JP2000226387A - Method for producing cyclic amido compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To readily obtain a cyclic amido compound useful as an active ingredient for a medicine or an aglochemical or a synthetic intermediate for the medicine or the aglochemical without using an expensive metal catalyst, capable of controlling by-product formation, in sufficient yield with enough purity by reacting a specific amido compound with an acid anhydride. SOLUTION: A compound of formula I [R1 is a (substituted) hydrocarbon group or a (substituted) heterocyclic group; X is a substitutable bifunctional group; Y is a (substituted) methylene group] or its salt is preferably reacted with an acid anhydride being a carbonic acid anhydride (e.g. acetic anhydride) preferably in the presence of an organic base such as 1,8-diazabicyclo[5.4.0]-7- undecene and the objective compound of formula II e.g. 1-[(1R,2R)-2-(2,4- difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triaxol-1-yl)propyl]-3- [4-(1H- tetrazol-1-yl)phenyl]-2-imidazolidinone} is obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an industrially advantageous method for producing active ingredients of pharmaceuticals, agricultural chemicals and the like or synthetic intermediates thereof.

[0002]

2. Description of the Related Art Various azole compounds having an antifungal activity have been known. For example, European Patent Application Publication No. 567982 (JP-A-6-29374)
In the official gazette, the formula:

Embedded image (Wherein, Ar ₁ represents a substituted phenyl group, and R ₁ and R ₂
Whether the same or different and each represents a hydrogen atom or a lower alkyl group, or may form a lower alkylene group linked, R ₃ represents a group attached through a carbon atom, R ₄
Represents a hydrogen atom or an acyl group, X ₁ represents a nitrogen atom or a methine group, and Y ₁ and Z ₁ represent the same or different methine groups which may be substituted with a nitrogen atom or a lower alkyl group. The azole compound represented by the formula (I) or a salt thereof is described in the above publication and JP-A-8-104676.

Embedded image (Wherein, Ar ₂ represents a halogenated phenyl group, R ₅ represents an aliphatic or aromatic hydrocarbon group which may have a substituent, or an aromatic bicyclic group which may have a substituent. ,
The imidazolone derivative represented by (R) represents a configuration is exemplified as a preferable group of compounds (hereinafter, sometimes referred to as compound (B)), and the production method thereof starts from (R) -lactic acid derivative. A synthesis method as a starting material is described.

[0003] European Patent Application Publication No. 6876
No. 72 (corresponding to JP-A-8-253452)
As a method for producing the above compound (B), a synthesis method using a (S) -lactic acid derivative as a starting material is described. Furthermore, the above-mentioned JP-A-8-104676 discloses a formula:

Embedded image (Wherein each symbol has the same meaning as described above), a preferred group of compounds [hereinafter may be referred to as compound (C). And a synthesis method in which the compound (B) is subjected to a reduction reaction. WO 9625410A1
(Japanese Unexamined Patent Publication No. 9-183768) has the formula:

Embedded image (Wherein, Ar ₃ represents a phenyl group which may be substituted,
R ₆ and R ₇ are the same or different and each represents a hydrogen atom or a lower alkyl group, or R ₆ and R ₇ are combined to form a lower alkylene group, R ₈ is a hydrogen atom or an acyl group, X ₂
Is a nitrogen atom or a methine group, A is Y ₂ ＺZ ₂ (Y ₂ and Z ₂ are the same or different and each represents a methine group optionally substituted by a nitrogen atom or a lower alkyl group) or a lower alkyl group Represents an ethylene group which may be substituted, n represents an integer of 0-2, and Az represents an azolyl group which may be substituted. An azole compound having antifungal activity or a salt thereof represented by the formula:

Embedded image (Wherein each symbol is as defined above), is exemplified as a preferred group of compounds [hereinafter sometimes referred to as compound (E)], and the production method thereof is (R)- A synthesis method using a lactic acid derivative or a (S) -lactic acid derivative as a starting material is described. The above-mentioned WO9625410A1 (Japanese Unexamined Patent Publication No. 9-183768)
No.) corresponds to the formula:

Embedded image (Wherein each symbol has the same meaning as described above), is exemplified as a preferable group of compounds represented by the following formula. Further, as a method for producing the same, the compound (E) is subjected to a reduction reaction. The law is described. The above publication contains, for example, the formula:

Embedded image (Wherein each symbol is as defined above) and a compound represented by the formula:

Embedded image (Wherein each symbol has the same meaning as described above), and a method for producing compounds (B) and (E) which are imidazolone derivatives by reacting with a compound represented by the following formula:

[0004]

The present invention relates to a compound of the formula useful as an objective compound or as an important synthetic intermediate thereof.

Embedded image (Wherein, R ¹ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and X represents a divalent group which may have a substituent. , Y represents a methylene group which may have a substituent).
An object of the present invention is to provide an industrial production method of a compound having an alkyl bond or a salt thereof (hereinafter, simply referred to as compound (II)). The present inventors have conducted various studies on the production method of compound (II) and found that the compound represented by the formula:

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof (hereinafter, simply referred to as compound (I)) and an acid anhydride, unexpectedly yields compound (II) ,
It was produced without using an expensive metal catalyst (such as palladium-carbon), and it was found that there were few by-products, the purification of the target product was easy, and the yield and purity of the target product were sufficiently satisfied. Based on this, the present invention has been completed.

[0005]

The present invention provides (1) a method for producing a compound (II), which comprises reacting a compound (I) with an acid anhydride, and (2) a method for producing the compound (II) in the presence of an organic base. (3) The method according to the above (1), wherein the organic base is pKa.
Is the organic base of 5 or more,
(4) the method according to (2), wherein the organic base is a basic amine; (5) the method according to (4), wherein the basic amine is an organic cyclic amine or a tertiary amine;
(6) The basic amines are trimethylamine, triethylamine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-
Diazabicyclo [5.4.0] -7-undecene, pyridine,
(7) The method according to the above (4), wherein the basic amine is 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2] which is picoline or dicyclohexylamine. .2] Octane or 1,8-diazabicyclo
(5.4.0) -7-undecene) according to the above (4), (8) the production method according to the above (1), wherein the acid anhydride is a carboxylic anhydride, and (9) the acid anhydride. The thing is the formula:

Embedded image (Wherein R ² and R ³ each represent a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, or R ² and R ³ are (Hereinafter referred to simply as compound (III)) represented by the formula (1), wherein (10) organic The amount of the base used is 0.5 to 20 with respect to 1 mol of the compound represented by the formula (I).
(11) The amount of the acid anhydride to be used is 0.1 mol per mol of the compound represented by the formula (I).
The method according to the above (1), which is 5 to 20 mol, (1)
2) X is a divalent group in which 1 to 4 atoms selected from a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom and a silicon atom are connected in series and may have a substituent; (13) The compound represented by the formula (I) is represented by the formula:

Embedded image (In the formula, R ⁴ represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent, and other symbols are as defined above.) The production method according to the above (1), which is a compound represented by the formula (14):

Embedded image (Wherein, R ¹ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and X represents a divalent group which may have a substituent. , Y represents a methylene group which may have a substituent, and Z represents an acyloxy group.)
Or a salt thereof [hereinafter simply referred to as compound (I)
V)], (15) a compound represented by the formula (IV):

Embedded image (Wherein, Z represents an acyloxy group, and the other symbols are as defined above).
And (16) a process for producing a compound (II), which comprises subjecting the compound (IV) to a ring closure reaction in the presence of an organic base.

The above formulas (I), (Ia), (II) and (I
In V) and (IVa), the “hydrocarbon group” in the “hydrocarbon group optionally having substituent (s)” represented by R ¹ includes an aliphatic hydrocarbon group, an aromatic hydrocarbon group, and an araliphatic group. Group hydrocarbon groups. Examples of the aliphatic hydrocarbon group include an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, and an alkynyl group. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, and n-alkyl. Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, etc. 6 lower alkyl groups (eg, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl) are preferred. Examples of the cycloalkyl group include a cycloalkyl group having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl, and particularly a cycloalkyl group having 3 to 6 carbon atoms (eg, ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) are preferred. Examples of the cycloalkylalkyl group include those having 4 to 12 carbon atoms such as cyclopropylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
And a cycloalkylalkyl group having 6 to 8 carbon atoms (eg, cyclopentylmethyl, cyclohexylmethyl) is particularly preferable. As the alkenyl group,
For example, vinyl, propenyl, butenyl, etc.
And alkenyl having 2 to 3 carbon atoms (eg, vinyl, propenyl) is preferable. Examples of the alkynyl group include those having 2 to 4 carbon atoms such as ethynyl, propynyl, and butynyl, and alkynyl having 2 to 3 carbon atoms (eg, ethynyl, propynyl) is particularly preferable.

The aromatic hydrocarbon groups include phenyl,
Those having 6 to 14 carbon atoms, such as naphthyl, biphenyl, anthryl and indenyl, are preferred, and especially those having 6 to 1 carbon atoms.
An aryl group of 0 (eg, phenyl, naphthyl) is preferred. The araliphatic hydrocarbon group may have 7 to 15 carbon atoms.
Aralkyl groups such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, indanyl, indanylmethyl, 1,2,3,4-tetrahydronaphthyl, 1,2,
3,4-tetrahydronaphthylmethyl and the like, and particularly, an aralkyl group having 7 to 11 carbon atoms (eg, benzyl,
Phenethyl, naphthylmethyl, etc.) are preferred.

The "heterocyclic group" of the "heterocyclic group optionally having substituent (s)" for R ¹ represents a group formed by removing one hydrogen atom bonded to the heterocyclic ring. Such a heterocyclic ring is, for example, a 5- to 8-membered ring containing 1 to several, preferably 1 to 4, hetero atoms such as a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom, or a fused ring thereof. Is shown. Specific examples of such a heterocyclic group include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,
3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- Thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, indolyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido [2,3-d] pyrimidyl, 1,5-, 1,
6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl, thieno [2,3-d] pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, etc. .

Examples of the substituent in the "hydrocarbon group which may have a substituent" and the "heterocyclic group which may have a substituent" represented by R ¹ include, for example, an aryl group (halogenated group). A heterocyclic group, an oxo group, a hydroxyl group, a C _1-6 alkoxy group, a C _3-10 cycloalkyloxy group, a C _6-10 aryloxy group, a C _7-19 aralkyloxy group, a heterocyclic group Oxy group, mercapto group, C _1-6 alkylthio group (the sulfur atom may be oxidized), C _3-10 cycloalkylthio group (the sulfur atom may be oxidized), C _{6- 10} arylthio group (the sulfur atom may be oxidized), C _7-19 aralkylthio group (the sulfur atom may be oxidized), heterocyclic thio group, heterocyclic sulfinyl group, heterocyclic ring Sulfonyl group, amino group, mono A C _1-6 alkylamino group,
Di-C _1-6 alkylamino group, tri-C _1-6 alkylammonio group, C _3-10 cycloalkylamino group, C _6-10 arylamino group, C _7-19 aralkylamino group, heterocyclic amino group, cyclic Amino group, nitro group, halogen atom, cyano group, carboxyl group, _C1-10 alkoxy-carbonyl group, _C6-10 aryloxy-carbonyl group, _C7-19 aralkyloxy-carbonyl group, _C6-10 aryl- Carbonyl group, C _1-6 alkanoyl group, C _3-5 alkenoyl group,
A C _6-10 aryl-carbonyloxy group, a C _2-6 alkanoyloxy group, a C _3-5 alkenoyloxy group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, Carbamoyloxy group, C _1-6 alkanoylamino group, C _6-10
Aryl-carbonylamino group, C _1-10 alkoxy-carboxamide group, C _6-10 aryloxy-carboxamide group, C _7-19 aralkyloxy-carboxamide group, C
_1-10 alkoxy-carbonyloxy group, C _6-10 aryloxy-carbonyloxy group, C _7-19 aralkyloxy-carbonyloxy group, C _3-10 cycloalkyloxy-
Examples thereof include a carbonyloxy group and an optionally substituted ureido group, and 1 to 4 identical or different groups may be present. Examples of the “aryl group” include phenyl, naphthyl, 2-fluorophenyl, 4-fluorophenyl, and 2,4-difluorophenyl,
Examples of the " _1-6 alkoxy group" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy and the like, and a "C _3-10 cycloalkyloxy group". "Is, for example, cyclopropyloxy, cyclohexyloxy and the like, and" C _6-10 aryloxy group "is, for example, phenoxy, naphthyloxy and the like.
_{As the "7-19} aralkyloxy group", for example, benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy and the like can be mentioned as a "C _1-6 alkylthio group (when the sulfur atom is oxidized). For example) includes methylthio, ethylthio, n
-Propylthio, n-butylthio, methylsulfinyl, methylsulfonyl and the like are described as "C _3-10 cycloalkylthio group (the sulfur atom may be oxidized)".
Examples thereof include cyclopropylthio, cyclohexylthio, cyclopentylsulfinyl, and cyclohexylsulfonyl. Examples of the “C _6-10 arylthio group (the sulfur atom may be oxidized)” include, for example, phenylthio, naphthylthio, phenylsulfinyl Phenylsulfonyl, and the like as the “C _7-19 aralkylthio group (the sulfur atom may be oxidized)” include, for example, benzylthio, phenylethylthio,
Benzhydryl Lucio, benzylsulfinyl and benzylsulfonyl is, as "mono-C _1-6 alkylamino group" for example, methylamino, ethylamino, n- propylamino, etc. n- butylamino is "di-C _1-6 Examples of the "alkylamino group" include dimethylamino,
Diethylamino, methylethylamino, di - (n- propyl) amino, di - such as (n- butyl) amino is, as "tri C _1-6 alkyl ammonio group" such as trimethylammonio is, "C _{3 As the -10} cycloalkylamino group, for example, cyclopropylamino, cyclopentylamino, cyclohexylamino and the like,
Examples of the “C _6-10 arylamino group” include anilino and N-methylanilino, and examples of the “C _7-19 aralkylamino group” include benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzyl Hydrylamino and the like, as "cyclic amino group", for example, 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, etc., and as "halogen atom", for example, fluorine, chlorine, bromine, iodine, etc. As the “C _1-10 alkoxy-carbonyl group”, for example, methoxycarbonyl, ethoxycarbonyl, n
-Propoxycarbonyl, isopropoxycarbonyl,
n-butoxycarbonyl, isobutoxycarbonyl, te
rt- butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc. norbornyl oxy carbonyl, - as "C _6-10 aryloxycarbonyl group" for example, phenoxycarbonyl, etc. naphthyloxycarbonyl is, "C _7-19 aralkyloxy - for example as a carbonyl group ", benzyloxycarbonyl, etc. benzhydryloxy carbonyl," C _6-10 aryl - as carbonyl group "for example, benzoyl, naphthoyl, phenyl acetyl," C _1-6 Examples of the "alkanoyl group" include formyl, acetyl, propionyl, butyryl, valeryl, and pivaloyl. Examples of the "C _3-5 alkenoyl group" include acryloyl and crotonoyl.
Examples of the “C _6-10 aryl-carbonyloxy group” include benzoyloxy, naphthoyloxy, phenylacetoxy and the like, and examples of the “C _2-6 alkanoyloxy group” include acetoxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy And “C _3-5 alkenoyloxy group” include, for example, acryloyloxy, crotonoyloxy, etc.
Examples of the “optionally substituted carbamoyl group” include a C _1-4 alkyl group (eg, methyl, ethyl, etc.), a phenyl group, a C _1-7 acyl group (eg, acetyl, propionyl, benzoyl, etc.), _A carbamoyl group optionally substituted with one or two substituents selected from _1-4 alkoxy-phenyl groups (eg, methoxyphenyl and the like),
And cyclic aminocarbonyl groups. Specific examples thereof include carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-phenylcarbamoyl, and N-acetyl. Carbamoyl, N-benzoylcarbamoyl, N- (p-methoxyphenyl) carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl, and the like are referred to as “optionally substituted thiocarbamoyl”. Examples of the “group” include a thiocarbamoyl group which may be substituted with one or two substituents selected from a C _1-4 alkyl group (eg, methyl, ethyl and the like), a phenyl group and the like. , Thiocarbamoyl, N-methylthiocarbamoyl, - phenyl thiocarbamoyl is, the "optionally substituted carbamoyloxy group", for example, C _1-4 alkyl group (e.g., methyl, ethyl, etc.), 1 or 2 substituents selected from a phenyl group A carbamoyloxy group which may be substituted with, for example, carbamoyloxy, N
-Methylcarbamoyloxy, N, N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, N-phenylcarbamoyloxy and the like, and examples of the "C _1-6 alkanoylamino group" include, for example, acetamido, propionamide, butyroamide, valeroamide, pivaloamide For example, as the “C _6-10 aryl-carbonylamino group”, for example, benzamide, naphthamide, phthalimide and the like, and as the “C _1-10 alkoxy-carboxamide group”, for example, methoxycarboxamide (CH
₃ OCONH-), ethoxy carboxamide, tert- etc. butoxy carboxamides found - as "C _6-10 aryloxy-carboxamide group" for example, phenoxy carboxamide (C ₆ H ₅ OCONH-), etc., "C _7-10
Examples of the “aralkyloxy-carboxamide group” include, for example, benzyloxycarboxamide (C ₆ H ₅ CH ₂ OC
ONH-), benzhydryloxycarboxamide and the like, as "C _1-10 alkoxy-carbonyloxy group", for example, methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyl Oxy, tert-butoxycarbonyloxy, n-pentyloxycarbonyloxy, n-hexyloxycarbonyloxy and the like. Examples of the “C _6-10 aryloxy-carbonyloxy group” include phenoxycarbonyloxy, naphthyloxycarbonyloxy and the like. , "C
Examples of the " _7-19 aralkyloxy-carbonyloxy group" include benzyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy, benzhydryloxycarbonyloxy and the like, and "C _3-10 cycloalkyl". Alkyloxy-
Examples of the "carbonyloxy group" include cyclopropyloxycarbonyloxy and cyclohexyloxycarbonyloxy, and examples of the "optionally substituted ureido group" include a _C1-4 alkyl group (eg, methyl, ethyl and the like), A ureide group which may be substituted with 1 to 3 substituents selected from a phenyl group and the like is used. For example, ureide, 1-methylureide, 3-methylureide, 3,3-dimethylureide, 1,3 -Dimethylureido, 3-phenylureido and the like.

When R ¹ is an aromatic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, these substituents include, in addition to those described above, For example, a C _1-6 alkyl group, a C _3-6 cycloalkyl group,
A C _4-7 cycloalkylalkyl group, a C _2-3 alkenyl group,
A C _2-3 alkynyl group, a C _6-10 aryl group, a C _7-11 aralkyl group and the like are used. As the “C _1-6 alkyl group”, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl, sec-butyl, tert-butyl and the like, as " _C3-6 cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, as " _C4-7 cycloalkylalkyl group", For example, cyclopropylmethyl,
Cyclopentylmethyl and the like are referred to as “C _2-3 alkenyl groups”
For example, vinyl, propenyl and the like are represented by "C
Examples of " _2-3 alkynyl group" include ethynyl, propynyl and the like, examples of "C _6-10 aryl group" include phenyl and naphthyl, and examples of "C _7-11 aralkyl group" include benzyl, phenethyl and naphthylmethyl. However, examples of the “C _1-6 halogenoalkyl group” include fluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,3,3-tetrafluoropropyl and the like. These substituents in the “hydrocarbon group which may have a substituent” and the “heterocyclic group which may have a substituent” represented by R ¹ are not limited to one, and may be the same or different. There may be a plurality (2 to 4).

The heterocyclic group, the heterocyclic oxy group, the heterocyclic thio group, the heterocyclic sulfinyl group, the heterocyclic sulfonyl group and the heterocyclic group in the heterocyclic amino group in the substituents of the above “hydrocarbon group” and “heterocyclic group” The group represents a group formed by removing one hydrogen atom bonded to a heterocyclic ring, and such a heterocyclic ring is, for example, a heteroatom such as a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom. One atom
A 5- to 8-membered ring containing 1 to 4 and preferably 1 to 4 or a condensed ring thereof. Such heterocyclic groups include, for example, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl,
2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-
Thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, indolyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido [2,3-d] pyrimidyl, 1,5- ,
1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl, thieno [2,3-d] pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, etc. These heterocyclic groups include C _1-4 alkyl groups (eg, methyl, ethyl and the like), hydroxyl groups, oxo groups, C _1-4 alkoxy groups (eg,
Methoxy, ethoxy, etc.).

In the above formulas (I), (II), (IV) and (IVa), the “divalent group” in the “divalent group which may have a substituent” represented by X is X is a carbon atom,
It is composed of one selected from a nitrogen atom, an oxygen atom, a sulfur atom, and a silicon atom, or a series of 2 to 4 atoms, such as a divalent hydrocarbon group, oxygen, nitrogen And a lower alkylene (methylene, ethylene, propylene, etc.) via one or two atoms selected from a sulfur atom and one or two and a lower alkylene (methylene, ethylene,
Propylene) in series.
Examples of the divalent group which may have a substituent include-
NR ⁴ —CH ₂ —, —NR ⁴ —CH ₂ CH ₂ —, —O—CH _{2
-, - O-CH 2 CH} 2 -, - S-CH 2 -, - S-CH 2
_{CH 2 -, - CH 2 -NR} 4 -CH 2 -, - CH 2 -O-C
A group represented by H ₂ —, —CH ₂ —S—CH ₂ — (wherein R ⁴ has the same meaning as described above);
⁴ -CH ₂ - (. Wherein R ⁴ is as defined above) are preferred. Examples of the methylene group which may have a substituent represented by Y include, for example, unsubstituted methylene and 1,1
Methylene in which one or two C _1-3 alkyl groups are substituted for methylene such as ethylene, 1,1-propylene, 2,2-propylene, 1,1-butylene, and 2,2-butylene; Among the compounds represented by the above (I), a compound represented by the formula (Ia) or a salt thereof (hereinafter, simply referred to as compound (Ia)) is preferable. In the formula (Ia), R ⁴
As the `` optionally substituted hydrocarbon group '' and `` optionally substituted heterocyclic group '' represented by
Those described in the R ¹ can be mentioned. As R ⁴ , a hydrocarbon group which may have a substituent is preferable, and as the hydrocarbon group, a C _1-6 alkyl group such as methyl, ethyl, propyl and isopropyl is particularly preferable.

As salts of the compounds represented by the formulas (I), (II), (IV) and (IVa), when these compounds have a basic group such as --NH ₂ as a substituent, Examples thereof include salts with inorganic acids, salts with organic acids, and salts with acidic amino acids. Preferable examples of the inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,
Salts with succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Preferred examples of the salt with an acidic amino acid include, for example,
Salts with aspartic acid, glutamic acid and the like can be mentioned. When the compound has an acidic group such as —COOH as a substituent, it may form a salt with an alkali metal such as lithium, sodium, and potassium. The reaction of the present invention is carried out by reacting compound (I) with an acid anhydride. Examples of the acid anhydride include a carboxylic acid anhydride and a sulfonic acid anhydride, and a carboxylic acid anhydride is preferable. Compound (III) as a carboxylic anhydride
Is mentioned. In the above formula (III), the “hydrocarbon group which may have a substituent” and the “heterocyclic group which may have a substituent” represented by R ² and R ³ include the above-mentioned R ¹ The above-mentioned is mentioned. When R ² and R ³ combine to form a ring which may have a substituent, it indicates that R ² , R ³ and —CO—O—CO— form a ring.
Examples of compound (III) include, for example, acetic anhydride, succinic anhydride, phthalic anhydride, propionic anhydride, butyric anhydride,
Isobutyric anhydride, valeric anhydride, cinnamic anhydride, benzoic anhydride, toluic anhydride, itaconic anhydride, glutaric anhydride, maleic anhydride, citraconic anhydride, glutaconic anhydride, diglycolic anhydride, diphenic anhydride, etc. No. Among them, acetic anhydride is preferably used.

The reaction of the present invention is preferably carried out in the presence or absence of a solvent, usually in the presence of an organic base. As the organic base, an organic base having a pKa of 5 or more in an aqueous solution,
Examples include basic amines. Examples of the basic amines include organic cyclic amines and tertiary amines. Examples of the organic cyclic amines include, for example, trimethylamine and triethylamine.
Examples of primary amines include 1,5-diazabicyclo [4.
3.0] Non-5-ene, 1,4-diazabicyclo [2.2.2]
Octane, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, picoline, dicyclohexylamine, etc., and 1,5-diazabicyclo [4.3.
0] non-5-ene, 1,4-diazabicyclo [2.2.2]
Octane, 1,8-diazabicyclo [5.4.0] -7-undecene is preferred. The solvent may be any solvent as long as it dissolves the compound (I) or a salt thereof and does not hinder the reaction. Examples thereof include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethylene, tetrahydrofuran, and dioxane. Ethers such as diethyl ether, diisopropyl ether, dimethylene glycol dimethyl ether and diethylene glycol diethyl ether; esters such as ethyl acetate and butyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; acetone and ethyl methyl ketone; Ketones, nitriles such as acetonitrile, benzonitrile, hydrocarbons such as cyclohexane, hexane, heptane, pentane, dimethylformamide, dimethylsulfoxide, dimethylacetamide Although such aprotic polar solvents such as hexamethylphosphoric triamide, are preferably used among them aprotic polar solvent. The amount of the acid anhydride to be used is 0.5 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (I).

The amount of the organic base to be used is generally 0.5 to 20 mol, preferably 1 to 5 mol, per 1 mol of compound (I). The amount of the solvent to be used is generally 0.1 mol per 1 mol of compound (I).
It is 1 to 100 liters, preferably 0.5 to 5 liters. In carrying out this reaction, compound (I), an acid anhydride,
The order of mixing the organic base and the solvent is not limited. For example, a method of sequentially adding and mixing the compound (I), the organic base, the acid anhydride and the solvent, or dissolving the compound (I) in the solvent and adding the compound It can be carried out by a method of adding and mixing a base and an acid anhydride. The reaction temperature is generally 0-200 ° C, preferably 50-90 ° C, and the reaction time is about 0.5-20 hours, preferably about 1-5 hours. Compound (II) which is the target compound of this reaction
Is obtained from the reaction solution by a usual method, for example, separation, concentration, distillation, crystallization, or the like, or a combination thereof.
Obtainable. Compound (IV) may be obtained in the above reaction of the present invention. When the reaction is carried out in the presence of a relatively weak base such as, for example, triethylamine, compound (IV) is obtained. In this case, in formula (IV), the acyloxy group represented by Z is an acyloxy moiety of an acid generated from the acid anhydride used. For example, when acetic anhydride is used as the acid anhydride, Z is an acetyloxy group. .
The salt of the compound represented by the formula (IV) is represented by the formula (I)
And the same as those described as the salt of the compound represented by Compound (IV) can be isolated and purified from the reaction solution by a conventional method, for example, separation, concentration, distillation, crystallization, or a combination thereof.
The reaction mixture of the present invention containing the compound (IV) may be used under the reaction conditions of the present invention, preferably in the presence of a relatively strong basic amine such as 1,8-diazabicyclo [5.4.0] -7-undecene. When the reaction is carried out, the ring is closed and the compound (I
I) can be produced.

The reaction of the present invention can be used for producing active ingredients such as pharmaceuticals and pesticides or synthetic intermediates thereof. For example, in compound (II), -X-CO- has the formula:

Embedded image [Wherein, Ar ₂ represents a halogenated phenyl group, and (R)
Represents a steric configuration], Y is methylene, and R ¹ is an aliphatic or aromatic hydrocarbon group which may have a substituent, or an aromatic which may have a substituent. The compound which is a group bicyclic group, that is, the compound (C) itself is a compound having an antifungal activity and is used as an active ingredient of medicines and agricultural chemicals (see JP-A-8-104676). Some of the other compounds (II) themselves exhibit antifungal activity, but can be led to other compounds by appropriately using known reactions. In the compound (I) which is a starting compound of the present invention, X is a compound represented by the formula:

Embedded image (Wherein R ⁴ has the same meaning as described above), that is, the compound (Ia) can be synthesized by a reaction represented by the following formula.

Embedded image (In the formula, X ¹ represents a leaving group, and other symbols are as defined above.) That is, a compound represented by the formula (V) [hereinafter, simply referred to as a compound (V)] is represented by the formula (VI) (Hereinafter simply referred to as compound (VI)) or a compound represented by formula (VII) [hereinafter referred to as compound (VII)] to produce compound (Ia). Examples of the leaving group represented by X ¹ include a phenyloxy group, a chlorophenyloxy group, and a nitrophenyloxy group, and among them, a phenyloxy group is preferable.

The reaction of compound (V) with compound (VI) or compound (VII) is carried out in the presence or absence of a base in a solvent that does not inhibit the reaction or in the absence of a solvent. In this reaction, the compound (VI) or the compound (VII) is preferably reacted in about 0.5 to 5 mol, more preferably about 0.7 to 1.5 mol, per 1 mol of the compound (V). preferable. When a base is used, examples of the base include inorganic bases (eg, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.) and organic bases (eg, triethylamine, pyridine, diisopropylethylamine, etc.). Particularly, organic bases such as triethylamine and pyridine are preferable. When a base is present, the amount of the base to be used is preferably about 0.5 to 10 times (molar ratio), particularly preferably about 0.9 to 5 times (molar ratio) based on Compound (V). . When a solvent is used, the solvent includes sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, and chloroform. , 1,
Halogenated hydrocarbons such as 2-dichloroethane, esters such as ethyl acetate, dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-
Amides such as 2-imidazolidinone and 1-methyl-2-pyrrolidone are exemplified. These solvents may be used alone or in combination of two or more at an appropriate ratio. When a solvent is used, the amount of the solvent used is the same as that of compound (V)
It is usually 0.1 to 100 liters, preferably 0.5 to 5 liters, per mole. Compound (V) and compound (V
In the reaction with I) or the compound (VII), the reaction temperature is suitably about -10 to 150 ° C, and about 0 to 120 ° C.
Is preferred. The reaction time is suitably from about 0.1 to 50 hours, preferably from about 0.5 to 30 hours. Compound (I), which is a starting compound of the present invention, can be synthesized, for example, by a reaction represented by the following formula.

Embedded image (In the formula, Q represents a general protecting group for a hydroxyl group, and other symbols are as defined above.) That is, first, a compound represented by the formula (VIII) [hereinafter, simply referred to as compound (VIII)] is used. A compound represented by the formula (X) [hereinafter simply referred to as compound (X)] is synthesized from the compound represented by the formula (IX) by a general amidation reaction, and then a general deprotection from the compound (X) is performed. Compound (I) by a group reaction
Can be manufactured. Compound (VIII) is known, for example, (±) -3-hydroxybutyric acid, (R)-(−)-3-
Hydroxybutyric acid, its sodium salt, DL-3-hydroxybutyric acid, its sodium salt, (S)-(+)-3-hydroxybutyric acid, its sodium salt, 4-hydroxybutyric acid, its sodium salt, 10-hydroxydecanoic acid, 12-Hydroxydodecanoic acid and 16-hydroxyhexadecanoic acid are commercially available, and are described, for example, in catalogs published by Aldrich.

[0018]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in more detail below with reference to Examples, Comparative Examples and Reference Examples, but the present invention is not limited thereto.

EXAMPLES Example 1 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-
Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-
Synthesis of yl) phenyl] -2-imidazolidinone N-[(1R, 2R) -2- (2,4-difluorophenyl) -2-
Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -N- (2-hydroxyethyl) -N′-
[4- (1H-tetrazol-1-yl) phenyl] urea 9.2
2 kg, 1,8-diazabicyclo [5.4.0] -7-undecene 9.27 kg, acetic anhydride 2.07 kg, and dimethylformamide 31 L were mixed and reacted by stirring at about 60 ° C. for about 2 hours. The reaction solution was cooled to about 30 ° C., and 46 L of ethyl acetate and 30 L of water were added to carry out liquid separation. The organic layer was concentrated, and methanol-denatured ethanol 32 was added to the residue.
L and 32 L of water were added. After cooling, the precipitated crystals were separated by a centrifuge, and methanol-denatured ethanol-water (1:
1) Washing was performed with 13 L of the mixed solution. Dry and dry 1-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone was obtained. 8.09 kg (yield: 90%)

Example 2 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-
Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-
Synthesis of yl) phenyl] -2-imidazolidinone N-[(1R, 2R) -2- (2,4-difluorophenyl) -2-
Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -N- (2-hydroxyethyl) -N′-
[4- (1H-tetrazol-1-yl) phenyl] urea 9.2
2 kg, 1,8-diazabicyclo [5.4.0] -7-undecene 9.27 kg, acetic anhydride 2.07 kg, and dimethylformamide 31 L were mixed and reacted by stirring at about 60 ° C. for about 2 hours. The reaction solution was cooled to about 30 ° C., and 46 L of ethyl acetate and 30 L of water were added to carry out liquid separation. 30 L of ethyl acetate was added to the aqueous layer to carry out liquid separation. Again, 30 L of ethyl acetate was added to the aqueous layer to carry out liquid separation. The organic layers were combined and washed with 20 L of an aqueous sodium hydroxide solution. 0.1N for organic layer
20 L of hydrochloric acid was added, and the pH was adjusted to 2 to 4 with dilute hydrochloric acid, followed by separation. 10 L of ethyl acetate was added to the aqueous layer to carry out liquid separation. The organic layers were combined and concentrated, and 32 L of methanol-denatured ethanol and 32 L of water were added to the residue. The mixture was stirred at about 60 ° C. for about 1 hour, at about 20 ° C. for about 1 hour, and at about 5 ° C. for about 1 hour. The precipitated crystals were separated and washed with 13 L of a cooled methanol-modified ethanol-water (1: 1) mixed solution.
Dry and dry 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] 8.27--3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone
kg (yield: 92%).

Example 3 N-[(1R, 2R) -2- (2,4-difluorophenyl) -2-
Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -N- (2-acetoxyethyl) -N′-
Synthesis of [4- (1H-tetrazol-1-yl) phenyl] urea N-[(1R, 2R) -2- (2,4-difluorophenyl) -2-
Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -N- (2-hydroxyethyl) -N′-
[4- (1H-tetrazol-1-yl) phenyl] urea 9.2
g, acetic anhydride 2.1 g, dimethylformamide 30 m
were mixed and reacted by stirring at about 60 ° C. for about 2 hours. After cooling, 50 ml of ethyl acetate and 30 L of water were added to carry out liquid separation. The organic layer was concentrated and N-[(1R, 2R) -2- (2,
4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -N-
(2-acetoxyethyl) -N '-[4- (1H-tetrazole-
9.87 g (yield: 99%) of 1-yl) phenyl] urea was obtained.

Example 4 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-
Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-
Synthesis of yl) phenyl] -2-imidazolidinone N-[(1R, 2R) -2- (2,4-difluorophenyl) -2-
Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -N- (2-acetoxyethyl) -N′-
[4- (1H-tetrazol-1-yl) phenyl] urea 10
g, 1,8-diazabicyclo [5.4.0] -7-undecene
9.3 g, acetic anhydride 2.1 g, dimethylformamide 3
0 ml were mixed and reacted by stirring at about 60 ° C. for about 2 hours. The reaction solution was cooled to about 30 ° C., and 45 ml of ethyl acetate and 30 ml of water were added to carry out liquid separation. The organic layer was concentrated, and 30 ml of methanol-denatured ethanol and 3 portions of water were added to the residue.
0 ml was added. After cooling, the precipitated crystals were separated, and 10 ml of a methanol-modified ethanol-water (1: 1) mixed solution was added.
And washed. Dry and dry 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3- [4- (1
[H-tetrazol-1-yl) phenyl] -2-imidazolidinone was obtained in an amount of 8.2 g (yield: 92%).

Reference Example 1 Synthesis of 1-p-nitrophenyl-1H-tetrazole 36 kg of 4-nitro-1-aminobenzene under a nitrogen stream,
22 kg of sodium azide and 47 kg of trimetrimethyl orthoformate were charged. Next, 215 kg of glacial acetic acid was mixed and reacted by stirring at about 80 ° C. After cooling, 215 kg of water was added, and the precipitated crystals were collected by filtration. The obtained 1-p-nitrophenyl-1H-tetrazole wet crystals were suspended in 150 kg of water, and stirred at 20 ° C. or lower for about 1 hour. The crystals were collected by filtration and washed with about 80 kg of water. The obtained wet crystals were dried to obtain 44 kg of 1-p-nitrophenyl-1H-tetrazole. Reference Example 2 Synthesis of 1-p-aminophenyl-1H-tetrazole 1-p-nitrophenyl-1H-tetrazole under a nitrogen stream
44 kg, water 88 kg mixed, heated to about 75 ℃,
85 kg of 34% sodium hydrosulfide was added dropwise while maintaining the temperature at 83 ° C. or lower. The reaction was carried out by stirring at about 80 ° C. After cooling, the crystals were collected by filtration and washed with 98 kg of water. 1
-p-Aminophenyl-1H-tetrazole wet crystal 41kg
I got

Reference Example 3 Crude 1- (4-phenoxycarbonylaminophenyl) -1H-
Synthesis of tetrazole Under nitrogen flow, 41 kg of 1-p-aminophenyl-1H-tetrazole wet crystals, 18 kg of sodium hydrogen carbonate, 1,4-
Dioxane (or tetrahydrofuran) 146k
g and 150 kg of water. At an internal temperature of 30 ° C. or lower, 31 kg of phenyl chlorocarbonate was added dropwise. The reaction was carried out by stirring at an internal temperature of 30 ° C. or lower. The crystals are collected by filtration and 35 kg of water
And washed. The wet crystals are dried and crude 1- (4-phenoxycarbonylaminophenyl) -1H-tetrazole 143k
g was obtained. Reference Example 4 Synthesis of 1- (4-phenoxycarbonylaminophenyl) -1H-tetrazole Crude 1- (4-phenoxycarbonylaminophenyl) -1H-
61.8 kg of tetrazole and 52 kg of ethyl acetate were mixed and stirred at an internal temperature of 77 to 80 ° C. for 1 hour. After dust filtration, the filtrate was cooled to an internal temperature of 20 ° C. or lower and stirred for 1 hour.
The crystals were collected by filtration and washed with 35 kg of ethyl acetate. The wet crystals were dried to obtain 23 kg of 1- (4-phenoxycarbonylaminophenyl) -1H-tetrazole. Reference Example 5 N-[(1R, 2R) -2- (2,4-difluorophenyl) -2-
Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -N- (2-hydroxyethyl) -N′-
Synthesis of [4- (1H-tetrazol-1-yl) phenyl] urea (2R, 3R) -2- (2,4-difluorophenyl) -3- [N-
(2-Hydroxyethyl) amino] -1- (1H-1,2,4-triazol-1-yl) -2-butanol 8.5 kg, ethyl acetate 115 L, 1- (4-phenoxycarbonylaminophenyl) -1H 7.44 kg of tetrazole and 3.76 L of triethylamine were mixed and reacted by stirring at about 50 ° C. for about 8 hours. After cooling, the precipitated crystals were collected by filtration and washed with 8 L of cold ethyl acetate. Dried and N-[(1R,
2R) -2- (2,4-difluorophenyl) -2-hydroxy-
1-methyl-3- (1H-1,2,4-triazol-1-yl)
Propyl] -N- (2-hydroxyethyl) -N ′-[4- (1H-
12 kg of tetrazol-1-yl) phenyl] urea was obtained.

[0024]

According to the present invention, a cyclic amide compound can be industrially advantageously produced.

Claims (16)

[Claims] [Claim 1] The formula: (Wherein, R ¹ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and X represents a divalent group which may have a substituent. , Y represents a methylene group which may have a substituent) or a salt thereof, and an acid anhydride. (Wherein R ¹ , X and Y have the same meanings as described above) or a salt thereof. 2. The process according to claim 1, wherein the reaction is carried out in the presence of an organic base. 3. The method according to claim 2, wherein the organic base is an organic base having a pKa of 5 or more. 4. The method according to claim 2, wherein the organic base is a basic amine.
Production method as described. 5. The method according to claim 4, wherein the basic amine is an organic cyclic amine or a tertiary amine. 6. The basic amines are trimethylamine, triethylamine, 1,5-diazabicyclo [4.3.0] nonone.
-5-ene, 1,4-diazabicyclo [2.2.2] octane,
The method according to claim 4, which is 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, picoline or dicyclohexylamine. 7. The method of claim 1, wherein the basic amine is 1,5-diazabicyclo.
[4.3.0] Non-5-ene, 1,4-diazabicyclo [2.
2.2] octane or 1,8-diazabicyclo [5.4.0]
-7-undecene). 8. The method according to claim 1, wherein the acid anhydride is a carboxylic acid anhydride. 9. An acid anhydride having the formula: ## STR3 ## (Wherein R ² and R ³ each represent a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, or R ² and R ³ are May form a ring which may have a substituent.). 10. The process according to claim 2, wherein the amount of the organic base used is 0.5 to 20 mol per 1 mol of the compound represented by the formula (I). 11. The method according to claim 1, wherein the amount of the acid anhydride is 0.5 to 20 mol per 1 mol of the compound represented by the formula (I). 12. X is a divalent group in which one to four atoms selected from a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom and a silicon atom are connected in series and may have a substituent. The method according to claim 1. 13. A compound represented by the formula (I): (Wherein, R ¹ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ⁴ represents a hydrogen atom or a hydrocarbon group which may have a substituent. The method according to claim 1, wherein the compound is a hydrogen group or a heterocyclic group which may have a substituent, and Y represents a methylene group which may have a substituent. 14. A compound represented by the formula: (Wherein, R ¹ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and X represents a divalent group which may have a substituent. , Y represents a methylene group which may have a substituent, and Z represents an acyloxy group.)
Or a salt thereof. 15. A compound represented by the formula (IV): (Wherein, R ¹ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and R ⁴ represents a hydrogen atom or a hydrocarbon group which may have a substituent. 15. A compound represented by a hydrogen group or a heterocyclic group which may have a substituent, Y represents a methylene group which may have a substituent, and Z represents an acyloxy group. Production method as described. 16. A compound represented by the formula: (Wherein, R ¹ represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, and X represents a divalent group which may have a substituent. , Y represents a methylene group which may have a substituent, and Z represents an acyloxy group.)
Wherein the compound represented by the formula (I) or a salt thereof is subjected to a ring-closure reaction in the presence of an organic base: (Wherein R ¹ , X and Y have the same meanings as described above) or a salt thereof.