Method for producing nitroso compound

Abstract

To provide a method for producing a nitroso compound that is industrially suitable, economical, and environmentally friendly.SOLUTION: The present invention provides a method for producing a nitroso compound of Formula (3), the method involving reacting a compound of Formula (1) with a compound of Formula (2) in the presence of a base (where R1, R2, R3, R4, R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, or a (C1-C4) alkoxy group).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a compound of the following formula (3), that is, a nitroso compound.

[0002] [ka] In the above formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is as described below. [Background technology]

[0003] The nitroso compound of formula (3) (hereinafter simply referred to as the compound of formula (3)) is useful as a production intermediate for biologically active organic compounds such as agricultural chemicals and medicines. WO2009 / 016841 (Patent Document 1) describes useful herbicides. Among them, compound No. II-194, i.e., fenquinotrione, is known as a herbicide having an extremely excellent herbicidal effect and high safety for paddy rice.

[0004] WO2013 / 089002 (Patent Document 2) discloses a production method as shown in the diagram below (see Examples 1, 3, 19, 20 to 23, etc.).

[0005] [ka]

[0006] As can be seen from the above diagram, 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 production method with fewer steps has been desired. In addition, 2,6-dichloronitrobenzene and ketomalonic acid diesters (e.g., DEMO in the above diagram) are relatively difficult to obtain, and more easily available raw materials have been desired.

[0007] On the other hand, JP 2018-70520 A (Patent Document 3) discloses that 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (3-1) can be produced by reacting 2-chloronitrobenzene (1-1) with p-anisidine (2-1). Furthermore, this document reports that a compound of formula (5-3) can be produced from 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (3-1). This method is shown in the diagram below.

[0008] [ka]

[0009] Compared with the method of WO2013 / 089002 (Patent Document 2), the method of JP 2018-70520 (Patent Document 3) can produce the compound of formula (5-3) using more readily available raw materials. However, since the method described in JP 2018-70520 (Patent Document 3) requires 2 to 3 equivalents of p-anisidine (2-1) relative to 2-chloronitrobenzene (1-1), it was desirable to reduce the amount of p-anisidine used. Furthermore, the working conditions of this method are low temperatures of -70°C to 0°C. In the method of WO2020 / 158925 (Patent Document 4), a large amount of ammonia is produced as a by-product, which must be removed in the next step, so it was desirable to reduce the amount of ammonia produced as a by-product.

[0010] 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. A specific example is shown in the figure below.

[0011] [ka] [Prior art documents] [Patent documents]

[0012] [Patent Document 1] WO2009 / 016841 [Patent Document 2] WO2013 / 089002 [Patent Document 3] Patent Publication No. 2018-70520 [Patent Document 4] WO2020 / 158925 [Non-patent literature]

[0013] [Non-Patent Document 1] Synlett (2015), 1352-1356 Summary of the Invention [Problem to be solved by the invention]

[0014] An object of the present invention is to provide an industrially advantageous, economical and environmentally friendly process for the preparation of the nitroso compound of formula (3).

[0015] A specific object of the present invention is to provide an industrially favorable process for preparing the compound of formula (3), which can solve one or more of the disadvantages or problems in the prior art mentioned above. [Means for solving the problem]

[0016] As a result of intensive research, the present inventors have discovered the present invention regarding a method for producing the compound of formula (3). Based on this discovery, the present inventors have completed the present invention.

[0017] That is, the present invention is as follows.

[0018] [I-1] A method for producing a compound of formula (3), comprising reacting a compound of formula (1) with a compound of formula (2) in the presence of a base: [ka] (where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom, a halogen atom, a (C1-C4) alkyl or a (C1-C4) alkoxy.

[0019] [I-2] The production method according to [I-1], in which a base is added, and then a reaction between the compound of formula (1) and the compound of formula (2) is carried out.

[0020] [I-3] The production method according to [I-1] or [I-2], wherein the base is a combination of lithium amide and a metal tert-butoxide.

[0021] [I-4] The production method according to [I-3], wherein the metal tert-butoxide is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide or magnesium di-tert-butoxide (preferably sodium tert-butoxide, lithium tert-butoxide or magnesium di-tert-butoxide).

[0022] [I-5] The production method according to [I-3], wherein the metal tert-butoxide is lithium tert-butoxide.

[0023] [I-6] The production method according to any one of [I-3] to [I-5], wherein the amount of lithium amide used is 1.5 to 3.0 equivalents relative to 1 equivalent of the compound of formula (2).

[0024] [I-7] The production method according to any one of [I-3] to [I-5], wherein the amount of lithium amide used is 1.8 to 2.8 equivalents relative to 1 equivalent of the compound of formula (2).

[0025] [I-8] The production method according to any one of [I-3] to [I-5], wherein the amount of lithium amide used is 2.0 to 2.5 equivalents relative to 1 equivalent of the compound of formula (2).

[0026] [I-9] The production method according to any one of [I-3] to [I-7], wherein the amount of the metal tert-butoxide used is 0.2 to 1.5 equivalents relative to 1 equivalent of the compound of formula (2).

[0027] [I-10] A method according to any one of [I-3] to [I-7], in which the amount of metal tert-butoxide used is 0.3 to 1.2 equivalents per equivalent of the compound of formula (2).

[0028] [I-11] A production method according to any one of [I-3] to [I-7], wherein the amount of the metal tert-butoxide used is 0.5 to 1.0 equivalent relative to 1 equivalent of the compound of formula (2).

[0029] [I-12] The production method according to any one of [I-1] to [I-11], wherein the reaction is carried out at -5°C to 80°C.

[0030] [I-13] The production method according to any one of [I-1] to [I-11], wherein the reaction is carried out at -5°C to 50°C.

[0031] [I-14] The production method according to any one of [I-1] to [I-11], wherein the reaction is carried out at 0°C to 50°C.

[0032] [I-15] The production method according to any one of [I-1] to [I-11], wherein the reaction is carried out at 0°C to 40°C.

[0033] [I-16] The production method according to any one of [I-1] to [I-15], wherein the reaction is carried out in the presence of a solvent.

[0034] [I-17] The production method according to [I-16], wherein the solvent is toluene, xylene, chlorobenzene, dichlorobenzene, or a mixture thereof.

[0035] [I-18] The production method according to [I-16], wherein the solvent is toluene, xylene, or a mixture thereof.

[0036] [I-19] The production method according to [I-16], wherein the solvent is toluene.

[0037] [I-20] A production method according to any one of [I-1] to [I-19], in which a tertiary alcohol is not added to the reaction.

[0038] [I-21] The production method according to any one of [I-1] to [I-20], which is carried out in the presence of an additive.

[0039] [I-22] The production method according to [I-21], wherein the additive is N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), 1,3-dimethyl-2-imidazolidinone (DMI), tetramethylurea, n-propylamine, isopropylamine, n-butylamine, n-pentylamine, or isopentylamine.

[0040] [I-23] The production method according to [I-21], wherein the additive is N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), 1,3-dimethyl-2-imidazolidinone (DMI), tetramethylurea, or n-butylamine.

[0041] [I-24] The method according to any one of [I-1] to [I-23], R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom or a chlorine atom; R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom or a (C1-C4)alkoxy.

[0042] [I-25] The method according to any one of [I-1] to [I-23], R 1 is a hydrogen atom or a chlorine atom; R 2 , R 3 and R 4 is a hydrogen atom; R 5 , R 6 , R 8 and R 9 is a hydrogen atom; R 7 is a hydrogen atom or methoxy.

[0043] [I-26] The method according to any one of [I-1] to [I-23], R 1 is a chlorine atom; R 2 , R 3 and R 4 is a hydrogen atom; R 5 , R 6 , R 8 and R9 is a hydrogen atom; R 7 The method for producing the same is as follows: Effect of the Invention

[0044] The present invention provides a novel method for producing a compound of formula (3), which is industrially favorable, economical, and environmentally friendly. The present invention provides a method for producing a compound of formula (3), which can solve one or more of the drawbacks or problems in the prior art described above. Specifically, the present invention has found a method for reducing the amount of lithium amide used, and further, by reducing the amount of lithium amide used, the amount of ammonia produced as a by-product can be reduced. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] The present invention will be described in detail below.

[0046] The following abbreviations and prefixes may be used herein and have the following meanings: Me: Methyl Et: Ethyl Pr, n-Pr and Pr-n: Propyl (i.e. normal propyl) i-Pr and Pr-i: isopropyl Bu, n-Bu and Bu-n: Butyl (i.e., normal butyl) s-Bu and Bu-s: sec-butyl (i.e., secondary butyl) i-Bu and Bu-i: Isobutyl t-Bu and Bu-t: tert-butyl (i.e., 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-:para t-BuOH: tert-butanol

[0047] Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0048] As used herein, general terms such as "alkyl" are intended to include both straight and branched chains, such as butyl and tert-butyl, while the specific term "butyl," for example, refers to straight chain "normal butyl" and not branched chain "tert-butyl," and branched chain isomers such as "tert-butyl" are specifically referred to when intended.

[0049] (Ca-Cb) means that the number of carbon atoms is a to b. For example, the "(C1-C4)" in "(C1-C4) alkyl" means that the alkyl group has 1 to 4 carbon atoms.

[0050] (C1-C6) alkyl means straight or branched alkyl 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, and the like. (C1-C4) alkyl means straight or branched alkyl having 1 to 4 carbon atoms. Examples of (C1-C4) alkyl are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl.

[0051] (C3-C6)cycloalkyl means a cycloalkyl having 3 to 6 carbon atoms. Examples of (C3-C6)cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0052] Examples of (C6-C10)aryl are phenyl, 1-naphthyl, and 2-naphthyl.

[0053] (C6-C10)aryl(C1-C4)alkyl means (C1-C4 alkyl) substituted with (C6-10)aryl, where the C6-10 aryl and C1-C4 alkyl moieties have the same meanings as defined above. 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, naphthalene-2-ylmethyl groups, and the like.

[0054] (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.

[0055] As used herein, the open-ended term "comprise(s) / comprising" may be optionally replaced with the exclusive phrase "consist(s) of / consisting of," respectively. In this specification, the phrase "after each addition" can be replaced with the phrase "after separately addition." As will be understood from the examples described later, "in the presence of a base" can be understood as, for example, but not limited to, "adding a base to the reaction system." Thus, in this specification, the phrase "after adding a base" can be replaced with, for example, the phrase "after adding lithium amide and metal tert-butoxide to the reaction system, respectively."

[0056] The method of the present invention will now be described.

[0057] The present invention provides a compound of formula (3) by reacting a compound of formula (1) with a compound of formula (2) in the presence of a base, which is a combination of lithium amide and a metal tert-butoxide.

[0058] [ka]

[0059] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is as defined above.)

[0060] (Raw material: compound of formula (1), i.e., nitro compound) The compound of formula (1), i.e., a nitro compound, is used as the raw material in the present invention. The compound of formula (1) is a known compound or can be produced from a known compound by a known method.

[0061] Specific examples of compounds of formula (1) include, but are not limited to, the following: Nitrobenzene, 2-chloronitrobenzene, 3-chloronitrobenzene, 4-chloronitrobenzene, 2-fluoronitrobenzene, 3-fluoronitrobenzene, 4-fluoronitrobenzene and the like.

[0062] From the viewpoints of yield, availability, cost, usefulness of the product, and the like, preferred specific examples of the compound of formula (1) include nitrobenzene, 2-chloronitrobenzene, and more preferably 2-chloronitrobenzene.

[0063] The amount of the compound of formula (1) used may be any amount as long as the reaction proceeds. However, from the viewpoints of yield, by-product suppression, economic efficiency, etc., in one embodiment, the amount of the compound of formula (1) (nitro compound) used is, for example, 0.7 equivalents to 2.0 equivalents, preferably 0.9 equivalents to 1.8 equivalents, more preferably 0.9 equivalents to 1.6 equivalents, even more preferably 0.9 equivalents to 1.5 equivalents, and particularly preferably 1.0 to 1.5 equivalents, relative to 1 equivalent of the compound of formula (2) (aniline compound). From the same viewpoint as above, in another embodiment, the amount of the compound of formula (1) used is, for example, 1.0 equivalents to 2.0 equivalents, preferably 1.0 equivalents to 1.8 equivalents, more preferably 1.0 equivalents to 1.6 equivalents, and particularly preferably 1.0 equivalents to 1.5 equivalents, relative to 1 equivalent of the compound of formula (2) (aniline compound).

[0064] In this specification, the definition of "equivalent of compound of formula (1) (nitro compound)" is as follows, or the term "equivalent" is interpreted according to the following example. For example, "1 equivalent of compound of formula (1) (nitro compound) per equivalent of compound of formula (2) (aniline compound)" means "1 mole of compound of formula (1) (nitro compound) per mole of compound of formula (2) (aniline compound)". For example, "0.5 equivalent of compound of formula (1) (nitro compound) per equivalent of compound of formula (2) (aniline compound)" means "0.5 mole of compound of formula (1) (nitro compound) per mole of compound of formula (2) (aniline compound)".

[0065] (Raw material: compound of general formula (2), i.e., aniline compound) The compound of formula (2), i.e., an aniline compound, is used as the raw material in the present invention. The compound of formula (2) is a known compound or can be produced from a known compound by a known method.

[0066] Specific examples of compounds 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, 4-t-butylaniline, and the like.

[0067] From the viewpoint of yield and / or usefulness of the product, preferred specific examples of the compound of formula (2) include aniline or 4-methoxyaniline. From the viewpoint of usefulness of the product, a more preferred specific example of the compound of formula (2) is 4-methoxyaniline.

[0068] From the viewpoint of improving economic efficiency and reducing environmental load, the use of an excess amount of 2-chloronitrobenzene is permitted. However, it is preferable to avoid the use of an excess amount of p-anisidine, but this is not limited thereto. For example, it has been found that p-anisidine is much more expensive than 2-chloronitrobenzene. In the method of JP 2018-70520 (Patent Document 3), 2 equivalents or more of p-anisidine are required as a raw material used in excess. In fact, 2 to 3 equivalents of p-anisidine are used in the examples of JP 2018-70520 (Patent Document 3). On the other hand, in the method of the present invention, 2 equivalents or less of 2-chloronitrobenzene is sufficient as a raw material used in excess. As shown in the examples described later, even 1 equivalent to 1.5 equivalents of 2-chloronitrobenzene gives a satisfactory yield.

[0069] (base) Examples of bases of the present invention include, but are not limited to: Lithium amide and lithium tert-butoxide, lithium amide and potassium tert-butoxide, lithium amide and sodium tert-butoxide, lithium amide and magnesium di-tert-butoxide, lithium amide and calcium di-tert-butoxide, lithium amide and cesium tert-butoxide, and any combinations thereof in any proportion.

[0070] Metal tert-butoxides are included in the base. Examples of metal tert-butoxides include, but are not limited to: Lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, magnesium di-tert-butoxide, calcium di-tert-butoxide, cesium tert-butoxide.

[0071] From the viewpoints of yield, by-product suppression, economic efficiency, and the like, preferred examples of the base include lithium amide and lithium tert-butoxide, and any combination thereof in any ratio.

[0072] The lithium amide and the metal tert-butoxide can be used in any ratio. For example, the ratio of the lithium amide and the metal tert-butoxide is 1.5 to 3.0 equivalents of the lithium amide and 0.5 to 1.5 equivalents of the metal tert-butoxide, preferably 1.8 to 2.5 equivalents of the lithium amide and 0.5 to 1.2 equivalents of the metal tert-butoxide, more preferably 2.0 to 2.2 equivalents of the lithium amide and 0.5 to 1.0 equivalent of the metal tert-butoxide.

[0073] The form of the base may be any form as long as the reaction proceeds. The form of the base can be appropriately selected by those skilled in the art.

[0074] The amount of base used may be any amount as long as the reaction proceeds. However, from the viewpoint of yield, by-product suppression, economic efficiency, etc., the amount of base used (total amount of compounds used) is, for example, in one embodiment, usually 2.0 equivalents or more, preferably 2.0 equivalents to 4.0 equivalents, more preferably 2.5 equivalents to 3.5 equivalents, and even more preferably 2.8 equivalents to 3.5 equivalents relative to 1 equivalent of the compound of formula (2) (aniline compound).

[0075] Specific examples of the amount of the base used are, relative to 1 equivalent of the compound of formula (2), preferably 1.5 to 3.0 equivalents, more preferably 1.5 to 2.5 equivalents, and even more preferably 2.0 to 2.2 equivalents of the lithium amide, and preferably 0.5 to 1.5 equivalents, more preferably 0.5 to 1.0 equivalent of the metal tert-butoxide.

[0076] As mentioned above, in this specification, the definition of "equivalent of base" is as follows, or the term "equivalent" is interpreted according to the following examples. For example, when the base is a monovalent base such as lithium amide (LiNH2), "1 equivalent of base per equivalent of the compound of formula (2) (aniline compound)" means "1 mole of base per mole of the compound of formula (2) (aniline compound)", and "0.5 equivalent of base per equivalent of the compound of formula (2) (aniline compound)" means "0.5 mole of base per mole of the compound of formula (2) (aniline compound)". As another example, when the base is a divalent base such as calcium hydride (CaH2), "1 equivalent of base per equivalent of the compound of formula (2) (aniline compound)" means "0.5 moles of base per mole of the compound of formula (2) (aniline compound)", and "0.5 equivalents of base per equivalent of the compound of formula (2) (aniline compound)" means "0.25 moles of base per mole of the compound of formula (2) (aniline compound)".

[0077] The base can be added to the reaction in a predetermined amount all at once, or it can be added in several portions or dropwise.

[0078] (Additives) Additives may be added to the reaction from the viewpoints of yield, by-product suppression, economic efficiency, etc. Preferred examples of additives include aprotic polar solvents (e.g., N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), 1,3-dimethyl-2-imidazolidinone (DMI), tetramethylurea, etc.), aliphatic amines (n-propylamine, isopropylamine, n-butylamine, n-pentylamine, isopentylamine, etc.), and any combination thereof in any ratio.

[0079] The additive may be any additive as long as the reaction proceeds. However, from the viewpoints of yield, by-product suppression, economic efficiency, etc., preferred examples of the additive are N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), 1,3-dimethyl-2-imidazolidinone (DMI), tetramethylurea, n-propylamine, isopropylamine, n-butylamine, n-pentylamine, and isopentylamine, more preferably N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), 1,3-dimethyl-2-imidazolidinone (DMI), tetramethylurea, and n-butylamine.

[0080] The amount of the additive used may be any amount as long as the reaction proceeds. However, from the viewpoints of yield, by-product suppression, economic efficiency, etc., the amount of the additive used is usually 0.1 equivalent or more, preferably 0.1 to 2.0 equivalents, more preferably 0.3 to 1.5 equivalents, and even more preferably 0.5 to 1.0 equivalent, relative to 1 equivalent of the compound of formula (2) (aniline compound).

[0081] (solvent) From the viewpoint of smooth progress of the reaction, the reaction is preferably carried out in the presence of a solvent. Examples of the solvent include, but are not limited to, aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, etc.), halogenated aliphatic hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., diethyl ether, diisopropyl ether, cyclopentyl methyl ether (CPME), tetrahydrofuran (THF), 1,4-dioxane, monoglyme, diglyme, etc.), amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), etc.), sulfoxides (e.g., dimethyl sulfoxide (DMSO), etc.), and any combination thereof in any ratio.

[0082] The solvent may be any solvent as long as the reaction proceeds. However, from the viewpoints of yield, by-product suppression, economic efficiency, etc., preferred examples of the solvent include toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and any combination thereof in any ratio, more preferably toluene, xylene, chlorobenzene, dichlorobenzene, further preferably toluene, xylene, and further preferably toluene.

[0083] The amount of the solvent used may be any amount as long as the reaction system can be sufficiently stirred. From the viewpoints of yield, suppression of by-products, economic efficiency, etc., the amount of the solvent used may be 10 L (liters) or less, preferably 0.1 to 10 L, more preferably 0.1 to 5 L, and even more preferably 0.5 to 5 L, per mole of the compound of formula (2) (aniline compound).

[0084] (Reaction temperature) From the viewpoints of yield, by-product suppression, economic efficiency, and the like, the reaction temperature is, in one embodiment, for example, -5°C (minus 5°C) to 80°C, preferably -5°C to 50°C, more preferably 0°C to 50°C, and even more preferably 0°C to 40°C; in another embodiment, for example, 0°C to 80°C, more preferably 0°C to 60°C, even more preferably 10°C to 80°C, even more preferably 20°C to 70°C, even more preferably 20°C to 40°C, and most preferably 25°C to 35°C; and in yet another embodiment, for example, -20°C (minus 20°C) to 60°C, preferably -10°C to 40°C, more preferably 0°C to 30°C, and even more preferably 0°C to 15°C.

[0085] (Reaction time) The reaction time is not particularly limited, but from the viewpoints of yield, suppression of by-products, economic efficiency, etc., the reaction time is, for example, 0.1 to 48 hours, preferably 1 to 48 hours, more preferably 1 to 36 hours, and further preferably 1 to 24 hours.

[0086] The compound of formula (3) can be used as a raw material for producing CAQ. As long as the reaction proceeds, the compound of formula (3) may be isolated and used in the next step, or may be further purified and used in the next step, or may be used in the next step without isolation. In addition, after the reaction is completed, for example, hydrochloric acid or acetic acid may be used as a post-treatment. In addition, after the reaction is completed, an inert gas such as nitrogen may be blown into the solution to remove by-products. The by-products may be removed under reduced pressure. An example of the by-product is ammonia.

[0087] (Product: Compound of formula (3), i.e., nitroso compound)

[0088] In terms of the usefulness of the product, specific examples of the compound of formula (3) include, but are not limited to, the following: 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline. EXAMPLES

[0089] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0090] In this specification, room temperature is between 10°C and 35°C.

[0091] The following instruments can be used to measure the properties and yields of the examples and comparative examples in this specification. In addition, the products obtained in the present invention are known compounds and were identified and quantified by conventional methods known to those skilled in the art. High performance liquid chromatography (HPLC) analysis; Model: LC-2010A HT (Shimadzu Corporation).

[0092] "OCNB" means "2-chloronitrobenzene," as shown below. [ka]

[0093] "pA" means "p-anisidine," as shown below. [ka]

[0094] "MNA" means "N-(4-methoxyphenyl)-2-nitroaniline," as shown below. [ka]

[0095] "DMM" means "dimethyl malonate," as shown below. [ka]

[0096] "DEM" means "diethyl malonate," as shown below. [ka]

[0097] "CAQ" means "5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid," as shown below. [ka]

[0098] In Example 6 of WO2020 / 158925, 3.1 equivalents of lithium amide are used per equivalent of p-anisidine. In the examples of the present application, 2.1 to 2.2 equivalents of lithium amide are used, which is a reduction of 0.9 to 1.0 equivalents of lithium amide compared to Example 6 of WO2020 / 158925. In other words, the amount of ammonia by-produced from lithium amide is also reduced by 0.9 to 1.0 equivalents.

[0099] Example 1 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0100] [ka]

[0101] Under a nitrogen stream, lithium amide (purity: 99.0%, 3.83 g, 165.0 mmol, 220 mol%) and lithium tert-butoxide (purity: 97.0%, 6.19 g, 75.0 mmol, 100 mol%) were suspended in toluene (15.02 g, 0.23 L / mol). A solution of 2-chloronitrobenzene (17.72 g, 112.5 mmol, 150 mol%) in toluene (3.0 g, 0.05 L / mol) was added at an internal temperature of 5-10°C, and a solution washed with toluene (5.57 g, 0.09 L / mol) was also added in the same manner. A solution of p-anisidine (9.24 g, 75.0 mmol, 100 mol%) in toluene (60.99 g, 0.94 L / mol) was added dropwise to the flask over 3 hours at an internal temperature of 0 to 5°C under a nitrogen atmosphere, and then the solution was washed with toluene (0.80 g, 0.01 L / mol) and stirred at the same temperature for 18 hours.

[0102] As a result of HPLC analysis (area percentage; 222 nm) of the reaction mixture, the main components in the reaction mixture, excluding the solvent and OCNB (raw material), were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 87.0%, p-Anisidine (raw material): 0.1%, MNA (by-product; Cl-substituted product (de-Cl product)): 2.4%.

[0103] The reaction mixture was analyzed by HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 85.3% (yield), p-Anisidine (raw material): 0.1% (recovery rate), MNA (by-product; Cl-substituted product (de-Cl product)): 2.7%.

[0104] Examples 2 to 6 The reaction and analysis were carried out in the same manner as in Example 1, except that the amount of lithium tert-butoxide and the reaction time were changed as shown in Table 1. The results are shown in Table 1. In addition, the results of Example 1 are also summarized in Table 1. It can be seen that the yield can be increased by appropriately adjusting the amount of lithium tert-butoxide used.

[0105] [Table 1]

[0106] Example 7 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0107] [ka]

[0108] Under a nitrogen stream, lithium amide (purity: 99.0%, 3.65 g, 157.0 mmol, 210 mol%) and lithium tert-butoxide (purity: 97.0%, 6.19 g, 75.0 mmol, 100 mol%) were suspended in toluene (15.02 g, 0.23 L / mol). A solution of 2-chloronitrobenzene (17.72 g, 112.50 mmol, 150 mol%) in toluene (3.0 g, 0.05 L / mol) was added at an internal temperature of 5-10°C, and a solution washed with toluene (5.57 g, 0.09 L / mol) was also added in the same manner. A solution of p-anisidine (9.24 g, 75.0 mmol, 100 mol%) in toluene (60.99 g, 0.94 L / mol) was added dropwise to the flask over 3 hours at an internal temperature of 0 to 5°C under a nitrogen atmosphere, and then the solution was washed with toluene (0.80 g, 0.01 L / mol) and stirred at the same temperature for 20 hours.

[0109] As a result of HPLC analysis (area percentage; 222 nm) of the reaction mixture, the main components in the reaction mixture, excluding the solvent and OCNB (raw material), were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 87.0%, p-Anisidine (raw material): 0.1%, MNA (by-product; Cl-substituted product (de-Cl product)): 2.5%.

[0110] The reaction mixture was analyzed by HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 83.4% (yield), p-Anisidine (raw material): 0.2% (recovery rate), MNA (by-product; Cl-substituted product (de-Cl product)): 2.7%.

[0111] Examples 8 to 15 The reaction and analysis were carried out in the same manner as in Example 7, except that the reaction scale, the amount of lithium tert-butoxide, and the reaction time were changed as shown in Table 2. The results are shown in Table 2. In addition, the results of Example 7 are also summarized in Table 2. It can be seen that the yield can be increased by appropriately adjusting the amount of lithium tert-butoxide used.

[0112] [Table 2]

[0113] Example 16 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0114] [ka]

[0115] Under a nitrogen stream, lithium amide (purity: 99.0%, 3.83 g, 165.0 mmol, 220 mol%) and lithium tert-butoxide (purity: 98.8%, 3.04 g, 37.5 mmol, 50 mol%) were suspended in toluene (19.79 g, 0.30 L / mol). A solution of 2-chloronitrobenzene (17.72 g, 112.5 mmol, 150 mol%) in toluene (3.0 g, 0.05 L / mol) was added at an internal temperature of 0-10°C, and a solution washed with toluene (0.80 g, 0.01 L / mol) was also added. Under a nitrogen atmosphere, N,N-dimethylformamide (DMF, 2.74 g, 37.5 mmol, 50 mol%) was added as an additive at an internal temperature of 0-5°C. A solution of p-anisidine (9.24 g, 75.0 mmol, 100 mol%) in toluene (60.99 g, 0.94 L / mol) was added dropwise over 3 hours at an internal temperature of 0-5°C, and then the solution washed with toluene (0.80 g, 0.01 L / mol) was added. The mixture was stirred at the same temperature for 24 hours.

[0116] As a result of HPLC analysis (area percentage; 222 nm) of the reaction mixture, the main components in the reaction mixture, excluding the solvent and OCNB (raw material), were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 86.1%, p-Anisidine (raw material): 0.6%, MNA (by-product; Cl-substituted product (de-Cl product)): 4.6%.

[0117] The reaction mixture was analyzed by HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 84.0% (yield), p-Anisidine (raw material): 1.3% (recovery rate), MNA (by-product; Cl-substituted product (de-Cl product)): 5.1%.

[0118] Examples 17 to 24 The reaction and analysis were carried out in the same manner as in Example 16, except that the reaction scale, additives, and reaction time were changed as shown in Table 3. The results are shown in Table 3. In addition, the results of Examples 6 and 16 are also summarized in Table 3. It can be seen that the yield is increased by using the additives.

[0119] [Table 3]

[0120] Example 25 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0121] [ka]

[0122] Under a nitrogen stream, lithium amide (purity: 99.0%, 5.10g, 220.0 mmol, 220 mol%) and lithium tert-butoxide (purity: 99.0%, 4.05 g, 50.0 mmol, 50 mol%) were suspended in toluene (25.30g, 0.29 L / mol). A solution of 2-chloronitrobenzene (23.63 g, 150.0 mmol, 150 mol%) in toluene (4.0 g, 0.05 L / mol) was added at an internal temperature of 0-10°C, and a solution washed with toluene (5.08 g, 0.06 L / mol) was also added. Under a nitrogen atmosphere, N,N-dimethylformamide (DMF, 3.65g, 50.0 mmol, 50 mol%) was added as an additive at an internal temperature of 0-10°C. A solution of p-anisidine (12.32 g, 100.0 mmol, 100 mol%) in toluene (85.61 g, 0.99 L / mol) was added dropwise over 16 hours at an internal temperature of 0-5°C, and then the solution washed with toluene (2.07 g, 0.02 L / mol) was added. The mixture was stirred at the same temperature for 4 hours.

[0123] As a result of HPLC analysis (area percentage; 222 nm) of the reaction mixture, the main components in the reaction mixture, excluding the solvent and OCNB (raw material), were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 87.1%, p-Anisidine (raw material): 0.7%, MNA (by-product; Cl-substituted product (de-Cl product)): 3.8%.

[0124] The reaction mixture was analyzed by HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 83.5% (yield), p-Anisidine (raw material): 1.9% (recovery rate), MNA (by-product; Cl-substituted product (de-Cl product)): 4.1%.

[0125] Example 26 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0126] [ka]

[0127] Under a nitrogen stream, lithium amide (purity: 99.0%, 3.83 g, 165.0 mmol, 220 mol%) and sodium tert-butoxide (purity: 97%, 7.43 g, 75 mmol, 100 mol%) were suspended in toluene (19.79 g, 0.30 L / mol). A solution of 2-chloronitrobenzene (17.72 g, 112.5 mmol, 150 mol%) in toluene (3.0 g, 0.05 L / mol) was added at an internal temperature of 0 to 10°C, and a solution washed with toluene (0.80 g, 0.01 L / mol) was also added in the same manner. A solution of p-anisidine (9.24 g, 75.0 mmol, 100 mol%) in toluene (60.99 g, 0.94 L / mol) was added dropwise to the flask over 3 hours at an internal temperature of 0 to 5°C under a nitrogen atmosphere, and then the solution was washed with toluene (0.80 g, 0.01 L / mol) and stirred at the same temperature for 24 hours.

[0128] As a result of HPLC analysis (area percentage; 222 nm) of the reaction mixture, the main components in the reaction mixture, excluding the solvent and OCNB (raw material), were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 66.0%,

[0129] The reaction mixture was analyzed by HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 68.0% (yield),

[0130] Example 27 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0131] [ka]

[0132] Under a nitrogen stream, lithium amide (purity: 99.0%, 3.83 g, 165.0 mmol, 220 mol%) and magnesium di-tert-butoxide (purity: 90.0%, 7.11 g, 37.5 mmol, 50 mol%) were suspended in toluene (19.79 g, 0.30 L / mol). A solution of 2-chloronitrobenzene (17.72 g, 112.5 mmol, 150 mol%) in toluene (3.0 g, 0.05 L / mol) was added at an internal temperature of 0-10°C, and a solution washed with toluene (0.80 g, 0.01 L / mol) was also added in the same manner. A solution of p-anisidine (9.24 g, 75.0 mmol, 100 mol%) in toluene (60.99 g, 0.94 L / mol) was added dropwise to the flask over 3 hours at an internal temperature of 0 to 5°C under a nitrogen atmosphere, and then the solution was washed with toluene (0.80 g, 0.01 L / mol) and stirred at the same temperature for 24 hours.

[0133] As a result of HPLC analysis (area percentage; 222 nm) of the reaction mixture, the main components in the reaction mixture, excluding the solvent and OCNB (raw material), were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 76.0%,

[0134] The reaction mixture was analyzed by HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-Chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 68.0% (yield).

[0135] Comparative Example 1 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0136] [ka]

[0137] Under a nitrogen stream, lithium amide (purity: 99.0%, 3.83 g, 165.0 mmol, 220 mol%) and lithium tert-butoxide (purity: 97.0%, 1.24 g, 15.0 mmol, 20 mol%) were suspended in toluene (15.02 g, 0.23 L / mol). A solution of 2-chloronitrobenzene (17.72 g, 112.5 mmol, 150 mol%) in toluene (3.00 g, 0.05 L / mol) was added at an internal temperature of 5-10°C, and a solution washed with toluene (5.57 g, 0.09 L / mol) was also added in the same manner. A solution of p-anisidine (9.24 g, 75.0 mmol, 100 mol%) in toluene (60.99 g, 0.94 L / mol) was added dropwise to the flask over 3 hours at an internal temperature of 0 to 5°C under a nitrogen atmosphere, and then the solution was washed with toluene (0.80 g, 0.01 L / mol) and stirred at the same temperature for 18 hours.

[0138] As a result of HPLC analysis (area percentage; 222 nm) of the reaction mixture, the main components in the reaction mixture, excluding the solvent and OCNB (raw material), were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 68.0%, p-Anisidine (raw material): 14.9%, MNA (by-product; Cl-substituted product (de-Cl product)): 6.4%,

[0139] The reaction mixture was analyzed by HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (target product): 53.3% (yield), p-Anisidine (raw material): 28.3% (recovery rate), MNA (by-product; Cl-substituted product (de-Cl product)): 5.6%.

[0140] Reference example 1 Preparation of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0141] [ka]

[0142] The internal temperature was kept at 0-10°C, and water (5.41 g, 300.22 mmol, 150 mol% (relative to p-anisidine)) was added dropwise to the reaction mixture obtained in Example 8 over 3 hours. After the addition, the mixture was stirred for 19.5 hours, and then ammonia was removed under reduced pressure. Subsequently, toluene (4.28 g, 46.45 mmol, 23 mol% (relative to p-anisidine)) was added, and the internal temperature was kept at 0-5°C, and diethyl malonate (32.03 g, 200.0 mmol, 100 mol% (relative to p-anisidine)) was added dropwise over 14 hours, and a solution washed with toluene (4.21 g, 0.02 L / mol) was added. The mixture was stirred at an internal temperature of 0-10°C for 2.5 hours (end point determined by analysis).

[0143] In another reaction vessel, water (150 mL, 0.75 L / mol) was added, and the internal temperature was raised to 50-55°C. The reaction mixture and 35% hydrochloric acid (66.67 g) that had been reacted previously were dropped simultaneously over 85 minutes, and the solution washed with toluene (4.28 g, 0.02 L / mol) was charged, and the pH was adjusted to 2.5. At the same temperature, 35% hydrochloric acid (23.57 g) was dropped over about 1 hour, and after stirring at the same temperature for 75 minutes, the internal temperature was cooled to 25-30°C, and the crystals were filtered. The crystals were washed with toluene (89.12 g) and water (57.39 g) in sequence. The obtained crystals were dried, and 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid (46.57 g, purity 98.34%, yield 69.2%) was obtained as the target product. [Industrial Applicability]

[0144] According to the present invention, an industrially preferable method for producing the compound of formula (3) is provided. The compound of formula (3) which can be produced by the method of the present invention is useful as an intermediate for agricultural chemicals and pharmaceuticals, particularly as an intermediate for herbicide. Furthermore, the method of the present invention is suitable for large-scale production such as pilot plant or industrial production. In other words, the method of the present invention is economical, environmentally friendly, and has high industrial applicability. In short, the present invention has high industrial applicability.

Claims

1. A method for preparing a compound of formula (3), comprising reacting a compound of formula (1) with a compound of formula (2) in the presence of a base: 【Chemistry 1】 (Here, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ are each independently a hydrogen atom, a halogen atom, a (C1-C4) alkyl or a (C1-C4) alkoxy.

2. 2. The method according to claim 1, wherein the base is a combination of lithium amide and a metal tert-butoxide.

3. 3. The method according to claim 2, wherein the metal tert-butoxide is sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide or magnesium di-tert-butoxide.

4. 3. The method according to claim 2, wherein the metal tert-butoxide is sodium tert-butoxide, lithium tert-butoxide or magnesium di-tert-butoxide.

5. 3. The method according to claim 2, wherein the metal tert-butoxide is lithium tert-butoxide.

6. The method according to any one of claims 2 to 5, wherein the amount of lithium amide used is 1.5 to 2.5 equivalents per equivalent of the compound of formula (2).

7. The method according to any one of claims 2 to 5, wherein the amount of lithium amide used is 1.8 to 2.2 equivalents per equivalent of the compound of formula (2).

8. The method according to any one of claims 2 to 5, wherein the amount of metal tert-butoxide used is 0.5 to 1.0 equivalent relative to 1 equivalent of the compound of formula (2).

9. The method according to any one of claims 1 to 5, wherein the reaction is carried out at a temperature of -5°C to 80°C.

10. The method according to any one of claims 1 to 5, wherein the reaction is carried out at a temperature of 0°C to 50°C.

11. The method according to any one of claims 1 to 5, R １ is a chlorine atom; R ２ , R ３ and R ４ is a hydrogen atom; R ５ , R ６ , R ８ and R ９ is a hydrogen atom; R ７ The method for producing the same is as follows:

Images