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

Abstract

This method for producing a nitroso compound of formula (3) involves reacting a compound of formula (1) with a compound of formula (2) in a dichloromethane solvent or an ether solvent in the presence of a tertiary alcohol and an alkali metal hydride.

Description

Method for producing nitroso compounds and quinoxaline compounds using dichloromethane or ether solvent

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

[0002] The present invention also relates to a method for producing a compound of the following formula (5), that is, a quinoxaline compound.

[0003]

[0004] The nitroso compound of formula (3) (hereinafter simply referred to as the compound of formula (3)) and the quinoxaline compound of formula (5) (hereinafter simply referred to as the compound of formula (5)) are useful as intermediates for producing physiologically active organic compounds such as agricultural chemicals and pharmaceuticals. WO2009 / 016841 (Patent Document 1) describes useful herbicides. Among them, Compound No. II-194, i.e., fenquinotrione, is known as a herbicide with extremely excellent herbicidal effect and high safety for paddy rice.

[0005] WO2013 / 089002 (Patent Document 2) discloses a production method as shown in the diagram below (see Examples 1, 3, 19, 20-23, etc.).

[0006]

[0007] As can be seen from the diagram above, the method described in WO2013 / 089002 (Patent Document 2) requires three processes (three steps) to produce the compound of formula (5-3) from 2,6-dichloronitrobenzene. Therefore, a production method with fewer processes has been desired. In addition, 2,6-dichloronitrobenzene and ketomalonic acid diesters (e.g., DEMO in the diagram above) are relatively difficult to obtain, and more easily available raw materials have been desired.

[0008] On the other hand, Japanese Patent Application Laid-Open 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-anisidine (2). Furthermore, this document reports that a compound of formula (5-3) can be produced from 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline (3). This method is shown in the diagram below.

[0009]

[0010] Compared to 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, the method of JP 2018-70520 (Patent Document 3) requires 2 to 3 equivalents of p-anisidine (2) relative to 2-chloronitrobenzene (1), and therefore it has been desired to reduce the amount of p-anisidine used.

[0011] In the method of WO2020 / 158925 (Patent Document 4), a method using lithium amide is described in Example 17, but lithium amide is expensive and its availability is limited, so a method using a base that is inexpensive and easily available has been desired. Furthermore, when lithium amide is used, ammonia is produced as a by-product, which requires consideration of the environment.

[0012] In addition, in the method of WO2020 / 158925 (Patent Document 4), a method using sodium hydride is also described in Example 18, but the yield of the compound of formula (5-1) is as low as 39.9%, and an improvement in the yield has been desired.

[0013] 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, which is not industrially desirable. A method that does not require extremely low temperatures has been desired. A specific example of this method is shown in the diagram below.

[0014]

[0015] WO2009 / 016841WO2013 / 089002 JP2018-70520A WO2020 / 158925

[0016] Synlett (2015), 1352-1356

[0017] An object of the present invention is to provide an industrially advantageous, economical and environmentally friendly method for producing the nitroso compound of formula (3) and the quinoxaline compound of formula (5).

[0018] A specific object of the present invention is to provide an industrially preferable method for producing the compound of formula (3) and the compound of formula (5), which can solve one or more of the drawbacks or problems in the prior art described above.

[0019] As a result of extensive research, the present inventors have discovered the present invention regarding methods for producing the compounds of formula (3) and formula (5). Based on this finding, the present inventors have completed the present invention.

[0020] That is, the present invention is as follows.

[0021] [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 tertiary alcohol and an alkali metal hydride in a dichloromethane solvent or an ether solvent:

[0022] [I-2] The production method according to [I-1], wherein the amount of alkali metal hydride used is greater than the amount of tertiary alcohol used in terms of equivalents.

[0023] [I-3] The production method according to [I-1] or [I-2], wherein the amount of alkali metal hydride used is 2.0 to 4.0 equivalents per equivalent of the compound of formula (2).

[0024] [I-4] The production method according to [I-1] or [I-2], wherein the amount of alkali metal hydride used is 2.2 to 3.8 equivalents per equivalent of the compound of formula (2).

[0025] [I-5] The production method according to any one of [I-1] to [I-4], wherein the amount of the tertiary alcohol used is 0.1 to 2.0 equivalents relative to 1 equivalent of the compound of formula (2).

[0026] [I-6] The production method according to any one of [I-1] to [I-4], wherein the amount of the tertiary alcohol used is 0.1 to 1.75 equivalents relative to 1 equivalent of the compound of formula (2).

[0027] [I-7] The production method according to any one of [I-1] to [I-4], wherein the amount of the tertiary alcohol used is 0.1 to 1.5 equivalents relative to 1 equivalent of the compound of formula (2).

[0028] [I-8] The production method according to any one of [I-1] to [I-7], wherein the reaction is carried out at 0°C to 70°C.

[0029] [I-9] The production method according to any one of [I-1] to [I-7], wherein the reaction is carried out at 10°C to 60°C.

[0030] [I-10] The production method according to any one of [I-1] to [I-7], wherein the reaction is carried out at 20°C to 50°C.

[0031] [I-11] The production method according to any one of [I-1] to [I-7], wherein the reaction is carried out at 30°C to 40°C.

[0032] [I-12] The production method according to any one of [I-1] to [I-11], wherein the tertiary alcohol is a compound of formula (6): (where R ４ , R ５ and R ６ may be the same or different and are amino(C1-C6)alkyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl; R ４ , R ５ and R ６Two selected from may be bonded to each other to form a ring.

[0033] [I-13] The method according to [I-12], wherein R ４ , R ５ and R ６ may be the same or different and are selected from methyl, ethyl, ethenyl, propyl, and aminomethyl.

[0034] [I-14] The production 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-methylpropan-2-ol.

[0035] [I-15] The production 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.

[0036] [I-16] The production method according to any one of [I-1] to [I-11], wherein the tertiary alcohol is tert-butanol.

[0037] [I-17] The production method according to any one of [I-1] to [I-16], wherein the alkali metal hydride is lithium hydride, sodium hydride, or potassium hydride.

[0038] [I-18] The production method according to any one of [I-1] to [I-16], wherein the alkali metal hydride is sodium hydride.

[0039] [I-19] The production method according to any one of [I-1] to [I-18], which is carried out using a metal tertiary alkoxide.

[0040] [I-20] The production method according to [I-19], wherein the metal tertiary alkoxide is sodium tert-butoxide, potassium tert-butoxide, or lithium tert-butoxide.

[0041] [I-21] The production method according to [I-19], wherein the metal tertiary alkoxide is sodium tert-butoxide or potassium tert-butoxide (preferably sodium tert-butoxide).

[0042] [I-22] The production method according to any one of [I-1] to [I-21], wherein the reaction is carried out in an ether solvent. [I-23] The production 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-butyl methyl ether, or cyclopentyl methyl ether.

[0043] [I-24] The production method according to any one of [I-1] to [I-23], wherein the ether solvent is diethyl ether, dibutyl ether, 2-methyltetrahydrofuran, tert-butyl methyl ether, or cyclopentyl methyl ether. [I-25] The production method according to any one of [I-1] to [I-21], wherein the reaction is carried out in a dichloromethane solvent.

[0044] [II-1] Formula (5): (where R ３ is a hydrogen atom, an alkali metal atom, or a (C1-C4) alkyl, the method comprising the following steps: Step (i) obtaining a compound of formula (3) by the method described in any one of [I-1] to [I-25]: Step (ii) Reacting a compound of formula (3) with a compound of formula (4) to obtain a compound of formula (5): (where R １ , R ２ and R ３ is as defined above.

[0045] [II-2] Formula (5): (where R ３ is a hydrogen atom, an alkali metal atom, or a (C1-C4) alkyl. The compound of formula (3) is produced by the method according to any one of [I-1] to [I-25].

[0046] [II-3] The production method according to [II-1], wherein the compound of formula (4) is dimethyl malonate or diethyl malonate.

[0047] [II-4] The production method according to any one of [II-1] to [II-3], wherein the reaction in step (ii) is carried out at a pH of 8 or higher.

[0048] [II-5] The production method according to any one of [II-1] to [II-3], wherein the reaction in step (ii) is carried out at a pH of 8 to 14.

[0049] [II-6] The production method according to any one of [II-1] to [II-5], wherein the reaction in step (ii) is carried out at a temperature of -25°C to 0°C.

[0050] [II-7] The production method according to any one of [II-1] to [II-5], wherein the reaction in step (ii) is carried out at a temperature of -20°C to -5°C.

[0051] [II-8] The production method according to any one of [II-1] to [II-7], wherein the reaction in step (ii) is carried out using acetic acid.

[0052] [II-9] The production method according to any one of [II-1] to [II-8], wherein the reaction in step (ii) is carried out in a dichloromethane solvent.

[0053] [II-10] The production method according to any one of [II-1] to [II-8], wherein the reaction in step (ii) is carried out in an ether solvent.

[0054] [II-11] The production method according to [II-10], wherein the ether solvent is diethyl ether, dimethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, or cyclopentyl methyl ether.

[0055] [II-12] The production method according to [II-10], wherein the ether solvent is diethyl ether, dibutyl ether, 2-methyltetrahydrofuran, tert-butyl methyl ether, or cyclopentyl methyl ether.

[0056] [II-13] The production method according to any one of [II-1] to [II-12], comprising: R １ and R ２ is methyl or ethyl; R ３ is a hydrogen atom, a lithium atom, a sodium atom, a potassium atom, methyl or ethyl.

[0057] [II-14] The production method according to any one of [II-1] to [II-12], comprising: R １ and R ２ is methyl or ethyl; R ３ is a hydrogen atom or a sodium atom.

[0058] [II-15] The production method according to any one of [II-1] to [II-12], comprising: R １ and R ２ is methyl or ethyl; R ３ A manufacturing method in which the atom is a hydrogen atom.

[0059] The present invention provides a novel method for producing the compounds of formula (3) and (5), which is industrially favorable, economical, and environmentally friendly. The present invention provides a method for producing the compounds of formula (3) and (5), which can solve one or more of the drawbacks or problems in the prior art described above.

[0060] The present invention will be described in detail below.

[0061] 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

[0062] Examples of halogen atoms include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.

[0063] 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.

[0064] (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 has 1 to 4 carbon atoms.

[0065] (C1-C6) alkyl means a straight or branched chain 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, etc. (C1-C4) alkyl means a straight or branched chain alkyl having 1 to 4 carbon atoms. Examples of (C1-C4) alkyl are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl. Amino(C1-C6) alkyl means a straight or branched chain alkyl having 1 to 6 carbon atoms substituted with an amino. Examples of amino(C1-C6) alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, etc. Amino(C1-C4)alkyl means a straight or branched chain alkyl having 1 to 4 carbon atoms substituted with an amino. Examples of amino(C1-C4)alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, etc.

[0066] (C3-C6)cycloalkyl means cycloalkyl having 3 to 6 carbon atoms. Examples of (C3-C6)cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0067] (C2-C6)alkenyl means a straight or branched chain alkenyl having from 2 to 6 carbon atoms. Examples of (C2-C6)alkenyl include, but are not limited to, vinyl (i.e., ethenyl), 1-propenyl, isopropenyl, 2-propenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 1-hexenyl, and the like.

[0068] (C2-C6)alkynyl means a straight or branched chain alkynyl having from 2 to 6 carbon atoms. Examples of (C2-C6)alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, and the like.

[0069] Examples of (C6-C10)aryl are phenyl, 1-naphthyl, and 2-naphthyl.

[0070] (C6-C10)aryl(C1-C4)alkyl means a (C1-C4)alkyl substituted by a (C6-10)aryl (wherein 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, naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, and the like.

[0071] (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.

[0072] Examples of the "ring" in the phrase "two may be bonded to each other to form a ring" include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, etc. The "ring" may be fused to another "ring".

[0073] Herein, the open-ended term "comprise(s)" can be arbitrarily replaced with the limiting phrase "consist(s) of" or "consisting of," respectively. Herein, the phrase "after adding each" can be replaced with the phrase "after adding separately." Herein, the phrases "in dichloromethane solvent" and "in the presence of dichloromethane as a solvent" can be interchangeable. Herein, the phrases "in an ether solvent" and "in the presence of an ether as a solvent" can be interchangeable. Herein, the phrases "in the presence of" and "use(s)" can be interchangeable. The "tertiary alcohol" used in the reaction may be added from the beginning of the reaction, or it may be a tertiary alcohol generated during the reaction from a tertiary alkoxide used as a reagent. For example, when sodium tert-butoxide and sodium hydride are used in this reaction, tert-butanol produced from sodium tert-butoxide in the reaction is included in the "tertiary alcohol".

[0074] The method of the present invention will now be described. (Step (i))

[0075] Step (i) will now be described.

[0076] Step (i) is a step of producing a compound of formula (3) by reacting a compound of formula (1) with a compound of formula (2) in the presence of a tertiary alcohol and an alkali metal hydride in a dichloromethane solvent or an ether solvent.

[0077]

[0078] (Raw material: Compound of formula (1)) The compound of formula (1) is used as the raw material in step (i).

[0079] 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, and the like, in one embodiment, the amount of the compound of formula (1) (nitro compound) used is, for example, 1.0 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, and more preferably 1.0 to 1.2 equivalents, relative to 1 equivalent of the compound of formula (2) (aniline compound). Furthermore, the amount used may 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 the ranges described herein. Therefore, the amount used may be, for example, 1.0 to 1.1 equivalents.

[0080] As used herein, 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 equivalents of compound of formula (1) (nitro compound) per equivalent of compound of formula (2) (aniline compound)" means "0.5 moles of compound of formula (1) (nitro compound) per mole of compound of formula (2) (aniline compound)."

[0081] (Raw Material: Compound of General Formula (2)) As the raw material in step (i), a compound of formula (2) is used.

[0082] From the standpoint of improving economic efficiency and reducing environmental impact, the use of an excess amount of 2-chloronitrobenzene is acceptable. However, while it is preferable to avoid the use of an excess amount of p-anisidine, this is not a limitation. For example, it has been found that p-anisidine is significantly more expensive than 2-chloronitrobenzene. In the method of JP 2018-70520 (Patent Document 3), two or more equivalents of p-anisidine are required as an excess raw material. In fact, the examples of JP 2018-70520 (Patent Document 3) use two to three equivalents of p-anisidine. On the other hand, in the method of the present invention, two or less equivalents of 2-chloronitrobenzene are sufficient as an excess raw material, and satisfactory yields are obtained, as shown in the examples described below.

[0083] (Alkali Metal Hydride in Step (i)) Examples of the alkali metal hydride in step (i) include, but are not limited to, lithium hydride, sodium hydride, potassium hydride, etc., preferably sodium hydride or potassium hydride, more preferably sodium hydride. Since all alkali metal hydrides are inexpensive and easily available bases, the method of the present invention is economical. Carrying out the reaction of step (i) using an alkaline earth metal hydride such as calcium hydride instead of an alkali metal hydride such as sodium hydride is equivalent to the present invention and falls within the scope of the present invention.

[0084] The amount of alkali metal hydride used in step (i) may be any amount as long as the reaction proceeds. However, from the viewpoints of yield, by-product suppression, economic efficiency, and the like, the amount of alkali metal hydride used in step (i) is, for example, usually 2.0 equivalents or more, 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, relative to 1 equivalent of the compound of formula (2) (aniline compound). In another embodiment, the amount of alkali metal hydride used in step (i) may be, for example, 2.0 to 3.5 equivalents, 2.2 to 3.5 equivalents, or 3.2 to 3.5 equivalents, relative to 1 equivalent of the compound of formula (2) (aniline compound). The amount of alkali metal hydride used in step (i) also includes any combination of the lower and upper limits of the ranges described herein. Therefore, the amount of alkali metal hydride used in step (i) may be, for example, 2.2 to 3.2 equivalents.

[0085] As mentioned 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 example. For example, when the base is a monovalent base such as sodium hydride (NaH), "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 equivalents 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)". As another example, when the base is calcium hydride (CaH ２ ), "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)".

[0086] The alkali metal hydride may be added in a predetermined amount to the reaction at once, or may be added in several divided portions or dropwise.

[0087] (Tertiary Alcohol in Step (i)) The tertiary alcohol in step (i) includes, for example, a compound of formula (6).

[0088] (where R ４ , R ５ and R ６ may be the same or different and are amino(C1-C6)alkyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl; R ４ , R ５ and R ６ Two selected from may be bonded to each other to form a ring.)

[0089] Examples of the tertiary alcohol 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, 2-methyl-1 Examples of tertiary alcohols include, but are not limited to, tert-phenyl-2-propanol, 2-methyl-1-phenyl-2-butanol, 1-amino-2-methylpropan-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-methylpropan-2-ol, etc., more preferably tert-butanol, 2-methyl-2-butanol, and 2-methyl-3-buten-2-ol. Tertiary alcohols may be used alone or in combination of two or more in any ratio. "Tert-butanol" is also called "tert-butyl alcohol."

[0090] The amount of the tertiary alcohol used in step (i) may be any amount as long as the reaction proceeds. However, from the viewpoints of yield, suppression of by-products, economic efficiency, etc., in one embodiment, the amount of the tertiary alcohol used in step (i) is, for example, 0.1 equivalents or more, preferably 0.1 to 2.0 equivalents, more preferably 0.1 to 1.75 equivalents, and even more preferably 0.1 to 1.5 equivalents, relative to 1 equivalent of the compound of formula (2) (aniline compound).

[0091] As mentioned 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 tert-butanol per equivalent of the compound of formula (2) (aniline compound)" means "1 mole of tert-butanol per mole of the compound of formula (2) (aniline compound)." For example, "0.5 equivalents of tert-butanol per equivalent of the compound of formula (2) (aniline compound)" means "0.5 moles of tert-butanol per mole of the compound of formula (2) (aniline compound)."

[0092] The tertiary alcohol may be added to the reaction in a predetermined amount all at once, or may be added in several divided portions or dropwise.

[0093] The tertiary alcohol may be generated from a metal tertiary alkoxide during 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.

[0094] When a metal tertiary alkoxide is used, the amount used may be any amount as long as the reaction proceeds. However, from the viewpoints of yield, suppression of by-products, economic efficiency, etc., the amount of the metal tertiary alkoxide used in step (i) is, for example, 0.1 equivalent or more, preferably 0.1 to 2.0 equivalents, more preferably 0.1 to 1.5 equivalents, and even more preferably 0.1 to 1.0 equivalent, relative to 1 equivalent of the compound of formula (2) (aniline compound).

[0095] (Solvent for Step (i)) From the viewpoints of smooth progress of the reaction, yield, suppression of by-products, economic efficiency, etc., the reaction of step (i) is carried out in the presence of a dichloromethane solvent or an ether solvent.

[0096] In step (i), dichloromethane solvent or ether solvent can be used. In one embodiment, dichloromethane solvent can be used. In another embodiment, ether solvent can be used. Examples of the ether solvent include dimethyl ether, diethyl ether, methyl ethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran, preferably, diethyl ether, dibutyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, and 2-methyltetrahydrofuran, more preferably.

[0097] The amount of solvent used in step (i) may be any amount as long as the reaction system can be sufficiently stirred and the effects of the present invention are exhibited. From the viewpoints of yield, by-product suppression, economic efficiency, etc., in one embodiment, the lower limit of the amount of solvent used is, for example, more than 0 L (zero liter), 0.1 L or more, 0.2 L or more, preferably 0.3 L or more, more preferably 0.4 L or more, 0.5 L or more, or 0.6 L or more per mole of the compound of formula (2) (aniline compound), but is not limited thereto. From the same viewpoints as above, in one embodiment, the upper limit of the amount of solvent used is, for example, 10 L (liter) or less, 5 L or less, preferably 2 L or less, 1 L or less, 1.5 L or less, 1.2 L or less, more preferably 0.8 L or less, or 0.7 L or less per mole of the compound of formula (2) (aniline compound), but is 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, combinations of upper and lower limits are as follows, but are not limited to these: From the same viewpoint as above, in one embodiment, the amount is 10 L (liters) or less, preferably 0.1 to 10 L, more preferably 0.1 to 5 L, even more preferably 0.2 to 5 L, even more preferably 0.2 to 2 L, and even more preferably 0.2 to 1 L, relative to 1 mole of the compound of formula (2) (aniline compound). Performing the reaction of step (i) using a solvent other than dichloromethane solvent or ether solvent in addition to dichloromethane solvent or ether solvent (i.e., a mixed solvent) is equivalent to the present invention and falls within the scope of the present invention.

[0098] (Reaction Temperature of Step (i)) From the viewpoints of yield, by-product suppression, economic efficiency, and the like, 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 the ranges described herein. Thus, the reaction temperature of step (i) may be, for example, 20°C to 40°C. In the method of the present invention, low temperatures such as -70°C to -30°C are not required, which is industrially preferable and environmentally friendly.

[0099] (Reaction Time of Step (i)) The reaction time of step (i) is not particularly limited. However, 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 even more preferably 1 to 24 hours.

[0100] The compound of formula (3) can be used as a raw material in step (ii). As long as the reaction in step (ii) proceeds, the compound of formula (3) may be isolated and used in the next step, further purified and used in the next step, or may be used in the next step without isolation. In addition, after the reaction in step (i), for example, hydrochloric acid or acetic acid may be used as a post-treatment for step (i). Furthermore, after the reaction in step (i), an inert gas such as nitrogen may be blown into the solution to remove by-products (as a post-treatment for step (i)). The removal of by-products may be carried out under reduced pressure. An example of a by-product is hydrogen.

[0101] (Step (ii))

[0102] Step (ii) will now be described.

[0103] Step (ii) is a step of reacting a compound of formula (3) with a compound of formula (4) to produce a compound of formula (5).

[0104] (where R １ and R ２ are each independently (C1-C4) alkyl; R ３ is a hydrogen atom, an alkali metal atom, or a (C1-C4) alkyl.

[0105] (Raw Material: Malonic Acid Diester Compound) The raw material used in step (ii) is a compound of formula (4), i.e., a malonic acid diester compound. The compound of formula (4) is a known compound or can be produced from a known compound by a known method.

[0106] Examples of the compound of formula (4) include, but are not limited to, dimethyl malonate, diethyl malonate, dipropyl malonate, diisopropyl malonate, dibutyl malonate, diisobutyl malonate, di-t-butyl malonate, etc., preferably dimethyl malonate and diethyl malonate.

[0107] The amount of the compound of formula (4) used may be any amount as long as the reaction proceeds. The amount of the compound of formula (4) used can be appropriately adjusted by those skilled in the art. However, from the viewpoints of yield, suppression of by-products, economic efficiency, etc., the amount is 1.0 mol to 3.0 mol, preferably 1.0 mol to 2.0 mol, per 1 mol of the compound of formula (3) (anisidine compound).

[0108] (Conditions for Step (ii)) The reaction in step (ii) is preferably carried out under basic conditions. In one embodiment, the reaction in step (ii) is generally carried out at pH 9 or higher, preferably pH 9 to pH 14, more preferably pH 9 to pH 12. In another embodiment, the reaction 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 may 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 may be any amount that allows the desired pH to be obtained. Therefore, the amount of acid used can be appropriately adjusted by those skilled in the art. In addition, the reaction in step (ii) may be carried out in the presence of a base. The base used in step (ii) may be any base as long as the reaction proceeds.

[0109] In step (ii), the reaction may be carried out using the remaining sodium hydride used in the reaction in step (i) as the base (the reaction may be carried out under basic conditions derived from the remaining sodium hydride), or a new base may be added. Examples of the new base added 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 hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkaline earth metal hydrogen carbonates (e.g., calcium hydrogen carbonate, etc.), Examples of the base used in step (ii) include organic bases (e.g., triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine, and N,N-dimethyl-4-aminopyridine). Examples of the base used in step (ii) also include alkali metal carboxylates (e.g., sodium acetate and potassium acetate). From the viewpoints of yield, suppression of by-products, economic efficiency, and the like, preferred specific examples of the base in step (ii) include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, triethylamine, and sodium acetate.

[0110] The base in step (ii) may be used alone or in any combination of two or more kinds in any ratio. The form of the base in step (ii) may be any form as long as the reaction proceeds. The form of the base in step (ii) can be appropriately selected by a person skilled in the art.

[0111] The amount of the base used in step (ii) may be any amount as long as the reaction proceeds. However, from the viewpoints of yield, suppression of by-products, economic efficiency, etc., the amount of the base used in step (ii) is, for example, usually 1 equivalent or more, preferably 1 to 20 equivalents, more preferably 1 to 15 equivalents, and even more preferably 1 to 10 equivalents, relative to 1 equivalent of the compound of formula (3) (anisidine compound). However, the amount of the base used in step (ii) can be appropriately adjusted by those skilled in the art.

[0112] (Water in Step (ii)) The reaction in step (ii) can be carried out in the presence or absence of water. However, the reaction in step (ii) is preferably carried out in the absence of water.

[0113] (Acetic Acid in Step (ii)) From the viewpoint of smooth progress of the reaction, etc., 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, preferably 0.5 mol to 3.0 mol, more preferably 1.0 mol to 2.5 mol per mol of the compound of Formula (3) (anisidine compound) in Step (ii).

[0114] (Solvent for Step (ii)) From the viewpoint of smooth progress of the reaction, the reaction for Step (ii) is preferably carried out in the presence of a solvent. The solvent and the amount used for Step (ii) may be the same as those for Step (i). In addition, water may be present, but the absence of water is preferred.

[0115] (Reaction Temperature in Step (ii)) The reaction temperature in step (ii) is not particularly limited. However, from the viewpoints of yield, suppression of by-products, economic efficiency, etc., the reaction temperature is, for example, −20° C. to 0° C. or lower, preferably −20° C. to less than 0° C., more preferably −20° C. to −5° C., even more preferably −20° C. to −8° C., and still more preferably −20° C. to −10° C.

[0116] (Reaction Time in Step (ii)) The reaction time in step (ii) is not particularly limited. From the viewpoints of yield, suppression of by-products, economic efficiency, etc., the reaction time is, for example, 0.1 to 48 hours, preferably 0.1 to 24 hours, and more preferably 0.5 to 15 hours.

[0117] (Post-treatment and purification) Formation of a carboxylate salt with a base or a salt and / or formation of a free carboxylic acid with an acid can be performed. For example, operations such as extraction of the product with water, extraction of the product with an organic solvent, crystallization with an acid, and crystallization with a base may be performed. For example, an aqueous solution containing the target sodium carboxylate may be treated with an acid to precipitate crystals of the target free carboxylic acid. The target sodium carboxylate may be extracted with water. An organic solvent solution containing the target free carboxylic acid may be treated with a base to precipitate crystals of the target sodium carboxylate. An aqueous solution containing the target sodium carboxylate may be treated with a potassium salt, lithium salt, or calcium salt to precipitate crystals of the potassium salt, lithium salt, or calcium salt of the carboxylic acid. The target free carboxylic acid may be extracted with an organic solvent. Furthermore, optionally, the target sodium carboxylate salt or the target free carboxylic acid, or an aqueous or organic solvent solution thereof, may be washed with appropriately selected water or an organic solvent, or any mixture thereof in any ratio. Furthermore, optionally, solvent recovery may be performed. For example, the solvent used in the reaction may be recovered, or the solvent used in post-treatment and purification may be recovered.

[0118] (Product of step (ii): Compound of formula (5), i.e., quinoxaline compound)

[0119] Specific examples of the compound of formula (5) obtained in step (ii) include, but are not limited to, 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid and its potassium salt, sodium salt, lithium salt, methyl ester, and ethyl ester. 5-Chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid is the same compound as 8-chloro-4-(4-methoxyphenyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylic acid according to the IUPAC nomenclature.

[0120] 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.

[0121] In this specification, room temperature is between 10°C and 35°C.

[0122] The following instruments can be used to measure the properties and yields in 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. pH measurement: A glass electrode hydrogen ion concentration indicator, model HM-20P or HM-30P (manufactured by DKK-TOA Corporation).

[0123] Step (i) (HPLC analysis: high performance liquid chromatography analysis) (HPLC analysis conditions) Instrument: Shimadzu Corporation i-series or equivalent Column: CERI (Chemicals Evaluation and Research Institute), L-column ODS (250*4.6 mm), particle size 5 μm Eluent: acetonitrile, 0.085 wt % phosphoric acid aqueous solution Gradient program

[0124] Flow rate: 1.0 mL / min Detection: UV 222 nm Column temperature: 40°C Injection volume: 5 μL

[0125] Step (ii) (HPLC analysis: high performance liquid chromatography analysis) (HPLC analysis conditions) Instrument: Shimadzu Corporation i-series or equivalent Column: CERI (Chemicals Evaluation and Research Institute), L-column ODS (250*4.6 mm), particle size 5 μm Eluent: methanol, 0.085 wt % phosphoric acid aqueous solution Gradient program

[0126] Flow rate: 1.0 mL / min Detection: UV 254 nm Column temperature: 40°C Injection volume: 5 μL

[0127] "OCNB" means "2-chloronitrobenzene," as shown below.

[0128] "pA" means "p-anisidine," as shown below.

[0129] "p-NO" means "3-chloro-N-(4-methoxyphenyl)-4-nitrosoaniline," as shown below.

[0130] "p-NO2" means "3-chloro-N-(4-methoxyphenyl)-4-nitroaniline" as shown below.

[0131] "MNA" means "N-(4-methoxyphenyl)-2-nitroaniline," as shown below.

[0132] "CMNA" means "3-chloro-N-(4-methoxyphenyl)-2-nitroaniline," as shown below.

[0133] "DMM" means "dimethyl malonate," as shown below.

[0134] "DEM" means "diethyl malonate," as shown below.

[0135] "CAQ" means "5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid" as shown below.

[0136] Regarding solvent abbreviations, 1,2-DCE means 1,2-dichloroethane, 1,2-DME means 1,2-dimethoxyethane, DMF means N,N-dimethylformamide, DMAc means N,N-dimethylacetamide, NMP means N-methylpyrrolidone, DMI means 1,3-dimethyl-2-imidazolidinone, and DMSO means dimethyl sulfoxide.

[0137] Example 1 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0138] Under a nitrogen atmosphere, sodium hydride (purity: 65.8%, dispersion in liquid paraffin, 583 mg, 16.0 mmol, 320 mol%) was suspended in dichloromethane (4.64 mL, 0.29 L / mol). A solution of tert-butanol (371 mg, 5.00 mmol, 100 mol%) in dichloromethane (0.16 mL, 0.03 L / mol) was added dropwise to the suspension at an internal temperature of 40°C over 30 minutes, followed by stirring at the same temperature for 30 minutes. The internal temperature was cooled to 30°C, and a solution of 2-chloronitrobenzene (827 mg, 5.25 mmol, 105 mol%) and p-anisidine (616 mg, 5.00 mmol, 100 mol%) 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 desired intermediate, 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline, was obtained.

[0139] HPLC analysis (area percentage; 222 nm) of the reaction mixture showed that the main components in the reaction mixture excluding the raw material (OCNB) were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 67%, p-anisidine: 0.1%, p-NO: 1.0%, p-NO2: 1.1%, MNA: 22%, CMNA: 3.4%.

[0140] The reaction mixture was analyzed by the HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 62.5% (yield).

[0141] Example 2 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0142] Under a nitrogen atmosphere, sodium hydride (purity: 65.7%, dispersed in liquid paraffin, 1.17 g, 32.0 mmol, 320 mol%) was suspended in dichloromethane (11.5 g, 0.27 L / mol). A solution of tert-butanol (0.74 g, 10.0 mmol, 100 mol%) in dichloromethane (0.42 g, 0.01 L / 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 cooled to 30°C, and a solution of 2-chloronitrobenzene (1.65 g, 10.5 mmol, 105 mol%) and p-anisidine (1.23 g, 10.0 mmol, 100 mol%) 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 desired intermediate, 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline, was obtained.

[0143] HPLC analysis (area percentage; 222 nm) of the reaction mixture showed that the main components in the reaction mixture excluding the raw material (OCNB) were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 63%, p-anisidine: 2.7%, p-NO: 0.9%, p-NO2: 1.8%, MNA: 21%, CMNA: 4.0%.

[0144] Examples 3 to 6 Reactions and analyses were carried out in the same manner as in Example 2, except that the tertiary alcohol was changed as shown in Table 3. 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.

[0145]

[0146] Example 7 Preparation of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0147] Under a nitrogen stream, sodium hydride (purity: 65.9%, dispersed in liquid paraffin, 11.65 g, 320 mmol, 320 mol%) was suspended in dichloromethane (123.15 g, 0.38 L / mol). A solution of tert-butanol (7.41 g, 100 mmol, 100 mol%) in dichloromethane (4.25 g, 0.03 L / mol) was added dropwise to the suspension at an internal temperature of 35-40°C over 3 hours, followed by stirring at the same temperature for 1 hour. The internal temperature was cooled to 30°C, and a solution of 2-chloronitrobenzene (16.54 g, 105.0 mmol, 105 mol%) and p-anisidine (12.32 g, 100.0 mmol, 100 mol%) in dichloromethane (25.48 g, 0.19 L / mol (based on p-anisidine)) 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. HPLC analysis (area percentage; 222 nm) of the reaction mixture revealed that the main components in the reaction mixture, excluding the starting material (OCNB), were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 66.7%.

[0148] The reaction mixture was analyzed by the HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 62.0%.

[0149] After the internal temperature was cooled to 0°C to 10°C, acetic acid (10.51 g, 175 mol% (relative to the anisidine compound)) was added dropwise over 1 hour. After the internal temperature was cooled to -20 to -5°C, diethyl malonate (16.02 g, 100 mmol, 100 mol% (relative to the anisidine compound)) was added dropwise over 2 hours. The mixture was stirred at the same temperature range for 12 hours to obtain a reaction mixture containing the sodium salt of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid. Water (48.78 mL) was added to another reaction vessel, and the internal temperature was cooled to 0°C to 10°C. The previously reacted reaction mixture and 35% hydrochloric acid (31.25 g) were added dropwise simultaneously over 70 minutes to adjust the pH to 1.0, and then the remaining 35% hydrochloric acid was completely added dropwise. After stirring at the same temperature for 1 hour, the crystals were filtered. The crystals were washed with water (27.19 g). The obtained crystals were dried to obtain the target product, 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid (18.30 g, yield 51.6% (based on p-anisidine)). In the method of this example, the target product can be produced from 2-chloronitrobenzene in two steps. Moreover, the target product can be obtained in high yield.

[0150] Example 8 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0151] Under a nitrogen stream, sodium hydride (purity: 65.0%, dispersion in liquid paraffin, 8.12 g, 220 mmol, 220 mol%) and NaOtBu (sodium tert-butoxide, purity: 99.0%, 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-anisidine (12.32 g, 100.0 mmol, 100 mol%) in dichloromethane (67.94 g, 0.12 L / mol (based on p-anisidine)) 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. HPLC analysis (area percentage; 222 nm) of the reaction mixture revealed that the main components in the reaction mixture, excluding the starting material (OCNB), were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 65.1%. The reaction mixture was analyzed using the HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 62.0%. When the present invention was considered after its completion, it was understood that in this example, tert-butanol produced from sodium tert-butoxide during the reaction functions as the "tertiary alcohol." Therefore, the method illustrated in this example also falls within the scope of the present invention as defined by the appended claims.

[0152] Example 9 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0153] Under a nitrogen stream, sodium hydride (purity: 65.9%, dispersed in liquid paraffin, 11.65 g, 320 mmol, 320 mol%) was suspended in dichloromethane (123.15 g, 0.38 L / mol). A solution of tert-butanol (7.41 g, 100 mmol, 100 mol%) in dichloromethane (4.25 g, 0.03 L / mol) was added dropwise to the suspension at an internal temperature of 35-40°C over 3 hours, followed by stirring at the same temperature for 1 hour. The internal temperature was cooled to 30°C, and a solution of 2-chloronitrobenzene (16.54 g, 105.0 mmol, 105 mol%) and p-anisidine (12.32 g, 100.0 mmol, 100 mol%) in dichloromethane (25.48 g, 0.19 L / mol (based on p-anisidine)) was added dropwise over 3 hours. The mixture was stirred at the same temperature for 11 hours to obtain a reaction mixture containing the target intermediate, 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline.

[0154] The reaction mixture was analyzed by the HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 62.5% (yield).

[0155] Examples 10 to 16 Reactions and analyses were carried out in the same manner as in Example 9, except that sodium hydride and t-BuOH were changed as shown in Table 4. The results are shown in Table 4. In addition, the results of Example 1 are also summarized in Table 4.

[0156]

[0157] Example 17 Preparation of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0158] Under a nitrogen stream, sodium hydride (purity: 65.9%, dispersed in liquid paraffin, 11.65 g, 320 mmol, 320 mol%) was suspended in dichloromethane (123.15 g, 0.38 L / mol). A solution of tert-butanol (7.41 g, 100 mmol, 100 mol%) in dichloromethane (4.25 g, 0.03 L / mol) was added dropwise to the suspension at an internal temperature of 35-40°C over 3 hours, followed by stirring at the same temperature for 1 hour. The internal temperature was cooled to 30°C, and a solution of 2-chloronitrobenzene (16.54 g, 105.0 mmol, 105 mol%) and p-anisidine (12.32 g, 100.0 mmol, 100 mol%) in dichloromethane (25.48 g, 0.19 L / mol (based on p-anisidine)) 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. After the internal temperature was cooled to 0°C to 10°C, acetic acid (10.51 g, 175 mol% (relative to the anisidine compound)) was added dropwise over 1 hour. After the internal temperature was cooled to -20 to -5°C, diethyl malonate (16.02 g, 100 mmol, 100 mol% (relative to the anisidine compound)) was added dropwise over 2 hours. The mixture was stirred at the same temperature for 12 hours, yielding a reaction mixture containing the sodium salt of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid.

[0159] The reaction mixture was analyzed by the HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid: 59.1% (yield). Since phosphoric acid is used in the HPLC analysis, it is detected as 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid.

[0160] Examples 18 to 20 Reactions and analyses were carried out in the same manner as in Example 17, except that the reaction temperature and the amount of acetic acid used in step (ii) were changed as shown in Table 5. The results are shown in Table 5. In addition, the results of Example 17 are also summarized in Table 5.

[0161]

[0162] Example 21 Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0163] Under a nitrogen atmosphere, sodium hydride (purity: 65.8%, dispersed in liquid paraffin, 583 mg, 16.0 mmol, 320 mol%) was suspended in diethyl ether (4.64 mL, 0.29 L / mol). A solution of tert-butanol (371 mg, 5.00 mmol, 100 mol%) in diethyl ether (0.16 mL, 0.01 L / mol) was added dropwise to the suspension at an internal temperature of 40°C over 30 minutes, followed by stirring at the same temperature for 30 minutes. The internal temperature was cooled to 30°C, and a solution of 2-chloronitrobenzene (827 mg, 5.25 mmol, 105 mol%) and p-anisidine (616 mg, 5.00 mmol, 100 mol%) 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 desired intermediate, 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline, was obtained.

[0164] The reaction mixture was analyzed by the HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 63.5% (yield).

[0165] Examples 22 to 25 Reactions and analyses were carried out in the same manner as in Example 21, except that the ether solvent was changed as shown in Table 6. The results are shown in Table 6. In addition, the results of Example 21 are also summarized in Table 6.

[0166]

[0167] Comparative Example 1: Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0168] Under a nitrogen atmosphere, sodium hydride (purity: 65.8%, dispersion in liquid paraffin, 583 mg, 16.0 mmol, 320 mol%) was suspended in toluene (4.64 mL, 0.29 L / mol). A toluene (0.16 mL, 0.01 L / mol) solution containing tert-butanol (371 mg, 5.00 mmol, 100 mol%) was added dropwise to the suspension at an internal temperature of 40°C over 30 minutes, followed by stirring at the same temperature for 30 minutes. The internal temperature was cooled to 30°C, and a solution of 2-chloronitrobenzene (827 mg, 5.25 mmol, 105 mol%) and p-anisidine (616 mg, 5.00 mmol, 100 mol%) 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. The reaction mixture was analyzed by the HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline: 52.4% (yield).

[0169] Comparative Examples 2 to 14 Reactions and analyses were carried out in the same manner as in Comparative Example 1, except that the solvent was changed as shown in Table 7. The results are shown in Table 7. In addition, the results of Comparative Example 1 are also summarized in Table 4. "Target Comp." and "Target Product" in the table are 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline. Comparative Examples 1 to 14 were carried out under the same reaction conditions and operating procedures as in Example 1, except that the solvent was changed.

[0170]

[0171] As shown in Comparative Examples 1 to 14, the methods using these solvents result in a yield that is 10% or more lower than the case where dichloromethane is used as the solvent in Example 1. It is clear that the methods of the Comparative Examples are industrially unfavorable and uneconomical.

[0172] Comparative Example 15: Preparation of 3-chloro-N-(4-methoxyphenyl)-2-nitrosoaniline

[0173] Under a nitrogen atmosphere, sodium hydride (purity: 65.8%, dispersed in liquid paraffin, 583 mg, 16.0 mmol, 320 mol%) was suspended in dichloromethane (4.64 mL, 0.29 L / mol). At an internal temperature of 30°C, a solution of 2-chloronitrobenzene (827 mg, 5.25 mmol, 105 mol%) and p-anisidine (616 mg, 5.00 mmol, 100 mol%) in dichloromethane (0.96 mL, 0.06 L / mol) was added dropwise over 2 hours. 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.

[0174] Comparative Examples 16 to 17 Reactions and analyses were carried out in the same manner as in Comparative Example 15, except that t-BuOH was changed as shown in Table 8. The results are shown in Table 8. In addition, the results of Comparative Example 15 are also summarized in Table 8.

[0175]

[0176] Comparative Example 18 Preparation of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid

[0177] Under a nitrogen stream, sodium hydride (purity: 65.9%, dispersed in liquid paraffin, 11.65 g, 320 mmol, 320 mol%) was suspended in dichloromethane (123.15 g, 0.38 L / mol). A solution of tert-butanol (7.41 g, 100 mmol, 100 mol%) in dichloromethane (4.25 g, 0.03 L / mol) was added dropwise to the suspension at an internal temperature of 35-40°C over 3 hours, followed by stirring at the same temperature for 1 hour. The internal temperature was cooled to 30°C, and a solution of 2-chloronitrobenzene (16.54 g, 105.0 mmol, 105 mol%) and p-anisidine (12.32 g, 100.0 mmol, 100 mol%) in dichloromethane (25.48 g, 0.19 L / mol (based on p-anisidine)) 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. After the internal temperature was cooled to 0°C to 10°C, acetic acid (10.51 g, 175 mol% (relative to the anisidine compound)) was added dropwise over 1 hour. After the internal temperature was cooled to -25°C, diethyl malonate (16.02 g, 100 mmol, 100 mol% (relative to the anisidine compound)) was added dropwise over 2 hours. The mixture was stirred at the same temperature for 12 hours, yielding a reaction mixture containing the sodium salt of 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid.

[0178] The reaction mixture was analyzed by the HPLC absolute calibration curve method to determine the yield, etc. The analytical results were as follows: 5-chloro-1-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid: 29.4% (yield).

[0179] According to the present invention, there is provided an industrially preferred method for producing the compound of formula (3) and the compound of formula (5). The compound of formula (3) and the compound of formula (5) that can be produced by the method of the present invention are useful as agricultural chemical intermediates and pharmaceutical intermediates, particularly as herbicide intermediates. 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 utility value. In short, the present invention has high industrial applicability.

Claims

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 tertiary alcohol and an alkali metal hydride in a dichloromethane or ether solvent:

2. The method according to claim 1, wherein the amount of alkali metal hydride used is 2.0 to 4.0 equivalents per equivalent of the compound of formula (2).

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

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

5. The method according to claim 1 or 2, wherein the tertiary alcohol is a compound of formula (6): (where R ４ , R ５ and R ６ may be the same or different and are amino(C1-C6)alkyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, or (C6-C10)aryl(C1-C4)alkyl; R ４ , R ５ and R ６ Two selected from may be bonded to each other to form a ring.

6. The production 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 method according to claim 1 or 2, wherein the reaction is carried out at a temperature of 20°C to 50°C.

8. The method according to claim 1 or 2, wherein the reaction is carried out at 30°C to 40°C.

9. The process according to claim 1 or 2, wherein the ether solvent is diethyl ether, dibutyl ether, 2-methyltetrahydrofuran, tert-butyl methyl ether or cyclopentyl methyl ether.

10. Formula (5): (where R ３ is a hydrogen atom, an alkali metal atom, or a (C1-C4) alkyl, the method comprising the steps of: Step (i) obtaining a compound of formula (3) by the method of claim 1 or 2: Step (ii) Reacting a compound of formula (3) with a compound of formula (4) to obtain a compound of formula (5): (where R １ , R ２ and R ３ is as defined above.

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

12. The method according to claim 10, wherein the reaction in step (ii) is carried out at a temperature of -20°C to 0°C.

13. The method according to claim 10, wherein the reaction in step (ii) is carried out at a temperature of -20°C to -5°C.

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

15. The manufacturing method according to claim 10, comprising: R １ and R ２ is methyl or ethyl; R ３ A manufacturing method in which the atom is a hydrogen atom.

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