RU2791465C2 - Preparation method of nitro compound and quinoxaline compound - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to the preparation method of a compound with formula (3) which is suitable as an intermediate for the production of physiologically active organic compounds such as agrochemicals, drugs, etc. The method includes reacting a compound with formula (1) with a compound with formula (2) using a tertiary alcohol and a base. The base is a compound selected from alkali metal hydrides and alkali metal amides, or a plurality of compounds including a base containing lithium as the first compound and a second compound selected from alkali metal hydrides, alkali metal amides, alkoxides, alkyl metals, alkali metals and organic bases. The reaction is carried out in the presence of a solvent, where the solvent contains toluene, xylene, chlorobenzene, dichlorobenzene or a mixture thereof, at -5°C-80°C. Each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ и R⁹ independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl or (C1-C4) alkoxy. The proposed method does not require a very low temperature and is cost-efficient and environmentally friendly.

EFFECT: invention also relates to the preparation method of a compound with formula (5).

29 cl, 2 tbl, 31 ex

Description

[Technical field]

[0001]

The present invention relates to a process for preparing a compound of the following formula (3), which is a nitroso compound.

[0002]

[Formula 1]

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are as defined below.

[0003]

The present invention also relates to a process for preparing a compound of the following formula (5), which is a quinoxaline compound.

[0004]

[formula 2]

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹² are as defined below.

[Prior Art]

[0005]

The nitroso compound of formula (3) (hereinafter referred to simply as the compound of formula (3)) and the quinoxaline compound of formula (5) (hereinafter referred to as simply the compound of formula (5)) are useful as intermediates for the production of physiologically active organic compounds. such as agrochemicals, pharmaceuticals and the like. WO2009/016841 (patent literature 1) describes useful herbicides. Among them, Compound No. II-62 and Compound No. II-194 are excellent herbicides. In particular, compound No. II-194, that is, fenquinotrion, is known as a herbicide having an extremely excellent weeding effect and high safety for paddy rice.

[0006]

In addition, WO2009/016841 (Patent Literature 1) also describes that the compound of formula (5) is useful as an intermediate for the production of herbicides (see in particular, for example, example 6).

[0007]

WO2013/089002 (patent literature 2) describes a production method as shown in the diagram below (see examples 1, 3, 19, 20-23 and the like).

[0008]

[formula 3]

[0009]

As can be seen from the above scheme, the method described in WO2013/089002 (Patent Literature 2) requires three steps to obtain a compound of formula (5), in particular a compound of formula (5-3), from 2,6-dichloronitrobenzene. Therefore, a production process with fewer steps is desirable. In addition, 2,6-dichloronitrobenzene and a diester of ketomalonic acid (eg, DEMO in the scheme above) are less readily available, and a more readily available feedstock is desirable.

[0010]

On the other hand, Japanese Patent Publication No. 2018-70520 (Patent Literature 3) describes that 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (3-1) can be obtained by reacting 2-chloronitrobenzene (1-1) with p-anisidine (2-1). In addition, this literature reports that the compound of formula (5-3) can be obtained from 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (3-1). This method is shown in the diagram below.

[0011]

[formula 4]

[0012]

Compared with the method of WO2013/089002 (patent literature 2), the compound of formula (5-3) can be obtained by using more readily available starting compounds in the method of Japanese Patent Publication No. 2018-70520 (patent literature 3). But in the method described in Japanese Patent Publication No. 2018-70520 (Patent Literature 3), 2 equivalents per 3 equivalents of para-anisidine (2-1) based on 2-chloronitrobenzene (1-1) is required, and therefore it is desirable to reduce the amount of p-anisidine used. In addition, the conditions of the examples of this method include a low temperature from -70°C to 0°C.

[0013]

Synlett (2015), 1352-1356 (non-patent literature 1) describes that the compound of formula (3) can be obtained in high yield. But this method requires a low temperature of -70°C to -30°C. A specific example is shown in the diagram below.

[0014]

[formula 5]

[0015]

In addition, Tetrahedron (2016), 8252-8260 (non-patent literature 2) describes that the compound of formula (3) can be obtained in moderate yield. This literature describes a method that includes starting the reaction at -65°C and then raising the temperature to room temperature. But this method also requires extremely low temperatures. A specific example is shown in the diagram below.

[0016]

[formula 6]

[0017]

As described above, the reaction conditions of the prior art include an extremely low temperature. Therefore, special manufacturing facilities are required and therefore these methods are not industrially preferred. Accordingly, a production process that does not require a very low temperature is desirable.

[List of citations]

[Patent Literature]

[0018]

[Patent Literature 1] WO2009/016841

[Patent Literature 2] WO2013/089002

[Patent Literature 3] Japanese Patent Laid-Open No. 2018-70520

[non-patent literature]

[0019]

[Non-Patent Literature 1] Synlett (2015), 1352-1356

[Non-Patent Literature 2] Tetrahedron (2016), 8252-8260

[Non-Patent Literature 3] Chemistry of Heterocyclic Compounds 2018, 54(9), 875-886

[Summary of the present invention]

[Technical problem]

[0020]

The purpose of the present invention is to provide processes for the preparation of a nitroso compound of formula (3) and a quinoxaline compound of formula (5), which process is industrially preferred, economical, and also environmentally friendly.

[0021]

A specific object of the present invention is to provide industrially preferred methods for the preparation of a compound of formula (3) and a compound of formula (5) that can overcome one or more of the disadvantages or problems in the conventional art described above.

[Solution to the problem]

[0022]

In view of the circumstances described above, the authors of the present invention carefully studied the methods for obtaining the compounds of formula (3) and the formula of the compound (5). As a result, it was surprisingly found that the problem can be solved by providing the following methods for preparing a compound (Formula 3) and a compound (Formula 5). Based on these findings, the present inventors have completed the present invention.

[0023]

Specifically, the present invention is as follows.

[0024]

[I-1] A method for producing a compound of formula (3), comprising reacting a compound of formula (1) with a compound of formula (2) using a tertiary alcohol and a base:

[formula 7]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ each independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl or (C1-C4) alkoxy.

[0025]

[I-2] The method according to [I-1], wherein the reaction of the compound of formula (1) with the compound of formula (2) is carried out after adding a tertiary alcohol and a base.

[0026]

[I-3] The method according to [I-1] or [I-2], wherein the amount of base used is greater than the amount of tertiary alcohol used, in terms of equivalents.

[0027]

[I-4] The method according to any one of [I-1] to [I-3], wherein the base is a compound selected from alkali metal hydrides and alkali metal amides, or a plurality of compounds including a base containing lithium as the first compounds, and another compound selected from alkali metal hydrides, alkali metal amides, alkoxides, alkyl metals, alkali metals and organic bases.

[0028]

[I-5] The method according to any one of [I-1] to [I-3], wherein the base is a compound selected from alkali metal hydrides and alkali metal amides, or a plurality of compounds including a base containing lithium as the first compounds, and another compound selected from alkali metal hydrides, alkali metal amides and alkoxides.

[0029]

[I-6] The method according to any one of [I-1] to [I-3], wherein the base is sodium hydride, lithium amide, two of lithium amide and sodium hydride, two of lithium amide and sodium amide, or two of lithium amide; and sodium tert-butoxide.

[0030]

[I-7] The method according to any one of [I-4] to [I-6], wherein the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2).

[0031]

[I-8] The method according to any one of [I-4] to [I-6], wherein the amount of base used is 2.5 equivalents-3.5 equivalents per 1 equivalent of the compound of formula (2).

[0032]

[I-9] The method according to any one of [I-4] to [I-6], wherein the amount of base used is 2.8 equivalents-3.5 equivalents per 1 equivalent of the compound of formula (2).

[0033]

[I-10] The method according to any one of [I-4] to [I-9], wherein the amount of tertiary alcohol used is 0.3 equivalents to 4.0 equivalents per 1 equivalent of the compound of formula (2).

[0034]

[I-11] The method according to any one of [I-4] to [I-9], wherein the amount of tertiary alcohol used is 0.5 equivalents-2.0 equivalents per 1 equivalent of the compound of formula (2).

[0035]

[I-12] The method according to any one of [I-4] to [I-9], wherein the amount of tertiary alcohol used is 0.5 equivalents to 1.5 equivalents per 1 equivalent of the compound of formula (2).

[0036]

[I-13] The method according to any one of [I-4]-[I-12], wherein the reaction is carried out at -5°C-80°C (preferably -5°C-50°C).

[0037]

[I-14] The method according to any one of [I-4]-[I-12], wherein the reaction is carried out at -5°C-50°C.

[0038]

[I-15] The method according to any one of [I-4]-[I-12], wherein the reaction is carried out at 0°C-50°C.

[0039]

[I-16] The method according to any one of [I-4]-[I-12], wherein the reaction is carried out at 0°C-40°C.

[0040]

[I-17] The method according to any one of [I-1] to [I-3], wherein the base is an alkali metal hydride.

[0041]

[I-18] The method according to any one of [I-1] to [I-3], wherein the base is sodium hydride.

[0042]

[I-19] The method according to [I-17] or [I-18], wherein the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2).

[0043]

[I-20] The method according to [I-17] or [I-18], wherein the amount of base used is 2.5 equivalents-3.5 equivalents per 1 equivalent of the compound of formula (2).

[0044]

[I-21] The method of [I-17] or [I-18], wherein the amount of base used is 2.8 equivalents-3.5 equivalents per 1 equivalent of the compound of formula (2).

[0045]

[I-22] The method according to any one of [I-17] to [I-21], wherein the amount of tertiary alcohol used is 0.3 equivalents to 4.0 equivalents per 1 equivalent of the compound of formula (2).

[0046]

[I-23] The method according to any one of [I-17] to [I-21], wherein the amount of tertiary alcohol used is 0.5 equivalents to 2.0 equivalents per 1 equivalent of the compound of formula (2).

[0047]

[I-24] The method according to any one of [I-17] to [I-21], wherein the amount of tertiary alcohol used is 0.5 equivalents to 1.5 equivalents per 1 equivalent of the compound of formula (2).

[0048]

[I-25] The method according to any one of [I-17] to [I-21], wherein the amount of tertiary alcohol used is 0.9 equivalents-2.1 equivalents per 1 equivalent of the compound of formula (2).

[0049]

[I-26] The method according to any one of [I-17]-[I-25], wherein the reaction is carried out at -5°C-80°C (preferably -5°C-50°C).

[0050]

[I-27] The method according to any one of [I-17]-[I-25], wherein the reaction is carried out at 0°C-50°C.

[0051]

[I-28] The method according to any one of [I-17]-[I-25], wherein the reaction is carried out at 20°C-70°C.

[0052]

[I-29] The method according to any one of [I-17]-[I-25], wherein the reaction is carried out at 20°C-40°C.

[0053]

[I-30] The method of any one of [I-1] to [I-3], wherein the base is an alkali metal amide.

[0054]

[I-31] The method of any one of [I-1] to [I-3], wherein the base is lithium amide.

[0055]

[I-32] The method of [I-30] or [I-31], wherein the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2).

[0056]

[I-33] The method according to [I-30] or [I-31], wherein the amount of base used is 2.5 equivalents-3.5 equivalents per 1 equivalent of the compound of formula (2).

[0057]

[I-34] The method of [I-30] or [I-31], wherein the amount of base used is 2.8 equivalents-3.5 equivalents per 1 equivalent of the compound of formula (2).

[0058]

[I-35] The method according to any one of [I-30]-[I-34], wherein the amount of tertiary alcohol used is 0.3 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2).

[0059]

[I-36] The method according to any one of [I-30]-[I-34], wherein the amount of tertiary alcohol used is 0.3 equivalents-2.5 equivalents per 1 equivalent of the compound of formula (2).

[0060]

[I-37] The method according to any one of [I-30]-[I-34], wherein the amount of tertiary alcohol used is 0.5 equivalents-2.0 equivalents per 1 equivalent of the compound of formula (2).

[0061]

[I-38] The method according to any one of [I-30] to [I-34], wherein the amount of tertiary alcohol used is 0.5 equivalents-1.5 equivalents per 1 equivalent of the compound of formula (2).

[0062]

[I-39] The method according to any one of [I-30]-[I-34], wherein the amount of tertiary alcohol used is 0.4 equivalents-1.1 equivalents per 1 equivalent of the compound of formula (2).

[0063]

[I-40] The method according to any one of [I-30]-[I-39], wherein the reaction is carried out at -5°C-80°C (preferably -5°C-50°C, more preferably -5°C -15°C).

[0064]

[I-41] The method according to any one of [I-30]-[I-39], wherein the reaction is carried out at 0°C-50°C.

[0065]

[I-42] The method according to any one of [I-30]-[I-39], wherein the reaction is carried out at 0°C-30°C.

[0066]

[I-43] The method according to any one of [I-30]-[I-39], wherein the reaction is carried out at 0°C-15°C.

[0067]

[I-44] The method of any one of [I-1]-[I-3], wherein the base includes a plurality of compounds.

[0068]

[I-45] The method according to any one of [I-1]-[I-3], wherein the base comprises two or three compounds.

[0069]

[I-46] The method according to any one of [I-1]-[I-3], wherein the base consists of two compounds.

[0070]

[I-47] The method of [I-44], wherein the plurality of compounds includes a lithium-containing base (preferably lithium amide) as the first compound and another compound selected from alkali metal hydrides, alkali metal amides, alkoxides, alkyl metals, alkali metals and organic bases.

[0071]

[I-48] The method of [I-45], wherein the two or three compounds comprise a lithium-containing base (preferably lithium amide) as the first compound, and one or two other compounds selected from alkali metal hydrides, alkali metal amides , alkoxides, alkyl metals, alkali metals and organic bases.

[0072]

[I-49] The method of [I-46], wherein the two compounds are a base containing lithium (preferably lithium amide) as the first compound, and the other compound selected from alkali metal hydrides, alkali metal amides, alkoxides, alkyl metals , alkali metals and organic bases.

[0073]

[I-50] The method of [I-44], wherein the plurality of compounds includes a lithium-containing base as the first compound and another compound selected from alkali metal hydrides, alkali metal amides, and alkoxides.

[0074]

[I-51] The method of [I-45], wherein the two or three compounds include a lithium-containing base as the first compound and one or two other compounds selected from alkali metal hydrides, alkali metal amides, and alkoxides.

[0075]

[I-52] The method of [I-46], wherein the two compounds are a base containing lithium as the first compound and another compound selected from alkali metal hydrides, alkali metal amides and alkoxides.

[0076]

[I-53] The method of [I-44], wherein the plurality of compounds includes lithium amide as the first compound, and another compound selected from alkali metal hydrides, alkali metal amides, and alkoxides.

[0077]

[I-54] The method of [I-45], wherein the two or three compounds include lithium amide as the first compound, and one or two other compounds selected from alkali metal hydrides, alkali metal amides, and alkoxides.

[0078]

[I-55] The method of [I-46], wherein the two compounds are lithium amide as the first compound, and the other compound selected from alkali metal hydrides, alkali metal amides, and alkoxides.

[0079]

[I-56] The method of [I-44], wherein the plurality of compounds includes two of lithium amide and sodium hydride, two of lithium amide and sodium amide, or two of lithium amide and sodium t-butoxide.

[0080]

[I-57] The method of [I-45], wherein the two or three compounds include two of lithium amide and sodium hydride, two of lithium amide and sodium amide, or two of lithium amide and sodium t-butoxide.

[0081]

[I-58] The method of [I-46], wherein the two compounds are two of lithium amide and sodium hydride, two of lithium amide and sodium amide, or two of lithium amide and sodium t-butoxide.

[0082]

[I-59] The method of [I-44], wherein the plurality of compounds includes two of lithium amide and sodium hydride.

[0083]

[I-60] The method of [I-45], wherein the two or three compounds comprise two of lithium amide and sodium hydride.

[0084]

[I-61] The method of [I-46], wherein the two compounds are lithium amide and sodium hydride.

[0085]

[I-62] The method according to any one of [I-44]-[I-61], wherein the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2).

[0086]

[I-63] The method according to any one of [I-44]-[I-61], wherein the amount of base used is 2.5 equivalents-3.5 equivalents per 1 equivalent of the compound of formula (2).

[0087]

[I-64] The method according to any one of [I-44]-[I-61], wherein the amount of base used is 2.8 equivalents-3.5 equivalents per 1 equivalent of the compound of formula (2).

[0088]

[I-65] The method according to any one of [I-44]-[I-64], wherein the amount of tertiary alcohol used is 0.3 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2).

[0089]

[I-66] The method according to any one of [I-44]-[I-64], wherein the amount of tertiary alcohol used is 0.3 equivalents-2.5 equivalents per 1 equivalent of the compound of formula (2).

[0090]

[I-67] The method according to any one of [I-44]-[I-64], wherein the amount of tertiary alcohol used is 0.5 equivalents to 2.5 equivalents per 1 equivalent of the compound of formula (2).

[0091]

[I-68] The method according to any one of [I-44]-[I-64], wherein the amount of tertiary alcohol used is 0.5 equivalents-2.0 equivalents per 1 equivalent of the compound of formula (2).

[0092]

[I-69] The method according to any one of [I-44]-[I-64], wherein the amount of tertiary alcohol used is 0.5 equivalents to 1.5 equivalents per 1 equivalent of the compound of formula (2).

[0093]

[I-70] The method according to any one of [I-47] to [I-69], wherein the ratio of the other compound is more than 0 equivalents and 2.0 equivalents or less per 1 equivalent of the first compound.

[0094]

[I-71] The method according to any one of [I-47] to [I-69], wherein the ratio of the other compound is more than 0 (zero) equivalent and 0.5 equivalent or less by 1 equivalent of the first compound.

[0095]

[I-72] The method according to any one of [I-47]-[I-69], wherein the ratio of the other compound is 0.2 equivalents-0.5 equivalents per 1 equivalent of the first compound.

[0096]

[I-73] The method according to any one of [I-44]-[I-72], wherein the reaction is carried out at -5°C-80°C (preferably -5°C-50°C).

[0097]

[I-74] The method according to any one of [I-44]-[I-72], wherein the reaction is carried out at 0°C-60°C.

[0098]

[I-75] The method according to any one of [I-44]-[I-72], wherein the reaction is carried out at 0°C-50°C.

[0099]

[I-76] The method according to any one of [I-44]-[I-72], wherein the reaction is carried out at 0°C-30°C.

[0100]

[I-77] The method according to any one of [I-1] to [I-76], wherein the tertiary alcohol is a compound of formula (6):

[formula 8]

where R ¹³ , R ¹⁴ , and R ¹⁵ may be the same or different and each is (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6- C10) aryl, or (C6-C10) aryl (C1-C4) alkyl, and two selected from R ¹³ , R ¹⁴ , and R ¹⁵ may be connected to each other to form a ring.

[0101]

[I-78] The method of [I-77], wherein R ¹³ , R ¹⁴ and R ¹⁵ may be the same or different and are selected from methyl, ethyl, ethenyl, ethynyl, propyl, benzyl and phenyl.

[0102]

[I-79] The method according to any one of [I-1]-[I-76], wherein the tertiary alcohol is selected from t-butanol, 2-methyl-2-butanol, 2-methyl-3-buten-2-ol, and 2-methyl-1-phenyl-2-propanol.

[0103]

[I-80] The method of any one of [I-1] to [I-76], wherein the tertiary alcohol is t-butanol.

[0104]

[I-81] The method according to any one of [I-1] to [I-80], wherein the reaction is carried out in the presence of a solvent.

[0105]

[I-82] The method of [I-81], wherein the reaction of a compound of formula (1) with a compound of formula (2) is carried out after adding a tertiary alcohol and a base to a solvent.

[0106]

[I-83] The method of [I-81] or [I-82], wherein the solvent is toluene, xylene, chlorobenzene, dichlorobenzene, or a mixture thereof.

[0107]

[I-84] The method of [I-81] or [I-82], wherein the solvent is toluene, xylene, or a mixture thereof.

[0108]

[I-85] The method of [I-81] or [I-82], wherein the solvent is toluene.

[0109]

[I-86] The method according to any one of [I-1]-[I-85], wherein

each R ¹ , R ² , R ³ , and R ⁴ independently represents a hydrogen atom, a fluorine atom or a chlorine atom; And

each R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ independently represents a hydrogen atom, (C1-C4) alkyl or (C1-C4) alkoxy.

[0110]

[I-87] The method according to any one of [I-1]-[I-85], wherein

each R ¹ , R ² , R ³ , and R ⁴ independently represents a hydrogen atom or a chlorine atom; And

each R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ independently represents a hydrogen atom or (C1-C4) alkoxy.

[0111]

[I-88] The method according to any one of [I-1]-[I-85], wherein

R ¹ represents a hydrogen atom or a chlorine atom;

each R ² , R ³ , and R ⁴ represents a hydrogen atom;

each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom; And

R ⁷ represents a hydrogen atom or methoxy.

[0112]

[I-89] The method according to any one of [I-1]-[I-85], wherein

R ¹ represents a hydrogen atom or a chlorine atom;

each R ² , R ³ and R ⁴ represents a hydrogen atom;

each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom; And

R ⁷ is methoxy.

[0113]

[I-90] The method according to any one of [I-1]-[I-85], wherein

R ¹ represents a chlorine atom;

each R ² , R ³ and R ⁴ represents a hydrogen atom;

each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom; And

R ⁷ is methoxy.

[0114]

[II-1] Method for producing the compound of formula (5):

[formula 9]

where each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl or (C1-C4) alkoxy ; And

R ¹² represents a hydrogen atom, an alkali metal atom or (C1-C4) alkyl,

and the method includes the following stages;

step (i) reacting a compound of formula (1) with a compound of formula (2) using a tertiary alcohol and a base to obtain a compound of formula (3):

[formula 10]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are, as defined above,

and where stage (i) is carried out by the method according to any one of [I-1]-[I-90],

step (ii) reacting a compound of formula (3) with a compound of formula (4) to obtain a compound of formula (5):

[formula 11]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above;

each R ¹⁰ and R ¹¹ is independently (C1-C4) alkyl; And

R ¹² is as defined above.

[0115]

[II-2] Method for producing the compound of formula (5):

[formula 12]

where each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl or (C1-C4) alkoxy ; And

R ¹² represents a hydrogen atom, an alkali metal atom or (C1-C4) alkyl,

the method comprising the use of a compound of formula (3):

[formula 13]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are, as defined above,

where the compound of formula (3) is obtained by the method according to any one of [I-1]-[I-90].

[0116]

[II-3] Method for producing the compound of formula (5):

[formula 14]

where each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl, or (C1-C4) alkoxy; And

R ¹² represents a hydrogen atom, an alkali metal atom or (C1-C4) alkyl,

the method comprising the use of a compound of formula (3):

[formula 15]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are, as defined above,

where as the compound of formula (3), a compound of formula (3) obtained by the method of any one of [I-1] to [I-90] is used.

[0117]

[II-4] Method for producing the compound of formula (5):

[formula 16]

where each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl, or (C1-C4) alkoxy; And

R ¹² represents a hydrogen atom, an alkali metal atom or (C1-C4) alkyl,

and the method includes the following stages;

step (i) of obtaining a compound of formula (3) by a method according to any one of [I-1]-[I-90]:

[formula 17]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are, as defined above,

step (ii) reacting a compound of formula (3) with a compound of formula (4) to obtain a compound of formula (5):

[formula 18]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined above.

[0118]

[II-5] The method according to [II-1] or [II-4], wherein the compound of formula (4) is dimethylmalonate or diethylmalonate.

[0119]

[II-6] The method according to [II-1] or [II-4], wherein the reaction in step (ii) is carried out at a pH of 8 or more.

[0120]

[II-7] The method according to [II-1] or [II-4], wherein the reaction in step (ii) is carried out at pH 8-14.

[0121]

[II-8] The method according to any one of [II-1], [II-4] to [II-7], wherein the reaction in step (ii) is carried out in the absence of a phase transfer catalyst.

[0122]

[II-9] The method according to any one of [II-1], [II-4] to [II-7], wherein the reaction in step (ii) is carried out in the presence of a phase transfer catalyst.

[0123]

[II-10] The method according to any one of [II-1], [II-4] to [II-9], wherein the reaction in step (ii) is carried out in the presence of water.

[0124]

[II-11] The method according to any one of [II-1]-[II-10], wherein

each R ¹ , R ² , R ³ and R ⁴ independently represents a hydrogen atom, a fluorine atom or a chlorine atom; And

each R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represents a hydrogen atom, (C1-C4) alkyl or (C1-C4) alkoxy.

[0125]

[II-12] The method according to any one of [II-1]-[II-10], wherein

each R ¹ , R ² , R ³ and R ⁴ independently represents a hydrogen atom or a chlorine atom; And

each R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ independently represents a hydrogen atom or (C1-C4) alkoxy.

[0126]

[II-13] The method according to any one of [II-1]-[II-10], wherein

R ¹ represents a hydrogen atom or a chlorine atom;

each R ² , R ³ and R ⁴ represents a hydrogen atom;

each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom; And

R ⁷ represents a hydrogen atom or methoxy.

[0127]

[II-14] The method according to any one of [II-1]-[II-10], wherein

R ¹ represents a hydrogen atom or a chlorine atom;

each R ² , R ³ and R ⁴ represents a hydrogen atom;

each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom; And

R ⁷ is methoxy.

[0128]

[II-15] The method according to any one of [II-1]-[II-10], wherein

R ¹ represents a chlorine atom;

each R ² , R ³ and R ⁴ represents a hydrogen atom;

each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom; And

R ⁷ is methoxy.

[0129]

[II-16] The method according to any one of [II-1]-[II-15], wherein

Each R ¹⁰ and R ¹¹ is methyl or ethyl; And

R ¹² represents a hydrogen atom, a lithium atom, a sodium atom, a potassium atom, methyl or ethyl.

[0130]

[II-17] The method according to any one of [II-1]-[II-15], wherein

each R ¹⁰ and R ¹¹ is methyl or ethyl; And

R ¹² represents a hydrogen atom, a lithium atom, a sodium atom, methyl, or ethyl.

[0131]

[II-18] The method according to any one of [II-1]-[II-15], wherein

each R ¹⁰ and R ¹¹ is methyl or ethyl; And

R ¹² represents a hydrogen atom, a lithium atom or a sodium atom.

[0132]

[II-19] The method according to any one of [II-1]-[II-15], wherein

each R ¹⁰ and R ¹¹ is methyl or ethyl; And

R ¹² represents a hydrogen atom.

[0133]

[III-1] A method for producing a compound of formula (3), comprising reacting a compound of formula (1) with a compound of formula (2) using a tertiary alcohol and a base:

[formula 19]

each where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl or (C1-C4) alkoxy .

[0134]

[III-2] The method according to [III-1], wherein the reaction of the compound of formula (1) with the compound of formula (2) is carried out after adding a tertiary alcohol and a base.

[0135]

[III-3] The method according to [III-1] or [III-2], wherein the amount of base used is greater than the amount of tertiary alcohol used, in terms of equivalents.

[0136]

[III-4] The method according to any one of [III-1] to [III-3], wherein the base is a compound selected from alkali metal hydrides and alkali metal amides, or a plurality of compounds, including a base containing lithium as the first compounds, and a second compound selected from alkali metal hydrides, alkali metal amides, alkoxides, alkyl metals, alkali metals and organic bases.

[0137]

[III-5] The method according to any one of [III-1]-[III-3], wherein the base is sodium hydride, lithium amide, two of lithium amide and sodium hydride, two of lithium amide and sodium amide, or two of lithium amide; and sodium tert-butoxide.

[0138]

[III-6] The method according to [III-4] or [III-5], wherein the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2), and the amount of tertiary alcohol used is 0, 3 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2).

[0139]

[III-7] The method according to any one of [III-1] to [III-3], wherein the base is an alkali metal hydride.

[0140]

[III-8] The method according to any one of [III-1]-[III-3], wherein the base is sodium hydride.

[0141]

[III-9] The method according to [III-7] or [III-8], wherein the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2), and the amount of tertiary alcohol used is 0, 3 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2).

[0142]

[III-10] The method according to any one of [III-1] to [III-3], wherein the base is an alkali metal amide.

[0143]

[III-11] The method according to any one of [III-1]-[III-3], wherein the base is lithium amide.

[0144]

[III-12] The method according to [III-10] or [III-11], wherein the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2), and the amount of tertiary alcohol used is 0, 3 equivalents-2.5 equivalents per 1 equivalent of the compound of formula (2).

[0145]

[III-13] The method according to any one of [III-1]-[III-3], wherein the base includes a plurality of compounds.

[0146]

[III-14] The method of [III-13], wherein the plurality of compounds comprises a lithium-containing base as the first compound and a second compound selected from alkali metal hydrides, alkali metal amides, alkoxides, alkyl metals, alkali metals, and organic bases .

[0147]

[III-15] The method of [III-13], wherein the plurality of compounds includes two of lithium amide and sodium hydride, two of lithium amide and sodium amide, or two of lithium amide and sodium t-butoxide.

[0148]

[III-16] The method of [III-13], wherein the plurality of compounds includes two of lithium amide and sodium hydride.

[0149]

[III-17] The method according to any one of [III-13]-[III-16], wherein the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2), and the amount of tertiary alcohol used is 0.3 equivalents-2.5 equivalents per 1 equivalent of the compound of formula (2).

[0150]

[III-18] The method according to any one of [III-1]-[III-17], wherein the tertiary alcohol is a compound of formula (6):

[formula 20]

where R ¹³ , R ¹⁴ and R ¹⁵ may be the same or different and each is (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6- C10) aryl, or (C6-C10) aryl (C1-C4) alkyl, and two selected from R ¹³ , R ¹⁴ , and R ¹⁵ may be connected to each other to form a ring.

[0151]

[III-19] The method according to any one of [III-1]-[III-17], wherein the tertiary alcohol is selected from t-butanol, 2-methyl-2-butanol, 2-methyl-3-buten-2-ol, and 2-methyl-1-phenyl-2-propanol.

[0152]

[III-20] The method according to any one of [III-1]-[III-19], wherein the reaction is carried out at -5°C-80°C.

[0153]

[III-21] The method according to any one of [III-1]-[III-19], wherein the reaction is carried out at 0°C-50°C.

[0154]

[III-22] The method according to any one of [III-1]-[III-21], wherein

R ¹ represents a hydrogen atom or a chlorine atom;

each R ² , R ³ and R 4 represents a hydrogen atom;

each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom; And

R ⁷ represents a hydrogen atom or methoxy.

[0155]

[III-23] The method according to any one of [III-1]-[III-21], wherein

R ¹ represents a chlorine atom;

each R ² , R ³ and R ⁴ represents a hydrogen atom;

each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom; And

R ⁷ is methoxy.

[0156]

[III-24] Method for obtaining the compound of formula (5):

[formula 21]

where each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl, or (C1-C4 ) alkoxy; And

R ¹² represents a hydrogen atom, an alkali metal atom or (C1-C4) alkyl,

and the method includes the following stages;

step (i) of obtaining a compound of formula (3) by a method according to any one of [III-1]-[III-23]:

[formula 22]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are, as defined above,

step (ii) reacting a compound of formula (3) with a compound of formula (4) to obtain a compound of formula (5):

[formula 23]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined above.

[0157]

[III-25] The method according to [III-24], wherein the reaction in step (ii) is carried out at a pH of 8 or more.

[0158]

[III-26] The method according to [III-24], wherein the reaction in step (ii) is carried out at pH 8-14.

[0159]

[III-27] The method according to any one of [III-24]-[III-26], wherein the reaction in step (ii) is carried out in the absence of a phase transfer catalyst.

[0160]

[III-28] The method according to any one of [III-24]-[III-26], wherein the reaction in step (ii) is carried out in the presence of a phase transfer catalyst.

[0161]

[III-29] The method according to any one of [III-24]-[III-28], wherein the reaction in step (ii) is carried out in the presence of water.

[0162]

[III-30] The method according to any one of [III-24]-[III-29], wherein

each R ¹⁰ and R ¹¹ is methyl or ethyl; And

R ¹² represents a hydrogen atom, a lithium atom, a sodium atom, a potassium atom, methyl or ethyl.

[0163]

[III-31] The method according to any one of [III-24]-[III-29], wherein

each R ¹⁰ and R ¹¹ is methyl or ethyl; And

R ¹² represents a hydrogen atom.

[Useful properties of the present invention]

[0164]

According to the present invention, novel methods are provided for the preparation of a compound of formula (3) and a compound of formula (5), the methods being industrially preferred, economical and also environmentally friendly. According to the present invention, methods for preparing a compound of formula (3) and a compound of formula (5) are provided that can solve one or more of the disadvantages or problems in the conventional art described above.

Description of Embodiments

[0165]

The present invention will be described in detail below.

[0166]

In the present invention, the following abbreviations and prefixes may be used and their meanings are as follows:

Me: methyl

Et: ethyl

Pr, n-Pr, and Pr-n: kerf (i.e. normal kerf)

i-Pr and Pr-i: isopropyl

Bu, n-Bu, and Bu-n: butyl (i.e. normal butyl)

s-Bu and Bu-s: sec-butyl (that is, sec-butyl)

i-Bu and Bu-i: isobutyl

t-Bu and Bu-t: tert-butyl (that is, tertiary butyl)

Ph: phenyl

n-: normal

s- and sec-: secondary

i- and iso-: iso

t- and tert-: tertiary

neo-: neo

c- and cyc-: cyclo

o-: ortho

m-: meta

p-: pair

tert-BuOH: tert-butanol

[0167]

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0168]

As used in the present invention, general terms such as "alkyl" are considered to include both straight chain and branched chains such as butyl and tert-butyl. On the other hand, for example, the specific term "butyl" means "normal butyl" with a normal chain and does not mean "tert-butyl" with a branched chain. Branched chain isomers such as "tert-butyl" are specifically mentioned in the assignment.

[0169]

(Ca-Cb) means that the number of carbon atoms is a-b. For example, "(C1-C4)" "(C1-C4) alkyl" means that the number of carbon atoms of alkyl is 1-4.

[0170]

(C1-C6) alkyl means straight or branched alkyl containing 1-6 carbon atoms. Examples of (C1-C6) alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl, and hexyl.

(C1-C4) alkyl means straight or branched chain alkyl containing 1-4 carbon atoms. Examples of (C1-C4) alkyl are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and t-butyl.

[0171]

(C3-C6) cycloalkyl means cycloalkyl containing 3-6 carbon atoms. Examples of (C3-C6) cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0172]

(C2-C6) alkenyl means a straight or branched chain alkenyl containing 2-6 carbon atoms. Examples of (C2-C6) alkenyl include, but are not limited to, vinyl (i.e., ethenyl), 1-propenyl, isopropenyl, 2-propenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl , 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl and 1-hexenyl.

[0173]

(C2-C6) alkynyl means a straight or branched chain alkynyl containing 2-6 carbon atoms. Examples of (C2-C6) alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 2-butynyl, 3-butynyl, 1-pentynyl, and 1-hexynyl .

[0174]

Examples of (C6-C10) aryl are phenyl, 1-naphthyl and 2-naphthyl.

[0175]

(C6-C10) aryl (C1-C4) alkyl means (C1-C4 alkyl) substituted with (C6-C10) aryl (in the present invention, C6-C10 aryl moiety and C1-C4 alkyl moiety have the same meanings as definitions higher). Examples of (C6-C10) aryl(C1-C4) alkyl include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthalene-1-ylmethyl, and naphthalene-2-ylmethyl.

[0176]

A (C1-C4) alkoxy is (C1-C4) alkyl-O- (in the present invention, (C1-C4) alkyl moiety has the same meaning as the definition above). Examples of (C1-C4) alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, and t-butoxy.

[0177]

Examples of the "ring" in the expression "two can be connected to each other to form a ring" include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, and cyclohexene. A "ring" can be condensed with another "ring".

[0178]

As used in the present invention, each of the non-limiting terms "include(s)/comprising" can optionally be replaced by the limiting expressions "consists of(s)/consisting of."

As used in the present invention, the expression "after ... each added" can be replaced by the expression "after ... added separately".

As can be seen from the examples described below, it is clear that the phrase "each of the tertiary alcohol and base is added" means, for example, that "each of the tertiary alcohol and base is added to the reaction system," but this is not to be interpreted as limiting. Therefore, as used in the present invention, the expression "after adding the tertiary alcohol and base" can be replaced by the expression, for example, "after adding the tertiary alcohol and base to the reaction system."

As used in the present invention, the expression "second connection" can be replaced by the expression "another connection".

[0179]

Next, the method of the present invention will be described.

[0180]

(Step (i))

[0181]

Next, step (i) will be described.

[0182]

Step (i) is the step of reacting a compound of formula (1) with a compound of formula (2) using a tertiary alcohol and a base to obtain a compound of formula (3).

[0183]

[formula 24]

[0184]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above.

[0185]

(Starting compound: compound of formula (1) which is a nitro compound)

As the starting compound in step (i), a compound of formula (1) is used, which is a nitro compound. The compound of formula (1) is a known compound, or it can be obtained from a known compound according to a known method.

[0186]

Specific examples of the compound of formula (1) include, but are not limited to, the following;

nitrobenzene, 2-chloronitrobenzene, 3-chloronitrobenzene, 4-chloronitrobenzene, 2-fluoro-nitrobenzene, 3-fluoro-nitrobenzene and 4-fluoro-nitrobenzene.

[0187]

In view of yield, availability, price, utility of the product, and the like, preferred specific examples of the compound of formula (1) include nitrobenzene and 2-chloronitrobenzene, more preferably 2-chloronitrobenzene.

[0188]

The applied amount of the compound of formula (1) may be an arbitrary amount, provided that the reaction proceeds. However, in one aspect, the amount of the compound of formula (1) (nitro compound) used is, for example, 0.7 equivalents-2.0 equivalents, preferably 0.9 equivalents-1.8 equivalents, more preferably 0.9 equivalents-1, 6 equivalents, more preferably 0.9 equivalents-1.5 equivalents, and particularly preferably 1.0-1.5 equivalents per 1 equivalent of the compound of formula (2) (aniline compound), in terms of yield, suppression of by-products, economic efficiency and the like. In terms as shown above, in another aspect, the applied amount of the compound of formula (1) (nitro compound) is, for example, 1.0 equivalent-2.0 equivalent, preferably 1.0 equivalent-1.8 equivalent, more preferably 1 0 equivalent-1.6 equivalents, and particularly preferably 1.0 equivalents-1.5 equivalents per 1 equivalent of the compound of formula (2) (aniline compound).

[0189]

As used in the present invention, the definition of "equivalent of the compound of formula (1) (nitro compound)" is as follows, or the term "equivalent" is interpreted according to the following examples. For example, "1 equivalent of compound of formula (1) (nitro compound) per 1 equivalent of compound of formula (2) (aniline compound)" means "1 mole of compound of formula (1) (nitro compound) per 1 mole of compound of formula (2) (aniline compound) ." For example, "0.5 equivalent of compound of formula (1) (nitro compound) per 1 equivalent of compound of formula (2) (aniline compound)" means "0.5 mol of compound of formula (1) (nitro compound) per 1 mol of compound of formula (2) (aniline compound)."

[0190]

(Starting compound: a compound of the general formula (2) which is an aniline compound)

As the starting compound in step (i), a compound of formula (2) is used, which is an aniline compound. The compound of formula (2) is a known compound, or it can be obtained from a known compound according to a known method.

[0191]

Specific examples of the compound of formula (2) include, but are not limited to, the following;

aniline, 4-methoxyaniline (i.e. p-anisidine), 4-ethoxyaniline, 4-n-propoxyaniline, 4-n-butoxyaniline, 4-methylaniline, 4-ethylaniline, 4-n-propylaniline, 4-n-butylaniline and 4 -tert-butylaniline.

[0192]

In terms of yield, product utility and/or the like, preferred specific examples of the compound of formula (2) include aniline or 4-methoxyaniline. From the point of view of the usefulness of the product and the like, a more preferred specific example of the compound of formula (2) is 4-methoxyaniline.

[0193]

From the point of view of improving the economy, reducing the environmental burden and the like, the use of an excess amount of 2-chloronitrobenzene or nitrobenzene is acceptable. On the other hand, the use of an excess amount of p-anisidine is preferably avoided, but this should not be understood as a limitation. For example, it is clear that p-anisidine is more expensive than 2-chloronitrobenzene and nitrobenzene. In the method of the published Japanese patent No. 2018-70520 (Patent Literature 3), 2 equivalents or more of p-anisidine is required as the only starting compound used. Indeed, in the examples of published Japanese patent No. 2018-70520 (Patent Literature 3), up to 2 equivalents-3 equivalents of p-anisidine are used. On the other hand, in the method of the present invention, 2 equivalents or less of 2-chloronitrobenzene or chloronitrobenzene is sufficient as the only starting compound used. As shown in the examples below, even 1 equivalent to 1.5 equivalents of 2-chloronitrobenzene or chloronitrobenzene provides a satisfactory yield.

[0194]

(Base in step (i))

Examples of the base in step (i) include, but are not limited to, the following;

alkali metal hydrides (eg lithium hydride, sodium hydride, and potassium hydride, preferably sodium hydride and potassium hydride, and more preferably sodium hydride),

alkaline earth metal hydrides (eg calcium hydride),

alkoxides (for example, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide and potassium isopropoxide, preferably tert-butoxide lithium, sodium t-butoxide and potassium t-butoxide, and more preferably sodium t-butoxide),

alkyl metals (for example, butyllithium, sec-butyllithium and tert-butyllithium),

alkali metal amides (for example, lithium amide, sodium amide, potassium amide, lithium diisopropylamide and potassium hexamethyldisilazide, preferably lithium amide, sodium amide and potassium amide, more preferably lithium amide and sodium amide, and more preferably lithium amide), alkali metals (for example , lithium metal, sodium metal, and potassium metal),

organic bases (e.g., trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0 ]non-5-ene (DBN), 1,4-diazabicyclo[2,2,2]octane (DABCO), pyridine, N,N-dimethyl-4-aminopyridine, N,N-dimethylaniline and N,N-diethylaniline ), And

any combination of them in any ratio.

[0195]

From the viewpoints of yield, suppression of by-products, economic efficiency, and the like, preferred examples of the base in step (i) include alkali metal hydrides, alkali metal amides, and any combination thereof in an arbitrary ratio. Preferred specific examples of the base in step (i) include lithium hydride, sodium hydride, potassium hydride, lithium amide, sodium amide and any combination thereof in an arbitrary ratio, more preferably lithium hydride, sodium hydride, potassium hydride and lithium amide, and more preferably hydride sodium and lithium amide.

[0196]

The base in step (i) may include multiple compounds. The first compound is preferably a base containing lithium. The second compound (also referred to as another compound) can be selected from alkali metal hydrides, alkali metal amides, alkoxides, alkyl metals, alkali metals, and organic bases.

[0197]

Examples of a lithium-containing base include, but are not limited to, lithium hydride, lithium amide, lithium diisopropylamide, lithium t-butoxide, butyl lithium, sec-butyl lithium, t-butyl lithium, lithium metal, lithium hydroxide, lithium carbonate, and lithium hydrogen carbonate. Preferred examples of the lithium containing base are lithium hydride, lithium amide, lithium diisopropylamide, lithium t-butoxide, butyllithium, sec-butyllithium, t-butyllithium and lithium metal, more preferably lithium hydride and lithium amide, and particularly preferably lithium amide.

[0198]

The first compound and the second compound may be used in an arbitrary ratio. The appropriate ratio is selected depending on the type of compounds used. In one aspect, for example, the ratio of the second compound to the first compound is greater than 0 (zero) equivalents and 3.0 equivalents or less, or greater than 0 (zero) equivalents and 2.0 equivalents or less, preferably greater than 0 (zero ) equivalent and 1.5 equivalents or less, more preferably greater than 0 (zero) equivalents and 1.0 equivalents or less, and more preferably greater than 0 (zero) equivalents and 0.5 equivalents or less. In another aspect, for example, the ratio of the second compound to the first compound is preferably 0.05 equivalents-1.5 equivalents, more preferably 0.1 equivalents-1.0 equivalents, and more preferably 0.2 equivalents-0.5 equivalents per 1 the equivalent of the first connection.

[0199]

A preferred specific example of a multiple compound combination is two of lithium amide and sodium hydride, two of lithium amide and sodium amide, or two of lithium amide and sodium t-butoxide, in one aspect. In the present invention, "multiple" means, for example, "two or more" and is preferably "two or three" or "two," more preferably "two." In another aspect, a preferred specific example of a multiple compound combination is two of lithium amide as the first compound and sodium hydride as the second compound, two of lithium amide as the first compound and sodium amide as the second compound, or two of lithium amide in as the first compound and sodium tert-butoxide as the second compound.

[0200]

The form of the base in step (i) may be any form, provided that the reaction proceeds. The shape of the base in step (i) may be suitably chosen by a person skilled in the art.

[0201]

The amount of base used in step (i) may be an arbitrary ratio, provided that the reaction proceeds. However, from the viewpoints of yield, suppression of by-products, economic efficiency and the like, when the base is an alkali metal hydride (preferably sodium hydride), the amount of base used in step (i) is, for example, usually 2.0 equivalents or more, preferably 2.0 equivalents-4.0 equivalents, more preferably 2.5 equivalents-3.5 equivalents, and more preferably 2.5 equivalents-3.1 equivalents per 1 equivalent of the compound of formula (2) (aniline compound), in one aspect , and, for example, preferably 2.8 equivalents-3.5 equivalents, in another aspect.

[0202]

In terms of the above, when the base is an alkali metal amide (preferably lithium amide), the amount of base used in step (i) is, for example, usually 2.0 equivalents or more, preferably 2.0 equivalents-4.0 equivalents, and more preferably 2.5 equivalents-3.5 equivalents per 1 equivalent of the compound of formula (2) (aniline compound) in one aspect, and, for example, preferably 2.8 equivalents-3.5 equivalents in another aspect.

[0203]

When the base includes a plurality of compounds, the amount of base used (total amount of compounds used) in step (i) is, for example, usually 2.0 equivalents or more, preferably 2.0 equivalents-4.0 equivalents, and more preferably 2.5 equivalents -3.5 equivalents per 1 equivalent of the compound of formula (2) (aniline compound), in one aspect, and, for example, more preferably 2.8 equivalents-3.5 equivalents, in another aspect.

[0204]

As described above, the definition of "base equivalent" as used in the present invention is as follows, or the term "equivalent" is interpreted in accordance with the following examples. For example, when the base is a monovalent base such as sodium hydride (NaH) and lithium amide (LiNH ₂ ), "1 equivalent of base per 1 equivalent of compound of formula (2) (aniline compound)" means "1 mol of base per 1 mol of compound of formula (2) (aniline compound)," and "0.5 equivalents of base per 1 equivalent of compound of formula (2) (aniline compound)" means "0.5 mol of base per 1 mol of compound of formula (2) (aniline compound). " As another example, when the base is a divalent base such as calcium hydride (CaH ₂ ), "1 equivalent of base per 1 equivalent of compound of formula (2) (aniline compound)" means "0.5 mol of base per 1 mol of compound of formula (2) (aniline compound)," and "0.5 equivalents of base per 1 equivalent of compound of formula (2) (aniline compound)" means "0.25 mol of base per 1 mol of compound of formula (2) (aniline compound)."

[0205]

A predetermined amount of the applied base can be added to the reaction at once. Alternatively, the base may be added in multiple portions or dropwise.

[0206]

(Tertiary alcohol in step (i))

The tertiary alcohol in step (i) includes a compound of formula (6).

[formula 25]

[0207]

where R ¹³ , R ¹⁴ and R ¹⁵ may be the same or different and each is (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6- C10) aryl or (C6-C10) aryl (C1-C4) alkyl, and two selected from R ¹³ , R ¹⁴ and R ¹⁵ may be connected to each other to form a ring.

[0208]

Examples of the tertiary alcohol in step (i) include, but are not limited to, t-butanol, 2-methyl-2-butanol, 2-methyl-2-pentanol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-3-buten-2-ol, 2-methyl-3-butyn-2-ol, 1-methylcyclopentanol, 1-ethylcyclopentanol, 1-propylcyclopentanol, 1-methylcyclohexanol, 1-ethylcyclohexanol, 1-propylcyclopentanol, 2- methyladamantanol, 3-phenyl-3-pentanol, 2-phenyl-2-butanol, 2-methyl-1-phenyl-2-propanol, 2-methyl-1-phenyl-2-butanol, 3-benzyl-3-hexanol, 2-α-naphthyl-2-propanol, and 2-methyl-1-β-naphthyl-2-propanol, preferably tert-butanol, 2-methyl-2-butanol, 2-methyl-2-pentanol, 3-methyl- 3-pentanol, 3-ethyl-3-pentanol, 2-methyl-3-buten-2-ol and 2-methyl-1-phenyl-2-propanol, and more preferably tert-butanol, 2-methyl-2-butanol , 2-methyl-3-buten-2-ol and 2-methyl-1-phenyl-2-propanol. These tertiary alcohols can be used alone or in combination of two or more in an arbitrary ratio. "T-butanol" is also called "tert-butyl alcohol."

[0209]

The amount of tertiary alcohol used in step (i) may be an arbitrary amount, provided that the reaction proceeds. However, from the viewpoints of yield, suppression of by-products, economic efficiency and the like, when the base is an alkali metal hydride (preferably sodium hydride), the amount of tertiary alcohol used in step (i) is, for example, 0.3 equivalents or more, preferably 0.3 equivalents-4.0 equivalents, more preferably 0.4 equivalents-2.1 equivalents, more preferably 0.5 equivalents-2.0 equivalents, and more preferably 0.5 equivalents-1.5 equivalents per 1 compound equivalent formula (2) (aniline compound), in one aspect, and preferably 0.4 equivalents-3.2 equivalents, more preferably 0.9 equivalents-2.1 equivalents, and more preferably 1.0 equivalents-2.0 equivalents per another aspect.

[0210]

In terms of what is presented above, when the base is an alkali metal amide (preferably lithium amide), the amount of tertiary alcohol used in step (i) is, for example, 0.3 equivalents or more, preferably 0.3 equivalents-4, 0 equivalent, more preferably 0.3 equivalent-2.5 equivalent, more preferably 0.5 equivalent-2.0 equivalent, and more preferably 0.5 equivalent-1.5 equivalent per 1 equivalent of the compound of formula (2) (aniline compound ), in one aspect, and preferably 0.4 equivalents-1.1 equivalents in another aspect.

[0211]

When the base includes a plurality of compounds, the amount of tertiary alcohol used in step (i) is, for example, 0.3 equivalents or more, preferably 0.3 equivalents-4.0 equivalents, and more preferably 0.3 equivalents-2.5 equivalents per 1 equivalent of a compound of formula (2) (aniline compound), in one aspect, and, for example, 0.5 equivalents-2.5 equivalents, preferably 0.5 equivalents-2.0 equivalents, and more preferably 0.5 equivalents-1 .5 equivalent, in another aspect.

[0212]

As described above, the definition of "tertiary alcohol equivalent" as used in the present invention is as follows, or the term "equivalent" is interpreted in accordance with the following examples. For example, "1 equivalent of tert-butanol per 1 equivalent of compound of formula (2) (aniline compound)" means "1 mole of tert-butanol per 1 mole of compound of formula (2) (aniline compound)." For example, "0.5 equivalents of tert-butanol per 1 equivalent of compound of formula (2) (aniline compound)" means "0.5 mole of tert-butanol per 1 mole of compound of formula (2) (aniline compound)."

[0213]

The predetermined amount of tertiary alcohol used can be added to the reaction immediately. Alternatively, the tertiary alcohol can be added in multiple portions or dropwise.

[0214]

(Solvent in step (i))

From the point of view of a smooth reaction and the like, the reaction in step (i) is preferably carried out in the presence of a solvent. Examples of the solvent in step (i) include, but are not limited to, the following; aromatic hydrocarbons (eg benzene, toluene, xylene, chlorobenzene and dichlorobenzene), halogenated aliphatic hydrocarbons (eg dichloromethane and 1,2-dichloroethane), ethers (eg diethyl ether, diisopropyl ether, cyclopentyl methyl ether (CPME), tetrahydrofuran (THF), 1,4-dioxane, monoglyme and diglyme), amides (e.g. N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP)), sulfoxides (e.g. dimethyl sulfoxide (DMSO)), and any combination of them in an arbitrary ratio.

[0215]

The solvent in step (i) may be any solvent, provided that the reaction in step (i) proceeds. However, from the viewpoint of yield, suppression of by-products, economic efficiency and the like, preferred examples of the solvent in step (i) include toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and any combination thereof in an arbitrary ratio, more preferably toluene, xylene, chlorobenzene and dichlorobenzene, more preferably toluene and xylene, and more preferably toluene.

[0216]

The amount of solvent used in step (i) may be an arbitrary amount, provided that the reaction system can be stirred sufficiently. In terms of yield, suppression of by-products, economic efficiency and the like, an exemplary range is 10 L (liters) or less, preferably 0.1-10 L, more preferably 0.1-5 L, and more preferably 0.5- 5 l per 1 mol of the compound of formula (2) (aniline compound).

[0217]

(Reaction temperature in step (i))

In terms of yield, suppression of by-products, economic efficiency and the like, when the base is an alkali metal hydride (preferably sodium hydride), the reaction temperature in step (i) is, for example, -5°C (minus 5°C) -80 °C, preferably -5°C-50°C, more preferably 0°C-50°C, and more preferably 0°C-40°C, in one aspect, and, for example, 0°C-80°C, preferably 10°C-80°C, more preferably 20°C-70°C, more preferably 20°C-40°C, and most preferably 25°C-35°C, in another aspect.

[0218]

In terms of what is presented above, when the base is an alkali metal amide (preferably lithium amide), the reaction temperature in step (i) is, for example, -5°C (minus 5°C)-80°C, preferably - 5°C-50°C, more preferably 0°C-50°C, and more preferably 0°C-40°C, in one aspect, and e.g. -20°C (minus 20°C)-60° C, preferably -10°C-40°C, more preferably 0°C-30°C, and more preferably 0°C-15°C, in another aspect.

[0219]

When the base includes a plurality of compounds, the reaction temperature in step (i) is, for example, -5°C (minus 5°C)-80°C, preferably -5°C-50°C, more preferably 0°C-50° C, and more preferably 0°C-40°C in one aspect, and is, for example, 0°C-80°C, more preferably 0°C-60°C, more preferably 10°C-80°C, more preferably 20°C-70°C, more preferably 20°C-40°C, and most preferably 25°C-35°C in another aspect. It is, for example, -20°C (minus 20°C)-60°C, preferably -10°C-40°C, more preferably 0°C-30°C, and more preferably 0°C-15°C in yet another aspect.

[0220]

(Reaction time in step (i))

The duration of the reaction in step (i) is not specifically limited. However, from the viewpoint of yield, suppression of by-products, economic efficiency and the like, the reaction time is, for example, 0.1 h-48 h, preferably 1 h-48 h, more preferably 1 h-36 h, and more preferably 1 h- 24 hours

[0221]

The compound of formula (3) can be used as the starting compound in step (ii). The compound of formula (3) can be isolated and used in the next step, further purified and used in the next step, or used in the next step without isolation, provided that the reaction in step (ii) proceeds. In addition, after completion of the reaction in step (i), hydrochloric acid or acetic acid can be used, for example, for post-processing in step (i). In addition, after completion of the reaction in step (i), an inert gas such as nitrogen can be blown through the solution to remove by-products (as post-processing in step (i)). Removal of by-products can be carried out under reduced pressure. Examples of by-products include ammonia.

[0222]

(Product in step (i); compound of formula (3) which is a nitroso compound)

[0223]

Specific examples of the compound of formula (3) obtained in step (i) include, but are not limited to, the following;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline,

N-(4-methoxyphenyl)-2-nitrosoaniline, and

3-chloro-2-nitroso-N-phenylaniline.

[0224]

In terms of product utility and the like, preferred specific examples of the compound of formula (3) include the following;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline and

N-(4-methoxyphenyl)-2-nitrosoaniline.

In terms of what is presented above, a preferred specific example of a compound of formula (3) is as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline.

[0225]

(Step (ii))

[0226]

Next, step (ii) will be described.

[0227]

Step (ii) is the step of reacting a compound of formula (3) with a compound of formula (4) to obtain a compound of formula (5).

[0228]

[formula 26]

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined above.

[0229]

(Starting compound; malonic acid diester compound)

As the starting compound in step (ii), a compound of formula (4) is used, which is a compound that is a diester of malonic acid. The compound of formula (4) is a known compound, or it can be obtained from a known compound according to a known method.

[0230]

Examples of the compound of formula (4) include, but are not limited to, dimethylmalonate, diethylmalonate, dipropylmalonate, diisopropylmalonate, dibutylmalonate, diisobutylmalonate, and di-t-butylmalonate, preferably dimethylmalonate and diethylmalonate.

[0231]

The applied amount of the compound of formula (4) may be an arbitrary amount, provided that the reaction proceeds. The applied amount of the compound of formula (4) can be adjusted accordingly by a person skilled in the art. However, from the viewpoint of yield, suppression of by-products, economic efficiency and the like, the applied amount of the compound of formula (4) is 1.0 mol-3.0 mol, preferably 1.0 mol-2.0 mol, and more preferably 1. 0 mol-1.5 mol per 1 mol of the compound of formula (3) (nitroso compound).

[0232]

(Conditions of step (ii))

The reaction in step (ii) is preferably carried out under basic conditions. In one aspect, the reaction of step (ii) is typically carried out at pH 9 or greater, preferably pH 9-pH 20, and more preferably pH 9-pH 14. In another aspect, the reaction of step (ii) is carried out at pH 8 or greater. , preferably pH 8-pH 20, and more preferably pH 8-pH 14. In yet another aspect, the reaction in step (ii) is carried out at pH 8-pH 12, preferably pH 9-pH 12 and more preferably pH 10-pH 12 Therefore, the pH can be adjusted prior to the reaction in step (ii). To adjust the pH, an acidic substance is used, and, for example, acetic acid and hydrochloric acid can be used. The amount of acid used is the amount with which the desired pH is obtained. Therefore, the amount of acid used can be suitably adjusted by one skilled in the art. In addition, the reaction in step (ii) can be carried out in the presence of a base. The base used in step (ii) may be any base provided that the reaction proceeds.

[0233]

Examples of the base in step (ii) include, but are not limited to, the following;

Alkali metal hydroxides (eg lithium hydroxide, sodium hydroxide and potassium hydroxide),

alkaline earth metal hydroxides (eg magnesium hydroxide, calcium hydroxide and barium hydroxide),

alkali metal carbonates (eg lithium carbonate, potassium carbonate, sodium carbonate and cesium carbonate),

alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate and barium carbonate),

alkali metal bicarbonates (eg lithium bicarbonate and sodium bicarbonate),

alkaline earth metal bicarbonates (eg calcium bicarbonate), and

organic bases (e.g. triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2,2,2]octane (DABCO), pyridine and N,N-dimethyl-4-aminopyridine).

From the viewpoints of yield, suppression of by-products, economic efficiency, and the like, specific examples of the base in step (ii) include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, and triethylamine.

[0234]

These bases in step (ii) may be used alone or in combination of two or more in an arbitrary ratio. The form of the base in step (ii) may be any form, provided that the reaction proceeds. The shape of the base in step (ii) may be suitably chosen by one of ordinary skill in the art.

[0235]

The amount of base used in step (ii) may be an arbitrary amount, provided that the reaction proceeds. However, from the viewpoints of yield, suppression of by-products, economic efficiency and the like, the amount of base used in step (ii) is, for example, usually 1 equivalent or more, preferably 1 equivalent-20 equivalents, more preferably 1 equivalent-15 equivalents, and more preferably 1 equivalent to 10 equivalents per 1 equivalent of the compound of formula (3) (nitroso compound). However, the amount of base used in step (ii) can be suitably selected by one of ordinary skill in the art.

[0236]

The reaction in step (ii) can be carried out in the presence or absence of a phase transfer catalyst. Whether a phase transfer catalyst is used or not can be appropriately determined by one skilled in the art. Examples of the phase transfer catalyst include, but are not limited to, quaternary ammonium salts (e.g., tetrabutylammonium bromide (TBAB), tetrabutylammonium hydrogen sulfate, and trimethylbenzylammonium chloride), quaternary phosphonium salts (e.g., tetrabutylphosphonium bromide, tetraoctylphosphonium bromide, and tetraphenylphosphonium bromide), and crown ethers (e.g. , 12-crown-4, 15-crown-5, and 18-crown-6).

[0237]

When the phase transfer catalyst is used in step (ii), the amount of phase transfer catalyst used in step (ii) is, for example, usually 0.001 mol-0.5 mol, preferably 0.005 mol-0.3 mol, per 1 mol of the compound of formula (3 ) (nitroso compound).

[0238]

(Water in step (ii))

The reaction in step (ii) can be carried out in the presence or absence of water. However, the reaction in step (ii) is preferably carried out in the presence of water. The amount of water used in step (ii) is, for example, usually 0.5 mol-10.0 mol, preferably 1.0 mol-5.0 mol, per 1 mol of the compound of formula (3) (nitroso compound). Water can be added separately or obtained from the hydrochloric acid used in pH adjustment above.

[0239]

(Solvent in step (ii))

From the point of view of the smoothness of the reaction and the like, the reaction in step (i) is preferably carried out in the presence of a solvent. The solvent, the amount of solvent used, and the like in step (ii) may be the same as in step (ii). In addition, water may be present.

[0240]

(Reaction temperature in step (ii))

The reaction temperature in step (ii) is not specifically limited. However, from the viewpoint of yield, suppression of by-products, economic efficiency and the like, the reaction temperature is, for example, -10°C-80°C, preferably 0°C-60°C, more preferably 0°C-30°C, and more preferably 0°C-20°C.

[0241]

(Reaction time in step (ii))

The duration of the reaction in step (ii) is not specifically limited. From the viewpoints of yield, suppression of by-products, economic efficiency and the like, the reaction time is, for example, 0.1 h-48 h, preferably 0.1 h-24 h, and more preferably 0.5 h-15 h.

[0242]

(Post-processing and cleaning)

It is possible to carry out the preparation of a carboxylate with a base or salt, and/or the preparation of a free carboxylic acid with an acid. For example, operations such as extracting the product with water, extracting the product with an organic solvent, precipitating the crystals with an acid, and precipitating the crystals with a base can be carried out. For example, an aqueous solution containing the target sodium carboxylate or lithium carboxylate or the like can be treated with an acid to precipitate crystals of the target free carboxylic acid.

Target sodium carboxylate or lithium carboxylate can be extracted with water. An organic solvent solution containing the desired free carboxylic acid or the like can be treated with a base to precipitate crystals of the desired sodium carboxylate or lithium carboxylate. An aqueous solution containing the desired sodium carboxylate or lithium carboxylate or the like can be treated with a potassium salt or a calcium salt to precipitate crystals of potassium carboxylate or calcium carboxylate. The desired free carboxylic acid can be extracted with an organic solvent.

In addition, in some cases, the target sodium carboxylate or lithium carboxylate or the target free carboxylic acid or an aqueous solution or an organic solvent solution thereof can be washed with water or an organic solvent or any mixed solvent thereof in an arbitrary ratio suitably selected. In addition, solvent recovery may be performed in some cases. For example, the solvent used in the reaction can be recovered, and the solvent used in post-processing and purification can be recovered.

[0243]

(Product in step (ii); compound of formula (5) which is a quinoxaline compound)

[0244]

Specific examples of the compound of formula (5) obtained in step (ii) include, but are not limited to, the following;

5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-ethoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-propoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-isopropoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-butoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-tert-butoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-methylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-ethylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-propylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-isopropylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-butylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-(4-tert-butylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

5-chloro-1-phenyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-ethoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-propoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-isopropoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-butoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-t-butoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-methylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-ethylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-propylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-isopropylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-butylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-(4-tert-butylphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

1-phenyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

And

their potassium salts, sodium salts, lithium salts, methyl esters and ethyl esters.

[0245]

In terms of product utility and the like, preferred specific examples of the compound of formula (5) include the following;

5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid and

1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid,

more preferably 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid.

[Examples]

[0246]

The present invention will be described in more detail by the following examples, but the present invention is in no way limited to these examples.

[0247]

As used in the present invention, room temperature is 10°C-35°C.

[0248]

In the present invention, the following equipment can be used to measure physical properties and yield in Examples and Comparative Examples. In addition, the products obtained in the present invention are known compounds, and which have been identified and quantified by conventional methods known to those skilled in the art.

pH measurement; type: HM-20P or HM-30P (manufactured by DKK-TOA CORPORATION) as a glass electrode hydrogen ion concentration indicator, and model: 3200I (manufactured by Agilent Technologies Japan, Ltd.) as an electrochemical meter.

Analysis by high performance liquid chromatography (HPLC); type: LC-2010A HT (manufactured by SHIMADZU CORPORATION).

[0249]

"OCNB" stands for "2-chloronitrobenzene" as shown below.

[formula 27]

[0250]

"p-A" stands for "p-anisidine" as shown below.

[formula 28]

[0251]

"MNA" stands for "N-(4-methoxyphenyl)-2-nitroaniline" as shown below.

[formula 29]

[0252]

"CMNA" stands for "3-chloro-N-(4-methoxyphenyl)-2-nitroaniline" as shown below.

[formula 30]

[0253]

"DMM" stands for "dimethylmalonate" as shown below.

[formula 31]

[0254]

"DEM" stands for "diethyl malonate" as shown below.

[formula 32]

[0255]

"CAQ" stands for "5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid" as shown below.

[formula 33]

[0256]

Example 1

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0257]

[formula 34]

[0258]

Sodium hydride (purity: 65.1%, dispersed in liquid paraffin, 5.5 g, 149.2 mmol, 296 mol%) was suspended in toluene (28.0 g, 0.64 l/mol) in a stream of nitrogen gas. A toluene (14.0 g, 0.32 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 99 mol%) was added dropwise to it at a temperature inside the flask of 55-60°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was cooled to 25-30°C, and a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) and 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) , dissolved in toluene (14.0 g, 0.32 l/mol) was added dropwise to it over 1 h. The mixture was stirred at the same temperature for 20 h.

[0259]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 50.7%,

OCNB (parent compound): 0.6%,

p-anisidine (parent compound): 0.1%

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 31.1%,

CMNA (by-product; nitro derivative corresponding to the desired product): 2.4%.

[0260]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 53.5% (yield),

OCNB (parent compound): 0.8% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 25.0%.

[0261]

Examples 2-4

The reaction and analysis were carried out in the same way as in Example 1, except that the amount of t-butanol was changed as shown in Table 1. The results are shown in Table 1. In addition, the results of Example 1 are also shown in Table 1.

[0262]

[Table 1]

Example
no base base (equivalents) tert-BuOH
equivalents) area % HPLC (254 nm) exit (%) target product OCNB p-Anisidine MNA CMNA target product OCNB MNA 1 NaH 3.0 1.0 50.7 0.6 0.1 31.1 2.4 53.5 0.8 25.0 2 NaH 3.0 0.5 48.5 1.2 0.2 31.9 1.9 49.6 2.1 24.8 3 NaH 3.0 2.0 55.9 3.0 0.4 26.1 1.8 50.2 5.2 17.8 4 NaH 3.0 3.1 49.7 6.8 0.9 25.9 2.2 48.2 19.7 17.0

[0263]

Example 5

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0264]

[formula 35]

[0265]

Lithium amide (purity: 95.0%, 3.72 g, 153.9 mmol, 306 mol%) was suspended in toluene (28.0 g, 0.64 l/mol) in a stream of nitrogen gas. A toluene (14.0 g, 0.32 l/mol) solution of tert-butanol (3.7 g, 49.9 mmol, 99 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature and a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) and 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (14.0 g, 0.32 l/mol) was added dropwise thereto over 1 h. The mixture was stirred at the same temperature for 20 h.

[0266]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 67.6%,

OCNB (parent compound): 11.2%,

p-anisidine (parent compound): 1.7%

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 6.6%,

CMNA (by-product; nitro derivative corresponding to the desired product): 3.0%.

[0267]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 74.9% (yield),

OCNB (parent compound): 4.3% (recovery),

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 2.8%.

[0268]

Examples 6-10

The reaction and analysis were carried out in the same manner as in Example 5, except that the amount of lithium amide and the amount of tert-butanol were changed as shown in Table 2. The results are shown in Table 2. In addition, the results of Example 5 are also shown in Table 2 It can be seen that the yield increases with appropriate adjustment of the amount of base and tert-butanol used.

[0269]

[Table 2]

Example No base Base (equivalents) tert-BuOH
(equivalents) area % HPLC (254 nm) exit (%) target product OCNB p-Anisidine MNA CMNA target product OCNB MNA 5 LiNH ₂ 3.1 1.0 67.6 11.2 1.7 6.6 3.0 74.9 4.3 2.8 6 LiNH ₂ 3.1 0.5 70.5 2.5 0.1 12.4 3.6 71.9 1.0 7.7 7 LiNH ₂ 3.1 1.5 67.5 13.1 1.8 6.4 3.4 56.1 29.5 2.1 8 LiNH ₂ 3.1 2.0 68.5 20.6 3.6 2.4 1.7 49.2 40.6 N.D. 9 LiNH ₂ 3.1 2.5 64.2 27.0 3.9 0.9 0.8 41.9 55.3 N.D. 10 LiNH ₂ 2.6 0.5 69.0 2.8 0.5 11.5 4.4 51.6 24.1 2.5

N.D=not detected

[0270]

Example 11

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0271]

[formula 36]

[0272]

Lithium amide (purity: 95.0%, 3.72 g, 153.9 mmol, 306 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of tert-butanol (3.7 g, 49.9 mmol, 99 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (2.0 g, 0.05 l/mol) was added to it, and then a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) dissolved in toluene (42.0 g, 0.96 L/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for 20 hours.

[0273]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 80.9%,

OCNB (parent compound): 1.1%,

p-anisidine (parent compound): 0.2%

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 5.2%,

CMNA (by-product; nitro derivative corresponding to the desired product): 3.4%.

[0274]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 75.0% (yield),

OCNB (original compound): traces (degree of extraction),

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 1.9%.

[0275]

Example 12

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0276]

[formula 37]

[0277]

Lithium amide (purity: 95.0%, 3.72 g, 153.9 mmol, 306 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of tert-butanol (3.7 g, 49.9 mmol, 99 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (11.8 g, 74.9 mmol, 149 mol%) dissolved in toluene (2.0 g, 0.05 l/mol) was added to it, and then a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) dissolved in toluene (42.0 g, 0.96 L/mol) was added dropwise over 1 h. The mixture was stirred at the same temperature within 20 hours

[0278]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 73.5%,

OCNB (parent compound): 14.4%,

p-anisidine (parent compound): 0.3%

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 3.3%,

CMNA (by-product; nitro derivative corresponding to the desired product): 2.1%.

[0279]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 84.1% (yield),

OCNB (parent compound): 48.0% (recovery),

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 1.1%.

[0280]

Example 13

Preparation of N-(4-methoxyphenyl)-2-nitrosoaniline

[0281]

[formula 38]

[0282]

Sodium hydride (purity: 65.1%, dispersed in liquid paraffin, 5.5 g, 149.2 mmol, 298 mol%) was suspended in toluene (28.0 g, 0.65 l/mol) in a stream of nitrogen gas. A toluene (14.0 g, 0.32 l/mol) solution of tert-butanol (3.7 g, 49.9 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 55°C-60°C for 30 minutes, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was cooled to 25-30°C, and a solution of p-anisidine (6.2 g, 50.0 mmol, 100 mol%) and nitrobenzene (6.2 g, 50.0 mmol, 100 mol%) dissolved in toluene (14.0 g, 0.32 l/mol) was added dropwise thereto over 1 h. The mixture was stirred at the same temperature for 20 h.

[0283]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 56.1%,

nitrobenzene (parent compound): 20.8%,

p-anisidine (starting compound): 0.7%.

[0284]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 51.3% (yield),

nitrobenzene (parent compound): 18.4% (recovery).

[0285]

Example 14

Preparation of N-(4-Methoxyphenyl)-2-nitrosoaniline

[0286]

[formula 39]

[0287]

Lithium amide (purity: 95.0%, 3.75 g, 155.2 mmol, 310 mol%) was suspended in toluene (28.1 g, 0.65 l/mol) in a stream of nitrogen gas. A toluene (14.0 g, 0.32 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, and a solution of p-anisidine (6.2 g, 50.0 mmol, 100 mol%) and nitrobenzene (6.2 g, 50.0 mmol, 100 mol%) dissolved in toluene (14.0 g, 0.32 l/mol) was added dropwise to it over 1 hour. The mixture was stirred at the same temperature for 20 hours.

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 55.1%,

nitrobenzene (parent compound): 12.7%,

p-anisidine (starting compound): 0.5%.

[0288]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 44.6% (yield),

nitrobenzene (parent compound): 30.3% (recovery).

[0289]

According to examples 1-14, the target nitroso compound can be obtained without requiring extremely low temperatures. In addition, according to examples 1 to 14, the applied amount of aniline compound, the starting compound, can be reduced.

[0290]

Example 15

Preparation of 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0291]

[formula 40]

[0292]

Stage (i)

Lithium amide (purity: 95.0%, 7.50 g, 310.3 mmol, 311 mol%) was suspended in toluene (56.1 g, 0.65 l/mol) in a stream of nitrogen gas. A toluene (28.0 g, 0.32 l/mol) solution of tert-butanol (7.4 g, 99.8 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. A solution of p-anisidine (12.3 g, 99.9 mmol, 100 mol%) and 2-chloronitrobenzene (15.8 g, 100.3 mmol, 100 mol%) dissolved in toluene (28.0 g, 0. 32 L/mol) was added dropwise thereto for 1 hour. The mixture was stirred at the same temperature for 20 hours. A reaction mixture was obtained containing the desired intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline.

[0293]

Stage (ii)

Water (1.8 g, 99.9 mmol, 100 mol% (relative to p-anisidine)) was added dropwise to the reaction mixture obtained in step (i) above at an internal flask temperature of 0-10°C. Then, diethylmalonate (16.0 g, 99.9 mmol, 100 mol% (relative to p-anisidine)) was added dropwise at the same temperature over 1 hour, and the mixture was stirred at the same temperature for 2 hours. Water (0.2 d) was added to it, and the mixture was further stirred for 2 hours.

[0294]

4% hydrochloric acid (231.8 g) was added dropwise thereto, adjusting the pH of the solution to 9.5. The temperature inside the flask was raised to 35-40°C, and the mixture was separated into toluene and water. The toluene phase was removed. The resulting aqueous phase was washed with toluene (43.5 g x twice), and then 35% hydrochloric acid (31.9 g) was added dropwise to the aqueous phase at an internal temperature of 25-30°. The mixture was stirred for 30 minutes and then the crystals were filtered. The crystals were washed with toluene (19.8 g) and water (25.0 g). The resulting crystals were dried to give 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid (21.1 g, 96.4% purity, 61.4% yield) in as the target product.

[0295]

Example 16

Preparation of 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0296]

[formula 41]

[0297]

Stage (i)

Lithium amide (purity: 95.0%, 3.7 g, 153.1 mmol, 306 mol%) was suspended in toluene (28.0 g, 0.65 l/mol) in a stream of nitrogen gas. A toluene (11.0 g, 0.25 l/mol) solution of tert-butanol (3.7 g, 49.9 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (3.0 g, 0.1 l/mol) was added to it, and then a solution of p-anisidine (6.2 g, 50.0 mmol, 100 mol%) dissolved in toluene (14.0 g, 0.3 L/mol) was added dropwise over 1 h. The mixture was stirred at the same temperature for 20 hours. A reaction mixture was obtained containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline.

[0298]

Stage (ii)

The temperature inside the flask was maintained at 0-10° C. and water (2.8 g, 155.4 mmol, 311 mol% (relative to p-anisidine)) was added dropwise to the reaction mixture obtained in step (i) above for 15 min. Then, diethylmalonate (8.0 g, 50.0 mmol, 100 mol% (relative to p-anisidine)) was added dropwise at the same temperature over 1 hour, and the mixture was stirred at the same temperature for 1 hour.

[0299]

4% hydrochloric acid (94.0 g) was dropped thereto over 1 hour to adjust the pH to 8.3. The temperature inside the flask was raised to 35-40° C., water (5.0 g) was added, and then the mixture was separated into toluene and water. The toluene phase was removed. The resulting aqueous phase was washed with toluene (21.8 g×twice), and then 35% hydrochloric acid (10.4 g) was added dropwise to the aqueous phase at an internal flask temperature of 20-30° for 1 hour. The mixture was stirred for 30 minutes, and then the crystals were filtered. The crystals were subsequently washed with toluene (9.9 g) and water (12.5 g). The resulting crystals were dried to give 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid (11.0 g, 95.7% purity, 66.5% yield) in as the target product.

[0300]

Example 17

Preparation of 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0301]

[formula 42]

[0302]

Stage (i)

Lithium amide (purity: 95.0%, 7.5 g, 310.3 mmol, 311 mol%) was suspended in toluene (20.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (4.0 g, 0.05 l/mol) solution of tert-butanol (7.4 g, 99.8 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (23.6 g, 149.8 mmol, 150 mol%) dissolved in toluene (4.0 g, 0.05 l/mol) was added to it, and then a solution of p-anisidine (12.3 g, 99.9 mmol, 100 mol%) dissolved in toluene (84.4 g, 0.97 L/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for 20 hours Then nitrogen was bubbled through the reaction solution for 8 hours, removing ammonia. A reaction mixture was obtained containing the desired intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline.

[0303]

Stage (ii)

The temperature inside the flask was maintained at 0-10° C. and water (2.3 g, 149.9 mmol, 150 mol% (relative to p-anisidine)) was added to the reaction mixture obtained in step (i) above. Then, diethylmalonate (16.0 g, 99.9 mmol, 100 mol% (relative to p-anisidine)) was added dropwise at the same temperature for 1 hour, and the mixture was stirred at the same temperature for 7 hours. 4% hydrochloric acid was added dropwise to it for 1 h, bringing the pH to 8.1. The temperature inside the flask was raised to 35-40° C., water (5.0 g) was added, and then the mixture was separated into toluene and water. The toluene phase was removed. The resulting aqueous phase was washed with toluene (43.5 g×twice), and then 35% hydrochloric acid (20.8 g) was added dropwise to the aqueous phase at an internal flask temperature of 20-30° for 1 hour. The mixture was stirred for 30 minutes, and then the crystals were filtered. The crystals were subsequently washed with toluene (19.8 g) and water (25.0 g). The resulting crystals were dried to give 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid (25.40 g, 98.0% purity, 75.3% yield) in as the target product.

[0304]

Example 18

Preparation of 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0305]

[formula 43]

[0306]

Sodium hydride (purity: 65.1%, dispersed in liquid paraffin, 10.9 g, 295.7 mmol, 296 mol%) was suspended in toluene (56.1 g, 0.65 l/mol) in a stream of nitrogen gas. A toluene (27.0 g, 0.31 l/mol) solution of tert-butanol (7.4 g, 99.8 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 55-60°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was cooled to 25-30°C, and a solution of 2-chloronitrobenzene (16.5 g, 104.7 mmol, 105 mol%) and p-anisidine (12.3 g, 99.9 mmol, 100 mol%) , dissolved in toluene (27.0 g, 0.31 L/mol) was added dropwise thereto over 1 h. The mixture was stirred at the same temperature for 2 h. The reaction mixture containing the desired intermediate 3-chloro-N- (4-Methoxyphenyl)-2-nitrosoaniline was obtained.

[0307]

Stage (ii)

The temperature inside the flask was cooled to 0°C-10°C, and then 35% hydrochloric acid (26.0 g) was added dropwise until a pH of 9.7 was reached. TBAB (3.2 g, 9.9 mmol, 10 mol% (relative to p-anisidine)) and dimethylmalonate (9.9 g, 74.9 mmol, 75 mol % (relative to p-anisidine)) were added. The mixture was stirred at the same temperature for 30 minutes and then a 48% KOH aqueous solution (4.3 g) was added dropwise over 2 hours to reach a pH of 13.3. The mixture was stirred for 2 hours and then a 48% KOH aqueous solution (19.1 g) was added dropwise over 3 hours. The mixture was stirred for 17 hours.

[0308]

4% hydrochloric acid (87.0 g) was added dropwise at the same temperature over 1 hour, adjusting the pH to 7.7. The temperature inside the flask was raised to 35-40°C, and the mixture was separated into toluene and water. The toluene phase was removed. The resulting aqueous phase was washed with toluene (43.5 g×twice), and then 35% hydrochloric acid (10.4 g) was added dropwise to the aqueous phase at an internal flask temperature of 25-30° for 2 hours. The mixture was stirred for 30 minutes, and then the crystals were filtered. The crystals were subsequently washed with toluene (19.8 g) and water (25.0 g). The resulting crystals were dried to give 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid (13.9 g, 95.2% purity, 39.9% yield) in as the target product.

[0309]

Example 19

Preparation of 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0310]

[formula 44]

[0311]

Stage (i)

Lithium amide (purity: 98.0%, 7.50 g, 320.1 mmol, 320 mol%) was suspended in toluene (20.0 g, 0.23 L/mol) in a reaction container under nitrogen gas flow. A toluene (4.0 g, 0.05 l/mol) solution of tert-butanol (7.4 g, 99.8 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (23.6 g, 149.8 mmol, 150 mol%) dissolved in toluene (4.0 g, 0.05 l/mol) was added to it, and then a solution of p-anisidine (12.3 g, 99.9 mmol, 100 mol%) dissolved in toluene (126.2 g, 1.46 L/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for 1 hour. A reaction mixture was obtained containing the desired intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline.

[0312]

Stage (ii)

The temperature inside the flask was maintained at 0-10° C. and water (2.7 g, 149.8 mmol, 150 mol% (relative to p-anisidine)) was added dropwise to the reaction mixture obtained in step (i) above over a period of 30 min. After dropping, the ammonia was removed under reduced pressure. Then, diethylmalonate (16.0 g, 99.9 mmol, 100 mol% (relative to p-anisidine)) was added dropwise at the same temperature over 2 hours, and the mixture was stirred at the same temperature for 1 hour (endpoint determined by analysis) .

[0313]

A mixed solution of tert-butanol (7.4 g, 99.8 mmol, 100 mol%) and water (75 ml, 0.8 L/mol) was added to another reaction container and the temperature inside the flask was cooled to 0-10°C . The previously reacted reaction mixture and 35% hydrochloric acid (23.7 g) were simultaneously added dropwise thereto over 30 minutes, adjusting the pH to 7.8. The temperature inside the flask was raised to 25-30° C. and 35% hydrochloric acid (20.8 g) was added dropwise over about 1 hour. The mixture was stirred at the same temperature for 30 minutes, and then the crystals were filtered. The crystals were subsequently washed with toluene (39.6 g) and water (25.0 g). The resulting crystals were dried to give 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid (24.37 g, 99.33% purity, 73.2% yield) in as the target product.

[0314]

According to examples 15-19, the target quinoxaline compound of formula (5) can be obtained without requiring extremely low temperatures. In addition, according to examples 15-19, the amount of aniline compound, the starting compound, used can be reduced.

[0315]

Example 20

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0316]

[formula 45]

[0317]

Lithium amide (purity: 95.0%, 2.54 g, 105.1 mmol, 210 mol%) and sodium hydride (purity: 66.3%, dispersed in liquid paraffin, 1.85 g, 51.1 mmol, 102 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (11.8 g, 74.9 mmol, 150 mol%) dissolved in toluene (2.0 g, 0.05 l/mol) was added to it, and then the temperature inside the flask was raised to 25°C-30°C. The temperature inside the flask was maintained at the same temperature and a solution of p-anisidine (6.16 g, 50.0 mmol, 100 mol%) dissolved in toluene (42.1 g, 0.97 L/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for 1 h.

[0318]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 68.2%,

OCNB (parent compound): 14.8%,

p-anisidine (parent compound): 0.1%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 8.7%,

CMNA (by-product; nitro derivative corresponding to the desired product): 2.1%.

[0319]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 81.0% (yield),

OCNB (parent compound): 45.9% (recovery),

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 6.9%.

[0320]

Example 21

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0321]

[formula 46]

[0322]

Lithium amide (purity: 95.0%, 1.87 g, 77.4 mmol, 155 mol%) and sodium hydride (purity: 66.3%, dispersed in liquid paraffin, 2.81 g, 77.6 mmol, 155 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (11.8 g, 74.9 mmol, 150 mol%) dissolved in toluene (2.0 g, 0.05 l/mol) was added to it, and then the temperature inside the flask was raised to 25°C-30°C. The temperature inside the flask was maintained at the same temperature and a solution of p-anisidine (6.16 g, 50.0 mmol, 100 mol%) dissolved in toluene (42.1 g, 0.97 L/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for 1 h.

[0323]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 51.0%,

OCNB (parent compound): 13.2%,

p-anisidine (parent compound): 0.2%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 23.0%,

CMNA (by-product; nitro derivative corresponding to the desired product): 3.5%.

[0324]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 57.9% (yield),

OCNB (parent compound): 45.4% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 20.0%.

[0325]

Example 22

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0326]

[formula 47]

[0327]

Lithium amide (purity: 95.0%, 1.2 g, 49.7 mmol, 99 mol%) and sodium hydride (purity: 66.3%, dispersed in liquid paraffin, 3.8 g, 105.0 mmol, 210 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (11.8 g, 74.9 mmol, 150 mol%) dissolved in toluene (2.0 g, 0.05 l/mol) was added to it, and then the temperature inside the flask was raised to 25°C-30°C. The temperature inside the flask was maintained at the same temperature and a solution of p-anisidine (6.16 g, 50.0 mmol, 100 mol%) dissolved in toluene (42.1 g, 0.97 L/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for 1 h.

[0328]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 42.8%,

OCNB (parent compound): 12.2%,

p-anisidine (parent compound): 0.3%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 28.1%,

CMNA (by-product; nitro derivative corresponding to the desired product): 5.4%.

[0329]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 51.7% (yield),

OCNB (parent compound): 44.8% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 26.0%.

[0330]

Example 23

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0331]

[formula 48]

[0332]

Lithium amide (purity: 98.0%, 2.46 g, 105.0 mmol, 210 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, and a solution of 2-chloronitrobenzene (11.8 g, 74.9 mmol, 150 mol%) dissolved in toluene (2.0 g, 0.05 l/mol) was added thereto. Then sodium amide (purity: 90.0%, 1.95 g, 45.0 mmol, 90 mol%) was added, and a solution of p-anisidine (6.16 g, 50.0 mmol, 100 mol%) dissolved in toluene (42.0 g, 0.97 l/mol) was added dropwise over 4 hours. The mixture was stirred at the same temperature for 17 hours.

[0333]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 53.9%,

OCNB (parent compound): 14.2%,

p-anisidine (parent compound): 0.2%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 18.8%,

CMNA (by-product; nitro derivative corresponding to the desired product): 3.5%.

[0334]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 61.6% (yield),

OCNB (parent compound): 48.1% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 16.2%.

[0335]

Example 24

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0336]

[formula 49]

[0337]

Lithium amide (purity: 98.0%, 2.46 g, 105.0 mmol, 210 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, and a solution of 2-chloronitrobenzene (11.8 g, 75.0 mmol, 150 mol%) dissolved in toluene (2.0 g, 0.05 L/mol) was added to it . Then sodium tert-butoxide (purity: 98.0%, 4.91 g, 50.1 mmol, 100 mol%), and p-anisidine solution (6.16 g, 50.0 mmol, 100 mol%) were added, dissolved in toluene (42.0 g, 0.97 l/mol) was added dropwise over 4 hours. The mixture was stirred at the same temperature for 17 hours.

[0338]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 47.5%,

OCNB (original compound): 21.8%,

p-anisidine (parent compound): 0.1%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 18.7%,

CMNA (by-product; nitro derivative corresponding to the desired product): 1.9%.

[0339]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 54.9% (yield),

OCNB (parent compound): 70.4% (recovery),

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 15.2%.

[0340]

Example 25

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0341]

[formula 50]

[0342]

Potassium hydride (purity: 30.0%, 20.72 g, 155.0 mmol, 310 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature and a solution of 2-chloronitrobenzene (11.82 g, 75.0 mmol, 150 mol%) dissolved in toluene (2.0 g, 0.05 L/mol) was added thereto. The temperature inside the flask was raised to 20°C and a solution of p-anisidine (6.16 g, 50.0 mmol, 100 mol%) dissolved in toluene (42.0 g, 0.97 L/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for 20 h.

[0343]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 42.6%,

OCNB (parent compound): 11.3%,

p-anisidine (parent compound): N.D,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 28.3%,

CMNA (by-product; nitro derivative corresponding to the desired product): 6.7%.

[0344]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 52.0% (yield),

OCNB (parent compound): 41.7% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 26.4%.

[0345]

Example 26

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0346]

[formula 51]

[0347]

Lithium amide (purity: 99.0%, 3.7 g, 160.0 mmol, 317 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 L/mol) solution of 2-methyl-2-butanol (4.4 g, 49.9 mmol, 99 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C in for 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (2.0 g, 0.05 l/mol) was added to it, and then a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) dissolved in toluene (42.0 g, 0.96 L/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for 20 hours.

[0348]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture, excluding the solvent and the like, were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 78.2%,

OCNB (parent compound): 0.2%,

p-anisidine (parent compound): 0.1%

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 4.1%,

CMNA (by-product; nitro derivative corresponding to the desired product): 1.7%.

[0349]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 74.0% (yield),

OCNB (original connection): traces,

MNA (by-product; Cl displacement compound (Cl removal compound)): 3.0%.

[0350]

Example 27

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0351]

[formula 52]

[0352]

Lithium amide (purity: 99.0%, 3.7 g, 160.0 mmol, 317 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of 2-methyl-1-phenyl-2-propanol (7.5 g, 49.9 mmol, 99 mol%) was added dropwise to it at an internal temperature of 0- 10°C for 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (2.0 g, 0.05 l/mol) was added to it, and then a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) dissolved in toluene (42.0 g, 0.96 L/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for 20 hours.

[0353]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 66.8%,

OCNB (parent compound): 0.4%,

p-anisidine (parent compound): 0.1%

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 7.9%,

CMNA (by-product; nitro derivative corresponding to the desired product): 0.3%.

[0354]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 65.7% (yield),

OCNB (parent compound): 1.3% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 5.9%.

[0355]

Example 28

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0356]

[formula 53]

[0357]

Lithium amide (purity: 99.0%, 3.7 g, 160.0 mmol, 317 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of 2-methyl-3-buten-2-ol (4.3 g, 49.9 mmol, 99 mol%) was added dropwise to it at an internal temperature of 0- 10°C for 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (2.0 g, 0.05 L/mol) was added to it, and then a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) dissolved in toluene (42.0 g, 0.96 l/mol) was added dropwise over 3 h. The mixture was stirred at the same temperature for within 20 hours

[0358]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 71.9%,

OCNB (original compound): 2.5%,

p-anisidine (parent compound): 0.1%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 5.8%,

CMNA (by-product; nitro derivative corresponding to the desired product): 1.8%.

[0359]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 78.8% (yield),

OCNB (parent compound): 3.0% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 4.8%.

[0360]

Example 29

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (2-methyl-3-phenyl-1-propanol)

[0361]

[formula 54]

[0362]

Sodium hydride (purity: 66.3%, dispersed in liquid paraffin, 5.4 g, 149.2 mmol, 296 mol%) was suspended in toluene (28.0 g, 0.64 l/mol) in a stream of nitrogen gas. A toluene (14.0 g, 0.32 l/mol) solution of 2-methyl-3-buten-2-ol (4.3 g, 49.9 mmol, 99 mol%) was added dropwise to it at an internal temperature of 55- 60°C for 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was cooled to 25-30°C, and a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) and 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) , dissolved in toluene (14.0 g, 0.32 l/mol) was added dropwise to it over 1 h. The mixture was stirred at the same temperature for 20 h.

[0363]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 55.0%,

OCNB (original compound): 2.5%,

p-anisidine (parent compound): 0.4%

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 28.8%,

CMNA (by-product; nitro derivative corresponding to the desired product): 3.5%.

[0364]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 45.0% (yield),

OCNB (parent compound): 6.2% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 18.0%.

[0365]

Example 30

Obtaining 3-Chloro-2-nitroso-N-phenylaniline

[0366]

[formula 55]

[0367]

Lithium amide (purity: 99.0%, 3.7 g, 160.0 mmol, 320 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (2.0 g, 0.05 L/mol) was added to it, and then a solution of aniline (4.65 g, 49.9 mmol, 100 mol%) dissolved in toluene (42.1 g, 0.97 l/mol) was added dropwise over 30 minutes. The mixture was stirred at the same temperature for 20 hours.

[0368]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-2-nitroso-N-phenylaniline (target product): 89.5%,

aniline (parent compound): N.D,

OCNB (parent compound): 1.6%.

[0369]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-2-nitroso-N-phenylaniline (target product): 91.5% (yield),

OCNB (parent compound): 5.0% (recovery).

[0370]

Example 31

Obtaining 3-Chloro-2-nitroso-N-phenylaniline

[0371]

[formula 56]

[0372]

Sodium hydride (purity: 66.3%, dispersed in liquid paraffin, 5.44 g, 150.3 mmol, 300 mol%) was suspended in toluene (28.0 g, 0.65 l/mol) in a stream of nitrogen gas. A toluene (14.0 g, 0.32 l/mol) solution of tert-butanol (3.71 g, 50.1 mmol, 100 mol%) was added dropwise to it at a temperature inside the flask of 55-60°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was cooled to 25-30°C, and a solution of aniline (4.66 g, 50.0 mmol, 100 mol%) and 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (14.0 g, 0.32 l/mol) was added dropwise thereto over 1 h. The mixture was stirred at the same temperature for 20 h.

[0373]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-2-nitroso-N-phenylaniline (target product): 54.9%,

OCNB (parent compound): 2.2%,

aniline (parent compound): N.D.

[0374]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-2-nitroso-N-phenylaniline (target product): 55.0% (yield),

OCNB (parent compound): 6.8% (recovery).

[0375]

According to examples 20-31, the target nitroso compound can be obtained without requiring extremely low temperatures. In addition, according to examples 20-31, the amount of aniline compound, the starting compound, used can be reduced.

[0376]

Comparative Example 1

The reaction and analysis was carried out in the same way as in example 1, except that t-butanol (t-BuOH) was not used.

[0377]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 0.5%,

OCNB (original compound): 82.6%,

p-anisidine (parent compound): 11.6%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 2.7%,

CMNA (by-product; nitro derivative corresponding to the desired product): 0.3%.

[0378]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): traces (yield),

OCNB (parent compound): 94.6% (recovery),

MNA (by-product; Cl substitution compound (Cl removal compound)): traces.

[0379]

Comparative Example 2

The reaction and analysis were carried out in the same way as in example 5, except that t-BuOH was not used.

[0380]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): N.D,

OCNB (parent compound): 87.4%,

p-anisidine (parent compound): 12.6%,

MNA (by-product; Cl substitution compound (Cl removal compound)): N.D,

CMNA (by-product; nitro derivative corresponding to target product): N.D.

[0381]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): N.D (yield),

OCNB (original compound): 100% (recovery),

MNA (by-product; Cl-displacing compound (Cl-removing compound)): N.D.

[0382]

Comparative Example 3

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0383]

[formula 57]

[0384]

Sodium tert-butoxide (purity: 98.0%, 5.96 g, 60.8 mmol, 304 mol%) was suspended in toluene (16.8 g, 0.97 l/mol) in a stream of nitrogen gas. The suspension was stirred at the temperature inside the flask 0-10°C for 30 min. The temperature inside the flask was maintained at the same temperature, and a solution of p-anisidine (2.46 g, 20.0 mmol, 100 mol%) and 2-chloronitrobenzene (3.15 g, 20.0 mmol, 100 mol%) dissolved in toluene (5.6 g, 0.32 l/mol) was added dropwise thereto over 1 h. The mixture was stirred at the same temperature for 20 h.

[0385]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 36.7%,

OCNB (parent compound): 17.6%,

p-anisidine (parent compound): 2.4%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 29.7%,

CMNA (by-product; nitro derivative corresponding to the desired product): 5.7%.

[0386]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 30.6% (yield),

OCNB (parent compound): 43.3% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 17.0%.

[0387]

Comparative Example 4

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0388]

[formula 58]

In a stream of nitrogen gas, lithium tert-butoxide (purity: 97.0%, 12.8 g, 155.1 mmol, 308 mol%) was suspended in toluene (42.0 g, 0.96 l/mol), and the suspension stirred at the temperature inside the flask 0°C-10°C for 30 min. The temperature inside the flask was maintained at the same temperature, and a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) and 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (14.0 g, 0.32 L/mol) was added dropwise thereto over 1 hour. The mixture was stirred at the same temperature for 20 hours. in a small amount, and most of the unreacted starting compounds remained.

[0389]

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 0.6%,

OCNB (parent compound): 76.9%,

p-anisidine (parent compound): 22.0%.

[0390]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): traces (yield),

OCNB (parent compound): 100.0% (recovery).

[0391]

Comparative Example 5

The method described in Tetrahedron (2016) 8252-8260 (Non-Patent Literature 2)

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0392]

[formula 59]

Under a stream of nitrogen gas, the temperature inside the flask was cooled to -65°C, and potassium tert-butoxide (purity: 97.0%, 3.4 g, 29.4 mmol, 294 mol%) was suspended in N,N-dimethylformamide ( DMF) (60.0 ml, 6.0 l/mol). As a result, the mixture froze. The temperature inside the flask was maintained at the same temperature, a solution of p-anisidine (1.23 g, 10.0 mmol, 100 mol%) dissolved in N,N-dimethylformamide (10.0 ml, 1.0 L/mol), was added to it, and then a solution of 2-chloronitrobenzene (1.58 g, 10.0 mmol, 100 mol%) dissolved in N,N-dimethylformamide (10.0 ml, 1.0 l/mol) was added dropwise. The mixture was stirred at the same temperature for 30 minutes. The cooling bath was then removed and the temperature raised to room temperature over 30 minutes. The mixture was stirred at room temperature for 50 minutes, and then the reaction mixture was poured into a saturated ammonium chloride aqueous solution (250.0 ml), followed by extraction with ethyl acetate (100.0 ml). The resulting organic layer was subsequently washed with water (50.0 ml) and brine (50.0 ml) to give an ethyl acetate solution containing the desired product.

[0393]

As a result of HPLC analysis (area percentage; 254 nm) of the obtained ethyl acetate solution, the main components were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 29.3%,

OCNB (parent compound): 0.7%,

p-anisidine (parent compound): 0.9%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 15.0%,

CMNA (by-product; nitro derivative corresponding to the desired product): 0.1%.

[0394]

The resulting ethyl acetate solution was analyzed by the HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 30.5%,

OCNB (parent compound): 0.7%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 11.3%.

[0395]

Comparative Example 6

The reaction and post-treatment were carried out in the same manner as described in Tetrahedron (2016) 8252-8260 (non-patent literature 2), except that the reaction temperature was changed to room temperature.

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0396]

[formula 60]

[0397]

Potassium tert-butoxide (purity: 97.0%, 3.4 g, 29.4 mmol, 302 mol%) was suspended in N,N-dimethylformamide (60.0 ml, 6.01 L/mol) under nitrogen gas flow . A solution of p-anisidine (1.2 g, 9.7 mmol, 100 mol%) dissolved in N,N-dimethylformamide (10.0 ml, 1.00 L/mol) was added thereto at room temperature, and then a solution of 2-chloronitrobenzene (1.5 g, 9.5 mmol, 98 mol%) dissolved in N,N-dimethylformamide (10.0 ml, 1.00 l/mol) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution (250.0 ml), followed by extraction with ethyl acetate (100.0 ml). The resulting organic layer was subsequently washed with water (50.0 ml) and brine (50.0 ml) to give an ethyl acetate solution containing the desired product.

[0398]

As a result of HPLC analysis (area percentage; 254 nm) of the obtained ethyl acetate solution, the main components were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 7.3%,

OCNB (parent compound): 3.6%,

p-anisidine (parent compound): 1.4%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 1.6%,

CMNA (by-product; nitro derivative corresponding to the desired product): 0.1%.

[0399]

The resulting ethyl acetate solution was analyzed by the HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 0.5%,

OCNB (parent compound): 10.8%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 1.2%.

[0400]

Comparative Example 7

The method described in Synlett (2015) 1352-1356 (non-patent literature 1)

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0401]

[formula 61]

Under a stream of nitrogen gas, the temperature inside the flask was cooled to -60°C, and potassium tert-butoxide (purity: 97.0%, 3.4 g, 29.4 mmol, 302 mol%) was suspended in N,N-dimethylformamide ( 50.0 ml, 5.13 l/mol). A solution of p-anisidine (1.2 g, 9.7 mmol, 100 mol%) dissolved in N,N-dimethylformamide (3.0 ml, 0.31 L/mol) was added thereto, and then a solution of 2 -chloronitrobenzene (1.5 g, 9.5 mmol, 98 mol%) dissolved in N,N-dimethylformamide (8.0 ml, 0.82 l/mol). The temperature inside the flask was maintained at the same temperature and the mixture was stirred for 30 minutes. The temperature inside the flask was raised to -30°C, and the mixture was stirred for 1 hour. The mixture was poured into a saturated aqueous ammonium chloride solution (250.0 ml), followed by extraction with ethyl acetate (100.0 ml). The resulting organic layer was subsequently washed with water (50.0 ml) and brine (50.0 ml) to give an ethyl acetate solution containing the desired product.

[0402]

As a result of HPLC analysis (area percentage; 254 nm) of the obtained ethyl acetate solution, the main components were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 22.2%,

OCNB (parent compound): 7.0%,

p-anisidine (parent compound): 0.9%,

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 31.1%,

CMNA (by-product; nitro derivative corresponding to the desired product): 0.2%.

[0403]

The resulting ethyl acetate solution was analyzed by the HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 18.2%,

OCNB (parent compound): 16.1%,

MNA (by-product; Cl displacement compound (Cl removal compound)): 4.2%.

[0404]

Comparative Example 8

The method described in Chemistry of Heterocyclic Compounds 2018, 54(9), 875-886 (non-patent literature 3)

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0405]

[formula 62]

[0406]

p-Anisidine (1.23 g, 10.0 mmol, 199 mol%) was dissolved in dimethyl sulfoxide (DMSO) (20.0 ml, 4.00 l/mol) under nitrogen gas flow. Sodium hydride (66.3%, dispersed in liquid paraffin, 0.36 g, 9.95 mmol, 198 mol%) was added thereto at room temperature, and then 2-chloronitrobenzene (0.79 g, 5.0 mmol) was added. , 100 mol%). The temperature inside the flask was maintained at room temperature and the mixture was stirred for 1 hour. The mixture was poured into brine cooled with ice water and the precipitated crystals were filtered. The obtained crystals were dissolved in toluene, obtaining a toluene solution containing the target product.

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 0.5%,

OCNB (original compound): 27.5%,

p-anisidine (parent compound): 1.5%

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 15.5%,

CMNA (by-product; nitro derivative corresponding to the desired product): 0.3%.

[0407]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 0.8% (yield),

OCNB (parent compound): 56.5% (recovery),

MNA (by-product; Cl displacement compound (Cl removal compound)): 8.0%.

[0408]

Comparative Example 9

Preparation of 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

As described above, in the method of Japanese Patent Publication No. 2018-70520 (patent literature 3), the reaction of 2-chloronitrobenzene requires low temperature. In Comparative Example 9, the method of Japanese Patent Publication No. 2018-70520 (Patent Literature 3) was carried out with the reaction temperature changed to 25-30°C, avoiding this low temperature. As a result, a low yield was obtained as described below. In the method of the published Japanese patent No. 2018-70520 (Patent Literature 3), this low temperature could not be avoided.

[0409]

[formula 63]

[0410]

Sodium hydride (66.3%, dispersed in liquid paraffin, 0.36 g, 9.95 mmol, 313 mol%) was suspended in THF (5 ml, 1.58 l/mol). Under a stream of nitrogen gas, a solution of p-anisidine (1.17 g, 9.50 mmol, 299 mol%) dissolved in THF (5 ml, 1.58 L/mol) was added while maintaining the temperature inside the flask at 55-60 °C and the mixture was stirred at the same temperature for 2 hours. The mixture was cooled to room temperature. Separately, 2-chloronitrobenzene (0.50 g, 3.17 mmol, 100 mol%) was dissolved in THF (5 ml, 1.58 L/mol) under nitrogen gas flow. The mixture prepared in advance using p-anisidine and sodium hydride was added thereto at 25-30° C. inside the flask, and the resulting mixture was stirred at the same temperature for 2 hours. The mixture was poured into a saturated ammonium chloride aqueous solution. The mixture was then subjected to extraction with ethyl acetate. The resulting organic layer was washed with saturated brine to give an ethyl acetate solution containing the desired product.

As a result of HPLC analysis (area percentage; 254 nm) of the reaction mixture, the main components in the reaction mixture excluding the solvent and the like were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 23.4%,

OCNB (parent compound): 0.9%,

p-anisidine (parent compound): N.D

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 34.5%,

CMNA (by-product; nitro derivative corresponding to the desired product): 2.1%.

[0411]

The reaction mixture was analyzed by HPLC absolute calibration curve method to obtain a yield and the like. The results of the analysis were as follows;

3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 31.0% (yield),

OCNB (parent compound): 3.8% (recovery),

MNA (by-product; Cl-displacing compound (Cl-removing compound)): 34.8%.

[0412]

Comparative Example 10

Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

The reaction and analysis were carried out as in example 5, except that a secondary alcohol (2-propanol, ie 2-propanol) was used instead of a tertiary alcohol (tert-butanol).

[0413]

[formula 64]

[0414]

Lithium amide (purity: 95.0%, 3.72 g, 153.9 mmol, 306 mol%) was suspended in toluene (10.0 g, 0.23 l/mol) in a stream of nitrogen gas. A toluene (2.0 g, 0.05 l/mol) solution of 2-propanol (2.99 g, 49.8 mmol, 99 mol%) was added dropwise to it at a temperature inside the flask of 0-10°C for 30 min, and then the mixture was stirred at the same temperature for 30 minutes. The temperature inside the flask was maintained at the same temperature, a solution of 2-chloronitrobenzene (7.9 g, 50.1 mmol, 100 mol%) dissolved in toluene (2.0 g, 0.05 l/mol) was added to it, and then a solution of p-anisidine (6.2 g, 50.3 mmol, 100 mol%) dissolved in toluene (37.0 g, 0.85 l/mol) was added dropwise. After dropping, the temperature was raised to 50° C. or more, and black smoke was generated. Therefore, the reaction stopped.

[0415]

As shown in Comparative Examples 1-4 and 9-10, it can be seen that when one of the tertiary alcohol and base is not used, the target nitrous compound of formula (3) cannot be obtained or is obtained in low yield.

As shown in Comparative Examples 5 to 8, even if the methods of the prior art were applied to the starting compounds having a combination of fenquinotrione herbicide substituents, the reactions did not proceed sufficiently. As a result, it was confirmed that the related art cannot be applied to the production of fenquinotrion herbicide.

For example, as shown in Comparative Example 8, the prior art, capable of producing a nitroso compound without requiring extremely low temperatures, does not provide a satisfactory yield when applied to the production of fenquinotrione herbicide.

[Industrial applicability]

[0416]

According to the present invention, industrially preferred methods for preparing a compound of formula (3) and a compound of formula (5) are provided. The compound of formula (3) and the compound of formula (5), which can be obtained by the methods of the present invention, are useful as intermediates for agricultural chemistry and medicine, especially as intermediates for herbicides. In addition, the methods of the present invention are suitable for large scale production such as pilot plant or commercial production. In other words, the methods of the present invention are economical as well as environmentally friendly and of high value for industrial applications. Thus, the present invention has a high industrial applicability.

Claims (59)

1. A process for preparing a compound of formula (3) comprising reacting a compound of formula (1) with a compound of formula (2) using a tertiary alcohol and a base: [Formula 1]

, where each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl or (C1-C4) alkoxy , where the base is a compound selected from alkali metal hydrides and alkali metal amides, or a plurality of compounds including a base containing lithium as the first compound and a second compound selected from alkali metal hydrides, alkali metal amides, alkoxides, alkyl metals, alkali metals and organic bases, where the reaction is carried out in the presence of a solvent, where the solvent contains toluene, xylene, chlorobenzene, dichlorobenzene or a mixture thereof, and where the reaction is carried out at -5°C-80°C. 2. The method of claim 1, wherein the reaction of a compound of formula (1) with a compound of formula (2) is carried out after addition of a tertiary alcohol and a base. 3. The method according to claim 1 or 2, wherein the amount of base used is greater than the amount of tertiary alcohol used, in terms of equivalents. 4. The method according to any one of paragraphs. 1-3, where the base is sodium hydride, lithium amide, two of lithium amide and sodium hydride, two of lithium amide and sodium amide, or two of lithium amide and sodium t-butoxide. 5. The method according to claim 4, wherein the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2) and the amount of tertiary alcohol used is 0.3 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2). 6. The method according to any one of paragraphs. 1-3, where the base is an alkali metal hydride. 7. The method according to any one of paragraphs. 1-3, where the base is sodium hydride. 8. The method according to claim 6 or 7, where the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2) and the amount of tertiary alcohol used is 0.3 equivalents-4.0 equivalents per 1 equivalent compounds of formula (2). 9. The method according to any one of paragraphs. 1-3, where the base is an alkali metal amide. 10. The method according to any one of paragraphs. 1-3, where the base is lithium amide. 11. The method according to claim 9 or 10, where the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2) and the amount of tertiary alcohol used is 0.3 equivalents-2.5 equivalents per 1 equivalent compounds of formula (2). 12. The method according to any one of paragraphs. 1-3, where the base includes a plurality of compounds. 13. The method of claim 12, wherein the plurality of compounds includes a lithium-containing base as the first compound and a second compound selected from alkali metal hydrides, alkali metal amides, alkoxides, alkyl metals, alkali metals, and organic bases. 14. The method of claim 12 wherein the plurality of compounds comprises two of lithium amide and sodium hydride, two of lithium amide and sodium amide, or two of lithium amide and sodium t-butoxide. 15. The method of claim 12 wherein the plurality of compounds includes two of lithium amide and sodium hydride. 16. The method according to any one of paragraphs. 12-15, where the amount of base used is 2.0 equivalents-4.0 equivalents per 1 equivalent of the compound of formula (2) and the amount of tertiary alcohol used is 0.3 equivalents-2.5 equivalents per 1 equivalent of the compound of formula (2). 17. The method according to any one of paragraphs. 1-16, where the tertiary alcohol is a compound of formula (6): [formula 2]

, where R ¹³ , R ¹⁴ and R ¹⁵ may be the same or different and each is (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10 ) aryl or (C6-C10) aryl (C1-C4) alkyl, and two selected from R ¹³ , R ¹⁴ and R ¹⁵ may be connected to each other to form a ring. 18. The method according to any one of paragraphs. 1-16 wherein the tertiary alcohol is selected from tert-butanol, 2-methyl-2-butanol, 2-methyl-3-buten-2-ol, and 2-methyl-1-phenyl-2-propanol. 19. The method according to any one of paragraphs. 1-18, where the reaction is carried out at 0-50°C. 20. The method according to any one of paragraphs. 1-19, where R ¹ represents a hydrogen atom or a chlorine atom; each R ² , R ³ and R ⁴ represents a hydrogen atom; each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom and R ⁷ represents a hydrogen atom or methoxy. 21. The method according to any one of paragraphs. 1-19, where R ¹ represents a chlorine atom; each R ² , R ³ and R ⁴ represents a hydrogen atom; each R ⁵ , R ⁶ , R ⁸ and R ⁹ represents a hydrogen atom and R ⁷ is methoxy. 22. Method for obtaining the compound of formula (5): [formula 3]

, where each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ independently represents a hydrogen atom, a halogen atom, (C1-C4) alkyl or (C1-C4) alkoxy And R ¹² represents a hydrogen atom, an alkali metal atom or (C1-C4) alkyl, including the following steps: stage (i) obtaining compounds of formula (3) by the method according to any one of paragraphs. 1-21 [formula 4]

, where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are, as defined above, step (ii) reacting a compound of formula (3) with a compound of formula (4) to obtain a compound of formula (5): [formula 5]

, where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined above, and R ¹⁰ and R ¹¹ are each independently (C1-C4) alkyl. 23. The method of claim 22 wherein the reaction in step (ii) is carried out at a pH of 8 or greater. 24. The method according to p. 22, where the reaction in stage (ii) is carried out at pH 8-14. 25. The method according to any one of paragraphs. 22-24, where the reaction in step (ii) is carried out in the absence of a phase transfer catalyst. 26. The method according to any one of paragraphs. 22-24, where the reaction in step (ii) is carried out in the presence of a phase transfer catalyst. 27. The method according to any one of paragraphs. 22-24, where the reaction in step (ii) is carried out in the presence of water. 28. The method according to any one of paragraphs. 22-27, where each R ¹⁰ and R ¹¹ represents methyl or ethyl and R ¹² represents a hydrogen atom, lithium atom, sodium atom, potassium atom, methyl or ethyl. 29. The method according to any one of paragraphs. 22-27, where each R ¹⁰ and R ¹¹ represents methyl or ethyl and R ¹² represents a hydrogen atom.