CN117597332A

CN117597332A - Process for producing uracil compound

Info

Publication number: CN117597332A
Application number: CN202280047464.0A
Authority: CN
Inventors: 石原拓真; 幸堀伸哉; 寺西贵昭
Original assignee: Nippon Soda Co Ltd
Current assignee: Nippon Soda Co Ltd
Priority date: 2021-07-13
Filing date: 2022-07-11
Publication date: 2024-02-23

Abstract

The present invention addresses the problem of providing an industrially advantageous process for producing a uracil compound, which is an intermediate for producing a 2, 6-dioxo-3, 6-dihydropyrimidine compound, and an ureido-methylene compound that is a raw material for the uracil compound. The present invention is characterized in that a uracil compound which is an intermediate for producing a 2, 6-dioxo-3, 6-dihydropyrimidine compound is produced by chemically reacting a compound represented by the following formula (II) or a salt thereof in the presence of an organic base or an inorganic base. In the formula (II), X ¹ Represents a hydrogen atom, or a substituted or unsubstituted C1-6 alkyl group, X ² Representing hydrogen atomsSubstituted or unsubstituted straight-chain C1-6 alkyl, etc., R ¹ Represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group or the like, R ² Represents a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group, R ³ Represents a substituted or unsubstituted C1-6 alkyl group or the like.

Description

Process for producing uracil compound

Technical Field

The present invention relates to a method for producing an uracil compound, which is an intermediate for producing a 2, 6-dioxo-3, 6-dihydropyrimidine compound that is useful as an active ingredient of an agricultural/horticultural fungicide, and an ureido-methylene compound that is a raw material for the uracil compound.

The present application claims priority from japanese patent application nos. 2021-115884, filed on 7/13/2021, and from japanese patent application nos. 2021-131516, filed on 8/12/2021, the contents of which are incorporated herein.

Background

Various compounds have been proposed which have a control activity against diseases of crops when agricultural and horticultural crops are cultivated. In order to actually use such a compound as an agricultural/horticultural fungicide, it is required that the efficacy is sufficiently high, that resistance to drugs is not easily generated, that phytotoxicity to plants is not caused, that soil pollution is not caused, and that toxicity to livestock, fish, and the like is low.

However, patent document 1 discloses a compound represented by formula (a) (sometimes referred to as "2, 6-dioxo-3, 6-dihydropyrimidine compound"), and the like. The compound has bactericidal activity, antifungal activity and the like.

[ chemical formula 1]

As an intermediate for producing the compound, a compound represented by the formula (B) and the like are disclosed.

[ chemical formula 2]

Prior art literature

Patent literature

Patent document 1: WO2021/085389A

Disclosure of Invention

Problems to be solved by the invention

The present invention addresses the problem of providing an industrially advantageous process for producing a uracil compound, which is an intermediate for producing a 2, 6-dioxo-3, 6-dihydropyrimidine compound, and an ureido-methylene compound that is a raw material for the uracil compound.

Means for solving the problems

The inventors of the present application have conducted intensive studies to solve the above-described problems, and as a result, have completed the present invention including the following aspects.

〔1〕

A process for producing a compound represented by the following formula (I) or a salt thereof, which comprises chemically reacting a compound represented by the following formula (II) or a salt thereof in the presence of an organic base or an inorganic base.

[ chemical formula 3]

In the formula (I) of the formula (I),

X ¹ represents a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group;

R ¹ represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group of a 5-6 membered ring;

R ² represents a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group;

X ² represents a hydrogen atom, a substituted or unsubstituted linear C1-6 alkyl group, a substituted or unsubstituted linear C2-6 alkenyl group, a substituted or unsubstituted linear C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, a substituted or unsubstituted 4-6 membered ring heterocyclic group, R ^N R ^N A group represented by N-and R ^N -CO-NR ^N -a group represented by R ^N -CO-CO-NR ^N -a group represented by R ^N -O-CO-NR ^N -a group represented by R ^N R ^N N-CO-NR ^N -a group represented by R ^N R ^N N-CO-CO-NR ^e -a group represented by R ^N -CS-NR ^N -a group represented by R ^N R ^N N-CS-NR ^N -a group represented by R ^N SO ₂ -NR ^N -a group represented by, or R ^N -C(＝NR ^N )-NR ^N -a group represented;

R ^N each independently represents a hydrogen atom, a substituted or unsubstituted linear C1-6 alkyl group, a substituted or unsubstituted linear C2-6 alkenyl group, a substituted or unsubstituted linear C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having a 4-6 membered ring, wherein R ^N And R is R ^N Together, divalent organic groups may be formed. A kind of electronic device

[ chemical formula 4]

[ in formula (II), R ¹ 、R ² 、X ¹ X is X ² Meaning the same as in formula (I),

R ³ represents a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, or a substituted or unsubstituted C6-10 aryl group. A kind of electronic device

〔2〕

The process according to [ 1 ]The method, wherein X ² R is R ^N The substituents on the straight-chain C1-6 alkyl, the substituents on the straight-chain C2-6 alkenyl, the substituents on the straight-chain C2-6 alkynyl, the substituents on the C3-6 cycloalkyl, the substituents on the C6-10 aryl, or the substituents on the heterocyclic group of the 4-6 membered ring are:

Selected from the group consisting of halo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, substituted or unsubstituted C2-6 alkynyloxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylsulfinyl, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkyloxy, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryloxy, substituted or unsubstituted C6-10 arylthio, substituted or unsubstituted C6-10 arylsulfinyl, substituted or unsubstituted C6-10 arylsulfonyl, substituted or unsubstituted 3-10 membered heterocyclic, substituted or unsubstituted 3-membered heterocyclic, substituted or unsubstituted heterocyclic, R, nitro, cyano ^a -CO-represented group, carboxyl group, R ^b -O-CO-represented group, R ^c R ^d A group represented by N-and R ^c R ^d A group represented by N-CO-, R ^c R ^d N-NR ^d -CO-represented group, R ^b SO ₂ -NR ^d -CO-represented group, R ^a -a group represented by CO-O-, R ^a -CO-NR ^e -a group represented by R ^a -CO-CO-NR ^e -a group represented by R ^a -CO-NR ^e -NR ^e -a group represented by R ^a -CO-NR ^e -NR ^e -CO-represented group, R ^b -O-CO-O-represented group, R ^b -O-CO-NR ^e -a group represented by R ^c R ^d A group represented by N-CO-O-, R ^c R ^d N-CO-NR ^e -a group represented by R ^c R ^d N-CO-CO-NR ^e -a group represented by R ^a -CS-NR ^e -a group represented by R ^c R ^d N-CS-NR ^e -a group represented by R ^b SO ₂ -NR ^e -a group represented by R ^c R ^d N-SO ₂ -a group represented by R ^a O-N＝CR ^f -a group represented by R ^h R ⁱ c=n-O-, R ^a -C(＝NR ^g )-NR ^e -a group represented by R ^c R ^d N-C(＝NR ^g ) -a group represented by R ^h R ⁱ S (=o) =n—co-, and R ^h R ⁱ S=n—co-, 1 or 2 or more substituents in the group consisting of groups represented by;

R ^a each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having a 3-10 membered ring,

R ^b each independently represents a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group of a 5-6 membered ring,

R ^c each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having 5 to 6 ring members,

R ^d Each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C1-6 alkoxy group, or a substituted or unsubstituted C6-10 aryl group, wherein R ^c And R is R ^d May together form a divalent organic group,

R ^e each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C1-6 alkoxy group, or a substituted or unsubstituted C6-10 aryl group,

R ^f represents a hydrogen atom, an amino group, or a substituted or unsubstituted C1-6 alkyl group,

R ^g each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C6-10 aryl group,

R ^h each independently represents a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C6-10 aryl group,

R ⁱ each independently represents a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C6-10 aryl group, wherein R ^h And R is R ⁱ May together form a divalent organic group;

when there are more than 2 substituents on the linear C1-6 alkyl group, 2 of them may form a divalent organic group together.

〔3〕

A compound represented by the formula (II) or a salt thereof.

[ chemical formula 5]

[ in the formula (II),

R ¹ Represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having 5-6 membered ring,

X ² represents a hydrogen atom, a substituted or unsubstituted linear C1-6 alkyl group, a substituted or unsubstituted linear C2-6 alkenyl group, a substituted or unsubstituted linear C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, a substituted or unsubstituted 4-6 membered ring heterocyclic group, R ^N R ^N N-representsR is a group of (2) ^N -CO-NR ^N -a group represented by R ^N -CO-CO-NR ^N -a group represented by R ^N -O-CO-NR ^N -a group represented by R ^N R ^N N-CO-NR ^N -a group represented by R ^N R ^N N-CO-CO-NR ^e -a group represented by R ^N -CS-NR ^N -a group represented by R ^N R ^N N-CS-NR ^N -a group represented by R ^N SO ₂ -NR ^N -a group represented by, or R ^N -C(＝NR ^N )-NR ^N -a group represented;

R ^N each independently represents a hydrogen atom, a substituted or unsubstituted linear C1-6 alkyl group, a substituted or unsubstituted linear C2-6 alkenyl group, a substituted or unsubstituted linear C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having 4 to 6 membered rings, R ^N And R is R ^N May together form a divalent organic group;

〔4〕

The compound according to [ 3 ], wherein X ² R is R ^N The substituents on the straight-chain C1-6 alkyl, the substituents on the straight-chain C2-6 alkenyl, the substituents on the straight-chain C2-6 alkynyl, the substituents on the C3-6 cycloalkyl, the substituents on the C6-10 aryl, or the substituents on the heterocyclic group of the 4-6 membered ring are:

selected from the group consisting of halo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, substituted or unsubstituted C2-6 alkynyloxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylsulfinyl, substituted or unsubstituted C1-6 alkylsulfonylC3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkyloxy, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryloxy, substituted or unsubstituted C6-10 arylthio, substituted or unsubstituted C6-10 arylsulfinyl, substituted or unsubstituted C6-10 arylsulfonyl, substituted or unsubstituted 3-10 membered heterocyclic group oxy, nitro, cyano, R ^a -CO-represented group, carboxyl group, R ^b -O-CO-represented group, R ^c R ^d A group represented by N-and R ^c R ^d A group represented by N-CO-, R ^c R ^d N-NR ^d -CO-represented group, R ^b SO ₂ -NR ^d -CO-represented group, R ^a -a group represented by CO-O-, R ^a -CO-NR ^e -a group represented by R ^a -CO-CO-NR ^e -a group represented by R ^a -CO-NR ^e -NR ^e -a group represented by R ^a -CO-NR ^e -NR ^e -CO-represented group, R ^b -O-CO-O-represented group, R ^b -O-CO-NR ^e -a group represented by R ^c R ^d A group represented by N-CO-O-, R ^c R ^d N-CO-NR ^e -a group represented by R ^c R ^d N-CO-CO-NR ^e -a group represented by R ^a -CS-NR ^e -a group represented by R ^c R ^d N-CS-NR ^e -a group represented by R ^b SO ₂ -NR ^e -a group represented by R ^c R ^d N-SO ₂ -a group represented by R ^a O-N＝CR ^f -a group represented by R ^h R ⁱ c=n-O-, R ^a -C(＝NR ^g )-NR ^e -a group represented by R ^c R ^d N-C(＝NR ^g ) -a group represented by R ^h R ⁱ S (=o) =n—co-, and R ^h R ⁱ S=n—co-, 1 or 2 or more substituents in the group consisting of groups represented by;

R ^a each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a substituted or unsubstituted C1-6 alkenyl groupSubstituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted heterocyclic group of 3-10 membered ring,

Effects of the invention

By using an ureido methylene compound as a raw material, an uracil compound which is an intermediate for producing a 2, 6-dioxo-3, 6-dihydropyrimidine compound can be industrially advantageously produced.

Detailed Description

[ uracil Compound and ureido methylene Compound ]

The present invention is a process for producing a compound represented by formula (I) or a salt thereof (sometimes referred to as "uracil compound"), which comprises chemically reacting a compound represented by formula (II) or a salt thereof (sometimes referred to as "ureido methylene compound") in the presence of an organic base or an inorganic base.

The following shows formula (I).

[ chemical formula 6]

Next, formula (II) is shown.

[ chemical formula 7]

Next, the meaning of the symbols in the formula (I) and the formula (II) will be described.

〔X ¹ 〕

X ¹ Represents a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group.

〔R ¹ 〕

R ¹ Represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group of a 5-6 membered ring.

〔R ² 〕

R ² Represents a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group.

〔X ² 、R ^N 〕

R ^N each independently represents a hydrogen atom, a substituted or unsubstituted linear C1-6 alkyl group, a substituted or unsubstituted linear C2-6 alkenyl group, a substituted or unsubstituted linear C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having a 4-6 membered ring.

Wherein R is ^N And R is R ^N Together, divalent organic groups may be formed.

〔R ³ 〕

R ³ Represents a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, or a substituted or unsubstituted C6-10 aryl group.

〔R ¹ 、R ² 、R ³ 、R ^N 、X ¹ X is X ² Specific examples of substituents in (a)

"C1-6 alkyl" may be straight-chain or branched. Examples of the "C1-6 alkyl" include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 2-methylbutyl, and isohexyl.

Examples of the "C2-6 alkenyl" include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.

Examples of the "C2-6 alkynyl" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-pentynyl, 1-hexynyl, and 1, 1-dimethyl-2-butynyl.

Examples of the "C3-6 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Examples of the "C6-10 aryl group" include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl (tetralinyl) and the like.

The "heterocyclic group of 4 to 6 membered ring" is a group containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom as constituent atoms of the ring. When the number of the hetero atoms is 2 or more, they may be the same or different. Examples of the "heterocyclic group having 4 to 6 ring members" include saturated heterocyclic groups having 4 to 6 ring members, heteroaryl groups having 5 to 6 ring members, and partially unsaturated heterocyclic groups having 5 to 6 ring members. The same applies to "heterocyclic group having 5 to 6 ring members" except for the case of 4 ring members.

Examples of the saturated heterocyclic group having a 4-membered ring include an azetidinyl group and an oxetanyl group.

Examples of the saturated heterocyclic group having a 5-to 6-membered ring include pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, morpholinyl, dioxolanyl, and dioxanyl groups.

Examples of the heteroaryl group having a 5-to 6-membered ring include heteroaryl groups having a 5-membered ring such as a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a tetrazolyl group; heteroaryl groups of 6-membered rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

Examples of the partially unsaturated heterocyclic group having 5 to 6 membered ring include partially unsaturated heterocyclic groups having 5 membered ring such as pyrrolinyl, dihydrofuryl, imidazolinyl, pyrazolinyl, oxazolinyl and isoxazolinyl; partially unsaturated heterocyclic groups of 6-membered ring such as dihydropyranyl group.

Examples of the "linear C1-6 alkyl" include methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.

Examples of the "straight-chain C2-6 alkenyl group" include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.

Examples of the "straight-chain C2-6 alkynyl" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, and 1-hexynyl.

The substituent on "C1-6 alkyl", "C2-6 alkenyl" or "C2-6 alkynyl" is preferably: halo groups such as fluoro, chloro, bromo and iodo; a hydroxyl group; c1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy; c1-6 haloalkoxy such as 2-chloro-n-propoxy, 2, 3-dichlorobenzoxy, trifluoromethoxy and the like; c3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; phenyl, naphthyl and other C6-10 aryl groups; c6-10 aryl groups substituted with 1 or more substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, halogen groups, C1-6 haloalkyl groups and C1-6 haloalkoxy groups, such as 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4-trifluoromethylphenyl groups; heteroaryl groups having a 5-membered ring such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc.; heteroaryl of 5 membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl groups having a 6-membered ring such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.; heteroaryl of a 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; or cyano.

The substituent on "C3-6 cycloalkyl", "C6-10 aryl" or "heterocyclic group of 5-6 membered ring" is preferably: halo groups such as fluoro, chloro, bromo and iodo; c1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl; c1-6 haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, 1, 2-dichloro-n-propyl, 1-fluoro-n-butyl and the like; a hydroxyl group; c1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy; c1-6 haloalkoxy such as 2-chloro-n-propoxy, 2, 3-dichlorobenzoxy, trifluoromethoxy and the like; phenyl, naphthyl and other C6-10 aryl groups; c6-10 aryl groups substituted with 1 or more substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, halogen groups, C1-6 haloalkyl groups and C1-6 haloalkoxy groups, such as 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4-trifluoromethylphenyl groups; heteroaryl groups having a 5-membered ring such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc.; heteroaryl of 5 membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl groups having a 6-membered ring such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.; heteroaryl of a 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; or cyano.

Further, as a substituent on the "C3-6 cycloalkyl" or "heterocyclic group of 5-6 membered ring", an oxo group is also preferable.

Examples of the "divalent organic groups which may be formed together" include a substituted or unsubstituted C2-5 alkylene group, a substituted or unsubstituted C1-3 alkyleneoxy C1-3 alkylene group, a substituted or unsubstituted C1-3 alkylenethio C1-3 alkylene group, and a substituted or unsubstituted C1-3 alkyleneimino C1-3 alkylene group.

Further, there may be mentioned-CH ₂ CH ₂ -Si(CH ₃ ) ₂ -CH ₂ CH ₂ -and the like 2-valent hydrocarbon groups containing silicon.

Examples of the "C2-5 alkylene" include dimethylene, trimethylene and tetramethylene.

Examples of the "C1-3 alkylene oxide C1-3 alkylene" include dimethyleneoxy dimethylene and the like.

Examples of the "C1-3 alkylene-thio-C1-3 alkylene" include dimethylene-thio-dimethylene.

Examples of the "C1-3 alkylidenimino C1-3 alkylene" include dimethyleneiminodimethylene and the like.

As used herein, the imino group of "C1-3 alkylidenimino C1-3 alkylene" refers to-NH-.

The substituents on "C2-5 alkylene", "C1-3 alkyleneoxy C1-3 alkylene", "C1-3 alkylenethio C1-3 alkylene" and "C1-3 alkyleneimino C1-3 alkylene" are preferably: halo groups such as fluoro, chloro, bromo and iodo; c1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; methylene (methylene); or a C1-6 haloalkyl group such as chloromethyl, chloroethyl, trifluoromethyl, 1, 2-dichloro-n-propyl, 1-fluoro-n-butyl, etc.

〔G〕

The substituent on the "linear C1-6 alkyl group", the substituent on the "linear C2-6 alkenyl group", the substituent on the "linear C2-6 alkynyl group", the substituent on the "C3-6 cycloalkyl group", the substituent on the "C6-10 aryl group" or the substituent on the "heterocyclic group of 4-6 membered ring" may be exemplified by 1 or 2 or more substituents selected from the following substituent groups (hereinafter, the substituent may be represented by the symbol "G").

In addition, in the case where there are 2 or more substituents (G), 2 of them may form a divalent organic group together.

The substituent groups are shown below.

Halo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, substituted or unsubstituted C2-6 alkynyloxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylsulfinyl, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkyloxy, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryloxy, substituted or unsubstituted C6-10 arylthio, substituted or unsubstituted C6-10 arylsulfinyl, substituted or unsubstituted C6-10 arylsulfonyl, substituted or unsubstituted 3-10 membered heterocyclic group, nitro, cyano, R ^a -CO-represented group, carboxyl group, R ^b -O-CO-represented group, R ^c R ^d A group represented by N-and R ^c R ^d A group represented by N-CO-, R ^c R ^d N-NR ^d -CO-represented group, R ^b SO ₂ -NR ^d -CO-represented group, R ^a -a group represented by CO-O-, R ^a -CO-NR ^e -a group represented by R ^a -CO-CO-NR ^e -a group represented by R ^a -CO-NR ^e -NR ^e -a group represented by R ^a -CO-NR ^e -NR ^e -CO-represented group, R ^b -O-CO-O-represented group, R ^b -O-CO-NR ^e Represented byRadicals, R ^c R ^d A group represented by N-CO-O-, R ^c R ^d N-CO-NR ^e -a group represented by R ^c R ^d N-CO-CO-NR ^e -a group represented by R ^a -CS-NR ^e -a group represented by R ^c R ^d N-CS-NR ^e -a group represented by R ^b SO ₂ -NR ^e -a group represented by R ^c R ^d N-SO ₂ -a group represented by R ^a O-N＝CR ^f -a group represented by R ^h R ^j c=n-O-, R ^a -C(＝NR ^g )-NR ^e -a group represented by R ^c R ^d N-C(＝NR ^g ) -a group represented by R ^h R ⁱ S (=o) =n—co-, and R ^h R ⁱ S=n—co-.

In the substituent group, R ^a Each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group of a 3-10 membered ring.

R ^b Each independently represents a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group of a 5-6 membered ring.

R ^c Each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group of a 5-6 membered ring.

R ^d Each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C1-6 alkoxy group, or a substituted or unsubstituted C6-10 aryl group, wherein R ^c And R is R ^d Together, divalent organic groups may be formed.

R ^e Each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C1-6 alkoxy group, or a substituted or unsubstituted C6-10 aryl group.

R ^f Represents a hydrogen atom, an amino group, or a substituted or unsubstituted C1-6 alkyl group.

R ^g Each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C6-10 aryl group.

R ^h Each independently represents a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C6-10 aryl group.

R ⁱ Each independently represents a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C6-10 aryl group, wherein R ^h And R is R ⁱ Together, divalent organic groups may be formed.

Examples of the "halo" in G include fluoro, chloro, bromo, and iodo.

The "C1-6 alkyl" in G may be a straight chain or branched chain. Examples of the "C1-6 alkyl" include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 2-methylbutyl, and isohexyl. Examples of the "C2-6 alkenyl" include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like. Examples of the "C2-6 alkynyl" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-pentynyl, 1-hexynyl, and 1, 1-dimethyl-2-butynyl.

Examples of the "C1-6 alkoxy" in G include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, and isohexyloxy. Examples of the "C2-6 alkenyloxy" include vinyloxy, allyloxy, propenyloxy, butenyloxy and the like. Examples of the "C2-6 alkynyloxy group" include ethynyloxy groups and propargyloxy groups.

Examples of the "C1-6 alkylthio group" in G include a methylthio group, an ethylthio group, a n-propylthio group, a n-butylthio group, a n-pentylthio group, a n-hexylthio group, and an isopropylthio group. Examples of the "C1-6 alkylsulfinyl" include methylsulfinyl, ethylsulfinyl, and tert-butylsulfinyl. Examples of the "C1-6 alkylsulfonyl" include methylsulfonyl, ethylsulfonyl, tert-butylsulfonyl and the like.

The substituents on "C1-6 alkyl", "C2-6 alkenyl", "C2-6 alkynyl", "C1-6 alkoxy", "C2-6 alkenyloxy", "C2-6 alkynyloxy", "C1-6 alkylthio", "C1-6 alkylsulfinyl" or "C1-6 alkylsulfonyl" in G are preferably: halo groups such as fluoro, chloro, bromo and iodo; a hydroxyl group; c1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy; c1-6 haloalkoxy such as 2-chloro-n-propoxy, 2, 3-dichlorobenzoxy, trifluoromethoxy and the like; c1-6 alkylthio groups such as methylthio and ethylthio: c1-6 alkylsulfinyl such as methylsulfinyl and ethylsulfinyl; c1-6 alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; c3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; phenyl, naphthyl and other C6-10 aryl groups; c6-10 aryl groups substituted with 1 or more substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, halogen groups, C1-6 haloalkyl groups and C1-6 haloalkoxy groups, such as 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4-trifluoromethylphenyl groups; heteroaryl groups having a 5-membered ring such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc.; heteroaryl of 5 membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl groups having a 6-membered ring such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.; heteroaryl of a 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; or cyano.

Examples of the "C3-6 cycloalkyl group" in G include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the "C3-6 cycloalkyloxy group" include cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group and the like.

Examples of the "C6-10 aryl" in G include phenyl and naphthyl. Examples of the "C6-10 aryloxy group" include phenoxy group and naphthoxy group.

Examples of the "C6-10 arylthio" in G include phenylthio and naphthylthio. Examples of the "C6-10 arylsulfinyl" include phenylsulfinyl and naphthylsulfinyl. Examples of the "C6-10 arylsulfonyl" include phenylsulfonyl and naphthylsulfonyl.

The "heterocyclic group having 3 to 10 ring members" in G is a group containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom as ring constituent atoms. When the number of the hetero atoms is 2 or more, they may be the same or different. May be either one of monocyclic ring and polycyclic ring.

Examples of the "heterocyclic group having 3 to 10 ring members" include saturated heterocyclic groups having 3 to 6 ring members, heteroaryl groups having 5 to 10 ring members, and partially unsaturated heterocyclic groups having 5 to 10 ring members.

Examples of the saturated heterocyclic group having 3 to 6 membered ring include aziridinyl, epoxy, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl and the like.

Examples of the heteroaryl group having a 5-to 10-membered ring include heteroaryl groups having a 5-membered ring such as a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a tetrazolyl group; heteroaryl groups having a 6-membered ring such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.; 9-membered heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl and the like; quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and other 10 membered heteroaryl groups.

Examples of the partially unsaturated heterocyclic group having 5 to 10 membered ring include a partially unsaturated heterocyclic group having 5 membered ring such as pyrrolinyl, dihydrofuryl, imidazolinyl, pyrazolinyl, oxazolinyl, isoxazolinyl and the like; partially unsaturated heterocyclic groups of 6-membered ring such as dihydropyranyl; partially unsaturated heterocyclic groups of 9-membered ring such as indolinyl, isoindolinyl, 2, 3-dihydrobenzofuranyl, 1, 3-dihydrobenzofuranyl and the like; partially unsaturated heterocyclic groups having 10-membered rings such as 1,2,3, 4-tetrahydroquinolinyl.

The "3-to 10-membered heterocyclic oxy group" in G has a structure in which a 3-to 10-membered heterocyclic group is bonded to an oxy group. Specific examples thereof include thiazolyloxy and pyridyloxy.

The substituents on "C3-6 cycloalkyl", "C3-6 cycloalkyloxy", "C6-10 aryl", "C6-10 aryloxy", "C6-10 arylthio", "C6-10 arylsulfinyl", "C6-10 arylsulfonyl", "3-10 membered ring heterocyclic group" or "3-10 membered ring heterocyclic group oxy" in G are preferably:

halo groups such as fluoro, chloro, bromo and iodo; c1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl; c1-6 haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, 1, 2-dichloro-n-propyl, 1-fluoro-n-butyl and the like; a hydroxyl group; c1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy; c1-6 haloalkoxy such as 2-chloro-n-propoxy, 2, 3-dichlorobenzoxy, trifluoromethoxy and the like; c3-6 cycloalkyl C1-6 alkoxy; c6-10 aryl C1-6 alkoxy; (C6-10 aryl group substituted with 1 or more substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy); heteroaryl C1-6 alkoxy of 5 membered ring; (heteroaryl of a 5-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy); heteroaryl C1-6 alkoxy of a 6 membered ring; (heteroaryl of a 6-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy); c1-6 alkylthio groups such as methylthio and ethylthio: c1-6 alkylsulfinyl such as methylsulfinyl and ethylsulfinyl; c1-6 alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; c1-6 haloalkylthio such as trifluoromethylthio and 2, 2-trifluoroethylthio: c1-6 haloalkylsulfinyl such as trifluoromethylsulfinyl and 2, 2-trifluoroethylsulfinyl; c1-6 haloalkylsulfonyl such as trifluoromethylsulfonyl and 2, 2-trifluoroethylsulfonyl; c3-6 cycloalkyl groups such as cyclopropyl and cyclobutyl; c3-6 cycloalkyl substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, C1-6 haloalkoxy and cyano; c3-6 cycloalkenyl; phenyl, naphthyl and other C6-10 aryl groups; c6-10 aryl groups substituted with 1 or more substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, halogen groups, C1-6 haloalkyl groups and C1-6 haloalkoxy groups, such as 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4-trifluoromethylphenyl groups; saturated heterocyclic groups of 3 to 4 membered rings such as aziridinyl, epoxy, azetidinyl and oxetanyl; saturated heterocyclic groups of 3-to 4-membered rings substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; saturated heterocyclic groups of 5 to 6 membered rings such as pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, and the like; saturated heterocyclic group of 5-to 6-membered ring substituted by any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl groups having a 5-membered ring such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc.; heteroaryl of 5 membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl groups having a 6-membered ring such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.; heteroaryl of a 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; a partially unsaturated heterocyclic group having a 5-membered ring such as pyrrolinyl, dihydrofuryl, imidazolinyl, pyrazolinyl, oxazolinyl, isoxazolinyl, etc.; a partially saturated heterocyclic group of a 5-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; partially unsaturated heterocyclic groups of 6-membered ring such as dihydropyranyl; a partially saturated heterocyclic group of a 6-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy;

R ^G1 -a group represented by CO- (wherein R ^G1 Represents a hydrogen atom; c1-6 alkyl; c1-6 alkyl substituted with any 1 or more substituents selected from halo, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, phenyl or heteroaryl of a 5-6 membered ring; (C6-10 aryl) C1-6 alkyl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; (heteroaryl of a 5-to 6-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy); c2-6 alkenyl; c2-6 halogenated alkenyl; c2-6 alkynyl; c2-6 haloalkynyl; c3-6 cycloalkyl; is C1-6 alkyl, C1-6 alkoxy,C3-6 cycloalkyl substituted by more than 1 substituent selected from halo, C1-6 haloalkyl, C1-6 haloalkoxy or cyano; c6-10 aryl; c6-10 aryl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl of 5-6 membered ring; or alternatively; heteroaryl of 5-to 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy. R is as follows ^G1 The same applies to the above. ) The method comprises the steps of carrying out a first treatment on the surface of the

A carboxyl group;

R ^G2 -O-CO-represented group (wherein R ^G2 Represents a C1-6 alkyl group; c1-6 alkyl substituted with any 1 or more substituents selected from halo, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, phenyl or heteroaryl of a 5-6 membered ring; (C6-10 aryl) C1-6 alkyl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; (heteroaryl of a 5-to 6-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy); c2-6 alkenyl; c2-6 halogenated alkenyl; c2-6 alkynyl; c2-6 haloalkynyl; c3-6 cycloalkyl; c3-6 cycloalkyl substituted by C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, C1-6 haloalkoxy or cyano; c6-10 aryl; c6-10 aryl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl of 5-6 membered ring; or alternatively; heteroaryl of 5-to 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy. R is as follows ^G2 The same applies to the above. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^G1 R ^G1 A group represented by N-wherein R ^G1 May be the same or different. R is R ^G1 Can form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-diine groupMethyl group. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^G1 R ^G1 A group represented by N-CO- (R in the formula ^G1 May be the same or different. R is R ^G1 May form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^G1 -a group represented by CO-O-;

R ^G1 -CO-NR ^G3 a group represented by (wherein R ^G3 Represents a hydrogen atom; c1-6 alkyl; c1-6 alkyl substituted with any 1 or more substituents selected from halo, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, phenyl or heteroaryl of a 5-6 membered ring; (C6-10 aryl) C1-6 alkyl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; or (heteroaryl of a 5-to 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy). R is as follows ^G3 The same applies to the above. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^G2 -a group represented by O-CO-O-;

R ^G2 -O-CO-NR ^G3 -a group represented;

R ^G1 R ^G1 A group represented by N-CO-O- (R in the formula ^G1 May be the same or different. R is R ^G1 May form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^G1 R ^G1 N-CO-NR ^G3 A group represented by (R in the formula ^G1 May be the same or different. R is R ^G1 May form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^G2 SO ₂ -NR ^G3 -a group represented;

R ^G1 R ^G1 N-SO ₂ a group represented by (R in the formula ^G1 May be the same or different. R is R ^G1 Can form together trimethylene and tetramethyleneMethylene, pentamethylene, or dimethyleneoxy dimethylene. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^G1 -O-N＝C(R ^G4 ) A group represented by (wherein R ^G4 Represents a hydrogen atom or a C1-6 alkyl group. ) The method comprises the steps of carrying out a first treatment on the surface of the

(R ^G1 ) ₂ A group represented by c=n-O (R in the formula ^G1 May be the same or different. R is R ^G1 May form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

Pentafluorosulfanyl, nitro or cyano.

Further, as the substituent on "C3-6 cycloalkyl", "C3-6 cycloalkyloxy", "heterocyclic group of 3-10 membered ring" or "heterocyclic oxy of 3-10 membered ring", oxo group is also preferable.

"R" in G ^a -CO-represented group "wherein R ^a Represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having a 3-10 membered ring.

As R ^a Examples of the "C1-6 alkyl" in (a) include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 2-methylbutyl, isohexyl and the like. Examples of the "C2-6 alkenyl" include vinyl and 1-propenyl. Examples of the "C2-6 alkynyl" include ethynyl and 1-propynyl.

As R ^a The substituents on "C1-6 alkyl", "C2-6 alkenyl" or "C2-6 alkynyl" in (a) are preferably: halo groups such as fluoro, chloro, bromo and iodo; a hydroxyl group; c1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy; c1-6 haloalkoxy such as 2-chloro-n-propoxy, 2, 3-dichlorobenzoxy, trifluoromethoxy and the like; c1-6 alkylthio groups such as methylthio and ethylthio: methylsulfinyl group ethylsulfenate C1-6 alkylsulfinyl such as acyl; c1-6 alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; a carboxyl group; c1-6 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl; c3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; phenyl, naphthyl and other C6-10 aryl groups; c6-10 aryl groups substituted with 1 or more substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, halogen groups, C1-6 haloalkyl groups and C1-6 haloalkoxy groups, such as 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4-trifluoromethylphenyl groups; heteroaryl groups having a 5-membered ring such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc.; heteroaryl of 5 membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl groups having a 6-membered ring such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.; heteroaryl of a 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; or cyano.

As R ^a Examples of the "C3-6 cycloalkyl" in (a) include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the "C6-10 aryl group" include phenyl, naphthyl, indenyl, indanyl, and tetrahydronaphthyl.

R ^a The "heterocyclic group having 3 to 10 ring members" in (a) is a group containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom as ring constituent atoms. When the number of the hetero atoms is 2 or more, they may be the same or different. May be either one of monocyclic ring and polycyclic ring.

As R ^a The substituents on "C3-6 cycloalkyl", "C6-10 aryl" or "heterocyclic group of 3-10 membered ring" in (a) are preferably:

halo groups such as fluoro, chloro, bromo and iodo; c1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl; c1-6 haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, 1, 2-dichloro-n-propyl, 1-fluoro-n-butyl and the like; a hydroxyl group; c1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy; c1-6 haloalkoxy such as 2-chloro-n-propoxy, 2, 3-dichlorobenzoxy, trifluoromethoxy and the like; c3-6 cycloalkyl C1-6 alkoxy; c6-10 aryl C1-6 alkoxy; (C6-10 aryl group substituted with 1 or more substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy); heteroaryl C1-6 alkoxy of 5 membered ring; (heteroaryl of a 5-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy); heteroaryl C1-6 alkoxy of a 6 membered ring; (heteroaryl of a 6-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy); c1-6 alkylthio groups such as methylthio and ethylthio: c1-6 alkylsulfinyl such as methylsulfinyl and ethylsulfinyl; c1-6 alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; c1-6 haloalkylthio such as trifluoromethylthio and 2, 2-trifluoroethylthio: c1-6 haloalkylsulfinyl such as trifluoromethylsulfinyl and 2, 2-trifluoroethylsulfinyl; c1-6 haloalkylsulfonyl such as trifluoromethylsulfonyl and 2, 2-trifluoroethylsulfonyl; c3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl and cyclopentyl; c3-6 cycloalkyl substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, C1-6 haloalkoxy and cyano; c3-6 cycloalkenyl; phenyl, naphthyl and other C6-10 aryl groups; c6-10 aryl groups substituted with 1 or more substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, halogen groups, C1-6 haloalkyl groups and C1-6 haloalkoxy groups, such as 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4-trifluoromethylphenyl groups; saturated heterocyclic groups of 3 to 4 membered rings such as aziridinyl, epoxy, azetidinyl and oxetanyl; saturated heterocyclic groups of 3-to 4-membered rings substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; saturated heterocyclic groups of 5 to 6 membered rings such as pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, and the like; saturated heterocyclic group of 5-to 6-membered ring substituted by any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl groups having a 5-membered ring such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc.; heteroaryl of 5 membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl groups having a 6-membered ring such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.; heteroaryl of a 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; a partially unsaturated heterocyclic group having a 5-membered ring such as pyrrolinyl, dihydrofuryl, imidazolinyl, pyrazolinyl, oxazolinyl, isoxazolinyl, etc.; a partially saturated heterocyclic group of a 5-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; partially unsaturated heterocyclic groups of 6-membered ring such as dihydropyranyl; a partially saturated heterocyclic group of a 6-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy;

R ^q1 -a group represented by CO- (wherein R ^q1 Represents a hydrogen atom; c1-6 alkyl; c1-6 alkyl substituted with any 1 or more substituents selected from halo, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, phenyl or heteroaryl of a 5-6 membered ring; (C6-10 aryl) C1-6 alkyl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; (heteroaryl of a 5-to 6-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy); c2-6 alkenyl; c2-6 halogenated alkenyl; c2-6 alkynyl;

c2-6 haloalkynyl; c3-6 cycloalkyl; by any of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, C1-6 haloalkoxy or cyanoC3-6 cycloalkyl substituted by more than 1 substituent; c6-10 aryl; c6-10 aryl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl of 5-6 membered ring; or alternatively; heteroaryl of 5-to 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy. R is as follows ^q1 The same applies to the above. ) The method comprises the steps of carrying out a first treatment on the surface of the

A carboxyl group;

R ^q2 -O-CO-represented group (wherein R ^q2 Represents a C1-6 alkyl group; c1-6 alkyl substituted with any 1 or more substituents selected from halo, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, phenyl or heteroaryl of a 5-6 membered ring; (C6-10 aryl) C1-6 alkyl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; (heteroaryl of a 5-to 6-membered ring substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy); c2-6 alkenyl; c2-6 halogenated alkenyl; c2-6 alkynyl; c2-6 haloalkynyl; c3-6 cycloalkyl; c3-6 cycloalkyl substituted with 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl, C1-6 haloalkoxy and cyano; c6-10 aryl; c6-10 aryl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; heteroaryl of 5-6 membered ring; or alternatively; heteroaryl of 5-to 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy. R is as follows ^q2 Is the same. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^q1 R ^q1 A group represented by N-wherein R ^q1 May be the same or different. R is R ^q1 May form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^q1 R ^q1 A group represented by N-CO- (R in the formula ^q1 May be the same or different. R is R ^q1 May form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^q1 -a group represented by CO-O-;

R ^q1 -CO-NR ^q3 a group represented by (wherein R ^q3 Represents a hydrogen atom; c1-6 alkyl; c1-6 alkyl substituted with any 1 or more substituents selected from halo, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, phenyl or heteroaryl of a 5-6 membered ring; (C6-10 aryl) C1-6 alkyl substituted with any 1 or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy; or (heteroaryl of a 5-to 6-membered ring substituted with any 1 or more substituents of C1-6 alkyl, C1-6 alkoxy, halo, C1-6 haloalkyl or C1-6 haloalkoxy). R is as follows ^q3 Is the same. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^q2 -a group represented by O-CO-O-;

R ^q2 -O-CO-NR ^q3 -a group represented;

R ^q1 R ^q1 A group represented by N-CO-O- (R in the formula ^q1 May be the same or different. R is R ^q1 May form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^q1 R ^q1 N-CO-NR ^q3 A group represented by (R in the formula ^q1 May be the same or different. R is R ^q1 May form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^q2 SO ₂ -NR ^q3 -a group represented;

R ^q1 R ^q1 N-SO ₂ a group represented by (R in the formula ^q1 May be the same or different. R is R ^q1 Can form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy groupA dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

R ^q1 -O-N＝C(R ^q4 ) A group represented by (wherein R ^q4 Represents a hydrogen atom or a C1-6 alkyl group. ) The method comprises the steps of carrying out a first treatment on the surface of the

(R ^q1 ) ₂ A group represented by c=n-O (R in the formula ^q1 May be the same or different. R is R ^q1 May form together with each other a trimethylene group, a tetramethylene group, a pentamethylene group, or a dimethyleneoxy-dimethylene group. ) The method comprises the steps of carrying out a first treatment on the surface of the

Pentafluorosulfanyl, nitro or cyano.

Further, as a substituent on the "C3-6 cycloalkyl" or "3-10 membered heterocyclic group", an oxo group is also preferable.

As "R ^a Specific examples of the group represented by-CO-include formyl, acetyl and isopropylcarbonyl.

"R" in G ^b -O-CO-represented group "wherein R ^b Represents a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having a 5-6 membered ring.

R ^b Specific examples of the substituent(s) in (a) include those represented by R ^a The substituents exemplified in (a) are the same.

As "R ^b Specific examples of the group represented by-O-CO-include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl and the like.

"R" in G ^c R ^d In the group "represented by N-, R ^c Represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having 5-6 membered ring, R ^d Represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C1-6 alkoxy group, or a substituted or unsubstituted C6-10 aryl.

R ^c Or R is ^d Specific examples of the substituent(s) in (a) include those represented by R ^a The substituents exemplified in (a) are the same.

As R ^d Examples of the "C1-6 alkoxy" in (a) include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, and isohexyloxy.

As R ^d The substituent on the "C1-6 alkoxy" in (a) is preferably: halo groups such as fluoro, chloro, bromo and iodo; a hydroxyl group; c1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy; c1-6 haloalkoxy such as 2-chloro-n-propoxy, 2, 3-dichlorobenzoxy, trifluoromethoxy and the like; c3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; phenyl, naphthyl and other C6-10 aryl groups; c6-10 aryl groups substituted with 1 or more substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, halogen groups, C1-6 haloalkyl groups and C1-6 haloalkoxy groups, such as 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4-trifluoromethylphenyl groups; or cyano.

Wherein R is ^c And R is R ^d Together, divalent organic groups may be formed.

Examples of the divalent organic group that can be formed include a substituted or unsubstituted C2-5 alkylene group, a substituted or unsubstituted C1-3 alkyleneoxy C1-3 alkylene group, a substituted or unsubstituted C1-3 alkylenethio C1-3 alkylene group, and a substituted or unsubstituted C1-3 alkyleneimino C1-3 alkylene group.

The substituents on "C2-5 alkylene", "C1-3 alkyleneoxy C1-3 alkylene", "C1-3 alkylenethio C1-3 alkylene" and "C1-3 alkyleneimino C1-3 alkylene" are preferably: halo groups such as fluoro, chloro, bromo and iodo; c1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; a methylene group; or a C1-6 haloalkyl group such as chloromethyl, chloroethyl, trifluoromethyl, 1, 2-dichloro-n-propyl, 1-fluoro-n-butyl, etc.

As "R ^c R ^d Specific examples of the "group represented by N" include an amino group, a methylamino group, a dimethylamino group, an isopropylamino group, and the like.

"R" in G ^c R ^d In the group "represented by N-CO-, R ^c R is R ^d Represents "R" as defined above ^c R ^d N-represents a group "in the same sense as those in the above.

As "R ^c R ^d Specific examples of the "group represented by N-CO-include carbamoyl, N-dimethylaminocarbonyl, N- (isopropyl) aminocarbonyl, N- (isopropyl) -N-methylaminocarbonyl and the like.

"R" in G ^c R ^d N-NR ^d -CO-represented group "wherein R ^c R is R ^d Represents "R" as defined above ^c R ^d N-represents a group "in the same sense as those in the above.

As "R ^c R ^d N-NR ^d Specific examples of the group represented by-CO-include 2, 2-dimethylhydrazine-1-carbonyl group and the like.

"R" in G ^b SO ₂ -NR ^d Represented by-CO-In the radical "R ^b Represents "R" as defined above ^b R in the group "represented by-O-CO- ^b The same meaning, R ^d Represents "R" as defined above ^c R ^d R in the group "represented by N ^d The same meaning.

As "R ^b SO ₂ -NR ^d Specific examples of the group represented by-CO-include a (methylsulfonyl) carbamoyl group, a (cyclopropylsulfonyl) carbamoyl group, a (((1-methylcyclopropyl) sulfonyl) carbamoyl group, and the like.

"R" in G ^a -CO-O-in the group "R ^a Represents "R" as defined above ^a R in the group-CO-represents ^a The same meaning.

As "R ^a Specific examples of the group represented by-CO-O-include an acetoxy group and the like.

"R" in G ^a -CO-NR ^e -in the radicals "represented by R ^a Represents "R" as defined above ^a R in the group-CO-represents ^a The same meaning.

R ^e Represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C1-6 alkoxy group, or a substituted or unsubstituted C6-10 aryl group.

R ^e Specific examples of the substituent(s) in (a) include those represented by R ^a The substituents exemplified in (a) are the same.

As "R ^a -CO-NR ^e Specific examples of the "group represented by" include an acetylamino group, a propionylamino group, a butyrylamino group, an isopropylcarbonylamino group and the like.

"R" in G ^a -CO-CO-NR ^e -in the radicals "represented by R ^a Represents "R" as defined above ^a R in the group-CO-represents ^a The same meaning. R is R ^e Represents "R" as defined above ^a -CO-NR ^e R in the radical "represented by ^e The same meaning.

As "R ^a -CO-CO-NR ^e Specific examples of the "group represented by" include an oxopropanamido group and the like。

"R" in G ^a -CO-NR ^e -NR ^e -in the radicals "represented by R ^a Represents "R" as defined above ^a R in the group-CO-represents ^a The same meaning. R is R ^e Represents "R" as defined above ^a -CO-NR ^e R in the radical "represented by ^e The same meaning.

As "R ^a -CO-NR ^e -NR ^e Specific examples of the "group represented by" include an acetyl hydrazino group and an isopropyl hydrazino group.

"R" in G ^a -CO-NR ^e -NR ^e -CO-represented group "wherein R ^a Represents "R" as defined above ^a R in the group-CO-represents ^a The same meaning. R is R ^e Represents "R" as defined above ^a -CO-NR ^e R in the radical "represented by ^e The same meaning.

As "R ^a -CO-NR ^e -NR ^e Specific examples of the group represented by-CO-include 2-acetylhydrazine-1-carbonyl group and the like.

"R" in G ^b -O-CO-O-represented group "wherein R ^b Represents "R" as defined above ^b R in the group "represented by-O-CO- ^b The same meaning.

As "R ^b Specific examples of the group represented by-O-CO-O-include methoxycarbonyloxy and ethoxycarbonyloxy.

"R" in G ^b -O-CO-NR ^e -in the radicals "represented by R ^b Represents "R" as defined above ^b R in the group "represented by-O-CO- ^b The same meaning. R is R ^e Represents "R" as defined above ^b -CO-NR ^e R in the radical "represented by ^e The same meaning.

As "R ^b -O-CO-NR ^e Specific examples of the "group represented by" include methoxycarbonylamino group and the like.

"R" in G ^c R ^d In the group "represented by N-CO-O-, R ^c R is R ^d Represents "R" as defined above ^c R ^d N-represents a group "in the same sense as those in the above.

As "R ^c R ^d Specific examples of the "group represented by N-CO-O-include a carbamoyloxy group, an N, N-dimethylaminocarbonyloxy group and the like.

"R" in G ^c R ^d N-CO-NR ^e -in the radicals "represented by R ^c R is R ^d Represents "R" as defined above ^c R ^d N-represents a group "in the same sense as those in the above. R is R ^e Represents "R" as defined above ^a -CO-NR ^e R in the radical "represented by ^e The same meaning.

As "R ^c R ^d N-CO-NR ^e Specific examples of the "group represented by" include a carbamoylamino group, an N, N-dimethylaminocarbonylamino group and the like.

"R" in G ^c R ^d N-CO-CO-NR ^e -in the radicals "represented by R ^c R is R ^d Represents "R" as defined above ^c R ^d N-represents a group "in the same sense as those in the above. R is R ^e Represents "R" as defined above ^a -CO-NR ^e R in the radical "represented by ^e The same meaning.

As "R ^c R ^d N-CO-CO-NR ^e Specific examples of the "group represented by" include a 2- (methylamino) -2-oxoacetamido group and a 2- (tert-butylamino) -2-oxoacetamido group.

"R" in G ^a -CS-NR ^e -in the radicals "represented by R ^a Represents "R" as defined above ^a R in the group-CO-represents ^a The same meaning. R is R ^e Represents "R" as defined above ^a -CO-NR ^e R in the radical "represented by ^e The same meaning.

As "R ^a -CS-NR ^e Specific examples of the "group represented by" include an ethane thioamide group, a propane thioamide group, a 2-methylpropane thioamide group, and the like.

"R" in G ^c R ^d N-CS-NR ^e -a group of formula"wherein R is ^c R is R ^d Represents "R" as defined above ^c R ^d N-represents a group "in the same sense as those in the above. R is R ^e Represents "R" as defined above ^a -CO-NR ^e R in the radical "represented by ^e The same meaning.

As "R ^c R ^d N-CS-NR ^e Specific examples of the "group represented by" include a 3, 3-dimethylthiourea group and the like.

"R" in G ^b SO ₂ -NR ^e -in the radicals "represented by R ^b Represents "R" as defined above ^b R in the group "represented by-O-CO- ^b The same meaning. R is R ^e Represents "R" as defined above ^a -CO-NR ^e R in the radical "represented by ^e The same meaning.

As "R ^b SO ₂ -NR ^e Specific examples of the "group represented by" include methanesulfonylamino group and the like.

"R" in G ^c R ^d N-SO ₂ -in the radicals "represented by R ^c R is R ^d Represents "R" as defined above ^c R ^d N-represents a group "in the same sense as those in the above.

As "R ^c R ^d N-SO ₂ Specific examples of the "group represented by" include an N, N-dimethylaminosulfonyl group and the like.

"R" in G ^a O-N＝CR ^f -in the radicals "represented by R ^a Represents "R" as defined above ^a R in the group-CO-represents ^a The same meaning.

R ^f Specific examples of the substituent(s) in (a) include those represented by R ^a The substituents exemplified in (a) are the same.

As "R ^a O-N＝CR ^f Specific examples of the "group represented by" include (hydroxyimino) methyl group, (ethoxyimino) methyl group, and the like.

"R" in G ^a -C(＝NR ^g )-NR ^e -in the radicals "represented by R ^a Represents "R" as defined above ^a R in the group-CO-represents ^a The same meaning. R is R ^e Represents "R" as defined above ^a -CO-NR ^e R in the radical "represented by ^e The same meaning.

R ^g Specific examples of the substituent(s) in (a) include those represented by R ^a The substituents exemplified in (a) are the same.

"R" in G ^c R ^d N-C(＝NR ^g ) -in the radicals "represented by R ^c R is R ^d Represents "R" as defined above ^c R ^d N-represents a group "in the same sense as those in the above. R is R ^g Represents "R" as defined above ^a -C(＝NR ^g )-NR ^e R in the radical "represented by ^g The same meaning.

"R" in G ^h R ⁱ S (=o) =n—co-, in the group "represented by R ^h Each independently represents a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C6-10 aryl group, R ⁱ Each independently represents a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C6-10 aryl group.

R ^h Or R is ⁱ Specific examples of the substituent(s) in (a) include those represented by R ^a The substituents exemplified in (a) are the same.

Wherein R is ^h And R is R ⁱ Together, divalent organic groups may be formed.

Examples of the divalent organic group that can be formed include a substituted or unsubstituted C2-5 alkylene group and a substituted or unsubstituted C1-3 alkyleneoxy C1-3 alkylene group.

The substituent on the "C2-5 alkylene" or "C1-3 alkyleneoxy C1-3 alkylene" is preferably: halo groups such as fluoro, chloro, bromo and iodo; c1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; or a C1-6 haloalkyl group such as chloromethyl, chloroethyl, trifluoromethyl, 1, 2-dichloro-n-propyl, 1-fluoro-n-butyl, etc.

"R" in G ^h R ⁱ S=n—co-, wherein R ^h Or R is ⁱ Represents "R" as defined above ^h R ⁱ S (=o) =n—co-, and their meaning in the group "indicated.

"R" in G ^h R ^j c=n-O-represented group "wherein R ^h R is R ^j Represents "R" as defined above ^h R ^j s=n-O-represents a group "in which they have the same meaning.

As "R ^h R ^j Specific examples of the group "represented by c=n—o-, include (propane-2-ylideneamino) oxy group and the like.

Examples of the divalent organic group in which 2 or more substituents (G) are present and which may be formed together include a substituted or unsubstituted C1-5 alkylene group, a substituted or unsubstituted oxy C1-4 alkylene group, a substituted or unsubstituted oxy C2-3 alkylene oxy group, and a substituted or unsubstituted C1-3 alkylene oxy C1-3 alkylene group.

Examples of the "C1-5 alkylene" include methylene, dimethylene, trimethylene and tetramethylene.

Examples of the "oxy C1-4 alkylene" include an oxymethylene group, an oxydimethylene group, and the like.

Examples of the "oxy group C2-3 alkylene oxide group" include an oxydimethyleneoxy group and the like.

The substituents on "C1-5 alkylene", "oxy C1-4 alkylene", "oxy C2-3 alkyleneoxy", "C1-3 alkyleneoxy C1-3 alkylene" are preferably: halo groups such as fluoro, chloro, bromo and iodo; c1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; or a C1-6 haloalkyl group such as chloromethyl, chloroethyl, trifluoromethyl, 1, 2-dichloro-n-propyl, 1-fluoro-n-butyl, etc.

[ salt ]

The salt of the compound is not particularly limited as long as it can be produced by an organic chemical method. For example, salts of inorganic acids such as hydrochloric acid and sulfuric acid; salts of organic acids such as acetic acid and lactic acid; salts of alkali metals such as lithium, sodium, potassium, etc.; salts of alkaline earth metals such as calcium and magnesium; salts of transition metals such as iron and copper; salts of organic bases such as triethylamine, tributylamine, pyridine, and hydrazine; ammonium salts, and the like.

[ method of manufacture ]

The present invention is a process for producing an uracil compound, which comprises chemically reacting an ureido methylene compound in the presence of an organic base or an inorganic base. The reaction synthesis route is shown as follows.

[ chemical formula 8]

The meaning of the symbols in the formula (I) and the formula (II) in the synthesis path means the same meaning as above. "base" means an organic base or an inorganic base.

Examples of the organic base include triethylamine, tributylamine, tetramethyl ethylenediamine, N-diisopropylamine, N-dimethylaniline, N, amine-based organic bases such as N-diethylaniline, 4-methylmorpholine, 1-azabicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene, guanidine, 1, 3-tetramethylguanidine, pyridine, 4- (dimethylamino) pyridine, 2, 6-dimethylpyridine, and picoline.

The amount of the organic base to be used is, for example, 0.5 to 8.0 mol, preferably 2.0 to 4.0 mol, based on the ureido methylene compound (1 mol).

Examples of the inorganic base include lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium acetate, sodium acetate, potassium acetate, sodium formate, potassium formate, calcium formate, trisodium phosphate, tripotassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, sodium hydride, and potassium hydride; sodium methoxide, sodium ethoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, and the like.

The amount of the inorganic base to be used is, for example, 0.5 to 8.0 mol, preferably 2.0 to 4.0 mol, based on the ureido methylene compound (1 mol).

The chemical reaction may be carried out in the absence of a solvent or in a solvent. In particular, when the ureido-methylene compound is in a liquid state at the temperature at the time of the chemical reaction, a solvent may not be used. In view of handleability, the chemical reaction is preferably carried out in an organic solvent, but the reaction is also carried out in an aqueous solvent. The organic solvent is not particularly limited as long as it is an organic solvent inactive to the ureido-methylene compound. Examples of the organic solvent include ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, and 1, 4-dioxane; halogenated hydrocarbons such as methylene chloride, chloroform, 1, 2-dichloroethane, chlorobenzene, dichlorobenzene, etc.; aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene, xylene, and mesitylene; nitriles such as acetonitrile; esters such as ethyl acetate; aprotic polar solvents such as N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, N' -dimethylpropyleneurea, hexamethylphosphoric triamide, and protic polar solvents such as methanol, ethanol, isopropanol, and ethylene glycol.

The amount of the organic solvent to be used is preferably 10 to 500 parts by mass relative to the ureido methylene compound (1 part by mass).

The temperature at which the chemical reaction is carried out is not particularly limited, and is, for example, room temperature to 80 ℃. The reaction time is not particularly limited, and is, for example, 0.5 to 24 hours.

The reaction can be performed by mixing the ureido-methylene compound with an organic base or an inorganic base and an organic solvent and then stirring the mixture.

[ method for producing ureido methylene Compound ]

The ureido methylene compound can be prepared by condensing a compound of formula (III) with a compound of formula (IV), as shown in the reaction synthesis path below.

[ chemical formula 9]

R in formula (III) ² 、R ³ 、X ¹ X is X ² The same meaning as in formula (II) is shown. R in formula (IV) ¹ R in the formula (II) ¹ The same meaning. The compound of formula (IV) may be used as its hydrochloride.

For example, it can be prepared by reacting a compound of formula (III) with a compound of formula (IV) in an alcoholic solvent. In this case, the reaction may be carried out in the presence of a base such as pyridine.

The compound of formula (III) can be prepared by condensing the compound of formula (V) with the compound of formula (VI) and the compound of formula (VII), as shown in the reaction synthesis path below.

[ chemical formula 10]

R in formula (V) ² R is R ³ The same meaning as in formula (II) is shown. X in formula (VI) ² X in the formula (II) ² The same meaning. X in formula (VII) ¹ X in the formula (II) ¹ The same meaning. R is R ^X Represents a C1-6 alkyl group.

For example, it can be prepared by reacting a compound of formula (V) with formula (VI) or formula (VII) in the presence of a Lewis acid or a Bronsted acid without using a solvent. Zinc (II) triflate is preferred. In addition, an alcohol solvent or the like may be used as the solvent.

[ 2, 6-dioxo-3, 6-dihydropyrimidine Compound such as Compound represented by formula (A) ]

By using the produced ureido compound, a 2, 6-dioxo-3, 6-dihydropyrimidine compound described in WO2021/085389A can be produced.

The 2, 6-dioxo-3, 6-dihydropyrimidine compounds that can be produced are shown in Table 1 below.

TABLE 1

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For some of the compounds in table 1, their melting points are shown. Each of which has a low melting point compound and a high melting point compound.

Compound No. I-1: low melting point (65-68 ℃ C.) and high melting point (121-124 ℃ C.)

Compound No. I-2: low melting point (91-92 ℃ C.) and high melting point (121-123 ℃ C.)

Compound No. I-3: low melting point (69-70 ℃ C.) and high melting point (88-90 ℃ C.)

Furthermore, for some compounds, their melting points are shown.

Compound No. I-20: melting Point (129-130 ℃ C.)

Compound No. I-21: melting Point (121-122 ℃ C.)

Compound No. I-22: melting Point (127-128 ℃ C.)

Compound No. I-23: melting Point (105-106 ℃ C.)

Compound No. I-24: melting Point (112-113 ℃ C.)

The present invention will be described more specifically with reference to the following examples. The present invention is not limited to the following examples.

[ example 1]

(E) Synthesis of 5- (1- (isopropoxyimino) ethyl) pyrimidine-2, 4 (1H, 3H) -dione

(Process 1) Synthesis of ethyl 3-oxo-2- (ureidomethylene) butyrate

[ chemical formula 11]

Urea (720 g) was dissolved in ethyl acetoacetate (1.28 kg) and trimethyl orthoformate (1.05 kg), zinc (II) triflate (181 g) was added, and after stirring at room temperature (23 ℃) for 8 hours, methanol (0.50L) was added, and stirring was carried out at room temperature (23 ℃) for two night.

Water was added to the reaction solution, and after stirring for two hours, crystals were removed by filtration. Then, the crystals were washed twice with water and hexane to give the objective compound (1.84 kg). The yield thereof was found to be 92%.

(step 2) Synthesis of ethyl 3- (isopropoxyimino) -2- (ureidomethylene) butyrate

[ chemical formula 12]

Ethyl 3-oxo-2- (ureidomethylene) butyrate (1.0 g) was dissolved in methanol (25 mL), and pyridine (443. Mu.L) and O-isopropylhydroxylamine hydrochloride (614 mg) were added thereto and stirred at room temperature (23 ℃ C.) overnight.

After addition of 1N aqueous hydrochloric acid, extraction was performed with chloroform and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure to give the target compound (1.0 g). Yield quat.

NMR data of the obtained target are shown below.

¹ H-NMR(CDCl ₃ )δ:11.38(0.01H,d,J＝12.6Hz),9.84(0.40H,d,J＝12.2Hz),9.71(0.01H,d,J＝11.9Hz),9.05(0.29H,d,J＝12.5Hz)8.57(0.40H,d,J＝4.2Hz)8.44(0.01H,d,J＝12.6Hz),7.99(0.29H,d,J＝12.2Hz),7.80-7.76(0.29H,m),7.50(0.40H,d,J＝12.2Hz),7.40-7.36(0.49H,m),7.08-7.04(0.01H,m),7.00(1.00H,brs),6.85(0.40H,brs),4.46-4.08(3.00H,m),1.95(1.35H,s),1.92(1.25H,s),1.87(0.37H,s),1.80(0.03H,s),1.27-1.05(9.00H,m).

(Process 3) Synthesis of (E) -5- (1- (isopropoxyimino) ethyl) pyrimidine-2, 4 (1H, 3H) -dione

[ chemical formula 13]

Ethyl 3- (isopropoxyimino) -2- (ureidomethylene) butyrate (1.0 g) was dissolved in ethanol (25 mL), and a 2N sodium ethoxide ethanol solution (5.0 mL) was added dropwise under ice cooling, followed by stirring at room temperature (23 ℃) overnight.

After adding a 1N aqueous hydrochloric acid solution to the reaction solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and recrystallization was performed using methanol to obtain the objective compound (895 mg). The yield thereof was found to be 85%.

NMR data of the obtained target are shown below.

¹ H-NMR(DMSO)δ:11.24(1.00H,brs),11.10(1.00H,brs),7.42(1.00H,d,J＝2.8Hz),4.28(1.00H,dq,J＝6.4Hz),1.99(3.00H,s),1.20(6.00H,d,J＝6.4Hz).

[ example 2 ]

(Process 1) Synthesis of methyl 3-oxo-2- (ureidomethylene) butyrate

[ chemical formula 14]

Urea (6.20 g) was dissolved in methyl acetoacetate (10.0 g) and trimethyl orthoformate (10.0 g), and zinc (II) triflate (1.56 g) was added thereto and stirred at room temperature (23 ℃) for three days. Water was added to the reaction solution, and after stirring for two hours, crystals were removed by filtration. Then, the crystals were washed with water and hexane to give the objective compound (11.6 g). The yield thereof was found to be 72%.

NMR data of the obtained target are shown below.

¹ H-NMR(DMSO)δ:11.39(0.61H,d,J＝12.6Hz),10.13-10.11(0.31H,m)8.47-8.40(0.86H,m),7.72(0.69H,brs),7.52(0.25H,brs),7.30(0.83H,brs),6.80(0.45H,brs),3.78(0.40H,s),3.70(1.70H,s),3.59(0.90H,s),2.41(2.42H,s),2.34(0.13H,s),2.25(0.45H,s).

(Process 2) Synthesis of methyl 3- (isopropoxyimino) -2- (ureido-methylene) butyrate

[ chemical formula 15]

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Methyl 3-oxo-2- (ureidomethylene) butyrate (465 mg) was dissolved in methanol (25 mL), and pyridine (237. Mu.L) and O-isopropylhydroxylamine hydrochloride (333 mg) were added thereto and stirred at room temperature (23 ℃ C.) overnight.

After addition of 1N aqueous hydrochloric acid, extraction was performed with chloroform and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure to obtain 606mg of the target compound. Yield quat.

NMR data of the obtained target are shown below.

¹ H-NMR(DMSO)δ:11.90(0.07H,d,J＝7.1Hz),10.00-9.88(0.72H,m),8.63-8.55(0.05H,m),8.16-7.97(0.22H,m),7.66-7.46(0.43H,m),5.34(0.13H,brs),4.97(0.94H,brs),4.81(0.44H,brs),4.38-4.27(1.00H,m),3.80-3.70(3.00H,m),2.14(0.80H,s),1.99(1.40H,s),1.97(0.33H,s),1.91(0.47H,s),1.31-1.16(6.00H,m).

[ chemical formula 16]

Methyl 3- (isopropoxyimino) -2- (ureido methylene) butyrate (606 mg) was dissolved in methanol (25 mL), and under ice-cooling, 6N aqueous sodium hydroxide solution (3.34 mL) was added dropwise thereto, followed by stirring at room temperature (23 ℃) overnight.

After adding a 1N aqueous hydrochloric acid solution to the reaction solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and the crystals were washed with hexane to give the objective compound (150 mg). The yield thereof was found to be 28%.

[ example 3 ]

[ chemical formula 17]

Ethyl 3-oxo-2- (ureidomethylene) butyrate (1.0 g) was dissolved in methanol (5.0 mL), and pyridine (406. Mu.L) and O-isopropylhydroxylamine hydrochloride (587 mg) were added thereto and the mixture was stirred at room temperature (23 ℃ C.) overnight.

After methanol (20 mL) was added, potassium carbonate (1.38 g) was added thereto under ice-cooling, and the mixture was stirred at room temperature (23 ℃ C.) overnight. After adding a 1N aqueous hydrochloric acid solution to the reaction solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystal was washed with hexane to obtain the objective compound (800 mg). The yield thereof was found to be 76%.

[ example 4 ]

[ chemical formula 18]

After methanol (20 mL) was added, a 6N sodium methoxide methanol solution (1.67 mL) was added thereto under ice-cooling, and the mixture was stirred at room temperature (23 ℃ C.) overnight.

After adding a 1N aqueous hydrochloric acid solution to the reaction solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystal was washed with hexane to obtain the objective compound (801 mg). The yield thereof was found to be 76%.

[ example 5 ]

[ chemical formula 19]

Ethyl 3-oxo-2- (ureidomethylene) butyrate (500 mg) was dissolved in methanol (2.5 mL), and pyridine (232. Mu.L) and O-isopropylhydroxylamine hydrochloride (333 mg) were added thereto and stirred at room temperature (23 ℃ C.) overnight.

1, 8-diazabicyclo [5.4.0] undec-7-ene (sometimes also referred to as DBU.) (1.52 g) was then added and stirred at 35℃overnight.

After adding a 1N aqueous hydrochloric acid solution to the reaction solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystal was washed with hexane to obtain the objective compound (161 mg). The yield thereof was found to be 31%.

[ example 6 ]

[ chemical formula 20]

Ethyl 3-oxo-2- (ureidomethylene) butyrate (1.0 g) was dissolved in methanol (5.0 mL), and pyridine (443. Mu.L) and O-isopropylhydroxylamine hydrochloride (614 mg) were added thereto and the mixture was stirred at room temperature (23 ℃ C.) overnight.

Then, after adding 6N aqueous sodium hydroxide solution (3.34 mL), the mixture was stirred at room temperature (23 ℃ C.) overnight.

After adding a 1N aqueous hydrochloric acid solution to the reaction solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with hexane to obtain the objective compound (1.04 g). The yield thereof was found to be 98%.

Example 7

[ chemical formula 21]

Ethyl 3-oxo-2- (ureidomethylene) butyrate (500 mg) was dissolved in MeOH (5 mL), pyridine (241. Mu.L) and O-isopropylhydroxylamine hydrochloride (335 mg) were added, and the mixture was stirred at room temperature (23 ℃ C.) overnight.

After addition of 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (sometimes also denoted as MTBD.) (765 mg), stirring was carried out at room temperature (23 ℃) overnight.

After adding a 1N aqueous hydrochloric acid solution to the reaction solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystal was washed with hexane to obtain the objective compound (430 mg). The yield thereof was found to be 81%.

Example 8

(E) Synthesis of 5- (1- (ethoxyimino) ethyl) pyrimidine-2, 4 (1H, 3H) -dione

(step 1) Synthesis of ethyl 3- (ethoxyimino) -2- (ureido methylene) butyrate

[ chemical formula 22]

Ethyl 3-oxo-2- (ureidomethylene) butyrate (500 mg) was dissolved in methanol (2.5 mL), and pyridine (241. Mu.L) and O-ethylhydroxylamine hydrochloride (291 mg) were added thereto and stirred at room temperature (23 ℃ C.) overnight.

After addition of 1N aqueous hydrochloric acid, extraction was performed with chloroform and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure to give the target compound (607 mg). Yield quat.

NMR data of the obtained target are shown below.

¹ H-NMR(CDCl ₃ )δ:10.07(0.35H,d,J＝12.0Hz),9.92(0.15H,d,J＝11.8Hz),8.60(0.03H,d,J＝11.7Hz),8.14(0.11H,d,J＝11.5Hz),7.68-7.44(0.35H,m),4.90(0.77H,brs),4.78(0.24H,brs),4.25-4.07(4.00H,m),2.15-1.89(3.00H,m),1.35-1.19(6.00H,m).

(Process 2) Synthesis of (E) -5- (1- (ethoxyimino) ethyl) pyrimidine-2, 4 (1H, 3H) -dione

[ chemical formula 23]

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Ethyl 3- (ethoxyimino) -2- (ureidomethylene) butyrate (607 mg) was dissolved in methanol (2.5 mL), and after adding 6N aqueous sodium hydroxide solution (1.67 mL), the mixture was stirred at room temperature (23 ℃) overnight.

After adding a 1N aqueous hydrochloric acid solution to the reaction solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with hexane to obtain the objective compound (150 mg). The yield thereof was found to be 30%.

NMR data of the obtained target are shown below.

¹ H-NMR(DMSO)δ:11.62(2.00H,brs),7.42(1.00H,d,J＝6.4Hz),4.06(2.00H,t,J＝6.8Hz),2.00(3.00H,d,J＝3.2Hz),1.22-1.17(3.00H,m).

[ example 9 ]

(E) Synthesis of (E) -3-allyl-5- (1- (isopropoxyimino) ethyl) pyrimidine-2, 4 (1H, 3H) -dione

[ chemical formula 24]

Ethyl 2- ((3-allylureido) methylene) -3-oxobutanoate (1.5 g) was dissolved in a mixed solution of ethanol (31.3 mL) and chloroform (31.3 mL), pyridine (503. Mu.L) and O-isopropylhydroxylamine hydrochloride (693 mg) were added, and the mixture was stirred at room temperature (23 ℃ C.) overnight.

The reaction solution was purified by silica gel column chromatography. Then, the resulting residue was dissolved in ethanol (14.5 mL), and a 2N sodium ethoxide ethanol solution (4.25 mL) was added dropwise under ice-cooling, followed by stirring at room temperature (23 ℃) overnight.

After addition of a saturated aqueous ammonium chloride solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography, whereby the objective compound (580 mg) was obtained. The yield thereof was found to be 37%.

NMR data of the synthetic intermediates and the target are shown below.

2- ((3-allylureido) methylene) -3- (isopropoxyimino) butanoic acid ethyl ester

¹ H-NMR(CDCl ₃ )δ:10.06(1.00H,brs),8.70-7.68(1.00H,m),5.91-5.81(1.00H,m),5.28-5.15(2.00H,m),5.00(1.00H,brs),4.22-4.27(1.00H,m),4.15-4.09(2.00H,m),3.92-3.90(2.00H,m),2.01(3.00H,s),1.33-1.18(9.00H,m).

(E) -3-allyl-5- (1- (isopropoxyimino) ethyl) pyrimidine-2, 4 (1 h,3 h) -dione

¹ H-NMR(CDCl ₃ )δ:9.43(1.00H,brs),7.43(1.00H,d,J＝6.0Hz),5.93-5.83(1.00H,m),5.30-5.13(2.00H,m),4.55(2.00H,J＝6.0Hz),4.38-4.32(1.00H,m),2.15(3.00H,s),1.26(6.00H,d,J＝6.0Hz).

[ example 10 ]

Synthesis of (S, E) - (1- (5- (1- (isopropoxyimino) ethyl) -2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -3-methylbutan-2-yl) carbamic acid tert-butyl ester

[ chemical formula 25]

Ethyl (S) -12-acetyl-6-isopropyl-2, 2-dimethyl-4, 9-dioxo-3-oxa-5, 8, 10-triazatridec-11-en-13-carboxylate (1.05 g) was dissolved in methanol (11.0 mL), and pyridine (241. Mu.L) and O-isopropylhydroxylamine hydrochloride (334 mg) were added thereto and stirred at room temperature (23 ℃ C.) overnight.

After addition of a saturated aqueous ammonium chloride solution, extraction was performed with chloroform, and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, dissolved in methanol (11.0 mL), and potassium carbonate (610 mg) was added thereto under ice-cooling, followed by stirring at room temperature (23 ℃) overnight.

After addition of 1N aqueous hydrochloric acid, extraction was performed with chloroform and drying was performed with sodium sulfate. The solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography, whereby the objective compound (370 mg) was obtained. The yield thereof was found to be 32%.

"Boc" in the above synthetic route refers to t-butoxycarbonyl group.

NMR data of the synthetic intermediates and the target are shown below.

(S) -12- (1- (isopropoxyimino) ethyl) -6-isopropyl-2, 2-dimethyl-4, 9-dioxo-3-oxa-5, 8, 10-triazatridec-11-en-13-carboxylic acid ethyl ester

¹ H-NMR(CDCl ₃ )δ:10.06-9.95(0.45H,m),8.62(0.62H,d,J＝4.4Hz),8.21(0.22H,d,J＝11.6Hz),7.70-7.66(0.57H,m)7.51-7.24(0.50H,m),5.86(0.21H,brs),5.72(0.24H,brs),5.11(0.28H,brs),4.63-4.13(3.73H,m),3.53-3.20(2.97H,m),2.18-1.91(3.00H,m),1.85-1.71(1.00H,m),1.49-1.39(9.00H,m),1.34-1.15(9.02H,m),0.98-0.90(6.19H,m).

(S, E) - (1- (5- (1- (isopropoxyimino) ethyl) -2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl) -3-methylbutan-2-yl) carbamic acid tert-butyl ester

¹ H-NMR(CDCl ₃ )δ:9.58(1.00H,brs),7.41(1.00H,d,J＝5.6Hz),4.66(1.00H,d,J＝9.9Hz),4.37-4.31(1.00H,m),4.17-4.10(1.00H,m),4.00-3.83(2.00H,m),2.16(3.00H,s),1.87-1.80(1.00H,m),1.37-1.24(15.0H,m),1.01-0.98(6.00H,m).

Particularly important uracil compounds in this application are (E) -5- (1- (isopropoxyimino) ethyl) pyrimidine-2, 4 (1H, 3H) -dione, and (E) -5- (1- (ethoxyimino) ethyl) pyrimidine-2, 4 (1H, 3H) -dione.

[ 2, 6-dioxo-3, 6-dihydropyrimidine Compounds ]

By using the produced ureido compound, the compounds shown in table 2 below can also be produced.

TABLE 2

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Claims

1. A process for producing a compound represented by the following formula (I) or a salt thereof, which comprises chemically reacting a compound represented by the following formula (II) or a salt thereof in the presence of an organic base or an inorganic base,

[ chemical formula 1]

In the formula (I) of the present invention,

R ^N each independently represents a hydrogen atom, a substituted or unsubstituted linear C1-6 alkyl group, a substituted or unsubstituted linear C2-6 alkenyl group, a substituted or unsubstituted linear C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having a 4-6 membered ring, wherein R ^N And R is R ^N May together form a divalent organic group;

[ chemical formula 2]

In the formula (II), R ¹ 、R ² 、X ¹ X is X ² Meaning the same as in formula (I),

2. The method of claim 1, wherein X ² R is R ^N The substituents on the straight-chain C1-6 alkyl, the substituents on the straight-chain C2-6 alkenyl, the substituents on the straight-chain C2-6 alkynyl, the substituents on the C3-6 cycloalkyl, the substituents on the C6-10 aryl, or the substituents on the heterocyclic group of the 4-6 membered ring are:

selected from the group consisting of halo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, hydroxy, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C2-6 alkenyloxy, substituted or unsubstituted C2-6 alkynyloxy, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylsulfinyl, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C3-6 cycloalkyloxy, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryloxy, substituted or unsubstituted C6-10 arylthio, substituted or unsubstituted C6-10 arylsulfinyl, substituted or unsubstituted C6-10 arylsulfonyl, substituted or unsubstituted 3-10 membered heterocyclic, substituted or unsubstituted 3-membered heterocyclic, substituted or unsubstituted heterocyclic, R, nitro, cyano ^a -CO-represented group, carboxyl group, R ^b -O-CO-represented group, R ^c R ^d A group represented by N-and R ^c R ^d A group represented by N-CO-, R ^c R ^d N-NR ^d -CO-represented group, R ^b SO ₂ -NR ^d -a group represented by CO-, a,R ^a -a group represented by CO-O-, R ^a -CO-NR ^e -a group represented by R ^a -CO-CO-NR ^e -a group represented by R ^a -CO-NR ^e -NR ^e -a group represented by R ^a -CO-NR ^e -NR ^e -CO-represented group, R ^b -O-CO-O-represented group, R ^b -O-CO-NR ^e -a group represented by R ^c R ^d A group represented by N-CO-O-, R ^c R ^d N-CO-NR ^e -a group represented by R ^c R ^d N-CO-CO-NR ^e -a group represented by R ^a -CS-NR ^e -a group represented by R ^c R ^d N-CS-NR ^e -a group represented by R ^b SO ₂ -NR ^e -a group represented by R ^c R ^d N-SO ₂ -a group represented by R ^a O-N＝CR ^f -a group represented by R ^h R ⁱ c=n-O-, R ^a -C(＝NR ^g )-NR ^e -a group represented by R ^c R ^d N-C(＝NR ^g ) -a group represented by R ^h R ⁱ S (=o) =n—co-, and R ^h R ⁱ S=n—co-, 1 or 2 or more substituents in the group consisting of groups represented by;

R ^c Each independently represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, or a substitutedOr an unsubstituted C6-10 aryl group, or a substituted or unsubstituted heterocyclic group having 5-6 membered ring,

3. A compound represented by the formula (II) or a salt thereof,

[ chemical formula 3]

In the formula (II) of the present invention,

R ¹ represents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, or a substituted or unsubstituted C26 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted heterocyclic group of 5-6 membered ring,

4. A compound or salt thereof according to claim 3 wherein X ² R is R ^N Substituents on linear C1-6 alkyl groups and linear C2-6 alkenyl groupsThe substituents, substituents on straight-chain C2-6 alkynyl, substituents on C3-6 cycloalkyl, substituents on C6-10 aryl, or substituents on heterocyclic groups of 4-6 membered rings are:

R ^g each independently ofRepresents a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted C6-10 aryl group,