Process for producing n-(hetero)aryl (meth)acrylamide compounds

Abstract

A method for producing an N-(hetero)aryl(meth)acrylamide compound, which includes a step of amidating a compound represented by the following general formula (1) with a compound represented by the following general formula (2) at a temperature exceeding 120°C to obtain a compound represented by the following general formula (3). R 1 represents a hydrogen atom or an aliphatic group, R 2 and R 4 represents a hydrogen atom, a chain aliphatic group, an aliphatic hydrocarbon ring group, an aryl group or a heterocyclic group, Ar represents an aromatic ring, R 3 represents an electron-withdrawing group, m represents an integer of 1 or more, and n represents an integer of 0 or more. R 4 is not an α-hydroxybenzyl group.

Description

TECHNICAL FIELD

[0001] The present application relates to a production method of N-(hetero)arylmeth)acrylamide compounds. BACKGROUND

[0002] N-(hetero)arylmeth)acrylamide compounds are used in various fields as high-functional polymers. For example, 4-sulfamoylphenyl methacrylamide is used in medical applications for drug delivery systems, and also used in lithographic printing plates to improve solvent resistance, alkali resistance, and the like.

[0003] N-(hetero)arylmeth)acrylamide compounds can be obtained by reacting a (meth)acrylic acid compound with an N-(hetero)aryl amine compound (amidation reaction). As for the amidation reaction itself, various methods have been proposed, for example, the symmetric anhydride method, the mixed anhydride method, the acid chloride method, the condensing agent method, and amine activation, and the like.

[0004] In the symmetric anhydride method, a (meth)acrylic acid is activated by converting it into an anhydride, and the (meth)acrylic anhydride is reacted with an N-(hetero)aryl amine compound to obtain an N-(hetero)arylmeth)acrylamide compound (for example, Patent Literature 1). In the (meth)acrylic anhydride used in this reaction, one of the two (meth)acrylic acid components constituting the anhydride becomes a (meth)acrylic acid as a by-product. Therefore, a large amount of the by-produced (meth)acrylic acid needs to be separated and removed, and the environmental burden is large. Also, the (meth)acrylic anhydride is a relatively expensive reagent, and there is a limitation in terms of cost.

[0005] In the mixed anhydride method, a (meth)acrylic acid is reacted with, for example, a chloroformate to prepare a mixed anhydride as an activated body of the (meth)acrylic acid. By reacting the mixed anhydride with an N-(hetero)aryl amine compound, an N-arylmeth)acrylamide compound can be obtained (for example, Patent Literature 2). In this mixed anhydride method, the above-mentioned chloroformate becomes a by-product. Therefore, after the reaction, a large amount of the by-product needs to be separated and removed, and it is still an environmentally burdensome method.

[0006] In the acid chloride method, a (meth)acryloyl chloride as an activated body of the (meth)acrylic acid is reacted with an N-(hetero)aryl amine compound to obtain an N-(hetero)arylmeth)acrylamide compound (for example, Patent Literature 3). The (meth)acryloyl chloride is expensive, and the acid chloride method is limited in terms of cost.

[0007] In the condensing agent method, the (meth)acrylic acid is activated by a condensing agent, and reacted with the N-(hetero)arylamide compound to obtain the N-(hetero)aryl(meth)acrylamide compound (for example, Patent Document 4). The condensing agent is generally an expensive reagent, and after the reaction, it is necessary to separate and remove the residue of the condensing agent. As a result, the operation becomes complicated, and the environmental burden becomes large.

[0008] In the amine activation method, the amino group of the N-(hetero)arylamide compound is activated by using an organic metal reagent such as n-butyllithium to generate an anion, and then reacted with the (meth)acrylic acid compound to obtain the N-(hetero)aryl(meth)acrylamide compound. The organic metal reagent is mostly a hydrous substance and can catch fire, and the reaction needs to be performed at an ultralow temperature. For this reason, it is difficult to scale up to an industrial production level.

[0009] Further, in the reaction of the (meth)acrylic acid compound and the N-(hetero)arylamide compound, in addition to the above problems, the following problem occurs. That is, there is a problem that in addition to the target N-(hetero)aryl(meth)acrylamide compound (1,2-adduct), a large amount of a by-product (1,4-adduct) generated by the reaction of the N-(hetero)arylamide compound at the double bond site of the (meth)acrylic acid compound is generated. In order to solve this problem, it is necessary to improve the regioselectivity of the reaction of the (meth)acrylic acid compound and the N-(hetero)arylamide compound. In order to cope with this problem, in Patent Document 5, it is proposed to perform the reaction in the presence of a catalytic amount of a dialkyltin oxide.

[0010] Further, in Patent Document 6, it is also proposed to synthesize the N-aryl(meth)acrylamide compound by activating the (meth)acrylate with a Lewis acid.

[0011] Prior Art Documents

[0012] Patent Documents

[0013] Patent Document 1: Specification of Chinese Patent No. 103467346

[0014] Patent Document 2: Japanese Patent Application Laid-Open No. 2008-151929

[0015] Patent Document 3: Japanese Patent Publication No. 49-010499

[0016] Patent Document 4: Specification of U.S. Patent Application Publication No. 2005 / 0107341

[0017] Patent Document 5: Japanese Patent Application Laid-Open No. 54-138513

[0018] Patent Document 6: Specification of Chinese Patent No. 109608367 SUMMARY

[0019] Technical Problem to be Solved by the Invention

[0020] As described above, in order to efficiently obtain an N-(hetero)arylmeth)acrylamide compound by the reaction of a (meth)acrylic acid compound and an N-(hetero)arylamine compound, it is important to suppress the generation of a 1,4-adduct as a by-product. As a result of the research by the present inventors, it has been found that if the N-(hetero)arylamine compound is a structure having an electron-withdrawing group as a substituent to the ring-forming atom of an aromatic ring (for example, sulfanilamide), the problem of the regioselectivity of the reaction becomes more apparent, and a 1,4-adduct is generated in an amount far exceeding that of the target 1,2-adduct. As an N-(hetero)arylmeth)acrylamide compound that can be obtained from such an N-(hetero)arylamine compound having an electron-withdrawing group, there is known an industrially important compound such as 4-sulfamoylphenyl methacrylamide described above.

[0021] The present application has been made in view of the above problem, and provides a method for producing an N-(hetero)arylmeth)acrylamide compound, which is capable of sufficiently suppressing the generation of a 1,4-adduct as a by-product even when an N-(hetero)arylamine compound having an electron-withdrawing group as a substituent to the ring-forming atom of an aromatic ring is used as a raw material in the production of an N-(hetero)arylmeth)acrylamide compound including a step of reacting a (meth)acrylic acid compound and an N-(hetero)arylamine compound, thereby obtaining a target N-(hetero)arylmeth)acrylamide compound with high selectivity, and appropriately suppressing the cost and environmental burden caused by the raw materials or reagents.

[0022] Means for Solving the Technical Problem

[0023] As a result of the intensive research by the present inventors in view of the above problem, it has been found that, in the production of an N-(hetero)arylmeth)acrylamide compound by reacting a (meth)acrylic acid compound and an N-(hetero)arylamine compound having the above-described electron-withdrawing group, the above problem can be solved by controlling the reaction temperature to be in a high-temperature region exceeding 120°C. That is, in order to improve the regioselectivity of the reaction in a chemical reaction, the reaction temperature is usually controlled to be in a low-temperature region, but it has been found that by controlling the reaction temperature to be in a high temperature exceeding 120°C, the regioselectivity of the reaction can be significantly improved even without using the above-described expensive activated body as a raw material, and without using a special reagent such as a condensing agent. The present application has been completed based on these insights and further repeated research.

[0024] That is, the problem of the present application is solved by the following method.

[0025] (1)

[0026] A method for producing an N-(hetero)aryl(meth)acrylamide compound, comprising a step of amidating a compound represented by the following general formula (1) with a compound represented by the following general formula (2) at a temperature exceeding 120°C to obtain a compound represented by the following general formula (3).

[0027] [Chemical Formula 1]

[0028]

[0029] [Chemical Formula 2]

[0030]

[0031] In each formula, R 1 represents a hydrogen atom or an aliphatic group. R 2 represents a hydrogen atom, a chain aliphatic group, an aliphatic hydrocarbon ring group, an aryl group or a heterocyclic group. Ar represents an aromatic ring. R 3 represents an electron-withdrawing group, and m is an integer of 1 or more. R 4 represents a chain aliphatic group, an aliphatic hydrocarbon ring group, an aryl group or a heterocyclic group, and n is an integer of 0 or more. Among them, R 4 is not an α-hydroxybenzyl group. The maximum value of m+n is the maximum value of the number of substituents that the ring-forming atom of Ar can have.

[0032] 〔2〕

[0033] The production method according to 〔1〕, wherein

[0034] The amidation reaction is performed in the presence of at least one reaction catalyst.

[0035] 〔3〕

[0036] The production method according to 〔2〕, wherein

[0037] The reaction catalyst is at least one of a Lewis acid, a Brønsted acid, a metal oxide and a phosphorus oxide compound.

[0038] 〔4〕

[0039] The production method according to 〔2〕, wherein

[0040] As the reaction catalyst, at least one of a Lewis acid, a Brønsted acid and a phosphorus oxide compound is used.

[0041] 〔5〕

[0042] The production method according to any one of 〔1〕 to 〔4〕, wherein

[0043] The reaction temperature of the amidation reaction is set to 130°C or higher.

[0044] 〔6〕

[0045] The production method according to [5], wherein

[0046] The reaction temperature of the amidation reaction is set to 140°C or higher.

[0047] 〔7〕

[0048] The production method according to any one of [1] to [6], wherein

[0049] The aforementioned Ar represents a benzene ring.

[0050] 〔8〕

[0051] The production method according to [7], wherein

[0052] The aforementioned R 1 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0053] 〔9〕

[0054] The production method according to [7] or [8], wherein

[0055] The aforementioned m is an integer of 1 to 3, and the aforementioned n is an integer of 0 to 4.

[0056] 〔10〕

[0057] The production method according to any one of [1] to [9], wherein

[0058] The reaction temperature of the amidation reaction is controlled by microwave irradiation.

[0059] 〔11〕

[0060] The production method according to any one of [1] to

[10] , wherein

[0061] The amidation reaction is performed as a flow-type reaction.

[0062] In the present invention or the present specification, a numerical range indicated using “~” means a range including the lower limit value and the upper limit value indicated before and after “~” as the lower limit value and the upper limit value, respectively.

[0063] In the present invention or the present specification, for a substituent not indicated as substituted or unsubstituted, it means that the group can have any substituent within a range not impairing the desired effect. The same applies to a compound not indicated as substituted or unsubstituted.

[0064] In this invention or specification, when referred to simply as a "substituent," groups selected from the substituent group Z described below are preferably applicable. Furthermore, when only the names of each group are described (for example, when only "alkyl" is described), as a preferred approach, a preferred range and specific examples of the groups corresponding to the substituent group Z (alkyl in the above case) can be applied.

[0065] In this invention or specification, when the number of carbon atoms of a certain group is specified, the number of carbon atoms refers to the total number of carbon atoms in the entire group. That is, when the group further has substituents, it refers to the total number of carbon atoms including the substituents.

[0066] In this specification, the term "~compound" refers to a compound having a common basic skeleton and encompassing a compound whose structure is altered by changing a portion of it within the scope of achieving the target effect (e.g., a compound in which a portion of hydrogen atoms are replaced with substituents). For example, the term "(meth)acrylic acid compound" refers to a compound derived from (meth)acrylic acid, in addition to (meth)acrylic acid, within the scope of achieving the target effect; and the term "N-(hetero)aryl(meth)acrylamide compound" refers to a compound derived from N-(hetero)aryl(meth)acrylamide, in addition to N-(hetero)aryl(meth)acrylamide, within the scope of achieving the target effect.

[0067] In this invention or specification, "(meth)acrylic acid" refers to a structure containing both methacrylic acid and acrylic acid. For example, "(meth)acrylic acid compound" refers to a methacrylic acid compound and / or an acrylic acid compound. Moreover, the term "methacrylic acid" is used in a broader sense than is usually understood. That is, as specified in general formula (1), in "CH2=C(R 1 In the CO-” structure, R 1 Not only limited to the form of methyl groups, but also as R 1 The term "methacrylic acid" (methacryloyl) is used because it refers to all forms of aliphatic groups. Furthermore, based on the above interpretation of the term "~compound," methacrylic acid compounds could be considered as being included within acrylic acid compounds; however, considering that "(meth)acrylic acid" is the commonly used expression in the chemical field, the expression "(meth)acrylic acid" is used instead.

[0068] In this invention or specification, "(hetero)aryl" refers to a structure comprising both heteroaryl (an aromatic heterocyclic group) and aryl (an aromatic hydrocarbon cyclic group).

[0069] Invention Effects

[0070] According to the present application, in the case where, as the raw material N- (hetero) aryl amine compound, a compound having an electron-withdrawing group as a substituent of a ring-forming atom of an aromatic ring is used, the generation of a 1,4-adduct as a by-product can be sufficiently suppressed, and a target N- (hetero) aryl (meth) acrylamide compound can be obtained with high selectivity. According to the present application, in the production of an N- (hetero) aryl (meth) acrylamide compound, the use of an expensive activated body or a special reagent is not required, and thus the cost and environmental load caused by the raw material or the reagent can also be appropriately reduced. DETAILED DESCRIPTION

[0071] The present application provides a production method of an N- (hetero) aryl (meth) acrylamide compound (hereinafter, referred to as the production method of the present application), which includes a step of amidating a compound represented by the following general formula (1) [ (meth) acrylate compound] and a compound represented by the following general formula (2) [N- (hetero) aryl amine compound] at a temperature exceeding 120°C to obtain a compound represented by the following general formula (3) [N- (hetero) aryl (meth) acrylamide compound].

[0072] [Chemical Formula 3]

[0073]

[0074] [Chemical Formula 4]

[0075]

[0076] In the general formula (1), R 1 represents a hydrogen atom or an aliphatic group. As R 1 The aliphatic group that can be used can be a saturated aliphatic group or an unsaturated aliphatic group. As R 1 The number of carbon atoms of the aliphatic group that can be used is preferably 1 to 20, more preferably 1 to 18, further preferably 1 to 15, further preferably 1 to 12, further preferably 1 to 10, further preferably 1 to 8, further preferably 1 to 6, further preferably 1 to 5. As R 1 The aliphatic group that can be used is preferably an aliphatic hydrocarbon group. The aliphatic hydrocarbon group is more preferably an alkyl group, an alkenyl group, or an alkynyl group.

[0077] As R 1The alkyl group that can be employed can be linear, can have a branched chain, and can form a ring. The number of carbon atoms of the alkyl group is preferably from 1 to 20 (the lower limit value of the number of carbon atoms when the alkyl group is a ring structure (cycloalkyl group) is 3, preferably 4, and more preferably 5. The same applies hereinafter.), more preferably from 1 to 18, further preferably from 1 to 15, further preferably from 1 to 12, further preferably from 1 to 10, further preferably from 1 to 8, further preferably from 1 to 6, and further preferably from 1 to 5. As R 1 The alkyl group that can be employed is preferably an unsubstituted alkyl group or a trifluoromethyl group. As R 1 The alkyl group that can be employed is more preferably a methyl group, a trifluoromethyl group, an ethyl group, a propyl group, or a butyl group, further preferably a methyl group, a trifluoromethyl group, or an ethyl group, and particularly preferably a methyl group.

[0078] As R 1 The alkenyl group that can be employed can be linear, can have a branched chain, and can form a ring. The number of carbon atoms of the alkenyl group is preferably from 2 to 20 (the lower limit value of the number of carbon atoms when the alkenyl group is a ring structure (cycloalkenyl group) is 3, preferably 4, and more preferably 5. The same applies hereinafter.), more preferably from 2 to 18, further preferably from 2 to 15, further preferably from 2 to 12, further preferably from 2 to 10, further preferably from 2 to 8, further preferably from 2 to 6, and further preferably from 2 to 5. As R 1 The alkenyl group that can be employed is preferably an unsubstituted alkenyl group. As R 1 The alkenyl group that can be employed is more preferably a vinyl group, an allyl group, or a dimethylallyl group.

[0079] As R 1 The alkynyl group that can be employed can be linear, can have a branched chain, and can form a ring. The number of carbon atoms of the alkynyl group is preferably from 2 to 20 (the lower limit value of the number of carbon atoms when the alkynyl group is a ring structure (cycloalkynyl group) is 3, preferably 4, and more preferably 5. The same applies hereinafter.), more preferably from 2 to 18, further preferably from 2 to 15, further preferably from 2 to 12, further preferably from 2 to 10, further preferably from 2 to 8, further preferably from 2 to 6, and further preferably from 2 to 5. As R 1 The alkynyl group that can be employed is preferably an unsubstituted alkynyl group. As R 1 The alkynyl group that can be employed is more preferably an ethynyl group or a propynyl group.

[0080] wherein R 1 is preferably a hydrogen atom or a methyl group.

[0081] In General Formula (1), R 2 represents a hydrogen atom, a chain aliphatic group, an aliphatic hydrocarbon ring group, an aryl group, or a heterocyclic group.

[0082] As R 2The chain aliphatic group that can be employed can be a chain saturated aliphatic group or a chain unsaturated aliphatic group. As R 2 The number of carbon atoms of the chain aliphatic group that can be employed is preferably from 1 to 20, more preferably from 1 to 18, further preferably from 1 to 15, further preferably from 1 to 12, further preferably from 1 to 10, further preferably from 1 to 8, further preferably from 1 to 6, further preferably from 1 to 5. As R 2 The chain aliphatic group that can be employed is preferably a chain aliphatic hydrocarbon group. The chain aliphatic hydrocarbon group is more preferably an alkyl group, an alkenyl group or an alkynyl group. As R 2 The preferred modes of the alkyl group, the alkenyl group and the alkynyl group that can be employed are the same as those of R 1 The preferred modes of the alkyl group, the alkenyl group and the alkynyl group that can be employed are the same as those of R

[0083] As R 2 The aliphatic hydrocarbon cyclic group that can be employed can be a saturated aliphatic hydrocarbon cyclic group or an unsaturated aliphatic hydrocarbon cyclic group. Also, it can be a fused ring. As R 2 The number of carbon atoms of the aliphatic hydrocarbon cyclic group that can be employed is preferably from 3 to 20, more preferably from 4 to 18, further preferably from 5 to 15, further preferably from 6 to 12, further preferably from 6 to 10. As R 2 The saturated aliphatic hydrocarbon cyclic group that can be employed is preferably a cycloalkyl group. Also, as R 2 The unsaturated aliphatic hydrocarbon cyclic group that can be employed is preferably a cycloalkenyl group or a cycloalkynyl group. As R 2 The number of ring-forming carbon atoms of the cycloalkyl group, the cycloalkenyl group and the cycloalkynyl group that can be employed is preferably from 4 to 10, more preferably from 5 to 8.

[0084] As R 2 The number of carbon atoms of the aryl group that can be employed is preferably from 6 to 40, more preferably from 6 to 30, further preferably from 6 to 20, further preferably from 6 to 15, further preferably from 6 to 12. As R 2 The aryl group that can be employed is more preferably a phenyl group or a naphthyl group, and is particularly preferably a phenyl group.

[0085] As R 2 The number of ring-forming atoms of the heterocyclic group that can be employed is preferably from 3 to 20, more preferably from 4 to 15, more preferably from 5 to 10. The heterocyclic ring can be aliphatic or aromatic. Also, it can have a fused ring structure. As R 2 In the case where the heterocyclic group that can be employed is a monocyclic ring, the number of ring-forming atoms is preferably 5 or 6. As the ring-forming heteroatoms (atoms other than carbon atoms) of the heterocyclic ring, for example, boron (B), nitrogen (N), oxygen (O), sulfur (S), selenium (Se) and tellurium (Te) can be mentioned, and it preferably has a heteroatom selected from nitrogen, oxygen and sulfur. As R 2As a saturated heterocyclic ring, examples of the heterocyclic ring of the heterocyclic group that can be used include a pyrrolidine ring, an imidazoline ring, a pyrazolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a 2-bora-l,3-dioxolane ring, a 1,3-thiazolidine ring, and the like. Also, as an unsaturated heterocyclic ring, examples of the heterocyclic ring of the heterocyclic group that can be used include a pyrrole ring, an imidazole ring, a thiophene ring, a pyrazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a triazole ring, a tetrazole ring, a furan ring, a benzothiazole ring, a benzoxazole ring, a benzotriazole ring, a benzoselenazole ring, a benzofuran ring, a benzothiophene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a triazine ring, a quinoline ring, an isoquinoline ring, a quinoxaline ring, a 2-pyrroline ring, a 2-imidazoline ring, a 3-pyrazoline ring, and the like.

[0086] As preferred examples of the compound represented by General Formula (1), examples include acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, phenyl acrylate, phenyl methacrylate, butyl acrylate, butyl methacrylate, isobutyl acrylate, isobutyl methacrylate, vinyl acrylate, vinyl methacrylate, allyl acrylate, allyl methacrylate, isopropyl acrylate, isopropyl methacrylate, t-butyl acrylate, t-butyl methacrylate, dodecyl acrylate, dodecyl methacrylate, hexyl acrylate, hexyl methacrylate, octadecyl acrylate, octadecyl methacrylate, 2-(chloromethyl)ethyl acrylate, 2-(chloromethyl)methyl acrylate, 2-(chloromethyl)acrylic acid, itaconic acid, diethyl itaconate, monomethyl itaconate, dimethyl itaconate, and t-butyl 2-(trifluoromethyl)acrylate.

[0087] In General Formula (2), the ring Ar represents an aromatic ring.

[0088] In the case where the aromatic ring that can be used as the ring Ar is an aromatic hydrocarbon ring, the number of carbon atoms of the aromatic hydrocarbon ring is preferably from 6 to 40, more preferably from 6 to 30, further preferably from 6 to 20, further preferably from 6 to 15, further preferably from 6 to 12. The aromatic hydrocarbon ring that can be used as the ring Ar can be a monocyclic ring or a fused ring. As preferred examples of the aromatic hydrocarbon ring, a benzene ring and a naphthalene ring can be given, of which a benzene ring is preferred.

[0089] In the case where the aromatic ring that can be employed as the ring Ar is an aromatic heterocycle, the aromatic heterocycle can be a monocyclic ring or a condensed ring. The number of ring-forming atoms of the aromatic heterocycle is preferably from 5 to 20, more preferably from 5 to 15, and further preferably from 5 to 10. Moreover, in the case where the aromatic heterocycle is a monocyclic ring, the number of ring-forming atoms is preferably 5 or 6. As the ring-forming hetero atom (atom other than carbon atom) of the aromatic heterocycle, for example, nitrogen (N), oxygen (O), sulfur (S), and selenium (Se) can be mentioned, and it is preferable to have a hetero atom selected from nitrogen, oxygen, and sulfur. As specific examples of the aromatic heterocycle that can be employed as the ring Ar, a pyrrole ring, an imidazole ring, a thiophene ring, a pyrazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a triazole ring, a tetrazole ring, a furan ring, a benzothiazole ring, a benzoxazole ring, a benzotriazole ring, a benzoselenazole ring, a benzofuran ring, a benzothiophene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a triazine ring, a quinoline ring, an isoquinoline ring, a quinoxaline ring, and the like can be mentioned.

[0090] R 3 represents an electron-withdrawing group. The electron-withdrawing group generally refers to a substituent having a positive Hammett's sigma value. The Hammett equation is an empirical equation that was proposed by L. P. Hammett in 1935 in order to quantitatively discuss the influence of a substituent on the reaction or equilibrium of a benzene derivative, and the equation has now been widely recognized as being appropriate. The substituent constant based on the Hammett equation can be found in a conventional reference book, for example, J. A. Dean, ed., "Lange's Handbook of Chemistry", 12th edition, 1979 (Mc Graw-Hill) or "Chemistry World" supplement, No. 122, pp. 96-103, 1979 (Nankoudo, Inc.) can be referred to.

[0091] As the R 3electron-withdrawing group, for example, acyl group (preferably, carbon number 2 to 20, more preferably, carbon number 2 to 10, further preferably, carbon number 2 to 5), alkoxycarbonyl group (preferably, carbon number 2 to 20, more preferably, carbon number 2 to 10, further preferably, carbon number 2 to 5), aryloxycarbonyl group (preferably, carbon number 7 to 20, more preferably, carbon number 7 to 10), carbamoyl group, alkylsulfonyl group (preferably, carbon number 1 to 20, more preferably, carbon number 1 to 10, further preferably, carbon number 2 to 5), arylsulfonyl group (preferably, carbon number 6 to 20, more preferably, carbon number 6 to 10), sulfamoyl group, trifluoromethyl group, cyano group, nitro group, halogen atom (for example, fluorine atom, chlorine atom), and the like. It is preferable that the group be selected from acyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, alkylsulfonyl group, arylsulfonyl group, sulfamoyl group, cyano group, nitro group, and halogen atom, more preferable that the group be selected from acyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, sulfamoyl group, cyano group, and halogen atom, and further preferable that the group be selected from acyl group, sulfamoyl group, and halogen atom.

[0092] R 3 m is an integer of 1 or more, which represents the number of R 3 In the compound represented by General Formula (2), the ring Ar has one or more electron-withdrawing groups as substituents. In the case where the ring Ar has two or more electron-withdrawing groups R 3 The two or more electron-withdrawing groups R 4 may be the same as or different from each other.

[0093] R 4 represents a chain aliphatic group, aliphatic hydrocarbon ring group, aryl group, or heterocyclic group.

[0094] The chain aliphatic group, aliphatic hydrocarbon ring group, aryl group, and heterocyclic group that can be used for R 2 have the same meaning and the same preferable mode as the chain aliphatic group, aliphatic hydrocarbon ring group, aryl group, and heterocyclic group that can be used for R 4 is not an a-hydroxybenzyl group. If R 4 is an a-hydroxybenzyl group, side reactions are particularly likely to occur, and many by-products are produced. From the same viewpoint, R 4 is more preferably free of a hydroxyl group. Furthermore, the compound represented by General Formula (2) is preferably a compound free of a hydroxyl group as a substituent.

[0095] n is an integer of 0 or more, which represents the number of R 4 In the case where the ring Ar has two or more R 4 The two or more R 1 may be the same as or different from each other.

[0096] The maximum (upper limit) of the total number (m + n) of m and n is the maximum number of substituents that the ring-forming atoms of the ring Ar can have. For example, in the case where the ring Ar in General Formula (2) is a benzene ring, since the ring Ar already has an amino group (-NH2) as a substituent, the maximum number of substituents that the ring Ar can have is 5.

[0097] In General Formula (2), it is preferable that m be an integer of 1 to 3 (preferably 1 or 2, more preferably 1), and n be an integer of 0 to 4 (preferably an integer of 0 to 3, more preferably an integer of 0 to 2, further preferably 0 or 1). At this time, the ring Ar is preferably a 5-membered ring or a 6-membered ring, more preferably a benzene ring.

[0098] As preferable specific examples of the compound represented by General Formula (2), sulfanilamide, 4-fluoroaniline, 4-aminoacetophenone, 2,4-difluoroaniline, 4-chloroaniline, 2-methyl-4-fluoroaniline, 4-bromoaniline, 2,4-dibromoaniline, 2,4-dichloroaniline, 2,4,6-trifluoroaniline, 2-fluoroaniline, pentafluoroaniline, 3-chloro-4-fluoroaniline, 4-trifluoromethylaniline, 4-nitroaniline, 2-fluoro-5-methylaniline, 4-aminobenzophenone, 2'-aminoacetophenone, 4-amino-3,5-dichloroacetophenone, 2-trifluoromethylaniline, 2-iodo-4-(trifluoromethyl)aniline, 4-amino-3-chlorotoluidine, 4-amino-3-bromotoluidine, 4-amino-3,5-dichlorotoluidine, 2-nitroaniline, 1-amino-4-fluoronaphthalene, 1-amino-4-bromonaphthalene, 1-amino-4-chloronaphthalene, 1-amino-4-nitronaphthalene, 3-amino-4-(trifluoromethyl)pyridine, and the like can be given.

[0099] In General Formula (3), R 1 , Ar, R 3 , R 4 , m and n have the same meanings as R 1 , Ar, R 3 , R 4 , m and n in General Formula (1) or General Formula (2), and the preferable modes are also the same.

[0100] <Substituent Group Z>

[0101] represents a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), an alkyl group [represents a substituted or unsubstituted alkyl group of straight chain, branched chain and cyclic. They include an alkyl group (preferably an alkyl group of 1 to 30 carbon atoms, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a t-butyl group, a n-octyl group, a eicosyl group, a 2-chloroethyl group, a 2-cyanoethyl group and a 2-ethylhexyl group), a cycloalkyl group (preferably a substituted or unsubstituted cycloalkyl group of 3 to 30 carbon atoms, for example, a cyclohexyl group, a cyclopentyl group and a 4-n-dodecylcyclohexyl group), a bicycloalkyl group (preferably a substituted or unsubstituted bicycloalkyl group of 5 to 30 carbon atoms, i.e., a monovalent group obtained by removing one hydrogen atom from a bicycloalkane of 5 to 30 carbon atoms. For example, a bicyclo[1,2,2]heptane-2-yl group, a bicyclo[2,2,2]octane-3-yl group), and also a tricyclo structure and the like having a more complex ring structure. The alkyl group in the substituent group described below (e.g., the alkyl group of an alkylthio group) also represents an alkyl group of such meaning.],

[0102] an alkenyl group [represents a substituted or unsubstituted alkenyl group of straight chain, branched chain and cyclic. They include an alkenyl group (preferably a substituted or unsubstituted alkenyl group of 2 to 30 carbon atoms, for example, a vinyl group, an allyl group, an isoprenyl group, a geranyl group and an oleyl group), a cycloalkenyl group (preferably a substituted or unsubstituted cycloalkenyl group of 3 to 30 carbon atoms, i.e., a monovalent group obtained by removing one hydrogen atom from a cycloalkene of 3 to 30 carbon atoms. For example, a 2-cyclopenten-1-yl group, a 2-cyclohexen-1-yl group), a bicycloalkenyl group (a substituted or unsubstituted bicycloalkenyl group, preferably a substituted or unsubstituted bicycloalkenyl group of 5 to 30 carbon atoms, i.e., a monovalent group obtained by removing one hydrogen atom from a bicycloalkene having one double bond. For example, a bicyclo[2,2,1]hept-2-en-1-yl group, a bicyclo[2,2,2]oct-2-en-4-yl group).], an alkynyl group (preferably a substituted or unsubstituted alkynyl group of 2 to 30 carbon atoms, for example, an ethynyl group, a propargyl group, a trimethylsilyl ethynyl group),

[0103] aryl (preferably a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, for example, phenyl, p-tolyl, naphthyl, m-chlorophenyl, and o-hexadecanoylaminophenyl), heterocyclic group (preferably a substituted or unsubstituted monovalent group obtained by removing one hydrogen atom from a 5- or 6-membered heterocyclic compound which is aromatic or non-aromatic, further preferably a 5- or 6-membered aromatic heterocyclic group having 3 to 30 carbon atoms. For example, 2-furyl, 2-thienyl, 2-pyrimidyl, 2-benzothiazolyl), cyano, nitro, carboxyl, alkoxy (preferably a substituted or unsubstituted alkoxy group having 1 to 30 carbon atoms, for example, methoxy, ethoxy, isopropoxy, t-butoxy, n-octyloxy, and 2-methoxyethoxy), aryloxy (preferably a substituted or unsubstituted aryloxy group having 6 to 30 carbon atoms, for example, phenoxy, 2-methylphenoxy, 4-t-butylphenoxy, 3-nitrophenoxy, and 2-tetradecanoylaminophenoxy),

[0104] silyloxy (preferably silyloxy having 3 to 20 carbon atoms, e.g., trimethylsiloxy, t-butyldimethylsiloxy), heterocyclic oxy (preferably substituted or unsubstituted heterocyclic oxy having 2 to 30 carbon atoms, 1-phenyltetrazol-5-yloxy, 2-tetrahydropyranyloxy), acyloxy (preferably formyloxy, substituted or unsubstituted alkylcarbonyloxy having 2 to 30 carbon atoms, substituted or unsubstituted arylcarbonyloxy having 6 to 30 carbon atoms, e.g., formyloxy, acetyloxy, pivaloyloxy, stearyl-oxy, benzoyloxy, and p-methoxyphenylcarbonyloxy), carbamoyloxy (preferably substituted or unsubstituted carbamoyloxy having 1 to 30 carbon atoms, e.g., N,N-dimethylcarbamoyloxy, N,N-diethylcarbamoyloxy, morpholinylcarbonyloxy, N,N-di-n-octylaminocarbonyloxy, and N-n-octylcarbamoyloxy), acyl (preferably formyl, substituted or unsubstituted alkylcarbonyl having 2 to 30 carbon atoms, substituted or unsubstituted arylcarbonyl having 7 to 30 carbon atoms, heterocyclic carbonyl bonded via a substituted or unsubstituted carbon atom having 4 to 30 carbon atoms to a carbonyl group, e.g., acetyl, trimethylacetyl, 2-chloroacetyl, stearyl, benzoyl, p-n-octyloxyphenylcarbonyl, 2-pyridylcarbonyl, and 2-furylcarbonyl), aryloxycarbonyl (preferably substituted or unsubstituted aryloxycarbonyl having 7 to 30 carbon atoms, e.g., phenoxycarbonyl, o-chlorophenoxycarbonyl, m-nitrophenoxycarbonyl, p-t-butylphenoxycarbonyl), alkoxycarbonyl (preferably substituted or unsubstituted alkoxycarbonyl having 2 to 30 carbon atoms, e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, n-octadecyloxycarbonyl), carbamoyl (preferably substituted or unsubstituted carbamoyl having 1 to 30 carbon atoms, e.g., carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N,N-di-n-octylcarbamoyl, N-(methylsulfonyl)carbamoyl),

[0105] an aryl or heterocyclic azo group (preferably a substituted or unsubstituted arylazo group having 6 to 30 carbon atoms, a substituted or unsubstituted heterocyclic azo group having 3 to 30 carbon atoms, for example, phenylazo, p-chlorophenylazo, 5-ethylthio-1,3,4-thiadiazol-2-azo), an imide group (preferably N-succinimide, N-phthalimide), a phosphine group (preferably a substituted or unsubstituted phosphine group having 2 to 30 carbon atoms, for example, dimethylphosphine, diphenylphosphine, methylphenyloxyphosphine), a phosphinyl group (preferably a substituted or unsubstituted phosphinyl group having 2 to 30 carbon atoms, for example, phosphinyl, dioctyloxyphosphinyl, and diethoxyphosphinyl), a phosphinyloxy group (preferably a substituted or unsubstituted phosphinyloxy group having 2 to 30 carbon atoms, for example, diphenyloxyphosphinyloxy, dioctyloxyphosphinyloxy), a phosphinylamino group (preferably a substituted or unsubstituted phosphinylamino group having 2 to 30 carbon atoms, for example, dimethyloxyphosphinylamino, dimethylamino-phosphinylamino), a silyl group (preferably a substituted or unsubstituted silyl group having 3 to 30 carbon atoms, for example, trimethylsilyl, t-butyldimethylsilyl, dimethylphenylsilyl).

[0106] Among the above-mentioned functional groups, as to the functional group having a hydrogen atom, it can be removed and substituted with a group selected from the above-mentioned substituent group Z.

[0107] The production method of the present application is characterized in that the compound represented by the above-mentioned general formula (1) is reacted with the compound represented by the above-mentioned general formula (2) at a temperature exceeding 120°C to amidate. By controlling the amidation reaction to be performed at a high temperature exceeding 120°C, the generation of the 1,4-adduct as a by-product can be effectively suppressed, and the compound represented by general formula (3) as the target 1,2-adduct can be obtained with high efficiency.

[0108] Among the above-mentioned functional groups, as to the functional group having a hydrogen atom, it can be removed and substituted with a group selected from the above-mentioned substituent group Z. 3 In the case where the compound represented by general formula (2) is used as the raw material amine compound, which does not have an electron-withdrawing group R 3Even in the case where the reaction is performed at a high temperature of around 100°C, as shown in the following comparative example, 1,4-adduct is generated in an amount of about 10 times or more than that of the target 1,2-adduct. The present application was completed in order to solve this new problem.

[0109] In the production method of the present application, the reaction temperature is controlled in a high temperature region exceeding 120°C. By controlling the reaction temperature, the generation efficiency of the target 1,2-adduct can be significantly improved even without using an expensive raw material activated body and without using a reagent such as a condensing agent. The reason is not certain, but it is considered as follows.

[0110] It is considered that in the case where the compound represented by General Formula (1) is reacted with the compound represented by General Formula (2), the following two reactions mainly occur. In the following scheme, the case where methacrylic acid is used as the compound represented by General Formula (1) and sulfanilamide is used as the compound represented by General Formula (2) is shown.

[0111] [Chemical Formula 5]

[0112]

[0113] The 1,4-addition reaction is reversible, and it is considered that by performing the reaction in a specific high temperature region, the reverse reaction of the 1,4-addition reaction (reverse Michael reaction) can be promoted, and the generation of the 1,2-adduct can be concentrated. It has not been known in what temperature region the reverse Michael reaction occurs so far, and in the case where it is known that side reactions are generally likely to occur when reacting at a high temperature, it was not clear at the time of filing the present application how the high temperature reaction prescribed in the present application would affect the amidation reaction. The present application can significantly improve the generation efficiency of the target 1,2-adduct without other special means by controlling the reaction temperature of the amidation reaction in a specific high temperature region, and even with inexpensive raw materials.

[0114] In the production method of the present application, as for the reaction (amidation reaction) of the compound represented by General Formula (1) and the compound represented by the following General Formula (2), the reaction temperature is controlled at a temperature exceeding 120°C, and it can be a batch reaction, or a flow reaction (flow-through reaction) in which a raw material mixed solution (refers to a reaction solution before the start of the reaction, and when a solvent, a catalyst, an additive, or the like other than the raw material is used, it is a mixed solution including them.) is circulated in a flow path while the reaction is performed. The flow reaction itself is known, and for example, International Publication No. 2020 / 066561, International Publication No. 2019 / 188749, International Publication No. 2018 / 180456, Japanese Patent Application Publication No. 2016-160124, and the like can be appropriately referred to.

[0115] The method of controlling the reaction temperature of over 120°C is not particularly limited, and for example, a thermostat can be used. Also, it is preferable to control the temperature by heating the raw material mixture with microwave irradiation. By using microwave heating, the raw material mixture can be instantaneously heated to a high temperature in a non-contact manner, and the reaction conditions of the amidation reaction can be accurately controlled. The production method of the present application is also preferably configured so that the amidation reaction is performed as a flow reaction, and the temperature control during the flow reaction is performed by microwave irradiation.

[0116] The reaction temperature of the amidation reaction is preferably 121°C or higher, more preferably 122°C or higher, further preferably 123°C or higher, further preferably 124°C or higher, further preferably 125°C or higher. Also, the reaction temperature is preferably 130°C or higher, more preferably 140°C or higher, further preferably 150°C or higher, further preferably 160°C or higher, further preferably 180°C or higher, further preferably 200°C or higher, further preferably 205°C or higher, further preferably 210°C or higher, further preferably 220°C or higher. Increasing the temperature tends to promote the reverse Michael reaction. Also, from the viewpoint of preventing excessive pressure increase in the reaction system, the reaction temperature of the amidation reaction is usually 500°C or lower, preferably 400°C or lower, more preferably 350°C or lower, further preferably 300°C or lower, further preferably 280°C or lower.

[0117] In the production method of the present application, when the amidation reaction is performed in a batch, the raw material mixture is usually heated after being sufficiently stirred. Also, it is preferable to perform the heating while stirring the raw material mixture.

[0118] When the amidation reaction is performed as a flow reaction, the raw material mixture is heated while flowing in the flow path to cause the amidation reaction. The flow reaction has the advantage that the reaction product can be continuously obtained while continuously supplying the raw material. For example, the raw material mixture can be mixed in a container, introduced into a flow path, and heated while flowing downstream to cause the amidation reaction. Also, a liquid containing the compound represented by General Formula (1) and a liquid containing the compound represented by General Formula (2) can be caused to flow in separate flow paths, the flow paths are combined, and the combined liquid is heated while flowing downstream to cause the amidation reaction.

[0119] In the above amidation reaction, the amount of use of the compound represented by General Formula (1) and the compound represented by General Formula (2) is not particularly limited as long as the compound represented by General Formula (3) as the target 1,2-adduct can be obtained. If the amount of use of the compound represented by General Formula (2) is large, there is a tendency that the amount of generation of the 1,4-adduct as a by-product becomes large, and generally, the compound represented by General Formula (1) is reacted in an amount of more than the compound represented by General Formula (2) on a molar basis. For example,

[0120] It is preferable that 1.2 ≤ [molar amount of the compound represented by General Formula (1)] / [molar amount of the compound represented by General Formula (2)] be satisfied,

[0121] It is more preferable that 1.5 ≤ [molar amount of the compound represented by General Formula (1)] / [molar amount of the compound represented by General Formula (2)] be satisfied,

[0122] It is further preferable that 1.8 ≤ [molar amount of the compound represented by General Formula (1)] / [molar amount of the compound represented by General Formula (2)] be satisfied,

[0123] It is further preferable that 2.0 ≤ [molar amount of the compound represented by General Formula (1)] / [molar amount of the compound represented by General Formula (2)] be satisfied.

[0124] Also, from the viewpoint of yield,

[0125] It is preferable that [molar amount of the compound represented by General Formula (1)] / [molar amount of the compound represented by General Formula (2)] ≤ 10.0 be satisfied,

[0126] It is more preferable that [molar amount of the compound represented by General Formula (1)] / [molar amount of the compound represented by General Formula (2)] ≤ 8.0 be satisfied,

[0127] It is still more preferable that [molar amount of the compound represented by General Formula (1)] / [molar amount of the compound represented by General Formula (2)] ≤ 7.0 be satisfied.

[0128] In the above amidation reaction, it is also preferable to use a solvent. It is considered that by using a solvent, the viscosity of the raw material mixture can be reduced, and the generation of side reactions can be more effectively suppressed as the mixing efficiency improves. As the solvent, an organic solvent capable of dissolving the reaction raw materials can be generally used. From the viewpoint of suppressing pressure rise, the above solvent is preferably a solvent having a boiling point of 100°C or higher, and more preferably a solvent having a boiling point of 150°C or higher. The boiling point is the boiling point at 0.1 MPa. If an alcoholic solvent, an ester solvent, or a non-cyclic amide solvent not having a urea bond is used as the above solvent, the progress of the above amidation reaction can sometimes be hindered, and thus it is preferable to use a solvent other than these solvents. As examples of the preferable solvent, nitrile solvents (solvents containing a compound having a nitrile group), ether solvents (solvents containing a compound having an ether bond), aliphatic hydrocarbon solvents (solvents containing an aliphatic hydrocarbon compound), aromatic hydrocarbon solvents (solvents containing an aromatic hydrocarbon compound), carbonate solvents (solvents containing a carbonate compound), ketone solvents (solvents containing a ketone compound), sulfoxide solvents (solvents containing a sulfoxide compound), sulfone solvents (solvents containing a sulfone compound), cyclic amide solvents (solvents containing a cyclic amide compound), and urea solvents (solvents containing a compound having a urea bond) can be given.

[0129] As examples of the nitrile solvents, acetonitrile, propionitrile, and the like can be given.

[0130] As examples of the ether solvents, diethyl ether, dibutyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, and the like can be given.

[0131] As examples of the aliphatic hydrocarbon solvents, hexane, heptane, octane, decane, and the like can be given.

[0132] As examples of the aromatic hydrocarbon solvents, benzene, toluene, xylene, dichlorobenzene, trifluorotoluene, nitrobenzene, and the like can be given.

[0133] As examples of the carbonate solvents, ethylene carbonate, propylene carbonate, and the like can be given.

[0134] As examples of the sulfoxide solvents, dimethyl sulfoxide, and the like can be given.

[0135] As examples of the sulfone solvents, 3-methylsulfolane, sulfolane, and the like can be given.

[0136] As examples of the cyclic amide solvents, N-methyl-2-pyrrolidone, and the like can be given.

[0137] As examples of the urea solvents, 1,3-dimethyl-2-imidazolidinone, N,N'-dimethylaceto urea, N,N,N',N'-tetramethylurea, and the like can be given.

[0138] In the case where a solvent is used in the amidation reaction described above, the amount of the solvent used can be appropriately set in consideration of the viscosity of the raw material mixture, the concentration of the reaction product, and the like. For example, the amount of the solvent used can be set to 1 to 100 parts by mass, and further preferably 5 to 60 parts by mass, and further preferably 10 to 30 parts by mass, relative to 100 parts by mass of the total amount of the compound represented by General Formula (1) and the compound represented by General Formula (2).

[0139] In the amidation reaction described above, it is also preferable to use a catalyst. By using a catalyst, the regioselectivity of the reaction can be further improved. It is preferable to use at least one of a Lewis acid, a Brønsted acid, a metal oxide, and a phosphorus oxide compound as a reaction catalyst.

[0140] A Lewis acid is a substance that can accept an electron pair. As the Lewis acid catalyst that can be used in the amidation reaction described above, for example, BF3·OEt2, AlBr3, AlCl3, ZnI2, MgCl2, TiCl4, TiCl3(OiPr), TiCl2(OiPr)2, TiCl(OiPr)3, Ti(OiPr)4, SnCl4, SnCl3, EtAlCl2, FeCl3, ZnCl2, TMSOTf, FeBr3, BBr3, Sc(OTf)2, Zn(OTf)2, La(OTf)3, Yb(OTf)3, Hf(OTf)4, BeCl2, CdCl2, GaCl3, and SbCl5, and the like can be given. Among them, a titanium compound is preferable, and TiCl4 is more preferable. In the formulae, Et represents an ethyl group, iPr represents an isopropyl group, Tf represents a trifluoromethylsulfonyl group, and TMS represents a trimethylsilyl group.

[0141] In the present application, in the case where a Lewis acid is used as a reaction catalyst, one or two or more kinds of the Lewis acids described above can be used.

[0142] A Brønsted acid refers to an acid that has a proton and can release or dissociate the proton. As specific examples of the Brønsted acid catalyst, hydrochloric acid, nitric acid, sulfuric acid, hydrofluoric acid, boric acid, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and Amberlyst (registered trademark) 15 hydrogen form can be given. Among them, a sulfonic acid compound is preferable.

[0143] In the present application, in the case where a Brønsted acid is used as a reaction catalyst, one or two or more kinds of the Brønsted acids described above can be used.

[0144] The metal oxide is not particularly limited as long as it is an oxide of a metal. For example, SiO2, SiO, MgO, Al2O3, GeO, NiO, SrO, Y2O3, ZrO2, CeO2, Fe2O3, Rb2O, Sc2O3, La2O3, Nd2O3, Sm2O3, Gd2O3, Dy2O3, Er2O3, Yb2O3, Ta2O3, Ta2O5, Nb2O5, HfO2, Ga2O3, and TiO2, etc. can be mentioned. Furthermore, a mixture containing a metal oxide such as a zeolite or a clay mineral can be used. Among them, TiO2is preferable.

[0145] In the present application, in the case where a metal oxide is used as a reaction catalyst, one or two or more of the above metal oxides can be used.

[0146] The phosphorus oxide compound is a compound having an oxygen atom directly bonded to a phosphorus atom. In the case where the phosphorus oxide compound is an acid such as phosphoric acid, polyphosphoric acid, etc. that can release or dissociate a proton, the phosphorus oxide compound is a Bronsted acid. However, in the present application or the specification, a compound that is both a Bronsted acid and a phosphorus oxide compound is positioned as a phosphorus oxide compound for convenience rather than the above Bronsted acid. As specific examples of the phosphorus oxide compound, diphosphorus pentoxide, hypophosphorous acid, phosphorous acid, and phosphoric acid can be mentioned. Furthermore, a polymeric phosphoric acid (polyphosphoric acid) such as pyrrolinic acid, triphosphoric acid, trimetaphosphoric acid, and tetrametaphosphoric acid, etc. is also preferable as the phosphorus oxide compound. Among them, diphosphorus pentoxide is preferable because it has an action of suppressing the dissociation of an electron-withdrawing group in a high-temperature reaction. One of the reasons for this is that diphosphorus pentoxide captures moisture that becomes the starting point of the above dissociation reaction. Eaton's reagent can be used as diphosphorus pentoxide.

[0147] In the present application, in the case where a phosphorus oxide compound is used as a reaction catalyst, one or two or more of the above phosphorus oxide compounds can be used.

[0148] The reaction time (time of exposure to a temperature exceeding 120°C) of the above amidation reaction is not particularly limited, and is appropriately adjusted within a range where the target reaction product is sufficiently obtained. For example, the reaction time can be set to 1 to 300 minutes, and is further preferably set to 2 to 240 minutes, and is further preferably set to 3 to 120 minutes, and is further preferably set to 4 to 90 minutes. If precise temperature control is performed such as microwave heating, the reaction time can be further shortened. The end of the reaction can be performed by cooling, etc.

[0149] In the production method of the present application, in order to prevent the addition polymerization reaction of the unsaturated double bond possessed by the compound represented by General Formula (1), it is also preferable to add a polymerization inhibitor. A general polymerization inhibitor can be used, and for example, TEMPO, 4-hydroxyTEMPO, etc. can be appropriately used.

[0150] In the production method of the present application, the compound represented by General Formula (3) is generated as a main reaction product in the reaction solution by the amidation reaction. The amount of the compound represented by General Formula (3) (1,2-adduct) to the amount of the 1,4-adduct as a by-product in the reaction solution after the amidation reaction (in the unpurified reaction solution) is preferably 0.1 or more in terms of a molar ratio.

[0151] It is preferably set to 0.3 ≤ [1,2-adduct] / [1,4-adduct],

[0152] It is more preferably set to 0.5 ≤ [1,2-adduct] / [1,4-adduct],

[0153] It is more preferably set to 0.8 ≤ [1,2-adduct] / [1,4-adduct],

[0154] It is more preferably set to 1.1 ≤ [1,2-adduct] / [1,4-adduct],

[0155] It is more preferably set to 1.2 ≤ [1,2-adduct] / [1,4-adduct],

[0156] It is more preferably set to 1.4 ≤ [1,2-adduct] / [1,4-adduct],

[0157] It is more preferably set to 1.7 ≤ [1,2-adduct] / [1,4-adduct],

[0158] It is further preferably set to 2.0 ≤ [1,2-adduct] / [1,4-adduct].

[0159] There is no limitation on the upper limit of the above molar ratio, and it is usually

[0160] [1,2-adduct] / [1,4-adduct] ≤ 10.0,

[0161] It can be [1,2-adduct] / [1,4-adduct] ≤ 8.0,

[0162] It can be [1,2-adduct] / [1,4-adduct] ≤ 6.0,

[0163] It can be [1,2-adduct] / [1,4-adduct] ≤ 5.0,

[0164] It can be further set to [1,2-adduct] / [1,4-adduct] ≤ 4.0.

[0165] The compound represented by General Formula (3) as the target 1,2-adduct can also be separated and purified from the reaction solution after the amidation reaction is completed. As the separation or purification method, a general method can be appropriately applied. For example, fast column chromatography, thin layer column chromatography, crystallization, recrystallization, distillation, or the like can be applied alone or in combination.

[0166] The present application is described in more detail according to examples, but the present application is not limited to these examples.

[0167] Example

[0168] [Example 1]

[0169] To a 2 mL vial for microwave reaction, 10 mg of 4-hydroxy TEMPO, 1.0 g (5.8 mmol, 1.0 eq.) of sulfanilamide, and 1.25 g (14.5 mmol, 2.5 eq.) of methacrylic acid were added to make a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction. No solvent was used in this reaction system.

[0170] <Reaction Conditions>

[0171] Temperature setting: 250°C

[0172] Pre-stirring: 2 minutes

[0173] Reaction time: 5 minutes

[0174] Stirring speed: 900 rpm

[0175] Absorption level: very high

[0176] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The obtained reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 0.4 / 1.0 (molar ratio).

[0177] [Example 2]

[0178] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 0.62 g (7.3 mmol, 2.5 eq.) of methacrylic acid, and 0.62 mL of sulfolane as a solvent were added to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and an amidation reaction was performed under the following reaction conditions.

[0179] Temperature set: 250°C

[0180] Pre-stirring: 2 minutes

[0181] Reaction time: 20 minutes

[0182] Stirring speed: 900 rpm

[0183] Absorption level: Very high

[0184] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The obtained reaction solution was analyzed by NMR, and the ratio of the amount of production of 1,2-adduct as a target product to the amount of production of 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 0.4 / 1.0 (molar ratio).

[0185] [Example 3]

[0186] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 1.25 g (14.5 mmol, 5.0 eq.) of methacrylic acid were added to prepare a reaction mixture, and then 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst was added, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and an amidation reaction was performed under the following reaction conditions.

[0187] Temperature set: 250°C

[0188] Pre-stirring: 2 minutes

[0189] Reaction time: 5 minutes

[0190] Stirring speed: 900 rpm

[0191] Absorption level: Very high

[0192] After the reaction was completed, the vial was opened by releasing the internal pressure using a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 1.2 / 1.0 (molar ratio).

[0193] [Example 4]

[0194] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 0.62 g (7.3 mmol, 2.5 eq.) of methacrylic acid, and 0.62 mL of sulfolane as a solvent were added to be mixed, and then 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst was added to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0195] Temperature setting: 250°C

[0196] Pre-stirring: 2 minutes

[0197] Reaction time: 5 minutes

[0198] Stirring speed: 900 rpm

[0199] Absorption level: very high

[0200] After the reaction was completed, the vial was opened by releasing the internal pressure using a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 3.1 / 1.0 (molar ratio).

[0201] [Example 5]

[0202] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 1.2 g (15 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were added to be mixed, and then 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst was added to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0203] Set temperature: 250°C

[0204] Pre-stirring: 2 minutes

[0205] Reaction time: 10 minutes

[0206] Stirring speed: 900 rpm

[0207] Absorption level: Very high

[0208] After the end of the reaction, the vial was opened after releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 3.4 / 1.0 (molar ratio).

[0209] To the vial after the end of the reaction, 2 mL of acetonitrile / water = 1 / 2 (molar ratio) was added, and stirring was performed at room temperature for 30 minutes. The resulting solid was taken up by suction filtration, and 1 mL of acetonitrile / water = 1 / 2 (molar ratio) was used for rinsing. The resulting solid was dried under reduced pressure, and 0.21 g of the target 1,2-adduct was obtained in a yield of 30%.

[0210] [Example 6]

[0211] To a 2 mL vial for a microwave reaction, 5 mg of 4-hydroxyTEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 0.62 g (7.3 mmol, 2.5 eq.) of methacrylic acid, and 0.62 mL of butyl acetate as a solvent were added to be mixed, and then 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride was added as a Lewis acid catalyst to make a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform an amidation reaction.

[0212] Set temperature: 150°C

[0213] Pre-stirring: 2 minutes

[0214] Reaction time: 5 minutes

[0215] Stirring speed: 900 rpm

[0216] Absorption level: Very high

[0217] After the reaction was completed, the vial was opened by releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 1.2 / 1.0 (molar ratio).

[0218] [Example 7]

[0219] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (3.7 mmol, 1.0 eq.) of 4'-aminoacetophenone, 1.6 g (18 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were added and mixed, followed by the addition of 70 mg (0.37 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0220] Temperature setting: 150°C

[0221] Pre-stirring: 2 minutes

[0222] Reaction time: 5 minutes

[0223] Stirring speed: 900 rpm

[0224] Absorption level: very high

[0225] After the reaction was completed, the vial was opened by releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 0.1 / 1.0 (molar ratio).

[0226] [Example 8]

[0227] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (4.0 mmol, 1.0 eq.) of 4-fluoro-2-methylaniline, 1.7 g (20 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, followed by the addition of 76 mg (0.40 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0228] Temperature set: 150°C

[0229] Pre-stirring: 2 minutes

[0230] Reaction time: 5 minutes

[0231] Stirring speed: 900 rpm

[0232] Absorption level: very high

[0233] After the completion of the reaction, the vial was opened after releasing the internal pressure with a syringe needle. The obtained reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 0.7 / 1.0 (molar ratio).

[0234] [Example 9]

[0235] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 1.5 g (15 mmol, 5.0 eq.) of methyl methacrylate, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, followed by the addition of 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0236] Temperature set: 250°C

[0237] Pre-stirring: 2 minutes

[0238] Reaction time: 5 minutes

[0239] Stirring speed: 900 rpm

[0240] Absorption level: Very high

[0241] After the reaction was complete, the vial was opened after releasing the internal pressure using a syringe. The reaction solution was analyzed using NMR, and the ratio of the amount of the 1,2-adduct (the target compound) formed to the amount of the 1,4-adduct (a byproduct) formed was determined by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 0.8 / 1.0 (molar ratio).

[0242] [Example 10]

[0243] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxyTEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfonamide, 2.4 g (15 mmol, 5.0 eq.) of phenyl methacrylate, and 0.25 mL of 1,3-dimethyl-2-imidazolinone (DMI) as a solvent were added and mixed. Then, 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride was added as a Lewis acid catalyst to prepare the reaction mixture, and the vial was sealed. The vial was placed in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the amidation reaction was carried out under the reaction conditions set below.

[0244] Set temperature: 250℃

[0245] Pre-stir: 2 minutes

[0246] Reaction time: 5 minutes

[0247] Mixing speed: 900 rpm

[0248] Absorption level: Very high

[0249] After the reaction was complete, the vial was opened after releasing the internal pressure using a syringe. The reaction solution was analyzed using NMR, and the ratio of the amount of the 1,2-adduct (the target compound) to the amount of the 1,4-adduct (a byproduct) was determined by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 1.9 / 1.0 (molar ratio).

[0250] [Example 11]

[0251] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (3.7 mmol, 1.0 eq.) of 4'-aminoacetophenone, 1.6 g (18 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, followed by the addition of 70 mg (0.37 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0252] Temperature set: 250°C

[0253] Pre-stirring: 2 minutes

[0254] Reaction time: 5 minutes

[0255] Stirring speed: 900 rpm

[0256] Absorption level: very high

[0257] After the completion of the reaction, the vial was opened after releasing the internal pressure with a syringe needle. The obtained reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 0.8 / 1.0 (molar ratio).

[0258] [Example 12]

[0259] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (3.9 mmol, 1.0 eq.) of 4-chloroaniline, 1.7 g (20 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, followed by the addition of 74 mg (0.39 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0260] Temperature set: 250°C

[0261] Pre-stirring: 2 minutes

[0262] Reaction time: 5 minutes

[0263] Stirring speed: 900 rpm

[0264] Absorption level: Very high

[0265] After the reaction was complete, the vial was opened after releasing the internal pressure using a syringe. The reaction solution was analyzed using NMR, and the ratio of the amount of the 1,2-adduct (the target compound) to the amount of the 1,4-adduct (a byproduct) was determined by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 1.4 / 1.0 (molar ratio).

[0266] [Example 13]

[0267] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxyTEMPO, 0.5 g (4.0 mmol, 1.0 eq.) of 4-fluoro-2-methylaniline, 1.7 g (20 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of 1,3-dimethyl-2-imidazolinone (DMI) as a solvent were added and mixed. Then, 76 mg (0.40 mmol, 0.1 eq.) of titanium tetrachloride was added as a Lewis acid catalyst to prepare the reaction mixture, and the vial was sealed. The vial was placed in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the amidation reaction was carried out under the reaction conditions set below.

[0268] Set temperature: 250℃

[0269] Pre-stir: 2 minutes

[0270] Reaction time: 5 minutes

[0271] Mixing speed: 900 rpm

[0272] Absorption level: Very high

[0273] After the reaction was complete, the vial was opened after releasing the internal pressure using a syringe. The reaction solution was analyzed using NMR, and the ratio of the amount of the 1,2-adduct (the target compound) to the amount of the 1,4-adduct (a byproduct) was determined by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 4.7 / 1.0 (molar ratio).

[0274] [Comparative Example 1]

[0275] To a 2 mL vial for microwave reaction, 10 mg of 4-hydroxy TEMPO, 1.0 g (5.8 mmol, 1.0 eq.) of sulfanilamide, 1.25 g (14.5 mmol, 2.5 eq.) of methacrylic acid were added to make a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform amidation reaction. No solvent was used in this reaction system.

[0276] <Reaction conditions>

[0277] Temperature set: 115°C

[0278] Pre-stirring: 2 minutes

[0279] Reaction time: 5 minutes

[0280] Stirring speed: 900 rpm

[0281] Absorption level: Very high

[0282] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The obtained reaction solution was analyzed by NMR, and as a result, no 1,2-adduct as the target product was observed, and only 1,4-adduct as a by-product was observed.

[0283] [Comparative Example 2]

[0284] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 1.5 g (15 mmol, 5.0 eq.) of methyl methacrylate, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, and then 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst was added to make a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform amidation reaction.

[0285] Temperature set: 115°C

[0286] Pre-stirring: 2 minutes

[0287] Reaction time: 5 minutes

[0288] Stirring speed: 900 rpm

[0289] Absorption level: Very high

[0290] After the reaction was completed, the vial was opened by releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and as a result, the 1,2-adduct as the target product was not observed, and only the 1,4-adduct as a by-product was observed.

[0291] [Comparative Example 3]

[0292] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 2.4 g (15 mmol, 5.0 eq.) of phenyl methacrylate, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, and then 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst was added to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0293] Temperature setting: 115°C

[0294] Pre-stirring: 2 minutes

[0295] Reaction time: 5 minutes

[0296] Stirring speed: 900 rpm

[0297] Absorption level: very high

[0298] After the reaction was completed, the vial was opened by releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and as a result, the 1,2-adduct as the target product was not observed, and only the 1,4-adduct as a by-product was observed.

[0299] [Comparative Example 4]

[0300] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 2.4 g (15 mmol, 5.0 eq.) of phenyl methacrylate, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, and then 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst was added to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0301] Temperature setting: 115°C

[0302] Pre-agitation: 2 minutes

[0303] Reaction time: 5 minutes

[0304] Agitation speed: 900 rpm

[0305] Absorption level: Very high

[0306] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 0.012 / 1.0 (molar ratio).

[0307] [Comparative Example 5]

[0308] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (3.9 mmol, 1.0 eq.) of 4-chloroaniline, 1.7 g (20 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were added and mixed, followed by the addition of 74 mg (0.39 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0309] Temperature setting: 115°C

[0310] Pre-agitation: 2 minutes

[0311] Reaction time: 5 minutes

[0312] Agitation speed: 900 rpm

[0313] Absorption level: Very high

[0314] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 0.063 / 1.0 (molar ratio).

[0315] [Comparative Example 6]

[0316] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (4.0 mmol, 1.0 eq.) of 4-fluoro-2-methylaniline, 1.7 g (20 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, followed by addition of 76 mg (0.40 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0317] Temperature set: 115°C

[0318] Pre-stirring: 2 minutes

[0319] Reaction time: 5 minutes

[0320] Stirring speed: 900 rpm

[0321] Absorption level: Very high

[0322] After completion of the reaction, the vial was opened after releasing the internal pressure with a syringe needle. The obtained reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 0.12 / 1.0 (molar ratio).

[0323] [Comparative Example 7]

[0324] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.5 mmol, 1.0 eq.) of (2-aminophenyl)(phenyl)methanol, and 1.1 g (13 mmol, 5.0 eq.) of methacrylic acid were mixed to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0325] Temperature set: 250°C

[0326] Pre-stirring: 2 minutes

[0327] Reaction time: 5 minutes

[0328] Stirring speed: 900 rpm

[0329] Absorption level: Very high

[0330] After the reaction was completed, the vial was opened by releasing the internal pressure using a syringe needle. The resulting reaction solution was analyzed by NMR, but there were many by-products, and the ratio of the 1,2-adduct to the 1,4-adduct could not be determined.

[0331] [Example 14]

[0332] To a 2 mL vial for a microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 0.62 g (7.3 mmol, 2.5 eq.) of methacrylic acid, and 0.25 mL of N-methylpyrrolidone (NMP) as a solvent were added and mixed, followed by the addition of 42 mg (0.29 mmol, 0.1 eq.) of phosphorus pentoxide as a phosphorus oxide compound catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and an amidation reaction was performed under the following reaction conditions.

[0333] Set temperature: 200°C

[0334] Pre-stirring: 0.5 minutes

[0335] Reaction time: 5 minutes

[0336] Stirring speed: 900 rpm

[0337] Absorption level: very high

[0338] After the reaction was completed, the vial was opened by releasing the internal pressure using a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as a target product to the amount of production of the 1,4-adduct as a by-product was determined by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 2.1 / 1.0 (molar ratio).

[0339] [Example 15]

[0340] To a 2 mL vial for a microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 0.62 g (7.3 mmol, 2.5 eq.) of methacrylic acid, and 0.25 mL of N-methylpyrrolidone (NMP) as a solvent were added and mixed, followed by the addition of 42 mg (0.29 mmol, 0.1 eq.) of phosphorus pentoxide as a phosphorus oxide compound catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and an amidation reaction was performed under the following reaction conditions.

[0341] Set temperature: 200°C

[0342] Pre-mixing: 0.5 minutes

[0343] Reaction time: 5 minutes

[0344] Stirring speed: 900 rpm

[0345] Absorption level: Very high

[0346] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 72 / 1.0 (molar ratio).

[0347] [Example 16]

[0348] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 0.62 g (7.3 mmol, 2.5 eq.) of methacrylic acid, and 0.25 mL of N-methylpyrrolidone (NMP) as a solvent were added to be mixed, followed by the addition of 0.17 g (1.2 mmol, 0.4 eq.) of phosphorus pentoxide as an oxidation phosphorus compound catalyst to make a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform amidation reaction.

[0349] Temperature setting: 200°C

[0350] Pre-mixing: 0.5 minutes

[0351] Reaction time: 5 minutes

[0352] Stirring speed: 900 rpm

[0353] Absorption level: Very high

[0354] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 72 / 1.0 (molar ratio).

[0355] To the vial after the reaction was completed, 2 mL of acetonitrile / water = 1 / 2 (molar ratio) was added, and stirring was performed at room temperature for 30 minutes. The resulting solid was taken up by suction filtration, and rinsing was performed with 1 mL of acetonitrile / water = 1 / 2 (molar ratio). The obtained solid was subjected to reduced pressure drying, and 0.50 g of the target 1,2-adduct was obtained at a yield of 70%.

[0356] [Example 17]

[0357] To a 2 mL vial for a microwave reaction, 5 mg of 4-hydroxyTEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 0.26 g (3.0 mmol, 1.05 eq.) of methacrylic acid, and 0.25 mL of N-methylpyrrolidone (NMP) as a solvent were mixed, followed by the addition of 0.17 g (1.2 mmol, 0.4 eq.) of phosphorus pentoxide as an oxidation phosphorus compound catalyst to make a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform an amidation reaction.

[0358] Temperature setting: 200°C

[0359] Pre-stirring: 0.5 minutes

[0360] Reaction time: 5 minutes

[0361] Stirring speed: 900 rpm

[0362] Absorption level: very high

[0363] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The obtained reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as a target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 10 / 1.0 (molar ratio).

[0364] [Example 18]

[0365] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 0.26 g (3.0 mmol, 1.05 eq.) of methacrylic acid, and 0.25 mL of N-methylpyrrolidone (NMP) as a solvent were mixed, followed by the addition of 0.17 g (1.2 mmol, 0.4 eq.) of phosphorus pentoxide as a phosphorus oxide compound catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0366] Set temperature: 225°C

[0367] Pre-stirring: 0.5 minutes

[0368] Reaction time: 5 minutes

[0369] Stirring speed: 900 rpm

[0370] Absorption level: very high

[0371] After the completion of the reaction, the vial was opened after releasing the internal pressure with a syringe needle. The obtained reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 12 / 1.0 (molar ratio).

[0372] [Example 19]

[0373] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 0.26 g (3.0 mmol, 1.05 eq.) of methacrylic acid, and 0.25 mL of N-methylpyrrolidone (NMP) as a solvent were mixed, followed by the addition of 0.17 g (1.2 mmol, 0.4 eq.) of phosphorus pentoxide as a phosphorus oxide compound catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0374] Set temperature: 150°C

[0375] Pre-stirring: 0.5 minutes

[0376] Reaction time: 5 minutes

[0377] Stirring speed: 900 rpm

[0378] Absorption level: Very high

[0379] After the reaction was complete, the vial was opened after releasing the internal pressure using a syringe. The reaction solution was analyzed using NMR, and the ratio of the amount of the 1,2-adduct (the target compound) to the amount of the 1,4-adduct (a byproduct) was determined by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 11 / 1.0 (molar ratio).

[0380] [Example 20]

[0381] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxyTEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfonamide, 0.26 g (3.0 mmol, 1.05 eq.) of methacrylic acid, and 0.25 mL of N-methylpyrrolidone (NMP) as a solvent were added and mixed. Then, 0.17 g (1.2 mmol, 0.4 eq.) of phosphorus pentoxide was added as a phosphorus oxide catalyst to prepare the reaction mixture. The vial was sealed and heated and stirred in an oil bath at 225 °C for 10 minutes.

[0382] After the reaction was complete, the vial was opened after releasing the internal pressure using a syringe. The reaction solution was analyzed using NMR, and the ratio of the amount of the 1,2-adduct (the target compound) to the amount of the 1,4-adduct (a byproduct) was determined by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 10 / 1.0 (molar ratio).

[0383] [Example 21]

[0384] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxyTEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfonamide, 1.2 g (15 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of 1,3-dimethyl-2-imidazolinone (DMI) as a solvent were added and mixed. Then, 28 mg (0.3 mmol, 0.1 eq.) of methanesulfonic acid was added as a Brønsted acid catalyst to prepare the reaction mixture, and the vial was sealed. The vial was placed in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the amidation reaction was carried out under the reaction conditions set below.

[0385] Set temperature: 250℃

[0386] Pre-stir: 2 minutes

[0387] Reaction time: 5 minutes

[0388] Mixing speed: 900 rpm

[0389] Absorption level: very high

[0390] After the reaction was completed, the vial was opened by releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 4.0 / 1.0 (molar ratio).

[0391] [Example 22]

[0392] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 1.2 g (15 mmol, 5.0 eq.) of methacrylic acid, and 0.25 mL of xylene as a solvent were added to prepare a reaction mixture, and then 28 mg (0.3 mmol, 0.1 eq.) of methanesulfonic acid as a Brønsted acid catalyst was added, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and an amidation reaction was performed under the following reaction conditions.

[0393] Temperature setting: 250°C

[0394] Pre-stirring: 2 minutes

[0395] Reaction time: 5 minutes

[0396] Stirring speed: 900 rpm

[0397] Absorption level: very high

[0398] After the reaction was completed, the vial was opened by releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 13 / 1.0 (molar ratio).

[0399] [Example 23]

[0400] To a 2 mL vial for microwave reaction, 10 mg of 4-hydroxy TEMPO, 1.0 g (5.8 mmol, 1.0 eq.) of sulfanilamide, and 1.25 g (14.5 mmol, 2.5 eq.) of methacrylic acid were added to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and an amidation reaction was performed under the following reaction conditions. No solvent was used in this reaction system.

[0401] <Reaction conditions>

[0402] Temperature set: 125°C

[0403] Pre-stirring: 2 minutes

[0404] Reaction time: 5 minutes

[0405] Stirring speed: 900 rpm

[0406] Absorption level: Very high

[0407] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 0.04 / 1.0 (molar ratio).

[0408] [Example 24]

[0409] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 1.5 g (15 mmol, 5.0 eq.) of methyl methacrylate, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were added to be mixed, followed by the addition of 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to make a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction device manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0410] Temperature set: 125°C

[0411] Pre-stirring: 2 minutes

[0412] Reaction time: 5 minutes

[0413] Stirring speed: 900 rpm

[0414] Absorption level: Very high

[0415] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. The result was [1,2-adduct] / [1,4-adduct] = 0.23 / 1.0 (molar ratio).

[0416] [Example 25]

[0417] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 2.4 g (15 mmol, 5.0 eq.) of phenyl methacrylate, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, followed by the addition of 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0418] Temperature set: 125°C

[0419] Pre-stirring: 2 minutes

[0420] Reaction time: 5 minutes

[0421] Stirring speed: 900 rpm

[0422] Absorption level: very high

[0423] After the completion of the reaction, the vial was opened after releasing the internal pressure with a syringe needle. The obtained reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as a by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 0.25 / 1.0 (molar ratio).

[0424] [Example 26]

[0425] To a 2 mL vial for microwave reaction, 5 mg of 4-hydroxy TEMPO, 0.5 g (2.9 mmol, 1.0 eq.) of sulfanilamide, 2.4 g (15 mmol, 5.0 eq.) of phenyl methacrylate, and 0.25 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed, followed by the addition of 55 mg (0.29 mmol, 0.1 eq.) of titanium tetrachloride as a Lewis acid catalyst to prepare a reaction mixture, and the vial was sealed. The vial was set in a microwave reaction apparatus manufactured by Biotage Japan Ltd., and the reaction conditions were set as follows to perform the amidation reaction.

[0426] Temperature set: 125°C

[0427] Pre-stirring: 2 minutes

[0428] Reaction time: 5 minutes

[0429] Stirring speed: 900 rpm

[0430] Absorption level: very high

[0431] After the reaction was completed, the vial was opened after releasing the internal pressure with a syringe needle. The resulting reaction solution was analyzed by NMR, and the ratio of the amount of production of the 1,2-adduct as the target product to the amount of production of the 1,4-adduct as the by-product was calculated by comparing the integral values. As a result, [1,2-adduct] / [1,4-adduct] = 0.1 / 1.0 (molar ratio).

[0432] [Example 27]

[0433] Into a 300 mL three-necked flask, 50.0 mg of 4-hydroxyTEMPO, 10.00 g (58.07 mmol, 1.0 eq.) of sulfanilamide, 8.75 g (101.63 mmol, 1.75 eq.) of methacrylic acid, and 20 mL of N-methylpyrrolidone (NMP) as a solvent were added, and mixed at 80°C. After nitrogen substitution into the test tube, 5.95 g (40.65 mmol, 0.7 eq.) of phosphorus pentoxide was added, and stirred for 4 hours at 125°C. After the reaction was completed, 30 mL of water / methanol = 9 / 1 (volume ratio) was added, stirred for 30 minutes at 40°C, and stirred for 30 minutes at 0°C. The precipitated solid was suction filtered, and washed twice with 20 mL of water / methanol = 9 / 1 (volume ratio). The resulting solid was dried under reduced pressure at 40°C for 2 hours, and 11.7 g of 4-sulfamoylphenyl methacrylamide as the target 1,2-adduct was obtained (yield 84%).

[0434] [Example 28]

[0435] Into a 30 mL test tube, 5.0 mg of 4-hydroxyTEMPO, 1.0 g (7.24 mmol, 1.0 eq.) of 4-nitroaniline, 1.09 g (12.67 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. After nitrogen substitution into the test tube, 0.74 g (5.1 mmol, 0.7 eq.) of phosphorus pentoxide was added, and stirred for 4 hours at 125°C.

[0436] After the reaction was completed, the resulting reaction solution 10 mg was diluted with a solvent 10 mL obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 76.44%, and the area% of the 1,4-adduct as the by-product was 2.24%.

[0437] [Example 29]

[0438] To a 30 mL test tube, 5.0 mg of 4-hydroxy TEMPO, 1.0 g (7.75 mmol, 1.0 eq.) of 2,4-difluoroaniline, 1.16 g (13.55 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.79 g (5.42 mmol, 0.7 eq.) of phosphorus pentoxide was added, and heating stirring was performed at 125°C for 4 hours.

[0439] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with a solvent 10 mL obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 by volume, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 95.90%, and the area% of the 1,4-adduct as a by-product was 0.29%.

[0440] [Example 30]

[0441] To a 30 mL test tube, 5.0 mg of 4-hydroxy TEMPO, 1.0 g (9.00 mmol, 1.0 eq.) of 2-fluoroaniline, 1.36 g (15.75 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.92 g (6.30 mmol, 0.7 eq.) of phosphorus pentoxide was added, and heating stirring was performed at 125°C for 4 hours.

[0442] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with a solvent 10 mL obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 by volume, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 95.90%, and the area% of the 1,4-adduct as a by-product was 0.29%.

[0443] [Example 31]

[0444] To a 30 mL test tube, 5.0 mg of 4-hydroxy TEMPO, 1.0 g (7.99 mmol, 1.0 eq.) of 4-fluoro-2-methylaniline, 1.20 g (13.98 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.82 g (5.59 mmol, 0.7 eq.) of phosphorus pentoxide was added, and heating stirring was performed at 125°C for 4 hours.

[0445] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 77.17%, and the area% of the 1,4-adduct as a by-product was 1.39%.

[0446] [Example 32]

[0447] Into a 30 mL test tube, 5.0 mg of 4-hydroxyTEMPO, 1.0 g (6.21 mmol, 1.0 eq.) of 4-(trifluoromethyl)aniline, 0.94 g (10.86 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. On the basis of nitrogen substitution into the test tube, 0.64 g (4.34 mmol, 0.7 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 4 hours.

[0448] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 70.59%, and the 1,4-adduct as a by-product was not observed.

[0449] [Example 33]

[0450] Into a 30 mL test tube, 5.0 mg of 4-hydroxyTEMPO, 1.0 g (7.84 mmol, 1.0 eq.) of 4-chloroaniline, 1.18 g (13.72 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. On the basis of nitrogen substitution into the test tube, 0.80 g (5.49 mmol, 0.7 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 4 hours.

[0451] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 71.20%, and the area% of the 1,4-adduct as a by-product was 2.02%.

[0452] [Example 34]

[0453] To a 30 mL test tube, 5.0 mg of 4-hydroxyTEMPO, 1.0 g (7.40 mmol, 1.0 eq.) of 4-acetanilide, 1.11 g (12.95 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.76 g (5.18 mmol, 0.7 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 4 hours.

[0454] After the reaction was completed, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 by volume, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 22.86%, and the area% of the 1,4-adduct as a by-product was 11.39%.

[0455] [Example 35]

[0456] To a 30 mL test tube, 5.0 mg of 4-hydroxyTEMPO, 1.0 g (4.78 mmol, 1.0 eq.) of 3,5-dimethoxycarbonylaniline, 0.72 g (8.37 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.49 g (3.35 mmol, 0.7 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 1 hour.

[0457] After the reaction was completed, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 by volume, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 82.31%, and the 1,4-adduct as a by-product was not observed.

[0458] [Example 36]

[0459] To a 30 mL test tube, 10 mg of 4-hydroxyTEMPO, 1.0 g (3.12 mmol, 1.0 eq.) of 2,2-bis(trifluoromethyl)benzidine, 0.94 g (10.93 mmol, 3.50 eq.) of methacrylic acid, and 4.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.64 g (4.37 mmol, 1.40 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 1 hour.

[0460] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 66.08%, and the 1,4-adduct as a by-product was not observed.

[0461] [Example 37]

[0462] To a 30 mL test tube, 5.0 mg of 4-hydroxyTEMPO, 1.0 g (6.21 mmol, 1.0 eq.) of 4-(trifluoromethyl)aniline, 0.94 g (10.86 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of diethyleneglycol dimethyl ether as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.64 g (4.34 mmol, 0.7 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 1 hour.

[0463] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 85.48%, and the 1,4-adduct as a by-product was not observed.

[0464] [Example 38]

[0465] To a 30 mL test tube, 5.0 mg of 4-hydroxyTEMPO, 1.0 g (6.62 mmol, 1.0 eq.) of methyl 4-aminobenzoate, 1.00 g (11.58 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.68 g (4.63 mmol, 0.70 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 1 hour.

[0466] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 48.66%, and the area% of the 1,4-adduct as a by-product was 2.13%.

[0467] [Example 39]

[0468] To a 30 mL test tube, 5.0 mg of 4-hydroxy TEMPO, 1.0 g (6.62 mmol, 1.0 eq.) of methyl 4-aminobenzoate, 1.00 g (11.58 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of sulfolane as a solvent were added and mixed. On the basis of nitrogen substitution in the test tube, 0.68 g (4.63 mmol, 0.70 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 1 hour.

[0469] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 by volume, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 58.40%, and the area% of the 1,4-adduct as a by-product was 1.60%.

[0470] [Example 40]

[0471] To a 30 mL test tube, 5.0 mg of 4-hydroxy TEMPO, 1.0 g (6.62 mmol, 1.0 eq.) of methyl 4-aminobenzoate, 1.00 g (11.58 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of sulfolane as a solvent were added and mixed. On the basis of nitrogen substitution in the test tube, 0.68 g (4.63 mmol, 0.70 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 1 hour.

[0472] After the completion of the reaction, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 by volume, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 58.40%, and the area% of the 1,4-adduct as a by-product was 1.60%.

[0473] [Example 41]

[0474] To a 30 mL test tube, 5.0 mg of 4-hydroxy TEMPO, 1.0 g (6.62 mmol, 1.0 eq.) of methyl 4-aminobenzoate, 1.00 g (11.58 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of sulfolane as a solvent were added and mixed. On the basis of nitrogen substitution in the test tube, 0.68 g (4.63 mmol, 0.70 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 1 hour.

[0475] After the reaction was completed, 10 mg of the resulting reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 30.83%, and the area% of the 1,4-adduct as a by-product was 1.39%.

[0476] [Example 42]

[0477] To a 30 mL test tube, 5.0 mg of 4-hydroxyTEMPO, 1.0 g (6.62 mmol, 1.0 eq.) of methyl 4-aminobenzoate, 1.00 g (11.58 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.68 g (4.63 mmol, 0.70 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 1 hour.

[0478] After the reaction was completed, 10 mg of the resulting reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 88.48%, and the area% of the 1,4-adduct as a by-product was 3.86%.

[0479] [Example 43]

[0480] To a 30 mL test tube, 5.0 mg of 4-hydroxyTEMPO, 1.0 g (6.21 mmol, 1.0 eq.) of 4-(trifluoromethyl)aniline, 0.94 g (10.86 mmol, 1.75 eq.) of methacrylic acid, and 2.0 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed. On the basis of nitrogen substitution in the test tube, 0.64 g (4.34 mmol, 0.7 eq.) of phosphorus pentoxide was added, and heating and stirring were performed at 125°C for 1 hour.

[0481] After the reaction was completed, 10 mg of the resulting reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 88.48%, and the area% of the 1,4-adduct as a by-product was 3.86%.

[0482] [Example 44]

[0483] To a 30 mL test tube, 5.0 mg of 4-hydroxy TEMPO, 1.0 g (7.75 mmol, 1.0 eq.) of 2,4-difluoroaniline, 0.98 g (13.55 mmol, 1.75 eq.) of acrylic acid, and 2.0 mL of N-methylpyrrolidone (NMP) as a solvent were mixed. 0.79 g (5.42 mmol, 0.7 eq.) of phosphorus pentoxide was added on the basis of nitrogen substitution in the test tube, and stirring was performed at 125°C for 1 hour.

[0484] After the reaction was completed, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 77.91%, and the 1,4-adduct as a by-product was not observed.

[0485] [Example 45]

[0486] To a 30 mL test tube, 5.0 mg of 4-hydroxy TEMPO, 1.0 g (7.75 mmol, 1.0 eq.) of 2,4-difluoroaniline, 0.98 g (13.55 mmol, 1.75 eq.) of acrylic acid, and 2.0 mL of 1,3-dimethyl-2-imidazolidinone (DMI) as a solvent were mixed. 0.79 g (5.42 mmol, 0.7 eq.) of phosphorus pentoxide was added on the basis of nitrogen substitution in the test tube, and stirring was performed at 125°C for 1 hour.

[0487] After the reaction was completed, 10 mg of the obtained reaction solution was diluted with 10 mL of a solvent obtained by mixing acetonitrile / dimethyl sulfoxide = 9 / 1 in terms of volume ratio, and analyzed by high-speed liquid chromatography. As a result, the area% of the 1,2-adduct as the target product was 77.91%, and the 1,4-adduct as a by-product was not observed.

[0488] The present application has been described together with embodiments thereof, but is not intended to be limited to any detail of the description unless specifically specified, and it is considered that the present application can be widely interpreted without departing from the spirit of the application shown in the appended claims.

[0489] This application claims priority based on Japanese Patent Application No. 2021-089874 filed on May 28, 2021, Japanese Patent Application No. 2021-188898 filed on November 19, 2021, and Japanese Patent Application No. 2022-046961 filed on March 23, 2022 in Japan, the contents of which are referred to herein and incorporated by reference as part of the description of this specification.

Claims

1. A method for producing an N-(hetero)aryl(meth)acrylamide compound, comprising a step of amidating a compound represented by the following general formula (1) with a compound represented by the following general formula (2) at a temperature exceeding 120°C to obtain a compound represented by the following general formula (3), [Chemical Formula 1] [Chemical Formula 2] In each of the formulae, R 1 represents a hydrogen atom or an aliphatic group, R 2 represents a hydrogen atom, a chain aliphatic group, an aliphatic hydrocarbon ring group, an aryl group or a heterocyclic group, Ar represents an aromatic ring, R 3 represents a group selected from an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a carbamoyl group, an alkylsulfonyl group, an arylsulfonyl group, a sulfamoyl group, a cyano group, a nitro group and a halogen atom, m is an integer of 1 or more, R 4 represents a chain aliphatic group, an aliphatic hydrocarbon ring group, an aryl group or a heterocyclic group, n is an integer of 0 or more, wherein, R 4 will not be an α-hydroxybenzyl group, the maximum value of m+n being the maximum number of substituents that the ring-forming atoms of Ar can have, The amidation reaction is performed in the presence of at least one reaction catalyst, The reaction catalyst is at least one of a Lewis acid, a Brønsted acid, a metal oxide, and a phosphorus oxide compound.

2. The method for producing according to claim 1, wherein As the reaction catalyst, at least one of a Lewis acid, a Brønsted acid, and a phosphorus oxide compound is used.

3. The method for producing according to claim 1 or 2, wherein The reaction temperature of the amidation reaction is set to 130°C or higher.

4. The method for producing according to claim 3, wherein The reaction temperature of the amidation reaction is set to 140°C or higher.

5. The method for producing according to claim 1 or 2, wherein The Ar represents a benzene ring.

6. The method for producing according to claim 5, wherein R represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. 1 R represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

7. The method for producing according to claim 5, wherein The m is an integer of 1 to 3, and the n is an integer of 0 to 4.

8. The method for producing according to claim 1 or 2, wherein The reaction temperature of the amidation reaction is controlled by microwave irradiation.

9. The method for producing according to claim 1 or 2, wherein The amidation reaction is performed in a flow type reaction.

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