KR20130069781A - Method for producing amino acid amide derivative having fluorine-containing carbamate group, production intermediate thereof, and method for producing ethylene diamine derivative - Google Patents

Abstract

A method for producing the compound represented by the general formula (2) by reacting the compound represented by the general formula (1) with ammonia.

Description

METHOD FOR PRODUCING AMINO ACID AMIDE DERIVATIVE HAVING FLUORINE-CONTAINING CARBAMATE GROUP, PRODUCTION INTERMEDIATE THEREOF, AND METHOD FOR PRODUCING ETHYLENE DIAMINE FIELD }

The present invention relates to a method for producing an amino acid amide derivative having a fluorine-containing carbamate group, an intermediate for producing the same, and a method for producing an ethylenediamine derivative.

It is known that amino acid amide derivatives having a fluorine-containing carbamate group are useful as intermediates of fungicides, as shown in Patent Document 1. When preparing such a compound group, it is important to prepare efficiently from the easily available amino acid.

Regarding the amino acid amide derivative having a fluorine-containing carbamate group, a conventional production technique is exemplified, and a method of reacting the amino acid amide with chloroformate-containing fluorinated alkyls as shown in Patent Document 1 may be mentioned. Here, chloroformate-containing fluorine-containing alkyls can be produced by a method of reacting fluorine-containing alcohol with phosgene, as shown in Patent Document 2.

However, the above method is economically disadvantageous because it uses an expensive and inexpensive amino acid amide. In addition, the reaction for synthesizing amino acid amides from amino acids generally requires a long time, and also has a low yield. Therefore, the development of a highly efficient manufacturing method which does not go through amino acid amide from an amino acid is needed.

From this background, there has been a demand for a method for efficiently producing amino acid amide derivatives having a fluorine-containing carbamate group.

Prior art literature

Patent literature

Patent Document 1: International Publication No. 2007/111024 Pamphlet

Patent Document 2: US Patent No. 3742010

Non-patent  literature

Non-Patent Document 1: Tetrahedron Letters No. 20, pp. 2021-2024 (1972)

Summary of the Invention

An object of the present invention is to provide a method advantageous for the industrial production of an amino acid amide derivative having a fluorine-containing carbamate group. Furthermore, it is an object of the present invention to provide a method advantageous for industrial production, including a step of producing the amino acid amide derivative with respect to the ethylenediamine derivative having a fluorine-containing carbamate group and an acyl group.

As a result of diligent study, the inventors of the present invention found that amino acids having a fluorinated carbamate group represented by the general formula (3) obtained by reacting an amino acid readily available in large quantities at low cost in the presence of an alkyl chloroformate-containing alkyl in the presence of a water are used as chlorinating agents. By using the compound represented by the general formula (1), and then reacting with ammonia is found to be an effective solution of the above problems, there is little waste, yield can be produced in good yield, and the advantages of maintaining the three-dimensional structure of amino acids It confirmed that it has and came to complete this invention.

That is, the present invention is as follows.

[1] general formula (1)

[Formula 1]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl It may represent an alkyl group and may form the ring structure which R <_3> and R <_4> couple | bonded with C2-C5, or R <_3>. Or R ₄ Or any of R ₂ and C ₂ to C 4 may form a ring structure.) By reacting a compound represented by ammonia with the general formula (2)

[Formula 2]

In the formula, R ₁ , R ₂ , R ₃ and R ₄ are as described above.

How to.

[2] In the formula (1), R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, R ₂ represents hydrogen or an alkyl group having 1 to 6 carbon atoms, R ₃ and R ₄ each independently represent hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and in R ₃ and R ₄ The manufacturing method as described in [1] which may form the ring structure which any of R <_{2> couple |} bonded with 3-4 carbon atoms.

[3] general formula (3)

(3)

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl It may represent an alkyl group and may form the ring structure which R <_3> and R <_4> couple | bonded with C2-C5, or R <_3>. Alternatively, any of R ₄ and R ₂ may form a ring structure in which 3 to 4 carbon atoms are bonded to each other.) By reacting the compound represented by the chlorinating agent with the general formula (1)

[Formula 4]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), followed by conversion to a compound represented by the following formula (2).

[Chemical Formula 5]

In the formula, R ₁ , R ₂ , R ₃ and R ₄ are as described above.

How to.

[4] In the formula (3), R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, R ₂ represents hydrogen or an alkyl group having 1 to 6 carbon atoms, R ₃ and R ₄ each independently represent hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and R ₃ and R ₄ The manufacturing method as described in [3] in which any and R <_2> may form the ring structure which _{couple |} bonded with 3-4 carbon atoms.

[5] general formula (4)

[Formula 6]

(In formula, R <_2> represents hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R <_3> and R <_4> respectively, Independently, hydrogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted A heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and may form a ring structure in which R ₃ and R ₄ are bonded with 2 to 5 carbon atoms, or with any of R ₃ or R ₄ And R ₂ may form a ring structure in which 3 to 4 carbon atoms are bonded.

General formula (5)

[Formula 7]

In the formula, R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, or a cycloalkyl group having 3 to 6 carbon atoms substituted with at least one fluorine atom. By reacting alkyl, General formula (3)

[Formula 8]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), followed by conversion to a compound represented by the following formula (1).

[Chemical Formula 9]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), followed by conversion to a compound represented by the following formula (2).

[Formula 10]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as above).

[6] In the formula (3), R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, R ₂ represents hydrogen or an alkyl group having 1 to 6 carbon atoms, R ₃ and R ₄ each independently represent hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and in R ₃ and R ₄ You may form the ring structure which R <_{2> couple |} bonded with 3-4 carbon atoms,

The manufacturing method as described in [5].

[7] general formula (1)

[Formula 11]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl It may represent an alkyl group and may form the ring structure which R <_3> and R <_4> couple | bonded with 2-5 carbon atoms, or the ring structure which R <_2> and R <_{2> couple |} bonded with 3-4 carbon atoms of R <_3> or R <_4> . May be formed. Compounds.

[8] In the formula (1), R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, R ₂ represents hydrogen or an alkyl group having 1 to 6 carbon atoms, R ₃ and R ₄ each independently represent hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and in R ₃ or R ₄ The compound as described in [7] which may form the ring structure which R <_{2> couple |} bonded with 3-4 carbon atoms.

[9] general formula (3 ')

[Chemical Formula 12]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ each independently represent hydrogen, A substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, Or a substituted or unsubstituted heteroarylalkyl group, and R ₃ and R ₄ may form a ring structure bonded with 2 to 5 carbon atoms, or any one of R ₃ or R ₄ and R ₂ are carbon atoms Combined into numbers 3 ~ 4 The compound represented by the structure may be formed.).

[10] In the formula (3 '), R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, R ₂ represents hydrogen or an alkyl group having 1 to 6 carbon atoms, R ₃ and R ₄ each independently represent hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, except when hydrogen is simultaneously. Moreover, the compound as described in [9] which may form the ring structure which R <_3> and R <_{2> couple |} bonded with C3-4 of any of R <_3> or R < ₄ >.

[11] In the formula (3 '), R ₁ represents a trifluoroethyl group, R ₂ represents hydrogen or an alkyl group having 1 to 6 carbon atoms, and R ₃ and R ₄ simultaneously represent hydrogen. Each independently, except hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted, represents an unsubstituted arylalkyl group, and any of R ₃ or R ₄ The compound as described in [9] in which one and R ₂ may form a ring structure in which 3 to 4 carbon atoms are bonded.

[12] general formula (1)

[Chemical Formula 13]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl It may represent an alkyl group and may form the ring structure which R <_3> and R <_4> couple | bonded with 2-5 carbon atoms, or the ring structure which R <_2> and R <_{2> couple |} bonded with 3-4 carbon atoms of R <_3> or R <_4> . May be formed. Is represented by the general formula (2) by which a compound, ammonia and the reaction

[Formula 14]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), and the compound represented by the general formula (2) is then reacted with a deoxidant to general Formula (6)

[Formula 15]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above), and then the compound represented by the formula (6) is subjected to catalytic hydrogenation in the presence of an acid. By carrying out, general formula (7)

[Chemical Formula 16]

(In formula, R <_1> , R <_2> , R <_3> and R <_4> are as having mentioned above.), Then, the compound represented by General formula (7) is converted into general formula (8).

[Chemical Formula 17]

Wherein R ₅ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, substituted or General formula (9) by reacting with a compound represented by an unsubstituted heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and X represents a leaving group.

[Chemical Formula 18]

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as described above.

[13] general formula (3)

[Chemical Formula 19]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl It may represent an alkyl group and may form the ring structure which R <_3> and R <_4> couple | bonded with 2-5 carbon atoms, or the ring structure which R <_2> and R <_{2> couple |} bonded with 3-4 carbon atoms of R <_3> or R <_4> . May be formed. Is by reacting with a chlorinating agent to the compound represented by the general formula (1)

[Chemical Formula 20]

(In formula, R <_1> , R <_2> , R <_3> and R <_4> are the same as the above.), Then, the compound represented by General formula (1) is reacted with ammonia in general, Formula (2)

[Chemical Formula 21]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), and the compound represented by the general formula (2) is then reacted with a deoxidant to general Formula (6)

[Chemical Formula 22]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above), and then the compound represented by the formula (6) is subjected to catalytic hydrogenation in the presence of an acid. By carrying out, general formula (7)

(23)

(In formula, R <_1> , R <_2> , R <_3> and R <_4> are as having mentioned above.), Then, the compound represented by General formula (7) is converted into general formula (8).

&Lt; EMI ID =

Wherein R ₅ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, substituted or General formula (9) by reacting with a compound represented by an unsubstituted heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and X represents a leaving group.

(25)

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as described above.

[14] general formula (4)

(26)

(In formula, R <_2> represents hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R <_3> and R <_4> respectively, Independently, hydrogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted A heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and may form a ring structure in which R ₃ and R ₄ are bonded with 2 to 5 carbon atoms, or R ₃ or R ₄ and R _And a ring structure in which _divalent carbon atoms of 3 to 4 are formed.

General formula (5)

(27)

In the formula, R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, or a cycloalkyl group having 3 to 6 carbon atoms substituted with at least one fluorine atom. By reacting alkyl, General formula (3)

(28)

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), and the compound is reacted with a chlorinating agent to give a general formula (1).

[Formula 29]

(In formula, R <_1> , R <_2> , R <_3> and R <_4> are the same as the above.), Then, the compound represented by General formula (1) is reacted with ammonia in general, Formula (2)

(30)

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), followed by reacting the compound represented by the general formula (2) with a deoxygenating agent. (6)

(31)

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above), and then the compound represented by the formula (6) is subjected to catalytic hydrogenation in the presence of an acid. By carrying out, general formula (7)

(32)

(In formula, R <_1> , R <_2> , R <_3> and R <_4> are as having mentioned above.), Then, the compound represented by General formula (7) is converted into general formula (8).

(33)

Wherein R ₅ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, substituted or General formula (9) by reacting with a compound represented by an unsubstituted heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and X represents a leaving group.

[Formula 34]

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as described above.

According to the present invention, there is provided a novel method for producing an amino acid amide derivative having a fluorine-containing carbamate group, a novel production intermediate, and also a new method for producing an amino acid amide derivative of the present invention as part of the process. A novel method for producing an ethylenediamine derivative having a mate group and an acyl group can be provided. In addition, the present invention has the advantages of maintaining the three-dimensional structure of the amino acid, less industrial waste, and higher yield. Therefore, this invention is excellent in environmental adaptability, economy, safety, and productivity, and is useful as an industrial manufacturing method.

Carrying out the invention  Form for

Hereinafter, the present invention will be described in detail.

<Method for Preparing Amino Acid Amide Derivative>

The manufacturing method of the amino acid amide derivative (compound of General formula (2)) which has a fluorine-containing carbamate group which concerns on this invention is represented by General formula (1) which is a novel manufacturing intermediate, as shown in following Reaction Formula (1). The compound to be reacted with ammonia.

(35)

In the compound represented by the general formula (1), R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom or a cycloalkyl group having 3 to 6 carbon atoms substituted with at least one fluorine atom.

R <_1> in General formula (1) is a C1-C6 alkyl group in a C1-C6 alkyl group substituted by at least 1 fluorine atom, and is methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, etc. Linear or isopropyl group, isobutyl group, sec-butyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethyl Propyl group, 1,2-dimethylpropyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group And branched ones such as 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group and 3,3-dimethylbutyl group. At least one of the hydrogen atoms of these alkyl groups should just be substituted by the fluorine atom.

R <_1> in General formula (1) is a C3-C6 cycloalkyl group in a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, and is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and cyclohexene It demonstrates practical skill.

In the compound represented by the general formula (1), R ₂ represents hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. .

The alkyl group having 1 to 6 carbon atoms in R ₂ in General Formula (1) is synonymous with that described in R ₁ in General Formula (1).

The cycloalkyl group having 3 to 6 carbon atoms in R ₂ in General Formula (1) is synonymous with that described in R ₁ in General Formula (1).

The substituent in the substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group in R ₂ in General Formula (1) is methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, cycloalkyl groups such as alkyl groups such as sec-butyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups, such as trifluoromethyl groups, difluoromethyl groups, bromodifluoromethyl groups, and trifluoroethyl groups Alkoxy groups such as fluorine-substituted alkyl groups, methoxy groups, ethoxy groups, propoxy groups, isopropoxy groups, butoxy groups, isobutoxy groups and sec-butoxy groups, trifluoromethoxy groups, difluoromethoxy groups and trifluoro Fluorine-substituted alkoxy groups, such as an ethoxy group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group Alkylsulfonyl groups, such as alkoxycarbonyl group, phenoxycarbonyl group, aryloxycarbonyl group, methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, trifluoromethanesulfonyl group, difluoromethanesulfonyl group, trifluoro Alkylcarbonyl groups, such as fluorine-substituted alkylsulfonyl groups, such as an ethane sulfonyl group, methylcarbonyl group, ethylcarbonyl group, propylcarbonyl group, and isopropylcarbonyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group, such as cyclohexylcarbonyl group, benzo Alkylcarbonyloxy groups, cyclopropylcarbonyloxy groups, cyclobutylcarbonyl jade, such as an arylcarbonyl group, methylcarbonyloxy group, ethylcarbonyloxy group, propylcarbonyloxy group, and isopropylcarbonyloxy group such as a diary Cyclic, cyclopentylcarbonyloxy group, cyclohexylcarbonyl An aryl-carbonyl-oxy, such as cyclo alkylcarbonyloxy group, benzoyloxy group and the like at the time. The number of substituents on an aryl group or heteroaryl group is not limited. In addition, when two or more aryl groups or heteroaryl groups are substituted, they may be comprised by the same or two or more types of substituents, and are not limited.

The aryl group in R ₂ in General Formula (1) represents a phenyl group, a naphthyl group, an enthranyl group, a phenanthryl group, or the like.

The heteroaryl group in R ₂ in the general formula (1) is a pyridyl group, a pyrimidyl group, a pyrazolyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, an indolyl group, a quinolyl group, a quinoxalyl group , Nitrogen-containing heterocyclic groups such as benzimidazolyl group, tetrahydrofuranyl group, furanyl group, pyranyl group, dioxanyl group, 2,3-dihydrobenzo [1,4] dioxynyl group, benzooxazolyl group, benzo Heterocyclic group containing 2 or more types of heteroatoms, such as an isoxazolyl group, is mentioned.

In the compound represented by the general formula (1), R ₃ and Each R ₄ is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, A substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heteroarylalkyl group is shown. Further, the R ₃ and R _4, and form a ring structure bonded with 2-5 carbon atoms, or, R ₃ or R ₄ by a one and R ₂ in the form a ring structure bonded to the carbon atoms 3-4 You may also In addition, the number of carbon atoms does not include the carbon atom to which R ₃ and R ₄ are bonded.

Formula (1) of the R ₃ and R ₄ substituted or a cycloalkyl group of unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted carbon atoms, 3-6 of the of the substituted or unsubstituted aryl group, a substituted or unsubstituted The substituent in the substituted arylalkyl group, substituted or unsubstituted heteroaryl group, or substituted or unsubstituted heteroarylalkyl group is methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl Cycloalkyl groups such as alkyl groups such as groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, fluorine-substituted alkyl groups such as trifluoromethyl groups, difluoromethyl groups, bromodifluoromethyl groups, and trifluoroethyl groups Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and sec-butoxy groups, trifluoromethoxy, difluoromethoxy and trifluoroethoxy groups Such as Alkoxycarbonyl, phenoxycarbonyl, aryloxycarbonyl, methanesulfo, such as fluorine-substituted alkoxy group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group Alkylsulfonyl groups, such as a silyl group, an ethanesulfonyl group, a propanesulfonyl group, butanesulfonyl group, a fluoro substituted alkylsulfonyl group, methylcarbonyl group, such as a trifluoromethanesulfonyl group, a difluoromethanesulfonyl group, and a trifluoroethanesulfonyl group, Alkylcarbonyl groups, such as an alkylcarbonyl group, such as an ethylcarbonyl group, a propylcarbonyl group, and an isopropyl carbonyl group, a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentyl carbonyl group, a cycloalkyl carbonyl group, such as a cyclohexylcarbonyl group, and a benzoyl group, methylcarbonyloxy group, and ethylcarbonyl group Carbonyloxy, Propyl Carbon Cycloalkyl carbon, such as an alkylcarbonyloxy group, such as a silyloxy group and an isopropyl carbonyloxy group, a cyclopropyl carbonyloxy group, a cyclobutyl carbonyloxy group, a cyclopentyl carbonyloxy group, and a cyclohexyl carbonyloxy group, etc. Aryl carbonyloxy groups, such as a silyloxy group and a benzoyloxy group, halogen atoms, such as fluorine, chlorine, bromine, iodine, etc. are illustrated. When an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, heteroaryl group, or heteroarylalkyl group has two or more substituents, it may be comprised by the same or two or more types of substituents, and is not limited.

The alkyl group having 1 to 6 carbon atoms in R ₃ or R ₄ in General Formula (1) is synonymous with that described in R ₁ in General Formula (1).

The C3-C6 cycloalkyl group in R ₃ or R ₄ in General Formula (1) is synonymous with that described in R ₁ in General Formula (1).

The aryl group in R ₃ or R ₄ in General Formula (1) is synonymous with that described in R ₁ in General Formula (1).

About the arylalkyl group in R <_3> or R <_4> in General formula (1), an aryl moiety is synonymous with the aryl group described by R <_2> in General formula (1), and an alkyl moiety represents a C1-C4 thing.

The heteroaryl group in R ₃ or R ₄ in General Formula (1) is synonymous with that described in R ₂ in General Formula (1).

The heteroaryl moiety in R <_3> or R <_4> in General formula (1) is a heteroaryl moiety synonymous with the heteroaryl group described by R <_2> in general formula (1), and an alkyl moiety represents a C1-C4 thing. .

In General formula (1), R <_1> represents the C1-C6 alkyl group substituted by at least 1 fluorine atom, R <_2> represents hydrogen or a C1-C6 alkyl group, and R <_3> and R <_4> are respectively It is preferable to represent hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group independently. Further, the R ₃ or one R ₂ and R ₄ is in the form a ring structure bonded to the carbon atoms 3-4.

When the compound represented by General formula (1) has a subsidiary point, an optically active substance or a racemate can be used.

In the compound represented by General formula (2), R <_1> , R <_2> , R <_3> and R <_4> are synonymous with what was described by General formula (1).

By reacting the compound represented by General Formula (1) with ammonia, the compound represented by General Formula (2) can be converted.

The amount of ammonia to be used is not particularly limited as long as it is equivalent to or higher than the compound represented by the general formula (1), but from an economic point of view, one equivalent or more and 15 equivalents or less are preferable.

When reacting the compound represented by General formula (1) with ammonia, a base can be used.

Examples of the base to be used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, pyridine, triethylamine, diisopropylethylamine, tributylamine, 1,8-dia Organic bases, such as a zabicyclo [5, 4, 0] -undec-7-ene, a 1, 4- diazabicyclo [2, 2, 0] octane, are illustrated. It can also be used independently and can also mix two or more types by arbitrary ratios.

The base is not used at all or may be used in an amount of 1 equivalent or more based on the compound represented by the general formula (1). In addition, the upper limit is preferably 10 equivalents or less from the economic point of view.

The solvent used when reacting the compound represented by the general formula (1) with ammonia is not particularly limited as long as the compound represented by the general formula (2) is produced. Specific examples of the solvent include halogen solvents such as dichloromethane and chloroform, aromatic solvents such as benzene, toluene and xylene, hydrocarbon solvents such as hexane and heptane, dimethylformamide, dimethylacetamide and 1-methyl-2- Urea such as amide solvents such as pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone Ether solvents such as solvents, diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, ester solvents such as ethyl acetate, butyl acetate and isopropyl acetate and water Can be. These solvents may be used alone or in combination of two or more thereof in any ratio.

Although the usage-amount of a solvent is not specifically limited, Usually, it is 2 times or more and 40 times or less with respect to the compound represented by General formula (1).

The reaction temperature at the time of reacting the compound represented by the general formula (1) with ammonia is not particularly limited as long as the compound represented by the general formulas (1) and (2) is not decomposed. It is 10 degrees C or more and 80 degrees C or less, or less than the boiling point of a solvent. However, when the compound represented by General formula (1) and (2) has a subsidiary point, since it will racemic when heated in presence of excess ammonia, 40 degrees C or less is preferable.

In addition, in this invention, as shown to following Reaction formula (2), the compound represented by General formula (1) is made to react the compound represented by General formula (3) which is a novel manufacturing intermediate with a chlorinating agent. The compound represented by General formula (2) can be manufactured by converting and then reacting with ammonia.

(36)

In the compound represented by the general formula (3), R ₁ , R ₂ , R ₃ and R ₄ are synonymous with those described in the general formula (1).

The chlorinating agent to be used is not limited as long as it does not decompose the compound represented by the general formula (3) or (1), but for example, thionyl chloride, oxalyl base, phosphorus oxychloride, phosphorus pentachloride or phosgene , Vilsmeier reagent and the like can be used.

Although the usage-amount of a chlorinating agent will not restrict | limit if it sets to make the target reaction advance, Usually, they are 1 equivalent or more and 20 equivalent or less with respect to the compound of General formula (3).

The solvent used when carrying out the reaction for obtaining the compound represented by the general formula (1) is not particularly limited as long as the reaction proceeds. Specific examples include aromatic solvents such as benzene, toluene and xylene, hydrocarbon solvents such as hexane and heptane, amide formamides such as dimethylformamide, dimethylacetamide and 1-methyl-2-pyrrolidone, and diethyl ether. And ether solvents such as diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, and ester solvents such as ethyl acetate, butyl acetate and isopropyl acetate. These solvents may be used alone or in combination of two or more thereof in any ratio.

Although it does not specifically limit about the usage-amount of a solvent, Usually, the weight of 1-40 times is preferable with respect to the weight of General formula (3).

Although the reaction form is not specifically limited, It is preferable to add a chlorinating agent to General formula (3) or General formula (3) diluted with the said solvent.

The reaction temperature is not particularly limited as long as the compound is not decomposed, but is usually -10 ° C or higher and 100 ° C or lower or below the boiling point of the solvent.

About the compound represented by General formula (1) obtained by the said reaction, the usage form in the next process is not specifically limited. Regarding the reaction solution containing the compound represented by the general formula (1), after performing normal post-treatment operation such as solvent distillation or the like, it is used for the next step without isolation and purification, or for use in the next step as it is as a reaction solution. It is possible.

Hereinafter, the preparation method of the compound represented by General formula (3) is described.

The compound represented by General formula (3) can be obtained by making amino acid and fluorine-substituted alkyl chloroformate react in water presence similarly to Nonpatent literature 1. As the fluorine-substituted alkyl chloroformate, a compound synthesized by a commercially available product or by the method of Patent Document 2 can be used.

As a method for preparing the compound represented by the general formula (3), it is possible to obtain efficiently by dissolving an amino acid in water and dropping and reacting alkyl chloroformate substituted with fluorine while maintaining the pH of the reaction solution at 11-13. have.

As an example of the compound represented by General formula (3), the compound represented by General formula (3 ') can be used.

[Formula 37]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ each independently represent hydrogen, A substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, Or a substituted or unsubstituted heteroarylalkyl group, and may form a ring structure in which R ₃ and R ₄ are bonded with 2 to 5 carbon atoms, or any one of R ₃ or R ₄ and R ₂ are carbon atoms Ring combined with 3 ~ 4 You may form a structure.)

In the said General formula (3 '), R <_1> shows a C1-C6 alkyl group substituted with at least 1 fluorine atom, R <_2> represents hydrogen or a C1-C6 alkyl group, R <_3> And R ₄ each independently represent hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, except when hydrogen is used. , It is preferable that it is a compound which may form the ring structure which R <_3> or R <_4> and R <_{2> couple |} bonded with 3-4 carbon atoms.

In the formula (3 '), R ₁ represents a trifluoroethyl group, R ₂ represents hydrogen or an alkyl group having 1 to 6 carbon atoms, and R ₃ and R ₄ simultaneously represent hydrogen Each independently, except hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and each of R ₃ or R ₄ It is further more preferable that it is a compound which may form the ring structure which and R <_{2> couple |} bonded with 3-4 carbon atoms.

When the compound represented by General formula (4) is used as an amino acid, the compound represented by General formula (2) which is a target compound can be manufactured. Specifically, as shown in the following reaction formula (3), a general formula that is a novel production intermediate by reacting a compound represented by the general formula (4) with a fluorine-substituted alkyl chloroformate represented by the general formula (5). The compound represented by (3) can be obtained. And the compound represented by General formula (2) is converted into the compound represented by General formula (1) by making it react with the compound represented by General formula (3), and a chlorinating agent, and then reacting with ammonia. It can manufacture.

(38)

R ₂ , R ₃ and R ₄ in the compound represented by the general formula (4) are the same as those described in the general formula (1), and R ₁ in the compound represented by the general formula (5) is the general formula. It is synonymous with what was described in (1). In addition, the said chlorinating agent can use said thing.

The compound represented by the general formula (4) is dissolved in water, and the fluorine-substituted alkyl chloroformate represented by the general formula (5) can be added dropwise and reacted while maintaining the pH of the reaction solution at 11 to 13. Moreover, it is also possible to manufacture, without isolating and refine | purifying from the compound represented by General formula (4) to the compound represented by General formula (2).

As mentioned above, it became possible to efficiently manufacture the compound represented by General formula (2), ie, the amino acid amide derivative which has a fluorine-containing carbamite group.

<New manufacturing method of ethylenediamine derivative>

The method for producing an ethylenediamine derivative (compound of formula (9)) having a fluorine-containing carbamate group and an acyl group according to the present invention is represented by the following schemes (1) to (3). The amino acid amide derivative (compound of formula (2)) having a fluorine-containing carbamate group obtained by any of the above methods is converted to a compound represented by formula (6) by reacting with an oxygen scavenger. Subsequently, the compound represented by the general formula (6) is converted to the compound represented by the general formula (7) by carrying out a catalytic hydrogenation reaction in the presence of an acid, and then the compound represented by the general formula (7) The compound represented by General formula (9) can be manufactured by making it react with the compound represented by General formula (8).

[Chemical Formula 39]

The compound represented by the general formula (6) is prepared by reacting the compound represented by the general formula (2) with the deoxidizer in advance.

Hereinafter, reaction of the compound represented by General formula (2) and a deoxidizer is demonstrated.

R <_1> , R <_2> , R <_3> and R <_4> in the compound represented by General formula (2) are synonymous with what was described by General formula (1).

Deoxygenating agent is a halogenating agent such as thionyl chloride, oxalyl chloride, phosgene, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide, mesyl chloride, tosyl chloride, N, N'-dish Carbodiimide derivatives such as clohexylcarbodiimide, N, N'-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, acetic anhydride, trifluoro acetic anhydride Anhydrides such as these, Vilsmeier reagent and the like.

Vilsmeier reagent is a general formula (10) prepared from formamide derivatives such as dimethylformamide and a halogenating agent.

[Formula 40]

(In formula, R <_6> and R <_7> respectively independently represents a C1-C3 alkyl group and Y represents a halogen atom.)

The compound represented by General formula (10) also contains the salt derived from a halogenating agent.

The alkyl group having 1 to 3 carbon atoms in R ₆ and R ₇ in General Formula (10) represents a methyl group, an ethyl group, a propyl group, or the like.

The halogen atom in Y in the general formula (10) is fluorine, chlorine, bromine, iodine or the like.

The use form of a deoxidizer is not restrict | limited, either, The method of adding a deoxidizer to a board | substrate, or the method of adding a deoxidizer to a board | substrate may be sufficient.

The form of use when the deoxidant is a Vilsmeier reagent is also not particularly limited. It is performed by the method of adding the compound represented by General formula (2) after preparing the Vilsmeier reagent in a solvent previously, or the method of charging a halogenating agent in the solvent containing the compound represented by General formula (2), and a formamide derivative. can do.

Although the usage-amount of a deoxidation agent will not be restrict | limited especially if it is 1 equivalent or more with respect to the compound represented by General formula (2), Usually, they are 1 equivalent or more and 10 equivalent or less.

The amount of deoxygenating agent used in the case of the Vilsmeier reagent is not particularly limited as long as the halogenating agent is at least 1 equivalent to the compound represented by the general formula (2) and the formamide derivative is at least the catalytic amount. Usually, a halogenating agent is 1 equivalent or more and 10 equivalents or less, and a formamide derivative is 0.1 equivalent or more and 10 equivalents or less with respect to the compound represented by General formula (2). The formamide derivative can also be used as a solvent.

The solvent used when converting from the compound represented by the general formula (2) to the compound represented by the general formula (6) is not particularly limited as long as it is an aprotic solvent. Specifically, halogen solvents such as dichloromethane and chloroform, aromatic solvents such as benzene, toluene and xylene, hydrocarbon solvents such as hexane and heptane, dimethylformamide, dimethylacetamide and 1-methyl-2-pi Amide solvents such as rolidone, ether solvents such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, nitrile solvents such as acetonitrile and propionitrile, 1 Urea solvents such as, 3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -piperidinone, ethyl acetate, butyl acetate, acetic acid Ester solvents such as isopropyl. It can also be used independently, and can also mix and use two or more types of solvents in arbitrary ratios.

Among the oxygen scavengers used in the present invention, the Vilsmeier reagent can be preferably applied.

Although it does not specifically limit about the usage-amount of a solvent, Usually, 3-40 times the weight is preferable with respect to the weight of the compound represented by General formula (2).

Although the reaction temperature at the time of converting into the compound represented by General formula (6) from the compound represented by General formula (2) is not specifically limited as long as reaction advances, -10 degreeC or more and 150 degrees C or less or a solvent Is below the boiling point. By such a simple reaction, the compound represented by the general formula (6) can be obtained in high yield. Therefore, it is useful as an industrial manufacturing method of the compound represented by General formula (6).

Next, the compound represented by General formula (6) obtained can be contact-hydrogenated in presence of acid, and can be converted into the compound represented by General formula (7).

Thereby, formation of a by-product is suppressed and the compound represented by General formula (7) can be obtained in a high yield.

In the compound represented by the general formula (7), R ₁ , R ₂ , R ₃ and R ₄ are synonymous with those described in the general formula (1).

The acid to be used is not limited as long as it does not decompose the compound represented by the general formula (6) or (7). For example, an organic acid or an inorganic acid can be used.

As an organic acid, formic acid, acetic acid, methanesulfonic acid, etc. are mentioned as an inorganic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. can be illustrated.

The amount of the acid used is not limited as long as the target reaction is set to proceed, but is usually 1 equivalent or more and 20 equivalents or less.

Regarding the catalytic hydrogenation method, a method performed by metals such as palladium, platinum, rhodium and ruthenium is exemplified. These metals can also be used in the form of metal oxides, metal chlorides and the like.

Although the quantity of the metals used at the time of performing a contact-hydrogenation method is not specifically limited when reaction advances, Equivalent or less is preferable with respect to the weight of General formula (6) from an economic viewpoint.

As the form of the metal to be used, those supported on activated carbon, SiO ₂ , Al ₂ O ₃ , BaSO ₄ , TiO ₂ , ZrO ₂ , MgO, ThO ₂ , diatomaceous earth and the like can be used. It does not matter the form, but from an economic point of view, it is preferable to use a reusable carrier.

The solvent used when performing the catalytic hydrogenation method is not particularly limited as long as the reaction proceeds. Specific examples include alcohol solvents such as methanol, ethanol and isopropanol, aromatic solvents such as benzene, toluene and xylene, hydrocarbon solvents such as hexane and heptane, dimethylformamide, dimethylacetamide and 1-methyl-2-pyrroli Ether solvents such as amide solvents such as don, ether solvents such as diethylpropyl, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, and ester solvents such as ethyl acetate, butyl acetate and isopropyl acetate , Water. It may be used independently and may mix two or more types by arbitrary ratios.

Although the usage-amount of a solvent is not specifically limited, Usually, the weight of 3-40 times with respect to the weight of General formula (6) is preferable.

Although the reaction form is not specifically limited, It is preferable to add General formula (6) or General formula (6) diluted with the said solvent to the solvent containing a metal and an acid in presence of a hydrogen source.

The reaction temperature is not particularly limited as long as the compound is set so as not to decompose, but is usually -10 ° C to 150 ° C or below the boiling point of the solvent.

The reaction pressure is not particularly limited and may be normal pressure or pressurization.

The hydrogen source used for the catalytic hydrogenation is not particularly limited as the reaction proceeds, but an internal hydrogen generation method using cyclohexene, formic acid, formate, and the like can be used in addition to hydrogen gas.

The cyclohexene, formic acid and formate equivalents used when the reaction is carried out by the internal hydrogen generation method are not particularly limited if the amount of hydrogen to be generated is set to 2 equivalents or more, but from 2 to 10 equivalents is preferable from an economic point of view. Do.

About the compound represented by General formula (7) obtained by the said reaction, the usage form in the next process is not specifically limited. The reaction solution containing the compound represented by the general formula (7) is used for the next step without performing isolation and purification after performing normal post-treatment operations such as solvent distillation and separation, or hydrochloric acid, sulfuric acid, phosphoric acid, or the like. It is possible to use an inorganic acid or an organic acid such as oxalic acid, fumaric acid, maleic acid, formic acid, acetic acid or methanesulfonic acid in the form of a salt in the next step.

The compound represented by General formula (7) also contains the salt formed with an inorganic acid or an organic acid. Examples of the inorganic acid include hydrochloric acid, sulfuric acid and phosphoric acid. Examples of the organic acid include oxalic acid, fumaric acid, maleic acid, formic acid, acetic acid and methanesulfonic acid.

It can be converted into the compound represented by General formula (9) by making the compound represented by General formula (7) obtained by the said process, and the compound represented by General formula (8) react.

R <_5> in the compound represented by General formula (8) is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, and substitution Or an unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group, and X represents a leaving group.

In R ₅ , a substituent in a substituted C1-C6 alkyl group, a substituted C3-C6 cycloalkyl group, a substituted aryl group, a substituted arylalkyl group, a substituted heteroaryl group, or a substituted heteroarylalkyl group is selected. Cycloalkyl groups such as alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl groups, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, and trifluoro Halogen-substituted alkyl groups such as methyl group, difluoromethyl group, bromodifluoromethyl group, trifluoroethyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, etc. Halogen such as cycloalkoxy groups such as alkoxy groups, cyclopropoxy groups, cyclobutoxy groups, cyclopentyloxy groups and cyclohexyloxy groups, trifluoromethoxy groups, difluoromethoxy groups and trifluoroethoxy groups Alkoxycarbonyl groups, cyclopropoxycarbonyl groups, cyclobutoxycarbonyl groups, such as substituted alkoxy groups, methoxycarbonyl groups, ethoxycarbonyl groups, propoxycarbonyl groups, isopropoxycarbonyl groups, butoxycarbonyl groups, isobutoxycarbonyl groups and sec-butoxycarbonyl groups Aryloxycarbonyl groups such as cycloalkoxycarbonyl groups such as pentyloxycarbonyl group and cyclohexyloxycarbonyl group and phenoxycarbonyl group, alkylthio groups such as methylthio group, ethylthio group, propylthio group and butylthio group, and trifluoromethylthio group Alkyl sulfinyl groups such as halogen-substituted alkylthio groups such as difluoromethylthio group and trifluoroethylthio group, methanesulfinyl group, ethanesulfinyl group, propanesulfinyl group and butanesulfinyl group, trifluoromethanesulfinyl group, Halogen-substituted alkylsulphies such as difluoromethanesulfinyl and trifluoroethanesulfinyl groups Halogen-substituted alkylsulfonyl groups, such as an alkylsulfonyl group, such as a silyl group, a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, butanesulfonyl group, a trifluoromethanesulfonyl group, a difluoromethanesulfonyl group, and a trifluoroethanesulfonyl group Arylcarbonyl groups such as alkylcarbonyl groups such as methylcarbonyl group, ethylcarbonyl, propylcarbonyl group and isopropylcarbonyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopropylcarbonyl group, cyclopentylcarbonyl group and cyclohexylcarbonyl group such as cycloalkylcarbonyl group and benzoyl group Alkylcarbonyloxy groups such as methylcarbonyloxy group, ethylcarbonyloxy group, propylcarbonyloxy group, isopropylcarbonyloxy group, cyclopropylcarbonyloxy group, cyclobutylcarbonyloxy group, cyclopentyl Cycloalkyl carbon such as carbonyloxy group and cyclohexylcarbonyloxy group Halogen atoms, such as an arylcarbonyloxy group, such as a silyloxy group and a benzoyloxy group, chlorine, fluorine, bromine, and iodine, are illustrated. The number of substituents on an aryl group or heteroaryl group is not limited. In addition, when two or more aryl groups or heteroaryl groups are substituted, they may be comprised by the same or two or more types of substituents, and are not limited.

The alkyl group having 1 to 6 carbon atoms in R ₅ in General Formula (8) is synonymous with that described in R ₁ in General Formula (1).

The cycloalkyl group having 3 to 6 carbon atoms in R ₅ in General Formula (8) is synonymous with that described in R ₁ in General Formula (1).

The aryl group in R ₅ in General Formula (8) is synonymous with that described in R ₂ in General Formula (1).

About an arylalkyl group in R <_5> in General formula (8), an aryl moiety is synonymous with the aryl group described by R <_2> in General formula (1), and an alkyl moiety shows a C1-C4 thing.

The heteroaryl group in R ₅ in the general formula (8) is a pyridyl group, a pyrimidyl group, a pyrazolyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, an indolyl group, a quinolyl group, a quinoxalyl group , Sulfur heterocycles such as nitrogen-containing heterocyclic groups such as benzimidazolyl groups, tetrahydrothienyl groups, thienyl groups, thiopyranyl groups, and benzothienyl groups, tetrahydrofuranyl groups, furanyl groups, pyranyl groups, dioxanyl groups, Oxygen-containing heterocyclic groups, such as a 2, 3- dihydro benzo [1, 4] dioxyyl group and a benzofuranyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, benzooxazolyl group, benzo Heterocyclic group containing 2 or more types of heteroatoms, such as an isoxazolyl group, a benzothiazolyl group, and benzoisothiazolyl, is mentioned.

About the heteroarylalkyl group in R <_5> in General formula (8), a heteroaryl group is synonymous with the heteroaryl group of R <_5> in General formula (8), and an alkyl site shows a C1-C4 thing.

In the compound represented by the general formula (8), X represents a leaving group.

Regarding the leaving group represented by X in the general formula (8), halogen atoms such as fluorine, chlorine, bromine and iodine, alkoxy groups such as methoxy group and ethoxy group, aryloxy groups such as phenoxy group and 4-nitrophenyl group, Aryl such as alkoxycarbonyloxy groups such as acyloxy groups such as acetyloxy group and benzoyloxy group, methoxycarbonyloxy group, ethoxycarbonyloxy group and isobutyloxycarbonyloxy group, and phenylcarbonyloxy group Alkylthio groups, such as a carbonyloxy group and a methylthio group, a 2, 5- dioxopyrrolidinyloxy group, a benzotriazolyloxy group, an imidazolyl group, etc. can be illustrated.

In the compound represented by the general formula (9), R ₁ , R ₂ , R ₃ , and R ₄ are synonymous with those described in the general formula (1), and R ₅ is synonymous with those described in the general formula (8). .

The amount of the compound represented by the general formula (8) is not particularly limited as long as it is equal to or more than the compound represented by the general formula (7), but from one to three equivalents is preferable from an economical standpoint.

When an acid is generated when the compound represented by the general formula (7) forms a salt with an acid, or when the compound represented by the general formula (7) reacts with the compound represented by the general formula (8), Can be used.

Examples of the base to be used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, pyridine, collidine, picoline, 4-dimethylaminopyridine, lutidine, triethylamine, Diisopropylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5, 4, 0] -undec-7-ene, 1,4-diazabicyclo [2, 2, 0 ] Organic bases, such as an octane and imidazole, are illustrated. It can be used independently and can also mix two or more types by arbitrary ratios.

When the compound represented by the general formula (7) forms a salt with an acid, the base may be used in an amount of 1 equivalent or more with respect to the acid, and when an acid is generated during the reaction, 1 equivalent or more may be used. As for the upper limit, 10 equivalent or less is preferable from an economic viewpoint.

The solvent used when reacting the compound represented by the general formula (7) with the compound represented by the general formula (8) is not particularly limited as long as the compound represented by the general formula (9) is produced. Specific examples of the solvent include halogen solvents such as dichloromethane and chloroform, aromatic solvents such as benzene, toluene and xylene, hydrocarbon solvents such as hexane and heptane, dimethylformamide, dimethylacetamide and 1-methyl-2-pi. Urea-based solvents such as amide solvents such as rolidone, 1,3-dimethyl-2-imidazolidinone, and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -piperidinone Solvents, ester solvents such as ethyl acetate, butyl acetate and isopropyl acetate, ether solvents such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, acetonitrile and pro Nitrile solvents such as pionitrile, alcohol solvents such as isopropanol and t-butyl alcohol, and water. It can also be used independently and can also mix two or more types by arbitrary ratios.

Although the usage-amount of a solvent is not specifically limited, Usually, it is 3 times or more and 40 times or less with respect to the compound represented by General formula (7).

The reaction temperature at the time of reacting the compound represented by the general formula (7) and the compound represented by the general formula (8) is not particularly limited as long as the compound is not decomposed, but is usually -10 ° C or higher. It is below the temperature or below the boiling point of the solvent.

As mentioned above, it became possible to efficiently manufacture the compound represented by General formula (9), ie, the ethylenediamine derivative which has a fluorine carbamite group and an acyl group.

[ Example ]

Although an Example demonstrates this invention further in detail below, this invention is not limited to these.

Purity analysis of the compounds was carried out by HPLC. Separation column: L-Columun ODS

φ4.6mm × 250mm (chemical evaluation research apparatus)

In the separation analysis of the optical isomer, a separation column: CHlRALPAK IA (250 mm x 4.6 mm I. D.) die cell chemical industry was used.

Example 1 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-alanine

(41)

Into a 1000 ml four-necked flask equipped with a stirring device, 50.8 g of L-alanine and 100 g of water were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining pH 12 ± 0.5 and 10 ° C. or less, a mixed solution of chloroformic acid 2,2,2-trifluoroethyl 93.59 and 200 g of toluene was dropwise loaded and stirred for 1 hour while maintaining the pH at pH 12 ± 0.5. . Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. The white solid compound obtained by concentrating an organic layer under reduced pressure was the title compound.

Quantity 24.5 g (20% of yield)

Example 2 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-alaninochloride

(42)

In a 100 ml four-necked flask equipped with a stirring device, 10 g of methylene chloride, 1.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-alanine, and N, N-dimethylformamide (hereinafter referred to as DMF) One drop was charged, cooled to 5 ° C, and 0.90 g of oxalyl chloride was added dropwise, followed by further stirring for 2 hours while maintaining 5 ° C. 10 g of methylene chloride was added to the oily residue obtained by concentration under reduced pressure, and after stirring for 10 minutes, an oily substance was obtained. The compound of the obtained oily substance was the title compound.

Weeping 1.08g (yield 99.5%)

Example 3 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-alanineamide

(43)

Into a 500 ml four-necked flask equipped with a stirring device, charged with 100 g of toluene, 19.3 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-alanine, and 0.4 g of DMF, and the temperature was raised to 55 ° C. After 30 g of phosgene was blown off, the mixture was further stirred for 2 hours while maintaining 55 ° C. Blowing N _2, and then extract the excess phosgene, concentrated under reduced pressure to give the oily residue was 34g. Into a 1000 ml four-necked flask equipped with a stirring device, 200 g of a 10 wt% NH ₃ aqueous solution was charged, cooled to 5 ° C., and the residue was added dropwise while maintaining 15 ° C. or less. After completion | finish of dripping, after stirring at 10 degreeC for 3 hours, the precipitate was filtered and dried under reduced pressure. The obtained white solid compound was the title compound.

Quantity 17.5 g (91% of yields)

Example 4 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-alaninonitrile

(44)

31.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-alanineamide and 35 ml of DMF were added to 350 ml of toluene, and stirred at room temperature, and 35 ml of toluene containing 22.01 g of oxalyl chloride was carefully added. Dropped. After stirring for 2 hours at the same temperature, 350 ml of water was added to the solution. Furthermore, after wash | cleaning the separated organic layer with 350 ml of water, the solvent was distilled off under reduced pressure. Subsequently, purification was performed by column chromatography. The obtained white solid was the title compound.

Quantity 25.83 g (91% of yield)

Example 5 Synthesis of (2S) -N2- (2,2,2-trifluoroethoxycarbonyl) -propane-1,2-diamine hydrochloride

[Chemical Formula 45]

To 40 ml of isopropyl alcohol (hereinafter referred to as IPA), 6.0 g of acetic acid, 0.5 g of 5% palladium carbon (water 49.5%, manufactured by N.E.Chem), and 3.2 g of ammonium formate were sequentially added and stirred sufficiently. 8 ml of IPA containing 2.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-alaninonitrile was added dropwise thereto at room temperature, followed by stirring at the same temperature for 2.5 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the residue. Subsequently, potassium carbonate was added and liquid-separated until the pH of an aqueous layer became about 10. Sodium sulfate was added to the separated organic layer, dried and filtered, and then 4N hydrogen chloride-ethyl acetate solution was added. When concentrated under reduced pressure, a white solid precipitated, which was filtered off to obtain the title compound.

White solid yield 2.05 g (85% yield)

Example 6 Synthesis of (2S) -N1-Toluoyl-N2- (2,2,2-trifluoroethoxycarbonyl) -propane-1,2-diamine

(46)

To 7 ml of water containing 0.45 g of sodium bicarbonate, 5 ml of ethyl acetate and (2S) -N1-toluoyl-N2- (2,2,2-trifluoroethoxycarbonyl) -propane-1,2-diamine 0.5 g was added and stirred, and 0.33 g of toluic acid chloride was dripped here. After stirring at room temperature for 2.5 hours, liquid separation was performed. Sodium sulfate was added to the organic layer, dried and filtered, and the solution was concentrated under reduced pressure. In addition, 8 ml of isopropyl ether (hereinafter referred to as IPE) was added thereto, and the precipitate was washed sufficiently before being filtered off. The white solid obtained was the title compound.

0.56 g (84%) yield of white solid

Example 7 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-isoleucine

[Formula 47]

Into a 500 ml four-necked flask equipped with a stirring device, 24.5 g of L-isoleucine and 50 g of water were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining pH 12 ± 0.5 and 10 ° C. or less, a mixed solution of 31.2 g of chloroformic acid 2,2,2-trifluoroethyl and 100 g of toluene was loaded dropwise, and stirred for 1 hour while maintaining the pH at pH 12 ± 0.5. did. Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. The compound of the white individual obtained by concentrating an organic layer under reduced pressure was the title compound.

Quantity 46 g (96% of yield)

(Example 8) Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-isoleucinochloride

(48)

Into a 200 ml four-necked flask equipped with a stirring device, 10 g of methylene chloride, 1.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-isoleucine, and 1 drop of DMF were charged and cooled to 5 ° C. After 0.74 g of oxalyl chloride was added dropwise, the mixture was further stirred for 2 hours while maintaining 5 ° C. After concentration under reduced pressure, 20 g of n-hexane was charged into the obtained residue and cooled to 5 캜. After stirring for 3 hours, the precipitate was filtered under a nitrogen stream, washed with n-hexane, and dried under reduced pressure at room temperature. The obtained white solid compound was the title compound.

Quantity 1.0 g (93% of yields)

Example 9 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-isoleucinamide

(49)

Into a 500 ml four-necked flask equipped with a stirring device, 24.5 g of L-isoleucine, 50 g of water, and 75 g of toluene were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining pH 12 ± 0.5 and 10 ° C. or less, a mixed solution of 31.2 g of 2,2,2-trifluoroethyl and 6 g of toluene was added dropwise thereto, and stirred for 1 hour while maintaining the pH at 12 ± 0.5. did. Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. After the azeotropic dehydration of the organic layer, the solution was transferred to a 500 ml four-necked flask equipped with a stirring device, 0.6 g of DMF was charged and cooled to 50 ° C., 25 g of phosgene was blown, followed by further stirring for 2 hours while maintaining 55 ° C. By blowing N _2, and then extract the excess phosgene, concentrated under reduced pressure to give the oily residue was 52g. 310 g of 10 wt% NH ₃ aqueous solution was charged into a 1000 ml four-necked flask equipped with a stirring device, cooled to 5 ° C., and the residue was added dropwise while maintaining 15 ° C. or less. After completion | finish of dripping, after stirring at 10 degreeC for 3 hours, the precipitate was filtered and dried under reduced pressure. The obtained white solid compound was the title compound.

Quantity 41.2 g (86% of yield)

Example 10 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-isorocinonitrile

(50)

To 50 ml of toluene, 5.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-isorocinamide and 5 ml of DMF were added, stirred at room temperature, and 5 ml of toluene containing 3.05 g of oxalyl chloride was added. I dripped deep. After stirring for 2 hours at the same temperature, 50 ml of water was added to the solution. Further, the separated organic layer was washed with 50 ml of water, and then the solvent was distilled off under reduced pressure. Subsequently, purification was performed by column chromatography. The obtained white solid was the title compound.

Colorless oily matter quantity 4.53 g (97% yield)

Example 11 Synthesis of (2S, 3S) -3-methyl-N2- (2,2,2-trifluoroethoxycarbonyl) -pentane-1,2-diamine hydrochloride

(51)

To 40 ml of IPA were added 6.8 g of acetic acid, 0.5 g of 5% palladium carbon (water content 49.5%, manufactured by N. E. Chem.) And 3.2 g of ammonium formate in this order, followed by thorough stirring. 10 ml of IPA containing 2.5 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-isoroycinonitrile was added dropwise at room temperature, followed by stirring at the same temperature for 2.5 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the residue. Subsequently, potassium carbonate was added and liquid-separated until the pH of an aqueous layer became about 10. Sodium sulfate was added to the separated organic layer, dried and filtered, and then 4N hydrogen chloride-ethyl acetate solution was added. Concentration under reduced pressure gave a white solid which was collected by filtration to obtain the title compound.

Pale peach solid 2.56 g (92% yield)

Example 12 Synthesis of (2S, 3S) -3-Methyl-N1-Toluoyl-N2- (2,2,2-trifluoroethoxycarbonyl) -pentane-1,2-diamine

(52)

To 7 ml of water containing 0.45 g of sodium bicarbonate, 5 ml of ethyl acetate and (2S, 3S) -3-methyl-N2- (2,2,2-trifluoroethoxycarbonyl) pentane-1,2-diamine 0.5 g of hydrochloride was added and stirred, and 0.33 g of toluic acid chloride was added dropwise thereto. After stirring at room temperature for 2.5 hours, liquid separation was performed. Sodium sulfate was added to the organic layer, dried and filtered, and the solution was concentrated under reduced pressure. Further, IPE8mI was added, and the precipitates were sufficiently washed and then filtered off.

The white solid obtained was the title compound.

0.56 g (87% yield) of white solid

Example 13 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-leucine

(53)

Into a 500 ml four-necked flask equipped with a stirring device, 25.2 g of L-leucine and 50 g of water were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining the pH 12 ± 0.5 and 10 ° C. or less, a mixed solution of 31.5 g of chloroformic acid 2,2,2-trifluoroethyl and 100 g of toluene was loaded dropwise, followed by stirring for 1 hour while maintaining the pH at pH 12 ± 0.5. . Hydrochloric acid was added dropwise to adjust the pH to 1.5fh, followed by raising the temperature to 60 ° C for liquid separation. The compound of the white solid obtained by concentrating an organic layer under reduced pressure was the title compound.

47.4 g (96% yield)

Example 14 Synthesis of Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-Royinochloride

[Formula 54]

Into a 100 ml four-necked flask equipped with a stirring device, 10 g of methylene chloride, 1.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-isoleucine, and 1 drop of DMF were charged and cooled to 5 ° C. After 0.74 g of oxalyl chloride was added dropwise, the mixture was further stirred for 2 hours while maintaining 5 ° C. 10 g of methylene chloride was added to the oily residue obtained by concentration under reduced pressure, and the mixture was concentrated under reduced pressure after stirring for 10 minutes, whereby an oily substance was obtained. The compound of the obtained oily substance was the title compound.

Quantity 1.07 g (100% of yield)

Example 15 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-leucineamide

(55)

Into a 500 ml four-necked flask equipped with a stirring device, 24.5 g of L-leucine, 50 g of water, and 75 g of toluene were charged, cooled to 5 ° C., and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining a pH of 12 ± 0.5 and 10 ° C. or less, a mixed solution of 31.3 g of chloroformic acid 2,2,2-trifluoroethyl and 6 g of toluene was loaded dropwise, and stirred for 1 hour while maintaining the pH at pH 12 ± 0.5. did. Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. After the azeotropic dehydration of the organic layer, the solution was transferred to a 500 ml four-necked flask equipped with a stirring device, 0.7 g of DMF was charged and cooled to 40 ° C, 30 g of phosgene was blown, followed by further stirring for 2 hours while maintaining 40 ° C. Blowing N _2, and then extract the excess phosgene, concentrated under reduced pressure to give the oily residue was 54g. 310 g of 10 wt% NH ₃ aqueous solution was charged into a 1000 ml four-necked flask equipped with a stirring device, cooled to 5 ° C., and the residue was added dropwise while maintaining 15 ° C. or less. After completion | finish of dripping, after stirring at 10 degreeC for 3 hours, the precipitate was filtered and dried under reduced pressure. The obtained white solid compound was the title compound.

Quantity 41.2 g (86% of yield)

(Example 16) Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-leucinonitrile

(56)

To 50 ml of toluene, 5.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-leucineamide and 5 ml of DMF were added, stirred at room temperature, and carefully 5 ml of toluene containing 3.05 g of oxalyl chloride was carefully added. Dropped. After stirring for 2 hours at the same temperature, 50 ml of water was added to the solution. Furthermore, after wash | cleaning the separated organic layer with 50 ml of water, the solvent was distilled off under reduced pressure. Subsequently, purification was performed by column chromatography. The obtained white solid was the title compound.

Quantity of yellow oily substance 4.41 g (95% yield)

Example 17 Synthesis of (2S) -4-methyl-N2- (2,2,2-trifluoroethoxycarbonyl) -pentane-1,2-diamine hydrochloride

(57)

6.0 g of acetic acid, 0.5 g of 5% palladium carbon (water 49.5%, manufactured by N.E.Chem), and 3.2 g of ammonium formate were added to 40 ml of IPA in order, and the mixture was sufficiently stirred. 10 ml of IPA containing 2.5 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-isoroycinonitrile was added dropwise at room temperature, followed by stirring at the same temperature for 2.5 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the residue. Subsequently, potassium carbonate was added and liquid-separated until the pH of an aqueous layer became about 10. Sodium sulfate was added to the separated organic layer, dried and filtered, and then 4N hydrogen chloride-ethyl acetate solution was added. Concentration under reduced pressure gave a white solid which was collected by filtration to obtain the title compound.

Light peach solid 2.32g (79% yield)

Example 18 Synthesis of (2S) -4-methyl-N1-toluoyl-N2- (2,2,2-trifluoroethoxycarbonyl) -pentane-1,2-diamine

(58)

To 7 ml of water containing 0.45 g of sodium hydrogen carbonate, 5 ml of ethyl acetate and (2S) -4-methyl-N2- (2,2,2-trifluoroethoxycarbonyl) -pentane-1,2-diamine hydrochloride 0.5 g was added and stirred, and 0.33 g of toluic acid chloride was dripped here. After stirring for 2.5 hours at room temperature, the solution was separated. Sodium sulfate was added to the organic layer, dried and filtered, and the solution was concentrated under reduced pressure. 8 ml of IPE was further added, and the precipitate was washed sufficiently before being filtered off. The white solid obtained was the title compound.

0.56 g (87% yield) of white solid

Example 19 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-phenylalanine

[Chemical Formula 59]

Into a 500 ml four-necked flask equipped with a stirring device, 25.6 g of L-phenylalanine and 40 g of water were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining pH 12 ± 0.5 and 10 ° C. or less, a mixed solution of 25.4 g of chloroformic acid 2,2,2-trifluoroethyl and 200 g of toluene was loaded dropwise, and stirred for 1 hour while maintaining the pH at pH 12 ± 0.5. did. Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. The compound of the white solid obtained by concentrating an organic layer under reduced pressure was the title compound.

Quantity 43.3 g (96% of yield)

Example 20 Synthesis of Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-phenylalaninechloride

(60)

Into a 200 ml four-necked flask equipped with a stirring device, 10 g of methylene chloride, 1.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-phenylalanine and 1 drop of DMF were charged and cooled to 5 ° C. After 0.70 g of oxalyl chloride was added dropwise, the mixture was further stirred for 2 hours while maintaining 5 ° C. Concentrated under reduced pressure, 100 g of n-hexane was charged to the obtained residue, and it cooled to 5 degreeC. After stirring for 3 hours, the precipitate was filtered under a nitrogen stream, washed with n-hexane, and dried under reduced pressure at room temperature. The obtained white solid compound was the title compound.

Quantity 1.0 g (94% of yields)

Example 21 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-phenylalanineamide

(61)

Into a 500 ml four-necked flask equipped with a stirring device, 16.5 g of L-phenylalanine, 35 g of water, and 75 g of toluene were charged, cooled to 5 ° C., and the pH was adjusted to 12 with 32 wt% NaOH. A mixed solution of 17 g of chloroformic acid 2,2,2-trifluoroethyl and 6 g of toluene was added dropwise while maintaining pH 12 ± 0.5 and 10 ° C., and stirred for 1 hour while maintaining the pH at pH 12 ± 0.5. . Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. After the azeotropic dehydration of the organic layer, the solution was transferred to a 500 ml four-necked flask equipped with a stirring device, charged with 0.4 g of DMF, cooled to 40 ° C, 30 g of phosgene was blown, and further stirred for 2 hours while maintaining 40 ° C. Blowing N _2, and then extract the excess phosgene, concentrated under reduced pressure to give the oily residue of 34g. Into a 1000 ml four-necked flask equipped with a stirring device, 200 g of a 10 wt% NH ₃ aqueous solution was charged, cooled to 5 ° C., and the residue was added dropwise while maintaining 15 ° C. or less. After completion | finish of dripping, after stirring at 10 degreeC for 3 hours, the precipitate was filtered and dried under reduced pressure. The obtained white solid compound was the title compound.

Quantity 24.9 g (86% of yield)

Example 22 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-phenylalaninonitrile

[Formula 62]

To 50 ml of toluene, 5.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-phenylalanineamide and 5 ml of DMF were added, stirred at room temperature, and 5 ml of toluene containing 3.05 g of oxalyl chloride was carefully added dropwise. did. After stirring for 2 hours at the same temperature, 50 ml of water was added to the solution. Further, the separated organic layer was washed with 50 ml of water, and then the solvent was distilled off under reduced pressure. Subsequently, purification was performed by column chromatography. The obtained white solid was the title compound.

3.97 g (85% yield) of white solid

Example 23 Synthesis of (2S) -N2- (2,2,2-trifluoroethoxycarbonyl) -3-phenyl-propane-1,2-diamine hydrochloride

(63)

6.0 g of acetic acid, 0.5 g of 5% palladium carbon (water 49.5%, manufactured by N.E.Chem), and 3.2 g of ammonium formate were added to 40 ml of IPA in order, and the mixture was sufficiently stirred. 10 ml of IPA containing 2.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-phenylalaninonitrile was added dropwise at room temperature, followed by stirring at the same temperature for 2.5 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the residue.

Subsequently, potassium carbonate was added and liquid-separated until the pH of an aqueous layer became about 10. Sodium sulfate was added to the separated organic layer, dried and filtered, and then 4N hydrogen chloride-ethyl acetate solution was added. Concentration under reduced pressure gave a white solid which was collected by filtration to obtain the title compound.

White solid yield 2.04 g (88% yield)

Example 24 Synthesis of (2S) -N1-Toluoyl-N2- (2,2,2-trifluoroethoxycarbonyl) -3-phenylpropane-1,2-diamine

&Lt; EMI ID =

To 7 ml of water containing 0.45 g of sodium bicarbonate, 5 ml of ethyl acetate and (2S) -N2- (2,2,2-trifluoroethoxycarbonyl) -3-phenyl-propane-1,2-diamine hydrochloride 0.3 g was added and stirred, and 0.18 g of toluic acid chloride was dripped here. After stirring at room temperature for 2.5 hours, liquid separation was performed. Sodium sulfate was added to the organic layer, dried and filtered, and the solution was concentrated under reduced pressure. In addition, 8 ml of IPE was added, and the precipitate was washed sufficiently before being filtered off. The white solid obtained was the title compound.

0.35 g (93% yield) of white solid

Example 25 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-proline

(65)

Into a 500 ml four-necked flask equipped with a stirring device, 25.4 g of L-proline and 50 g of water were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining pH 12 ± 0.5 and 10 ° C. or less, a mixed solution of 36.2 g of chloroformic acid 2,2,2-trifluoroethyl and 100 g of toluene was loaded dropwise, and stirred for 1 hour while maintaining the pH at pH 12 ± 0.5. did. Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. The compound of the oily substance obtained by concentrating an organic layer under reduced pressure was the title compound.

Quantity 51.1 g (96% of yield)

Example 26 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-prolinochloride

[Formula 66]

Into a 200 ml four-necked flask equipped with a stirring device, 10 g of methylene chloride, 1.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-proline and 1 drop of DMF were charged and cooled to 5 ° C. After 0.70 g of oxalyl chloride was added dropwise, the mixture was further stirred for 2 hours while maintaining 5 ° C. 10 g of methylene chloride was added to the oily residue obtained by concentration under reduced pressure, and the mixture was concentrated under reduced pressure after stirring for 10 minutes, whereby an oily substance was obtained. The compound of the obtained oily substance was the title compound.

Quantity 1.07 g (99% of yield)

Example 27 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-prolineamide

(67)

Into a 500 ml four-necked flask equipped with a stirring device, 11.5 g of L-proline, 30 g of water, and 60 g of toluene were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. A mixed solution of 17 g of chloroformic acid 2,2,2-trifluoroethyl and 6 g of toluene was added dropwise while maintaining pH 12 ± 0.5 and 10 ° C., and stirred for 1 hour while maintaining the pH at pH 12 ± 0.5. . Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. After the azeotropic dehydration of the organic layer, the solution was transferred to a 500 ml four-necked flask equipped with a stirring device, charged with 0.4 g of DMF, cooled to 40 ° C, 30 g of phosgene was blown, and further stirred for 2 hours while maintaining 40 ° C. Blowing N _2, and then extract the excess phosgene, concentrated under reduced pressure to give the oily residue was 29g. Into a 1000 ml four-necked flask equipped with a stirring device, 200 g of a 10 wt% NH ₃ aqueous solution was charged, cooled to 5 ° C., and the residue was added dropwise while maintaining 15 ° C. or less. After completion | finish of dripping, after stirring at 10 degreeC for 3 hours, the precipitate was filtered and dried under reduced pressure. The obtained white solid compound was the title compound.

Quantity 20.6 g (86% of yield)

Example 28 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-prolinonitrile

(68)

5.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-prolineamide and 5 ml of DMF were added to 50 ml of toluene, stirred at room temperature, and 5 ml of toluene containing 3.05 g of oxalyl chloride was carefully added dropwise. did. After stirring for 2 hours at the same temperature, 50 ml of water was added to the solution. Furthermore, after wash | cleaning the separated organic layer with 50 ml of water, the solvent was distilled off under reduced pressure. Subsequently, purification was performed by column chromatography. The obtained white solid was the title compound.

Yellow transparent oily substance quantity 4.13 g (89% yield)

Example 29 Synthesis of (2S) -N- (2,2,2-trifluoroethoxycarbonyl) -2- (amino methyl) -pyrrolidine hydrochloride

[Formula 69]

6.0 g of acetic acid, 0.5 g of 5% palladium carbon (water 49.5%, manufactured by N.E.Chem), and 3.2 g of ammonium formate were added to 40 ml of IPA in order, and the mixture was sufficiently stirred. 10 ml of IPA containing 2.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-prolinonitrile was added dropwise at room temperature, followed by stirring at the same temperature for 2.5 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the residue. Subsequently, potassium carbonate was added and liquid-separated until the pH of an aqueous layer became about 10. Sodium sulfate was added to the separated organic layer, dried and filtered, and then 4N hydrogen chloride-ethyl acetate solution was added. Concentration under reduced pressure gave a white solid which was collected by filtration to obtain the title compound.

White solid yield 1.67 g (71% yield)

Example 30 Synthesis of (2S) -N- (2,2,2-trifluoroethoxycarbonyl) -2- (N-toluoyl-aminomethyl) -pyrrolidine

(70)

To 7 ml of water containing 0.45 g of sodium bicarbonate, 5 ml of ethyl acetate and ((2S) -N- (2,2,2-trifluoroethoxycarbonyl) -2- (aminomethyl) -pyrrolidine hydrochloride 0.5 g was added and stirred, and 0.33 g of toluic acid chloride was added dropwise thereto, after stirring at room temperature for 2.5 hours, the solution was separated, sodium sulfate was added to the organic layer, dried and filtered, and the solution was concentrated under reduced pressure. The precipitate was added, and the precipitate was washed thoroughly before being filtered off. The white solid obtained was the title compound.

White solid 0.50g (80% yield)

Example 31 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-valine

(71)

Into a 1000 ml four-necked flask equipped with a stirring device, 100 g of L-valine and 150 g of water were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining pH 12 ± 0.5 and 10 degrees C or less, the mixed solution of 140 g of chloroformic acid 2,2,2- trifluoroethyl and 400 g of toluene was dripped, and also it stirred for 1 hour, maintaining pH at 12 ± 0.5. . Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. The compound of the white solid obtained by concentrating an organic layer under reduced pressure was the title compound.

Quantity 203.4g (98% of yield)

LC-MS M + 1 (244)

Example 32 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-valerylchloride

(72)

In a 200 ml four-necked flask equipped with a stirring device, 20.4 g of toluene, 13.6 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-valine, N, N-dimethylformamide (hereinafter DMF) 0.17g was charged, it heated up at 40 degreeC, 9.4g of phosgene was blown, and it stirred for 2 hours, maintaining 40 degreeC. Blowing N _2, and then extract the excess phosgene, it was concentrated under reduced pressure, and the oily residue was purified to give 16g. 50 g of n-hexane was charged into a 300 ml four-necked flask equipped with a stirring device, and the oily residue was slowly added thereto and then cooled to 5 ° C. After stirring for 3 hours, the precipitate was filtered under a nitrogen stream, washed with n-hexane, and dried under reduced pressure at room temperature. The obtained white solid compound was the title compound.

Quantity 13.6 g (93% of yields)

Example 33 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-valineamide

(73)

In a 1000 ml four-necked flask equipped with a stirring device, 407 g of toluene, 196 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-valine, 5.9 g of N, N-dimethylformamide (hereinafter DMF) Was charged, the temperature was raised to 55 ° C, 95.8g of phosgene was blown, and the mixture was further stirred for 2 hours while maintaining 55 ° C. Blowing N _2, and then extract the excess phosgene, and concentration under reduced pressure, to obtain 223g of the oily residue. 1390 g of 10 wt% NH ₃ aqueous solution was charged into a 2000 ml four-necked flask equipped with a stirring device, cooled to 5 ° C, and the residue was added dropwise while maintaining 15 ° C or less. After completion | finish of dripping, after stirring at 10 degreeC for 3 hours, the precipitate was filtered and dried under reduced pressure. The obtained white individual compound was the title compound. HPLC analysis using a chiral column revealed no Form D (0.02% of detection limit).

Quantity 177.8 g (91% of yields)

Example 34 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-valineamide

&Lt; EMI ID =

Into a 200 ml four-necked flask equipped with a stirring device, 18 g of L-valine, 22 g of water and 52 g of toluene were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining pH 12 ± 0.5 and 10 ° C. or less, a mixed solution of 25.7 g of chloroformic acid 2,2,2-trifluoroethyl and 6.4 g of toluene was loaded dropwise, and the pH was maintained at pH 12 ± 0.5 for 1 hour. Stirred. Hydrochloric acid was added dropwise thereto, the pH was adjusted to 1.5, and the temperature was increased to 60 ° C for separation. After the azeotropic dehydration of the organic layer, the solution was transferred to a 200 ml four-necked flask equipped with a stirring device, charged with 0.5 g of DMF, cooled to 40 ° C, 23.5 g of phosgene was blown, and further stirred for 2 hours while maintaining 40 ° C. . N ₂ was blown in and excess phosgene was extracted. Into a 200 ml four-necked flask equipped with a stirring device, 67.6 g of DMF was charged and cooled to 5 ° C, and the reaction solution was loaded dropwise. 6.3 g of NH ₃ gas was blown in while maintaining 15 degrees C or less, and also it stirred for 1 hour, maintaining 15 degrees C or less.

After excess NH ₃ was removed under reduced pressure, water and acetonitrile were added to make a homogeneous solution, and analyzed by HPLC, yielding 36.1 g (yield 97%) of the title compound.

Example 35 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-valinonitrile

(75)

35.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-valinamide and 35 ml of DMF were added to 350 ml of toluene, stirred at room temperature, and 35 ml of toluene containing 22.01 g of oxalyl chloride was carefully added dropwise. did. After stirring for 2 hours at the same temperature, 350 ml of water was added to the solution. Furthermore, after wash | cleaning the separated organic layer with 350 ml of water, the solvent was distilled off under reduced pressure. Subsequently, by distilling, the fraction of 116-122 degreeC in 0.3 mmHg was fractionated. The colorless transparent oily material obtained was the title compound.

Quantity 29.89 g (92% of yield)

Example 36 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-valinonitrile by a method of previously adjusting the Vilsmeier reagent

To 5 ml of toluene containing 1 ml of DMF, a 5 ml solution of toluene containing 433 µl of oxalyl chloride was added dropwise at room temperature. After stirring for 30 minutes, 1.0 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-valineamide was charged and reacted for 3 hours. The organic layer was washed with water and purified by silica gel chromatography to obtain N- (2,2,2-trifluoroethoxycarbonyl) -L-valinonitrile.

0.92 g of water (yield> 99%)

(Example 37) Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -L-valinonitrile by adjusting the Vilsmeier reagent in advance using phosgene

6.7 g of phosgene was blown into 50 ml of toluene containing 5.9 ml of DMF at 5 캜. After stirring for 30 minutes, 7.4 g of N- (2,2,2-trifluoroethoxycarbonyl) -L-valineamide was charged and reacted for 3 hours. The organic layer was washed with water and purified by silica gel chromatography to obtain N- (2,2,2-trifluoroethoxycarbonyl) -L-valinonitrile.

Quantity 6.80 g (yield> 99%)

Example 38 Synthesis of (2S) -3-methyl-N2- (2,2,2-trifluoroethoxycarbonyl) -butane-1,2-diamine hydrochloride

[Formula 76]

26.8 g of acetic acid, 2.0 g of 5% palladium carbon (water 49.5%, manufactured by NEChem), and 14.1 g of ammonium formate were added to 180 ml of IPA in order, and the mixture was sufficiently stirred. 10 ml of IPA containing 10.0 g of oxycarbonyl) -L-valinonitrile was added dropwise at room temperature, followed by stirring at the same temperature for 2.5 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the residue. Subsequently, potassium carbonate was added and liquid-separated until the pH of an aqueous layer became about 10. Sodium sulfate was added to the separated organic layer, dried and filtered, and then 4N hydrogen chloride-ethyl acetate solution was added. Concentration under reduced pressure gave a white solid which was collected by filtration to obtain the title compound.

White solid quantity 10.5 g (89% yield)

(Example 39) By the method of feeding a raw material using an autoclave (2

S) -3-Methyl-N2- (2,2,2-trifluoroethoxycarbonyl) -butane-1,2-diamine hydrochloride

In an autoclave, 50 ml of IPA containing 47.8 g of acetic acid and 4.0 g of 5% palladium carbon (water 49.5%, manufactured by NEChem) was converted to 0.95 MPa with hydrogen gas, followed by N- (2,2,2-trifluoro 111 ml of IPA containing 19.8 g of ethoxycarbonyl) -L-valinonitrile was fed at 20 ° C. over 6 hours.

After completion | finish of feed, after stirring for 30 minutes, catalyst was removed and it concentrated under reduced pressure. At this point, the reaction yield was 99% when the free compound of the title compound was quantified by high performance liquid chromatography. Water and acetic acid were added to the residue, and then the aqueous layer was separated into pH 10.7 with an aqueous 8% by weight aqueous sodium hydroxide solution. The organic layer was dried over sodium sulfate, filtered, and 20 ml of 4N hydrogen chloride-ethyl acetate solution was added. Concentration under reduced pressure gave a white solid which was collected by filtration to obtain the title compound.

Quantity 22.29 (95%)

Example 40 Synthesis of (2S) -3-Methyl-N1-toluoyl-N2- (2,2,2-trifluoroethoxycarbonyl) -butane-1,2-diamine (Part 1)

[Formula 77]

To 25 ml of water containing 1.91 g of sodium bicarbonate, 20 ml of ethyl acetate and (2S) -3-methyl-N2- (2,2,2-trifluoroethoxycarbonyl) -butane-1,2-diamine hydrochloride 2.0 g was added and stirred, and 1.40 g of toluylate was dripped here. After stirring at room temperature for 2.5 hours, liquid separation was performed. Sodium sulfate was added to the organic layer, dried and filtered, and the filtrate was concentrated under reduced pressure. In addition, 30 ml of IPE was added, and the precipitate was washed sufficiently before being filtered off. The white solid obtained was the title compound.

Quantity 2.33 g (89% of yield)

Example 41 Synthesis of (2S) -3-methyl-N1-toluoyl-N2- (2,2,2-trifluoroethoxycarbonyl) -butane-1,2-diamine (Part 2)

After adding 2.0 g of (2S) -3-methyl-N 2-(2,2,2-trifluoroethoxycarbonyl) -butane-1,2-thiamine hydrochloride to a mixed solution of 20 ml of ethyl acetate and 30 ml of water, The pH was adjusted to 8 with 8 wt% sodium hydroxide solution. Subsequently, the ethyl acetate solution and 1.4 wt% sodium hydroxide solution containing 1.4 g of toluylate were dripped maintaining pH7.5-8.5. After the reaction was completed, liquid separation was performed, and the organic layer was dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure, IPE was then added, and the precipitate was collected by filtration.

The white solid obtained was the title compound.

Quantity 2.19 g (84% of yields)

Example 42 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -D-valine

(78)

Into a 1000 ml four-necked flask equipped with a stirring device, 50.7 g of D-valine and 76 g of water were charged, cooled to 5 ° C, and the pH was adjusted to 12 with 32 wt% NaOH. While maintaining a pH of 12 ± 0.5 and 10 ° C. or less, a mixed solution of 72.5 g of 2,2,2-trifluoroethyl and 222 g of chloroformic acid was added dropwise, followed by stirring for 1 hour while maintaining the pH at 12 ± 0.5. did. Hydrochloric acid was added dropwise, the pH was adjusted to 1.5, and the temperature was raised to 60 ° C for separation. The compound of the white solid obtained by concentrating an organic layer under reduced pressure was the title compound.

Quantity 102.4g (yield 97.3%)

Example 43 Synthesis of N- (2,2,2-trifluoroethoxycarbonyl) -D-valine amide

(79)

Into a 500 ml four-necked flask equipped with a stirring device, charged with 181 g of toluene, 86.6 g of N- (2,2,2-trifluoroethoxycarbonyl) -D-valine, and 1.3 g of DMF, the temperature was raised to 50 ° C. After blowing 58.5g of phosgene, it stirred for 2 hours, keeping 50 degreeC. N ₂ was blown in and excess phosgene was extracted. 161 g of DMF was charged into a 2000 ml four-necked flask equipped with a stirring device, cooled to 5 ° C, and the reaction solution was loaded dropwise. While maintaining less than 15 ℃, the NH ₃ gas blown 15.2g, and further while maintaining less than 15 ℃ stirred for one hour. After excess NH ₃ was removed under reduced pressure, water and acetonitrile were added to form a homogeneous solution, and analyzed by HPLC, to obtain the title compound as 78.5 g (yield 91%). As a result of HPLC analysis using a chiral column, L body was not detected (detection limit 0.02%).

Claims (14)

In general formula (1)
[Formula 1]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl It may represent an alkyl group and may form the ring structure which R <_3> and R <_4> couple | bonded with 2-5 carbon atoms, or the ring structure which R <_2> and R <_{2> couple |} bonded with 3-4 carbon atoms of R <_3> or R <_4> . May be formed. Is represented by the general formula (2) by which a compound, ammonia and the reaction
(2)

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above). The method of claim 1,
In said general formula (1), R <_1> shows a C1-C6 alkyl group substituted by at least 1 fluorine atom, R <_2> represents hydrogen or a C1-C6 alkyl group, and R <_3> and R ₄ each independently represents hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and any one of R ₃ and R ₄ The manufacturing method which may form the ring structure which R <_{2> couple |} bonded with 3-4 carbon atoms. General formula (3)
(3)

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl represents an alkyl group, and, R ₃ and R ₄ is to form a ring structure bonded with 2-5 carbon atoms, or R ₃ or R ₄ combined is one and R ₂ of a number of carbon atoms 3 to 4 ring structure May be formed). By which the compound reacting with a chlorinating agent, the general formula (1)
[Chemical Formula 4]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), followed by conversion to a compound represented by the following formula (2).
[Chemical Formula 5]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above). The method of claim 3,
In the said General formula (3), R <_1> shows a C1-C6 alkyl group substituted by at least 1 fluorine atom, R <_2> represents hydrogen or a C1-C6 alkyl group, and R <_3> and R ₄ each independently represent hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and any one of R ₃ and R ₄ And R ₂ may form a ring structure in which 3 to 4 carbon atoms are bonded. In general formula (4)
[Chemical Formula 6]

(In formula, R <_2> represents hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R <_3> and R <_4> respectively, Independently, hydrogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted Heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and may form a ring structure in which R ₃ and R ₄ are bonded with 2 to 5 carbon atoms, or with any one of R ₃ or R ₄ R ₂ may form a ring structure in which 3 to 4 carbon atoms are bonded.
Compound and
General formula (5)
(7)

In the formula, R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, or a cycloalkyl group having 3 to 6 carbon atoms substituted with at least one fluorine atom. By reacting alkyl, General formula (3)
[Chemical Formula 8]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), and the compound is reacted with a chlorinating agent to give a general formula (1).
[Chemical Formula 9]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), followed by conversion to a compound represented by the following formula (2).
[Formula 10]

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above). 6. The method of claim 5,
In said general formula (3), R <_1> shows a C1-C6 alkyl group substituted by at least 1 fluorine atom, R <_2> represents hydrogen or a C1-C6 alkyl group, and R <_3> and R ₄ each independently represents hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and any one of R ₃ and R ₄ The manufacturing method which may form the ring structure which R <_{2> couple |} bonded with 3-4 carbon atoms. In general formula (1)
(11)

(In formula, R <^1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl It may represent an alkyl group and may form the ring structure which R <_3> and R <_4> couple | bonded with 2-5 carbon atoms, or the ring structure which R <_2> and R <_{2> couple |} bonded with 3-4 carbon atoms of R <_3> or R <_4> . May be formed. Compounds. 8. In the formula (1), R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, and R ₂ represents hydrogen or an alkyl group having 1 to 6 carbon atoms. R ₃ and R ₄ each independently represent hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and R ₃ or The compound which may form the ring structure which any of R <_4> and R <_{2> couple |} bonded with 3-4 carbon atoms. General formula (3 ')
[Chemical Formula 12]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ each independently represent hydrogen, A substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, Or a substituted or unsubstituted heteroarylalkyl group,
Further, the R ₃ and R _4, and form a ring structure bonded with 2-5 carbon atoms, or R ₃ or R ₄ may also form a ring structure which combines a one and R ₂ of a number of carbon atoms 3 to 4 Compound represented by.). The method of claim 9,
In said general formula (3 '), R <_1> shows a C1-C6 alkyl group substituted by at least 1 fluorine atom, R <_2> represents hydrogen or a C1-C6 alkyl group, and R <_3> and R ₄ independently represents hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, except when hydrogen is used at the same time. The compound which may form the ring structure which R <_2> and R <_{2> couple |} bonded with 3-4 carbon atoms with either of R <_3> or R <_4> . The compound according to claim 9, wherein in formula (3 '), R ₁ represents a trifluoroethyl group, R ₂ represents hydrogen or an alkyl group having 1 to 6 carbon atoms, and R ₃ and R ₄ simultaneously Except for hydrogen, each independently represents hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group, and R ₃ or R _The compound which may form the ring structure which any of ₄ and R <_{2> couple |} bonded with 3-4 carbon atoms. In general formula (1)
[Chemical Formula 13]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl It may represent an alkyl group and may form the ring structure which R <_3> and R <_4> couple | bonded with 2-5 carbon atoms, or the ring structure which R <_2> and R <_{2> couple |} bonded with 3-4 carbon atoms of R <_3> or R <_4> . May be formed. Is represented by the general formula (2) by which a compound, ammonia and the reaction
[Chemical Formula 14]

Is converted into a compound represented by (wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined above),
Subsequently, the compound represented by the general formula (2) is reacted with an oxygen scavenger to yield the general formula (6).
[Chemical Formula 15]

Is converted into a compound represented by (wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined above),
Subsequently, the compound represented by the formula (6) is subjected to a catalytic hydrogenation reaction in the presence of an acid to give the formula (7).
[Chemical Formula 16]

Is converted into a compound represented by (wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined above),
Subsequently, the compound represented by General formula (7) is substituted with General formula (8)
[Chemical Formula 17]

Wherein R ₅ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, substituted or General formula (9) by reacting with a compound represented by an unsubstituted heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and X represents a leaving group.
[Chemical Formula 18]

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as described above. General formula (3)
[Chemical Formula 19]

(In formula, R <_1> represents a C1-C6 alkyl group substituted with at least 1 fluorine atom, or a C3-C6 cycloalkyl group substituted with at least 1 fluorine atom, R <_2> is hydrogen and C1-C6 An alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R ₃ and R ₄ are each independently hydrogen, a substituted or unsubstituted C 1 -C An alkyl group of 6, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroaryl It may represent an alkyl group and may form the ring structure which R <_3> and R <_4> couple | bonded with 2-5 carbon atoms, or the ring structure which R <_2> and R <_{2> couple |} bonded with 3-4 carbon atoms of R <_3> or R <_4> . May be formed. Is by reacting with a chlorinating agent to the compound represented by the general formula (1)
[Chemical Formula 20]

(In formula, R <_1> , R <_2> , R <_3> and R <_4> are the same as the above.), Then, the compound represented by General formula (1) is reacted with ammonia in general, Formula (2)
[Chemical Formula 21]

Is converted into a compound represented by (wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined above),
Subsequently, the compound represented by the general formula (2) is reacted with an oxygen scavenger to yield the general formula (6).
[Chemical Formula 22]

Is converted into a compound represented by (wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined above),
Subsequently, the compound represented by the formula (6) is subjected to a catalytic hydrogenation reaction in the presence of an acid to give the formula (7).
(23)

Is converted into a compound represented by (wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined above),
Subsequently, the compound represented by General formula (7) is substituted with General formula (8)
[Formula 24]

Wherein R ₅ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, substituted or General formula (9) by reacting with a compound represented by an unsubstituted heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and X represents a leaving group.
(25)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined above). In general formula (4)
(26)

(In formula, R <_2> represents hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R <_3> and R <_4> respectively, Independently, hydrogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted Heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and may form a ring structure in which R ₃ and R ₄ are bonded with 2 to 5 carbon atoms, or with any one of R ₃ or R ₄ And R ₂ may form a ring structure in which 3 to 4 carbon atoms are bonded.
General formula (5)
(27)

In the formula, R ₁ represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, or a cycloalkyl group having 3 to 6 carbon atoms substituted with at least one fluorine atom. By reacting alkyl, General formula (3)
(28)

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as described above), and the compound is reacted with a chlorinating agent to give a general formula (1).
[Formula 29]

(In formula, R <_1> , R <_2> , R <_3> and R <_4> are the same as the above.), Then, the compound represented by General formula (1) is reacted with ammonia in general, Formula (2)
(30)

Is converted into a compound represented by (wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined above),
Subsequently, the compound represented by the general formula (2) is reacted with an oxygen scavenger to yield the general formula (6).
(31)

Is converted into a compound represented by (wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined above),
Subsequently, the compound represented by the formula (6) is subjected to a catalytic hydrogenation reaction in the presence of an acid to give the formula (7).
(32)

Is converted into a compound represented by (wherein, R ₁ , R ₂ , R ₃ and R ₄ are as defined above),
Subsequently, the compound represented by General formula (7) is substituted with General formula (8)
(33)

Wherein R ₅ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, substituted or General formula (9) by reacting with a compound represented by an unsubstituted heteroaryl group or a substituted or unsubstituted heteroarylalkyl group, and X represents a leaving group.
(34)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined above).