JP2003226676A - Alfa-alkyl-fluoro, trifluoromethyl or trifluoromethoxy- substituted benzylamine, n-alkyl alfa-alkyl-fluoro, trifluoro- or trifluoromethoxy-substituted benzylamine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide novel compounds such as an α-alkyl fluoro-, trifluoromethyl- or trifluoromethoxy-substituted benzylamine, a N-alkyl-α- alkyl-fluoro-, trifluoromethyl or trifluoromethoxy-substituted benzylamine and N-alkyl-trifluoromethoxy-substituted benzylamine, which are useful as important intermediates for medicines and agrochemicals. <P>SOLUTION: Fluoro, trifluoromethyl or trifluoromethoxy-substituted phenyl alkyl ketone is subjected to the dehydration reaction with benzylamine to convert to an imine. Further, the imine is hydrogenated and hydrogenolyzed to produce the α-alkyl fluoro, trifluoromethyl or trifluoromethoxy-substituted benzylamine of high purity in a high yield. N-alkyl-trifluoromethoxy-substituted benzylamine also can be produced efficiently in an similar manner. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy-substituted benzylamine, N-alkyl-α-alkyl-fluoro, which is an important intermediate for medicines and agricultural chemicals. , Trifluoromethyl or trifluoromethoxy substituted benzylamines and N-alkyl-trifluoromethoxy substituted benzylamines.

[0002]

BACKGROUND OF THE INVENTION α-Alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamines, N-alkyl-α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamines and N-alkyl-trifluoromethoxys. Substituted benzylamines are important intermediates in medicine and pesticides.
For example, α-methyl-3,5-bis-trifluoromethylbenzylamine, N-methyl-α-methyl-3,5-
Bis-trifluoromethylbenzylamine and N-methyl-α-cyclopropyl-3,5-bis-trifluoromethylbenzylamine are important intermediates for tachykinin antagonists (Patent Document 1) and (Patent Document 2). . α-Methyl-4-fluorobenzylamine is an intermediate of compounds showing anti-HIV activity (Patent Document 3). Patent Document 4 discloses α-methyl-2-trifluoromethylbenzylamine, α-methyl-3-trifluoromethylbenzylamine, α-methyl-4-trifluoromethylbenzylamine, α-methyl-3,5-. Bis-trifluoromethylbenzylamine, α-methyl-3-fluorobenzylamine and α-methyl-4-fluorobenzylamine have been reported to be intermediates for herpesvirus inhibitors. Further, Patent Document 5 discloses α-methyl-2-fluorobenzylamine, α-methyl-3-fluorobenzylamine, α-methyl-4-fluorobenzylamine and α-methyl-3,5-difluorobenzylamine. It is reported to be an intermediate of a compound having an ileal type bile acid transporter inhibitory action. In Patent Document 6,
α-methyl-3-trifluoromethylbenzylamine,
α-Ethyl-4-fluorobenzylamine and α-methyl-4-trifluoromethoxybenzylamine have been used as intermediates for pest control agents. α-methyl-
4-Fluorobenzylamine and α-methyl-2-fluorobenzylamine are used as intermediates for body parasitic control agents (Patent Document 7). Also, α-methyl-4
-Trifluoromethoxybenzylamine is an intermediate for fungicides (Patent Document 8). α-Ethyl-4-fluorobenzylamine is an intermediate for herbicides (Patent Document 9).
Patent Document 10 discloses a method for producing α-cyclopropyl-3-trifluoromethylbenzylamine and α-cyclopropyl-3,5-bis-trifluoromethylbenzylamine as an intermediate for an antihypertensive agent. α-
Ethyl-3,5-bis-trifluoromethylbenzylamine is an intermediate for tachykinin antagonists (Patent Document 1).
1). N-methyl-α-methyl-3-trifluoromethylbenzylamine is used as a raw material for kinetics study of elimination reaction (Non-Patent Document 1). N-methyl-α-methyl-3,5-bis-trifluoromethylbenzylamine is an intermediate of neurokinin 1 receptor antagonist (Patent Document 12). α-Methyl-4-trifluoromethoxybenzylamine is an intermediate of a plant disease controlling agent (Patent Document 1).
3). α-Ethyl-4-trifluoromethoxybenzylamine is an intermediate of a bactericide (Patent Document 14).

[0003]

[Patent Document 1] US Pat. No. 5,594,022

[Patent Document 2] International Publication No. 01/25219 Pamphlet

[Patent Document 3] International Publication No. 01/96283 Pamphlet

[Patent Document 4] International Publication No. 00/34269 Pamphlet

[Patent Document 5] European Patent Application Publication No. 1070703

[Patent Document 6] JP-A-5-201999

[Patent Document 7] JP-A-5-221996

[Patent Document 8] International Publication No. 01/64644 Pamphlet

[Patent Document 9] US Pat. No. 4,201,569

[Patent Document 10] Japanese Patent Application Laid-Open No. 51-016662

[Patent Document 11] International Publication No. 2001/087866 Pamphlet

[Patent Document 12] Japanese Patent Laid-Open No. 2000-247957

[Patent Document 13] US Pat. No. 4,946,867

[Patent Document 14] European Patent Application Publication No. 370704

[Non-Patent Document 1] J. Amer. Chem. Soc., (USA), 1989.
Year 111, No. 6, p. 2252-2257

[0004]

The object of the present invention is to provide novel compounds, α-alkyl-fluoro, trifluoromethyl- or trifluoromethoxy-substituted benzylamines, N-alkyl-α, which are important intermediates for pharmaceuticals and agricultural chemicals. -Alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine and N-alkyl-
To provide a trifluoromethoxy substituted benzylamine.

As disclosed in Patent Documents 1 to 14, α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine, N-alkyl-α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy. Substituted benzylamine and N
Despite being utilized as an intermediate for various pharmaceuticals and agricultural chemicals, -alkyl-trifluoromethoxy-substituted benzylamines have not been reported at all regarding the compounds of the present invention. Therefore, until now, it has not been possible to utilize the compounds targeted by the present invention as intermediates in the development of pharmaceuticals and agricultural chemicals.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have dehydrated and condensed fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenylalkylketones with benzylamine to give imines. By converting and further subjecting the imine to hydrogenation and hydrogenolysis, the α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy-substituted benzylamine targeted by the present invention can be produced with high chemical purity and in good yield. Found. Further, by condensing fluoro, trifluoromethyl or trifluoromethoxy substituted phenyl alkyl ketone or trifluoromethoxy substituted benzaldehyde with an alkylamine, and further adding a hydride reducing agent into the reaction system, the N-alkyl which is the object of the present invention can be obtained. It has been found that -α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine or N-alkyl-trifluoromethoxy substituted benzylamine can be produced with high chemical purity and in good yield.

Α-alkyl-fluoro in the present invention,
A method for making trifluoromethyl or trifluoromethoxy substituted benzylamine is shown in Scheme 1 below.

[0008]

[Chemical 27]

[In Scheme 1, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and n
Represents an integer of 1 to 5, R ¹ represents an arbitrary substitution position, Ph represents a phenyl group, and the wavy line of the imine in the center represents E.
, Z-form or a mixture thereof, and the wavy line of α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy-substituted benzylamine at the right end represents a racemate.

[0010]

[Chemical 28]

[In the formula, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and n is 1 to 5
Represents an integer of R ¹ , and R ¹ has an arbitrary substitution position], and a fluoro-, trifluoromethyl-, or trifluoromethoxy-substituted phenylalkylketone represented by the formula [19]

[0012]

[Chemical 29]

## STR1 ## In the formula, Ph represents a phenyl group, which is dehydrated and condensed with benzylamine to give a compound of the general formula

[0014]

[Chemical 30]

[Wherein R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and n represents 1 to 5]
Represents an integer, R ¹ has an arbitrary substitution position, Ph represents a phenyl group, and a wavy line represents an E-form, a Z-form, or a mixture thereof], and the imine is hydrogenated. By hydrogenolysis with
1]

[0016]

[Chemical 31]

[In the formula, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and n is 1 to 5
[Wherein R ¹ has an arbitrary substitution position and a wavy line represents a racemate], and an α-alkyl-fluoro, trifluoromethyl- or trifluoromethoxy-substituted benzylamine targeted by the present invention Provide the means to do. Moreover, the compound shown by General formula [21] which is a novel compound is provided.

Further, N-alkyl-α-in the present invention
A method for making alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamines and N-alkyl-trifluoromethoxy substituted benzylamines is shown in Scheme 2 below.

[0019]

[Chemical 32]

[In Scheme 2, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R ³ represents 1 carbon atom. To 6 are lower alkyl groups, n is an integer of 1 to 5, R ¹ is an arbitrary substitution position, and the wavy line represents a racemate.] That is, the present invention is represented by the general formula [18]

[0021]

[Chemical 33]

[In the formula, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and n is 1 to 5
Represents an integer, and R ¹ has an arbitrary substitution position], or a fluoro, trifluoromethyl or trifluoromethoxy-substituted phenylalkylketone, or a general formula [22]

[0023]

[Chemical 34]

[In the formula, n represents an integer of 1 to 5, and OC
The F ₃ group has an arbitrary substitution position] and a trifluoromethoxy-substituted benzaldehyde represented by the general formula [23]

[0025]

[Chemical 35]

[Wherein R ³ represents a lower alkyl group having 1 to 6 carbon atoms] is condensed, and a hydride reducing agent is added to the reaction system to give a compound represented by the general formula [24].

[0027]

[Chemical 36]

[Wherein R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and R ³ represents a lower alkyl group having 1 to 6 carbon atoms] Represents an alkyl group, n represents an integer of 1 to 5, R ¹ represents an arbitrary substitution position, and a wavy line represents a racemate], which is an object of the present invention, N-alkyl-α-alkyl- A fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine, or
General formula [25]

[0029]

[Chemical 37]

In the present invention, R ³ represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, and the OCF ₃ group has an arbitrary substitution position. Means are provided for preparing N-alkyl-trifluoromethoxy substituted benzylamines of interest. Further, the present invention provides a compound represented by the general formula [24] or the general formula [25], which is a novel compound.

[0031]

BEST MODE FOR CARRYING OUT THE INVENTION The α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine, N-alkyl-α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine and N of the present invention are described below. The -alkyl-trifluoromethoxy-substituted benzylamine will be described in detail.

The α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine represented by the general formula [21] of the present invention is a fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine represented by the general formula [18]. The phenyl alkyl ketone is represented by the formula [1
9] is dehydrated and condensed with benzylamine to be converted to an imine represented by the general formula [20], and the imine can be hydrogenated and hydrolyzed to produce a compound having a high chemical purity and a high yield. In addition, the general formula [2
4] is an N-alkyl-α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine, or an N-alkyl-trifluoromethoxy substituted benzylamine represented by the general formula [25] A fluoro, trifluoromethyl or trifluoromethoxy substituted phenyl alkyl ketone represented by [18] or a trifluoromethoxy substituted benzaldehyde represented by the general formula [22] is condensed with an alkylamine represented by the general formula [23]. Further, by adding a hydride reducing agent to the reaction system, it is possible to manufacture with high chemical purity and high yield.

The (R ¹ ) _n of the fluoro, trifluoromethyl or trifluoromethoxy-substituted phenylalkylketone represented by the general formula [18] is 2-fluoro, 3
-Fluoro, 4-fluoro, 2,3-difluoro, 2,
4-difluoro, 2,5-difluoro, 2,6-difluoro, 3,4-difluoro, 3,5-difluoro, 2,
3,4-trifluoro, 2,3,5-trifluoro,
2,3,6-trifluoro, 2,4,5-trifluoro, 2,4,6-trifluoro, 3,4,5-trifluoro, 2,3,4,5-tetrafluoro, 2,3 , 4,
6-tetrafluoro, 2,3,5,6-tetrafluoro, 2,3,4,5,6-pentafluoro, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 2,3 -Bis-trifluoromethyl, 2,
4-bis-trifluoromethyl, 2,5-bis-trifluoromethyl, 2,6-bis-trifluoromethyl,
3,4-bis-trifluoromethyl, 3,5-bis-trifluoromethyl, 2,3,4-tris-trifluoromethyl, 2,3,5-tris-trifluoromethyl,
2,3,6-tris-trifluoromethyl, 2,4,5
-Tris-trifluoromethyl, 2,4,6-tris-
Trifluoromethyl, 3,4,5-tris-trifluoromethyl, 2,3,4,5-tetrakis-trifluoromethyl, 2,3,4,6-tetrakis-trifluoromethyl, 2,3,5 6-tetrakis-trifluoromethyl, 2,3,4,5,6-pentakis-trifluoromethyl, 2-trifluoromethoxy, 3-trifluoromethoxy, 4-trifluoromethoxy, 2,3-bis-trifluoro Methoxy, 2,4-bis-trifluoromethoxy, 2,5-bis-trifluoromethoxy, 2,6-
Bis-trifluoromethoxy, 3,4-bis-trifluoromethoxy, 3,5-bis-trifluoromethoxy,
2,3,4-tris-trifluoromethoxy, 2,3
5-tris-trifluoromethoxy, 2,3,6-tris-trifluoromethoxy, 2,4,5-tris-trifluoromethoxy, 2,4,6-tris-trifluoromethoxy, 3,4,5- Tris-trifluoromethoxy, 2,3,4,5-tetrakis-trifluoromethoxy, 2,3,4,6-tetrakis-trifluoromethoxy, 2,3,5,6-tetrakis-trifluoromethoxy, 2, 3,4,5,6-pentakis-trifluoromethoxy may be mentioned.

R ² of the fluoro, trifluoromethyl or trifluoromethoxy substituted phenylalkylketone represented by the general formula [18] is methyl, ethyl or 1
-Propyl, 2-propyl, cyclopropyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, t-butyl, cyclobutyl, 1-pentyl, 2-pentyl, 3-
Examples include pentyl, neopentyl, t-amyl, cyclopentyl, 1-hexyl, 2-hexyl, 3-hexyl, cyclohexyl and the like.

Α-Alkyl-represented by the general formula [21]
Examples of fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine include α-ethyl-2-fluorobenzylamine, α-isopropyl-2-fluorobenzylamine, α-cyclopropyl-2-fluorobenzylamine, α-t- Butyl-2-fluorobenzylamine, α-ethyl-3-fluorobenzylamine,
α-isopropyl-3-fluorobenzylamine, α-
Cyclopropyl-3-fluorobenzylamine, α-t
-Butyl-3-fluorobenzylamine, α-isopropyl-4-fluorobenzylamine, α-cyclopropyl-4-fluorobenzylamine, α-t-butyl-4
-Fluorobenzylamine, α-ethyl-2,3-difluorobenzylamine, α-isopropyl-2,3-difluorobenzylamine, α-cyclopropyl-2,3
-Difluorobenzylamine, α-t-butyl-2,3
-Difluorobenzylamine, α-ethyl-2,4-difluorobenzylamine, α-isopropyl-2,4-
Difluorobenzylamine, α-cyclopropyl-2,
4-difluorobenzylamine, α-t-butyl-2,
4-difluorobenzylamine, α-ethyl-2,5-
Difluorobenzylamine, α-isopropyl-2,5
-Difluorobenzylamine, α-cyclopropyl-
2,5-difluorobenzylamine, α-t-butyl-
2,5-difluorobenzylamine, α-ethyl-2,
6-difluorobenzylamine, α-isopropyl-
2,6-difluorobenzylamine, α-cyclopropyl-2,6-difluorobenzylamine, α-t-butyl-2,6-difluorobenzylamine, α-ethyl-
3,4-difluorobenzylamine, α-isopropyl-3,4-difluorobenzylamine, α-cyclopropyl-3,4-difluorobenzylamine, α-t-butyl-3,4-difluorobenzylamine, α-ethyl -3,5-Difluorobenzylamine, α-isopropyl-3,5-difluorobenzylamine, α-cyclopropyl-3,5-difluorobenzylamine, α-t-
Butyl-3,5-difluorobenzylamine, α-ethyl-2,3,4-trifluorobenzylamine, α-isopropyl-2,3,4-trifluorobenzylamine, α-cyclopropyl-2,3,4 -Trifluorobenzylamine, α-t-butyl-2,3,4-trifluorobenzylamine, α-ethyl-2,3,5-trifluorobenzylamine, α-isopropyl-2,3,5
-Trifluorobenzylamine, α-cyclopropyl-
2,3,5-trifluorobenzylamine, α-t-butyl-2,3,5-trifluorobenzylamine, α-
Ethyl-2,3,6-trifluorobenzylamine, α
-Isopropyl-2,3,6-trifluorobenzylamine, α-cyclopropyl-2,3,6-trifluorobenzylamine, α-t-butyl-2,3,6-trifluorobenzylamine, α-ethyl -2,4,5-trifluorobenzylamine, α-isopropyl-2,4
5-trifluorobenzylamine, α-cyclopropyl-2,4,5-trifluorobenzylamine, α-t-
Butyl-2,4,5-trifluorobenzylamine, α
-Ethyl-2,4,6-trifluorobenzylamine,
α-isopropyl-2,4,6-trifluorobenzylamine, α-cyclopropyl-2,4,6-trifluorobenzylamine, α-t-butyl-2,4,6-trifluorobenzylamine, α- Ethyl-3,4,5-trifluorobenzylamine, α-isopropyl-3,
4,5-Trifluorobenzylamine, α-cyclopropyl-3,4,5-trifluorobenzylamine, α-
t-Butyl-3,4,5-trifluorobenzylamine, α-ethyl-2,3,4,5-tetrafluorobenzylamine, α-isopropyl-2,3,4,5-tetrafluorobenzylamine, α -Cyclopropyl-2,
3,4,5-Tetrafluorobenzylamine, α-t-
Butyl-2,3,4,5-tetrafluorobenzylamine, α-ethyl-2,3,4,6-tetrafluorobenzylamine, α-isopropyl-2,3,4,6-tetrafluorobenzylamine, α -Cyclopropyl-2,
3,4,6-Tetrafluorobenzylamine, α-t-
Butyl-2,3,4,6-tetrafluorobenzylamine, α-ethyl-2,3,5,6-tetrafluorobenzylamine, α-isopropyl-2,3,5,6-tetrafluorobenzylamine, α -Cyclopropyl-2,
3,5,6-tetrafluorobenzylamine, α-t-
Butyl-2,3,5,6-tetrafluorobenzylamine, α-ethyl-2,3,4,5,6-pentafluorobenzylamine, α-isopropyl-2,3,4,5,
6-pentafluorobenzylamine, α-cyclopropyl-2,3,4,5,6-pentafluorobenzylamine, α-t-butyl-2,3,4,5,6-pentafluorobenzylamine, α- Ethyl-2-trifluoromethylbenzylamine, α-isopropyl-2-trifluoromethylbenzylamine, α-cyclopropyl-2-
Trifluoromethylbenzylamine, α-t-butyl-
2-trifluoromethylbenzylamine, α-ethyl-
3-trifluoromethylbenzylamine, α-isopropyl-3-trifluoromethylbenzylamine, α-t
-Butyl-3-trifluoromethylbenzylamine, α
-Ethyl-4-trifluoromethylbenzylamine, α
-Isopropyl-4-trifluoromethylbenzylamine, α-cyclopropyl-4-trifluoromethylbenzylamine, α-t-butyl-4-trifluoromethylbenzylamine, α-ethyl-2,3-bis-trifluoro Methylbenzylamine, α-isopropyl-2,3
-Bis-trifluoromethylbenzylamine, α-cyclopropyl-2,3-bis-trifluoromethylbenzylamine, α-t-butyl-2,3-bis-trifluoromethylbenzylamine, α-ethyl-2, 4-bis-
Trifluoromethylbenzylamine, α-isopropyl-2,4-bis-trifluoromethylbenzylamine,
α-cyclopropyl-2,4-bis-trifluoromethylbenzylamine, α-t-butyl-2,4-bis-trifluoromethylbenzylamine, α-ethyl-2,5
-Bis-trifluoromethylbenzylamine, α-isopropyl-2,5-bis-trifluoromethylbenzylamine, α-cyclopropyl-2,5-bis-trifluoromethylbenzylamine, α-t-butyl-2, 5-
Bis-trifluoromethylbenzylamine, α-ethyl-2,6-bis-trifluoromethylbenzylamine,
α-isopropyl-2,6-bis-trifluoromethylbenzylamine, α-cyclopropyl-2,6-bis-
Trifluoromethylbenzylamine, α-t-butyl-
2,6-bis-trifluoromethylbenzylamine, α
-Ethyl-3,4-bis-trifluoromethylbenzylamine, α-isopropyl-3,4-bis-trifluoromethylbenzylamine, α-cyclopropyl-3,4
-Bis-trifluoromethylbenzylamine, α-t-
Butyl-3,4-bis-trifluoromethylbenzylamine, α-isopropyl-3,5-bis-trifluoromethylbenzylamine, α-t-butyl-3,5-bis-trifluoromethylbenzylamine, α- Ethyl-
2,3,4-tris-trifluoromethylbenzylamine, α-isopropyl-2,3,4-tris-trifluoromethylbenzylamine, α-cyclopropyl-2,
3,4-tris-trifluoromethylbenzylamine,
α-t-butyl-2,3,4-tris-trifluoromethylbenzylamine, α-ethyl-2,3,5-tris-trifluoromethylbenzylamine, α-isopropyl-2,3,5-tris- Trifluoromethylbenzylamine, α-cyclopropyl-2,3,5-tris-trifluoromethylbenzylamine, α-t-butyl-
2,3,5-Tris-trifluoromethylbenzylamine, α-ethyl-2,3,6-tris-trifluoromethylbenzylamine, α-isopropyl-2,3,6-
Tris-trifluoromethylbenzylamine, α-cyclopropyl-2,3,6-tris-trifluoromethylbenzylamine, α-t-butyl-2,3,6-tris-trifluoromethylbenzylamine, α-ethyl −
2,4,5-Tris-trifluoromethylbenzylamine, α-isopropyl-2,4,5-tris-trifluoromethylbenzylamine, α-cyclopropyl-2,
4,5-tris-trifluoromethylbenzylamine,
α-t-butyl-2,4,5-tris-trifluoromethylbenzylamine, α-ethyl-2,4,6-tris-trifluoromethylbenzylamine, α-isopropyl-2,4,6-tris- Trifluoromethylbenzylamine, α-cyclopropyl-2,4,6-tris-trifluoromethylbenzylamine, α-t-butyl-
2,4,6-Tris-trifluoromethylbenzylamine, α-ethyl-3,4,5-tris-trifluoromethylbenzylamine, α-isopropyl-3,4,5-
Tris-trifluoromethylbenzylamine, α-cyclopropyl-3,4,5-tris-trifluoromethylbenzylamine, α-t-butyl-3,4,5-tris-trifluoromethylbenzylamine, α-ethyl −
2,3,4,5-tetrakis-trifluoromethylbenzylamine, α-isopropyl-2,3,4,5-tetrakis-trifluoromethylbenzylamine, α-cyclopropyl-2,3,4,5-tetrakis -Trifluoromethylbenzylamine, α-t-butyl-2,3,
4,5-Tetrakis-trifluoromethylbenzylamine, α-ethyl-2,3,4,6-tetrakis-trifluoromethylbenzylamine, α-isopropyl-2,
3,4,6-Tetrakis-trifluoromethylbenzylamine, α-cyclopropyl-2,3,4,6-tetrakis-trifluoromethylbenzylamine, α-t-butyl-2,3,4,6-tetrakis -Trifluoromethylbenzylamine, α-ethyl-2,3,5,6-tetrakis-trifluoromethylbenzylamine, α-isopropyl-2,3,5,6-tetrakis-trifluoromethylbenzylamine, α-cyclo Propyl-2,3
5,6-Tetrakis-trifluoromethylbenzylamine, α-t-butyl-2,3,5,6-tetrakis-trifluoromethylbenzylamine, α-ethyl-2,
3,4,5,6-pentakis-trifluoromethylbenzylamine, α-isopropyl-2,3,4,5,6-
Pentakis-trifluoromethylbenzylamine, α-
Cyclopropyl-2,3,4,5,6-pentakis-trifluoromethylbenzylamine, α-t-butyl-
2,3,4,5,6-pentakis-trifluoromethylbenzylamine, α-methyl-2-trifluoromethoxybenzylamine, α-ethyl-2-trifluoromethoxybenzylamine, α-isopropyl-2-trifluoro Methoxybenzylamine, α-cyclopropyl-2
-Trifluoromethoxybenzylamine, α-t-butyl-2-trifluoromethoxybenzylamine, α-methyl-3-trifluoromethoxybenzylamine, α-
Ethyl-3-trifluoromethoxybenzylamine, α
-Isopropyl-3-trifluoromethoxybenzylamine, α-cyclopropyl-3-trifluoromethoxybenzylamine, α-t-butyl-3-trifluoromethoxybenzylamine, α-isopropyl-4-trifluoromethoxybenzylamine, α-cyclopropyl-
4-trifluoromethoxybenzylamine, α-t-butyl-4-trifluoromethoxybenzylamine, α-
Methyl-2,3-bis-trifluoromethoxybenzylamine, α-ethyl-2,3-bis-trifluoromethoxybenzylamine, α-isopropyl-2,3-bis-trifluoromethoxybenzylamine, α-cyclopropyl -2,3-Bis-trifluoromethoxybenzylamine, α-t-butyl-2,3-bis-trifluoromethoxybenzylamine, α-methyl-2,4-bis-
Trifluoromethoxybenzylamine, α-ethyl-
2,4-bis-trifluoromethoxybenzylamine,
α-isopropyl-2,4-bis-trifluoromethoxybenzylamine, α-cyclopropyl-2,4-bis-trifluoromethoxybenzylamine, α-t-butyl-2,4-bis-trifluoromethoxybenzylamine , Α-methyl-2,5-bis-trifluoromethoxybenzylamine, α-ethyl-2,5-bis-trifluoromethoxybenzylamine, α-isopropyl-2,
5-bis-trifluoromethoxybenzylamine, α-
Cyclopropyl-2,5-bis-trifluoromethoxybenzylamine, α-t-butyl-2,5-bis-trifluoromethoxybenzylamine, α-methyl-2,6
-Bis-trifluoromethoxybenzylamine, α-ethyl-2,6-bis-trifluoromethoxybenzylamine, α-isopropyl-2,6-bis-trifluoromethoxybenzylamine, α-cyclopropyl-2,6
-Bis-trifluoromethoxybenzylamine, α-t
-Butyl-2,6-bis-trifluoromethoxybenzylamine, α-methyl-3,4-bis-trifluoromethoxybenzylamine, α-ethyl-3,4-bis-trifluoromethoxybenzylamine, α-isopropyl -3,4-bis-trifluoromethoxybenzylamine, α-cyclopropyl-3,4-bis-trifluoromethoxybenzylamine, α-t-butyl-3,4-bis-trifluoromethoxybenzylamine, α- Methyl-3,5-bis-trifluoromethoxybenzylamine, α-ethyl-3,5-bis-trifluoromethoxybenzylamine, α-isopropyl-3,5-bis-trifluoromethoxybenzylamine, α-cyclopropyl -3,5-bis-trifluoromethoxybenzylamine, α-t-butyl-3,5 Bis - trifluoromethoxy benzylamine, alpha-methyl-2,3,4-tris - trifluoromethoxy benzylamine, alpha-ethyl -
2,3,4-Tris-trifluoromethoxybenzylamine, α-isopropyl-2,3,4-tris-trifluoromethoxybenzylamine, α-cyclopropyl-
2,3,4-Tris-trifluoromethoxybenzylamine, α-t-butyl-2,3,4-tris-trifluoromethoxybenzylamine, α-methyl-2,3,5
-Tris-trifluoromethoxybenzylamine, α-
Ethyl-2,3,5-tris-trifluoromethoxybenzylamine, α-isopropyl-2,3,5-tris-trifluoromethoxybenzylamine, α-cyclopropyl-2,3,5-tris-trifluoromethoxy Benzylamine, α-t-butyl-2,3,5-tris-
Trifluoromethoxybenzylamine, α-methyl-
2,3,6-Tris-trifluoromethoxybenzylamine, α-ethyl-2,3,6-tris-trifluoromethoxybenzylamine, α-isopropyl-2,3
6-tris-trifluoromethoxybenzylamine, α
-Cyclopropyl-2,3,6-tris-trifluoromethoxybenzylamine, α-t-butyl-2,3,6
-Tris-trifluoromethoxybenzylamine, α-
Methyl-2,4,5-tris-trifluoromethoxybenzylamine, α-ethyl-2,4,5-tris-trifluoromethoxybenzylamine, α-isopropyl-
2,4,5-Tris-trifluoromethoxybenzylamine, α-cyclopropyl-2,4,5-tris-trifluoromethoxybenzylamine, α-t-butyl-
2,4,5-Tris-trifluoromethoxybenzylamine, α-methyl-2,4,6-tris-trifluoromethoxybenzylamine, α-ethyl-2,4,6-tris-trifluoromethoxybenzylamine, α-isopropyl-2,4,6-tris-trifluoromethoxybenzylamine, α-cyclopropyl-2,4,6-tris-trifluoromethoxybenzylamine, α-t-
Butyl-2,4,6-tris-trifluoromethoxybenzylamine, α-methyl-3,4,5-tris-trifluoromethoxybenzylamine, α-ethyl-3,
4,5-Tris-trifluoromethoxybenzylamine, α-isopropyl-3,4,5-tris-trifluoromethoxybenzylamine, α-cyclopropyl-
3,4,5-Tris-trifluoromethoxybenzylamine, α-t-butyl-3,4,5-tris-trifluoromethoxybenzylamine, α-methyl-2,3,3
4,5-Tetrakis-trifluoromethoxybenzylamine, α-ethyl-2,3,4,5-tetrakis-trifluoromethoxybenzylamine, α-isopropyl-
2,3,4,5-tetrakis-trifluoromethoxybenzylamine, α-cyclopropyl-2,3,4,5-
Tetrakis-trifluoromethoxybenzylamine, α
-T-butyl-2,3,4,5-tetrakis-trifluoromethoxybenzylamine, α-methyl-2,3
4,6-Tetrakis-trifluoromethoxybenzylamine, α-ethyl-2,3,4,6-tetrakis-trifluoromethoxybenzylamine, α-isopropyl-
2,3,4,6-Tetrakis-trifluoromethoxybenzylamine, α-cyclopropyl-2,3,4,6-
Tetrakis-trifluoromethoxybenzylamine, α
-T-butyl-2,3,4,6-tetrakis-trifluoromethoxybenzylamine, α-methyl-2,3
5,6-Tetrakis-trifluoromethoxybenzylamine, α-ethyl-2,3,5,6-tetrakis-trifluoromethoxybenzylamine, α-isopropyl-
2,3,5,6-Tetrakis-trifluoromethoxybenzylamine, α-cyclopropyl-2,3,5,6-
Tetrakis-trifluoromethoxybenzylamine, α
-T-butyl-2,3,5,6-tetrakis-trifluoromethoxybenzylamine, α-methyl-2,3
4,5,6-Pentakis-trifluoromethoxybenzylamine, α-ethyl-2,3,4,5,6-pentakis-trifluoromethoxybenzylamine, α-isopropyl-2,3,4,5,6- Pentakis-trifluoromethoxybenzylamine, α-cyclopropyl-2,
3,4,5,6-Pentakis-trifluoromethoxybenzylamine, α-t-butyl-2,3,4,5,6-
Examples include pentakis-trifluoromethoxybenzylamine.

Examples of the trifluoromethoxy-substituted benzaldehyde represented by the general formula [22] include 2-trifluoromethoxybenzaldehyde, 3-trifluoromethoxybenzaldehyde, 4-trifluoromethoxybenzaldehyde and 2,3-bis-trifluoromethoxybenzaldehyde. 2,4-bis-trifluoromethoxybenzaldehyde, 2,5-bis-trifluoromethoxybenzaldehyde, 2,6-bis-trifluoromethoxybenzaldehyde, 3,4-bis-trifluoromethoxybenzaldehyde, 3,5-bis -Trifluoromethoxybenzaldehyde, 2,3,4-tris-trifluoromethoxybenzaldehyde, 2,3,5-tris-trifluoromethoxybenzaldehyde, 2,3,6
-Tris-trifluoromethoxybenzaldehyde,
2,4,5-Tris-trifluoromethoxybenzaldehyde, 2,4,6-tris-trifluoromethoxybenzaldehyde, 3,4,5-tris-trifluoromethoxybenzaldehyde, 2,3,4,5-tetrakis-tri Fluoromethoxybenzaldehyde, 2,3
4,6-tetrakis-trifluoromethoxybenzaldehyde, 2,3,5,6-tetrakis-trifluoromethoxybenzaldehyde and 2,3,4,5,6-pentakis-trifluoromethoxybenzaldehyde can be mentioned.

R ³ of the alkylamine represented by the general formula [23] is methyl, ethyl, 1-propyl, 2-
Propyl, cyclopropyl, 1-butyl, 2-butyl,
2-methyl-1-propyl, t-butyl, cyclobutyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, t-amyl, cyclopentyl, 1-hexyl, 2-hexyl, 3-hexyl, cyclohexyl and the like can be mentioned. To be

N-alkyl-represented by the general formula [24]
α-alkyl-fluoro, trifluoromethyl or
Examples of the rifluoromethoxy-substituted benzylamine include N-
Methyl-α-methyl-2-fluorobenzylamine, N
-Methyl-α-ethyl-2-fluorobenzylamine,
N-methyl-α-isopropyl-2-fluorobenzyl
Amine, N-methyl-α-cyclopropyl-2-fluor
Robenzylamine, N-methyl-α-t-butyl-2-
Fluorobenzylamine, N-methyl-α-methyl-3
-Fluorobenzylamine, N-methyl-α-ethyl-
3-fluorobenzylamine, N-methyl-α-isop
Ropyl-3-fluorobenzylamine, N-methyl-α
-Cyclopropyl-3-fluorobenzylamine, N-
Methyl-α-t-butyl-3-fluorobenzylami
N-methyl-α-methyl-4-fluorobenzyl
Min, N-methyl-α-ethyl-4-fluorobenzyl
Amine, N-methyl-α-isopropyl-4-fluoro
Benzylamine, N-methyl-α-cyclopropyl-4
-Fluorobenzylamine, N-methyl-α-t-butyl
Lu-4-fluorobenzylamine, N-methyl-α-me
Tyl-2,3-difluorobenzylamine, N-methyl
-Α-ethyl-2,3-difluorobenzylamine, N
-Methyl-α-isopropyl-2,3-difluoroben
Ziramine, N-methyl-α-cyclopropyl-2,3
-Difluorobenzylamine, N-methyl-α-t-bu
Tyl-2,3-difluorobenzylamine, N-methyl
-Α-methyl-2,4-difluorobenzylamine, N
-Methyl-α-ethyl-2,4-difluorobenzyl
Min, N-methyl-α-isopropyl-2,4-diflu
Orobenzylamine, N-methyl-α-cyclopropyl
-2,4-difluorobenzylamine, N-methyl-α
-T-butyl-2,4-difluorobenzylamine, N
-Methyl-α-methyl-2,5-difluorobenzyl
Min, N-methyl-α-ethyl-2,5-difluorobe
And N-methyl-α-isopropyl-2,5
-Difluorobenzylamine, N-methyl-α-cyclo
Propyl-2,5-difluorobenzylamine, N-me
Cyl-α-t-butyl-2,5-difluorobenzyl
Min, N-methyl-α-methyl-2,6-difluorobe
Nylamine, N-methyl-α-ethyl-2,6-diph
Luorobenzylamine, N-methyl-α-isopropyl
-2,6-Difluorobenzylamine, N-methyl-α
-Cyclopropyl-2,6-difluorobenzylami
N, N-methyl-α-t-butyl-2,6-difluoro
Benzylamine, N-methyl-α-methyl-3,4-di
Fluorobenzylamine, N-methyl-α-ethyl-
3,4-difluorobenzylamine, N-methyl-α-
Isopropyl-3,4-difluorobenzylamine, N
-Methyl-α-cyclopropyl-3,4-difluorobe
And N-methyl-α-t-butyl-3,4-
Difluorobenzylamine, N-methyl-α-methyl-
3,5-difluorobenzylamine, N-methyl-α-
Ethyl-3,5-difluorobenzylamine, N-methyl
Le-α-isopropyl-3,5-difluorobenzyl
Min, N-methyl-α-cyclopropyl-3,5-diph
Luorobenzylamine, N-methyl-α-t-butyl-
3,5-difluorobenzylamine, N-methyl-α-
Methyl-2,3,4-trifluorobenzylamine, N
-Methyl-α-ethyl-2,3,4-trifluoroben
Dilamine, N-methyl-α-isopropyl-2,3
4-trifluorobenzylamine, N-methyl-α-si
Clopropyl-2,3,4-trifluorobenzylami
N-methyl-α-t-butyl-2,3,4-trif
Luorobenzylamine, N-methyl-α-methyl-2,
3,5-trifluorobenzylamine, N-methyl-α
-Ethyl-2,3,5-trifluorobenzylamine,
N-methyl-α-isopropyl-2,3,5-triflu
Orobenzylamine, N-methyl-α-cyclopropyl
-2,3,5-trifluorobenzylamine, N-methyl
Ru-α-t-butyl-2,3,5-trifluorobenzi
Luamine, N-methyl-α-methyl-2,3,6-tri
Fluorobenzylamine, N-methyl-α-ethyl-
2,3,6-trifluorobenzylamine, N-methyl
-Α-isopropyl-2,3,6-trifluorobenzyl
Luamine, N-methyl-α-cyclopropyl-2,3,
6-trifluorobenzylamine, N-methyl-α-t
-Butyl-2,3,6-trifluorobenzylamine,
N-methyl-α-methyl-2,4,5-trifluorobe
N-diamine, N-methyl-α-ethyl-2,4,5-
Trifluorobenzylamine, N-methyl-α-isop
Ropil-2,4,5-trifluorobenzylamine, N
-Methyl-α-cyclopropyl-2,4,5-triflu
Orobenzylamine, N-methyl-α-t-butyl-
2,4,5-Trifluorobenzylamine, N-methyl
-Α-methyl-2,4,6-trifluorobenzylami
N, N-methyl-α-ethyl-2,4,6-trifluor
Robenzylamine, N-methyl-α-isopropyl-
2,4,6-trifluorobenzylamine, N-methyl
-Α-Cyclopropyl-2,4,6-trifluoroben
Ziramine, N-methyl-α-t-butyl-2,4,6
-Trifluorobenzylamine, N-methyl-α-methyl
Le-3,4,5-trifluorobenzylamine, N-me
Cyl-α-ethyl-3,4,5-trifluorobenzyl
Amine, N-methyl-α-isopropyl-3,4,5-
Trifluorobenzylamine, N-methyl-α-cyclo
Propyl-3,4,5-trifluorobenzylamine,
N-methyl-α-t-butyl-3,4,5-trifluoro
Robenzylamine, N-methyl-α-methyl-2,3
4,5-Tetrafluorobenzylamine, N-methyl-
α-ethyl-2,3,4,5-tetrafluorobenzyl
Amine, N-methyl-α-isopropyl-2,3,4
5-tetrafluorobenzylamine, N-methyl-α-
Cyclopropyl-2,3,4,5-tetrafluoroben
Ziramine, N-methyl-α-t-butyl-2,3
4,5-Tetrafluorobenzylamine, N-methyl-
α-methyl-2,3,4,6-tetrafluorobenzyl
Amine, N-methyl-α-ethyl-2,3,4,6-te
Trafluorobenzylamine, N-methyl-α-isop
Ropyr-2,3,4,6-tetrafluorobenzylami
N, N-methyl-α-cyclopropyl-2,3,4,6
-Tetrafluorobenzylamine, N-methyl-α-t
-Butyl-2,3,4,6-tetrafluorobenzyl
Min, N-methyl-α-methyl-2,3,5,6-teto
Rafluorobenzylamine, N-methyl-α-ethyl-
2,3,5,6-tetrafluorobenzylamine, N-
Methyl-α-isopropyl-2,3,5,6-tetraf
Luorobenzylamine, N-methyl-α-cyclopropyl
Le-2,3,5,6-tetrafluorobenzylamine,
N-methyl-α-t-butyl-2,3,5,6-tetra
Fluorobenzylamine, N-methyl-α-methyl-
2,3,4,5,6-pentafluorobenzylamine,
N-methyl-α-ethyl-2,3,4,5,6-penta
Fluorobenzylamine, N-methyl-α-isopropyl
Le-2,3,4,5,6-pentafluorobenzylami
N-methyl-α-cyclopropyl-2,3,4,
5,6-Pentafluorobenzylamine, N-methyl-
α-t-butyl-2,3,4,5,6-pentafluoro
Benzylamine, N-methyl-α-methyl-2-trif
Luoromethylbenzylamine, N-methyl-α-ethyl
-2-Trifluoromethylbenzylamine, N-methyl
-Α-isopropyl-2-trifluoromethylbenzyl
Amine, N-methyl-α-cyclopropyl-2-trif
Luoromethylbenzylamine, N-methyl-α-t-bu
Cyl-2-trifluoromethylbenzylamine, N-me
Cyl-α-ethyl-3-trifluoromethylbenzyla
Min, N-methyl-α-isopropyl-3-trifluor
Romethylbenzylamine, N-methyl-α-cyclopro
Pyr-3-trifluoromethylbenzylamine, N-me
Cyl-α-t-butyl-3-trifluoromethylbenzi
Luamine, N-methyl-α-methyl-4-trifluoro
Methylbenzylamine, N-methyl-α-ethyl-4-
Trifluoromethylbenzylamine, N-methyl-α-
Isopropyl-4-trifluoromethylbenzylami
N-methyl-α-cyclopropyl-4-trifluor
Romethylbenzylamine, N-methyl-α-t-butyl
-4-trifluoromethylbenzylamine, N-methyl
-Α-methyl-2,3-bis-trifluoromethylben
Ziramine, N-methyl-α-ethyl-2,3-bis-
Trifluoromethylbenzylamine, N-methyl-α-
Isopropyl-2,3-bis-trifluoromethylben
Ziramine, N-methyl-α-cyclopropyl-2,3
-Bis-trifluoromethylbenzylamine, N-methyl
Le-α-t-butyl-2,3-bis-trifluoromethy
Rubenzylamine, N-methyl-α-methyl-2,4-
Bis-trifluoromethylbenzylamine, N-methyl
-Α-ethyl-2,4-bis-trifluoromethylben
Ziramine, N-methyl-α-isopropyl-2,4-
Bis-trifluoromethylbenzylamine, N-methyl
-Α-Cyclopropyl-2,4-bis-trifluorome
Cylbenzylamine, N-methyl-α-t-butyl-
2,4-bis-trifluoromethylbenzylamine, N
-Methyl-α-methyl-2,5-bis-trifluorome
Cylbenzylamine, N-methyl-α-ethyl-2,5
-Bis-trifluoromethylbenzylamine, N-methyl
Le-α-isopropyl-2,5-bis-trifluorome
Cylbenzylamine, N-methyl-α-cyclopropyl
-2,5-bis-trifluoromethylbenzylamine,
N-methyl-α-t-butyl-2,5-bis-triflu
Oromethylbenzylamine, N-methyl-α-methyl-
2,6-bis-trifluoromethylbenzylamine, N
-Methyl-α-ethyl-2,6-bis-trifluorome
Cylbenzylamine, N-methyl-α-isopropyl-
2,6-bis-trifluoromethylbenzylamine, N
-Methyl-α-cyclopropyl-2,6-bis-trif
Luoromethylbenzylamine, N-methyl-α-t-bu
Cyl-2,6-bis-trifluoromethylbenzylami
N, N-methyl-α-methyl-3,4-bis-triflu
Oromethylbenzylamine, N-methyl-α-ethyl-
3,4-bis-trifluoromethylbenzylamine, N
-Methyl-α-isopropyl-3,4-bis-triflu
Oromethylbenzylamine, N-methyl-α-cyclop
Ropyr-3,4-bis-trifluoromethylbenzyla
Min, N-methyl-α-t-butyl-3,4-bis-to
Lifluoromethylbenzylamine, N-methyl-α-E
Cyl-3,5-bis-trifluoromethylbenzylami
N, N-methyl-α-isopropyl-3,5-bis-to
Lifluoromethylbenzylamine, N-methyl-α-t
-Butyl-3,5-bis-trifluoromethylbenzyl
Amine, N-methyl-α-methyl-2,3,4-tris
-Trifluoromethylbenzylamine, N-methyl-α
-Ethyl-2,3,4-tris-trifluoromethyl ester
Benzylamine, N-methyl-α-isopropyl-2,
3,4-tris-trifluoromethylbenzylamine,
N-methyl-α-cyclopropyl-2,3,4-tris
-Trifluoromethylbenzylamine, N-methyl-α
-T-butyl-2,3,4-tris-trifluoromethyi
Rubenzylamine, N-methyl-α-methyl-2,3,
5-tris-trifluoromethylbenzylamine, N-
Methyl-α-ethyl-2,3,5-tris-trifluor
Romethylbenzylamine, N-methyl-α-isopropyl
Le-2,3,5-tris-trifluoromethylbenzyl
Amine, N-methyl-α-cyclopropyl-2,3,5
-Tris-trifluoromethylbenzylamine, N-me
Cyl-α-t-butyl-2,3,5-tris-triflu
Oromethylbenzylamine, N-methyl-α-methyl-
2,3,6-Tris-trifluoromethylbenzylami
N-methyl-α-ethyl-2,3,6-tris-to
Lifluoromethylbenzylamine, N-methyl-α-ii
Sopropyl-2,3,6-tris-trifluoromethyl
Benzylamine, N-methyl-α-cyclopropyl-
2,3,6-Tris-trifluoromethylbenzylami
N-methyl-α-t-butyl-2,3,6-tris
-Trifluoromethylbenzylamine, N-methyl-α
-Methyl-2,4,5-tris-trifluoromethyl ester
N-diamine, N-methyl-α-ethyl-2,4,5-
Tris-trifluoromethylbenzylamine, N-methyl
Le-α-isopropyl-2,4,5-tris-triflu
Oromethylbenzylamine, N-methyl-α-cyclop
Ropil-2,4,5-tris-trifluoromethylben
Ziramine, N-methyl-α-t-butyl-2,4,5
-Tris-trifluoromethylbenzylamine, N-me
Cyl-α-methyl-2,4,6-tris-trifluoro
Methylbenzylamine, N-methyl-α-ethyl-2,
4,6-tris-trifluoromethylbenzylamine,
N-methyl-α-isopropyl-2,4,6-tris-
Trifluoromethylbenzylamine, N-methyl-α-
Cyclopropyl-2,4,6-tris-trifluorome
Cylbenzylamine, N-methyl-α-t-butyl-
2,4,6-Tris-trifluoromethylbenzylami
N, N-methyl-α-methyl-3,4,5-tris-to
Lifluoromethylbenzylamine, N-methyl-α-E
Chill-3,4,5-tris-trifluoromethylbenzi
Luamine, N-methyl-α-isopropyl-3,4,5
-Tris-trifluoromethylbenzylamine, N-me
Cyl-α-cyclopropyl-3,4,5-tris-tri
Fluoromethylbenzylamine, N-methyl-α-t-
Butyl-3,4,5-tris-trifluoromethylben
Ziramine, N-methyl-α-methyl-2,3,4,5
-Tetrakis-trifluoromethylbenzylamine, N
-Methyl-α-ethyl-2,3,4,5-tetrakis-
Trifluoromethylbenzylamine, N-methyl-α-
Isopropyl-2,3,4,5-tetrakis-triflu
Oromethylbenzylamine, N-methyl-α-cyclop
Ropil-2,3,4,5-tetrakis-trifluorome
Cylbenzylamine, N-methyl-α-t-butyl-
2,3,4,5-tetrakis-trifluoromethylben
Ziramine, N-methyl-α-methyl-2,3,4,6
-Tetrakis-trifluoromethylbenzylamine, N
-Methyl-α-ethyl-2,3,4,6-tetrakis-
Trifluoromethylbenzylamine, N-methyl-α-
Isopropyl-2,3,4,6-tetrakis-triflu
Oromethylbenzylamine, N-methyl-α-cyclop
Ropil-2,3,4,6-tetrakis-trifluorome
Cylbenzylamine, N-methyl-α-t-butyl-
2,3,4,6-tetrakis-trifluoromethylben
Ziramine, N-methyl-α-methyl-2,3,5,6
-Tetrakis-trifluoromethylbenzylamine, N
-Methyl-α-ethyl-2,3,5,6-tetrakis-
Trifluoromethylbenzylamine, N-methyl-α-
Isopropyl-2,3,5,6-tetrakis-triflu
Oromethylbenzylamine, N-methyl-α-cyclop
Ropil-2,3,5,6-tetrakis-trifluorome
Cylbenzylamine, N-methyl-α-t-butyl-
2,3,5,6-tetrakis-trifluoromethylben
Zilamine, N-methyl-α-methyl-2,3,4
5,6-pentakis-trifluoromethylbenzylami
N-methyl-α-ethyl-2,3,4,5,6-pe
N-kis-trifluoromethylbenzylamine, N-me
Cyl-α-isopropyl-2,3,4,5,6-penta
Kiss-trifluoromethylbenzylamine, N-methyl
-Α-cyclopropyl-2,3,4,5,6-pentaki
S-trifluoromethylbenzylamine, N-methyl-
α-t-butyl-2,3,4,5,6-pentakisto
Lifluoromethylbenzylamine, N-methyl-α-me
Cyl-2-trifluoromethoxybenzylamine, N-
Methyl-α-ethyl-2-trifluoromethoxybenzyl
Luamine, N-methyl-α-isopropyl-2-trif
Luoromethoxybenzylamine, N-methyl-α-siku
Ropropyl-2-trifluoromethoxybenzylami
N-methyl-α-t-butyl-2-trifluorome
Toxybenzylamine, N-methyl-α-methyl-3-
Trifluoromethoxybenzylamine, N-methyl-α
-Ethyl-3-trifluoromethoxybenzylamine,
N-methyl-α-isopropyl-3-trifluorometho
Xybenzylamine, N-methyl-α-cyclopropyl
-3-Trifluoromethoxybenzylamine, N-methyl
Le-α-t-butyl-3-trifluoromethoxybenzi
Luamine, N-methyl-α-methyl-4-trifluoro
Methoxybenzylamine, N-methyl-α-ethyl-4
-Trifluoromethoxybenzylamine, N-methyl-
α-isopropyl-4-trifluoromethoxybenzyl
Amine, N-methyl-α-cyclopropyl-4-trif
Luoromethoxybenzylamine, N-methyl-α-t-
Butyl-4-trifluoromethoxybenzylamine, N
-Methyl-α-methyl-2,3-bis-trifluorome
Toxybenzylamine, N-methyl-α-ethyl-2,
3-bis-trifluoromethoxybenzylamine, N-
Methyl-α-isopropyl-2,3-bis-trifluor
Romethoxybenzylamine, N-methyl-α-cyclop
Ropil-2,3-bis-trifluoromethoxybenzyl
Amine, N-methyl-α-t-butyl-2,3-bis-
Trifluoromethoxybenzylamine, N-methyl-α
-Methyl-2,4-bis-trifluoromethoxybenzyl
Lumine, N-methyl-α-ethyl-2,4-bis-to
Lifluoromethoxybenzylamine, N-methyl-α-
Isopropyl-2,4-bis-trifluoromethoxy ester
Benzylamine, N-methyl-α-cyclopropyl-2,
4-bis-trifluoromethoxybenzylamine, N-
Methyl-α-t-butyl-2,4-bis-trifluoro
Methoxybenzylamine, N-methyl-α-methyl-
2,5-bis-trifluoromethoxybenzylamine,
N-methyl-α-ethyl-2,5-bis-trifluoro
Methoxybenzylamine, N-methyl-α-isopropyl
Le-2,5-bis-trifluoromethoxybenzylami
N-methyl-α-cyclopropyl-2,5-bis-
Trifluoromethoxybenzylamine, N-methyl-α
-T-butyl-2,5-bis-trifluoromethoxy ester
N-diamine, N-methyl-α-methyl-2,6-bis
-Trifluoromethoxybenzylamine, N-methyl-
α-Ethyl-2,6-bis-trifluoromethoxyben
Ziramine, N-methyl-α-isopropyl-2,6-
Bis-trifluoromethoxybenzylamine, N-methyl
Le-α-cyclopropyl-2,6-bis-trifluoro
Methoxybenzylamine, N-methyl-α-t-butyl
-2,6-bis-trifluoromethoxybenzylami
N, N-methyl-α-methyl-3,4-bis-triflu
Oromethoxybenzylamine, N-methyl-α-ethyl
-3,4-bis-trifluoromethoxybenzylami
N-methyl-α-isopropyl-3,4-bis-
Lifluoromethoxybenzylamine, N-methyl-α-
Cyclopropyl-3,4-bis-trifluoromethoxy
Benzylamine, N-methyl-α-t-butyl-3,4
-Bis-trifluoromethoxybenzylamine, N-me
Cyl-α-methyl-3,5-bis-trifluoromethoxy
Cibenzylamine, N-methyl-α-ethyl-3,5-
Bis-trifluoromethoxybenzylamine, N-methyl
Le-α-isopropyl-3,5-bis-trifluorome
Toxybenzylamine, N-methyl-α-cyclopropene
Le-3,5-bis-trifluoromethoxybenzylami
N-methyl-α-t-butyl-3,5-bis-tri
Fluoromethoxybenzylamine, N-methyl-α-me
Chill-2,3,4-tris-trifluoromethoxyben
Ziramine, N-methyl-α-ethyl-2,3,4-to
Lis-trifluoromethoxybenzylamine, N-methyl
Le-α-isopropyl-2,3,4-tris-triflu
Oromethoxybenzylamine, N-methyl-α-cyclo
Propyl-2,3,4-tris-trifluoromethoxy
Benzylamine, N-methyl-α-t-butyl-2,
3,4-tris-trifluoromethoxybenzylami
N, N-methyl-α-methyl-2,3,5-tris-to
Lifluoromethoxybenzylamine, N-methyl-α-
Ethyl-2,3,5-tris-trifluoromethoxy ester
Benzylamine, N-methyl-α-isopropyl-2,
3,5-tris-trifluoromethoxybenzylami
N, N-methyl-α-cyclopropyl-2,3,5-to
Lis-trifluoromethoxybenzylamine, N-methyl
Le-α-t-butyl-2,3,5-tris-trifluor
Romethoxybenzylamine, N-methyl-α-methyl-
2,3,6-tris-trifluoromethoxybenzyl
Min, N-methyl-α-ethyl-2,3,6-tris-
Trifluoromethoxybenzylamine, N-methyl-α
-Isopropyl-2,3,6-tris-trifluorome
Toxybenzylamine, N-methyl-α-cyclopropene
Le-2,3,6-tris-trifluoromethoxybenzi
Luamine, N-methyl-α-t-butyl-2,3,6-
Tris-trifluoromethoxybenzylamine, N-me
Cyl-α-methyl-2,4,5-tris-trifluoro
Methoxybenzylamine, N-methyl-α-ethyl-
2,4,5-Tris-trifluoromethoxybenzyl
Min, N-methyl-α-isopropyl-2,4,5-to
Lis-trifluoromethoxybenzylamine, N-methyl
Le-α-cyclopropyl-2,4,5-tris-trif
Luoromethoxybenzylamine, N-methyl-α-t-
Butyl-2,4,5-tris-trifluoromethoxy ester
And N-methyl-α-methyl-2,4,6-
Tris-trifluoromethoxybenzylamine, N-me
Cyl-α-ethyl-2,4,6-tris-trifluoro
Methoxybenzylamine, N-methyl-α-isopropyl
Le-2,4,6-tris-trifluoromethoxybenzi
Luamine, N-methyl-α-cyclopropyl-2,4,
6-tris-trifluoromethoxybenzylamine, N
-Methyl-α-t-butyl-2,4,6-tris-tri
Fluoromethoxybenzylamine, N-methyl-α-me
Cyl-3,4,5-tris-trifluoromethoxyben
Ziramine, N-methyl-α-ethyl-3,4,5-to
Lis-trifluoromethoxybenzylamine, N-methyl
Le-α-isopropyl-3,4,5-tris-triflu
Oromethoxybenzylamine, N-methyl-α-cyclo
Propyl-3,4,5-tris-trifluoromethoxy
Benzylamine, N-methyl-α-t-butyl-3,
4,5-Tris-trifluoromethoxybenzylami
N, N-methyl-α-methyl-2,3,4,5-tetra
Kiss-trifluoromethoxybenzylamine, N-methyl
Le-α-ethyl-2,3,4,5-tetrakis-trif
Luoromethoxybenzylamine, N-methyl-α-iso
Propyl-2,3,4,5-tetrakis-trifluoro
Methoxybenzylamine, N-methyl-α-cyclopro
Pill-2,3,4,5-tetrakis-trifluorometh
Xybenzylamine, N-methyl-α-t-butyl-
2,3,4,5-tetrakis-trifluoromethoxy ester
Benzylamine, N-methyl-α-methyl-2,3,4,
6-tetrakis-trifluoromethoxybenzylami
N, N-methyl-α-ethyl-2,3,4,6-tetra
Kiss-trifluoromethoxybenzylamine, N-methyl
Le-α-isopropyl-2,3,4,6-tetrakis-
Trifluoromethoxybenzylamine, N-methyl-α
-Cyclopropyl-2,3,4,6-tetrakis-tri
Fluoromethoxybenzylamine, N-methyl-α-t
-Butyl-2,3,4,6-tetrakis-trifluoro
Methoxybenzylamine, N-methyl-α-methyl-
2,3,5,6-tetrakis-trifluoromethoxy ester
N-diamine, N-methyl-α-ethyl-2,3,5,
6-tetrakis-trifluoromethoxybenzylami
N-methyl-α-isopropyl-2,3,5,6-
Tetrakis-trifluoromethoxybenzylamine, N
-Methyl-α-cyclopropyl-2,3,5,6-teto
Lakis-trifluoromethoxybenzylamine, N-me
Cyl-α-t-butyl-2,3,5,6-tetrakis-
Trifluoromethoxybenzylamine, N-methyl-α
-Methyl-2,3,4,5,6-pentakis-triflu
Oromethoxybenzylamine, N-methyl-α-ethyl
-2,3,4,5,6-pentakis-trifluorometh
Xybenzylamine, N-methyl-α-isopropyl-
2,3,4,5,6-pentakis-trifluoromethoxy
Cibenzylamine, N-methyl-α-cyclopropyl-
2,3,4,5,6-pentakis-trifluoromethoxy
Cibenzylamine, N-methyl-α-t-butyl-2,
3,4,5,6-pentakis-trifluoromethoxy ester
And the like.

N-alkyl-represented by the general formula [25]
As a trifluoromethoxy-substituted benzylamine, N
-Methyl-2-trifluoromethoxybenzylamine,
N-methyl-3-trifluoromethoxybenzylamine, N-methyl-4-trifluoromethoxybenzylamine, N-methyl-2,3-bis-trifluoromethoxybenzylamine, N-methyl-2,4-bis- Trifluoromethoxybenzylamine, N-methyl-2,5-
Bis-trifluoromethoxybenzylamine, N-methyl-2,6-bis-trifluoromethoxybenzylamine, N-methyl-3,4-bis-trifluoromethoxybenzylamine, N-methyl-3,5-bis- Trifluoromethoxybenzylamine, N-methyl-2,3,4
-Tris-trifluoromethoxybenzylamine, N-
Methyl-2,3,5-tris-trifluoromethoxybenzylamine, N-methyl-2,3,6-tris-trifluoromethoxybenzylamine, N-methyl-2,
4,5-Tris-trifluoromethoxybenzylamine, N-methyl-2,4,6-tris-trifluoromethoxybenzylamine, N-methyl-3,4,5-tris-trifluoromethoxybenzylamine, N- Methyl-2,3,4,5-tetrakis-trifluoromethoxybenzylamine, N-methyl-2,3,4,6-tetrakis-trifluoromethoxybenzylamine, N-methyl-2,3,5,6- Tetrakis-trifluoromethoxybenzylamine, N-methyl-2,3,4,5,6-
Examples include pentakis-trifluoromethoxybenzylamine.

Many of the fluoro-, trifluoromethyl-, or trifluoromethoxy-substituted phenylalkylketones represented by the general formula [18] are known compounds. In the case of new compounds, Tetrahedron Lett. , N
It can be easily synthesized by the method described on page 53, page 4647, 1970, etc. That is, the general formula [26]

[0041]

[Chemical 38]

[Wherein R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, and n is 1
Represents an integer from 5 to 5, R ¹ is an arbitrary substitution position, X 1
Represents a halogen of F, Cl, Br, I], wherein a fluoro, trifluoromethyl or trifluoromethoxy-substituted benzoyl halide represented by the formula [27] is prepared from alkyl lithium and copper iodide.

[0043]

[Chemical Formula 39]

[In the formula, R ² represents a lower alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, 1-propyl, 2-propyl, cyclopropyl, 1-butyl, 2-
Butyl, 2-methyl-1-propyl, t-butyl, cyclobutyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, t-amyl, cyclopentyl, 1-
Hexyl, 2-hexyl, 3-hexyl, cyclohexyl, etc.] can be easily synthesized by reacting an organic copper reagent represented by the formula [1] at a low temperature in a nitrogen atmosphere.

Some of the trifluoromethoxy-substituted benzaldehydes represented by the general formula [22] are known compounds. In the case of new compounds, J. Am. Chem. So
c. , Vol. It can be easily synthesized by the method described in pages 96, 7761, 1974. That is, the general formula [28]

[0046]

[Chemical 40]

[In the formula, n represents an integer of 1 to 5, and OC
The F ₃ group has an arbitrary substitution position, and X represents halogen of Cl, Br, and I], and a halogenated trifluoromethoxy-substituted benzene represented by the general formula [29]

[0048]

[Chemical 41]

[In the formula, R ^1's independently represent a lower alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, 1-
Propyl, 2-propyl, cyclopropyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, t-butyl, cyclobutyl, 1-pentyl, 2-pentyl, 3-
Pentyl, neopentyl, t-amyl, cyclopentyl, 1-hexyl, 2-hexyl, 3-hexyl, cyclohexyl, etc.] in the presence of a trialkylamine represented by the general formula [30]

[0050]

[Chemical 42]

[In the formula, Ph represents a phenyl group, and X represents C
It represents halogen of 1, Br, and I], and can be easily synthesized by reacting with hydrogen and carbon monoxide.

The process for producing the α-alkyl-fluoro, trifluoromethyl- or trifluoromethoxy-substituted benzylamine represented by the general formula [21] of the present invention comprises the following two steps (first step; dehydration condensation, first step). Two steps; hydrogenation and hydrogenolysis). (First Step; Dehydration Condensation) Since this step is dehydration condensation of the fluoro, trifluoromethyl or trifluoromethoxy substituted phenylalkyl ketone represented by the general formula [18] and the benzylamine represented by the formula [19], The reaction is carried out under acidic conditions while removing by-product water. Preferably, a reaction solvent that is immiscible with water, has a smaller specific gravity than water, and is azeotropic with water is used to remove water by-produced in the Dean-Stark tube under reflux conditions.

The amount of benzylamine used may be 1 molar equivalent or more based on fluoro, trifluoromethyl or trifluoromethoxy-substituted phenylalkylketone, and usually 1 to 10 molar equivalents are preferable, and 1 to 10 molar equivalents are particularly preferable. 5 molar equivalents are more preferred.

As the acid catalyst, benzenesulfonic acid, p
-Toluenesulfonic acid, 10-camphorsulfonic acid and other organic acids, and hydrochloric acid, sulfuric acid, phosphoric acid, zinc chloride, titanium tetrachloride and other inorganic acids. Among them, p-toluenesulfonic acid, sulfuric acid and zinc chloride are preferable, and p-toluenesulfonic acid and zinc chloride are more preferable.

The acid catalyst may be used in a catalytic amount with respect to fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenylalkylketone, and usually 0.001 to 0.9 molar equivalents are preferable, and particularly preferable. 0.
More preferably 005 to 0.5 molar equivalent.

As the reaction solvent, benzene, toluene,
Aromatic hydrocarbons such as ethylbenzene, xylene and mesitylene are preferable, and toluene is particularly preferable. These reaction solvents can be used alone or in combination.

As the amount of the reaction solvent to be used, the amount of the reaction solvent which is theoretically required to azeotropically remove the amount of by-produced water is required, but the amount of the reaction solvent is extremely reduced by using the Dean-Stark tube. You can

The temperature conditions may be in the range from the azeotropic temperature of the reaction solvent used and water to the boiling point of the reaction solvent, and particularly preferably around the boiling point of the reaction solvent used.

The reaction time is within 72 hours, but it usually differs depending on the reaction substrate and reaction conditions adopted, and therefore the progress of the reaction is analyzed by an analytical means such as gas chromatography, thin layer chromatography, HPLC and NMR. It is preferable that the reaction is terminated and the reaction is terminated when the raw materials almost disappear.

As the post-treatment, a crude product can be obtained by carrying out a usual post-treatment operation after completion of the reaction.
Particularly, benzylamine used in excess can be selectively removed by washing the organic layer containing imine with an aqueous solution of ammonium chloride. The crude product can be subjected to purification operations such as activated carbon, distillation, recrystallization, column chromatography and the like, if necessary, to obtain the desired imine represented by the general formula [20] with high chemical purity.

(Second Step: Hydrogenation and Hydrogenolysis) Hydrogenation and hydrogenolysis of the imine obtained in the first step are carried out in a hydrogen atmosphere by using a metal catalyst.

This step proceeds well by catalytic reduction using a transition metal catalyst.

As the transition metal catalyst, platinum oxide, platinum /
Activated carbon, platinum catalyst such as platinum black, reduced nickel, Raney nickel, nickel catalyst such as Raney nickel with platinum, cobalt catalyst such as Raney cobalt, reduced copper, copper catalyst such as copper-chromium oxide, zinc such as zinc-chromium oxide Catalyst, ruthenium oxide, ruthenium catalyst such as ruthenium / activated carbon, rhodium / activated carbon, rhodium / alumina, rhodium catalyst such as rhodium-platinum oxide, iridium catalyst such as iridium black, rhenium catalyst such as rhenium oxide, palladium / activated carbon, hydroxide Palladium, palladium black, palladium / barium sulfate, palladium / strontium carbonate,
Palladium / calcium carbonate, palladium / calcium carbonate-lead diacetate, palladium / barium sulfate-quinoline, palladium / alumina, palladium sponge, palladium chloride, palladium acetate, palladium acetylacetonate, bis (dibenzylideneacetone) palladium, tetrakis (tri) Phenylphosphine) palladium, dichloro [bis (triphenylphosphine)] palladium, dichloro [bis (diphenylphosphino) methane] palladium, dichloro [bis (diphenylphosphino) ethane] palladium, dichloro [1,3-bis (diphenylphos) Phino) propane] palladium, dichloro [1,4-bis (diphenylphosphino) butane] palladium, dichloro (1,5-cyclooctadiene) palladium, dichloro [bis Benzonitrile) palladium, dichloro [bis (acetonitrile) palladium,
Examples thereof include palladium catalysts such as acetic acid [bis (triphenylphosphine)] palladium. Of these, platinum catalysts, rhodium catalysts and palladium catalysts are preferable, and particularly platinum / activated carbon, rhodium / activated carbon and palladium /
Activated carbon is more preferred. These transition metal catalysts can be used alone or in combination. When a catalyst in which a metal is supported on a carrier is used, the supported amount is 0.1 to
It is 50% by weight, preferably 0.5 to 30% by weight, and more preferably 1 to 20% by weight. Further, in order to enhance the safety of handling or to prevent the oxidation of the metal surface, those stored in water or mineral oil can be used.

The amount of the transition metal catalyst used is 0.0005 to 2.5% by weight in terms of metal, usually 0.005 to 1.5% by weight, particularly 0.01 ˜1.0 wt% is more preferred.

The amount of hydrogen used is as follows:
It may be used in an amount of 2 molar equivalents or more, and the reaction system is usually carried out in a hydrogen atmosphere, so a large excess is used.

The hydrogen pressure is 0.01 to 10 MPa, preferably 0.05 to 5.0 MPa, and more preferably 0.1 to 2.0 MPa.

As the hydrogen source, formic acid, ammonium formate, hydrazine and the like can be used in addition to molecular hydrogen.

The temperature condition is from -50 to + 150 ° C, usually from -25 to + 120 ° C, and especially from 0 to
+ 100 ° C is more preferable.

The reaction time is 72 hours or less, but it usually differs depending on the reaction substrate and reaction conditions adopted. It is preferable that the reaction is terminated and the reaction is terminated when the raw materials almost disappear.

This reaction may proceed smoothly by adding acid or ammonia as an additive.

As the acid of the additive, acetic acid, propionic acid, butyric acid, p-toluenesulfonic acid, organic acid such as 10-camphorsulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, etc. Inorganic acids may be mentioned. Among them, acetic acid, propionic acid, hydrochloric acid, sulfuric acid and hydrobromic acid are preferable, and acetic acid, hydrochloric acid and sulfuric acid are more preferable.

As the additive ammonia, ammonia gas or ammonia gas is used as methanol or i
It is also possible to use a commercially available alcoholic solution dissolved in propanol.

The amount of the additive used is represented by the general formula [20].
With respect to the imine represented by, 0.1 molar equivalents or more may be used, usually 0.1 to 100 molar equivalents are preferable,
Particularly, 0.1 to 50 molar equivalents are more preferable.

As the reaction solvent, aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, methylene chloride, chloroform, etc.
Halogenated hydrocarbon type such as 1,2-dichloroethane, diethyl ether, tetrahydrofuran, t-butyl methyl ether, ether type such as 1,4-dioxane, ester type such as ethyl acetate and n-butyl acetate, methanol,
Examples thereof include alcohols such as ethanol, n-propanol and i-propanol. Among them, toluene, ethyl acetate, methanol, ethanol and i-propanol are preferable, and particularly methanol, ethanol and i-propanol are more preferable. These reaction solvents can be used alone or in combination.

As the post-treatment, a crude product can be obtained by carrying out a usual post-treatment operation after the completion of the reaction.
The crude product is subjected to a purification operation such as activated carbon, distillation, recrystallization, recrystallization of a salt of an organic acid or an inorganic acid, column chromatography and the like, if necessary, to give a compound of the desired general formula [2
[1] [alpha] -alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine can be obtained with high chemical purity.

The N-alkyl-α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy-substituted benzylamine represented by the general formula [24] of the present invention, or the N-alkyl-tri represented by the general formula [25] The fluoromethoxy-substituted benzylamine has the general formula [18]
The fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenylalkyl ketone represented by or the trifluoromethoxy-substituted benzaldehyde represented by the general formula [22] is condensed with the alkylamine represented by the general formula [23], and further reacted. By adding a hydride reducing agent to the system, it can be produced with high chemical purity and high yield.

As the alkylamine, a neat compound including a gas at room temperature is used, but a commercially available alkylamine solution such as methanol or tetrahydrofuran can also be used.

The alkylamine may be used in an amount of 1 molar equivalent or more with respect to fluoro, trifluoromethyl or trifluoromethoxy substituted phenyl alkyl ketone or trifluoromethoxy substituted benzaldehyde, and usually 1 to 20 molar equivalents. Is preferable, and 1 to 10 molar equivalents is particularly preferable.

The temperature conditions for condensation are -100 to +1.
It is 50 ° C., and normally −40 to + 100 ° C. is preferable.

The reaction time of the condensation is completed within 72 hours, but it usually depends on the reaction substrate and reaction conditions adopted, and therefore the reaction can be performed by an analytical means such as gas chromatography, thin layer chromatography, HPLC, NMR and the like. The progress is tracked, and a hydride reducing agent is added to the reaction system when the raw materials almost disappear.

As the hydride reducing agent, (iB
u)₂AlH, (i-Bu)₃Al, [2,6- (t-B
u)₂-4-MePh] Al (i-Bu)₂, LiAlH
_Four, LiAlH (OMe)₃, LiAlH (Ot-B
u)₃, NaAlH₂(OCH₂CH₂OCH₃)₂Etc. al
Minium hydride system, diborane, BH₃・ THF,
BH₃・ SMe₂, BH₃・ NMe₃, 9-BBN, NaB
H_Four, NaBH_Four-CeCl ₃, LiBH_Four, Zn (B
H_Four)₂, Ca (BH_Four)₂, Lin-BuBH₃, NaB
H (OMe)₃, NaBH (OAc)₃, NaBH₃C
N, Et_FourNBH_Four, Me_FourNBH (OAc)₃, (N-B
u)_FourNBH₃CN, (n-Bu)_FourNBH (OAc) ₃,
Li (s-Bu)₃BH, K (s-Bu)₃BH, LiS
ia₃BH, KSia ₃BH, LiEt₃BH, KPh₃B
H, (Ph₃P)₂CuBH_Four, ThxBH₂, Sia₂B
H, catechol borane, IpcBH₂, Ipc₂Such as BH
Boron hydride system, Et₃SiH, PhMe₂Si
H, Ph₂SiH₂, PhSiH₃-Mo (CO)₆Etc.
An example is an iodine hydride system. Here Bu is
Group, Ph is a phenyl group, Me is a methyl group, and THF is the
Trahydrofuran, 9-BBN is 9-borabicyclo
[3,3,1] nonane, Ac is an acetyl group, Sia is a
Iamyl group, Et is ethyl group, Thx is texyl group, I
pc represents an isopinocampheyl group, respectively.
You Among them, LiAlH_Four, Diborane, NaBH_FourAnd
And LiBH_FourIs preferred, especially NaBH_FourIs more preferred
Yes. These hydride reducing agents are present in various inorganic salts.
It can also be used in office.

The hydride reducing agent may be used in an amount of 0.25 molar equivalent or more with respect to fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenyl alkyl ketone or trifluoromethoxy-substituted benzaldehyde, and is usually 0. 25 to 10 molar equivalents are preferable, and 0.25 to 7.0 molar equivalents are particularly preferable.

Examples of the reaction solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, methylene chloride and chloroform.
Halogenated hydrocarbon type such as 1,2-dichloroethane, diethyl ether, tetrahydrofuran, t-butyl methyl ether, ether type such as 1,4-dioxane, ester type such as ethyl acetate and n-butyl acetate, methanol,
Examples thereof include alcohols such as ethanol, n-propanol and i-propanol. Among them, toluene, tetrahydrofuran, ethyl acetate, methanol, ethanol and i-propanol are preferable, and tetrahydrofuran, methanol, ethanol and i-propanol are particularly preferable. These reaction solvents can be used alone or in combination.

The amount of the reaction solvent used is 0.25 to 50 with respect to 1 mmol of fluoro, trifluoromethyl or trifluoromethoxy substituted phenyl alkyl ketone or trifluoromethoxy substituted benzaldehyde.
In general, 0.25 to 25 ml is preferable, and 0.25 to 15 ml is particularly preferable.

The temperature conditions for hydride reduction are:
100 to + 150 ° C, usually -40 to + 100 ° C
Is preferred.

The reaction time for hydride reduction is 7
Although it will be completed within 2 hours, it usually depends on the reaction substrate and reaction conditions adopted, so the progress of the reaction is tracked by analytical means such as gas chromatography, thin layer chromatography, HPLC, NMR, etc. It is preferable to terminate the reaction at the time.

As the post-treatment, a crude product can be obtained by carrying out an ordinary post-treatment operation after the completion of the reaction.
The crude product is subjected to a purification operation such as activated carbon, distillation, recrystallization, recrystallization of a salt of an organic acid or an inorganic acid, column chromatography and the like, if necessary, to give a compound of the desired general formula [2
[4]] N-alkyl-α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine, or N-alkyl-trifluoromethoxy substituted benzylamine represented by the general formula [25] with high chemical purity. Can be obtained at

[0088]

EXAMPLES The embodiments of the present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[Example 1] α-Ethyl-3,5-difluorobenzylamine (dehydration condensation) To 20 ml of toluene, 2.0 g of 3 ', 5'-difluoropropiophenone (11.75 mmol, 1
eq), benzylamine 1.39 g (12.93 mmo)
1, 1.1eq) and zinc chloride 0.16g (1.18mm)
(0.1 eq., 0.1 eq.) was added, and the mixture was stirred for 18 hours under heating and refluxing conditions, and water produced as a by-product was removed using a Dean-Stark tube.
The reaction completed liquid was washed with 5% sodium hydroxide aqueous solution, 1.5N ammonium chloride aqueous solution and water in this order. The collected organic layer is dried over anhydrous sodium sulfate, filtered, concentrated, and dried in vacuum.

[0090]

[Chemical 43]

2.92 g of a crude imine product of the following formula was obtained. The conversion rate of the crude product was 96% as determined by gas chromatography (hereinafter referred to as GC). Further, the isomer ratio of the crude product was determined by ¹ H-NMR, and was E form: Z form = 80: 20. (E form) ¹ H-NMR (reference substance: TMS, solvent: CD
Cl ₃ ), δ ppm: 1.16 (t, 8.0 Hz, 3
H), 2.77 (q, 8.0 Hz, 2H), 4.79.
(S, 2H), 7.23-7.45 (Ar-H, 8
H). (Z-form) ¹ H-NMR (reference substance: TMS, solvent: CD
Cl ₃ ), δ ppm: 1.15 (t, 7.2 Hz, 3
H), 2.60 (q, 7.2 Hz, 2H), 4.41
(S, 2H), 7.23-7.45 (Ar-H, 8
H). (Hydrogenation and hydrogenolysis) 0.50 g (1.93 m) of a crude imine product produced by dehydration condensation in 2 ml of methanol.
mol, 1 eq) and 5% palladium / activated carbon (5
(0 wt% hydrous product) 25 mg, hydrogen pressure 0.5MP
It was set to a and stirred at 60 ° C. for 15 minutes. The reaction-completed liquid was filtered through Celite, concentrated, and dried under vacuum.

[0092]

[Chemical 44]

0.14 g (yield 43%) of a crude product of α-ethyl-3,5-difluorobenzylamine represented by:
Got ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 0.87 (t, 7.6 Hz, 3H),
1.66 (dq, 6.8Hz, 7.6Hz, 2H),
1.70 (br, 1H), 3.81 (t, 6.8 Hz,
1H), 6.67 (tt, 2.4Hz, 8.8Hz, A
r-H, 1H), 6.86 (d, 8.0 Hz, Ar-
H, 2H).

Example 2 α-Ethyl-3-trifluoromethylbenzylamine (dehydration condensation) To 10 ml of toluene, 2.0 g of 3'-trifluoromethylpropiophenone (9.89 mmol,
1 eq), benzylamine 1.17 g (10.88 mm
ol, 1.1 eq) and zinc chloride 0.14 g (0.99 m
mol, 0.1 eq) was added, and the mixture was stirred under heating and refluxing conditions for 17 hours, and by-produced water was removed using a Dean-Stark tube. The reaction completed solution was adjusted to 5% sodium hydroxide aqueous solution, 1.5
The aqueous solution was washed with N ammonium chloride aqueous solution and water in this order. The collected organic layer is dried over anhydrous sodium sulfate, filtered, concentrated, and dried in vacuum.

[0095]

[Chemical formula 45]

2.88 g of a crude imine product of the following formula was obtained. The conversion of the crude product is 90%, determined by GC.
Met. In addition, the isomer ratio of the crude product is ¹ H-NMR
And E form: Z form = 79: 21. (E form) ¹ H-NMR (reference substance: TMS, solvent: CD
Cl ₃ ), δ ppm: 1.16 (t, 7.6 Hz, 3
H), 2.84 (q, 7.6 Hz, 2H), 4.82
(S, 2H), 7.22-8.11 (Ar-H, 9
H). (Z-form) ¹ H-NMR (reference substance: TMS, solvent: CD
Cl ₃ ), δ ppm: 1.16 (t, 7.6 Hz, 3
H), 2.65 (q, 7.6 Hz, 2H), 4.40
(S, 2H), 7.22-8.11 (Ar-H, 9
H). (Hydrogenation and hydrogenolysis) 0.87 g (2.99 m) of a crude imine product produced by dehydration condensation in 3 ml of methanol.
mol, 1 eq) and 5% palladium / activated carbon (5
(0 wt% water-containing product) 43 mg, and hydrogen pressure 0.5MP
It was set to a and stirred at 60 ° C. for 17 hours. The reaction-completed liquid was filtered through Celite, concentrated, and dried under vacuum.

[0097]

[Chemical formula 46]

0.42 g (yield 69) of a crude product of α-ethyl-3-trifluoromethylbenzylamine represented by
%) Was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 0.88 (t, 7.2 Hz, 3H),
1.72 (ddq, 3.2Hz, 6.8Hz, 7.2H
z, 2H), 2.14 (br, 1H), 3.91 (t,
6.8 Hz, 1H), 7.42-7.60 (Ar-H,
4H).

Example 3 α-Methyl-3-trifluoromethoxybenzylamine (dehydrated condensation) To 10 ml of toluene, 2.00 g of 3'-trifluoromethoxyacetophenone (9.80 mmo)
1, 1 eq), benzylamine 1.16 g (10.78)
mmol, 1.1 eq) and zinc chloride 0.13 g (0.9
8 mmol, 0.1 eq) was added, and 1 was added under the condition of heating under reflux.
The mixture was stirred for 6 hours, and by-product water was removed using a Dean-Stark tube. The reaction completed liquid was a 5% aqueous sodium hydroxide solution, 1.
It was washed with a 5N ammonium chloride aqueous solution and water in this order. The collected organic layer is dried over anhydrous sodium sulfate, filtered, concentrated, and dried in vacuum.

[0100]

[Chemical 47]

2.68 g of a crude imine product of the formula: was obtained. The conversion of the crude product is determined by GC and is 100
%Met. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 2.32 (t, 0.8 Hz, 3H),
4.74 (s, 2H), 7.24-7.80 (Ar-
H, 8H). (Hydrogenation and hydrogenolysis) 0.45 g (1.52 m) of a crude imine product produced by dehydration condensation in 2 ml of methanol.
mol, 1 eq) and 5% palladium / activated carbon (5
(0 wt% water content) 23 mg was added, and the hydrogen pressure was 0.5 MPa.
And stirred at 60 ° C. for 18 hours. The reaction-completed liquid was filtered through Celite, concentrated, and dried under vacuum.

[0102]

[Chemical 48]

0.25 g of a crude product of α-methyl-3-trifluoromethoxybenzylamine represented by
0%). ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 1.40 (d, 6.8 Hz, 3H),
2.19 (br, 1H), 4.16 (q, 6.8 Hz,
1H), 7.09-7.37 (Ar-H, 4H).

Example 4 α-Ethyl-3-trifluoromethoxybenzylamine (dehydration condensation) To 9.2 ml of toluene, 2.0 g of 3'-trifluoromethoxypropiophenone (9.17 mmo) was added.
1, 1 eq), benzylamine 1.08 g (10.09)
mmol, 1.1 eq) and zinc chloride 0.13 g (0.9
2 mmol, 0.1 eq) was added, and 1 was added under the condition of heating under reflux.
The mixture was stirred for 8 hours, and by-product water was removed using a Dean-Stark tube. The reaction completed liquid was a 5% aqueous sodium hydroxide solution, 1.
It was washed with a 5N ammonium chloride aqueous solution and water in this order. The collected organic layer is dried over anhydrous sodium sulfate, filtered, concentrated, and dried in vacuum.

[0105]

[Chemical 49]

2.78 g of a crude imine product of the following formula was obtained. The conversion of the crude product is 90%, determined by GC.
Met. In addition, the isomer ratio of the crude product is ¹ H-NMR
And E form: Z form = 74: 26. (E form) ¹ H-NMR (reference substance: TMS, solvent: CD
Cl ₃ ), δ ppm: 1.16 (t, 7.6 Hz, 3
H), 2.80 (q, 7.6 Hz, 2H), 4.79.
(S, 2H), 7.21-7.79 (Ar-H, 9
H). (Z-form) ¹ H-NMR (reference substance: TMS, solvent: CD
Cl ₃ ), δ ppm: 1.15 (t, 7.6 Hz, 3
H), 2.63 (q, 7.6 Hz, 2H), 4.41
(S, 2H), 7.22-8.11 (Ar-H, 9
H). (Hydrogenation and hydrogenolysis) To 3.2 ml of methanol, 1.00 g of a crude imine product produced by dehydration condensation (3.2
5 mmol, 1 eq) and 5% palladium / activated carbon (containing 50% by weight of water) 50 mg were added, and the hydrogen pressure was adjusted to 0.5M.
It was set to Pa and stirred at 60 ° C. for 17 hours. The reaction-completed liquid was filtered through Celite, concentrated, and dried under vacuum.

[0107]

[Chemical 50]

0.40 g of a crude product of α-ethyl-3-trifluoromethoxybenzylamine represented by the formula (yield 6
6%) was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 0.87 (t, 7.2Hz, 3H),
1.69 (ddq, 3.2Hz, 6.8Hz, 7.2H
z, 2H), 1.76 (br, 1H), 3.85 (t,
6.8 Hz, 1H), 7.09-7.37 (Ar-H,
4H).

[Example 5] N-methyl-α-methyl-4
-Fluorobenzylamine pressure resistant reactor with 4'-fluoroacetophenone 1.81
g (13.1 mmol), methylamine (40% MeO
H solution) (5.1 g, 65.7 mmol, 5.0 eq) and methanol (13 ml) were added, and the mixture was stirred at 60 ° C. for 18 hours. At 0 ° C., 0.55 g (14.5 mmol, 1.1 eq) of sodium borohydride was added to the condensation solution,
Further, the mixture was stirred at the same temperature for 3 hours. The reaction was stopped with 1N HCl aqueous solution, neutralized with 3N NaOH aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum dried.

[0110]

[Chemical 51]

N-methyl-α-methyl-4- represented by
1.70 g of crude product of fluorobenzylamine (yield 8
5%, G.I. C. Purity (meaning the purity of the target product obtained by gas chromatography) 99%) was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 1.33 (d, 6.4 Hz, 3H),
1.65 (br, 1H), 2.29 (s, 3H), 3.
64 (q, 6.4 Hz, 1H), 7.01 (Ar-H,
2H), 7.26 (Ar-H, 2H).

Example 6 N′-butyl-α-methyl-4-fluorobenzylamine proof pressure reactor was charged with 4′-fluoroacetophenone 2.00.
g (14.5 mmol), n-butylamine 2.65 g
(36.2 mmol, 2.5 eq) and methanol 14.
5 ml was added and the mixture was stirred at room temperature for 24 hours. To the condensation solution, at 0 ° C., 0.60 g (1
5.9 mmol, 1.1 eq) was added, and the mixture was further stirred at the same temperature for 3 hours. Stop the reaction with 1N HCl aqueous solution,
Neutralize with 3N NaOH aqueous solution, extract with ethyl acetate, wash with saturated saline, dry over anhydrous sodium sulfate, filter, concentrate, and vacuum dry.

[0113]

[Chemical 52]

N-n-butyl-α-methyl-represented by
2.46 g (yield 87%, GC purity 99%) of a crude product of 4-fluorobenzylamine was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 0.87 (t, 7.2Hz, 3H),
1.26-1.34 (m, 2H), 1.32 (d, 6.
8Hz, 3H), 1.39-1.44 (m, 3H),
2.38 (dt, 11.2Hz, 6.8Hz, 1H),
2.47 (dt, 11.2Hz, 6.8Hz, 1H),
3.73 (q, 6.8 Hz, 1H), 6.97-7.0
1 (Ar-H, 2H), 7.25-7.28 (Ar-
H, 2H).

[Example 7] N-methyl-α-ethyl-2
-Fluorobenzylamine pressure resistant reactor with 2'-fluoropropiophenone 2.0
0 g (13.1 mmol), methylamine (40% Me
OH solution) 5.1 g (65.7 mmol, 5.0 eq)
And 13 ml of methanol were added, and the mixture was stirred at 60 ° C. for 18 hours. To the condensation solution, 0.55 g (14.5 mmol, 1.1 eq) of sodium borohydride was added at 0 ° C., and the mixture was further stirred at the same temperature for 3 hours. The reaction was stopped with 1N HCl aqueous solution, neutralized with 3N NaOH aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum dried.

[0116]

[Chemical 53]

N-methyl-α-ethyl-2-
1.89 g of a crude product of fluorobenzylamine (yield 8
6%, G.I. C. Purity 99%) was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 8.40 (t, 7.6 Hz, 3H),
1.50 (br, 1H), 1.62-1.73 (m, 1
H), 1.75-1.86 (m, 1H), 2.29.
(S, 3H), 3.77 (dd, 5.6Hz, 7.6H
z, 1H), 6.98-7.03 (Ar-H, 1H),
7.10-7.14 (Ar-H, 1H), 7.17-
7.23 (Ar-H, 1H), 7.28-7.34 (A
r-H, 1H).

[Example 8] N-methyl-α-methyl-4
-Trifluoromethylbenzylamine In a pressure resistant reactor, 4'-trifluoromethylacetophenone 2.45 g (13.1 mmol), methylamine (4
0% MeOH solution) 5.1 g (65.7 mmol, 5.
0 eq) and 13 ml of methanol were added, and the mixture was added to 18
Stir for hours. 0.50 g (14.5 mmol, 1.1e) of sodium borohydride was added to the condensation solution at 0 ° C.
q) was added, and the mixture was further stirred at the same temperature for 3 hours. 1 NHC
The reaction was stopped with 1 L aqueous solution, neutralized with 3N NaOH aqueous solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum dried.

[0119]

[Chemical 54]

N-methyl-α-methyl-4- represented by
Crude product of trifluoromethylbenzylamine 2.10
g (yield 79%, GC purity 99%) was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 1.51 (d, 6.8 Hz, 3H),
2.35 (s, 2H), 3.88Hz (q, 6.8H
z, 1H), 5.16 (br, 6.8Hz, 1H),
7.54 (Ar-H, 2H), 7.63 (Ar-H, 2
H).

[Example 9] N-ethyl-α-methyl-4
-Trifluoromethylbenzylamine In a pressure resistant reactor, 2.45 g (13.1 mmol) of 4'-trifluoromethylacetophenone, ethylamine (6
0% MeOH solution 4.94 g (65.7 mmol,
5.0 eq) and 13 ml of methanol were added, and the mixture was stirred at 60 ° C. for 18 hours. 0.50 g (14.5 mmol, 1.1 of sodium borohydride was added to the condensation solution at 0 degreeC.
eq) was added, and the mixture was further stirred at the same temperature for 3 hours. 1 NH
The reaction was stopped with Cl aqueous solution, neutralized with 3N NaOH aqueous solution, extracted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated and vacuum dried.

[0122]

[Chemical 55]

N-ethyl-α-methyl-4- represented by
Crude product of trifluoromethylbenzylamine 2.31
g (yield 81%, GC purity 99%) was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 1.08 (t, 7.2 Hz, 3H),
1.35 (d, 6.8 Hz, 3H), 1.35 (br,
1H), 2.38-2.60 (m, 2H), 3.85.
(Q, 6.8 Hz, 1H), 7.44 (Ar-H, 2
H), 7.58 (Ar-H, 2H).

[Example 10] N-methyl-α-ethyl-
In a pressure resistant reactor of 3-trifluoromethylbenzylamine, 2.00 g (9.9 mmol) of 3'-trifluoromethylpropiophenone and methylamine (4
0% MeOH solution 3.84 g (49.5 mmol,
5.0 eq) and 10 ml of methanol were added, and the mixture was stirred at 60 ° C. for 18 hours. At 0 ° C., 0.41 g (10.9 mmol, 1.1) of sodium borohydride was added to the condensation solution.
eq) was added, and the mixture was further stirred at the same temperature for 3 hours. 1 NH
The reaction was stopped with Cl aqueous solution, neutralized with 3N NaOH aqueous solution, extracted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated and vacuum dried.

[0125]

[Chemical 56]

N-methyl-α-ethyl-3-represented by
Crude product of trifluoromethylbenzylamine 21.9
1 g (yield 89%, GC purity 99%) was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 0.81 (t, 7.6 Hz, 3H),
1.56 (br, 1H), 1.58-1.69 (m, 1
H), 1.71-1.80 (m, 1H), 2.27.
(S, 3H), 3.45 (dd, 6.0Hz, 7.6H
z, 1H), 7.41-7.55 (Ar-H, 5H).

[Example 11] N-ethyl-α-methyl-
In a 3,5-bis-trifluoromethylbenzylamine pressure resistant reactor, 3.36 g (13.1 mmol) of 3, '5'-bis-trifluoromethylacetophenone and 4.94 g of ethylamine (60% MeOH solution) (65. 7 m
mol, 5.0 eq) and 13 ml of methanol were added,
The mixture was stirred at 60 ° C for 18 hours. At 0 ° C. to the condensation solution,
Sodium borohydride 0.55g (14.5mmo
1, 1.1 eq) was added, and the mixture was further stirred at the same temperature for 3 hours. The reaction was stopped with 1N HCl aqueous solution, 3N NaOH
Neutralize with aqueous solution, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and vacuum dry.

[0128]

[Chemical 57]

N-ethyl-α-methyl-3 represented by
3.18 g (yield 85%, GC purity 99%) of a crude product of 5-bis-trifluoromethylbenzylamine was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 1.09 (t, 7.2 Hz, 3H),
1.37 (d, 6.4 Hz, 3H), 1.40 (br,
1H), 2.36-2.49 (m, 1H), 2.49-
2.63 (m, 1H), 3.92 (q, 6.4Hz, 1
H), 7.75 (Ar-H, 1H), 7.81 (Ar-
H, 2H).

Example 12 N-methyl-α-n-butyl-3,5-bis-trifluoromethylbenzylamine 2.95 g of 3,5-bis-trifluoromethylphenyl n-butyl ketone was placed in a pressure resistant reactor. (9.9 mmol),
3.84 g (4% of methylamine (40% MeOH solution))
(9.5 mmol, 5.0 eq) and 10 ml of methanol were added, and the mixture was stirred at 60 ° C. for 18 hours. In the condensation solution,
Sodium borohydride 0.41 g (10.9
mmol, 1.1 eq) was added, and the mixture was further stirred at the same temperature for 3 hours. The reaction was stopped with 1N HCl aqueous solution, 3NN
Neutralize with aqueous aOH solution, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate and vacuum dry.

[0131]

[Chemical 58]

N-methyl-α-n-butyl-represented by
Crude product of 3,5-bis-trifluoromethylbenzylamine (1.91 g, yield 89%, GC purity 99%)
Got ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 0.86 (t, 7.2Hz, 3H),
1.04-1.18 (m, 1H), 1.18-1.37
(M, 3H), 1.55-1.68 (m, 1H), 1.
68-1.82 (m, 1H), 2.26 (s, 3H),
2.60 (br, 1H), 3.60 (t, 7.2 Hz,
1H), 7.76 (Ar-H, 2H), 7.78 (Ar
-H, 1H).

[Example 13] N-methyl-α-methyl-
In a pressure resistant reactor of 4-trifluoromethoxybenzylamine, 2.67 g (13.1 mmol) of 4′-trifluoromethoxyacetophenone and 5.1 g (65.7 mmol, 40% MeOH solution) of methylamine (40% MeOH solution).
5.0 eq) and 13 ml of methanol were added, and the mixture was stirred at 60 ° C. for 18 hours. 0.50 g (14.5 mmol, 1.1 of sodium borohydride was added to the condensation solution at 0 degreeC.
eq) was added, and the mixture was further stirred at the same temperature for 3 hours. 1 NH
The reaction was stopped with Cl aqueous solution, neutralized with 3N NaOH aqueous solution, extracted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated and vacuum dried.

[0134]

[Chemical 59]

N-methyl-α-methyl-4- represented by
Crude product of trifluoromethoxybenzylamine 2.4
1 g (yield 84%, GC purity 99%) was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 1.34 (d, 6.8 Hz, 3H),
1.63 (br, 1H), 2.30 (s, 3H), 3.
67 (q, 6.8 Hz, 1H), 7.17 (Ar-H,
2H), 7.33 (Ar-H, 2H).

Example 14 N-methyl-α-ethyl-
In a pressure resistant reactor of 3-trifluoromethoxybenzylamine, 1.00 g (4.6 mmol) of 3'-trifluoromethoxypropiophenone and 1.78 g (22.9 mmo) of methylamine (40% MeOH solution).
1, 5.0 eq) and methanol (4.6 ml) were added to give 6
The mixture was stirred at 0 ° C for 16 hours. 0.19 g (5.0 mmol, sodium borohydride) was added to the condensation solution at 0 ° C.
1.1 eq) was added, and the mixture was further stirred at the same temperature for 3 hours.
The reaction was stopped with 1N HCl aqueous solution, neutralized with 3N NaOH aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum dried.

[0137]

[Chemical 60]

N-methyl-α-ethyl-3-represented by
Crude product of trifluoromethoxybenzylamine 0.9
3 g (yield 87%, GC purity 99%) was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 0.81 (t, 7.2 Hz, 3H),
1.56-1.67 (m, 1H), 1.69-1.78
(M, 1H), 2.30 (s, 3H), 3.40 (d
d, 6.0 Hz, 7.6 Hz, 1H), 7.08-
7.36 (Ar-H, 5H).

Example 15 N-Ethyl-3-trifluoromethoxybenzylamine A pressure resistant reactor was charged with 2.00 g (10.5 mmol) of 3-trifluoromethoxybenzaldehyde and 1.98 g of ethylamine (60% MeOH solution). 26.3 mmo
1, 2.5 eq) and 10.5 ml of methanol are added,
Stir at room temperature for 14 hours. 0.40 g (11.6 mmol, sodium borohydride) was added to the condensation solution at 0 ° C.
1.1 eq) was added, and the mixture was further stirred at the same temperature for 3 hours.
The reaction was stopped with 1N HCl aqueous solution, neutralized with 3N NaOH aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum dried.

[0140]

[Chemical formula 61]

2.06 g of a crude product of N-ethyl-3-trifluoromethoxybenzylamine represented by the formula (yield 9
0%, G.I. C. Purity 99%) was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 1.13 (t, 7.2 Hz, 3H),
1.41 (br, 1H), 2.68 (q, 7.2 Hz,
2H), 3.81 (s, 2H), 7.08-7.10.
(Ar-H, 1H), 7.20-7.34 (Ar-
H, 4H).

Example 16 N-n-butyl-3-trifluoromethoxybenzylamine In a pressure resistant reactor, 2.00 g (10.5 mmol) of 3-trifluoromethoxybenzaldehyde and 1.92 g (26. 3 mmol, 2.5 eq) and 10.5 ml of methanol were added, and the mixture was stirred at room temperature for 16 hours. To the condensation solution, at 0 ° C., 0.44 g (11.6 mmol, 1.1 eq) of sodium borohydride was added,
Further, the mixture was stirred at the same temperature for 4 hours. The reaction was stopped with 1N HCl aqueous solution, neutralized with 3N NaOH aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum dried.

[0143]

[Chemical formula 62]

2.18 g (yield 84%, GC purity 99%) of a crude product of N-n-butyl-3-trifluoromethoxybenzylamine represented by: was obtained. ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ),
δ ppm: 0.91 (t, 7.6 Hz, 3H),
1.31-1.40 (m, 2H), 1.46-1.53
(M, br, 3H), 2.62 (t, 7.2Hz, 2
H), 3.81 (s, 2H), 7.08-7.10 (A
r-H, 1H), 7.20-7.35 (Ar-H, 4
H).

[0145]

EFFECT OF THE INVENTION A novel compound α-alkyl-fluoro, trifluoromethyl- or trifluoromethoxy-substituted benzylamine, N-, which is an important intermediate for pharmaceuticals and agricultural chemicals.
Provided are an alkyl-α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy-substituted benzylamine and an N-alkyl-trifluoromethoxy-substituted benzylamine, and an efficient production method thereof.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Katsu Kuriyama             2805 Imafuku Nakadai Centra, Kawagoe City, Saitama Prefecture             Le Glass Co., Ltd. (72) Inventor Yasumoto Manabu             2805 Imafuku Nakadai Centra, Kawagoe City, Saitama Prefecture             Le Glass Co., Ltd. (72) Inventor Kento Inomiya             2805 Imafuku Nakadai Centra, Kawagoe City, Saitama Prefecture             Le Glass Co., Ltd. (72) Inventor Takashi Otsuka             2805 Imafuku Nakadai Centra, Kawagoe City, Saitama Prefecture             Le Glass Co., Ltd. (72) Inventor Koji Ueda             2805 Imafuku Nakadai Centra, Kawagoe City, Saitama Prefecture             Le Glass Co., Ltd. F-term (reference) 4H006 AA01 AA02 AB01 AB20 AB84                       AC52 BA21 BA25 BA26 BA55                       BA66 BC10 BC11 BC30 BC34                       BE14 BE20                 4H039 CA71 CA99 CB30 CE40 CL25    (54) [Title of Invention] α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylami                     Amine, N-alkyl-α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy                     Substituted benzylamine and N-alkyl-trifluoromethoxy substituted benzylamine

Claims (19)

[Claims] 1. A general formula [1]: [Wherein R ¹ represents a lower alkyl group having 2 to 6 carbon atoms, n represents an integer of 1 to 5, F represents an arbitrary substitution position, and a wavy line represents a racemate] α- Alkyl-fluoro substituted benzylamine (however, α-ethyl-4
-Except fluorobenzylamine). 2. A general formula [2]: [In the formula, n represents an integer of 1 to 5, F has an arbitrary substitution position, and a wavy line represents a racemate]. Α-ethyl-fluoro-substituted benzylamine (provided that α-ethyl-
(Except 4-fluorobenzylamine). 3. A general formula [3]: [Wherein R ¹ represents a lower alkyl group having 1 to 6 carbon atoms, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and n
Represents an integer of 1 to 5, F represents an arbitrary substitution position,
Wavy line represents a racemate]] N-alkyl-α-
Alkyl-fluoro substituted benzylamine. 4. A general formula [4]: [Wherein R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, F represents an arbitrary substitution position, and a wavy line represents a racemate] Alkyl-α-methyl-fluoro substituted benzylamine. 5. A general formula [5]: [Wherein R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, F represents an arbitrary substitution position, and a wavy line represents a racemate] Alkyl-α-ethyl-fluoro substituted benzylamine. 6. A general formula [6]: [Wherein R ¹ represents a lower alkyl group having 2 to 6 carbon atoms, n represents an integer of 1 to 5, CF ₃ group has an arbitrary substitution position, and a wavy line represents a racemate] α-alkyl-trifluoromethyl-substituted benzylamine (provided that α-cyclopropyl-3-trifluoromethylbenzylamine, α-ethyl-3,5-bis-trifluoromethylbenzylamine and α-cyclopropyl-3,
(Except 5-bis-trifluoromethylbenzylamine). 7. A general formula [7]: [In the formula, n represents an integer of 1 to 5, the CF ₃ group has an arbitrary substitution position, and the wavy line represents a racemate]
-Ethyl-trifluoromethyl-substituted benzylamine, with the exception of α-ethyl-3,5-bis-trifluoromethylbenzylamine. 8. A general formula [8]: [Wherein R ¹ represents a lower alkyl group having 1 to 6 carbon atoms, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and n
Represents an integer of 1 to 5, the CF ₃ group has an arbitrary substitution position, and the wavy line represents a racemate].] N-alkyl-α-alkyl-trifluoromethyl-substituted benzylamine (provided that N-methyl -Α-methyl-3-trifluoromethylbenzylamine, N-methyl-α-methyl-3,
5-bis-trifluoromethylbenzylamine and N
-Methyl-α-cyclopropyl-3,5-bis-trifluoromethylbenzylamine). 9. A compound represented by the general formula [9]: [In the formula, R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, CF ₃ group has an arbitrary substitution position, and a wavy line represents a racemate] N-alkyl-α-methyl-trifluoromethyl substituted benzylamine. However, N-methyl-α-methyl-3-trifluoromethylbenzylamine and N-methyl-α-methyl-3,5-bis-trifluoromethylbenzylamine are excluded. 10. A general formula [10]: [In the formula, R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, CF ₃ group has an arbitrary substitution position, and a wavy line represents a racemate] N-alkyl-α-ethyl-trifluoromethyl substituted benzylamine. 11. A compound represented by the general formula [11]: [In the formula, R ¹ represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, OCF ₃ group has an arbitrary substitution position, and a wavy line represents a racemate] α-
Alkyl-trifluoromethoxy substituted benzylamines, with the exception of α-methyl-4-trifluoromethoxybenzylamine and α-ethyl-4-trifluoromethoxybenzylamine. 12. A compound represented by the general formula [12]: [In the formula, n represents an integer of 1 to 5, the OCF ₃ group has an arbitrary substitution position, and the wavy line represents a racemate]. Α-methyl-trifluoromethoxy-substituted benzylamine (provided that α- Except methyl-4-trifluoromethoxybenzylamine). 13. A compound represented by the general formula [13]: [In the formula, n represents an integer of 1 to 5, the OCF ₃ group has an arbitrary substitution position, and the wavy line represents a racemate], α-ethyl-trifluoromethoxy-substituted benzylamine (provided that α- Excluding ethyl-4-trifluoromethoxybenzylamine). 14. A compound represented by the general formula [14]: [Wherein R ¹ represents a lower alkyl group having 1 to 6 carbon atoms, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and n
Represents an integer of 1 to 5, the OCF ₃ group has an arbitrary substitution position, and the wavy line represents a racemate]]-N-alkyl-α-alkyl-trifluoromethoxy-substituted benzylamine. 15. A compound represented by the general formula [15]: [In the formula, R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, OCF ₃ group has an arbitrary substitution position, and a wavy line represents a racemate] N-
Alkyl-α-methyl-trifluoromethoxy substituted benzylamine. 16. A compound represented by the general formula [16]: [In the formula, R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, OCF ₃ group has an arbitrary substitution position, and a wavy line represents a racemate] N-
Alkyl-α-ethyl-trifluoromethoxy substituted benzylamine. 17. A compound represented by the general formula [17]: [In the formula, R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, and the OCF ₃ group has an arbitrary substitution position.] N-alkyl-trifluoromethoxy Substituted benzylamine. 18. A compound represented by the general formula [18]: [In the formula, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, and R ¹ represents Can be substituted at any position] by a fluoro-, trifluoromethyl- or trifluoromethoxy-substituted phenylalkylketone represented by the formula [19] [In the formula, Ph represents a phenyl group] and dehydration-condensation with benzylamine represented by the general formula [20] [In the formula, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, and R ¹ represents It has an arbitrary substitution position, Ph represents a phenyl group, and the wavy line represents an E-form, a Z-form, or a mixture thereof.
By converting to an imine represented by the formula (1), and further hydrogenating and hydrolyzing the imine, a compound represented by the general formula [21] [In the formula, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, and R ¹ represents [Alpha] -alkyl according to claim 1, claim 2, claim 7, claim 11, claim 12 or claim 13, wherein the wavy line represents a racemate. -A method for producing a fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine. 19. A compound represented by the general formula [18]: [In the formula, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, and R ¹ represents [Optionally substituted position]], a fluoro-, trifluoromethyl-, or trifluoromethoxy-substituted phenylalkylketone, or a compound represented by the general formula [22] [Wherein n represents an integer of 1 to 5 and the OCF ₃ group takes an arbitrary substitution position], a trifluoromethoxy-substituted benzaldehyde represented by the general formula [23] [Wherein R ³ represents a lower alkyl group having 1 to 6 carbon atoms] is condensed, and a hydride reducing agent is added to the reaction system to give a compound of the general formula [24] [In the formula, R ¹ represents a fluorine atom, a trifluoromethyl group or a trifluoromethoxy group, R ² represents a lower alkyl group having 1 to 6 carbon atoms, and R ³ represents a lower alkyl group having 1 to 6 carbon atoms. , N is an integer of 1 to 5, R ¹
Represents an arbitrary substitution position, and the wavy line represents a racemate]. [Claim 3, Claim 4, Claim 5, Claim 8, Claim 9, Claim 14, Claim 15] And an N-alkyl-α-alkyl-fluoro, trifluoromethyl or trifluoromethoxy substituted benzylamine according to claim 16, or a compound represented by the general formula [25] 18. The N according to claim 17, wherein R ³ represents a lower alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 5, and the OCF ₃ group has an arbitrary substitution position. A method for producing an alkyl-trifluoromethoxy substituted benzylamine.