halo (C ₁ -C ₆ ) alkoxy group, (C ₂ -C ₆ ) alkenyloxy group, halo (C ₂ -C ₆ ) alkenyloxy group , (C ₂ -C ₆ ) alkynyloxy 1 to 5 substituents selected from a group, a halo (C ₂ -C ₆ ) alkynyloxy group, a (C ₃ -C ₆ ) cycloalkoxy group or a halo (C ₃ -C ₆ ) cycloalkoxy group on the ring An aryl (C ₁ -C ₆ ) alkyl group; a heterocyclic group; or the same or different, a halogen atom, a cyano group, a nitro group, a formyl group, a (C ₁ -C ₆ ) alkyl group, a halo (C ₁ -C ₆ ) alkyl group, (C ₁ -C ₆ ) alkoxy group, halo (C ₁ -C ₆ ) alkoxy group, (C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₈ ) alkoxy group, (C ₁ -C ₆ ) alkylthio group, halo (C ₁ -C ₆ ) alkylthio group, (C ₁ -C ₈ ) alkylsulfinyl group, halo (C ₁ -C ₆ ) alkylsulfinyl group, (C ₁ -C ₆ ) alkylsulfonyl Group, halo (C ₁ -C ₆ A heterocyclic group having 1 to 5 substituents selected from a) alkylsulfonyl group, (C ₁ -C ₆ ) alkylcarbonyl group, carboxyl group or (C ₁ -C ₆ ) alkoxycarbonyl group on the ring;
R ¹ may be combined with R ² to form a C ₁ -C ₆ cyclo ring, which may be the same or different, and is a halogen atom, (C ₁ -C ₆ ) alkyl. It may have one or more substituents selected from a group, a halo (C ₁ -C ₆ ) alkyl group, a (C ₁ -C ₆ ) alkoxy group or a halo (C ₁ -C ₆ ) alkoxy group.
R ³ is hydrogen atom; halogen atom; nitro group; cyano group; formyl group; (C ₁ -C ₆ ) alkyl group; (C ₃ -C ₆ ) cycloalkyl group; (C ₂ -C ₆ ) alkenyl group; (C ₂ -C ₆ ) alkynyl group; halo (C ₁ -C ₆ ) alkyl group; halo (C ₃ -C ₆ ) cycloalkyl group; halo (C ₂ -C ₆ ) alkenyl group; halo (C ₂ -C ₆₎ alkynyl; _{(C 1} -C ₆₎ alkoxy _{(C 1} -C ₆₎ alkyl group; _{(C 3} -C ₆₎ cycloalkyl _{(C 1} -C ₆₎ alkyl group; _{(C 1} -C ₆₎ alkylthio (C ₁ -C ₆ ) alkyl group; (C ₁ -C ₆ ) alkylsulfinyl (C ₁ -C ₆ ) alkyl group; (C ₁ -C ₆ ) alkylsulfonyl (C ₁ -C ₆ ) alkyl group; halo ( C ₁ -C ₆₎ alkoxy _{(C 1} -C ₆₎ alkyl group; Ha _{(C 3} -C ₆₎ cycloalkyl _{(C 1} -C ₆₎ alkyl group;
Halo (C ₁ -C ₆ ) alkylthio (C ₁ -C ₆ ) alkyl group; halo (C ₁ -C ₆ ) alkylsulfinyl (C ₁ -C ₆ ) alkyl group; halo (C ₁ -C ₆ ) alkylsulfonyl ( C ₁ -C ₆ ) alkyl group; (C ₁ -C ₆ ) alkoxyhalo (C ₁ -C ₆ ) alkyl group; halo (C ₁ -C ₆ ) alkoxyhalo (C ₁ -C ₆ ) alkyl group: aryl group They may be the same or different, and may be a halogen atom, cyano group, nitro group, (C ₁ -C ₆ ) alkyl group, halo (C ₁ -C ₆ ) alkyl group, (C ₁ -C ₆ ) alkoxy group, halo ( C ₁ -C ₆ ) alkoxy group, (C ₂ -C ₆ ) alkenyloxy group, halo (C ₂ -C ₆ ) alkenyloxy group, (C ₂ -C ₆ ) alkynyloxy group, halo (C ₂ -C ₆₎ ) alkynyloxy group, _{(C 3} -C ₆₎ Kuroarukokishi group or a halo (C ₃ -C ₆₎ 1-5 substituents selected from the cycloalkoxy group an aryl group having on the ring; a heterocyclic group; may be or the same or different, a halogen atom, a cyano group , Nitro group, formyl group, (C ₁ -C ₆ ) alkyl group, halo (C ₁ -C ₆ ) alkyl group, (C ₁ -C ₆ ) alkoxy group, halo (C ₁ -C ₆ ) alkoxy group, ( A C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₈ ) alkoxy group, a (C ₁ -C ₆ ) alkylthio group, a halo (C ₁ -C ₆ ) alkylthio group, a (C ₁ -C ₈ ) alkylsulfinyl group, Halo (C ₁ -C ₆ ) alkylsulfinyl group, (C ₁ -C ₆ ) alkylsulfonyl group, halo (C ₁ -C ₆ ) alkylsulfonyl group, (C ₁ -C ₆ ) alkylcarbonyl group, carboxyl group or ( C -C ₆₎ 1-5 substituents selected from alkoxycarbonyl groups showing a heterocyclic group having on the ring.
R ⁴ represents a hydrogen atom; (C ₁ -C ₆ ) alkyl group; (C ₃ -C ₆ ) cycloalkyl group; (C ₂ -C ₆ ) alkenyl group; (C ₂ -C ₆ ) alkynyl group; halo ( A C ₁ -C ₆ ) alkyl group; a halo (C ₃ -C ₆ ) cycloalkyl group; a halo (C ₂ -C ₆ ) alkenyl group; or a halo (C ₂ -C ₆ ) alkynyl group. } Or a salt thereof,
General formula (II)
MXR (II)
{In the formula, M represents an alkali metal atom, X represents an oxygen atom or a sulfur atom, R represents a (C ₁ -C ₆ ) alkyl group; a halo (C ₁ -C ₆ ) alkyl group; (C ₃ -C indicating or halo _{(C 3} -C ₆₎ cycloalkyl group; ₆₎ cycloalkyl group. } Is reacted in the presence of a Lewis acid,
Formula (I)

{Wherein R ¹ , R ² , R ³ , R ⁴ , R, and X are the same as above. } The manufacturing method of the aniline derivative or its salt shown by these. R ¹ and R ² may be the same or different, (C ₁ -C ₆ ) alkyl group; (C ₂ -C ₆ ) alkenyl group; (C ₂ -C ₆ ) alkynyl group; (C ₃ -C ₆ ) A halo (C ₁ -C ₆ ) alkyl group; a halo (C ₂ -C ₆ ) alkenyl group; a halo (C ₂ -C ₆ ) alkynyl group; or a halo (C ₃ -C ₆ ) cycloalkyl group; R ³ is hydrogen atom; halogen atom; (C ₁ -C ₆ ) alkyl group; (C ₃ -C ₆ ) cycloalkyl group; (C ₂ -C ₆ ) alkenyl group; (C ₂ -C ₆ ) alkynyl A halo (C ₁ -C ₆ ) alkyl group; a halo (C ₃ -C ₆ ) cycloalkyl group; a halo (C ₂ -C ₆ ) alkenyl group; a halo (C ₂ -C ₆ ) alkynyl group; (C ₁ -C ₆₎ alkoxy _{(C 1} -C ₆₎ alkyl group; _{(C 3} -C ₆₎ sheet Roarukiru _{(C 1} -C ₆₎ alkyl group; indicates or halo _{(C 1} -C ₆₎ alkoxy _{(C 1} -C ₆₎ alkyl group, ^{R 4} is a hydrogen atom; _{(C 1} -C ₆₎ alkyl group; ( C ₃ -C ₆ ) cycloalkyl group; (C ₂ -C ₆ ) alkenyl group; or (C ₂ -C ₆ ) alkynyl group, wherein R is (C _1-
The method for producing an aniline derivative or a salt thereof according to claim 1, which represents a C ₆ ) alkyl group; or a halo (C ₁ -C ₆ ) alkyl group, and X represents an oxygen atom or a sulfur atom. R ¹ and R ² represent a halo (C ₁ -C ₆ ) alkyl group, R ³ represents a (C ₁ -C ₆ ) alkyl group, R ⁴ represents a hydrogen atom, and R represents (C ₁ -C ₆₎ The method for producing an aniline derivative or a salt thereof according to claim 1, which represents an alkyl group.   The Lewis acid is boric acid, iron halide, magnesium halide, zinc halide, zinc hydroxide, triisopropoxyaluminum, or a lanthanoid metal salt of trifluoromethanesulfonic acid. Manufacturing method.   The production method according to any one of claims 1 to 3, wherein the Lewis acid is zinc halide, triisopropoxyaluminum, or a lanthanoid metal salt of trifluoromethanesulfonic acid.   The amount of the Lewis acid used is 0.05 to 3 molar equivalents relative to the fluoroalkylaniline derivative represented by the general formula (III) or a salt thereof. Production method.