JP2002088048A - Method for producing n-t-butoxycarbonylnitroanline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an N-t-butoxycarbonylnitroaniline derivative useful as an intermediate for medicines, agrochemicals, and the like. SOLUTION: This method for producing the N-t-butoxycarbonylnitroaniline derivative represented by the general formula (2) [X is H, a halogen, an alkyl, a haloalkyl, an alkoxy, a phenylalkyl, benzoyl (which may be substituted by a halogen, amino, nitro or alkyl), an alkoxycarbonyl, a phenylalkoxy, or the like; (n) is an integer of 0 to 4; Boc is t-butoxycarbonyl], characterized by reacting a nitroaniline compound represented by the general formula (1) with di-t-butyl dicarbonate in the presence of an alkali metal derivative or an alkaline earth metal derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an Nt represented by the following general formula (4) useful as an intermediate for pharmaceuticals, agricultural chemicals and the like.
A process for producing a butoxycarbonylnitroaniline derivative.

[0002]

2. Description of the Related Art Conventionally, Nt-
A general method for producing a butoxycarbonylnitroaniline derivative is, for example, a method for converting a nitroaniline compound to 4-N, N-
A method is known in which di-t-butyl dicarbonate is reacted in the presence of a base such as dimethylaminopyridine to perform Nt-butoxycarbonylation and then N-alkylation (JP-A-9-295970). ).

[0003]

However, in the above-mentioned method, the yield of Nt-butoxycarbonylation is as low as about 50%, and Nt-butoxycarbonylation is high because it contains many impurities. However, there are problems in terms of yield and operation, such as the necessity of purification such as crystallization at the stage of the above, and it is not always satisfactory as an industrial production method.

[0004] Therefore, it has been desired to develop an industrially advantageous method for producing the Nt-butoxycarbonylnitroaniline derivative represented by the general formulas (2) and (4).

The inventors of the present invention have conducted intensive studies in order to solve such a problem, and as a result, it has been found that nitroaniline compounds have a concentration of about 1: 1.
The present inventors have found that Nt-butoxycarbonylation proceeds selectively by using 6 mole times or more of an alkali metal hydride as a base, and that an Nt-butoxycarbonylnitroaniline derivative can be synthesized in good yield. Was completed.

[0006]

That is, the present invention provides a compound represented by the following general formula (1): (Wherein X is the same or different and is a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group,
A phenylalkyl group, a benzoyl group (optionally substituted with halogen, amino, nitro or alkyl), an alkoxycarbonyl group, a phenylalkoxy group, a phenyl group (optionally substituted with halogen, amino, nitro or alkyl), N-alkylacylamino group, N-aralkylacylamino group, alkylthio group, aralkylthio group, arylthio group, formyl group, N, N-dialkylamino group, optionally substituted alkenyl group, optionally substituted It shows an alkynyl group and a piperidyl group, and n shows the integer of 0-4. Alternatively, quinoline, fluorene, and naphthalene may be represented by the entire benzene ring and Xn. ) And a nitroaniline compound
reacting with t-butyl dicarbonate in the presence of an alkali metal derivative or an alkaline earth metal derivative; (Wherein, X and n represent the same meaning as described above, and Boc represents a t-butoxycarbonyl group).
And a method for producing a -butoxycarbonylnitroaniline derivative, and the resulting derivative is represented by the general formula (3): R ¹ -Y (wherein R ¹ is an optionally substituted alkyl group or an optionally substituted alkenyl group) Represents an alkynyl group which may be substituted, Y is a hydroxy group, a halogen atom or an OSO ₂ R ² group (R ² is an alkoxy group, an alkyl group (the alkyl group may be substituted with a halogen atom); Or a compound represented by the formula (4), wherein the compound is represented by an aryl group (the aryl group may be substituted with an alkyl group or a halogen atom). (Wherein, R ¹ , X and n have the same meanings as described above;
oc represents a t-butoxycarbonyl group. The present invention provides a method for producing an Nt-butoxycarbonylnitroaniline derivative represented by the following formula:

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The production method of the present invention is as described above, but the Nt-butoxycarbonylnitroaniline derivative represented by the general formula (2) may be isolated and used in the next step.
In the case of producing an Nt-disubstituted Nt-butoxycarbonylnitroaniline derivative represented by the general formula (4), the N-disubstituted product is reacted with a compound represented by the general formula (3) without isolation. Is usually preferred industrially.

First, a method for producing an Nt-butoxycarbonylnitroaniline derivative represented by the general formula (2) will be described.

In the compounds represented by the general formulas (1), (2) and (4), the halogen atom of X is fluorine,
Examples of chlorine, bromine and iodine include alkyl groups, haloalkyl groups, alkoxy groups, phenylalkyl groups, alkoxycarbonyl groups, phenylalkoxy groups, N-alkylacylamino groups, N, N-dialkylamino groups and alkylthio groups. Has 1 to 10 carbon atoms
Alkyl group. Examples of the alkyl moiety of the N-aralkyl acylamino group and the aralkylthio group include an alkyl group having 1 to 6 carbon atoms, and examples of the aryl moiety include a phenyl group and a naphthyl group. Examples of the arylthio group include a phenylthio group and a naphthylthio group. Examples of the acyl group of the N-alkylacylamino group and the N-aralkylacylamino group include a formyl group, an acetyl group, a benzoyl group, a pivaloyl group, a trifluoroacetyl group, a trichloroacetyl group, and the like. Examples of the “alkenyl group” include a halogen atom, an alkoxy group having 1 to 6 carbon atoms, and an alkoxy group having 6 to 1 carbon atoms.
0 aryl, 6 to 10 carbon atoms, and 2 to 10 carbon atoms which may be substituted with a substituent selected from halogenoaryl and the like.
Examples of the alkenyl group of which may be substituted may include a halogen atom, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, and an aryl group having 6 to 10 carbon atoms.
Examples thereof include an alkynyl group having 2 to 10 carbon atoms which may be substituted with a substituent selected from a halogenoaryl, a trialkylsilyl group and the like. Examples of the alkenyl group which may be substituted include a vinyl group, 2,2-dimethylvinyl group, 1-propenyl group, 1-butenyl group and cyclohexenyl group. Examples of the alkynyl group which may be substituted include trimethylsilyl. Examples include an ethynyl group, a 1-propynyl group, a 1-butyryl group, and the like.

Specific examples of the nitroaniline compound (1) used in the present invention include 2-nitroaniline,
-Bromo-4,6-dinitroaniline, 6-chloro-
2,4-dinitroaniline, 2,4-dinitroaniline, 2,6-dinitroaniline, 2,4-dinitro-5
-Fluoroaniline, 4-methoxy-2-nitroaniline, 4-ethoxy-2-nitroaniline, 4-amino-
3-nitrobenzophenone, 4-amino-3-nitrobenzofluoride, 2,6-dinitro-4-methylaniline, 2,4-dichloro-6-nitroaniline, 4,6-
Dimethyl-2-nitroaniline, 2-methyl-6-nitroaniline, 4,5-dichloro-2-nitroaniline,
5-chloro-2-nitroaniline, 4,5-dimethyl-
2-nitroaniline, 5-methyl-2-nitroaniline, 4-fluoro-2-nitroaniline, 4-chloro-
2-nitroaniline, 4-methyl-2-nitroaniline, 4,5-difluoro-2-nitroaniline, 2,4
-Dibromo-6-nitroaniline, 4-amino-3-nitrobenzonitrile, methyl 4-amino-3-nitrobenzoate, 2-amino-3-nitro-9-fluorene, 4-benzyloxy-2-nitroaniline, 3,3
'-Dinitrobenzidine, 2,4-dimethyl-3,6-
Dinitroaniline, 2,4-dinitro-6-phenylaniline, 4-methoxy-3-methyl-6-nitroaniline, 3-bromo-4-methoxy-6-nitroaniline,
3-amino-2-nitrofluorene, 5-ethoxy-4
-Fluoro-2-nitroaniline, 2,4-difluoro-6-nitroaniline, 5-chloro-4-methyl-2-
Nitroaniline, 4-ethyl-2-nitroaniline, 4
-Nitroaniline, 2-bromo-4,6-dinitroaniline, 6-chloro-2,4-dinitroaniline, 2,5
-Dimethoxy-4-nitroaniline, 2-cyano-4-
Nitroaniline, 2-methoxy-4-nitroaniline,
2-amino-5-nitrobenzophenone, 2-amino-
5-nitrobenzotrifluoride, 2,6-dibromo-
4-nitroaniline, 2-chloro-4-nitroaniline, 2,6-dichloro-4-nitroaniline, 2-methyl-4-nitroaniline, 5-methoxy-2-methyl-
4-nitroaniline, 5-amino-2-nitrobenzotrifluoride, 2-bromo-6-chloro-4-nitroaniline, 2-ethoxy-4-nitroaniline, 2-bromo-4-nitroaniline, 2,5 -Dichloro-4-nitroaniline, 2,5-dimethyl-4-nitroaniline,
5-nitro-2-biphenylamine, 5-methyl-4-
Nitro-o-anisidine, 3-chloro-6-methyl-4
-Nitroaniline, 2-amino-3,5-dinitrobenzonitrile, 6-bromo-2-cyano-4-nitroaniline, 3-chloro-4-nitroaniline, 3-methyl-
4-nitroaniline, 4,5-dinitro-2-methylaniline, 5-chloro-2-methoxy-4-nitroaniline, 6-chloro-2-cyano-4-nitroaniline,
3,5-dimethyl-4-nitroaniline, 2-chloro-
4-nitro-5-piperidin-1-yl-phenylamine, 2,6-dimethyl-4-nitroaniline, ethyl 2
-Amino-4-chloro-5-nitrobenzoate, 2-
(Benzyloxy) -4-nitroaniline, methyl 2-
Amino-5-nitrobenzoate, 4,6-dinitro-
o-Toluidine, 3,5-dichloro-4-nitroaniline, 2-sec-butyl-4,6-dinitro-phenylamine, 2-amino-5-nitro-2'-chlorobenzophenone, 2-chloro-6 Methyl-4-nitroaniline, 4-nitro-2,5-diethoxyaniline, N-methyl- (2-amino-3-nitro) -acetanilide,
2-amino-5-nitro-4- (p-toluylthio)-
Anisole, 5-amino-6-nitroquinoline, 2-amino-1-nitronaphthalene, 2-nitro-1-naphthylamine, 1-amino-4-nitronaphthalene, 2-bromo-4-nitro-1-naphthylamine and the like No.

The alkali metal or alkaline earth metal derivative used in the present invention is, for example, preferably an alkali metal hydride or an alkaline earth metal hydride, particularly preferably an alkali metal hydride, and particularly preferably sodium hydride. Is more preferred. The amount of the alkali metal or alkaline earth metal derivative used is usually
Usually about 1.6 to nitroaniline compound (1)
It is about 5 mole times, preferably about 1.8 to 3 mole times.

The amount of di-t-butyl dicarbonate used in the present invention is usually about 0.8 to 1.5 mol times, preferably 0.9 to 1.5 mol times based on the nitroaniline compound (1). It is about 3 mole times.

In the present reaction, a solvent is usually used. Examples of such a solvent include ether solvents such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dimethoxyethane and dioxane, dimethylformamide, dimethylacetamide and dimethylsulfone. Examples thereof include polar solvents such as foxide, aromatic hydrocarbons such as toluene, xylene, and benzene, halogenated hydrocarbon solvents such as chlorobenzene, and hydrocarbon solvents such as hexane and heptane. Preferably tetrahydrofuran, diethyl ether, t-butyl methyl ether, dimethoxyethane,
Ether solvents such as dioxane and polar solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide are used. These solvents may be used alone or as a mixture of two or more.

In these solvents, the product Nt-
The concentration of the butoxycarbonylnitroaniline derivative (2) is not particularly limited, but is usually preferably adjusted to 0.1 to 50% by weight, preferably 1 to 20% by weight for the reaction. .

Although the reaction temperature is not particularly limited, it can be generally selected from a temperature higher than the freezing point of the system to a reflux temperature, preferably from -10 ° C to a reflux temperature.

[0016] The reaction time is usually in the range of 0.1 to 60 hours to sufficiently achieve the purpose.

After completion of the reaction, the desired product can be obtained usually by adding the reaction solution to water and performing extraction, concentration, etc., and if necessary, purification by column chromatography, crystallization, etc. You can also. Further, the reaction solution after the completion of the reaction can be used as it is in the next step.

Next, Nt- represented by the general formula (4)
A method for producing a butoxycarbonylnitroaniline derivative will be described. R of the compound represented by the general formula (3)
^{In 1} , the “optionally substituted alkyl group” is selected from, for example, halogen atoms, alkoxy having 1 to 6 carbons, aryl having 6 to 10 carbons, halogenoaryl having 6 to 10 carbons, and the like. Examples thereof include an alkyl group having 1 to 10 carbon atoms which may be substituted with a substituent, and examples of the "optionally substituted alkenyl group" include:
Halogen atom, alkoxy group having 1 to 6 carbon atoms, 6 carbon atoms
Examples of the “optionally substituted alkynyl group” include an alkenyl group having 2 to 10 carbon atoms which may be substituted with a substituent selected from aryl having 10 to 10 and halogenoaryl having 6 to 10 carbon atoms. An alkynyl group having 2 to 10 carbon atoms which may be substituted with a substituent selected from a halogen atom, an alkoxy having 1 to 6 carbon atoms, an aryl having 6 to 10 carbon atoms, and a halogenoaryl having 6 to 10 carbon atoms. Is mentioned.

In Y of the compound represented by the general formula (3), examples of the halogen atom include chlorine, bromine and iodine, and the R ² alkoxy group of the “OSO ₂ R ² group” has 1 to 10 carbon atoms. And an alkyl group having 1 to 1 carbon atoms which may be substituted with a halogen atom.
An alkyl group having 10 carbon atoms is exemplified, and an aryl group is an aryl group having 6 to 10 carbon atoms which may be substituted with a halogen atom.

Specific examples of the compound represented by formula (3) used in the present invention include: alkyl halides such as methyl chloride, propyl chloride, butyl chloride, allyl chloride, benzyl chloride, methyl bromide, Ethyl bromide, propyl bromide, butyl bromide, isobutyl bromide, isopropyl bromide, pentyl bromide, benzyl bromide, ethyl bromoacetate, methyl bromoacetate, t-butyl bromoacetate, benzyl bromoacetate, ethyl iodoacetate, iodine Methyl iodide, ethyl iodide, pentyl iodide, allyl iodide, isobutyl iodide, isopropyl iodide, isopentyl iodide, cyclohexyl iodide, butyl iodide, propyl iodide, heptyl iodide and the like; Methanesulfonic acid alkyl ester, chloromethanesulfonic acid alkyl ester, p-toluene Sulfonic acid alkyl ester, trifluoromethanesulfonic acid alkyl ester, nonafluorobutanesulfonic acid alkyl ester, dialkyl sulfate (as the alkyl group, methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, allyl group, benzyl group And the like).

The amount of the compound represented by the general formula (3) used in the reaction is not particularly limited, but
If the amount is too large, it is not economical and purification becomes difficult.
About 2 mole times.

In the present reaction, a solvent is usually used. Examples of such a solvent include ether solvents such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dimethoxyethane and dioxane, dimethylformamide, dimethylacetamide and dimethylsulfone. Examples thereof include polar solvents such as foxide, aromatic hydrocarbons such as toluene, xylene, and benzene, halogenated hydrocarbon solvents such as chlorobenzene, and hydrocarbon solvents such as hexane and heptane. Preferably tetrahydrofuran, diethyl ether, t-butyl methyl ether, dimethoxyethane,
Ether solvents such as dioxane and polar solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide are used. These solvents may be used alone or as a mixture of two or more.

The reaction temperature is not particularly limited, but can be generally selected from a temperature higher than the freezing point of the system to a reflux temperature, preferably from -10 ° C to a reflux temperature.

[0024] The reaction time is usually in the range of 0.1 to 60 hours to sufficiently achieve the purpose.

After completion of the reaction, the desired product can be obtained by performing the usual post-treatment operations such as extraction and concentration, and, if necessary, purification by column chromatography, crystallization or the like. You can also.

[0026]

According to the present invention, an Nt-butoxycarbonylnitroaniline derivative can be industrially advantageously produced.

[0027]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 "Production of Nt-butoxycarbonyl-2-nitroaniline" 1.30 g of sodium hydride (containing 60%) (2.24 times the molar amount of the nitroaniline compound) in 20.24 g of tetrahydrofuran And ice-cooled. To this suspension was added 22.20 g of a solution of 2.00 g of 2-nitroaniline in tetrahydrofuran, and the mixture was stirred for 10 minutes, and then heated to room temperature and stirred for 30 minutes. Di-t is added to this mixture.
6.92 g of a solution of 3.41 g of -butyl dicarbonate in tetrahydrofuran was added at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was added to ice water, extracted with toluene and separated, and the organic layer was analyzed by high performance liquid chromatography to find that the yield of the desired product was 96%. ¹ H-NMR (300 MHz, CDCl ₃ ): d 9.66 (1H, brs), 8.57 (1
H, d), 8.54 (1H, d), 7.61 (1H, dt), 7.08 (1H, dt),
1.55 (9H, s) .; ¹³ C-NMR (75 MHz, CDCl ₃ ): d152.58,
136.33, 136.12, 126.20, 122.20, 121.06, 82.20, 2
8.58.

Example 2 "Production of Nt-butoxycarbonyl-2-nitroaniline" The charged amount of sodium hydride (containing 60%) was 1.
03 g (1.8 mol times based on nitroaniline compound)
The same operation as in Example 1 was performed except for changing to. As a result, the yield of the target product was 75%.

Example 3 "Production of Nt-butoxycarbonyl-4-nitroaniline" 1.30 g of sodium hydride (containing 60%) was suspended in 20.03 g of tetrahydrofuran and cooled with ice.
To this suspension, 22.51 g of a solution of 2.00 g of 4-nitroaniline in tetrahydrofuran was added, and the mixture was stirred for 10 minutes.
Then, the mixture was heated to room temperature and stirred for 30 minutes. 3.44 g of di-t-butyl dicarbonate was added to this mixture at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was added to ice water, extracted with toluene and separated, and the organic layer was analyzed by high performance liquid chromatography to find that the yield of the desired product was 97%. ¹ H-NMR (300 MHz, CDCl ₃ ): d 8.20-8.13 (2H, m), 7.57
-7.50 (2H, m), 7.00 (1H, brs), 1.53 (9H, s) .; ¹³ C
-NMR (75MHz, CDCl ₃ ): d 151.92, 144.57, 142.62, 12
5.19, 117.51, 81.95, 28.20.

Example 4 "Production of Nt-butoxycarbonyl-5-chloro-2-nitroaniline" sodium hydride (containing 60%)
1.10 g was suspended in 20.43 g of tetrahydrofuran and cooled with ice. To this suspension was added a solution of 1.99 g of 5-chloro-2-nitroaniline in 22.7 of tetrahydrofuran.
Add 4 g, stir for 10 minutes, then warm to room temperature and add 3 g
Stirred for 0 minutes. To this mixture, 5.51 g of a tetrahydrofuran solution of 2.75 g of di-t-butyl dicarbonate was added at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was added to ice water, extracted with toluene and separated, and the organic layer was analyzed by high performance liquid chromatography. The yield of the target compound was 99%.
Met. ¹ H-NMR (300 MHz, CDCl ₃ ): d 9.77 (1H, brs), 8.70-8.
68 (1H, m), 8.16-8.13 (1H, m), 7.08-7.02 (1H, m),
1.54 (9H, s) .; ¹³ C-NMR (75 MHz, CDCl ₃ ): d 152.23,
143.03, 137.33, 134.37, 127.46, 122.47, 120.56, 8
2.80, 28.53.

Example 5 "Production of Nt-butoxycarbonyl-4-cyano-2-nitroaniline" sodium hydride (containing 60%)
1.06 g was suspended in 19.92 g of tetrahydrofuran and cooled with ice. To this suspension was added a solution of 2.00 g of 4-cyano-2-nitroaniline in 20.7 of tetrahydrofuran.
Add 5 g, stir for 10 minutes, then warm to room temperature and add 1 g
Stirred for hours. To this mixture, 4.79 g of a tetrahydrofuran solution of 2.89 g of di-t-butyl dicarbonate was added at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was added to ice water, extracted with toluene and separated, and the organic layer was analyzed by high performance liquid chromatography. The yield of the target compound was 99%.
Met. ¹ H-NMR (300 MHz, CDCl ₃ ): d 9.90 (1H, brs), 8.81 (1
H, d), 8.53 (1H, d), 7.82 (1H, dd), 1.56 (9H, s).
; ¹³ C-NMR (75 MHz, CDCl ₃ ): d 151.78, 140.01, 138.3
9, 135.31, 130.79, 121.62, 117.18, 105.64, 83.61,
28.45.

Example 6 "Production of Nt-butoxycarbonyl-4-nitro-1-naphthylamine" sodium hydride (containing 60%)
0.92 g was suspended in 19.44 g of tetrahydrofuran and cooled with ice. To this suspension was added a solution of 4-nitro-1-naphthylamine (2.00 g) in tetrahydrofuran (20.7 g).
Add 8 g, stir for 10 minutes, then warm to room temperature and add 1 g
Stirred for hours. To this mixture, 5.09 g of a tetrahydrofuran solution of 2.52 g of di-t-butyl dicarbonate was added at room temperature, and the mixture was stirred for 4 hours. The reaction mixture was added to ice water, extracted with toluene, separated, and the organic layer was analyzed by high performance liquid chromatography. The yield of the desired product was 80%.
Met.

Example 7 "Preparation of Nt-butoxycarbonyl-4-methoxycarbonyl-2-nitroaniline" sodium hydride (6
0.57 g) in 9.87 g of tetrahydrofuran
And ice-cooled. To this suspension, 9.86 g of a tetrahydrofuran solution of 0.95 g of 4-methoxycarbonyl-2-nitroaniline was added, and the mixture was stirred for 10 minutes, and then heated to room temperature and stirred for 1 hour. Di-t is added to this mixture.
2.67 g of a tetrahydrofuran solution of 1.30 g of -butyl dicarbonate was added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was added to an ice-cooled saturated aqueous ammonium chloride solution,
Extraction and separation with toluene, and analysis of the organic layer by high performance liquid chromatography revealed that the yield of the desired product was 80%.

Example 8 "Production of Nt-butoxycarbonyl-5-methoxy-2-nitroaniline" sodium hydride (containing 60%)
0.72 g was suspended in 7.05 g of tetrahydrofuran and cooled with ice. To this suspension was added a solution of 5-methoxy-2-nitroaniline (1.00 g) in tetrahydrofuran (8.2).
Add 1 g, stir for 10 minutes, then warm to room temperature and add 1 g
Stirred for hours. 1.46 g of di-t-butyl dicarbonate was added to this mixture at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was added to ice water, extracted with toluene and separated, and the organic layer was analyzed by high performance liquid chromatography to find that the yield of the desired product was 92%.

Example 9 "Preparation of Nt-butoxycarbonyl-N-methyl-5-chloro-2-nitroaniline" sodium hydride (6
1.01 g of tetrahydrofuran 18.73)
g and suspended on ice. To this suspension was added 5-chloro-
22.76 g of a tetrahydrofuran solution of 2.00 g of 2-nitroaniline was added, and the mixture was stirred for 10 minutes, and then heated to room temperature and stirred for 30 minutes. To this mixture was added 5.75 g of a tetrahydrofuran solution of 2.77 g of di-t-butyl dicarbonate at room temperature, and the mixture was stirred for 2 hours. 3.74 g of a tetrahydrofuran solution of 1.86 g of methyl iodide was added to the reaction mixture at room temperature, the temperature was raised to 60 ° C., and the mixture was stirred for 10 hours. The reaction mixture was added to ice water, extracted with toluene and separated, and the organic layer was analyzed by high performance liquid chromatography to find that the yield of the desired product was 86%. ¹ H-NMR (300 MHz, CDCl ₃ ): d 7.91-7.87 (1H, m), 7.36
-7.32 (2H, m), 3.30 (3H, s), 1.31 (9H, s) .; ¹³ CN
MR (75MHz, CDCl ₃ ): d 144.74, 139.40, 138.72, 128.
94, 127.11, 126.06, 82.09, 37.32, 27.74.

Example 10 "Production of Nt-butoxycarbonyl-N-methyl-2-nitroaniline" sodium hydride (containing 60%)
1.25 g was suspended in 16.02 g of tetrahydrofuran and cooled with ice. To this suspension was added 2-nitroaniline 1.
22.68 g of a 99 g solution of tetrahydrofuran was added,
The mixture was stirred for 10 minutes, then heated to room temperature and stirred for 30 minutes. The mixture was added to di-tert-butyl dicarbonate 3.4.
4 g of a tetrahydrofuran solution (6.89 g) was added at room temperature, and the mixture was stirred for 2 hours. Toluene was added to the reaction mixture.
04 g and 2.03 g of dimethyl sulfate were added at room temperature and stirred for 2 hours. The reaction mixture was added to ice water, extracted with toluene and separated, and the organic layer was analyzed by high performance liquid chromatography to find that the yield of the desired product was 92%.

Example 11 "Production of Nt-butoxycarbonyl-N-methyl-5-methoxy-2-nitroaniline" 13.10 g of sodium hydride (containing 60%) was added to tetrahydrofuran 17
The suspension was suspended in 5.31 g and cooled with ice. To this suspension,
227.53 g of a solution of 25.03 g of methoxy-2-nitroaniline in tetrahydrofuran was added, and the mixture was stirred for 10 minutes.
Then, the mixture was heated to room temperature and stirred for 30 minutes. 35.73 g of di-t-butyl dicarbonate was added to this mixture at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added toluene 24
9.76 g and dimethyl sulfate 28.74 g were added at room temperature,
Stir for 2 hours. The reaction mixture was added to ice water, extracted with toluene and separated, and the organic layer was analyzed by high performance liquid chromatography to find that the yield of the desired product was 94%.

Production Example "Preparation of Nt-butoxycarbonyl-2-nitroaniline" The amount of sodium hydride (containing 60%) was set at 0.1%.
85 g (1.5 mole times based on nitroaniline compound)
The same operation as in Example 1 was performed except for changing to. As a result, the yield of the target product was 48%.

[Procedure amendment]

[Submission date] July 18, 2001 (2001.7.1)
8)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0005

[Correction method] Change

[Correction contents]

The inventors of the present invention have conducted intensive studies in order to solve such problems, and as a result, have found that an Nt-butoxycarbonylnitroaniline derivative can be synthesized with high yield.
The present invention has been reached.

Claims (7)

[Claims] 1. The general formula (1) (Wherein X is the same or different and is a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group,
A phenylalkyl group, a benzoyl group (optionally substituted with halogen, amino, nitro or alkyl), an alkoxycarbonyl group, a phenylalkoxy group, a phenyl group (optionally substituted with halogen, amino, nitro or alkyl), N-alkylacylamino group, N-aralkylacylamino group, alkylthio group, aralkylthio group, arylthio group, formyl group, N, N-dialkylamino group, optionally substituted alkenyl group, optionally substituted It shows an alkynyl group and a piperidyl group, and n shows the integer of 0-4. Alternatively, the whole benzene ring and Xn may represent quinoline, fluorene, or naphthalene. ) And a nitroaniline compound
reacting with t-butyl dicarbonate in the presence of an alkali metal derivative or an alkaline earth metal derivative, general formula (2) (Wherein, X and n have the same meanings as described above, and Boc represents a t-butoxycarbonyl group).
A method for producing a butoxycarbonylnitroaniline derivative. 2. The general formula (1) (Wherein X is the same or different and is a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group,
A phenylalkyl group, a benzoyl group (optionally substituted with halogen, amino, nitro or alkyl), an alkoxycarbonyl group, a phenylalkoxy group, a phenyl group (optionally substituted with halogen, amino, nitro or alkyl), N-alkylacylamino group, N-aralkylacylamino group, alkylthio group, aralkylthio group, arylthio group, formyl group, N, N-dialkylamino group, optionally substituted alkenyl group, optionally substituted It shows an alkynyl group and a piperidyl group, and n shows the integer of 0-4. Alternatively, the whole benzene ring and Xn may represent quinoline, fluorene, or naphthalene. ) And a nitroaniline compound
reacting with t-butyl dicarbonate in the presence of an alkali metal derivative or an alkaline earth metal derivative; and then reacting with the general formula (3) R ¹ -Y (where R ¹ is a hydrogen atom, A good alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkynyl group, wherein Y is a hydroxy group, a halogen atom or an OSO ₂ R ² group (R ² is an alkoxy group,
An alkyl group (the alkyl group may be substituted with a halogen atom), or an aryl group (the aryl group may be substituted with an alkyl group or a halogen atom)
Represents Wherein the compound represented by the general formula (4) is reacted: (Wherein, R ¹ , X and n have the same meanings as described above;
oc represents a t-butoxycarbonyl group. )), A method for producing an Nt-butoxycarbonylnitroaniline derivative. 3. The method according to claim 1, wherein the alkali or alkaline earth metal derivative is an alkali or alkaline earth metal hydride. 4. The amount of the alkali or alkaline earth metal derivative used is 1.6 to 5 times the molar amount of the nitroaniline compound represented by the general formula (1).
Or the production method according to 3. 5. The use amount of the alkali or alkaline earth metal derivative is 1.8 to 3 times the molar amount of the nitroaniline compound represented by the general formula (1).
Or the production method according to 3. 6. The process according to claim 1, wherein the nitro group is present at the o- or p-position of the amino group in the compounds represented by the general formulas (1) and (2). 7. The method according to claim 1, wherein the nitroaniline compound represented by the general formula (1) is 5-methoxy-2-nitroaniline.