Process for producing nitroso compound and quinoxaline compound using dichloromethane solvent or ether solvent

Abstract

A production method of a nitroso compound of the following formula (3) comprising reacting a compound of the following formula (1) with a compound of the following formula (2) in a dichloromethane solvent or an ether solvent in the presence of a tertiary alcohol and an alkali metal hydride.

Description

Technical Field

[0001] The present invention relates to a method for manufacturing compounds of the following formula (3), namely nitroso compounds.

[0002] [Chemistry 1]

[0003] The present invention also relates to a method for manufacturing compounds of the following formula (5), namely quinoxaline compounds.

[0004] [Chemistry 2] Background Technology

[0005] Nitrosyl compounds of formula (3) (hereinafter referred to as compounds of formula (3)) and quinoxaline compounds of formula (5) (hereinafter referred to as compounds of formula (5)) are useful as intermediates in the manufacture of physiologically active organic compounds such as pesticides and pharmaceuticals. Useful herbicides are described in WO2009 / 016841 (Patent Document 1). Among them, compound No. II-194, namely fenquinotrione, is known as a herbicide with excellent weeding effect and high safety for rice.

[0006] WO2013 / 089002 (Patent Document 2) discloses a manufacturing method as shown in the figure below (see Examples 1, 3, 19, 20-23, etc.).

[0007] [Chemistry 3]

[0008] As shown in the figure above, the method described in WO2013 / 089002 (Patent Document 2) requires three steps to produce the compound of formula (5-3) from 2,6-dichloronitrobenzene. Therefore, a manufacturing method with fewer steps is desired. Furthermore, 2,6-dichloronitrobenzene and ketomalonide (e.g., DEMO in the figure above) are relatively difficult to obtain; therefore, more readily available raw materials are desired.

[0009] On the other hand, Japanese Patent Application Publication No. 2018-70520 (Patent Document 3) discloses that 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (3) can be produced by reacting 2-chloronitrobenzene (1) with p-methoxyaniline (2). Furthermore, this document also reports that compounds of formula (5-3) can be produced from 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (3). The method is shown in the figure below.

[0010] [Chemistry 4]

[0011] Compared to the method in WO2013 / 089002 (Patent Document 2), the method in Japanese Patent Application Publication No. 2018-70520 (Patent Document 3) allows for the production of compounds of formula (5-3) using more readily available raw materials. However, the method described in Japanese Patent Application Publication No. 2018-70520 (Patent Document 3) requires 2 to 3 equivalents of p-methoxyaniline (2) relative to 2-chloronitrobenzene (1), thus it is desirable to reduce the amount of p-methoxyaniline used.

[0012] [Chemistry 5]

[0013] In the method described in WO2020 / 158925 (Patent Document 4), Example 17 describes a method using lithium amide. However, since lithium amide is expensive and its availability is limited, it is desirable to use a method using an inexpensive and readily available base. Furthermore, when using lithium amide, the environmental impact needs to be considered because ammonia is generated as a byproduct.

[0014] [Chemistry 6]

[0015] In addition, although the method using sodium hydride is described in Example 18 in WO2020 / 158925 (Patent Document 4), the yield of the compound of formula (5-1) is as low as 39.9%, and it is desirable to improve the yield.

[0016] Synlett (2015), 1352-1356 (Non-Patent Document 1) discloses that the compound of formula (3) can be produced in high yield. However, this method requires low temperatures of -70°C to -30°C, and is therefore not industrially preferred. Methods that do not require extremely low temperatures are desirable. Specific examples of this method are shown in the figure below.

[0017] [Chemistry 7]

[0018] Existing technical documents

[0019] Patent documents

[0020] Patent Document 1: WO2009 / 016841

[0021] Patent Document 2: WO2013 / 089002

[0022] Patent Document 3: Japanese Patent Application Publication No. 2018-70520

[0023] Patent Document 4: WO2020 / 158925

[0024] Non-patent literature

[0025] Non-patent literature 1: Synlett (2015), 1352-1356 Summary of the Invention

[0026] The problem that the invention aims to solve

[0027] The purpose of this invention is to provide an industrially preferred, economical, and environmentally friendly method for manufacturing nitroso compounds of formula (3) and quinoxaline compounds of formula (5).

[0028] The specific object of the present invention is to provide an industrially preferred method for manufacturing compounds of formula (3) and formula (5) that can solve one or more of the disadvantages or problems in the prior art.

[0029] Methods for solving problems

[0030] Through in-depth research, the inventors discovered the present invention, which relates to the methods for manufacturing compounds of formula (3) and formula (5). Based on this discovery, the inventors completed the present invention.

[0031] That is, the present invention is as follows.

[0032] [I-1] A method for manufacturing a compound of formula (3), comprising: In the presence of tertiary alcohols and alkali metal hydrides, the compound of formula (1) is reacted with the compound of formula (2) in dichloromethane or ether solvent. [Chemistry 8] .

[0033] [I-2] According to the manufacturing method described in [I-1], the amount of alkali metal hydride used is greater than the amount of tertiary alcohol used in terms of equivalent conversion.

[0034] [I-3] The manufacturing method according to [I-1] or [I-2] is wherein the amount of alkali metal hydride used is 2.0 to 4.0 equivalents relative to 1 equivalent of the compound of formula (2).

[0035] [I-4] The manufacturing method according to [I-1] or [I-2] is wherein the amount of alkali metal hydride used is 2.2 to 3.8 equivalents relative to 1 equivalent of the compound of formula (2).

[0036] [I-5] The manufacturing method according to any one of [I-1] to [I-4], wherein the amount of tertiary alcohol used is 0.1 equivalent to 2.0 equivalent relative to the compound of formula (2).

[0037] [I-6] The manufacturing method according to any one of [I-1] to [I-4], wherein the amount of tertiary alcohol used is 0.1 equivalent to 1.75 equivalent relative to the compound of formula (2).

[0038] [I-7] The manufacturing method according to any one of [I-1] to [I-4], wherein the amount of tertiary alcohol used is 0.1 equivalent to 1.5 equivalent relative to the compound of formula (2).

[0039] [I-8] The manufacturing method according to any one of [I-1] to [I-7], wherein the reaction is carried out at 0°C to 70°C.

[0040] [I-9] The manufacturing method according to any one of [I-1] to [I-7], wherein the reaction is carried out at 10°C to 60°C.

[0041] [I-10] The manufacturing method according to any one of [I-1] to [I-7], wherein the reaction is carried out at 20°C to 50°C.

[0042] [I-11] The manufacturing method according to any one of [I-1] to [I-7], wherein the reaction is carried out at 30°C to 40°C.

[0043] [I-12] The manufacturing method according to any one of [I-1] to [I-11], wherein the tertiary alcohol is a compound of formula (6).

[0044] [Chemistry 9]

[0045] (Here, R) 4 R 5 and R 6 They can be the same or different, and are amino(C1-C6)alkyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl, from R 4 R 5 and R 6 The two selected can combine to form a ring.

[0046] [I-13] According to the manufacturing method described in [I-12], wherein R 4 R 5 and R 6 Same or different, selected from methyl, ethyl, vinyl, propyl, aminomethyl.

[0047] [I-14] The manufacturing method according to any one of [I-1] to [I-11], wherein the tertiary alcohol is tert-butanol, 2-methyl-2-butanol, 3-methyl-3-pentanol, 2-methyl-3-buten-2-ol or 1-amino-2-methylpropane-2-ol.

[0048] [I-15] The manufacturing method according to any one of [I-1] to [I-11], wherein the tertiary alcohol is tert-butanol, 2-methyl-2-butanol or 2-methyl-3-buten-2-ol.

[0049] [I-16] The manufacturing method according to any one of [I-1] to [I-11], wherein the tertiary alcohol is tert-butanol.

[0050] [I-17] The manufacturing method according to any one of [I-1] to [I-16], wherein the alkali metal hydride is lithium hydride, sodium hydride or potassium hydride.

[0051] [I-18] The manufacturing method according to any one of [I-1] to [I-16], wherein the alkali metal hydride is sodium hydride.

[0052] [I-19] The manufacturing method according to any one of [I-1] to [I-18], wherein a metal tertiary alkoxide is used.

[0053] [I-20] The manufacturing method according to [I-19], wherein the metal tertiary alkoxide is sodium tert-butoxide, potassium tert-butoxide, or lithium tert-butoxide.

[0054] [I-21] The manufacturing method according to [I-19], wherein the metal tertiary alkoxide is sodium tert-butoxide or potassium tert-butoxide (preferably sodium tert-butoxide).

[0055] [I-22] The manufacturing method according to any one of [I-1] to [I-21], wherein the reaction is carried out in an ether solvent.

[0056] [I-23] The manufacturing method according to any one of [I-1] to [I-22], wherein the ether solvent is diethyl ether, dimethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether or cyclopentylmethyl ether.

[0057] [I-24] The manufacturing method according to any one of [I-1] to [I-23], wherein the ether solvent is diethyl ether, dibutyl ether, 2-methyltetrahydrofuran, tert-butylmethyl ether or cyclopentylmethyl ether.

[0058] [I-25] The manufacturing method according to any one of [I-1] to [I-21], wherein the reaction is carried out in a dichloromethane solvent.

[0059] [II-1] A method for manufacturing a compound of formula (5), [Chemistry 10]

[0060] (Here, R) 3 It is a hydrogen atom, an alkali metal atom, or a (C1-C4) alkyl group.

[0061] The method includes the following steps: Step (i) obtaining the compound of formula (3) by any one of [I-1] to [I-25]; and [Chemistry 11]

[0062] Step (ii) involves reacting the compound of formula (3) with the compound of formula (4) to obtain the compound of formula (5).

[0063] [Chemistry 12]

[0064] (Here, R) 1 R 2 and R 3 As defined above.

[0065] [II-2] A method of manufacturing a compound of formula (5) using a compound of formula (3), [Chemistry 14]

[0066] [Chemistry 13]

[0067] (Here, R) 3 It is a hydrogen atom, an alkali metal atom, or a (C1-C4) alkyl group.

[0068] The characteristic feature is that the compound of formula (3) is manufactured by any one of the methods described in [I-1] to [I-25].

[0069] [II-3] According to the manufacturing method described in [II-1], wherein the compound of formula (4) is dimethyl malonate or diethyl malonate.

[0070] [II-4] The manufacturing method according to any one of [II-1] to [II-3], wherein the reaction of step (ii) is carried out at pH 8 or above.

[0071] [II-5] The manufacturing method according to any one of [II-1] to [II-3], wherein the reaction of step (ii) is carried out at pH 8 to 14.

[0072] [II-6] The manufacturing method according to any one of [II-1] to [II-5], wherein the reaction of step (ii) is carried out at -25°C to 0°C.

[0073] [II-7] The manufacturing method according to any one of [II-1] to [II-5], wherein the reaction of step (ii) is carried out at -20°C to -5°C.

[0074] [II-8] The manufacturing method according to any one of [II-1] to [II-7], wherein the reaction in step (ii) is carried out using acetic acid.

[0075] [II-9] The manufacturing method according to any one of [II-1] to [II-8], wherein the reaction of step (ii) is carried out in a dichloromethane solvent.

[0076] [II-10] The manufacturing method according to any one of [II-1] to [II-8], wherein the reaction of step (ii) is carried out in an ether solvent.

[0077] [II-11] According to the manufacturing method described in [II-10], the ether solvent is diethyl ether, dimethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether or cyclopentylmethyl ether.

[0078] [II-12] According to the manufacturing method described in [II-10], the ether solvent is diethyl ether, dibutyl ether, 2-methyltetrahydrofuran, tert-butylmethyl ether or cyclopentylmethyl ether.

[0079] [II-13] The manufacturing method according to any one of [II-1] to [II-12], wherein, R 1 and R 2 It is methyl or ethyl; R 3 It can be a hydrogen atom, lithium atom, sodium atom, potassium atom, methyl or ethyl atom.

[0080] [II-14] The manufacturing method according to any one of [II-1] to [II-12], wherein, R 1 and R 2 It is methyl or ethyl; R 3 It consists of hydrogen or sodium atoms.

[0081] [II-15]The production method according to any one of [II-1] to [II-12], wherein, R 1 and R 2 are methyl or ethyl; R 3 is a hydrogen atom.

[0082] Effects of the Invention

[0083] The present invention provides a novel industrially preferable, economical, and environmentally friendly method for producing the compound of formula (3) and the compound of formula (5). According to the present invention, there is provided a method for producing the compound of formula (3) and the compound of formula (5) that can solve one or more of the above disadvantages or problems in the prior art. Detailed Description of the Embodiments

[0084] Hereinafter, the present invention will be described in detail.

[0085] In the present specification, the following abbreviations and prefixes may be used, and their meanings are as follows.

[0086] Me: methyl

[0087] Et: ethyl

[0088] Pr, n-Pr and Pr-n: propyl (i.e., n-propyl)

[0089] i-Pr and Pr-i: isopropyl

[0090] Bu, n-Bu and Bu-n: butyl (i.e., n-butyl)

[0091] s-Bu and Bu-s: sec-butyl (i.e., secondary butyl)

[0092] i-Bu and Bu-i: isobutyl

[0093] t-Bu and Bu-t: tert-butyl (i.e., tertiary butyl)

[0094] Ph: phenyl

[0095] n-: normal

[0096] s- and sec-: secondary

[0097] i- and iso-: iso

[0098] t- and tert-: tertiary

[0099] nco-: neo

[0100] c- and cyc-: cyclo

[0101] o-: ortho

[0102] m-: space

[0103] p-: to

[0104] t-BuOH: tert-butanol

[0105] Examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

[0106] In this specification, general terms such as "alkyl" are interpreted to include both straight-chain and branched types, such as butyl and tert-butyl. On the other hand, for example, the specific term "butyl" refers to the straight-chain "n-butyl" and not the branched "tert-butyl". Furthermore, branched isomers such as "tert-butyl" are specifically mentioned where intended.

[0107] (Ca-Cb) indicates that the number of carbon atoms is a to b. For example, "(C1-C4)alkyl" indicates that the number of carbon atoms in the alkyl group is 1 to 4.

[0108] (C1-C6)alkyl refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples of (C1-C6)alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

[0109] (C1-C4)alkyl refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples of (C1-C4)alkyl are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl.

[0110] Amino (C1-C6)alkyl refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms with an amino substituent. Examples of amino (C1-C6)alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, and 6-aminohexyl.

[0111] Amino (C1-C4)alkyl refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms with an amino substituent. Examples of amino (C1-C4)alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, and 4-aminobutyl.

[0112] (C3-C6)cycloalkyl refers to cycloalkyl groups having 3 to 6 carbon atoms. Examples of (C3-C6)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0113] (C2-C6)alkenyl refers to straight-chain or branched alkenyl groups having 2 to 6 carbon atoms. Examples of (C2-C6)alkenyl include 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, 1-hexenyl, etc., but are not limited to these.

[0114] (C2-C6) alkynyl refers to a straight-chain or branched alkynyl group having 2 to 6 carbon atoms. Examples of (C2-C6) alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, etc., but are not limited to these.

[0115] Examples of (C6-C10) aryl groups are phenyl, 1-naphthyl, and 2-naphthyl.

[0116] (C6-C10)aryl(C1-C4)alkyl refers to (C1-C4)alkyl groups with (C6-10) aryl substitutions (wherein the C6-10 aryl moiety and the C1-C4 alkyl moiety have the same meaning as defined above). Examples of (C6-C10)aryl(C1-C4)alkyl groups include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphth-1-ylmethyl, and naphth-2-ylmethyl.

[0117] (C1-C4)alkoxy means (C1-C4)alkyl-O- (wherein the (C1-C4)alkyl moiety has the same meaning as defined above). Examples of (C1-C4)alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, and tert-butoxy.

[0118] Examples of "rings" in the phrase "two that can combine to form a ring" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, and cyclohexene, but are not limited to these. The "ring" can also condense with another "ring".

[0119] In this specification, the non-restrictive term "comprise(s) / comprising" can be arbitrarily replaced with the restrictive phrase "consist(s) of / consisting of".

[0120] In this manual, the statement "after adding them separately" can be replaced with the statement "after each of them is added".

[0121] In this specification, the phrases "in dichloromethane solvent" and "in the presence of dichloromethane as solvent" are interchangeable.

[0122] In this specification, the phrases "in an ether solvent" and "in the presence of an ether as a solvent" are interchangeable.

[0123] In this specification, the phrases "in the presence of" and "use(s) / using" are interchangeable.

[0124] The "tertiary alcohol" used in the reaction can be added at the start of the reaction, or it can be a tertiary alcohol generated during the reaction from a tertiary alkoxide used as a reactant. For example, when sodium tert-butoxide and sodium hydride are used in this reaction, the tert-butanol generated from sodium tert-butoxide during the reaction is included in the "tertiary alcohol" category.

[0125] The method of the present invention will be described.

[0126] (Process (i))

[0127] The process (i) is described.

[0128] Step (i) is a process of reacting the compound of formula (1) with the compound of formula (2) in the presence of a tertiary alcohol and an alkali metal hydride in a dichloromethane solvent or an ether solvent to produce the compound of formula (3).

[0129] [Chemistry 15]

[0130] (Raw material: compound of formula (1))

[0131] The compound of formula (1) is used as the raw material for process (i).

[0132] The amount of compound (1) used can be arbitrary, provided the reaction proceeds. However, from the viewpoints of yield, byproduct suppression, and economic efficiency, in one embodiment, the amount of compound (nitro compound) used relative to, for example, compound (aniline compound) of formula (2) is 1.0 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, and more preferably 1.0 to 1.2 equivalents. Furthermore, the amount used can be 1.05 to 1.2 equivalents or 1.05 to 1.1 equivalents. The amount used also includes any combination of the lower and upper limits of these ranges described in this specification. Therefore, the amount used can be, for example, 1.0 to 1.1 equivalents.

[0133] In this specification, the definition of “equivalent of compound (nitro compound) of formula (1)” is as follows, or the term “equivalent” is interpreted according to the following examples. For example, “1 equivalent of compound (nitro compound) of formula (2) relative to 1 equivalent of compound (aniline compound)” means “1 mole of compound (nitro compound) of formula (2) relative to 1 mole of compound (aniline compound). For example, “0.5 equivalent of compound (nitro compound) of formula (2) relative to 1 equivalent of compound (aniline compound)” means “0.5 moles of compound (nitro compound) of formula (1) relative to 1 mole of compound (2) (aniline compound).

[0134] (Raw material: Compound of general formula (2))

[0135] The compound of formula (2) is used as the raw material for process (i).

[0136] From the perspective of improving economic efficiency and reducing environmental impact, the use of excess 2-chloronitrobenzene is permissible. However, the use of excess p-methoxyaniline is preferably avoided, but this is not a limitation. For example, p-methoxyaniline is known to be much more expensive than 2-chloronitrobenzene. In the method of Japanese Patent Application Publication No. 2018-70520 (Patent Document 3), more than 2 equivalents of p-methoxyaniline are required as the raw material for excess use. In fact, 2 to 3 equivalents of p-methoxyaniline were used in the examples of Japanese Patent Application Publication No. 2018-70520 (Patent Document 3). On the other hand, in the method of the present invention, less than 2 equivalents of 2-chloronitrobenzene is sufficient as the raw material for excess use, and satisfactory yields can be provided as shown in the examples described later.

[0137] (Alkali metal hydride of process (i))

[0138] Examples of alkali metal hydrides used in step (i) include lithium hydride, sodium hydride, potassium hydride, etc., with sodium hydride and potassium hydride being preferred, and sodium hydride being more preferred, but not limited thereto. Since alkali metal hydrides are inexpensive and readily available bases, the method of the present invention is economical. Using alkaline earth metal hydrides such as calcium hydride instead of alkali metal hydrides such as sodium hydride to carry out the reaction in step (i) is an equivalent of the present invention and falls within the scope of the present invention.

[0139] As long as the reaction proceeds, the amount of alkali metal hydride used in step (i) can be any amount. However, from the viewpoints of yield, by-product suppression, and economic efficiency, in one embodiment, the amount of alkali metal hydride used in step (i) is typically 2.0 equivalents or more relative to, for example, 1 equivalent of the compound (aniline compound) of formula (2), preferably 2.0 to 4.0 equivalents, more preferably 2.5 to 3.8 equivalents, and even more preferably 3.0 to 3.5 equivalents. In another embodiment, the amount of alkali metal hydride used in step (i) can be 2.0 to 3.5 equivalents, 2.2 to 3.5 equivalents, or 3.2 to 3.5 equivalents relative to, for example, 1 equivalent of the compound (aniline compound) of formula (2). The amount of alkali metal hydride used in step (i) also includes any combination of the lower and upper limits of these ranges described in this specification. Therefore, the amount of alkali metal hydride used in step (i) can be, for example, 2.2 equivalents to 3.2 equivalents.

[0140] As stated above, in this specification, the definition of "equivalent of alkali metal hydride" is as follows, or the term "equivalent" is interpreted according to the following examples. For example, when it is a monovalent base such as sodium hydride (NaH), "1 equivalent of base relative to 1 equivalent of compound (aniline compound) of formula (2)" means "1 mole of base relative to 1 mole of compound (aniline compound) of formula (2)", and "0.5 equivalent of base relative to 1 equivalent of compound (aniline compound) of formula (2)" means "0.5 moles of base relative to 1 mole of compound (aniline compound) of formula (2)". As another example, when the base is a divalent base such as calcium hydride (CaH2), “1 equivalent of base relative to 1 equivalent of compound (aniline compound) of formula (2)” means “0.5 moles of base relative to 1 mole of compound (aniline compound) of formula (2)”, and “0.5 equivalent of base relative to 1 equivalent of compound (aniline compound) of formula (2)” means “0.25 moles of base relative to 1 mole of compound (aniline compound) of formula (2)”.

[0141] Alkali metal hydrides can be added to the reaction in a single, predetermined amount. Alternatively, they can be added in multiple portions or dropwise.

[0142] (tertiary alcohols in process (i))

[0143] As a tertiary alcohol in step (i), for example, a compound of formula (6) can be cited.

[0144] [Chemistry 16]

[0145] (Here, R) 4 R 5 and R 6They can be the same or different, and are amino(C1-C6)alkyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl, from R 4 R 5 and R 6 The two selected can combine to form a ring.

[0146] Examples of tertiary alcohols in step (i) include tert-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, and 2-methyl-1-phenyl 2-Propanol, 2-methyl-1-phenyl-2-butanol, 1-amino-2-methylpropane-2-ol, 3-benzyl-3-hexanol, 2-α-naphthyl-2-propanol, 2-methyl-1-β-naphthyl-2-propanol, etc., preferably tert-butanol, 2-methyl-2-butanol, 3-methyl-3-pentanol, 2-methyl-3-buten-2-ol, 1-amino-2-methylpropane-2-ol, etc., more preferably tert-butanol, 2-methyl-2-butanol, 2-methyl-3-buten-2-ol, but not limited thereto. Tertiary alcohols can be used alone or in combination of two or more in any proportion. "Tert-butanol" is also called "tert-butyl alcohol".

[0147] As long as the reaction proceeds, the amount of tertiary alcohol used in step (i) can be any amount. However, from the viewpoints of yield, byproduct suppression, and economic efficiency, in one embodiment, the amount of tertiary alcohol used in step (i) is 0.1 equivalents or more relative to 1 equivalent of, for example, the compound (aniline compound) of formula (2), preferably 0.1 equivalents to 2.0 equivalents, more preferably 0.1 equivalents to 1.75 equivalents, and even more preferably 0.1 equivalents to 1.5 equivalents.

[0148] As stated above, in this specification, the definition of "equivalent of tertiary alcohol" is as follows, or the term "equivalent" is interpreted according to the following examples. For example, "1 equivalent of tertiary butanol relative to 1 equivalent of a compound of formula (2) (aniline compound)" means "1 mole of tertiary butanol relative to 1 mole of a compound of formula (2) (aniline compound)". For example, "0.5 equivalents of tertiary butanol relative to 1 equivalent of a compound of formula (2) (aniline compound)" means "0.5 moles of tertiary butanol relative to 1 mole of a compound of formula (2) (aniline compound)".

[0149] Tertiary alcohols can be added to the reaction in a single, predetermined amount. Alternatively, they can be added in multiple portions or dropwise.

[0150] The tertiary alcohol can be formed from a metal tertiary alkoxide in the reaction. In this case, the metal tertiary alkoxide used includes, but is not limited to, sodium tert-butoxide, potassium tert-butoxide, and lithium tert-butoxide. Sodium tert-butoxide or potassium tert-butoxide is preferred, and sodium tert-butoxide is more preferred.

[0151] As long as the reaction proceeds, the amount of metal tertiary alkoxide used can be arbitrary. However, from the viewpoints of yield, byproduct suppression, and economic efficiency, the amount of metal tertiary alkoxide used in step (i) is, for example, 0.1 equivalents or more relative to the compound (aniline compound) of formula (2), preferably 0.1 equivalents to 2.0 equivalents, more preferably 0.1 equivalents to 1.5 equivalents, and even more preferably 0.1 equivalents to 1.0 equivalents.

[0152] (Solvent in step (i))

[0153] From the perspectives of smooth reaction progress, yield, by-product suppression, and economic efficiency, the reaction in step (i) is carried out in the presence of dichloromethane or ether solvent as a solvent.

[0154] In step (i), dichloromethane or ether solvents can be used. In one approach, dichloromethane solvent can be used. In another approach, ether solvents can be used. Examples of ether solvents preferably include dimethyl ether, diethyl ether, methyl ethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, or 2-methyltetrahydrofuran, more preferably diethyl ether, dibutyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, or 2-methyltetrahydrofuran.

[0155] The amount of solvent used in step (i) can be any amount, as long as the reaction system can be sufficiently stirred and the effects of the present invention can be demonstrated. From the viewpoints of yield, by-product suppression, and economic efficiency, in one embodiment, the lower limit of the amount of solvent used is, for example, more than 0 L, more than 0.1 L, more than 0.2 L, preferably more than 0.3 L, more preferably more than 0.4 L, more than 0.5 L, more than 0.6 L, but not limited thereto. From the same viewpoint as above, in one embodiment, the upper limit of the amount of solvent used is, for example, less than 10 L, less than 5 L, preferably less than 2 L, less than 1 L, less than 1.5 L, less than 1.2 L, more preferably less than 0.8 L, less than 0.7 L, but not limited thereto. The range of the amount of dichloromethane used is, for example, an appropriate and arbitrary combination of the above lower and upper limits. For example, the combination of the upper and lower limits is as follows, but not limited thereto: From the same viewpoint as above, in one manner, the amount of the compound (aniline compound) relative to 1 mole of formula (2) is 10 L or less, preferably 0.1 to 10 L, more preferably 0.1 to 5 L, further preferably 0.2 to 5 L, further preferably 0.2 to 2 L, and even more preferably 0.2 to 1 L. The practice of carrying out the reaction of step (i) using solvents other than dichloromethane or ether solvents (i.e., mixed solvents) is an equivalent of the present invention and falls within the scope of the present invention.

[0156] (Reaction temperature of process (i))

[0157] From the viewpoints of yield, by-product suppression, and economic efficiency, the reaction temperature of step (i) is, in one embodiment, for example, 0°C to 70°C, preferably 10°C to 60°C, more preferably 20°C to 50°C, and even more preferably 30°C to 40°C. In another embodiment, the reaction temperature of step (i) is, for example, 25°C to 35°C. Examples of the reaction temperature of step (i) also include any combination of the lower and upper limits of these ranges described in this specification. Therefore, the reaction temperature of step (i) can be, for example, 20°C to 40°C. In the method of the present invention, a low temperature such as -70°C to -30°C is not required, which is therefore industrially preferred and environmentally friendly.

[0158] (Reaction time of process (i))

[0159] There is no particular limitation on the reaction time of step (i). However, from the viewpoints of yield, by-product suppression, and economic efficiency, the reaction time is, for example, 0.1 hours to 48 hours, preferably 1 hour to 48 hours, more preferably 1 hour to 36 hours, and even more preferably 1 hour to 24 hours.

[0160] The compound of formula (3) can be used as a raw material for step (ii). Regarding the compound of formula (3), as long as the reaction in step (ii) proceeds, it can be separated and used in the next step, further purified and used in the next step, or used in the next step without separation. Additionally, after the reaction in step (i) is completed, hydrochloric acid or acetic acid can be used, for example, as a post-treatment of step (i). Furthermore, after the reaction in step (i) is completed, (as a post-treatment of step (i)) an inert gas such as nitrogen can be blown into the solution to remove byproducts. The removal of byproducts can be carried out under reduced pressure. Hydrogen can be cited as an example of a byproduct.

[0161] (Process (ii))

[0162] The process (ii) is described.

[0163] Step (ii) is the process of reacting the compound of formula (3) with the compound of formula (4) to produce the compound of formula (5).

[0164] [Chemistry 17]

[0165] (Here, R) 1 and R 2 Each is independently a (C1-C4) alkyl group; R 3 It can be a hydrogen atom, an alkali metal atom, or a (C1-C4) alkyl group. (Raw material; malonate diester compound) As a raw material for step (ii), a compound of formula (4), namely a malondiester compound, is used. The compound of formula (4) is a known compound, or can be manufactured from a known compound by a known method.

[0166] Examples of compounds in formula (4) include dimethyl malonate, diethyl malonate, dipropyl malonate, diisopropyl malonate, dibutyl malonate, diisobutyl malonate, ditert-butyl malonate, etc., preferably including dimethyl malonate and diethyl malonate, but not limited thereto.

[0167] As long as the reaction proceeds, the amount of compound in formula (4) can be any amount. The amount of compound in formula (4) can be adjusted appropriately by those skilled in the art. However, from the viewpoints of yield, byproduct suppression, and economic efficiency, it is preferable to use 1.0 to 3.0 moles of compound (methoxyaniline compound) in formula (3), and more preferably 1.0 to 2.0 moles.

[0168] (Conditions of process (ii))

[0169] The reaction in step (ii) is preferably carried out under alkaline conditions. In one embodiment, the reaction in step (ii) is typically carried out at pH 9 or higher, preferably pH 9 to pH 14, and more preferably pH 9 to pH 12. In another embodiment, it is carried out at pH 8 or higher, preferably pH 8 to pH 14, more preferably pH 8 to pH 12, and even more preferably pH 10 to pH 12. Therefore, the pH can be adjusted before the reaction in step (ii). The pH can be adjusted using an acidic substance, such as acetic acid or hydrochloric acid. The amount of acid used is only needed to achieve the desired pH. Therefore, the amount of acid used can be appropriately adjusted by those skilled in the art. Alternatively, the reaction in step (ii) can be carried out in the presence of a base. The base used in step (ii) can be any base, as long as the reaction proceeds.

[0170] In step (ii), the remaining sodium hydride used in the reaction of step (i) can be used as a base for the reaction (the reaction can be carried out under alkaline conditions derived from the residual sodium hydride), or a new base can be added. Examples of adding a new base in step (ii) include, but are not limited to, the following: Alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.); Alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.); Alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.); Alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, barium carbonate, etc.); Alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, etc.); Alkaline earth metal bicarbonates (e.g., calcium bicarbonate, etc.); 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, N,N-dimethyl-4-aminopyridine, etc.) etc.

[0171] In addition, examples of alkalis used in process (ii) include alkali metal carboxylates (e.g., sodium acetate and potassium acetate).

[0172] From the perspectives of yield, by-product suppression, and economic efficiency, specific examples of preferred alkalis for step (ii) include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, triethylamine, and sodium acetate.

[0173] The base in step (ii) can be used alone or in combination of two or more in any proportion. The base in step (ii) can be in any form, as long as the reaction proceeds. The form of the base in step (ii) can be appropriately selected by those skilled in the art.

[0174] As long as the reaction proceeds, the amount of alkali used in step (ii) can be arbitrary. However, from the viewpoints of yield, by-product suppression, and economic efficiency, the amount of alkali used in step (ii) is typically 1 equivalent or more relative to the compound (methoxyaniline compound) of formula (3), preferably 1 to 20 equivalents, more preferably 1 to 15 equivalents, and even more preferably 1 to 10 equivalents. However, the amount of alkali used in step (ii) can be appropriately adjusted by those skilled in the art.

[0175] (Water in process (ii))

[0176] 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 absence of water.

[0177] (Acetic acid in process (ii))

[0178] From the viewpoint of ensuring the smooth progress of the reaction, the reaction in step (ii) is preferably carried out using acetic acid. The amount of acetic acid used in step (ii) is usually 0.5 mol to 5.0 mol relative to 1 mole of the compound of formula (3) (methoxyaniline compound) in step (ii), preferably 0.5 mol to 3.0 mol, and more preferably 1.0 mol to 2.5 mol.

[0179] (Solvent in step (ii))

[0180] From the viewpoint of ensuring the smooth progress of the reaction, the reaction in step (ii) is preferably carried out in the presence of a solvent. The solvent and its amount in step (ii) can be the same as in step (i). In addition, water may be present, but it is preferable that water is not present.

[0181] (Reaction temperature of process (ii))

[0182] There is no particular limitation on the reaction temperature of step (ii). However, from the viewpoints of yield, by-product suppression, and economic efficiency, the reaction temperature is preferably -20°C to below 0°C, more preferably -20°C to less than 0°C, even more preferably -20°C to -5°C, further preferably -20°C to -8°C, and even more preferably -20°C to -10°C.

[0183] (Reaction time of process (ii))

[0184] There is no particular limitation on the reaction time of step (ii). From the viewpoints of yield, by-product suppression, and economic efficiency, the reaction time is, for example, 0.1 hours to 48 hours, preferably 0.1 hours to 24 hours, and more preferably 0.5 hours to 15 hours.

[0185] (Post-processing and refining)

[0186] The system can be used to generate carboxylate salts based on bases or salts and / or free carboxylate salts based on acids. For example, it can perform operations such as water extraction of the product, organic solvent extraction of the product, crystallization using acids, and crystallization using bases. For instance, an aqueous solution containing the sodium carboxylate of the target substance can be treated with acid to crystallize the free carboxylate of the target substance. The sodium carboxylate of the target substance can also be extracted with water. An organic solvent solution containing the free carboxylate of the target substance can also be treated with a base to crystallize the sodium carboxylate of the target substance. An aqueous solution containing the sodium carboxylate of the target substance can also be treated with a potassium, lithium, or calcium salt to crystallize the potassium, lithium, or calcium carboxylate. The free carboxylate of the target substance can also be extracted with an organic solvent.

[0187] Furthermore, depending on the circumstances, the sodium carboxylate salt or free carboxylic acid of the target substance, or their aqueous or organic solvent solutions, may be washed with appropriately selected water or organic solvents, or any mixture thereof in any proportion. Additionally, depending on the circumstances, solvent recovery may also be performed. For example, solvents used in the reaction may be recovered, as may solvents used in post-treatment and purification.

[0188] (The product of step (ii): the compound of formula (5), i.e., the quinoxaline compound)

[0189] Specific examples of compounds of formula (5) obtained in step (ii) include, but are not limited to, the following compounds: 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid and its potassium, sodium, lithium, methyl, and ethyl salts.

[0190] 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid represents the same compound as 8-chloro-4-(4-methoxyphenyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylic acid under IUPAC nomenclature.

[0191] Example

[0192] The present invention will be further described in detail below through embodiments, but the present invention is not limited to these embodiments in any way.

[0193] In this instruction manual, the room temperature is 10°C to 35°C.

[0194] In this specification, the physical properties and yields of the examples and comparative examples can be determined using the following instruments. Furthermore, the products obtained in this invention are known compounds and can be identified and quantified using conventional methods known to those skilled in the art.

[0195] pH measurement: Use a glass electrode type hydrogen ion concentration indicator, model: HM-20P or HM-30P (manufactured by Toa DKK Corporation).

[0196] Process (i) (HPLC analysis: High Performance Liquid Chromatography)

[0197] (HPLC analysis conditions)

[0198] Instruments: i-series instruments or equivalent manufactured by Shimadzu Corporation.

[0199] Column: CERI (Chemical Research Institute for Evaluation and Research), L-column ODS (250 4.6 mm), particle size 5 μm

[0200] Eluent: Acetonitrile, 0.085wt% phosphoric acid aqueous solution

[0201] gradient procedure

[0202] [Table 1]

[0203] Flow rate: 1.0 mL / min

[0204] Detection: UV222nm

[0205] Column temperature: 40℃

[0206] Injection volume: 5μL

[0207] Process (ii) (HPLC analysis: high performance liquid chromatography)

[0208] (HPLC analysis conditions)

[0209] Instruments: i-series instruments or equivalent manufactured by Shimadzu Corporation.

[0210] Column: CERI (Chemical Research Institute for Evaluation and Research), L-column ODS (250 4.6 mm), particle size 5 μm

[0211] Eluent: Methanol, 0.085wt% aqueous phosphoric acid solution

[0212] gradient procedure

[0213] [Table 2]

[0214] Flow rate: 1.0 mL / min

[0215] Detection: UV254nm

[0216] Column temperature: 40℃

[0217] Injection volume: 5μL

[0218] “OCNB” refers to “2-chloronitrobenzene” as shown below.

[0219] [Chemistry 18]

[0220] "pA" refers to "p-methoxyaniline" as shown below.

[0221] [Chemistry 19]

[0222] “p-NO” refers to “3-chloro-N-(4-methoxyphenyl)-4-nitrosoaniline” as shown below.

[0223] [Chemistry 20]

[0224] “p-NO2” refers to “3-chloro-N-(4-methoxyphenyl)-4-nitroaniline” as shown below.

[0225] [Chemistry 21]

[0226] “MNA” refers to “N-(4-methoxyphenyl)-2-nitroaniline” as shown below.

[0227] [Chemistry 22]

[0228] “CMNA” refers to “3-chloro-N-(4-methoxyphenyl)-2-nitroaniline” as shown below.

[0229] [Chemistry 23]

[0230] “DMM” refers to “dimethyl malonate” as shown below.

[0231] [Chemistry 24]

[0232] “DEM” refers to “Diethyl malonate” as shown below.

[0233] [Chemistry 25]

[0234] “CAQ” refers to “5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid” as shown below.

[0235] [Chemistry 26]

[0236] Abbreviations for solvents, 1,2-DCE refers to 1,2-dichloroethane. 1,2-DME refers to 1,2-dimethoxyethane. DMF stands for N,N-dimethylformamide. DMAc refers to N,N-dimethylacetamide. NMP refers to N-methylpyrrolidone. DMI refers to 1,3-dimethyl-2-imidazolidineone. DMSO stands for dimethyl sulfoxide.

[0237] Example 1

[0238] Production of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0239] [Chemistry 27]

[0240] Sodium hydride (purity: 65.8%, liquid paraffin dispersion, 583 mg, 16.0 mmol, 320 mol%) was suspended in dichloromethane (4.64 mL, 0.29 L / mol) under a nitrogen stream. A solution of dichloromethane (0.16 mL, 0.03 L / mol) containing tert-butanol (371 mg, 5.00 mmol, 100 mol%) was added dropwise over 30 minutes at an internal temperature of 40 °C, followed by stirring at the same temperature for 30 minutes. The internal temperature was then cooled to 30 °C, and a solution of 2-chloronitrobenzene (827 mg, 5.25 mmol, 105 mol%) and p-methoxyaniline (616 mg, 5.00 mmol, 100 mol%) dissolved in dichloromethane (0.96 mL, 0.19 L / mol) was added dropwise over 1 hour. The mixture was stirred at the same temperature for 18 hours. A reaction mixture containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was obtained.

[0241] The results of HPLC analysis (area percentage; 222 nm) of the reaction mixture show the following main components in the reaction mixture other than the starting material (OCNB): 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 67%, p-Methoxyaniline: 0.1%, p-NO: 1.0% p-NO2: 1.1% MNA: 22% CMNA: 3.4%.

[0242] The reaction mixture was analyzed using HPLC absolute calibration curve method to determine the yield, etc. The analytical results are as follows: 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 62.5% (yield).

[0243] Example 2

[0244] Production of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0245] [Chemistry 28]

[0246] Sodium hydride (purity: 65.7%, liquid paraffin dispersion, 1.17 g, 32.0 mmol, 320 mol%) was suspended in dichloromethane (11.5 g, 0.27 L / mol) under a nitrogen stream. A solution of dichloromethane (0.42 g, 0.01 L / mol) containing tert-butanol (0.74 g, 10.0 mmol, 100 mol%) was added dropwise over 1 hour at an internal temperature of 40 °C, followed by stirring at the same temperature for 1 hour. The internal temperature was then cooled to 30 °C, and a solution of 2-chloronitrobenzene (1.65 g, 10.5 mmol, 105 mol%) and p-methoxyaniline (1.23 g, 10.0 mmol, 100 mol%) dissolved in dichloromethane (1.70 g, 0.04 L / mol) was added dropwise over 2 hours. The mixture was stirred at the same temperature for 3 hours. A reaction mixture containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was obtained.

[0247] The results of HPLC analysis (area percentage; 222 nm) of the reaction mixture show the following main components in the reaction mixture other than the starting material (OCNB): 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 63%, p-Methoxyaniline: 2.7%, p-NO: 0.9% p-NO2: 1.8% MNA: 21%, CMNA: 4.0%.

[0248] Examples 3-6

[0249] Except for the modification of the tertiary alcohol as shown in Table 3, the reaction and analysis were performed in the same manner as in Example 2. The results are shown in Table 3. In addition, the results of Example 2 are also summarized in Table 3. “Target Comp.” in the table is 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline.

[0250] [Table 3]

[0251] Example 7

[0252] Preparation of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0253] [Chemistry 29]

[0254] Under a nitrogen stream, sodium hydride (purity: 65.9%, liquid paraffin dispersion, 11.65 g, 320 mmol, 320 mol%) was suspended in dichloromethane (123.15 g, 0.38 L / mol). At an internal temperature of 35–40 °C, a solution of dichloromethane (4.25 g, 0.03 L / mol) containing tert-butanol (7.41 g, 100 mmol, 100 mol%) was added dropwise over 3 hours, followed by stirring at the same temperature for 1 hour. The internal temperature was then cooled to 30 °C, and a solution of 2-chloronitrobenzene (16.54 g, 105.0 mmol, 105 mol%) and p-methoxyaniline (12.32 g, 100.0 mmol, 100 mol%) dissolved in dichloromethane (25.48 g, 0.19 L / mol (based on p-methoxyaniline)) was added dropwise over 3 hours. The mixture was stirred at the same temperature for 11 hours. A reaction mixture containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was obtained.

[0255] The results of HPLC analysis (area percentage; 222 nm) of the reaction mixture show the following main components in the reaction mixture other than the starting material (OCNB).

[0256] 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 66.7%.

[0257] The reaction mixture was analyzed using HPLC absolute calibration curve method to determine the yield, etc. The analytical results are as follows.

[0258] 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 62.0%.

[0259] After cooling the internal temperature to 0°C–10°C, acetic acid (10.51 g, 175 mol% (relative to the methoxyaniline compound)) was added dropwise over 1 hour. After cooling the internal temperature to -20°C–-5°C, diethyl malonate (16.02 g, 100 mmol, 100 mol% (relative to the methoxyaniline compound)) was added dropwise over 2 hours. The mixture was stirred for 12 hours at the same temperature range to give a reaction mixture containing the sodium salt of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaloline-3-carboxylic acid.

[0260] Add water (48.78 mL) to another reaction vessel and cool the internal temperature to 0–10 °C. Over 70 minutes, simultaneously add the reaction mixture from the previous reaction and 35% hydrochloric acid (31.25 g) to adjust the pH to 1.0, then add the remaining 35% hydrochloric acid. Stir at the same temperature for 1 hour, then filter to crystallize.

[0261] The crystals were washed with water (27.19 g). The resulting crystals were dried to give 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaloline-3-carboxylic acid (18.30 g, yield 51.6% (relative to p-methoxyaniline)) as the target product.

[0262] In the method of the embodiment, the target product can be produced from 2-chloronitrobenzene in two steps. Moreover, the target product is obtained in high yield.

[0263] Example 8

[0264] Production of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0265] [Chemistry 30]

[0266] Under a nitrogen stream, sodium hydride (65.0% purity, liquid paraffin dispersion, 8.12 g, 220 mmol, 220 mol) and NaOtBu (sodium tert-butoxide, 99.0% purity, 9.74 g, 100 mol) were suspended in dichloromethane (67.94 g, 0.51 L / mol). The internal temperature was raised to 31 °C, and a solution of 2-chloronitrobenzene (16.54 g, 105.0 mmol, 105 mol) and p-methoxyaniline (12.32 g, 100.0 mmol, 100 mol) dissolved in dichloromethane (67.94 g, 0.12 L / mol based on p-methoxyaniline) was added dropwise over 1 hour. The mixture was stirred at the same temperature for 17 hours. A reaction mixture containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was obtained.

[0267] The results of HPLC analysis (area percentage; 222 nm) of the reaction mixture show the following main components in the reaction mixture other than the starting material (OCNB).

[0268] 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 65.1%.

[0269] The reaction mixture was analyzed using HPLC absolute calibration curve method to determine the yield, etc. The analytical results are as follows.

[0270] 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 62.0%.

[0271] Upon examination of this invention after its completion, it was understood that in this embodiment, the tert-butanol generated from sodium tert-butoxide during the reaction acts as a "tert-butanol". Therefore, the method shown in this embodiment also falls within the scope of the invention as defined by the appended claims.

[0272] Example 9

[0273] Production of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0274] [Chemistry 31]

[0275] Under a nitrogen stream, sodium hydride (purity: 65.9%, liquid paraffin dispersion, 11.65 g, 320 mmol, 320 mol%) was suspended in dichloromethane (123.15 g, 0.38 L / mol). At an internal temperature of 35–40 °C, a solution of dichloromethane (4.25 g, 0.03 L / mol) containing tert-butanol (7.41 g, 100 mmol, 100 mol%) was added dropwise over 3 hours, followed by stirring at the same temperature for 1 hour. The internal temperature was then cooled to 30 °C, and a solution of 2-chloronitrobenzene (16.54 g, 105.0 mmol, 105 mol%) and p-methoxyaniline (12.32 g, 100.0 mmol, 100 mol%) dissolved in dichloromethane (25.48 g, 0.19 L / mol (based on p-methoxyaniline)) was added dropwise over 3 hours. The mixture was stirred at the same temperature for 11 hours. A reaction mixture containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was obtained.

[0276] The reaction mixture was analyzed using HPLC absolute calibration curve method to determine the yield, etc. The analytical results are as follows: 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 62.5% (yield).

[0277] Examples 10-16

[0278] Except for the changes in sodium hydride and t-BuOH as shown in Table 4, the reaction and analysis were performed in the same manner as in Example 9. The results are shown in Table 4. In addition, the results of Example 1 are also summarized in Table 4.

[0279] [Table 4]

[0280] Example 17

[0281] Preparation of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0282] [Chemistry 32]

[0283] Under a nitrogen stream, sodium hydride (purity: 65.9%, liquid paraffin dispersion, 11.65 g, 320 mmol, 320 mol%) was suspended in dichloromethane (123.15 g, 0.38 L / mol). At an internal temperature of 35–40 °C, a solution of dichloromethane (4.25 g, 0.03 L / mol) containing tert-butanol (7.41 g, 100 mmol, 100 mol%) was added dropwise over 3 hours, followed by stirring at the same temperature for 1 hour. The internal temperature was then cooled to 30 °C, and a solution of 2-chloronitrobenzene (16.54 g, 105.0 mmol, 105 mol%) and p-methoxyaniline (12.32 g, 100.0 mmol, 100 mol%) dissolved in dichloromethane (25.48 g, 0.19 L / mol (based on p-methoxyaniline)) was added dropwise over 3 hours. The mixture was stirred at the same temperature for 11 hours. A reaction mixture containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was obtained.

[0284] After cooling the internal temperature to 0°C–10°C, acetic acid (10.51 g, 175 mol% (relative to the methoxyaniline compound)) was added dropwise over 1 hour. After cooling the internal temperature to -20°C–-5°C, diethyl malonate (16.02 g, 100 mmol, 100 mol% (relative to the methoxyaniline compound)) was added dropwise over 2 hours. The mixture was stirred for 12 hours at the same temperature range to give a reaction mixture containing the sodium salt of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaloline-3-carboxylic acid.

[0285] The reaction mixture was analyzed using HPLC absolute calibration curve method to determine the yield, etc. The analytical results are as follows: 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid: 59.1% (yield).

[0286] Phosphoric acid was used in the HPLC analysis, and therefore it was detected as 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid.

[0287] Examples 18-20

[0288] Except for changing the reaction temperature and the amount of acetic acid used in step (ii) as shown in Table 5, the reaction and analysis were performed in the same manner as in Example 17. The results are shown in Table 5. In addition, the results of Example 17 are also summarized in Table 5.

[0289] [Table 5]

[0290] Example 21

[0291] Production of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0292] [Chemistry 33]

[0293] Sodium hydride (purity: 65.8%, liquid paraffin dispersion, 583 mg, 16.0 mmol, 320 mol%) was suspended in diethyl ether (4.64 mL, 0.29 L / mol) under a nitrogen stream. A solution of diethyl ether (0.16 mL, 0.01 L / mol) containing tert-butanol (371 mg, 5.00 mmol, 100 mol%) was added dropwise over 30 minutes at an internal temperature of 40 °C, followed by stirring at the same temperature for 30 minutes. The internal temperature was then cooled to 30 °C, and a solution of 2-chloronitrobenzene (827 mg, 5.25 mmol, 105 mol%) and p-methoxyaniline (616 mg, 5.00 mmol, 100 mol%) dissolved in diethyl ether (0.96 mL, 0.06 L / mol) was added dropwise over 1 hour. The mixture was stirred at the same temperature for 18 hours. A reaction mixture containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was obtained.

[0294] The reaction mixture was analyzed using HPLC absolute calibration curve method to determine the yield, etc. The analytical results are as follows: 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 63.5% (yield).

[0295] Examples 22-25

[0296] Except for changing the ether solvent to the solvents shown in Table 6, the reaction and analysis were carried out in the same manner as in Example 21. The results are shown in Table 6. In addition, the results of Example 21 are also summarized in Table 6.

[0297] [Table 6]

[0298] Comparative Example 1

[0299] Production of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0300] [Chemistry 34]

[0301] Sodium hydride (purity: 65.8%, liquid paraffin dispersion, 583 mg, 16.0 mmol, 320 mol%) was suspended in toluene (4.64 mL, 0.29 L / mol) under a nitrogen stream. A solution of toluene (0.16 mL, 0.01 L / mol) containing tert-butanol (371 mg, 5.00 mmol, 100 mol%) was added dropwise over 30 minutes at an internal temperature of 40 °C, followed by stirring at the same temperature for 30 minutes. The internal temperature was then cooled to 30 °C, and a solution of 2-chloronitrobenzene (827 mg, 5.25 mmol, 105 mol%) and p-methoxyaniline (616 mg, 5.00 mmol, 100 mol%) dissolved in toluene (0.96 mL, 0.06 L / mol) was added dropwise over 1 hour. The mixture was stirred at the same temperature for 18 hours. A reaction mixture containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was obtained.

[0302] The reaction mixture was analyzed using HPLC absolute calibration curve method to determine the yield, etc. The analytical results are as follows: 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 52.4% (yield).

[0303] Comparative Examples 2-14

[0304] Except for changing the solvent to that shown in Table 7, the reaction and analysis were performed in the same manner as in Comparative Example 1. The results are shown in Table 7. In addition, Table 7 also summarizes the results of Comparative Example 1. “Target Comp.” and “Target Product” in the table refer to 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline. Comparative Examples 1 to 14 were carried out under the same reaction conditions and in the same order of operations, except that the solvent in Example 1 was changed.

[0305] [Table 7]

[0306] As shown in Comparative Examples 1-14, the yield was reduced by more than 10% in the method using these solvents compared to the case of using dichloromethane as a solvent in Example 1. It can be understood that the method of the comparative examples is not industrially preferred and is uneconomical.

[0307] Comparative Example 15

[0308] Production of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0309] [Chemistry 35]

[0310] Sodium hydride (purity: 65.8%, liquid paraffin dispersion, 583 mg, 16.0 mmol, 320 mol%) was suspended in dichloromethane (4.64 mL, 0.29 L / mol) under a nitrogen stream. A solution of 2-chloronitrobenzene (827 mg, 5.25 mmol, 105 mol%) and p-methoxyaniline (616 mg, 5.00 mmol, 100 mol%) dissolved in dichloromethane (0.96 mL, 0.06 L / mol) was added dropwise over 2 hours at 30 °C. The mixture was stirred at the same temperature for 3 hours, but the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was not obtained.

[0311] Comparative Examples 16-17

[0312] Except that the t-BuOH was changed to that shown in Table 8, the reaction and analysis were performed in the same manner as in Comparative Example 15. The results are shown in Table 8. In addition, Table 8 also summarizes the results of Comparative Example 15.

[0313] [Table 8]

[0314] Comparative Example 18

[0315] Preparation of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0316] [Chemistry 36]

[0317] Under a nitrogen stream, sodium hydride (purity: 65.9%, liquid paraffin dispersion, 11.65 g, 320 mmol, 320 mol%) was suspended in dichloromethane (123.15 g, 0.38 L / mol). At an internal temperature of 35–40 °C, a solution of dichloromethane (4.25 g, 0.03 L / mol) containing tert-butanol (7.41 g, 100 mmol, 100 mol%) was added dropwise over 3 hours, followed by stirring at the same temperature for 1 hour. The internal temperature was then cooled to 30 °C, and a solution of 2-chloronitrobenzene (16.54 g, 105.0 mmol, 105 mol%) and p-methoxyaniline (12.32 g, 100.0 mmol, 100 mol%) dissolved in dichloromethane (25.48 g, 0.19 L / mol (based on p-methoxyaniline)) was added dropwise over 3 hours. The mixture was stirred at the same temperature for 11 hours. A reaction mixture containing the target intermediate 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline was obtained.

[0318] After cooling the internal temperature to 0°C–10°C, acetic acid (10.51 g, 175 mol% (relative to the methoxyaniline compound)) was added dropwise over 1 hour. After cooling the internal temperature to -25°C, diethyl malonate (16.02 g, 100 mmol, 100 mol% (relative to the methoxyaniline compound)) was added dropwise over 2 hours. The mixture was stirred for 12 hours at the same temperature range to give a reaction mixture containing sodium 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaloline-3-carboxylate.

[0319] The reaction mixture was analyzed using HPLC absolute calibration curve method to determine the yield, etc. The analytical results are as follows: 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid: 29.4% (yield).

[0320] Industrial applicability

[0321] According to the present invention, industrially preferred methods for manufacturing compounds of formula (3) and formula (5) are provided. Compounds of formula (3) and formula (5) prepared by the method of the present invention are useful as pesticide intermediates and pharmaceutical intermediates, particularly herbicide intermediates. Furthermore, the method of the present invention is suitable for large-scale manufacturing, such as in pilot plants or industrial production. In other words, the method of the present invention is economical, environmentally friendly, and has high industrial applicability. In summary, the present invention has high industrial applicability.

Claims

1. A method for manufacturing a compound of formula (3), comprising: In the presence of tertiary alcohols and alkali metal hydrides, the compound of formula (1) is reacted with the compound of formula (2) in dichloromethane or ether solvent. [Chemistry 1] 。 2. The manufacturing method according to claim 1, wherein, The amount of alkali metal hydride used is 2.0 to 4.0 equivalents relative to 1 equivalent of the compound of formula (2).

3. The manufacturing method according to claim 1 or 2, wherein, The alkali metal hydride is sodium hydride.

4. The manufacturing method according to claim 1 or 2, wherein, The amount of tertiary alcohol used is 0.1 to 2.0 equivalents relative to 1 equivalent of the compound of formula (2).

5. The manufacturing method according to claim 1 or 2, wherein, Tertiary alcohols are compounds of formula (6). [Chemistry 2] Here, R 4 R 5 and R 6 They can be the same or different, and are amino(C1-C6)alkyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl, from R 4 R 5 and R 6 The two selected can combine to form a ring.

6. The manufacturing method according to claim 1 or 2, wherein, The tertiary alcohol is selected from tert-butanol, 2-methyl-2-butanol and 2-methyl-3-buten-2-ol.

7. The manufacturing method according to claim 1 or 2, wherein, The reaction is carried out at 20℃~50℃.

8. The manufacturing method according to claim 1 or 2, wherein, The reaction is carried out at 30℃~40℃.

9. The manufacturing method according to claim 1 or 2, wherein, The ether solvent is diethyl ether, dibutyl ether, 2-methyltetrahydrofuran, tert-butylmethyl ether or cyclopentylmethyl ether.

10. A method for manufacturing a compound of formula (5), [Chemistry 3] Here, R 3 It is a hydrogen atom, an alkali metal atom, or a (C1-C4) alkyl group. The method includes the following steps: Step (i) obtaining the compound of formula (3) by the method of claim 1 or 2; and [Chemistry 4] Step (ii) involves reacting the compound of formula (3) with the compound of formula (4) to obtain the compound of formula (5). [Chemistry 5] Here, R 1 R 2 and R 3 As defined above.

11. The manufacturing method according to claim 10, wherein, The reaction in step (ii) is carried out using acetic acid.

12. The manufacturing method according to claim 10, wherein, The reaction in process (ii) is carried out at -20°C to 0°C.

13. The manufacturing method according to claim 10, wherein, The reaction in process (ii) is carried out at -20°C to -5°C.

14. The manufacturing method according to claim 10, wherein, R 1 and R 2 It is methyl or ethyl; R 3 It can be a hydrogen atom, lithium atom, sodium atom, potassium atom, methyl or ethyl atom.

15. The manufacturing method according to claim 10, wherein, R 1 and R 2 It is methyl or ethyl; R 3 It is a hydrogen atom.

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