JP2008007460A - Fluorine-containing phenylalanine derivative and method for producing the same - Google Patents

Abstract

で示される新規な含フッ素アミノ酸誘導体を合成し、スピロ型キラル相間移動触媒存在下不斉アルキル化を行い、次いで加水分解することにより新規なα−トリフルオロエチル化フェニルアラニン誘導体を調製する。
【選択図】 なしPROBLEM TO BE SOLVED: To provide a novel trifluoroethylated phenylalanine derivative useful industrially.
SOLUTION: The following formula (5)

Is synthesized, subjected to asymmetric alkylation in the presence of a spiro-type chiral phase transfer catalyst, and then hydrolyzed to prepare a novel α-trifluoroethylated phenylalanine derivative.
[Selection figure] None

Description

  The present invention relates to a novel fluorine-containing phenylalanine derivative, an intermediate thereof, and a production method thereof. Fluorine-containing amino acids are compounds that are expected as synthetic intermediates for pharmaceuticals.

  The compounds of the present invention are not known. As a synthesis method of amino acids using a chiral phase transfer catalyst related to the present invention, for example, the following general formula (10)

In the optically active spiro quaternary ammonium salt represented by
Compound (A) wherein R ¹ = hydrogen atom, X ⁻ = bromide ion,
Compound (B) wherein R ¹ = phenyl group, X ⁻ = bromide ion,
Compound (C) wherein R ¹ = 3,5-bis (trifluoromethyl) phenyl group, X ⁻ = bromide ion
A method for producing an optically active phenylalanine derivative in which a methyl group or an allyl group is introduced at the α-position is known [see Patent Document 1, Non-Patent Document 1].

JP 2001-48866 A K. Maruoka et. al. J. et al. Am. Chem. Soc. 2000, 122, 5228-5229

  As described above, in the conventional method, synthesis examples of the compound of the present invention are not known. In addition, when a method of introducing two alkyl groups at the α-position using a glycine derivative described in Non-Patent Document 1 as a raw material is applied to the preparation of the compound of the present invention, 2,2,2-trifluoroethyl iodide and There was a problem that this reaction did not proceed and the object of the present invention could not be obtained.

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a novel α-trifluoroethylated phenylalanine derivative and a method for producing the same.

  As a result of earnestly examining the method for solving the above problems, the present inventor previously reacted glycine derivative with lithium diisopropylamide and then reacted with 2,2,2-trifluoroethyl iodide to obtain a novel intermediate, Next, it was found that a novel α-2,2,2-trifluoroethylated phenylalanine derivative can be synthesized by reacting with a specific benzyl bromide derivative in the presence of a specific chiral phase transfer catalyst, and to complete the present invention. It came.

  That is, this invention is a fluorine-containing phenylalanine derivative as shown below, and its manufacturing method.

  [1] The following general formula (1)

[In the general formula (1), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
An α-trifluoroethylated phenylalanine derivative represented by the formula:

  [2] The following general formula (2)

[In the general formula (2), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
An α-trifluoroethylated phenylalanine derivative represented by the formula:

  [3] In the general formula (1) or (2), R is a hydrogen atom, a halogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. The α-trifluoroethylated phenylalanine derivative according to the above [1] or [2].

  [4] In the general formula (1) or (2), R is a hydrogen atom, a fluorine atom, or a trifluoromethyl group, and the α-tri described in the above [1] or [2] Fluoroethylated phenylalanine derivative.

  [5] The following general formula (3)

[In the general formula (3), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
An α-trifluoroethylated phenylalanine derivative represented by the formula:

  [6] The following general formula (4)

[In the general formula (4), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
An α-trifluoroethylated phenylalanine derivative represented by the formula:

  [7] In the general formula (3) or (4), R is a hydrogen atom, a halogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. The α-trifluoroethylated phenylalanine derivative according to the above [5] or [6].

  [8] The α-tri described in [5] or [6] above, wherein in the general formula (3) or general formula (4), R is a hydrogen atom, a fluorine atom or a trifluoromethyl group. Fluoroethylated phenylalanine derivative.

  [9] The α-trifluoroethylated phenylalanine derivative according to the above [1], wherein the α-trifluoroethylated phenylalanine derivative represented by the general formula (3) is hydrolyzed in the presence of an acid. Production method.

  [10] The α-trifluoroethylated phenylalanine derivative according to the above [2], wherein the α-trifluoroethylated phenylalanine derivative represented by the general formula (4) is hydrolyzed in the presence of an acid. Production method.

  [11] In the general formula (3) or (4), R is a hydrogen atom, a halogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. The production method according to [9] or [10] above.

  [12] The production method of the above-mentioned [9] or [10], wherein in the general formula (3) or general formula (4), R is a hydrogen atom, a fluorine atom or a trifluoromethyl group.

  [13] The following formula (5)

A 4,4,4-trifluoro-2-aminobutanoic acid derivative represented by the formula:

  [14] A 4,4,4-trifluoro-2-aminobutanoic acid derivative represented by the above formula (5) and the following general formula (6)

[In the general formula (6), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
A benzyl bromide derivative represented by the following formula (7)

The method for producing an α-trifluoroethylated phenylalanine derivative according to the above [5], wherein the reaction is carried out in the presence of a chiral phase transfer catalyst represented by

  [15] A 4,4,4-trifluoro-2-aminobutanoic acid derivative represented by the above formula (5) and a benzyl bromide derivative represented by the above general formula (6) are represented by the following formula (7):

The method for producing an α-trifluoroethylated phenylalanine derivative as described in [6] above, wherein the reaction is carried out in the presence of a chiral phase transfer catalyst and an alkali.

  [16] In the above general formula (6), R is a hydrogen atom, a halogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. Or [alpha] -trifluoroethylated phenylalanine derivative according to [15].

  [17] The α-trifluoroethylated phenylalanine derivative according to the above [14] or [15], wherein in the general formula (6), R is a hydrogen atom, a fluorine atom or a trifluoromethyl group.

  [18] The following formula (9)

The glycine derivative represented by formula (4) is reacted with lithium isopyramide and then reacted with 2,2,2-trifluoroethyl iodide. A process for producing 2-aminobutanoic acid derivatives.

  According to the present invention, a novel α-trifluoroethylated phenylalanine derivative and a production method thereof, and an intermediate for production and a production method thereof are provided.

  That is, the glycine derivative represented by the above formula (9) is reacted with lithium isopropylamide, and then reacted with 2,2,2-trifluoroethyl iodide, thereby producing a novel compound represented by the above formula (5). Fluorine-containing amino acid derivatives can be prepared.

  Further, by carrying out asymmetric alkylation of the novel fluorine-containing amino acid derivative represented by the above formula (5) in the presence of the above spiro-type chiral phase transfer catalyst, the above general formula (3) or (4) The indicated α-trifluoroethylated phenylalanine derivatives can be prepared.

Then, the α-trifluoroethylated phenylalanine derivative represented by the general formula (3) or the general formula (4) is hydrolyzed in the presence of an acid, so that the general formula (1) or the general formula (2) is obtained.
A novel α-trifluoroethylated phenylalanine derivative represented by the following formula can be prepared.

  Fluorine-containing abnormal amino acids are compounds useful as synthetic raw materials for pharmaceuticals, and the present invention is extremely significant industrially.

  Hereinafter, the present invention will be described in detail.

  In the present invention, the α-trifluoroethylated phenylalanine derivative represented by the general formula (1) is not particularly limited. Specifically, R is a linear or branched alkyl having 1 to 10 carbon atoms. In the case of a group, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-methylphenyl) propionate, tert-butyl (S) -2- (2 , 2,2-trifluoroethyl) -2-amino-3- (3-methylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3 -(4-methylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-ethylphenyl) propionate, t tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-ethylphenyl) propionate, tert-butyl (S) -2- (2,2,2 -Trifluoroethyl) -2-amino-3- (4-ethylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2- n-propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoro Ethyl) -2-amino-3- (2-iso-propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-iso -Propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-iso-propylphenyl) propionate, tert-butyl (S)- 2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-butylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-butylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4 n-butylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-tert-butylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-tert-butylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) ) -2-Amino-3- (4-tert-butylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n- Pentylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-pentylphenyl) propiate Tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-pentylphenyl) propionate, tert-butyl (S) -2- (2 , 2,2-trifluoroethyl) -2-amino-3- (2-n-hexylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- Amino-3- (3-n-hexylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-hexylphenyl) ) Propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-heptylphenyl) propionate, tert-butyl (S) -2- 2,2,2-trifluoroethyl) -2-amino-3- (3-n-heptylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- Amino-3- (4-n-heptylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-octylphenyl) propionate , Tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-octylphenyl) propionate, tert-butyl (S) -2- (2, 2,2-trifluoroethyl) -2-amino-3- (4-n-octylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- Mino-3- (2-n-nonylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-nonylphenyl) propionate , Tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-nonylphenyl) propionate, tert-butyl (S) -2- (2, 2,2-trifluoroethyl) -2-amino-3- (2-n-decylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino- 3- (3-n-decylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-decylphenyl) propionate Like it is exemplified.

  In the case where R is a linear or branched alkoxy group having 1 to 10 carbon atoms, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2- Methoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-methoxyphenyl) propionate, tert-butyl (S) -2- ( 2,2,2-trifluoroethyl) -2-amino-3- (4-methoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino- 3- (2-ethoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-ethoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-ethoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2 -Trifluoroethyl) -2-amino-3- (2-n-propoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- ( 3-n-propoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-propoxyphenyl) propionate, tert-butyl ( S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-iso-propoxyphenyl) propionate, tert-butyl (S) -2- ( , 2,2-trifluoroethyl) -2-amino-3- (3-iso-propoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino -3- (4-iso-propoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-butoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-butoxyphenyl) propionate, tert-butyl (S) -2- (2,2 , 2-trifluoroethyl) -2-amino-3- (4-n-butoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) ) -2-Amino-3- (2-tert-butoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-tert- Butoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-tert-butoxyphenyl) propionate, tert-butyl (S) -2 -(2,2,2-trifluoroethyl) -2-amino-3- (2-n-pentyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-pentyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- Mino-3- (4-n-pentyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-hexyloxy) Phenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-hexyloxyphenyl) propionate, tert-butyl (S)- 2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-hexyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoro Ethyl) -2-amino-3- (2-n-heptyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3 (3-n-heptyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-heptyloxyphenyl) propionate, tert -Butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-octyloxyphenyl) propionate, tert-butyl (S) -2- (2,2 , 2-trifluoroethyl) -2-amino-3- (3-n-octyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino- 3- (4-n-octyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n Nonyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-nonyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-nonyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoro Ethyl) -2-amino-3- (2-n-decyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3- n-decyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-decyloxypheny) ) Propionate and the like.

  Moreover, when R is a hydrogen atom, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3-phenylpropionate is exemplified.

  When R is a halogen atom, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-fluorophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-fluorophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl)- 2-amino-3- (4-fluorophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-chlorophenyl) propionate, tert- Butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-chlorophenyl) propionate, tert-butyl (S) -2- (2 2,2-trifluoroethyl) -2-amino-3- (4-chlorophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- ( 2-Bromophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-bromophenyl) propionate, tert-butyl (S) -2 -(2,2,2-trifluoroethyl) -2-amino-3- (4-bromophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- Amino-3- (2-iodophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-iodophenyl) Ropioneto, tert- butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-iodophenyl) propionate and the like.

  Further, when R is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino -3- (2-trifluoromethylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-trifluoromethylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-trifluoromethylphenyl) propionate, tert-butyl (S) -2- (2,2 , 2-trifluoroethyl) -2-amino-3- [2- (2,2,2-trifluoroethyl) phenyl] propionate, tert-butyl (S) -2- (2,2,2- Trifluoroethyl) -2-amino-3- [3- (2,2,2-trifluoroethyl) phenyl] propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl)- 2-Amino-3- [4- (2,2,2-trifluoroethyl) phenyl] propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3 -(2-pentafluoroethylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-pentafluoroethylphenyl) propionate, tert- Examples include butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-pentafluoroethylphenyl) propionate.

  Further, the α-trifluoroethylated phenylalanine derivative represented by the general formula (2) is not particularly limited. Specifically, R is a linear or branched alkyl group having 1 to 10 carbon atoms. Tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-methylphenyl) propionate, tert-butyl (R) -2- (2,2 , 2-trifluoroethyl) -2-amino-3- (3-methylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- ( 4-methylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-ethylphenyl) propionate, tert-butyl Tyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-ethylphenyl) propionate, tert-butyl (R) -2- (2,2,2-tri Fluoroethyl) -2-amino-3- (4-ethylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n- Propylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-propylphenyl) propionate, tert-butyl (R) -2 -(2,2,2-trifluoroethyl) -2-amino-3- (4-n-propylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) 2-amino-3- (2-iso-propylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-iso-propylphenyl) ) Propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-iso-propylphenyl) propionate, tert-butyl (R) -2- ( 2,2,2-trifluoroethyl) -2-amino-3- (2-n-butylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- Amino-3- (3-n-butylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-butyl) Phenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-tert-butylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-tert-butylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2 -Amino-3- (4-tert-butylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-pentylphenyl) Propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-pentylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-pentylphenyl) propionate, tert-butyl (R) -2- (2,2 , 2-trifluoroethyl) -2-amino-3- (2-n-hexylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino- 3- (3-n-hexylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-hexylphenyl) propionate Tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-heptylphenyl) propionate, tert-butyl (R) -2- (2, 2, -Trifluoroethyl) -2-amino-3- (3-n-heptylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- ( 4-n-heptylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-octylphenyl) propionate, tert-butyl ( R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-octylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trimethyl) Fluoroethyl) -2-amino-3- (4-n-octylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3 (2-n-nonylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-nonylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-nonylphenyl) propionate, tert-butyl (R) -2- (2,2,2- Trifluoroethyl) -2-amino-3- (2-n-decylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3 -N-decylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-decylphenyl) propionate, etc. It is.

  When R is a linear or branched alkoxy group having 1 to 10 carbon atoms, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2- Methoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-methoxyphenyl) propionate, tert-butyl (R) -2- ( 2,2,2-trifluoroethyl) -2-amino-3- (4-methoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino- 3- (2-ethoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-ethoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-ethoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2 -Trifluoroethyl) -2-amino-3- (2-n-propoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- ( 3-n-propoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-propoxyphenyl) propionate, tert-butyl ( R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-iso-propoxyphenyl) propionate, tert-butyl (R) -2- ( , 2,2-trifluoroethyl) -2-amino-3- (3-iso-propoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino -3- (4-iso-propoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-butoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-butoxyphenyl) propionate, tert-butyl (R) -2- (2,2 , 2-trifluoroethyl) -2-amino-3- (4-n-butoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) ) -2-Amino-3- (2-tert-butoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-tert- Butoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-tert-butoxyphenyl) propionate, tert-butyl (R) -2 -(2,2,2-trifluoroethyl) -2-amino-3- (2-n-pentyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-pentyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- Mino-3- (4-n-pentyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-hexyloxy) Phenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-hexyloxyphenyl) propionate, tert-butyl (R)- 2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-hexyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoro Ethyl) -2-amino-3- (2-n-heptyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3 (3-n-heptyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-heptyloxyphenyl) propionate, tert -Butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n-octyloxyphenyl) propionate, tert-butyl (R) -2- (2,2 , 2-trifluoroethyl) -2-amino-3- (3-n-octyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino- 3- (4-n-octyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-n Nonyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-n-nonyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-nonyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoro Ethyl) -2-amino-3- (2-n-decyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3- n-decyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-n-decyloxypheny) ) Propionate and the like.

  Moreover, when R is a hydrogen atom, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3-phenylpropionate is exemplified.

  When R is a halogen atom, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-fluorophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-fluorophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl)- 2-amino-3- (4-fluorophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (2-chlorophenyl) propionate, tert- Butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-chlorophenyl) propionate, tert-butyl (R) -2- (2 2,2-trifluoroethyl) -2-amino-3- (4-chlorophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- ( 2-bromophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-bromophenyl) propionate, tert-butyl (R) -2 -(2,2,2-trifluoroethyl) -2-amino-3- (4-bromophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- Amino-3- (2-iodophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-iodophenyl) Ropioneto, tert- butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-iodophenyl) propionate and the like.

  Further, when R is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino -3- (2-trifluoromethylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-trifluoromethylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-trifluoromethylphenyl) propionate, tert-butyl (R) -2- (2,2 , 2-trifluoroethyl) -2-amino-3- [2- (2,2,2-trifluoroethyl) phenyl] propionate, tert-butyl (R) -2- (2,2,2- Trifluoroethyl) -2-amino-3- [3- (2,2,2-trifluoroethyl) phenyl] propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl)- 2-Amino-3- [4- (2,2,2-trifluoroethyl) phenyl] propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3 -(2-pentafluoroethylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (3-pentafluoroethylphenyl) propionate, tert- Examples include butyl (R) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-pentafluoroethylphenyl) propionate.

  The α-trifluoroethylated phenylalanine derivative represented by the above general formula (1) or general formula (2) of the present invention corresponds to the iminoglycine derivative represented by the above general formula (3) or general formula (4), respectively. Can be obtained by hydrolysis in the presence of an acid.

  Although it does not specifically limit as a compound shown by the said General formula (3) of this invention, Specifically, when R is a C1-C10 linear or branched alkyl group, it is tert- butyl. (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-methylphenyl) propionate, tert-butyl (S) -2- (2,2 , 2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-methylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-Chlorophenyl) imino-3- (4-methylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenylimino)- -(2-ethylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-ethylphenyl) propionate, tert -Butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-ethylphenyl) propionate, tert-butyl (S) -2- (2 , 2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) ) -2- (4-Chlorophenyl) imino-3- (3-n-propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-tri Fluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4- Chlorophenyl) imino-3- (2-iso-propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3 -Iso-propylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-iso-propylphenyl) propionate, tert-Butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n- Tilphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-butylphenyl) propionate, tert-butyl ( S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-butylphenyl) propionate, tert-butyl (S) -2- (2, 2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-tert-butylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-Chlorophenyl) imino-3- (3-tert-butylphenyl) propionate, tert-butyl (S) -2- (2,2,2 Trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-tert-butylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- ( 4-chlorophenyl) imino-3- (2-n-pentylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-pentylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-pentylphenyl) Propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n- Xylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-hexylphenyl) propionate, tert- Butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-hexylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-heptylphenyl) propionate, tert-butyl (S) -2- (2,2,2-tri Fluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-heptylphenyl) propionate, tert-butyl (S) -2- (2,2,2-to (Rifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-heptylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- ( 4-chlorophenyl) imino-3- (2-n-octylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-octylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-octylphenyl) Propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-nonyl) Nyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-nonylphenyl) propionate, tert-butyl ( S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-nonylphenyl) propionate, tert-butyl (S) -2- (2, 2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-decylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-Chlorophenyl) imino-3- (3-n-decylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl 2- (4-chlorophenyl) imino-3-(4-n-decyl-phenyl) propionate and the like.

  When R is a linear or branched alkoxy group having 1 to 10 carbon atoms, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino- 3- (2-methoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-methoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-methoxyphenyl) propionate, tert-butyl (S) -2- ( 2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-ethoxyphenyl) propionate, tert-butyl (S) -2- (2 , 2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-ethoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl)- 2- (4-Chlorophenyl) imino-3- (4-ethoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3 -(2-n-propoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-propoxyphenyl) ) Propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n- Ropoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-iso-propoxyphenyl) propionate, tert- Butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-iso-propoxyphenyl) propionate, tert-butyl (S) -2- ( 2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-iso-propoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoro Ethyl) -2- (4-chlorophenyl) imino-3- (2-n-butoxyphenyl) propionate, tert-butyl (S) 2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-butoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2 -Trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-butoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-Chlorophenyl) imino-3- (2-tert-butoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3 -(3-tert-butoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) Imino-3- (4-tert-butoxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n) -Pentyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-pentyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-pentyloxyphenyl) propionate, tert-butyl (S)- 2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-hexyloxyphenyl) propiyl Onate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-hexyloxyphenyl) propionate, tert-butyl ( S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-hexyloxyphenyl) propionate, tert-butyl (S) -2- ( 2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-heptyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-tri Fluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-heptyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2- Trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-heptyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-Chlorophenyl) imino-3- (2-n-octyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino- 3- (3-n-octyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n- Octyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imi -3- (2-n-nonyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n -Nonyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-nonyloxyphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-decyloxyphenyl) propionate, tert-butyl (S)- 2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-decyloxyphenyl) propionate, ter - butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3-(4-n-decyl-oxy) propionate and the like.

  Moreover, when R is a hydrogen atom, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3-phenylpropionate is exemplified.

  When R is a halogen atom, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-fluorophenyl) propionate, tert -Butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-fluorophenyl) propionate, tert-butyl (S) -2- (2 , 2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-fluorophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl)- 2- (4-Chlorophenyl) imino-3- (2-chlorophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl)- 2- (4-Chlorophenyl) imino-3- (3-chlorophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-Chlorophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-bromophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-bromophenyl) propionate, tert-butyl (S) -2- (2,2 , 2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-bromophenyl) propionate, tert-butyl (S)- 2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-iodophenyl) propionate, tert-butyl (S) -2- (2,2,2-tri Fluoroethyl) -2- (4-chlorophenyl) imino-3- (3-iodophenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) ) Imino-3- (4-iodophenyl) propionate and the like.

  Further, when R is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- ( 4-chlorophenyl) imino-3- (2-trifluoromethylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-trifluoromethylphenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-trifluoromethylphenyl) Propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- [2- (2,2,2- Trifluoroethyl) phenyl] propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- [3- (2,2,2- Trifluoroethyl) phenyl] propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- [4- (2,2,2- Trifluoroethyl) phenyl] propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-pentafluoroethylphenyl) propionate, tert-Butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-pentafluoroethyl Phenyl) propionate, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-pentafluoroethylphenyl) propionate, etc. .

  In addition, the α-trifluoroethylated phenylalanine derivative represented by the general formula (4) is not particularly limited. Specifically, R is a linear or branched alkyl group having 1 to 10 carbon atoms. Tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-methylphenyl) propionate, tert-butyl (R) -2 -(2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-methylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoro Ethyl) -2- (4-chlorophenyl) imino-3- (4-methylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl)- 2- (4-Chlorophenyl) imino-3- (2-ethylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3 -(3-ethylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-ethylphenyl) propionate, tert -Butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-propylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-propylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-propylphenyl) propionate, tert-butyl (R) -2- ( 2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-iso-propylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoro Ethyl) -2- (4-chlorophenyl) imino-3- (3-iso-propylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4- Chlorophenyl) imino-3- (4-iso-propylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-c Rophenyl) imino-3- (2-n-butylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3 -N-butylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-butylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-tert-butylphenyl) propionate, tert-butyl (R) -2 -(2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-tert-butylphenyl) propionate, ter -Butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-tert-butylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-pentylphenyl) propionate, tert-butyl (R) -2- (2,2,2-tri Fluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-pentylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4 -Chlorophenyl) imino-3- (4-n-pentylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chloro Phenyl) imino-3- (2-n-hexylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- ( 3-n-hexylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-hexylphenyl) ) Propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-heptylphenyl) propionate, tert-butyl (R ) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-heptylphenyl) propionate, tert- Butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-heptylphenyl) propionate, tert-butyl (R) -2- ( 2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-octylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoro Ethyl) -2- (4-chlorophenyl) imino-3- (3-n-octylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4- Chlorophenyl) imino-3- (4-n-octylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chloropheny L) imino-3- (2-n-nonylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3) -N-nonylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-nonylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-decylphenyl) propionate, tert-butyl (R) -2 -(2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-decylphenyl) propionate, tert-butyl (R) -2 Examples include-(2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-decylphenyl) propionate.

  When R is a linear or branched alkoxy group having 1 to 10 carbon atoms, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino- 3- (2-methoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-methoxyphenyl) propionate, tert-Butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-methoxyphenyl) propionate, tert-butyl (R) -2- ( 2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-ethoxyphenyl) propionate, tert-butyl (R) -2- (2 , 2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-ethoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl)- 2- (4-Chlorophenyl) imino-3- (4-ethoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3 -(2-n-propoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-propoxyphenyl) ) Propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n- (Lopoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-iso-propoxyphenyl) propionate, tert- Butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-iso-propoxyphenyl) propionate, tert-butyl (R) -2- ( 2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-iso-propoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoro Ethyl) -2- (4-chlorophenyl) imino-3- (2-n-butoxyphenyl) propionate, tert-butyl (R) 2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-butoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2 -Trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-butoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-Chlorophenyl) imino-3- (2-tert-butoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3 -(3-tert-butoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) Imino-3- (4-tert-butoxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n) -Pentyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-pentyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-pentyloxyphenyl) propionate, tert-butyl (R)- 2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-hexyloxyphenyl) propiyl Onate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-hexyloxyphenyl) propionate, tert-butyl ( R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-hexyloxyphenyl) propionate, tert-butyl (R) -2- ( 2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-heptyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-tri Fluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-heptyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2- Trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-heptyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-Chlorophenyl) imino-3- (2-n-octyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino- 3- (3-n-octyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n- Octyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imi -3- (2-n-nonyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n -Nonyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-n-nonyloxyphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-n-decyloxyphenyl) propionate, tert-butyl (R)- 2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-n-decyloxyphenyl) propionate, ter - butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3-(4-n-decyl-oxy) propionate and the like.

  Moreover, when R is a hydrogen atom, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3-phenylpropionate is exemplified.

  When R is a halogen atom, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-fluorophenyl) propionate, tert -Butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-fluorophenyl) propionate, tert-butyl (R) -2- (2 , 2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-fluorophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl)- 2- (4-Chlorophenyl) imino-3- (2-chlorophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl)- 2- (4-Chlorophenyl) imino-3- (3-chlorophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-Chlorophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-bromophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-bromophenyl) propionate, tert-butyl (R) -2- (2,2 , 2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-bromophenyl) propionate, tert-butyl (R)- 2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-iodophenyl) propionate, tert-butyl (R) -2- (2,2,2-tri Fluoroethyl) -2- (4-chlorophenyl) imino-3- (3-iodophenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) ) Imino-3- (4-iodophenyl) propionate and the like.

  Further, when R is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- ( 4-chlorophenyl) imino-3- (2-trifluoromethylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-trifluoromethylphenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-trifluoromethylphenyl) Propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- [2- (2,2,2- Trifluoroethyl) phenyl] propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- [3- (2,2,2- Trifluoroethyl) phenyl] propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- [4- (2,2,2- Trifluoroethyl) phenyl] propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (2-pentafluoroethylphenyl) propionate, tert-Butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (3-pentafluoroethyl Phenyl) propionate, tert-butyl (R) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-pentafluoroethylphenyl) propionate, etc. .

  Although it does not specifically limit as an acid used for reaction which obtains the compound of the said General formula (1) or General formula (2) of this invention, For example, 0.1N-3N hydrochloric acid aqueous solution, 0.1N-3N An aqueous solution of sulfuric acid, an aqueous solution of 0.1N to 1N citric acid and the like can be suitably used. Specifically, the compound represented by the general formula (3) or the general formula (4) is dissolved in a solvent such as toluene, tetrahydrofuran, or dichloromethane, and then 1.1 equivalents to 5 with respect to the substrate. By adding an equal amount of the above-mentioned acid and reacting at 0 ° C. to 30 ° C. for 1 to 6 hours with stirring, the target product represented by the above general formula (1) or general formula (2) of the present invention is obtained. obtain.

  Tert-butyl 4,4,4-trifluoro-2- (4-chlorophenyl) iminobutyrate which is a compound represented by the above formula (5) of the present invention is, for example, tert-butyl 2- (4-chlorophenyl). After iminoacetate is reacted with lithium isopropylamide in an ether solvent such as THF at −20 ° C. to −80 ° C. to form a lithium ester enolate, 2,2,2-trifluoroiodo is formed at 30 ° C. to −80 ° C. It can be prepared by reacting with ethane for 4-24 hours.

  In the above reaction, the amount of lithium isopropylamide used is usually in the range of 1.0 equivalent to 1.3 equivalents with respect to tert-butyl 2- (4-chlorophenyl) iminoacetate used in the reaction. Prepared an ester enolate reacted at −20 ° C. to −80 ° C. for 10 minutes to 2 hours, and then 1.0 to 1.5 equivalents of 2,2,2-trifluoroiodoethane at −80 ° C. Then, the mixture is heated to 20 ° C. and reacted for 4 to 24 hours to obtain the target product, tert-butyl 4,4,4-trifluoro-2- (4-chlorophenyl) iminobutyrate. After the reaction, it is washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated, and used in the next reaction.

  The method for preparing the compound represented by the general formula (3) or the general formula (4) of the present invention is not particularly limited, but specifically, tert-butyl represented by the above formula (5) 4, 4,4-trifluoro-2- (4-chlorophenyl) iminobutyrate and the benzyl bromide derivative represented by the above general formula (6) are converted into spirobis [{(S) -1,1 represented by the above formula (7). '-Bi- {4,6-bis (octyldimethylsilyl) naphthyl}}-2,2'-dimethyl] ammonium bromide or spirobis [{(R) -1,1'- represented by the above formula (8) Bi- {4,6-bis (octyldimethylsilyl) naphthyl}}-2,2′-dimethyl] ammonium bromide and alkali in the presence of −20 ° C. to 0 ° C. to give the above general formula (3) Or general It can be prepared α- trifluoroethyl phenylalanine derivative represented by (4). When the catalyst of the above formula (7) is used, the (S) isomer represented by the above general formula (3) is given, and when the catalyst of the above formula (8) is used, it is represented by the above general formula (4) ( R) Give body.

  Although it does not specifically limit as a benzyl bromide derivative shown by the said General formula (6) of this invention, Specifically, when R is a C1-C10 linear or branched alkyl group, 2- Methylbenzyl bromide, 3-methylbenzyl bromide, 4-methylbenzyl bromide, 2-ethylbenzyl bromide, 3-ethylbenzyl bromide, 4-ethylbenzyl bromide, 2-n-propylbenzyl bromide, 3-n-propylbenzyl bromide, 4-n-propylbenzyl bromide, 2-iso-propylbenzyl bromide, 3-iso-propylbenzyl bromide, 4-iso-propylbenzyl bromide, 2-n-butylbenzyl bromide, 3-n-butylbenzyl bromide, 4- n-butylbenzyl bromide, 2-tert-butylbenzyl bromide 3-tert-butylbenzyl bromide, 4-tert-butylbenzyl bromide, 2-n-pentylbenzyl bromide, 3-n-pentylbenzyl bromide, 4-n-pentylbenzyl bromide, 2-n-hexylbenzyl bromide 3-n-hexylbenzyl bromide, 4-n-hexylbenzyl bromide, 2-n-heptylbenzyl bromide, 3-n-heptylbenzyl bromide, 4-n-heptylbenzyl bromide, 2-n-octylbenzyl bromide 3-n-octylbenzyl bromide, 4-n-octylbenzyl bromide, 2-n-nonylbenzyl bromide, 3-n-nonylbenzyl bromide, 4-n-nonylbenzyl bromide, 2-n-decylbenzyl bromide, 3 -N-decylbenzyl bromide, 4-n-decyl Njiruburomido like.

  When R is a linear or branched alkoxy group having 1 to 10 carbon atoms, 2-methoxybenzyl bromide, 3-methoxybenzyl bromide, 4-methoxybenzyl bromide, 2-ethoxybenzyl bromide, 3-ethoxybenzyl bromide, 4-ethoxybenzyl bromide, 2-n-propoxybenzyl bromide, 3-n-propoxybenzyl bromide, 4-n-propoxybenzyl bromide, 2-iso-propoxybenzyl bromide, 3-iso-propoxybenzyl bromide, 4- iso-propoxybenzyl bromide, 2-n-butoxybenzyl bromide, 3-n-butoxybenzyl bromide, 4-n-butoxybenzyl bromide, 2-tert-butoxybenzyl bromide, 3-tert-butbenzylbenzyl bromide, 4-tert- Butoxibe Dilbromide, 2-n-pentyloxybenzyl bromide, 3-n-pentyloxybenzyl bromide, 4-n-pentyloxybenzyl bromide, 2-n-hexyloxybenzyl bromide, 3-n-hexyloxybenzyl bromide, 4 -N-hexyloxybenzyl bromide, 2-n-heptyloxybenzyl bromide, 3-n-heptyloxybenzyl bromide, 4-n-heptyloxybenzyl bromide, 2-n-octyloxybenzyl bromide, 3-n-octyl Oxybenzyl bromide, 4-n-octyloxybenzyl bromide, 2-n-nonyloxybenzyl bromide, 3-n-nonyloxybenzyl bromide, 4-n-nonyloxybenzyl bromide, 2-n-decyloxybenzyl bromide, 3 -N-decyloxy Benzyl bromide, etc., 4-n-decyloxy-benzyl bromide are exemplified.

  Moreover, when R is a hydrogen atom, benzyl bromide is illustrated.

  When R is a halogen atom, 2-fluorobenzyl bromide, 3-fluorobenzyl bromide, 4-fluorobenzyl bromide, 2-chlorobenzyl bromide, 3-chlorobenzyl bromide, 4-chlorobenzyl bromide, 2-bromobenzyl bromide 3-bromobenzyl bromide, 4-bromobenzyl bromide, 2-iodobenzyl bromide, 3-iodobenzyl bromide, 4-iodobenzyl bromide and the like.

  Further, when R is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom, 2-trifluoromethylbenzyl bromide, 3-trifluoromethylbenzyl bromide, 4-trifluoromethylbenzyl bromide, 2- (2,2,2-trifluoroethyl) benzyl bromide, 3- (2,2,2-trifluoroethyl) benzyl bromide, 4- (2,2,2-trifluoroethyl) benzyl bromide, 2- Examples include pentafluoroethyl benzyl bromide, 3-pentafluoroethyl benzyl bromide, 4-pentafluoroethyl benzyl bromide and the like.

  The chiral phase transfer catalyst represented by the above formula (7) or formula (8) of the present invention is optically active (S) -1,1′-bi-by, for example, the method described in JP-A-2005-41791. It can be prepared by 11 reactions using 2-naphthol or (R) -1,1′-bi-2-naphthol as a raw material.

  The amount of the chiral phase transfer catalyst represented by the above formula (7) or formula (8) of the present invention is the amount of tert-butyl 4,4,4-trifluoro-2- represented by the above formula (5) used in the reaction. The amount is usually in the range of 0.03 mol% to 5 mol%, preferably in the range of 0.05 mol% to 2 mol%, relative to (4-chlorophenyl) iminobutyrate.

  As the solvent applicable to the reaction for obtaining the compound represented by the general formula (3) or the general formula (4) of the present invention, any solvent can be used as long as it is inert to the reaction, and the solvent is particularly limited. Preferably, aromatic hydrocarbons such as toluene, benzene, ethylbenzene and mesitylene, and ethers such as diethyl ether and THF are preferable.

  The amount of the solvent applicable to the reaction for obtaining the compound represented by the general formula (3) or the general formula (4) of the present invention is tert-butyl 4,4 represented by the above formula (5) used for the reaction. , 4-trifluoro-2- (4-chlorophenyl) iminobutyrate is usually in a range of 3 to 200 times by weight, preferably in a range of 5 to 100 times by weight. is there.

  Examples of the alkali applicable to the reaction for obtaining the compound represented by the general formula (3) or the general formula (4) of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, and hydroxide. Cesium, cesium hydroxide monohydrate, etc., and tert-butyl 4,4,4-trifluoro-2- (4-chlorophenyl) iminobutylate represented by the above formula (5) used in the reaction Usually, it is used in the range of 1 mol amount to 30 mol amount. As an alkali addition method, it may be used by dissolving in a solvent used for the reaction, or powder may be added.

  The reaction temperature of the reaction for obtaining the compound represented by the general formula (3) or the general formula (4) of the present invention is usually in the range of 0 ° C to -20 ° C, and the reaction time is usually 15 minutes to 24 minutes. It is a range of time.

  After completion of the reaction for obtaining the compound represented by the general formula (3) or the general formula (4) of the present invention, for example, washing with a saturated aqueous sodium bicarbonate solution, drying over magnesium sulfate, filtration, and concentration, the above general formula. The target product represented by (3) or general formula (4) is obtained. In addition, after completion of the reaction, it is also possible to add an acid without isolation and derive to an α-trifluoroethylated phenylalanine derivative represented by the above general formula (1) or general formula (2).

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

Reference Example 1 Preparation of tert-butyl 2- (4-chlorophenyl) iminoacetate In a 500 ml three-necked round bottom flask equipped with a dropping funnel and a stirrer, tert-butyl 2-aminoacetate hydrochloride (glycine tert-butyl ester) -Hydrochloric acid salt, 9.09 g, 54.23 mmol), p-chlorobenzaldehyde (7.62 g, 54.23 mmol), magnesium sulfate (9.79 g, 81.34 mmol) and dichloromethane (28 g) were charged and stirred at room temperature. . Next, triethylamine (10.97 g, 108.5 mmol) diluted with dichloromethane (11 g) was added dropwise thereto over 1.5 hours, and the mixture was further stirred at room temperature for 20 hours.

  After completion of the reaction, the mixture was filtered, and the filtrate was concentrated, dried under reduced pressure at 40 ° C., dissolved in diethyl ether (200 ml), washed with saturated aqueous sodium bicarbonate (200 ml × 2), dried over magnesium sulfate (5 g), filtered, Concentration and drying under reduced pressure gave the target tert-butyl 2- (4-chlorophenyl) iminoacetate (13.36 g, 52.66 mmol) as a pale yellow oil (yield: 97.1%).

Example 1 Preparation of tert-butyl 4,4,4-trifluoro-2- (4-chlorophenyl) iminobutylate A 300 ml eggplant-shaped flask equipped with a stir bar was purged with nitrogen, and then diisopropylamine (5.18 g, 51.2 mmol) and anhydrous THF (170 ml) were charged and cooled to −40 ° C. with stirring. Next, n-butyllithium (1.6M hexane solution, 29.5 ml, 47.2 mmol) was added dropwise thereto over 10 minutes, and the mixture was stirred at the same temperature for 30 minutes to prepare a THF solution of lithium isopropylamide. Further, the mixture was cooled to −80 ° C., and a solution of tert-butyl 2- (4-chlorophenyl) iminoacetate (10.0 g, 39.41 mmol) prepared in Reference Example 1 in THF (100 ml) was added dropwise over 30 minutes. The mixture was stirred at the same temperature for 30 minutes to prepare an ester enolate. To this was added 2,2,2-trifluoroiodomethane (9.10 g, 43.35 mmol) dropwise over 10 minutes, stirred at the same temperature for 30 minutes, then returned to room temperature over 2 hours, and further at the same temperature. Stir for 12 hours.

  After completion of the reaction, the reaction product was washed with 100 ml of saturated aqueous sodium bicarbonate (100 ml × 2 times), dried over magnesium sulfate (10 g), filtered, concentrated and dried under reduced pressure to obtain 4,4,4-trifluoro-2- (4-Chlorophenyl) iminobutyrate (12.6 g, 37.5 mmol) was obtained as a reddish brown oil (yield 95%).

¹ H-NMR (200 MHz, CDCl ₃ ) σ 8.37 (s, 1H), 7.79 (d, 2H, J = 8.0 Hz), 7.47 (d, 2H, J = 8.0 Hz), 4.29-4.22 (m, 1H), 3.15-2.61 (m, 2H), 1.53 (s, 9H).

Example 2 Preparation of tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3-phenylpropionate 50 ml eggplant-shaped flask with stir bar Tert-butyl 4,4,4-trifluoro-2- (4-chlorophenyl) iminobutyrate (465 mg, 1.38 mmol), spirobis [{(S) -1,1′-bi-phenyl ester] prepared in Example 1. -{4,6-Bis (octyldimethylsilyl) naphthyl}}-2,2'-dimethyl] ammonium bromide (15 mg, 0.0074 mmol) and toluene (15 ml) were charged and cooled to -10 ° C while stirring. Next, benzyl bromide (382 mg, 1.44 mmol) was added thereto, cesium hydroxide monohydrate (1.43 g, 7.44 mmol) was further added, and the reaction was performed at the same temperature for 6 hours.

  After completion of the reaction, the product was washed with saturated aqueous sodium hydrogen carbonate (5 ml × 2 times), dried over magnesium sulfate (1 g), filtered, concentrated and dried to obtain the target tert-butyl (S) -2- (2, 2, 2-Trifluoroethyl) -2- (4-chlorophenyl) imino-3-phenylpropionate (330 mg, 0.775 mmol) was obtained as a brown oil (yield 56%).

¹ H-NMR (200 MHz, CDCl ₃ ) σ 8.25 (s, 1H), 7.79-7.00 (m, 9H), 3.35 (q, 2H, J = 12 Hz), 3.2 2.75 (m, 2H), 1.57 (s, 9H).

The molecular weight was measured by inducing benzoylamide. MS (m / z) 407 (M ^<+> ).

Example 3 Preparation of tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3-phenylpropionate Example 2 was added to a 50 ml eggplant-shaped flask equipped with a stir bar. Tert-Butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3-phenylpropionate (150 mg, 0.352 mmol) and toluene (8 ml) prepared in The temperature was adjusted to 0 ° C. with stirring. Next, 18 ml of 0.5N HCl solution was added thereto, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the organic layer was removed and the resulting aqueous layer was washed with diethyl ether (5 ml × 2 times). Powdered sodium bicarbonate was added to the aqueous layer to make PH alkaline, and then dichloromethane (5 ml × 5 times). Extraction, drying with magnesium sulfate, filtration, and concentration yield a crude target product, which is purified by silica gel thin layer chromatography (hexane / ethyl acetate = 2/1 vol / vol) to yield the target product, tert-butyl ( S) -2- (2,2,2-trifluoroethyl) -2-amino-3-phenylpropionate (71.9 g, 0.237 mmol) was obtained as a colorless oil (yield 49%). In the measurement with an AD-H column (Hexane / Isopropanol = 9/1 vol / vol) manufactured by Daicel Corporation, the optical purity was 92.1% ee.

¹ H-NMR (200 MHz, CDCl ₃ ) σ 7.39-7.26 (m, 5H), 3.20 (d, 1H, J = 13.2 Hz), 2.85 (d, 1H, J = 18) .2 Hz), 3.05-2.81 (m, 1H), 2.58-2.34 (m, 1H), 1.85 (bs, 2H), 1.52 (s, 9H).

¹³ C-NMR (50.3 MHz, CDCl ₃ ) σ 173.20, 135.55, 134.56, 130.37, 128.74, 128.37, 127.42, 123.21, 116.80, 82 .52, 59.11, 46.64, 43.48, 42.95, 42.41, 27.86.

The molecular weight was measured by inducing benzoylamide. MS (m / z) 425 (M ^<+> ).

Example 4 Preparation of tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-fluorophenyl) propionate Benzyl bromide of Example 2 The same operation as in Example 2 was performed except that 4-fluorobenzyl bromide was replaced with tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl). ) Imino-3- (4-fluorophenyl) propionate was obtained as a brown oil (75% yield).

¹ H-NMR (200 MHz, CDCl ₃ ) σ 8.24 (s, 1H), 7.79-7.00 (m, 8H), 3.33 (q, 2H, J = 12 Hz), 3.2 2.75 (m, 2H), 1.57 (s, 9H).

Example 5 Preparation of tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-fluorophenyl) propionate tert-Butyl (S) prepared in Example 4 ) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-fluorophenyl) propionate (150 mg, 0.338 mmol) and the same operation as in Example 3. The desired product, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-fluorophenyl) propionate (96.5 mg, 0.300 mmol) was added to a colorless oil. (Yield 89%).

  In the measurement with an AD-H column (Hexane / Isopropanol = 9/1 vol / vol) manufactured by Daicel Corporation, the optical purity was 92.5% ee.

¹ H-NMR (200 MHz, CDCl ₃ ) σ 7.29-7.22 (m, 2H), 7.10-7.02 (m, 2H), 3.16 (d, 1H, J = 13.2 Hz) ), 2.83 (d, 1H, J = 13.2 Hz), 3.02-2.83 (m, 1H), 2.56-2.32 (m, 1H), 1.81 (bs, 2H) ), 1.51 (s, 9H).

¹³ C-NMR (50.3 MHz, CDCl ₃ ) σ 173.07, 164.63, 159.74, 131.79, 130.37, 128.66, 120.99, 117.60, 115.02, 111 .11, 105.28, 100.99, 95.96, 92.00, 82.65, 59.08, 45.75, 42.84, 27.84.

The molecular weight was measured by inducing benzoylamide. MS (m / z) 475 (M ^<+> ).

Example 6 Preparation of tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-trifluoromethylphenyl) propionate The same operation as in Example 2 was carried out except that benzyl bromide was replaced with 4-trifluoromethylbenzyl bromide, and the target tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-Chlorophenyl) imino-3- (4-trifluoromethylphenyl) propionate was obtained as a brown oil (yield 73%).

¹ H-NMR (200 MHz, CDCl ₃ ) σ 8.23 (s, 1H), 7.79-7.00 (m, 8H), 3.351 (q, 2H, J = 13.0 Hz), 3. 2-2.75 (m, 2H), 1.56 (s, 9H).

Example 7 Preparation of tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-trifluoromethylphenyl) propionate tert-Butyl prepared in Example 6 Example 3 Using (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3- (4-trifluoromethylphenyl) propionate (150 mg, 0.304 mmol) Tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3- (4-trifluoromethylphenyl) propionate (102.6 mg, 0. 276 mmol) as a colorless oil (yield 91%). After induction into benzoylamide, the optical purity was 94.0% ee in the measurement with an AD-H column (hexane / isopropanol = 9/1 vol / vol) manufactured by Daicel.

¹ H-NMR (200 MHz, CDCl ₃ ) σ 7.65 (d, 2H, J = 8.0 Hz), 7.43 (d, 2H, J = 8.0 Hz), 3.26 (d, 1H, J = 13.2 Hz), 2.95 (d, 1H, J = 13.4 Hz), 3.05-2.76 (m, 1H), 2.61-2.37 (m, 1H), 1.95 (Bs, 2H), 1.52 (s, 9H).

¹³ C-NMR (50.3 MHz, CDCl ₃ ) σ 183.43, 172.72, 138.75, 130.77, 125.3, 125.09, 83.01, 59.11, 48.35, 46 19, 43.33, 27.86.

Example 8
After reacting tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2- (4-chlorophenyl) imino-3-phenylpropionate at 0 ° C. in the same manner as in Example 2. Then, tert-butyl (S) -2- (2,2,2-trifluoroethyl) -2-amino-3-phenylpropionate was prepared by the same operation as in Example 3 without isolating the product. did. The yield of the obtained target product was 58%, and the optical purity was 89.2% ee as measured by an AD-H column (hexane / isopropanol = 9/1 vol / vol) manufactured by Daicel.

Claims (18)

The following general formula (1)

[In the general formula (1), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
An α-trifluoroethylated phenylalanine derivative represented by the formula: The following general formula (2)

[In the general formula (2), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
An α-trifluoroethylated phenylalanine derivative represented by the formula: The general formula (1) or the general formula (2), wherein R is a hydrogen atom, a halogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. The α-trifluoroethylated phenylalanine derivative according to claim 1 or 2. The α-trifluoroethylated phenylalanine derivative according to claim 1 or 2, wherein R is a hydrogen atom, a fluorine atom or a trifluoromethyl group in the general formula (1) or (2). . The following general formula (3)

[In the general formula (3), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
An α-trifluoroethylated phenylalanine derivative represented by the formula: The following general formula (4)

[In the general formula (4), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
An α-trifluoroethylated phenylalanine derivative represented by the formula: The general formula (3) or the general formula (4), wherein R is a hydrogen atom, a halogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted by a halogen atom. The α-trifluoroethylated phenylalanine derivative according to claim 5 or 6. The α-trifluoroethylated phenylalanine derivative according to claim 5 or 6, wherein R is a hydrogen atom, a fluorine atom or a trifluoromethyl group in the general formula (3) or the general formula (4). . The α-trifluoroethylated phenylalanine derivative according to claim 1, wherein the α-trifluoroethylated phenylalanine derivative represented by the general formula (3) according to claim 5 is hydrolyzed in the presence of an acid. Manufacturing method. The α-trifluoroethylated phenylalanine derivative according to claim 2, wherein the α-trifluoroethylated phenylalanine derivative represented by the general formula (4) according to claim 6 is hydrolyzed in the presence of an acid. Manufacturing method. The general formula (3) or the general formula (4), wherein R is a hydrogen atom, a halogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. The manufacturing method of Claim 9 or Claim 10. 11. The production method according to claim 9, wherein in general formula (3) or general formula (4), R is a hydrogen atom, a fluorine atom, or a trifluoromethyl group. Following formula (5)

A 4,4,4-trifluoro-2-aminobutanoic acid derivative represented by the formula: The 4,4,4-trifluoro-2-aminobutanoic acid derivative represented by the formula (5) according to claim 13 and the following general formula (6)

[In the general formula (6), R is substituted with a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms, a hydrogen atom, a halogen atom, or a halogen atom. The C1-C4 linear or branched alkyl group made is shown. ]
A benzyl bromide derivative represented by the following formula (7)

The method for producing an α-trifluoroethylated phenylalanine derivative according to claim 5, wherein the reaction is carried out in the presence of a chiral phase transfer catalyst represented by the formula (1) and an alkali. A 4,4,4-trifluoro-2-aminobutanoic acid derivative represented by the formula (5) according to claim 13 and a benzyl bromide derivative represented by the general formula (6) according to claim 14 are represented by the following formula ( 7)

The method for producing an α-trifluoroethylated phenylalanine derivative according to claim 6, wherein the reaction is carried out in the presence of a chiral phase transfer catalyst and an alkali. The general formula (6), wherein R is a hydrogen atom, a halogen atom, or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom. The α-trifluoroethylated phenylalanine derivative described. The α-trifluoroethylated phenylalanine derivative according to claim 14 or 15, wherein in the general formula (6), R is a hydrogen atom, a fluorine atom or a trifluoromethyl group. Following formula (9)

The glycine derivative represented by formula (4) is reacted with 2,2,2-trifluoroethyl iodide after reacting with lithium isopyramide. A method for producing a 2-aminobutanoic acid derivative.