WO2001004088A1 - Process for the preparation of aniline derivatives - Google Patents

Abstract

A process for preparing hydrochlorides of compounds of general formula (2): (wherein R1 is lower alkyl; R4 and R5 are each hydrogen or the like; Y1, Y2, Y3 and Y4 are each hydrogen or the like; and n is 0 or 1), characterized by converting a compound of general formula (1): (wherein X is halogeno) into a phthalimide, conducting the deblocking of the phthalimido group, conducting both the conversion of the resulting amino group into a carbamate group and the reduction of the nitro group in one pot, conducting both the conversion of the obtained compound into an acylthiourea and the hydrolysis of the resulting compound in one pot, alkylating the resulting thiourea group, removing the amino-protecting group with hydrochloric acid and an alcohol, and then crystallizing the resulting compound by the addition of an organic solvent without the removal of the hydrochloric acid and the alcohol. This process permits reduction in the number of steps as compared with those of the prior art, improvement in the working atmosphere by virtue of the use of safer reagents and solvents, enhancement in the safeness of working, and so on, thus being useful as an industrial process.

Description

 Specification

 Method for producing aniline derivatives

The present invention relates to a method for producing an aniline derivative _(see Background Art).

 General formula (2)

(In the formula, represents a lower alkyl group. R ₄ and R ₅ may be the same or different and are each a hydrogen atom, a lower alkyl group, or together form a 3- to 8-membered ring. Υ ₂ , Υ ₃ , Υ ₄ may be the same or different, and each is a lower alkoxy group, a lower alkyl group, a lower alkyl group which may be substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group. A cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, or ΝΥ ΝΥ ₅ Υ ₆ , wherein Υ ₅ and Υ ₆ may be the same or different, and , A hydrogen atom, a lower alkyl group, or may be taken together to form a 3- to 8-membered ring, and η represents an integer of 0 or 1.) No. 6,906,006, which has a nitric oxide synthase inhibitory action, As such therapeutic agent for vascular disorders known to be useful. Methods for producing these compounds are described in the publication and the like.

However, the production methods described in these methods involve the use of column chromatography for purification, the use of many steps, and the use of reagents (such as hydrazine) that are difficult to use in large-scale production. It was difficult to put it into practical use as a typical manufacturing method. Disclosure of the invention

 As a result of intensive studies, the present inventors have found an efficient method for producing and purifying an inorganic acid salt of the compound represented by the general formula (2), and have completed the present invention.

That is, the present invention provides a method for producing an aniline derivative shown below (in the following general formula, X represents a halogen atom. Represents a lower alkyl group. R ₂ represents a lower alkoxy group) R ₃ represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and R ₄ and R ₅ may be the same or different, and each represents a hydrogen atom or a lower alkyl group. Or 一 緒₂ , Υ ₃ , Υ ₄ may be the same or different and each represents a hydrogen atom, a halogen atom, or an aromatic group. Represents a lower alkoxy group, a lower alkyl group which may be substituted by a hydrocarbon group, or a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, and Μ indicates an Alkyri metal or DBU. Η is an integer of 0 or 1. Indicate the number.

General formula (1)

で表される化合物から、 一般式 （2)

From the compound represented by the general formula (2)

HN f,,

义 丄 ha T ( ^CH 2) rT? -NH ₂

で表される化合物と反応させることにより、 一般式 （4) A method for producing a compound represented by H (2), wherein the compound represented by the general formula (1) is

By reacting with the compound represented by the general formula (4)

で表される化合物を得、 この化合物のフタルイミド基を脱保護反応に付し、 一般 式 （5)

A compound represented by the general formula (5) is obtained by subjecting the phthalimide group of this compound to a deprotection reaction.

で表される化合物を得、 この化合物のアミノ基を力ルバメート化し、 一般式（6)

A compound represented by the general formula (6)

で表される化合物を得、 この化合物のニトロ基を還元して、 一般式 （7)

で表される化合物を得、 この化合物を一般式 （8)

Is obtained by reducing the nitro group of this compound to obtain a compound represented by the general formula (7)

And the compound represented by the general formula (8)

で表される化合物と反応させることにより、 一般式 （9)

By reacting with the compound represented by the general formula (9)

0 s

1 J 丄 NO, (CH ₂ ) _n -9-NHCOR ₂

R ₃ N NR ₄

HH ^τ 4 " ⁴ A compound represented by the formula (9) is obtained, and this compound is reacted with a base and water and Ζ or an alcohol to obtain a compound represented by the general formula (10)

^{_{J s L v T 1 (CH}} 2) n -C · 5 -NHCOR 2

H ₂ N Person NZR ₄

To give the compound represented by H丫4 ⁴ (10), alkylation of Chiourea group of this compound, general formula (1 1)

で表される化合物を得、 この化合物のァミノ基の保護基の脱保護反応を脱保護剤 を用いて行うことにより、 一般式 （2)

A compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent.

で表される化合物を製造する方法において、 次の （a) および （b) のうち、 少 なくとも 1つを行うことを特徴とする製造方法。

A method for producing a compound represented by the formula: wherein at least one of the following (a) and (b) is carried out.

 (a) The amino group of the compound represented by the general formula (5) is converted into a compound by the formula (6) to obtain a compound represented by the general formula (6). Perform the reaction to obtain the compound represented in one pot;

 (b) reacting the compound represented by the general formula (7) with the compound represented by the general formula (8) to obtain a compound represented by the general formula (9); And a reaction with Z or an alcohol to obtain a compound represented by the general formula (10) in one pot.

Further, the present invention provides a method for producing an aniline derivative shown below (in the following general formula, X represents a halogen atom. 1 ^ represents a lower alkyl group. R ₂ represents Represents a lower alkoxy group, R ₃ represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and ₄ or ₅ may be the same or different, and each represents a hydrogen atom, Y or Y ₂ , Υ ₃ , Υ ₄ may be the same or different, and may represent a lower alkyl group or may form a _3- to 8-membered ring together; , A halogen atom, a lower alkoxy group which may be substituted with an aromatic hydrocarbon group, a lower alkyl group, and a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent. Indicates metal or DBU η is an integer of 0 or 1 Indicate the number.

で表される化合物から、 一般式 （2) General formula (1)

From the compound represented by the general formula (2)

で表される化合物を製造する方法であって、 一般式 （1) で表される化合物を、 一般式 （3)

A method for producing a compound represented by the general formula (1):

で表される化合物と反応させることにより、 一般式 （4)

By reacting with the compound represented by the general formula (4)

で表される化合物を得、 この化合物のフ夕ルイミド基を脱保護反応に付し、 7ΊΧ 式 （5)

で表される化合物を得、 この化合物のアミノ基を力ルバメート化し、 一般式（6)

The compound represented by the formula is obtained, and the imide group of this compound is subjected to a deprotection reaction.

A compound represented by the general formula (6)

で表される化合物を得、 この化合物のニトロ基を還元して、 一般式 （7)

Is obtained by reducing the nitro group of this compound to obtain a compound represented by the general formula (7)

f,

J J- (CH ₂ ) _n -C-NHCOR ₂

A compound represented by Y v ₄ R ₄ (7) is obtained, and this compound is represented by the general formula (8)

0

 X

By reacting with the compound represented by F — NCS ₍₈₎ , the compound represented by the general formula (9)

0 s ^

1 JI ÷ (CH ₂ ) _n -C-NHCOR ₂

HH ^γ 3 ^γ 4 " ⁴ (9) is obtained, and this compound is reacted with a base and water or Ζ or an alcohol to obtain a compound represented by the general formula (10)

R R

 s

で表される化合物を得、 この化合物のチォゥレア基をアルキル化し、 一般式 （1 1 )

Is obtained by alkylating the thioperia group of the compound, and represented by the general formula (11)

で表される化合物を得、 この化合物のァミノ基の保護基の脱保護反応を無機酸お よびアルコール類からなる脱保護剤を用いて行うことにより、 一般式 （2 )

The compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid and an alcohol.

で表される化合物を製造した後、 さらに該無機酸および該アルコール類を留去す ることなく、 有機溶媒を加えることによって晶析させることにより上記一般式 ( 2 ) で表される化合物の該無機酸塩を製造する方法。

After producing the compound represented by the formula, the compound represented by the general formula (2) is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohols. A method for producing an inorganic acid salt.

The present invention also provides a method for producing the aniline derivative shown below (in the following general formula, represents a lower alkyl group. R ₂ represents a lower alkoxy group. R ₃ represents Represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and R ₄ and R ₅ may be the same or different and each represent a hydrogen atom, a lower alkyl group, or Υ ₂ , Υ ₃ , and Υ ₄ may be the same or different and are each substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group. Good low-grade alkoxy A cyclic group, a lower alkyl group, an optionally substituted cyclic alkyl group having 3 to 6 carbon atoms, γ

Or represents the f one NY ₅ Y _6, wherein, Y _5, Upsilon _6, which may be the same or different, are each a hydrogen atom, a lower alkyl group, or, the connexion 3-8 membered ring such together It may be formed. η represents an integer of 0 or 1. ):

で表される化合物から、 一般式 （2)

で表される化合物を製造する方法であって、 一般式 （5) で表される化合物のァ ミノ基を力ルバメート化し、 一般式 （6) General formula (5) R-

From the compound represented by the general formula (2)

A method for producing a compound represented by the general formula (5), which comprises converting an amino group of a compound represented by the general formula (5)

I (CH.) _N -C-NHC0R ₂

で表される化合物を得、 この化合物を一般式 （8) 0 ヾ 4 The compound represented by (6) is obtained, and the nitro group of this compound is reduced to obtain the compound represented by the general formula (7)

And the compound represented by the general formula (8)

0

 By reacting with the compound represented by R Λ NCS (8), the compound represented by the general formula (9)

丄 Hana (CH ₂ ) _n -?-NHCOR ₂

R3 N _N N R

 A compound represented by H-containing H (9) is obtained, and this compound is reacted with a base and water and / or alcohols to obtain a compound represented by the general formula (10).

JJ I jj- (CH ₂ ) _n -C-NHCOR ₂

H ₂ N with NR ₄

A compound represented by H ^Y 3 ^Y " ⁴ (io) is obtained, and the thiopereyl group of this compound is alkylated to obtain a compound represented by the general formula (11)

_{( 1 χ )} で表される化合物を得、 この化合物のァミノ基の保護基の脱保護反応を脱保護剤 を用いて行うことにより、 一般式 （2)

で表される化合物から、 一般式 （2)

_The compound represented by formula (2) is obtained by obtaining a compound represented by formula ₍₁₎ and performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent.

From the compound represented by the general formula (2)

(₂) で表される化合物を製造する方法であって、 一般式 （5) で表される化合物のァ ミノ基を力ルバメート化し、 一般式 （6)

A process for producing a compound represented by _(2), a § amino group of the compound represented by the general formula (5) to force Rubameto of the general formula (6)

で表される化合物を得、 この化合物のニトロ基を還元して、 一般式 （7)

Is obtained by reducing the nitro group of this compound to obtain a compound represented by the general formula (7)

And then (CH ₂ ) _n -?-NHCOR ₂

A compound represented by H ₂ NR ₄ (α) is obtained, and this compound is represented by the general formula (8)

0

 II

(9) で表される化合物を得、 この化合物を塩基と水および またはアルコール類と反 応させることにより、 一般式 （10) By reacting with the compound represented by FUNICS ₍₈₎ , the compound represented by the general formula (9)

By obtaining a compound represented by the formula (9), and reacting the compound with a base and water and / or alcohols, the compound represented by the general formula (10)

で表される化合物を製造した後、 さらに該無機酸および該アルコール類を留去す ることなく、 有機溶媒を加えることによって晶析させることにより上記一般式 (2) で表される化合物の該無機酸塩を製造する方法。

The compound represented by the general formula (2) is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohol after producing the compound represented by the general formula (2). A method for producing an inorganic acid salt.

The present invention also provides a method for producing an aniline derivative shown below. In the following general formula, represents a lower alkyl group. R ₂ represents a lower alkoxy group. R ₃ represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group. R ₄ and R _5, which may be the same or different, are each a hydrogen atom, or a lower alkyl group, or, connexion 3 may form a 8-membered ring such together. Y physician Upsilon _2, Upsilon ₃ , Upsilon ₄ may be the same or different and are each a water atom, a halogen atom, an aromatic hydrocarbon optionally substituted lower an alkoxy group, lower alkyl, which may have a substituent A good cyclic alkyl group having 3 to 6 carbon atoms, or — — ₅ Υ ₆ , wherein Υ ₅ and Υ ₆ may be the same or different, and are each a hydrogen atom, a lower alkyl group, or And together form a 3- to 8-membered ring . There η is an integer of 0 or 1).:

General formula (7) 1 R

Shito, Ji (CH ₂ ) _n -?-NHCOR ₂

 H N

3 Y ₄ -R

 The compound represented by the general formula (2)

(2) で表される化合物を製造する方法であって、 一般式 （7) で表される化合物を- 般式 （8)

A method for producing a compound represented by the general formula (7), wherein the compound represented by the general formula (7) is

0

で表される化合物を得、 この化合物を塩基と水および Zまたはアルコール類と反 応させることにより、 一般式 （10) By reacting with the compound represented by R ₃ ′ NCS ( ₈ ), the compound represented by the general formula (9)

The compound represented by the general formula (10) is obtained by reacting this compound with a base, water and Z or an alcohol.

Y;

 S f,, ヽ 丫.

U 丄 ノ ÷ (CH ₂ ) _n -C-NHCOR ₂

H ₂ N N N R ₄

A compound represented by H ^γ 3 ^γ 4 ⁴ (l 0) is obtained, and the thioperia group of this compound is alkylated to obtain a compound represented by the general formula (11)

で表される化合物を得、 この化合物のァミノ基の保護基の脱保護反応を脱保護剤 を用いて行うことにより、 一般式 （2)

A compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent.

で表される化合物を製造する方法において、 一般式 （7) で表される化合物を一 般式 （8) で表される化合物と反応させることにより、 一般式 （9) で表される 化合物を得、 この化合物を塩基と水および Zまたはアルコール類と反応させるこ とにより、 一般式 （10) で表される化合物を得る反応をワンポットで行うこと を特徴とする製造方法。

In the method for producing the compound represented by the general formula (7), the compound represented by the general formula (9) is reacted with the compound represented by the general formula (8) to thereby form the compound represented by the general formula (9). Reacting this compound with water and Z or alcohols. Wherein the reaction for obtaining the compound represented by the general formula (10) is carried out in one pot.

The present invention also provides a method for producing the aniline derivative shown below (in the following general formula, represents a lower alkyl group. R ₂ represents a lower alkoxy group. R ₃ represents Represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and R ₄ and R ₅ may be the same or different and each represent a hydrogen atom, a lower alkyl group, or Υ ₂ , Υ ₃ , and Υ ₄ may be the same or different and are each substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group. A lower alkoxy group, a lower alkyl group, an optionally substituted cyclic alkyl group having 3 to 6 carbon atoms, or — ΝΥ ₅ Υ ₆ , wherein Υ ₅ and は₆ are May be the same or different, . The atom, lower alkyl group, or together a connexion 3-8 membered ring may form the shape of η is an integer of 0 or 1).:

General formula (7)

(7) で表される化合物から一般式 （2)

The compound represented by the general formula (2)

で表される化合物を製造する方法であって、 一般式 （7) で表される化合物を- 般式 (8) O

A method for producing a compound represented by the general formula (7) O

 By reacting with the compound represented by R Λ NCS (8), the compound represented by the general formula (9)

で表される化合物を得、 この化合物を塩基と水および Zまたはアルコール類と反 応させることにより、 一般式 （10)

The compound represented by the general formula (10) is obtained by reacting this compound with a base, water and Z or an alcohol.

で表される化合物を製造した後、 さらに該無機酸および該アルコール類を留去す ることなく、 有機溶媒を加えることによって晶析させることにより上記一般式

After producing the compound represented by the formula, the compound is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohol, thereby obtaining the compound represented by the above general formula.

A method for producing the inorganic acid salt of the compound represented by (2).

The present invention also provides a method for producing an aniline derivative shown below (in the following general formula, R ₂ represents a lower alkoxy group. R ₄ and R ₅ may be the same or different. Each represents a hydrogen atom, a lower alkyl group, or may be taken together to form a _3- to 8-membered ring, and Y ₂ , Υ ₃ , Υ ₄ may be the same or different, A hydrogen atom, a halogen atom, a lower alkoxy group which may be substituted with an aromatic hydrocarbon group, a lower alkyl group, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, or shows an ΝΥ ₅ Υ _6, wherein, Upsilon _5, Upsilon _6, which may be the same or different, are each a hydrogen atom, a lower alkyl group, or forms a together a connexion 3-8 membered ring Η represents an integer of 0 or 1.) :

General formula (5)

で表される化合物のアミノ基を力ルバメート化し、 一般式 （6)

The amino group of the compound represented by the formula

で表される化合物を得、 この化合物のニトロ基を還元して、 一般式 （7) ュ J-(CH₂)_n-C-NHCOR₂

Is obtained by reducing the nitro group of this compound to obtain a compound represented by the general formula (7) J J- (CH ₂ ) _n -C-NHCOR ₂

A method for producing a compound represented by Y v ₄ (7), wherein all of the reactions are performed in one pot.

The present invention also provides a method for producing a thioperia derivative shown below (in the following general formula, R ₂ represents a lower alkoxy group. R ₃ represents a lower alkyl group, a lower alkoxy group, or And R ₄ and R ₅ may be the same or different and each represent a hydrogen atom or a lower alkyl group, or together form a 3- to 8-membered ring Υ ₂ , Υ ₃ , Υ ₄ may be the same or different, and each is a lower alkoxy group, a lower alkyl group, a lower alkyl group which may be substituted with a hydrogen atom, a halogen atom, an aromatic hydrocarbon group, an optionally substituted cyclic alkyl group having 3 to 6 carbon atoms or, represents a _ΝΥ ₅ Υ _6, wherein, Upsilon _5, Upsilon _6, which may be the same or different, are each a hydrogen atom , Lower alkyl groups, Or may be taken together to form a 3- to 8-membered ring, and η represents an integer of 0 or 1.):

General formula (7)

で表される化合物を一般式 （8)

The compound represented by the general formula (8)

0

で表される化合物を得、 この化合物を、 塩基と水および Ζまたはアルコール類と 反応させることにより、 一般式 （10) By reacting with the compound represented by R Λ NCS (8), the compound represented by the general formula (9)

The compound represented by the general formula (10) is obtained by reacting the compound with a base and water and Ζ or an alcohol.

(10) で表される化合物を製造する方法であって、 前記反応のすべてをワンポッ卜で行 うことを特徴とする製造方法。

A method for producing the compound represented by (10), wherein all of the reactions are carried out in one pot.

Further, the present invention provides a method for producing an aniline derivative shown below (in the following general formula, represents a lower alkyl group. R ₂ represents a lower alkoxy group. R ₄ and R ₅ may be the same or different, and each represents a hydrogen atom or a lower alkyl group, or may be taken together to form a _3- to 8-membered ring, Y or Y ₂ , Υ ₃ , Upsilon ₄ may be the same or different, are each a hydrogen atom, a halogen atom, an aromatic hydrocarbon optionally substituted lower alkoxy group optionally substituted with a group, a lower alkyl group, optionally cyclic may have a substituent Represents an alkyl group having 3 to 6 carbon atoms, or 一₅ Υ ₆ , wherein Υ ₅ and Υ ₆ may be the same or different, and each represents a hydrogen atom, a lower alkyl group, or May form a 3- to 8-membered ring Η represents an integer of 0 or 1.):

 General formula (11)

で表される化合物のァミノ基の保護基の脱保護反応を無機酸およびアルコール類 力、らなる脱保護剤を用いて行った後、 該無機酸および該アルコール類を留去する ことなく、 有機溶媒を加えることによって晶析させることを特徴とする、 一般式

After the deprotection reaction of the protecting group for the amino group of the compound represented by the formula (I) is performed using a deprotecting agent such as an inorganic acid and an alcohol, the organic acid is removed without distilling off the inorganic acid and the alcohol. General formula characterized by crystallization by adding a solvent

(2)

RT

で表される化合物の該無機酸塩を製造する方法。

A method for producing the inorganic acid salt of a compound represented by the formula:

 Further, the present invention provides a compound represented by the general formula (11), wherein the deprotection reaction of the protecting group for the amino group is carried out by using a deprotecting agent comprising an inorganic acid as the deprotecting agent. It is intended to provide a method for producing a compound represented by the formula (2) or an inorganic acid salt thereof.

Further, the present invention is to provide a method of manufacturing Anirin derivative represented by the following (in the following formulas, is a lower alkyl group. 1 ₂ Oyobi ₆ may be the same or different Each represents a lower alkoxy group, R ₃ represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and R ₄ and R ₅ may be the same or different, and each represents a hydrogen atom Or a lower alkyl group or may be taken together to form a _3- to 8-membered ring Υ ₂ , Υ ₃ , Υ 4 may be the same or different, and each represents a hydrogen atom, a halogen, atoms, an aromatic hydrocarbon lower alkoxy group optionally substituted with a group, a lower alkyl group, a cyclic ring which may have a substituent alkyl group of 3-6 carbon atoms, or represents an ΝΥ ₅ Υ ₆ , Where Υ ₅ , Υ ₆ May be the same or different, and may each be a hydrogen atom, a lower alkyl group, or may be taken together to form a 3- to 8-membered ring.η represents an integer of 0 or 1.) :

で表される化合物から一般式 （2) —General formula (12)

From the compound represented by the general formula (2)

で表される化合物を製造する方法であって、 一般式 （12) で表される化合物を 一般式 （8)

A method for producing a compound represented by the general formula (12)

0

 u

By reacting with the compound represented by Ra ^ NCS ( ₈₎ , the general formula (13)

0 S, C0R ₂

义 义 丄 Ha ~ ( ^CH 2) f? -N,

To R ₃ NR, C0R ₆

HH ′ ″ ⁴ A compound represented by the formula (13) is obtained, and this compound is reacted with a base and water and / or an alcohol to obtain a compound represented by the general formula (14) / ¹ ^

H ₂ N Person NR, C0R ₆

^H'γ ^ (14) Is obtained by alkylating the thioperia group of this compound,

で表される化合物を得、 この化合物のァミノ基の保護基の脱保護反応を無機酸か らなる脱保護剤を用いて行うことにより、 一般式 （2)

The compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid.

で表される化合物を製造する方法において、 一般式 （12) で表される化合物を 一般式 （8) で表される化合物と反応させることにより、 一般式 （13) で表さ れる化合物を得、 この化合物を塩基と水および Ζまたはアルコール類と反応させ ることにより、 一般式 （14) で表される化合物を得る反応をワンポットで行う ことを特徴とする製造方法。

In the method for producing a compound represented by the general formula (12), a compound represented by the general formula (13) is obtained by reacting a compound represented by the general formula (12) with a compound represented by the general formula (8). A process for producing a compound represented by the general formula (14) in a one-pot reaction by reacting the compound with a base, water, water or an alcohol.

Further, the present invention is, in there is provided a method of manufacturing Anirin derivative represented by the following (the following general formula, 1 ^ is a lower alkyl group. Feet ₂ Oyobi 1 ^ ₆ are the same or different Each represents a lower alkoxy group, R ₃ represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group, and R ₄ and R ₅ may be the same or different, Each represents a hydrogen atom, a lower alkyl group, or may be taken together to form a _3- to 8-membered ring, Υ ₂ , Υ ₃ , Υ 4 may be the same or different, a hydrogen atom, a halogen atom, an aromatic hydrocarbon lower alkoxy group optionally substituted with a group, a lower alkyl group, a cyclic ring which may have a substituent alkyl group of 3-6 carbon atoms, or, one Nyuupushiron ₅ indicates Upsilon _6, wherein, Upsilon ₅ Upsilon ₆ may be the same or different, are each a hydrogen atom, a lower Alkyl groups or together may form a 3- to 8-membered ring. n represents an integer of 0 or 1. ):

General formula (12)

で表される化合物から一般式 （2)

From the compound represented by the general formula (2)

HN V ⁵

 RiS '"Ν'γ ^ R,

A method for producing a compound represented by H ^γ 3 " ⁴ (2), which comprises converting a compound represented by the general formula (12) into a compound represented by the general formula (8):

0

 X

By reaction with R ₃ C NCS compound represented by _(8), the general formula (13)

R ₃

で表される化合物を得、 この化合物を塩基と水および/またはアルコール類と反 応させることにより、 一般式 （14)

で表される化合物を得、 この化合物のチォゥレア基をアルキル化し、 一般式 （1 5 )

The compound represented by the general formula (14) is obtained by reacting the compound with a base and water and / or alcohols.

A compound represented by the formula:

_{( 1 5 )} で表される化合物を得、 この化合物のァミノ基の保護基の脱保護反応を無機酸お よびアルコール類からなる脱保護剤を用いて行うことにより、 一般式 （2 )

By obtaining a compound represented by ₍₁₅₎ and performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid and an alcohol, the compound represented by the general formula (2)

で表される化合物を製造した後、 さらに該無機酸および該アルコール類を留去す ることなく、 有機溶媒を加えることによって晶析させることにより上記一般式

After producing the compound represented by the formula, the compound is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohol, thereby obtaining the compound represented by the above general formula.

(2) A method for producing the inorganic acid salt of the compound represented by (2). BEST MODE FOR CARRYING OUT THE INVENTION

 The following terms in the present invention have the following meanings unless otherwise indicated.

The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon chains, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl. Group, tert-butyl group, pentyl group, hexyl group and the like. As the lower alkyl group in the above, a methyl group, an ethyl group, and an isopropyl group are preferable, a methyl group and an ethyl group are more preferable, and an ethyl group is particularly preferable.

In R ₄ and R ₅ , the lower alkyl group which may form a 3- to 8-membered ring together is a linear or branched alkyl group having 1 to 6 carbon atoms or 3 carbon atoms. A cyclic alkyl group having from 1 to 6 carbon atoms. Examples of the linear or branched alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, sec Mono-butyl, tert-butyl, pentyl, hexyl, etc. Examples of the cyclic alkyl group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Examples thereof include a cycloheptyl group and a cyclooctyl group, and a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group and a cyclopentyl group are preferred.

As R ₄ and R ₅ , a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group are preferable, and a hydrogen atom, a methyl group, an ethyl group, A cyclopropyl group, a cyclobutyl group and a cyclopentyl group are preferred, and a hydrogen atom is particularly preferred.

As the lower alkyl group for Y, ₂ , ₃ and ₄ , a methyl group and an ethyl group are preferred.

In Υ ₂ , Υ ₃ , and Υ ₄ , among the optionally substituted cyclic C 3-6 alkyl groups, examples of the cyclic C 3-6 alkyl group include a cyclopropyl group and a cyclobutyl group And a cyclopentyl group and a cyclohexyl group, and a cyclopropyl group, a cyclobutyl group and a cyclopentyl group are preferred.

Upsilon _2, Upsilon _3, in Upsilon _4, the alkyl group having 3 to 6 carbon atoms cyclic ring which may have a substituent, examples of the substituent include methyl group, Echiru group, .eta. propyl group and isopropyl group And a methyl group and an ethyl group are preferred.

The lower alkoxy group means an alkoxy group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methoxy, ethoxy, η-propoxy, isopropoxy, and η. —Butoxy, sec —butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy And so on. As the lower alkoxy group for R ₂ , R ₃ and R ₆ , a methoxy group, an ethoxy group and a tert-butoxy group are preferred.

Υρ Υ _2, Υ _3, the aromatic hydrocarbon substituted lower § alkoxy group optionally substituted with a group in Upsilon _4, a methoxy group, an ethoxy group, _eta - propoxy group, iso epoxy group, .eta. butoxy group, sec _ Butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, benzyloxy group and the like are preferable, and methoxy group, ethoxy group and benzyloxy group are particularly preferable.

 Examples of the aromatic hydrocarbon group include a phenyl group, a tolyl group, and a naphthyl group, and a phenyl group is preferable.

 Halogen atom refers to fluorine, chlorine, bromine and iodine.

 As the halogen atom for X, chlorine and bromine are preferable.

The halogen atom in Y ₂ , ₃ and ₄ is preferably a chlorine atom, a fluorine atom or a bromine atom, more preferably a chlorine atom or a fluorine atom.

In the formulas ( ₅₎ and ( ₆₎ , the 3- to 8-membered ring which may be formed together includes, for example, an aziridine-1-yl group, an azeridin-1-yl group, a pyrrolidine-1-yl group, a piperidine — 1-yl group, preferably pyrrolidine-1-yl group and piperidine-1-yl group, more preferably pyrrolidine-1-yl group.

Upsilon _5, as Upsilon ₆ is a hydrogen atom, a methyl group, Echiru group, pyrrolidin - 1 Iru group, piperidine - 1-I le group are preferable, a hydrogen atom, a methyl group, Echiru group, Pi port lysine - 1 An r group is preferred.

Upsilon _2, Upsilon _3, as the Upsilon _4, preferably a hydrogen atom, a fluorine atom, a chlorine atom, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methoxy group, an ethoxy group, Benjiruokishi group, represented by -ΝΥ ₅ Υ ₆ that group (wherein, Upsilon _5, Upsilon ₆ in. to represent the the same meaning) is more preferably a hydrogen atom, a methyl group is preferable.

Y _2, Upsilon _3, among Upsilon _4, any two, preferably in the range of three or four of the hydrogen atoms, preferably further in the range of any three of the hydrogen atoms.

 η represents an integer of 0 or 1, and is preferably 0.

In the general formula (2) of the present invention, the group represented by — (CH ₂ ) _n CR ₄ R ₅ NH ₂ is preferably a meta-position or a para-position with respect to the alkylisothioperia group, Further Is preferably in the meta position.

 Examples of the alkali metal in I ^ include lithium, sodium, potassium, rubidium, and cesium, with sodium and potassium being preferred. Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, pentanol, and hexanol.

 Examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid and the like. Examples of the organic acid include acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid, and trifluoroacetic acid.

 DBU means 1,8-diazabicyclo [5.4.0] pendase 7-ene.

 Examples of the diluting agent include di-tert-butyl dicarbonate, tert-butylazidoformate, 2-tert-butoxycarbonyloxyimino-2--2-phenylacetonitrile, and S-tert-butoxy. Carbonyl-4,6-dimethyl-12-mercaptopyrimidine; [p_ (tert-butoxycarbonyloxy) phenyl] dimethylsulfonium methanesulfonate;

 Performing the reaction in one pot means that when performing a plurality of reactions, the reactions are performed without isolating or purifying the reaction product of each reaction. The in-pot reaction referred to here includes not only a case where a single reaction vessel is used, but also a case where a plurality of reaction vessels are used without isolation and purification, for example, when a reaction vessel is moved.

 Esters include methyl acetate, ethyl acetate, butyl acetate and the like. Examples of ethers include getyl ether, tetrahydrofuran, dioxane, and the like.

An example of the production method of the present invention is shown below (reaction route 1). Reaction path 1 Phthalimidization

1) Force bamate

 Deprotection »Reaction 2) S-source reaction

 (Five)

义 丄 Bee (CH ₂ ) fr9-NHCOR ₂

H 丫 3 ^Y 4 ⁴

(10)

(Ten)

Alki JUi-Dani Deprotection If Reaction

 (11)

HN ^

_R ^R 1 s ° Person WY / A ^™™ 2 or (2) hydrochloride

3 Y ₄

 (2)

(In the formula, X,. 1 ^ is that a halogen atom, a lower alkyl group. R ₂ represents a lower alkoxy group. 1 ₄ Oyobi 1 ^ ₅ may be the same or different, Each may be a hydrogen atom, a lower alkyl group, or may be taken together to form a _3- to 8-membered ring, and Υ ₂ , Υ ₃ , Υ ₄ may be the same or different, and Atom, halogen atom, lower alkoxy group, lower alkyl group, cyclic group which may have a substituent Represents an alkyl group having 3 to 6 carbon atoms. n represents an integer of 0 or 1. Hereinafter, each step will be described along Reaction Path 1.

 First, a compound represented by the general formula (4) is obtained by reacting a compound represented by the general formula (1) with a compound represented by the general formula (3). The compound represented by the general formula (3) used in the phthalimidation reaction includes, for example, alkali metal salts of phthalimide such as sodium phthalimide and potassium phthalimide, and phthalimide DBU salt. Is preferred. The solvent to be used is preferably a solvent that does not affect the reaction, for example, dimethylformamide, acetonitrile, and the like are preferable, and dimethylformamide is particularly preferable. The reaction temperature is preferably about 0 to 80 T: more preferably about 30 ° C. The reaction time is preferably from about 30 minutes to 3 hours, particularly preferably from 1 hour to 2 hours.

 The obtained compound represented by the general formula (4) is subjected to a deprotection reaction to deprotect a phthalimide group. Examples of the deprotecting agent include hydrazine, a methylamine methanol solution, a methylamine aqueous solution and the like, and preferably a methylamine methanol solution and a methylamine aqueous solution. Of these, a 40% methylamine methanol solution and a 40% methylamine aqueous solution are preferable, and a 40% methylamine methanol solution is particularly preferable. The solvent used is preferably a solvent that does not affect the reaction, for example, methanol, acetonitrile, and the like are preferable, and methanol is particularly preferable. The reaction temperature is preferably from 0 ° C. to the boiling point of the reaction mixture, and particularly preferably a temperature near the boiling point of the reaction mixture. The reaction time is about 30 minutes to 5 hours, preferably about 1 hour to 2 hours.

The obtained compound represented by the general formula (5) is reacted with a carboxylate agent to convert an amino group into a propyl bamate, and the nitro group is reduced, whereby the compound represented by the general formula (7) is obtained. Get. Here, it is preferable to perform the two-step reaction of the formation of a solvent and the reduction of a nitro group in one pot. In the first-stage amino group-forming reaction, for example, di-tert-butyl dicarbonate, tert-butyl azidoformate, 2-tert-butoxycarponyloxy minnow 2 —Phenylacetonitrile, S—tert-butoxycarbonyl _ 4, 6-Dimethyl-2-mercaptopyrimidine, [p- (tert-butoxycarbonyloxy) phenyl] dimethylsulfonium methanesulfonate, etc., and di-tert-butyl dicarbonate is preferred. The solvent used is preferably a solvent that does not affect the reaction, for example, ethyl acetate, toluene, tert-methyl methyl ether, and the like are preferable, and ethyl acetate is particularly preferable. The reaction temperature is preferably from 110 to the boiling point of the reaction mixture, more preferably from 5 ° C to the boiling point of the reaction mixture. The reaction time is about 30 minutes to 3 hours, preferably about 2 hours.

 The reduction reaction of the nitro group in the second step can be performed by a usual catalytic hydrogenation reaction, but catalytic hydrogenation using a palladium-carbon catalyst is preferable. As the hydrogen source, ammonium formate and the like can be used in addition to hydrogen. When hydrogen is used as the hydrogen source, the catalytic hydrogenation reaction may be performed under pressure. The solvent used is preferably a solvent that does not affect the reaction, for example, alcohols are preferable, and methanol is particularly preferable. The reaction temperature is preferably from 1 ° C. to the boiling point of the reaction mixture, particularly preferably about 40 to 60. The reaction time is about 1 to 5 hours, preferably about 2 to 3 hours.

The obtained compound represented by the general formula (7) is reacted with the compound represented by the general formula (8) to form an acylthiodiarea. Next, the acyl group is removed by hydrolysis or solvolysis. Here, the acylthioureation, hydrolysis or solvolysis reaction is preferably performed in one pot. In the first step of the acylthioureation reaction, the solvent used is preferably a solvent that does not affect the reaction, for example, acetone, toluene, ethyl acetate and the like are preferable, and acetone is particularly preferable. The reaction temperature is preferably a temperature from 0 "C to the boiling point of the reaction mixture. The reaction time is from about 30 minutes to about 3 hours, and preferably from about 30 minutes to about 1 hour. The removal is carried out by a conventional method of hydrolysis or solvolysis of an acyl group, preferably by deprotection under basic conditions, for example, potassium carbonate, sodium hydroxide, or carbonate. Inorganic bases such as sodium hydrogen and the like, metal alkoxides such as sodium methoxide and sodium methoxide, etc. are preferable, and potassium carbonate is preferable.The reaction solvent used does not affect the reaction. Solvent is preferable, for example, water, alcohols and the like are preferable, and methanol is particularly preferable. The reaction temperature includes a temperature from 0 to the boiling point of the reaction mixture, and a temperature near the boiling point of the reaction mixture is preferable. The reaction time is about 30 minutes to about 1 hour, preferably about 30 minutes. If this acylthioureation, hydrolysis or carosol decomposition reaction is performed in one pot, after the completion of the first-stage acylthioureation reaction, only the second-stage reaction solvent and base need to be added, and the first-stage reaction solvent is distilled off. do not have to. As the compound represented by the general formula (8) used in the acylthioureation reaction, a commercially available compound may be used, or the compound may be synthesized from an acid halide and a thiocyanic acid compound. Here, examples of the compound represented by the general formula (8) include benzoyl thiocyanate and ethoxycarbonyl isothiocyanate, and benzoyl thiocyanate is preferable. When the compound represented by the general formula (8) is synthesized from an acid halide and a thiocyanate compound, a known method, for example, described in JP-A-8-269006 Examples of the acid halide used include, for example, benzoyl chloride, acetyl chloride, and the like. Benzoyl chloride is preferred.Examples of the thioic acid compound used include: Examples thereof include metal salts of potassium thiocyanate such as potassium thiocyanate and sodium thiocyanate, and ammonium thiocyanate, with sodium thiocyanate being preferred.

 An alkylating agent is allowed to act on the obtained compound represented by the general formula (10) to alkylate the thiourea group. Examples of the alkylating agent include an alkyl halide, a dialkyl sulfate, and an alkyl sulfonate, and an alkyl halide is preferable. The solvent to be used is preferably a solvent which does not affect the reaction, for example, acetone, ethyl acetate, acetonitrile, alcohols and the like are preferable, and ethyl acetate is particularly preferable. The reaction temperature is preferably from room temperature to the boiling point of the reaction mixture, and particularly preferably a temperature near the boiling point of the reaction mixture. The reaction time is preferably about 30 minutes to 3 hours, particularly preferably about 1 hour to 2 hours.

The deprotection reaction of the protecting group for the amino group of the compound represented by the general formula (11) is carried out by a usual deprotection method. Examples of the deprotecting agent include inorganic acids and organic acids, with inorganic acids being preferred. Examples of inorganic acids include hydrochloric acid, sulfuric acid, nitric acid And hydrochloric acid is preferred. Examples of the solvent used in the deprotection reaction include alcohols, and ethanol is preferable, but alcohols need not be used. That is, the deprotecting agent used in this deprotection reaction is preferably an ethanolic hydrochloric acid solution, particularly preferably a 4N ethanolic hydrochloric acid solution. The reaction temperature is from 0 to the boiling point of the reaction mixture, and preferably about 50. The reaction time is about 30 minutes to 3 hours, preferably about 2 hours.

 The obtained inorganic acid salt of the compound represented by the general formula (2) may optionally be subjected to a reaction solvent after the completion of the deprotection reaction of the protecting group for the amino group of the compound represented by the general formula (11). It can be produced by crystallization by adding an organic solvent or the like without leaving. Examples of the organic solvent include esters and ethers, and esters are preferable, and ethyl acetate is particularly preferable. The crystallization temperature is preferably from about 0 to room temperature, particularly preferably about 25. The crystallization time is preferably about 1 to 3 hours, particularly preferably about 1.5 to 2 hours.

 The inorganic acid salt of the compound represented by the general formula (2) is produced by adding an inorganic acid and an organic solvent to the compound represented by the general formula (2), if necessary. be able to.

A compound represented by the general formula (2), wherein at least one of Y and Y ₂ , ₃ and Υ ₄ is — Υ ₅ Υ ₆ (where Υ ₅ and Υ ₆ are May be the same or different, and may each be a hydrogen atom, a lower alkyl group, or may be taken together to form a 3- to 8-membered ring.) Is a compound represented by the general formula (4) there are, Upsilon have Upsilon _2, Upsilon _3, among Upsilon _4, at least one of an ΝΥ ₅ Υ ₆ compounds (here, Upsilon _5, Upsilon ₆ represent. as defined above) as the starting raw material, It can be produced by performing the same steps as the steps following the deprotection reaction of the general formula (4) in the above reaction route 1. Here, a compound represented by the general formula (4), wherein at least one of Υ ₂ , Υ ₃ and Υ ₄ is — ΝΥ ₅ Υ ₆ (where Υ _{5 and} 、 6 are ) Can be produced by a known method, for example, a method described in JP-A-8-269006.

In addition, the compound represented by the general formula (2) is obtained by using the compound represented by the general formula (5) as a starting material, after the reaction of the reaction formula 1 with the compound represented by the general formula (5). It can be manufactured by going through the same steps as the above steps. Here, the compound represented by the general formula (5) can be obtained by a known method, for example, a method described in Japanese Patent Application Laid-Open No. 8-269006, in addition to the method disclosed in the present specification. Can also be manufactured.

 In addition, the compound represented by the general formula (2) is obtained by using the compound represented by the general formula (7) as a starting material in the same manner as the subsequent steps of the acylthiourea-forming reaction of the general formula (7) in the above reaction path 1. It can be manufactured through a process. Where the general formula

The compound represented by (7) can be produced by a known method, for example, a method described in JP-A-8-269006, in addition to the method disclosed in the present specification. Can be

 In addition, the compound represented by the general formula (2) is obtained by using the compound represented by the general formula (12) as a starting material in the same manner as in the steps after the acylthiourea reaction of the general formula (7) in the above reaction path 1. Can be produced through the steps of Here, the compound represented by the general formula (12) can be produced by a known method, for example, a method described in JP-A-8-269006. Further, the compound represented by the general formula (12) can be obtained by starting from the compound represented by the general formula (1) as a starting material, for example, the method disclosed in the present specification, for example, Examples 50 and 51. It can also be manufactured by a manufacturing method. Example

 Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

In the following examples, the multiple of the capacity with respect to the weight value indicates a capacity obtained by multiplying the multiple of the capacity per 1 kg of weight by 1 L. For example, “dissolving 3-nitrobenzyl chloride in dimethylformamide (5 times the weight of 3-nitrobenzyl chloride)” means “3-nitrobenzyl chloride is 5 L of dimethyl per 1 kg of 3-nitrobenzyl chloride. Dissolves in formamide. " Example 1: Synthesis of N —— (3-nitro-benzyl) phthalimide Dissolve 3-nitrobenzoyl chloride in dimethylformamide (5 times the weight of 3-nitrobenzyl chloride), add potassium phthalimide (1.1 equivalents to 3-nitrobenzyl chloride), and add the internal temperature. Stir at 0 ° C for 2 hours. Water (10 times the weight of the salt of 3-nitrobenzyl) is added to the reaction mixture, and the mixture is stirred at an internal temperature of 30 for 30 minutes. The resulting suspension is filtered and dried under reduced pressure at 55 for 2 hours to give the title compound. Example 2: Synthesis of tert-butyl N- (3-aminobenzyl) potassium rubbamate 40% methylamine was added to a mixture of the compound obtained in Example 1 and methanol (10 times the weight of the compound obtained in Example 1). A methanol solution (10 equivalents to the compound obtained in Example 1) is added, and the mixture is refluxed for 1 hour. After concentrating the reaction mixture under reduced pressure, ethyl acetate (8 times the weight of the compound obtained in Example 1) is added. The suspension was cooled to 5 ° C, di-tert-butyl dicarbonate (1.8 equivalents to the compound obtained in Example 1) was added, and the mixture was stirred at 5 for 30 minutes. After stirring at 25 ° C for 30 minutes, the mixture is heated under reflux for 1 hour. The mixture is cooled to 5 ° C, a 40% methanol solution of methylamine (1.2 equivalents to the compound obtained in Example 1) is added, and the mixture is stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and after purging with nitrogen, methanol (5 times the weight of the compound obtained in Example 1) and 10% palladium-carbon (50% water content, 2 mol 1%) is added to the obtained compound, and the mixture is heated at an internal temperature of 50. Subsequently, the atmosphere is replaced with hydrogen and stirred for 3 hours. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. Methanol (5 times the weight of the compound obtained in Example 1) and water (7 times the weight of the compound obtained in Example 1) are reduced to 25%. After stirring for 30 minutes, water (1 volume of the compound obtained in Example 1) was added, and the mixture was stirred for 30 minutes, cooled to 0, and stirred for 1 hour. The resulting suspension is filtered and the filtrate is dried under reduced pressure at 40 for 2 hours to give the title compound. Example 3: N- (3-thioureidobenzyl) -powered rubamic acid! : Synthesis of ert_butyl

Sodium thiocyanate (1.2 equivalents to the compound obtained in Example 2) After cooling a mixture of acetone and acetone (6 times the weight of the compound obtained in Example 2) to 5 ° C, benzoyl chloride (1.1 equivalents to the compound obtained in Example 2) was added, and 3 After stirring for 0 minutes, a solution of the compound obtained in Example 2 in acetone (4 times the weight of the compound obtained in Example 2) is added. After stirring at 5 for 5 minutes, heat to reflux for 30 minutes. After cooling the reaction solution to 30, methanol (5 times the weight of the compound obtained in Example 2) and lithium carbonate (1.2 equivalents to the compound obtained in Example 2) were added, and Heat to reflux for 0 minutes. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water (each 5 times the compound weight obtained in Example 2) were added. The mixture was heated and refluxed to dissolve the concentrate. The ethyl acetate layer is concentrated under reduced pressure. Ethyl acetate (8 times the weight of the compound obtained in Example 2) was added to this concentrate, and the mixture was heated under reflux to dissolve. After cooling to 60, seed crystals (the title compound, compound weight obtained in Example 2) were added. 0.3% by weight) and stir for 1 hour. After cooling to 301 :, add n-hexane (8 times the weight of the compound obtained in Example 2) and stir for 15 minutes. The resulting suspension is filtered, and the filtrate is dried under reduced pressure at 50 for 2 hours to give the title compound. Example 4: Synthesis of tert-butyl N- (3- (S-methylisothioureido) benzyl) caprate

To a mixture of the compound obtained in Example 3 and ethyl acetate (5 times the weight of the compound obtained in Example 3) was added methyl iodide (1.5% by weight of the compound obtained in Example 3) as a reactant. And reflux for 1.5 hours. The reaction solution is cooled to 25 ° C, methanol (1.5 times the weight of the compound obtained in Example 3) is added, and the mixture is heated and dissolved. The organic layer is washed twice with an aqueous saturated sodium bicarbonate solution (5 times the weight of the compound obtained in Example 3), and then washed with saturated saline (5 times the weight of the compound obtained in Example 3). The organic layer was concentrated under reduced pressure, ethanol (3 times the weight of the compound obtained in Example 3) was added to dissolve the concentrate, and water was added at 25 (1.8 of the weight of the compound obtained in Example 3). ) And seed crystals (the title compound, 0.1% by weight of the compound obtained in Example 3) and stirred for 1 hour. Further, water (2 times the weight of the compound obtained in Example 3) is added, and the mixture is stirred at 0 for 1 hour. The suspension is filtered, and the residue is dried under reduced pressure at 50 ° C for 2 hours to obtain the title compound. Example 5: Synthesis of N- (3-aminomethylphenyl) -1-S-methylisothiourea.dihydrochloride

To the compound obtained in Example 4 is added a 4 N ethanol solution of hydrochloric acid (4 times the weight of the compound obtained in Example 4), and the mixture is stirred at 50 for 1.5 hours. The reaction solution is cooled to 25 T :, ethyl acetate (6 times the weight of the compound obtained in Example 4) is added, and the mixture is stirred at 25 with 1.5 hours. The suspension is filtered and the filtrate is dried under reduced pressure at 50 for 2 hours to give the title compound. Example 6: Synthesis of tert-butyl N- (3- (S-ethylisothioureido) benzyl) carbamate

The title compound was obtained in the same manner as in Example 4 using the compound obtained in Example 3 as a starting material and acetyl iodide as a reactant. Example 7: Synthesis of N- (3-aminomethylphenyl) -l-S-ethylisothiodrea, dihydrochloride

Using the compound obtained in Example 6 as a starting material, the title compound is obtained in the same manner as in Example 5. Example 50 Synthesis of di-tert-butyl N- (3-nitrobenzyl) iminodicarboxylate

3-Nitrobenzyl chloride was dissolved in dimethylformamide (2 times the weight of 3-nitrobenzyl chloride), and sodium hydride (1.1 equivalents to 3-nitrobenzyl chloride) and iminodicarboxylic acid At 0, add dropwise to a solution of tert-butyl (1.1 equivalents to 3-nitrobenzyl chloride) in dimethylformamide (3 times the weight of 3-nitrobenzyl chloride). The mixture is stirred at 25 for 1 hour, then heated to 80 and stirred for 1 hour. The reaction solution is concentrated under reduced pressure, water is added, extracted with ethyl acetate, washed with saturated saline, and the organic layer is concentrated under reduced pressure to obtain the title compound. Example 51 Synthesis of N- (3-aminobenzyl) iminodicarboxylic acid di-tert-butyl

 After replacing with nitrogen the compound obtained in Example 50, methanol (5 times the weight of the compound obtained in Example 1) and 10% palladium-carbon (50% water content, obtained in Example 1) 2 mol 1%) to the resulting compound, and heat to an internal temperature of 50. Subsequently, the atmosphere is replaced with hydrogen and stirred for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Methanol (5 times the weight of the compound obtained in Example 1) and water (7 times the weight of the compound obtained in Example 1) were diluted with 25. After stirring for 30 minutes, water (1 volume of the compound obtained in Example 1) is added, and the mixture is stirred for 30 minutes, cooled to 0, and stirred for 1 hour. The resulting suspension is filtered and the filtrate is dried under reduced pressure at 40 for 2 hours to give the title compound. Example 52 2: Synthesis of di-tert-butyl N- (3-thioperidobenzyl) iminodicarboxylate

 Using the compound obtained in Example 51 as a starting material, the title compound is obtained in the same manner as in Example 3. Example 53 Synthesis of di-tert-butyl N- (3- (S-methylthioureidobenzyl) iminodicarboxylate

 Using the compound obtained in Example 52 as a starting material, the title compound is obtained in the same manner as in Example 4. Example 54 Synthesis of N- (3- (aminomethylphenyl) -S-methylisothiourea dihydrochloride

Using the compound obtained in Example 53 as a starting material, the title compound is obtained in the same manner as in Example 5. Example 55 Synthesis of di-tert-butyl N- (3- (S-ethylthioureidobenzyl) iminodicarboxylate Using the compound obtained in Example 52 as a starting material, the title compound is obtained in the same manner as in Example 6. Example 56: Synthesis of N- (3- (aminomethylphenyl) -S-ethylisothiourea dihydrochloride

Using the compound obtained in Example 55 as a starting material, the title compound is obtained in the same manner as in Example 7. Tables 1 to 5 further show production examples according to the present invention. The table shows the chemical formulas of the starting materials and the final products and the preparation methods. In the “Production method” in the table, for example, “1, 2, 3, 4, 5” means the same as the method described in Examples 1, 2, 3, 4, and 5 described above. Means to do.

Table 1

表一 2

Table 1 2

表— 3

Table 3

表— 4

Table—4

表一 5

Table 1 5

また、 表— 1から表一 5にあげられる最終生成物の構造式名を以下に示す。 実施例 5、 5 4

The names of the structural formulas of the final products shown in Tables 1 to 5 are shown below. Examples 5, 5 4

 N- (3-Aminomethylphenyl) mono S-methylisothioprea dihydrochloride Examples 7, 56

 N- (3-Aminomethylphenyl) -S-ethylisothiopurea 'dihydrochloride Example 8

 N- (3-aminomethyl-4-fluorophenyl) mono-S-methylisothiourea.dihydrochloride

Example 9

 N- (3-aminomethyl-4-fluorophenyl) -S-ethylisothiourea dihydrochloride

Example 10

 N- (3-aminomethyl-2-chlorophenol) -S-methylisothiourea dihydrochloride

Example 1 1

 N- (3-Aminomethyl-1-2-chlorophenyl) -S-ethylisothioprea 'dihydrochloride

Example 1 2, 6 3

 N- (3-Aminomethyl-2-methylphenyl) -S-methylisothiourea dihydrochloride

 Examples 13 and 6 4

 N— (3-Aminomethyl-1-2-methylphenyl) -1-S-ethylisothiourea-Example 14

 N- (3-aminomethyl-4-methoxyphenyl) -S-methylisothiourea dihydrochloride

 Example 15

N- (3-aminomethyl-4-methoxyphenyl) mono-S-ethylisothioureate Example 16

 N- (3- (1-aminoethyl) phenyl) mono-S-methylisothiourea-dihydrochloride

Example 17

 N- (3- (1-aminoethyl) phenyl) -S-ethylisothioprea.dihydrochloride

Example 18

 N- (3- (1-amino-1-methylethyl) phenyl) -S-methylisothiourea dihydrochloride

Example 19

 N- (3- (1-Amino-1-methylethyl) phenyl) S-ethylisothioprea dihydrochloride

Example 20

 N- (3-aminomethyl-14-ethoxyphenyl) -1-S-methylisothiourea dihydrochloride

Example 21

 N- (3-aminomethyl-4-ethoxyphenyl) -S-ethylisothiourea dihydrochloride

Example 22

 N- (3-aminomethyl-4-benzyloxyphenyl) -S-methylisothioprea dihydrochloride

Example 23

 N- (3-Aminomethyl-1-4-benzyloxyphenyl) -1-S-ethylisothioprea dihydrochloride

 Example 24

 N- (3- (1-amino-1-methylethyl) 1-4-methoxyphenyl) 1S-methylisothioprea 'dihydrochloride

 Example 25

N- (3- (1-amino-1-methylethyl) 1-4-methoxyphenyl) S 1-ethylisothiourea dihydrochloride

Example 26

 N- (3- (1-Aminocyclopropyl) phenyl) -S-methylisothiourea dihydrochloride

Example 27

 N- (3- (1-aminocyclopropyl) phenyl) S-ethylisothiourea dihydrochloride

Example 28

 N- (3- (1-aminocyclobutyl) phenyl) mono-S-methylisothiourea dihydrochloride

Example 29

 N- (3- (1-aminocyclopropyl) phenyl) S-ethylisothiourea dihydrochloride

Example 30

 N— (3- (1-aminopropyl) phenyl) S-methylisothiopereic acid

Example 31

 N- (3- (1-aminopropyl) phenyl) -S-ethylisothiopurea = hydrochloride

 Example 32

 N- (3-aminomethyl-4-dimethylaminophenyl) mono-S-methylisothioprea dihydrochloride

 Example 33

 N- (3-aminomethyl-4-dimethylaminophenyl) mono-S-ethylisothiourea dihydrochloride

 Example 34

 N- (3-Aminomethyl-4-1 (pyrrolidine-1-1yl) phenyl) -S-Methylisothiourea trihydrochloride

Example 35 N- (3-Aminomethyl-1- 4- (pyrrolidine-11-yl) phenyl) -S-ethylisothiourea trihydrochloride

Example 36

 N- (3- (1-aminocyclopentyl) phenyl) mono-S-methylisothiourea dihydrochloride

Example 37

 N- (3- (1-aminocyclopentyl) phenyl) 1-S-ethylisothiourea dihydrochloride

Example 38

 N- (4- (2-aminoethyl) phenyl) mono-S-methylisothiourea-dihydrochloride

Example 39

 N- (4- (2-aminoethyl) phenyl) -S-ethylisothiourea dihydrochloride

Example 40

 N- (3-aminomethyl-4-methylphenyl) -S-methylisothiourea dihydrochloride

Example 41

 N— (3-Aminomethyl-4-methylphenyl) -S-ethylisothiourea dihydrochloride

Examples 42 and 57

 N— (3-Aminomethyl-4-ethylfurphenyl) -S-methylisothioprea dihydrochloride:

 Examples 43 and 58

 N— (3-Aminomethyl-4-ethylphenyl) -S-ethylisothiourea dihydrochloride

 Examples 44 and 59

N- (3-Aminomethyl-4-methylaminophenyl) -S-methylisothioperia trihydrochloride Example 45, 60

 N- (3-Aminomethyl-14-methylaminophenyl) -S-ethylisothiourea .Trihydrochloride

Examples 46 and 61

 N- (3-Aminomethyl-1-4-ethylaminophenyl) 1-S-methylisothioperia trihydrochloride

Examples 47 and 62

 N- (3-Aminomethyl-4-ethylaminophenyl) S-ethylisothioperia trihydrochloride

Example 48

 N- (3-Aminomethyl _4_ (N-ethyl-N-methylamino) phenyl) —S-methylisothioprea trihydrochloride

Example 49

 N— (3-aminomethyl-4_ (N-ethyl _N-methylamino) phenyl) —S-ethylisothiourea trihydrochloride

Example 65

 N- (3-Aminomethyl-2,4-dimethoxyphenyl) mono-S-methylisothiourea dihydrochloride

Example 66

 N- (3-Aminomethyl-2,4-dimethoxyphenyl) -S-ethylisothioprea dihydrochloride Example 67: Synthesis of N- (3_nitro-12-methylbenzyl) phthalimide

3-Nitro-2-methylbenzyl chloride (5.0 kg) was dissolved in dimethylformamide (23.6 kg), potassium phthalimide (5.5 kg) was added, and the mixture was stirred at an internal temperature of 30 for 2 hours. . Water (50.0 kg) was added to the reaction solution, and the mixture was stirred at an internal temperature of 30 for 30 minutes. The obtained suspension was filtered and dried under reduced pressure at 55 ° C for 2 hours to obtain the title compound (8.1 kg, yield 100%, pale yellow crystalline powder). - Dragon R (CDC 1 _3, pm)

 8.0 to 7.5 (6H, m), 7.2 to 7.3 (1H, t), 4.9 (2H, s), 2.6 (3H, s).

_{^{1 3 C- NMR (CDC 1 3}} , p pm)

 167.9, 151.4, 136.9, 134.3 32.5, 131.8 130.3, 126.5, 123.5, 23.4, 39.2, 14.7.

Melting point: 150.3. Example 68: Synthesis of t-rt-butyl N- (3-amino-2-methylbenzyl) caprate

 To a mixture of the compound (6.5 kg) obtained in Example 67 and methanol (51.4 kg) was added a 40% methylamine-methanol solution (17.0 kg), and the mixture was heated under reflux for 1 hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate (47.0 kg) was added. Cool the suspension to 5 ° C, add di-tert-butyl dicarbonate (8.6 kg), stir at 5 for 30 minutes, stir at 25 ° C for 30 minutes, and heat for 1 hour Refluxed. The mixture was cooled to 51 :, a 40% methylamine-methanol solution (2.1 kg) was added, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and after purging with nitrogen, methanol (25.7 kg) and 10% palladium-carbon (0.9 kg) were added to the concentrate, and the mixture was heated to an internal temperature of 30. Subsequently, the atmosphere was replaced with hydrogen and stirred for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, methanol (25.7 kg) and water (45.5 kg) were added at 25, and the mixture was stirred for 30 minutes, and then water (6.5 kg) was further added. After stirring for 30 minutes, the mixture was cooled to 0 and stirred for 1 hour. The resulting suspension is filtered and the filtrate is filtered.

The mixture was dried under reduced pressure at 40 for 2 hours to give the title compound (3.8 kg, yield 73.7%, white crystalline powder).

_{NMR (CDC 1 3, p pm} )

 7.1-6.9 (1H, t), 6.7-6.6 (2H, dd), 4.7 (1H, br), 4.3 (2H, d), 3.6 (2H , S), 2.1 (3H, s), 1.

5 (9H, s).

_{^{13 C- NMR (CDC 1 3,}} pm) 155.5, 145.0, 137.0, 133.8, 126.4, 123.1, 120.6, 119.2, 11.4, 43.4, 28.4, 12.2.

Melting point: 80.2 Example 69: Synthesis of t-butyl n- (3-thioureido-2-methylbenzyl) tetrabutyl rubinate

 After cooling a mixture of sodium thiocyanate (1.5 kg) and acetone (16.6 kg) to 5, adding benzoyl chloride (2.3 kg) and stirring for 30 minutes, it was obtained in Example 68. The compound (3.5 kg) was added. After stirring at 5 for 5 minutes, the mixture was heated under reflux for 30 minutes. After cooling the reaction solution to 30 ° C, methanol (13.9 kg) and potassium carbonate (2.5 kg) were added, and the mixture was heated under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate and water (15.8 kg and 17.5 kg) were added, and the mixture was heated under reflux to dissolve the concentrate, cooled to 30 and the ethyl acetate layer was concentrated under reduced pressure. . Ethyl acetate (25.3 kg) was added to this concentrate, and the mixture was heated under reflux to dissolve. After cooling to 60 ^, seed crystals (llg) were added and the mixture was stirred for 1 hour. After cooling to 30, n-hexane (18.5 kg) was added and the mixture was stirred for 15 minutes. The resulting suspension was filtered, and the precipitate was dried under reduced pressure at 5 O: for 2 hours to give the title compound (3.8 kg, 85.2%, white crystalline powder).

_{XH- NMR (CDC 1 3> P} pm)

 8.5 (1H, s), 7.3 to 7.1 (3H, m), 5.0 (1H, br), 4.3 (2H, s), 2.2 (3H, s), 1.4 (9H, s).

_{^{1 3 C- NMR (CDC 1 3}} , pm)

 181.3, 155.7, 139.1, 135.1, 134.0, 128.0, 127.1, 126.6, 79.8, 42.8, 28.3, 13.3.

 Melting point: 158.3 Example 70: Synthesis of monobutyl N- (3- (S-methylisothioperido) -l-methylbenzyl) tetrabutyl rubinate

Compound obtained in Example 69 (3.4 kg) and ethyl acetate (15.3 kg) The mixture was heated under reflux for 1.5 hours using iodo chill (2.7 k) as a reactant. The reaction solution was cooled to 25, methanol (4.0 kg) was added, and the mixture was dissolved by heating. The organic layer was washed twice with a saturated aqueous sodium hydrogen carbonate solution (17.0 kg), and then washed with a saturated saline solution (17.0 kg). The organic layer was concentrated under reduced pressure, ethanol (8.0 kg) was added to dissolve the concentrate, water (6.2 kg) and seed crystals (3.4 g) were added at 25 ° C, and the mixture was stirred for 1 hour. . Further, water (6.8 kg) was added, and the mixture was stirred at 0 for 1 hour. The suspension was filtered, and the precipitate was dried under reduced pressure at 50 for 2 hours to give the title compound (3.2 kg, yield 86.8%, white crystalline powder).

_{XH- NMR (CDC 1 3, P} pm)

 7.; ~ 7.0 (1H, t), 7.0 to 6.9 (1H, t), 6.8 to 6.7

(1H, t), 4.7 (1H, br), 4.3 (1H, br), 4.3 (2H, d), 3.1-3.0 (2H, m), 2.2 (4H, s), 2.1 (3H, br)

1.5 (12H, s).

_{^{13 C- NMR (CDC 1 3,}} p pm)

 155.7, 153.4, 147.9, 137.8, 128., 126.6,

123.0, 120.5, 79.4, 43.2, 31.0, 287, 25.0,

15.1, 12.9.

Melting point: 97.2V, Example 7 1: Synthesis of N- (3-aminomethyl-2-methylphenyl) -S-methylisothioperia dihydrochloride

 To a compound (2.8 kg) obtained in Example 70 was added a 4N hydrochloric acid ethanol solution (10.

3 kg) and stirred at 50 for 1.5 hours. The reaction solution was cooled to 25, ethyl acetate (15.2 kg) was added, and the mixture was stirred at 25 for 1.5 hours. The suspension was filtered, and the precipitate was dried under reduced pressure at 50 ° C for 2 hours to give the title compound (2.35 kg, yield 91.6%, white crystalline powder).

^X H—NMR (DMS〇, p pm)

 1 1.9 (1H, br), 9.7 (1H, br), 8.7 (3H, s), 7.

6-7.5 (1H, d), 7.4-7.3 (1H, t), 7.3-7.2 (1H, s), 4.0 (2H, s), 3.6 (1H, s), 3.3 (2H, s), 2.2 (3H, s), 1.3 (3H, t).

1 ³ C—NMR (DMS〇, pm)

 134.6, 133.8, 130.2, 127.7, 1269, 125.3, 25.4, 14.1, 13.6.

 Table 1 6

Industrial applicability

 According to the production method of the present invention, (i) the purification in each reaction step required to obtain a purified product of the final product can be performed only by recrystallization without using column chromatography; Π) — Carbamate formation of the amino group of the compound represented by the general formula (5) and reduction reaction of the nitro group of the compound represented by the general formula (6) can be performed in one pot. The number of steps can be reduced as compared to conventional production methods, such as the ability to convert the compound represented by acylthiourea and the removal of the acyl group by hydrolysis or solvolysis in one pot; (Iii) Crystallization can be achieved only by adding an organic solvent without removing the reaction solvent such as hydrochloric acid to obtain a purified product of the final product. (Iv) Solvent with higher hydrophobicity By using Since liquid-liquid separation can be performed simply by adding water without distilling off the solvent, the number of steps can be reduced compared to the conventional production method. (V) More safety The use of high reagents and solvents can improve the working environment, and it has excellent effects such as safer working for workers, and is useful as an industrial manufacturing method.

Claims

The scope of the claims 1. A method for producing an aniline derivative shown below (in the following general formula, X represents a halogen atom, represents a lower alkyl group, R ₂ represents a lower alkoxy group, and R ₃ represents a lower alkyl group. R ₄ and R ₅ may be the same or different and each represent a hydrogen atom or a lower alkyl group, or represent a lower alkyl group or an aromatic hydrocarbon group; Υ ₂ , Υ ₃ , Υ ₄ may be the same or different, and may be substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group, respectively. A good lower alkoxy group, a lower alkyl group, an optionally substituted cyclic alkyl group having 3 to 6 carbon atoms, Ιν ^ represents an alkali metal or DBU, and n is an integer of 0 or 1. ): General formula (1)

From the compound represented by the general formula (2)

A method for producing a compound represented by the general formula (1):

By reacting with the compound represented by the general formula (4)

A compound represented by the general formula (5) is obtained by subjecting the phthalimide group of this compound to a deprotection reaction.

A compound represented by the general formula (6)

Is obtained by reducing the nitro group of this compound to obtain a compound represented by the general formula (7)

A compound represented by the formula (7) is obtained. 0  By reacting with the compound represented by R Λ NCS (8), the compound represented by the general formula (9)

The compound represented by the formula (10) is obtained by reacting the compound represented by the formula ( ₉ ) with a base and water and / or alcohols. 义 LJ- (CH ₂ ) _n -C-NHCOR ₂ To H ₂ N NZR ₄ A compound represented by H '3 丫 4 ^n- (10) is obtained, and the thiourea group of this compound is alkylated to obtain a compound represented by the general formula (1 1)

(!!) A compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent.

A method for producing a compound represented by the formula: wherein at least one of the following (a) and (b) is carried out.  (a) The amino group of the compound represented by the general formula (5) is converted into a compound by the formula (6) to obtain a compound represented by the general formula (6). Perform the reaction to obtain the compound represented in one pot;  (b) reacting the compound represented by the general formula (7) with the compound represented by the general formula (8) to obtain a compound represented by the general formula (9); And / or by reacting with an alcohol to obtain a compound represented by the general formula (10) in one pot.  2. A method for producing a compound represented by the general formula (2) by performing a deprotection reaction of a protecting group for an amino group of the compound represented by the general formula (11) using a deprotecting agent. The method according to claim 1, wherein the deprotecting agent is a deprotecting agent comprising an inorganic acid.  3. A method for producing a compound represented by the general formula (2) by performing a deprotection reaction of a protecting group for an amino group of the compound represented by the general formula (11) using a deprotecting agent. The method according to claim 1, wherein the deprotecting agent is a deprotecting agent comprising an inorganic acid and an alcohol. 4. A method for producing an aniline derivative shown below (in the following general formula, X represents a halogen atom, represents a lower alkyl group, R ₂ represents a lower alkoxy group, and R ₃ represents a lower alkyl group. R ₄ and R ₅ may be the same or different and each represent a hydrogen atom or a lower alkyl group, or represent a lower alkyl group or an aromatic hydrocarbon group; May form a 3- to 8-membered ring No. Y and Υ ₂ , Υ ₃ , and Υ ₄ may be the same or different, and each is a lower alkoxy group, a lower alkyl group, or a substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group. And a cyclic alkyl group having 3 to 6 carbon atoms which may have a group. Mi indicates an alkali metal or DBU. n represents an integer of 0 or 1. ): General formula (1)

From the compound represented by (1), general formula (2)

A method for producing a compound represented by the general formula (1) ¹

By reacting with the compound represented by the general formula (4) Y ¾ |  f

A compound represented by the general formula (5) is obtained by subjecting the phthalimide group of this compound to a deprotection reaction. 丄 .r (CH ₂ ) _n -C-NH ₂ 2 Υ ₃ Υ ₄ "4 A compound represented by the formula (5) is obtained.

Is obtained by reducing the nitro group of this compound to obtain a compound represented by the general formula (7)

A compound represented by the formula (7) is obtained. 0 R NCS ₍₈₎ By reacting with the compound represented by the general formula (9)

The compound represented by the general formula (10) is obtained by reacting this compound with a base, water and Z or an alcohol. II L ÷ (CH ₂ ) _n -C-NHCOR ₂ H ₂ N NR ₄ A compound represented by H ^γ 3 ^γ 4 ⁴ (10) is obtained, and the thioperia group of this compound is alkylated to obtain a compound represented by the general formula (11)

The compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid and an alcohol. HN f,] V ⁵ Person NR ₄ After producing the compound represented by ^Hγ 3 ^{Y 4} (2), the compound is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohol, thereby obtaining the compound represented by the above general formula. A method for producing the inorganic acid salt of the compound represented by (2).  5. The method according to claim 4, wherein at least one of the following (a) and (b) is performed.  (a) Carbamate the amino group of the compound represented by the general formula (5) to obtain a compound represented by the general formula (6), and reduce the nitro group of the compound to obtain a compound represented by the general formula (7). The reaction to obtain the compound to be performed is performed in one pot;  (b) reacting the compound represented by the general formula (7) with the compound represented by the general formula (8) to obtain a compound represented by the general formula (9); And a reaction with Z or an alcohol to obtain a compound represented by the general formula (10) in one pot. 6. A method for producing an aniline derivative shown below (in the following general formula, represents a lower alkyl group. R ₂ represents a lower alkoxy group. R ₃ represents a lower alkyl group, a lower alkoxy group, or R ₄ and R ₅ may be the same or different and each represent a hydrogen atom, a lower alkyl group, or together form a 3- to 8-membered ring Y ₂ , Υ ₃ , and Υ ₄ may be the same or different, and each is a lower alkoxy group or a lower alkyl group which may be substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group. group, an alkyl group having a carbon number 3-6 good cyclic may have a substituent, or shows an ΝΥ ₅ Υ _6, wherein, Upsilon _5, Upsilon _6, which may be the same or different, each , A hydrogen atom, a lower alkyl group, or A 3- to 8-membered ring may be formed as a link.η represents an integer of 0 or 1.): General formula (5) 丄 J- (CH ₂ ) _n -C-NH ₂ 0 ₂ N ゝ R _{4 (5)} From the compound represented by the general formula (2)

A method for producing a compound represented by the general formula (5), which comprises converting an amino group of a compound represented by the general formula (5) 丄 ノ, j- (CH ₂ ) _n -C-NHCOR ₂ A compound represented by Y ₄ ^R ₄ (6) is obtained, and the nitro group of this compound is reduced to obtain a compound represented by the general formula (7) .J- ¹ (CH ₂ ) _n -C-NHCOR ₂ Η ₂ Ν ' _Υ Ά R _{4 t} , γ3 ^{γ を 得 4} (7) is obtained, and this compound is represented by the general formula (8) 0  II By reaction with R ₃ C NCS compound represented by _(8), the general formula (9) 0 s ¹ f? 5 ηΛ JLy X ( ^CH 2) n-?-HCOR ₂  R3 Ν γ γ γ. R 化合物 Η Υ ₃ Υ. Compound (9) is obtained, and this compound is reacted with a base and water and Ζ or alcohols. The general formula (10)

And alkylating the thioperia group of this compound to obtain a compound represented by the general formula (1)

A compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent. ΒΛ

A method for producing the compound represented by (2), wherein at least one of the following (a) and (b) is performed.  (a) The amino group of the compound represented by the general formula (5) is converted into a compound by the formula (6) to obtain a compound represented by the general formula (6). Perform the reaction to obtain the compound represented in one pot; (b) reacting the compound represented by the general formula (7) with the compound represented by the general formula (8) to obtain a compound represented by the general formula (9); And / or by reacting with an alcohol to obtain a compound represented by the general formula (10) in one pot. 7. The method for producing the compound represented by the general formula (2) by performing a deprotection reaction of the protecting group for the amino group of the compound represented by the general formula (11) using a deprotecting agent. The method according to claim 6, wherein the deprotecting agent is a deprotecting agent comprising an inorganic acid.  8. — The method for producing the compound represented by the general formula (2) by performing a deprotection reaction of the protecting group for the amino group of the compound represented by the general formula (11) using a deprotecting agent. 7. The method according to claim 6, wherein the deprotecting agent is a deprotecting agent comprising an inorganic acid and an alcohol. 9. A method for producing an aniline derivative shown below (in the following general formula, represents a lower alkyl group. R ₂ represents a lower alkoxy group. R ₃ represents a lower alkyl group, a lower alkoxy group, or R ₄ and R ₅ may be the same or different and each represent a hydrogen atom, a lower alkyl group, or together form a 3- to 8-membered ring Y ₂ , Υ ₃ , and Υ ₄ may be the same or different, and each is a lower alkoxy group or a lower alkyl group which may be substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group. Or a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, or — ΝΥ ₅ Υ ₆ , wherein Υ ₅ and Υ ₆ may be the same or different, and , A hydrogen atom, a lower alkyl group, or . The connexion 3-8 membered ring may be formed such the η is an integer of 0 or 1).:  General formula (5)

From the compound represented by the general formula (2)

A method for producing a compound represented by the general formula (5), wherein an amino group of the compound represented by the general formula (5) is converted into a compound by the method of formula (6) / T (CH ₂ ) _n -C-NHCOR ₂ A compound represented by YY ₄ (6) is obtained, and the nitro group of the compound is reduced to obtain a compound represented by the general formula (7)

And the compound represented by the general formula (8) 0  u By reacting with the compound represented by F — NCS ( ₈₎ , the compound represented by the general formula (9)

By obtaining a compound represented by the formula (9), and reacting the compound with a base and water and / or an alcohol, the compound represented by the general formula (10)

And alkylating the thioperia group of this compound to obtain a compound represented by the general formula (1)

The compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid and an alcohol. HN Person ¹ , -.7T ¹ (CH ₂ ) _n -C-NH ₂  RTS After preparing the compound represented by γ ₃ Υ (2), the compound is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohol to obtain the compound represented by the general formula (2). A method for producing the inorganic acid salt of the compound represented.  10. The method according to claim 9, wherein at least one of the following (a) and (b) is performed.  (a) —Carbamate the amino group of the compound represented by the general formula (5) to obtain a compound represented by the general formula (6), and reduce the nitro group of the compound to obtain a compound represented by the general formula (7). Perform the reaction to obtain the compound represented in one pot; (b) reacting the compound represented by the general formula (7) with the compound represented by the general formula (8) to obtain a compound represented by the general formula (9); And / or by reacting with alcohols, represented by the general formula (10) The reaction to obtain the compound is performed in one pot. 1 1. Method for producing an aniline derivative shown below (in the following general formula, represents a lower alkyl group. R ₂ represents a lower alkoxy group. R ₃ represents a lower alkyl group, a lower alkoxy group, or And R ₄ and R ₅ may be the same or different and each represent a hydrogen atom or a lower alkyl group, or together form a 3 to 8 membered ring Y or Y ₂ , Υ ₃ , Υ ₄ may be the same or different, and each is a lower alkoxy group, a lower alkoxy group which may be substituted with a hydrogen atom, a halogen atom, or an aromatic hydrocarbon group. An alkyl group, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, or — ΝΥ ₅ Υ ₆ , wherein 、 ₅ and Υ ₆ may be the same or different , Respectively, a hydrogen atom, a lower alkyl group, , It is together a connexion 3 may form a 8-membered ring eta, an integer of 0 or 1)..: General formula (7)

The compound represented by the general formula (2)

A method for producing a compound represented by the general formula (7) 0  II f — NCS ( ₈₎ By reacting with the compound represented by the general formula (9)

The compound represented by the general formula (10) is obtained by reacting this compound with a base, water and Z or an alcohol.

A compound represented by the formula (10) is obtained, and the thioperia group of the compound is alkylated to obtain a compound represented by the general formula (11) HN f,. ⁵ U 丄 ノ,-(CH ₂ ) _n -C-NHCOR ₂ A compound represented by ^H'3Π4 (ι ι) is obtained, and the deprotection reaction of the protecting group for the amino group of the compound is carried out using a deprotecting agent to obtain a compound represented by the general formula (2)

In the method for producing a compound represented by the general formula (7), a compound represented by the general formula (7) is reacted with a compound represented by the general formula (8) to obtain a compound represented by the general formula (9) A process for obtaining a compound and reacting the compound with a base and water or Z or an alcohol to obtain a compound represented by the general formula (10) in a one-pot process.  12. A method for producing a compound represented by the general formula (2) by performing a deprotection reaction of a protecting group for an amino group of the compound represented by the general formula (11) using a deprotecting agent. 12. The method according to claim 11, wherein the deprotecting agent is a deprotecting agent comprising an inorganic acid.  13. A method for producing a compound represented by the general formula (2) by performing a deprotection reaction of a protecting group for an amino group of the compound represented by the general formula (11) using a deprotecting agent. 12. The method according to claim 11, wherein the deprotecting agent is a deprotecting agent comprising an inorganic acid and an alcohol. 14. A method for producing an aniline derivative shown below (in the following general formula, represents a lower alkyl group. R ₂ represents a lower alkoxy group. R ₃ represents a lower alkyl group, a lower alkoxy group, or R ₄ and R 5 may be the same or different and each represents a hydrogen atom or a lower alkyl group, or represents a 3- to 8-membered ring; Υ ₂ , Υ ₃ , Υ ₄ may be the same or different and are each a hydrogen atom, a halogen atom, a lower alkoxy group which may be substituted by an aromatic hydrocarbon group, a lower alkyl group, A cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, or — ΝΥ ₅ Υ ₆ , wherein Υ ₅ and Υ ₆ may be the same or different, Hydrogen atom, lower alkyl group, or May together form a 3- to 8-membered ring, and η represents an integer of 0 or 1.):  General formula (7) Jj- (CH ₂ ) _n -C-NHCOR ₂ From the compound represented by R4 (7), formula (2)

A method for producing a compound represented by the general formula (7) 0  X F-NCS ₍₈₎ is reacted with a compound represented by the general formula (9) A

The compound represented by the general formula (10) is obtained by reacting the compound with a base and water and Ζ or an alcohol.

Is obtained by alkylating the thioperia group of this compound,

The compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid and an alcohol.

The compound represented by the general formula (2) is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohol after producing the compound represented by the general formula (2). A method for producing an inorganic acid salt.  15. By reacting the compound represented by the general formula (7) with the compound represented by the general formula (8), a compound represented by the general formula (9) is obtained. 15. The production method according to claim 14, wherein a reaction for obtaining a compound represented by the general formula (10) by reacting with an alcohol is performed in one pot.  16. The process for producing an inorganic acid salt of a compound represented by the general formula (2) by crystallization by adding an organic solvent, wherein the organic solvent is ethyl acetate. The production method according to any one of 5, 9, 10, 14, and 15.  17. —The reaction of deprotecting the phthalimide group of the compound represented by the general formula (4) to obtain the compound represented by the general formula (5) is carried out using a methylamine methanol solution or a methylamine aqueous solution. The method according to any one of claims 1 to 5, wherein the method is carried out by using the compound as a deprotecting agent.  18. The manufacturing method according to claim 4, wherein both of the following (a) and (b) are performed.  (a) The phthalimide group of the compound represented by the general formula (4) is subjected to a deprotection reaction, and the reaction to obtain the compound represented by the general formula (5) is performed by deprotecting a methanol solution of methylamine or an aqueous solution of methylamine. Performed as an agent; (b) Crystallization by adding an organic solvent gives the compound represented by the general formula (2). In the step of producing the inorganic acid salt of the compound to be used, ethyl acetate is used as an organic solvent.  19. Claims 1 to 5, characterized in that the reaction of converting the amino group of the compound represented by the general formula (5) into an amino group and obtaining the compound represented by the general formula (6) is performed in ethyl acetate. 19. The production method according to any one of 10, 17, and 18.  20. The method according to any one of claims 4, 5, 9, and 10, wherein both of the following (a) and (b) are performed.  (a) Carbamate the amino group of the compound represented by the general formula (5) to obtain a compound represented by the general formula (6) in ethyl acetate;  (b) In the step of producing an inorganic acid salt of the compound represented by the general formula (2) by crystallization by adding an organic solvent, ethyl acetate is used as an organic solvent.  21. — In the reaction of reacting the compound represented by the general formula (9) with a base and water and Z or an alcohol to obtain the compound represented by the general formula (10), The production method according to any one of claims 1 to 20, wherein: is potassium carbonate, water, and Z or methanol.  22. The reaction according to claim 1, wherein the reaction for alkylating the thioperia group of the compound represented by the general formula (10) to obtain the compound represented by the general formula (11) is performed in ethyl acetate. The production method according to any one of the preceding claims.  23. The deprotecting agent for protecting the amino group of the compound represented by the general formula (11), wherein the deprotecting agent is a deprotecting agent comprising hydrochloric acid. 13. The production method according to any one of 6, 7, 11, and 12.  24. The deprotecting agent for the protecting group of the amino group of the compound represented by the general formula (11), wherein the deprotecting agent is a deprotecting agent comprising hydrochloric acid and alcohols. 24. The production method according to any one of 23.  25. The method according to claim 1, wherein in the deprotection reaction of the protecting group for the amino group of the compound represented by the general formula (11), the deprotecting agent is a deprotecting agent comprising hydrochloric acid and ethanol. 25. The production method according to any one of items 24 to 24. 26. Claim 1 or Claim 2 characterized by performing both (a) and (b): Is the production method described in 2.  (a) — a reaction in which the phthalimide group of the compound represented by the general formula (4) is subjected to a deprotection reaction to obtain a compound represented by the general formula (5), using a methanol solution of methylamine or methylamine; Performed using an aqueous solution as a deprotecting agent;  (b) In the deprotection reaction of the amino-protecting group of the compound represented by the general formula (11), the deprotecting agent is a deprotecting agent comprising hydrochloric acid.  27. The method according to any one of claims 1, 2, 6, 7, and 26, wherein both of the following (a) and (b) are performed.  (a) reacting the amino group of the compound represented by the general formula (5) with an amino group to obtain a compound represented by the general formula (6) in ethyl acetate;  (b) In the deprotection reaction of the amino-protecting group of the compound represented by the general formula (11), the deprotecting agent is a deprotecting agent comprising hydrochloric acid.  28. The compound represented by the general formula (2) is obtained by performing the deprotection reaction of the protecting group of the amino group of the compound represented by the general formula (11) using a deprotecting agent composed of an inorganic acid and an alcohol. The process according to any one of claims 1 to 22, wherein in the step of producing the compound, the deprotecting agent comprising an inorganic acid and an alcohol is a deprotecting agent comprising an inorganic acid and an ethanol solution. Method. 29. A method for producing an aniline derivative shown below (in the following general formula, R ₂ represents a lower alkoxy group. R ₄ and R ₅ may be the same or different and are each a hydrogen atom or a lower alkyl. Y or Υ ₂ , Υ ₃ , Υ ₄ may be the same or different, and each represents a hydrogen atom or a halogen atom. aromatic hydrocarbon-lower alkoxy group which may be substituted with a group, a lower alkyl group, a cyclic ring which may have a substituent § alkyl group of 3-6 carbon atoms, or represents an ΝΥ ₅ Υ ₆ Wherein Υ ₅ and Υ ₆ may be the same or different and may each be a hydrogen atom, a lower alkyl group, or may be taken together to form a 3- to 8-membered ring. Indicates an integer of 0 or 1.): General formula (5)

The amino group of the compound represented by the formula By reducing the toro group, the general formula (7)

A method for producing a compound represented by the formula: wherein all of the reactions are carried out in one pot.  30. The process according to claim 29, wherein the reaction of converting the amino group of the compound represented by the general formula (5) to a compound to obtain the compound represented by the general formula (6) is performed in ethyl acetate. Method. 31. Method for producing an aniline derivative shown below (in the following general formula, R ₂ represents a lower alkoxy group. R ₃ represents a lower alkyl group, a lower alkoxy group, or an aromatic hydrocarbon group. . R ₄ and R ₅ may be the same or different, are each a hydrogen atom, or a lower alkyl group, or may form together a connexion 3-8 membered ring. Upsilon _2, Upsilon _3, Upsilon ₄ is be the same or different rather good, are each a hydrogen atom, a halogen atom, an aromatic hydrocarbon optionally substituted lower alkoxy group optionally substituted with a group, a lower alkyl group, which may have a substituent A good cyclic alkyl group having 3 to 6 carbon atoms, or — — ₅ Υ ₆ , wherein Y _c and Y ₆ are the same or May be different, each being a hydrogen atom, a lower alkyl group, or A 3- to 8-membered ring may be formed. n represents an integer of 0 or 1. ): General formula (7)

The compound represented by the general formula (8) 70 By reacting with the compound represented by R ₃ NCS ₍₈₎ , the compound represented by the general formula (9) I 0 righteousness S丄r * c ^x switch _{ΐ (CH 2) n -?} - NHCOR 2 HH ^γ 3 ^γ " ⁴ A compound represented by the formula (9) is obtained, and this compound is reacted with a base and water and / or alcohols to obtain a compound represented by the general formula (10)

A method for producing the compound represented by (10), wherein all of the reactions are carried out in one pot. 32. A compound represented by the general formula (9) is treated with a base and water or Z or an alcohol. 31. The reaction for obtaining a compound represented by the general formula (10) by reacting with the above, wherein the base and water and / or alcohols are potassium carbonate and water and Z or methanol. The manufacturing method as described. 33. A method for producing an aniline derivative shown below (in the following general formula, shaku represents a lower alkyl group. R ₂ represents a lower alkoxy group. R ₄ and R ₅ may be the same or different. Each independently represents a hydrogen atom, a lower alkyl group, or may be taken together to form a _3- to 8-membered ring, Υ ₂ , Υ ₃ , Υ ₄ may be the same or different, A hydrogen atom, a halogen atom, a lower alkoxy group which may be substituted with an aromatic hydrocarbon group, a lower alkyl group, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, or ΝΥ ₅ Υ indicates _6, wherein, Upsilon _5, Upsilon _6, which may be the same or different, are each a hydrogen atom, a lower alkyl group, or, be formed together, such connexion 3-8 membered ring Η represents an integer of 0 or 1.): General formula (11)

After performing the deprotection reaction of the protecting group for the amino group of the compound represented by the formula (1) by using a deprotecting agent composed of an inorganic acid and an alcohol, the reaction is carried out without distilling off the inorganic acid and the alcohol. Wherein the crystallization is carried out by adding an organic solvent. r FU  HN Person L jr ( ^CH 2) nC-NH ₂ Y. A method for producing the inorganic acid salt of the compound represented by (2). 34. The method according to claim 33, wherein the deprotecting agent comprising an inorganic acid and an alcohol is a deprotecting agent comprising an inorganic acid and ethanol.  35. The method according to claim 33, wherein the inorganic acid is hydrochloric acid.  36. The method according to any one of claims 33 to 35, wherein the organic solvent is ethyl acetate. 37. A method for producing an aniline derivative shown below (in the following general formula, 1 ^ represents a lower alkyl group. The scale _{2 and the} scale ₆ may be the same or different, each having a lower alkoxy group. shown. R ₃ 2 represents a lower alkyl group, a lower alkoxy group, or, in. feet ₄ Oyobi 1 ₅ illustrating the aromatic hydrocarbon group and may be the same or different, are each a hydrogen atom, a lower alkyl group or shows, or over緖may form a 3-8 membered ring _{to. Y 2, Υ 3, Υ} 4 may be the same or different, are each a hydrogen atom, a halogen atom, an aromatic A lower alkoxy group, a lower alkyl group, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, or Υ _{5 6,} which may be substituted with a group hydrocarbon group. , Υ _5, Υ _6, which may be the same or be different , Are each a hydrogen atom, a lower alkyl group, or may η be formed from 3 to 8-membered ring Te summer together, represent an integer of 0 or 1):.. General formula (12)

From the compound represented by the general formula (2)

A method for producing a compound represented by the general formula (12) 0  J By reacting with the compound represented by R ₃ ′ NCS ( ₈₎ , the compound represented by the general formula (13)

The compound represented by the general formula (14) is obtained by reacting the compound with a base and water and / or alcohols.

And alkylating the thioperia group of the compound to obtain a compound represented by the general formula (5)

The compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid. HN People Yu A. /, \ ^(CH 2? One NH ₂  R S ,, N V V R,  H '4  In the method for producing a compound represented by Y (2), a compound represented by the general formula (12) is reacted with a compound represented by the general formula (8) to obtain a compound represented by the general formula (13). A process for obtaining a compound represented by the general formula (14) by reacting the compound with a base and water and / or an alcohol to obtain a compound represented by the general formula (14). In 38. the manufacturing method (the following general formula Anirin derivative shown below, 1 ^ is a lower alkyl group. Feet ₂ Oyobi 1 ₆ may be the same or different, each a lower alkoxy group R ₃ represents a lower alkyl group, a lower alkoxy group or an aromatic hydrocarbon group, and R ₄ and R ₅ may be the same or different and each represent a hydrogen atom or a lower alkyl group. Or together may form a _3- to 8-membered ring, and Y ₂ , Υ ₃ , ₄ may be the same or different and each represents a hydrogen atom, a halogen atom, an aromatic hydrocarbon group. in substituted but it may also have a lower alkoxy group, a lower alkyl group, a cyclic ring which may have a substituent alkyl group of 3-6 carbon atoms, or represents a _ΝΥ _{5 Υ 6,} wherein, Upsilon _5, Υ _6, which may be the same or may be different Are each a hydrogen atom, a lower alkyl group, or may η be formed from 3 to 8-membered ring Te summer together, represent an integer of 0 or 1):.. General formula (12)

₍₁₂₎ From the compound represented by the general formula (2)

A method for producing a compound represented by the general formula (12) 0  J ('By reacting with the compound represented by NCS ₍₈₎ 2,

The compound represented by the general formula (14) is obtained by reacting the compound with a base and water or Z or an alcohol.

Is obtained by alkylating the thioperia group of this compound,

The compound represented by the general formula (2) is obtained by performing a deprotection reaction of a protecting group for an amino group of the compound using a deprotecting agent comprising an inorganic acid and an alcohol.

After producing the compound represented by the formula, the compound represented by the general formula (2) is crystallized by adding an organic solvent without distilling off the inorganic acid and the alcohols. A production method characterized by obtaining an inorganic acid salt.  39. — By reacting the compound represented by the general formula (12) with the compound represented by the general formula (8), a compound represented by the general formula (13) is obtained. 39. The method according to claim 38, wherein a reaction for obtaining a compound represented by the general formula (14) is carried out in one pot by reacting with an alcohol.