JP2006182761A - Acetonitrile compounds and agricultural and horticultural fungicides - Google Patents

Abstract

【選択図】なし
It is an object of the present invention to provide a novel acetonitrile compound that exhibits a high therapeutic effect, rain resistance effect, and phytotoxicity safety effect at lower doses against plant diseases, particularly downy mildew and plague. . It is another object of the present invention to provide a fungicide containing these compounds as an active ingredient, particularly an agricultural and horticultural fungicide.
The present invention provides a compound (including optical isomers) represented by the following general formula (I) or a salt thereof, and further an agricultural and horticultural fungicide containing the compound.

[Selection figure] None

Description

  The present invention relates to an acetonitrile compound and a fungicide containing the same as an active ingredient, particularly an agricultural and horticultural fungicide.

  In recent years, compounds described as having the bactericidal activity include the compounds described in the following (1) to (4). These compounds show control effects against plant diseases, in particular downy mildew and plague.

  (1) It is known that the compound represented by the following general formula (A) or (B) has bactericidal activity (see Patent Document 1 or 2). All of the compounds represented by the general formula (A) or (B) are characterized by having a phenylpropargyl ether moiety.

(2) It is known that α-oxy or α-thiocarboxylic acid phenethylamide derivatives represented by the following general formula (C) or (D) have bactericidal activity (see Patent Document 3 or 4). R ³ in the general formula (C) or (D) is a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group.

  (3) It is known that glyoxylic acid amides represented by the following general formula (E) have bactericidal activity (see Patent Document 5). The compound represented by the general formula (E) has an α-iminocarboxylic acid amide structure.

  (4) It is known that the compound represented by the following general formula (F) has bactericidal activity (see Patent Document 6). Patent Document 6 exemplifies a compound represented by (F ′) as a specific example of the compound represented by Formula (F).

  The compound represented by the general formula (F ′) is characterized by having dimethoxy on the phenyl ring of the phenethylamide moiety. Depending on the method described in Patent Document 6, the range in which the substituent (dimethoxy) on the phenyl ring of the phenethylamide moiety in formula (F ′) can be changed is limited.

  On the other hand, pesticides are often used prophylactically (for example, used before plant diseases develop to prevent the invasion of pathogenic bacteria). However, in recent years, in addition to preventive effects due to demands for reducing the burden on the environment of pesticides or saving labor, it exhibits further therapeutic effects (for example, cures disease even if used after plant disease has occurred) Development of agricultural chemicals that can be done is desired. In addition, it is indispensable to have rain resistance in order for agricultural chemicals, particularly fungicides, to exert a stable control effect. In addition, it is desired to develop a highly safe pesticide that is free from phytotoxicity on agricultural products.

However, the therapeutic effects of the above-mentioned compounds on plant diseases are not sufficient. Also, the rain resistance effect against downy mildew and plague is not satisfactory. Also, it is not necessarily safe for agricultural products.
Special table 2002-534494 gazette Special table 2003-533502 gazette International Publication No. 03/42167 Pamphlet International Publication No. 03/42168 Pamphlet Special table 2003-515566 gazette JP-T 8-511772 Publication

An object of the present invention is to improve such problems and to provide a novel acetonitrile compound that exhibits a high therapeutic effect at a lower dose against plant diseases, particularly downy mildew and plague.
Moreover, this invention makes it a subject to provide the novel acetonitrile compound which exhibits a high rain-resistant effect with a lower dose with respect to downy mildew and a plague.
Moreover, this invention makes it a subject to provide the novel acetonitrile compound which exhibits high safety | security without a phytotoxicity with respect to agricultural crops.
It is another object of the present invention to provide a fungicide containing these compounds as an active ingredient, particularly an agricultural and horticultural fungicide.

  In order to solve the above-mentioned problems, the present inventors have synthesized various compounds and intensively studied their bactericidal action. As a result, the acetonitrile compound represented by the following general formula (I) shows a high therapeutic effect at a lower dose against plant diseases, particularly downy mildew and plague, and higher at a lower dose. It has been found that it exhibits a rain resistance effect. In addition, they have found that the crops exhibit high safety without chemical damage. Further, the present invention was completed by finding that a composition containing it as an active ingredient is useful as an agricultural and horticultural fungicide.

Therefore, 1st invention of this application is related with the acetonitrile compound or its salt represented with the following general formula (I).
Here, the acetonitrile compound represented by the general formula (I) may be an optical isomer.

In general formula (I):
R ¹ represents a hydrogen atom; a chain or cycloalkyl group optionally having a halogen atom, an alkoxy group or a cyano group; an alkenyl group optionally having a halogen atom; and optionally having a halogen atom. An alkynyl group; or an alkylcarbonyl group,
R ² represents a hydrogen atom or an alkyl group,
m represents an integer of 0 to 2,
X represents a halogen atom; an alkoxy group or a chain or cycloalkyl group which may have a halogen atom; an alkenyl group which may have a halogen atom: an alkynyl group which may have a halogen atom; A chain or a cycloalkoxy group that may have a halogen atom; an alkenyloxy group that may have a halogen atom; an alkynyloxy group that may have a halogen atom; An alkylthio group, an alkylsulfinyl group or an alkylsulfonyl group; a phenyl group; a phenoxy group; a cyano group; a nitro group; a formyl group; a carboxyl group; an alkylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, and an alkynyloxycarbonyl group. Selected carbonyl ; 1 or an amino group which may have a two alkyl groups; a benzyl group; or the following general formula (II)

(In the general formula (II), R ³ represents a hydrogen atom or an alkyl group, and R ⁴ represents an alkyl group, an alkenyl group, or an alkynyl group.)
A substituent represented by
n represents an integer of 0 to 5,
when n is 2 or more, each X may be the same or different;
Two Xs may be bonded to two adjacent carbons of the phenyl ring carbon, and the two Xs together may represent an alkylenedioxy group or an alkylene group.

  A second invention of the present application relates to an agricultural and horticultural fungicide containing the acetonitrile compound represented by the above general formula (I) or a salt thereof.

<Acetonitrile compound of the present invention>
The acetonitrile compound of the present invention is a compound represented by the general formula (I). The acetonitrile compound of the present invention can be a salt. For example, when the compound represented by the general formula (I) is treated with a base such as sodium hydride or potassium carbonate, the hydrogen on the nitrogen atom of the phenethylamide moiety can be eliminated to form a basic salt.

Moreover, the acetonitrile compound of the present invention has a chiral center (asymmetric center) at the position of the α-position of the carbonyl carbon of the amide moiety as shown in the general formula (I). The acetonitrile compound of the present invention may be a mixture of enantiomers about the chiral center, or may be an optical isomer consisting of only one enantiomer (R-form or S-form). In the case of a mixture of enantiomers, the ratio of both isomers is not particularly limited, and may be a racemate containing equal amounts of both isomers, or a mixture having a high ratio of either isomer. Also good.
The optical purity or enantiomeric excess of the acetonitrile compound of the present invention can be determined by HPLC using an optical resolution column, NMR using a shift reagent, or the like.

Hereinafter, each substituent represented by R ¹ , R ² and X in the general formula (I), and m and n will be described. However, R ¹ , R ² and X, and m and n in the general formula (I) are not limited to the examples shown here.

In the general formula (I), R ¹ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, or an alkylcarbonyl group. In the present specification, an alkyl group means a saturated hydrocarbon group, an alkenyl group means a hydrocarbon group having at least one carbon double bond, and an alkynyl group means a carbon group having at least one carbon triple bond. It means a hydrogen group.

The alkyl group represented by R ¹ may be a chain alkyl group or a cyclic cycloalkyl group. The alkyl group represented by R ¹ may be an unsubstituted alkyl group, but may have any atom or substituent, and may be a haloalkyl group having a halogen atom, an alkoxyalkyl group having an alkoxy group, or a cyano group. It may be a cyanoalkyl group having

Examples of the chain alkyl group represented by R ¹ include a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group , Neopentyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 3,3-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group Examples thereof include a 1-ethylbutyl group, a 1-methyl-1-ethylpropyl group, a 1,2-dimethylbutyl group, a 2-methyl-1-ethylpropyl group, and a 2,2-dimethylbutyl group. Of these, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like are preferable.
Examples of the cycloalkyl group represented by R ¹ include cycloalkyl groups having 3 to 7 carbon atoms. The cycloalkyl group may have a branched chain having 1 to 6 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 2-methylcyclopropyl group, a 2-methylcyclopentyl group, and a 2-methylcyclohexyl group. Of these, a cyclopropyl group is preferable.

Examples of the halogen atom contained in the haloalkyl group represented by R ¹ include fluorine, chlorine, bromine and iodine atoms. Examples of the haloalkyl group represented by R ¹ include an alkyl group obtained by substituting any hydrogen atom of the aforementioned alkyl group with a halogen atom such as fluorine, chlorine, bromine or iodine. Specifically, for example, trifluoromethyl group, fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, dichloromethyl group, trichloromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2- Bromoethyl group, 1-fluoroethyl group, 1,1-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 1-fluoropropyl group, 3-fluoropropyl group, 2-chloropropyl group A 3-chloropropyl group, 3-iodopropyl group, 1-fluorobutyl group, 4-fluorobutyl group, 1-chlorobutyl group and the like can be mentioned. Of these, a trifluoromethyl group is preferable.

The alkoxy group of the alkoxyalkyl group represented by R ¹ is preferably a linear or branched alkoxy having 1 to 6 carbon atoms.
Examples of the alkoxyalkyl group represented by R ¹ include a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, an isopropoxymethyl group, an n-butoxymethyl group, an isobutoxymethyl group, a sec-butoxymethyl group, and a tert-butoxy group. Methyl group, n-pentyloxymethyl group, isopentyloxymethyl group, n-hexyloxymethyl group, methoxyethyl group, ethoxyethyl group, n-propoxyethyl group, isopropoxyethyl group, n-butoxyethyl group, isobutoxy Examples thereof include an ethyl group, sec-butoxyethyl group, tert-butoxyethyl group, methoxypropyl group, ethoxypropyl group, n-propoxypropyl group, isopropoxypropyl group, and n-butoxypropyl group. Among these, Preferably, a methoxymethyl group and an ethoxymethyl group are mentioned.

Examples of the cyanoalkyl group represented by R ¹ include a linear or branched cyanoalkyl group having 2 to 4 carbon atoms. Specific examples include a cyanomethyl group, a 2-cyanoethyl group, a 1-cyanoethyl group, and a 3-cyanopropyl group. More preferably, a cyanomethyl group is mentioned.

The alkenyl group represented by R ¹ may be a chain alkenyl group or a cyclic cycloalkenyl group. The alkenyl group represented by R ¹ may have any atom or substituent, and may be a haloalkenyl group having a halogen atom.

Examples of the alkenyl group represented by R ¹ include linear or branched alkenyl groups having 2 to 6 carbon atoms. Specifically, for example, vinyl group, 1-propenyl group, 2-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2-ethyl-2-propenyl group, 2-butenyl group 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-ethyl-2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2- Examples thereof include a hexenyl group, a 3-hexenyl group, and a 4-hexenyl group. Of these, 1-propenyl group, 2-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2-ethyl-2-propenyl group, 2-butenyl group, 3- A butenyl group is mentioned.

The halogen atom contained in the haloalkenyl group represented by R ¹ may be any atom of fluorine, chlorine, bromine or iodine. Examples of the haloalkenyl group include alkenyl groups in which the hydrogen atom of the alkenyl group is substituted with a halogen atom such as fluorine, chlorine, bromine or iodine. Specifically, for example, 2-fluorovinyl group, 3-chloro-2-propenyl group, 3,3-dichloro-2-propenyl group, 2-fluoro-1-propenyl group, 3,3,3-trifluoro- A 1-propenyl group, 4-chloro-3-butenyl group, 2-chloro-3-methyl-1-butenyl group, 2-fluoro-5-hexenyl group and the like can be mentioned. Among these, 3,3,3-trifluoro-1-propenyl group is preferable.

The alkynyl group represented by R ¹ may be an unsubstituted alkynyl group, but may have any atom or substituent, and may be a haloalkynyl group having a halogen atom or the like.
Examples of the alkynyl group represented by R ¹ include linear or branched alkynyl groups having 2 to 6 carbon atoms. Specifically, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-methyl-2-propynyl group, 1,1-dimethyl-2-propynyl group, 2-butynyl group, 1-methyl-2- Butynyl group, 1-ethyl-2-butynyl group, 3-butynyl group, 2-methyl-3-butynyl group, 2-pentynyl group, 4-pentynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group Or a 5-hexynyl group etc. can be mentioned. Of these, preferred are ethynyl group, 1-propynyl group, 2-propynyl group, 1,1-dimethyl-2-propynyl group, 2-butynyl group and 2-pentynyl group.
Examples of the haloalkynyl group represented by R ¹ include an alkynyl group in which the hydrogen atom of the alkynyl group is substituted with a halogen atom such as fluorine, chlorine, bromine or iodine. Specifically, for example, 2-fluoroethynyl group, 2-chloroethynyl group, 3-chloro-2-propynyl group, 4-fluoro-3-butynyl group, 5-chloro-4-pentynyl group, 6-bromo-5 -A hexynyl group etc. can be mentioned. Of these, a 3-chloro-2-propynyl group is preferable.

Examples of the alkylcarbonyl group represented by R ¹ include linear or branched alkylcarbonyl groups having an alkyl moiety of 1 to 6 carbon atoms. Specific examples include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a sec-butylcarbonyl group, and a tert-butylcarbonyl group. it can. Of these, a methylcarbonyl group is preferable.

As described above, R ¹ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or an alkylcarbonyl group, preferably an unsubstituted chain alkyl group having 1 to 4 carbon atoms (more preferably an ethyl group or n- Propyl group), an alkenyl group having 2 to 4 carbon atoms (more preferably 2-propenyl group), an alkynyl group having 2 to 4 carbon atoms (more preferably 2-propynyl group or 2-butynyl group), or a cyanomethyl group. Can be mentioned. Most preferred is a 2-propynyl group.

In the general formula (I), R ² represents a hydrogen atom or an alkyl group, preferably a hydrogen atom. Examples of the alkyl group represented by R ² include a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group , Neopentyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 3,3-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group Examples thereof include a 1-ethylbutyl group, a 1-methyl-1-ethylpropyl group, a 1,2-dimethylbutyl group, a 2-methyl-1-ethylpropyl group, and a 2,2-dimethylbutyl group. Of these, a methyl group is preferable.

  In general formula (I), m represents 0 or an integer of 1 or 2. From the viewpoint of bactericidal activity, compounds with m = 0 or 2 (more preferably m = 0) are preferable. Moreover, the compound of m = 2 may have a remarkable effect at the point of the residual effect of bactericidal activity.

In the general formula (I), X is bonded to any carbon of the phenyl ring carbon.
X is halogen atom; alkyl group; alkenyl group; alkynyl group; hydroxy group; aliphatic oxy group; aromatic oxy group; alkylthio group, alkylsulfinyl group, alkylsulfonyl group; phenyl group; phenoxy group; cyano group; A formyl group; a carboxyl group; a carbonyl group; an amino group; a benzyl group; or a substituent represented by formula (II).

Examples of the halogen atom represented by X include fluorine, chlorine, bromine and iodine atoms.
The alkyl group represented by X may be either a chain alkyl group or a cyclic cycloalkyl group. Moreover, although an unsubstituted alkyl group may be sufficient, substituted alkyl groups, such as a haloalkyl group or an alkoxyalkyl group, may be sufficient.
The chain alkyl group, cycloalkyl group, haloalkyl group, and alkoxyalkyl group represented by X are specifically the same groups as the chain alkyl group, cycloalkyl group, haloalkyl group, and alkoxyalkyl group represented by R ^1. Can be mentioned.

The alkenyl group represented by X is a substituted alkenyl group such as an unsubstituted alkenyl group or a haloalkenyl group. Examples of the alkenyl group or haloalkenyl group represented by X include the same groups as the alkenyl group or haloalkenyl group represented by R ¹ .
The alkynyl group represented by X is a substituted alkynyl group such as an unsubstituted alkynyl group or a haloalkynyl group. Examples of the alkynyl group or haloalkynyl group represented by X include the same groups as the alkynyl group or haloalkynyl group represented by R ¹ .

Examples of the aliphatic oxy group represented by X include an alkoxy group, an alkenyloxy group, and an alkynyloxy group.
The alkoxy group represented by X is a chain alkoxy group or a cyclic cycloalkoxy group. The alkoxy group represented by X may be an unsubstituted alkoxy group or a substituted alkoxy group such as a haloalkoxy group.
Examples of the chain alkoxy group represented by X include linear or branched alkoxy groups having 1 to 6 carbon atoms. Specifically, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, Examples thereof include an n-hexyloxy group. Among these, Preferably, a methoxy group and an ethoxy group are mentioned.
Examples of the cycloalkoxy group represented by X include cycloalkyloxy groups having 3 to 7 carbon atoms. The cycloalkoxy group may have a branched chain having 1 to 6 carbon atoms. Specific examples include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group. Of these, a cyclopropyloxy group is preferable.
Examples of the haloalkoxy group represented by X include linear or branched haloalkoxy groups having 1 to 6 carbon atoms. Specifically, for example, fluoromethoxy group, chloromethoxy group, bromomethoxy group, iodomethoxy group, difluoromethoxy group, trifluoromethoxy group, 1-fluoroethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2 , 2,2-trifluoroethoxy group, pentafluoroethoxy group, 1-fluoropropoxy group, 3-fluoropropoxy group, 2-chloropropoxy group, 3-chloropropoxy group, 1-fluorobutoxy group, 4-fluorobutoxy group A 1-chlorobutoxy group can be exemplified. Of these, a trifluoromethoxy group and a difluoromethoxy group are preferable.

The alkenyloxy group represented by X may be an unsubstituted alkenyloxy group or a substituted alkenyloxy group such as a haloalkenyloxy group.
Examples of the unsubstituted alkenyloxy group represented by X include linear or branched alkenyloxy groups having 3 to 6 carbon atoms. Specifically, for example, 2-propenyloxy group, 1-methyl-2-propenyloxy group, 1-ethyl-2-propenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 2,2-dimethyl-3- A butenyloxy group, a 4-pentenyloxy group, a 5-hexenyloxy group, and the like can be given. Of these, a 2-propenyloxy group is preferable.
Examples of the haloalkenyloxy group represented by X include a haloalkenyloxy group in which the hydrogen atom of the alkenyloxy group is substituted with a halogen atom such as fluorine, chlorine, bromine or iodine. Specifically, for example, 3-chloro-2-propenyloxy group, 3,3-dichloro-2-propenyloxy group, 2-fluoro-1-propenyloxy group, 3,3,3-trifluoro-1-propenyl Examples thereof include an oxy group, 4-chloro-3-butenyloxy group, 2-chloro-3-methyl-1-butenyloxy group, and 2-fluoro-5-hexenyloxy group. Among these, 3,3,3-trifluoro-1-propenyloxy group is preferable.

The alkynyloxy group represented by X may be an unsubstituted alkynyloxy group or a substituted alkynyloxy group such as a haloalkynyloxy group.
Examples of the unsubstituted alkynyloxy group represented by X include linear or branched alkynyloxy groups having 3 to 6 carbon atoms. Specifically, for example, 2-propynyloxy group, 1-methyl-2-propynyloxy group, 1-ethyl-2-propynyloxy group, 2-butynyloxy group, 3-butynyloxy group, 4-pentynyloxy group, 5 And -hexynyloxy group. Of these, a 2-propynyloxy group is preferable.
Examples of the haloalkynyloxy group represented by X include a haloalkynyloxy group in which the hydrogen atom of the alkynyloxy group is substituted with a halogen atom such as fluorine, chlorine, bromine or iodine. Specifically, for example, 3-chloro-2-propynyloxy group, 3-fluoro-2-propynyloxy group, 4-fluoro-3-butynyloxy group, 5-chloro-4-pentynyloxy group, 6-bromo- And 5-hexynyloxy group. Of these, a 3-fluoro-2-propynyloxy group is preferable.

  Examples of the aromatic oxy group represented by X include a substituted or unsubstituted phenoxy group.

The alkylthio group represented by X may be an unsubstituted alkylthio group or a substituted alkylthio group such as a haloalkylthio group.
Examples of the unsubstituted alkylthio group represented by X include linear or branched alkylthio groups having 1 to 4 carbon atoms. Specific examples include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-butylthio group, and a tert-butylthio group. Of these, a methylthio group is preferable.
Examples of the haloalkylthio group represented by X include linear or branched haloalkylthio groups having 1 to 6 carbon atoms. Specifically, for example, fluoromethylthio group, chloromethylthio group, bromomethylthio group, iodomethylthio group, difluoromethylthio group, trifluoromethylthio group, 1-fluoroethylthio group, 2-fluoroethylthio group, 2-chloroethylthio group Group, 2,2,2-trifluoroethylthio group, pentafluoroethylthio group, 1-fluoropropylthio group, 3-fluoropropylthio group, 2-chloropropylthio group, 3-chloropropylthio group, 1- Examples thereof include a fluorobutylthio group, a 4-fluorobutylthio group, and a 1-chlorobutylthio group. Of these, a trifluoromethylthio group and a difluoromethylthio group are preferable.

Examples of the alkylsulfinyl group represented by X include linear or branched alkylsulfinyl groups having an alkyl moiety of 1 to 4 carbon atoms. Specific examples include a methylsulfinyl group, an ethylsulfinyl group, an n-propylsulfinyl group, an isopropylsulfinyl group, an n-butylsulfinyl group, an isobutylsulfinyl group, a sec-butylsulfinyl group, and a tert-butylsulfinyl group. it can. Of these, a methylsulfinyl group is preferable. The alkylsulfinyl group may be a substituted alkylsulfinyl group such as a haloalkylsulfinyl group.
Examples of the alkylsulfonyl group represented by X include linear or branched alkylsulfonyl groups having an alkyl moiety of 1 to 4 carbon atoms. Specific examples include a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an isopropylsulfonyl group, an n-butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, and a tert-butylsulfonyl group. it can. Of these, a methylsulfonyl group is preferable. The alkylsulfonyl group may be a substituted alkylsulfonyl group such as a haloalkylsulfonyl group.

Examples of the carbonyl group represented by X include an alkylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, and an alkynyloxycarbonyl group.
Examples of the alkylcarbonyl group represented by X include linear or branched alkylcarbonyl groups having an alkyl moiety of 1 to 6 carbon atoms. Specific examples include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a sec-butylcarbonyl group, and a tert-butylcarbonyl group. it can. Of these, a methylcarbonyl group is preferable.
Examples of the alkoxycarbonyl group represented by X include linear or branched alkoxycarbonyl groups having an alkoxy moiety of 1 to 6 carbon atoms. Specific examples include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group and the like. be able to. Of these, a methoxycarbonyl group and an ethoxycarbonyl group are preferable.
Examples of the alkenyloxycarbonyl group represented by X include linear or branched alkenyloxycarbonyl groups in which the alkenyloxy moiety has 2 to 6 carbon atoms. Specifically, for example, vinyloxycarbonyl group, 1-propenyloxycarbonyl group, 2-propenyloxycarbonyl group, 1-methyl-2-propenyloxycarbonyl group, 2-butenyloxycarbonyl group, 3-butenyloxycarbonyl Group, 2-pentenyloxycarbonyl group, 3-pentenyloxycarbonyl group and the like. Of these, vinyloxycarbonyl group and 2-propenyloxycarbonyl group are preferable.
Examples of the alkynyloxycarbonyl group represented by X include linear or branched alkynyloxycarbonyl groups having an alkynyloxy moiety of 3 to 6 carbon atoms. Specifically, for example, 2-propynyloxycarbonyl group, 1-methyl-2-propynyloxycarbonyl group, 2-butynyloxycarbonyl group, 3-butynyloxycarbonyl group, 2-pentynyloxycarbonyl group, 4- Examples thereof include a pentynyloxycarbonyl group. Of these, a 2-propynyloxycarbonyl group is preferable.

The amino group represented by X may be an unsubstituted amino group or a substituted amino group such as a monoalkylamino group or a dialkylamino group.
Examples of the monoalkylamino group represented by X include an alkylamino group in which the alkyl moiety is a linear or branched alkyl having 1 to 6 carbon atoms. Specifically, for example, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino Group, isopentylamino group, 2-methylbutylamino group, neopentylamino group, n-hexylamino group, 4-methylpentylamino group, 3-methylpentylamino group, 2-methylpentylamino group, 3,3- Dimethylbutylamino group, 1,1-dimethylbutylamino group, 1,3-dimethylbutylamino group, 2,3-dimethylbutylamino group, 1-ethylbutylamino group, 1-methyl-1-ethylpropylamino group, Examples thereof include a 1,2-dimethylbutylamino group, a 2-methyl-1-ethylpropylamino group, and a 2,2-dimethylbutylamino group. Of these, a methylamino group is preferable.
Examples of the dialkylamino group represented by X include dialkylamino groups in which each alkyl moiety is a linear or branched alkyl having 1 to 6 carbon atoms. Specifically, for example, dimethylamino group, diethylamino group, di-n-propylamino group, diisopropylamino group, di-n-butylamino group, ethylmethylamino group, n-propylmethylamino group, isopropylmethylamino group, n- Examples thereof include a butylmethylamino group, an ethyl n-propylamino group, an ethylisopropylamino group, and an ethyl n-butylamino group. Of these, a dimethylamino group is preferable.

In the substituent represented by the general formula (II), R ³ represents a hydrogen atom or an alkyl group, and R ⁴ represents an alkyl group, an alkenyl group, or an alkynyl group. However, R ³ and R ⁴ in the general formula (II) are not limited to the examples shown here.
Examples of the alkyl group represented by R ³ and R ⁴ include linear or branched alkyl groups having 1 to 6 carbon atoms. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group , Neopentyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 3,3-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group Examples thereof include a 1-ethylbutyl group, a 1-methyl-1-ethylpropyl group, a 1,2-dimethylbutyl group, a 2-methyl-1-ethylpropyl group, and a 2,2-dimethylbutyl group. Of these, a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like are preferable.

Examples of the alkenyl group represented by R ⁴ include linear or branched alkenyl groups having 2 to 6 carbon atoms. Specifically, for example, vinyl group, 1-propenyl group, 2-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2-ethyl-2-propenyl group, 2-butenyl group 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-ethyl-2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2- Examples thereof include a hexenyl group, a 3-hexenyl group, and a 4-hexenyl group. Of these, a 1-propenyl group, 2-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group and the like are preferable.

Examples of the alkynyl group represented by R ⁴ include linear or branched alkynyl groups having 2 to 6 carbon atoms. Specifically, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-methyl-2-propynyl group, 1,1-dimethyl-2-propynyl group, 2-butynyl group, 1-methyl-2- Butynyl group, 1-ethyl-2-butynyl group, 3-butynyl group, 2-methyl-3-butynyl group, 2-pentynyl group, 4-pentynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group Or a 5-hexynyl group etc. can be mentioned. Of these, preferred are ethynyl group, 1-propynyl group, 2-propynyl group, 1,1-dimethyl-2-propynyl group and the like.

X represents a group arbitrarily selected from the above-mentioned groups, preferably a halogen atom; an alkoxy group or an alkyl group optionally having a halogen atom (preferably having 1 to 4 carbon atoms); a halogen atom An alkoxy group (preferably having 1 to 3 carbon atoms); an alkenyloxy group (preferably having 2 to 3 carbon atoms); an alkynyloxy group (preferably having 2 to 3 carbon atoms); an alkylthio group (preferably having 1 carbon atom). ˜2); a hydroxy group, or a cyano group.
Of these, more preferably fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, methoxymethyl Group, trifluoromethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, trifluoromethoxy group, difluoromethoxy group, vinyloxy group, 2-propenyloxy group, 2-propynyloxy group, methylthio group, ethylthio Group, hydroxy group, cyano group and the like.

In the general formula (I), n indicating the number of substituents X is an integer of 0 to 5, preferably 0 to 3, and more preferably 0 to 2. Needless to say, a hydrogen atom is bonded to the benzene ring carbon to which the substituent X is not bonded.
When n is 1 or more, one of the substituents X is preferably bonded to the 4-position phenyl ring carbon with respect to the bonding position of — (CH ₂ ) _m —. When n is 2 or more, each substituent X may be the same or different, and two of them are phenyl ring carbons at the 3- and 4-positions relative to the bonding position of — (CH ₂ ) _m —. It is preferable that it is couple | bonded with.

Further, two Xs in the general formula (I) are bonded to two adjacent carbons among phenyl ring carbons, and the two Xs together form an alkylenedioxy group or an alkylene group. Also good.
Examples of the alkylenedioxy group formed by combining the two Xs include an alkylenedioxy group having an alkylene moiety of 1 to 3 carbon atoms, such as a methylenedioxy group and an ethylenedioxy group. It is done. Moreover, as an alkylene group, a C3-C5 alkylene group like a trimethylene group, a tetramethylene group, a pentamethylene group etc. can be mentioned, for example. Of these, a trimethylene group, a tetramethylene group, and the like are preferable.
Xn is more preferably 4-halide (especially 4-chloro, bromo or iodo) or 3,4-dihalide (especially 3,4-dichloro).

  The compound represented by the general formula (I) of the present invention has an asymmetric carbon (for example, the α-position carbon of phenethylamide). Therefore, these compounds may have optical isomers. The compounds of the present invention include all such possible optical isomers, including pure or substantially pure optical isomers or mixtures in which they are mixed in any proportion.

Next, although the specific example of a compound represented by general formula (I) is shown in Table 1, the compound of this invention is not limited only to the compound illustrated here. In the column of Xn in Table 1, “−” indicates that n = 0 and all are hydrogen atoms, and the number in the column of Xn indicates the substitution position in the phenyl ring of the substituent X ( Refer to the following formula).
In Table 1, “Me” represents a methyl group, “Et” represents an ethyl group, “Pr” represents a propyl group, “Bu” represents a butyl group, and “Ph” represents a phenyl group. “Cyclo-C ₃ H ₅ —” represents cyclopropyl.
The compound numbers in Table 1 are also referred to in the following Table 2, Examples, Formulation Examples and Test Examples.
In the column of R ² in Table 1, when neither R-form nor S-form is indicated (Compound Nos. 1 to 194, 237 to 267), it indicates a mixture of R-form and S-form. Further, when R-form or S-form is indicated (Compound Nos. 195 to 236), a pure configuration in which the absolute configuration of the chiral center at the α-position carbon of the carbonyl carbon of the amide moiety is R-form or S-form, respectively. Or it shows that it is a substantially pure optical isomer.

  Next, the proton NMR data of a part of the acetonitrile compound of the present invention (compound represented by the general formula (I)) is shown in Table 2. NMR data were measured with a JNM-LA300 spectrometer (manufactured by JEOL Ltd.) and all δ values were shown in ppm.

  Among the acetonitrile compounds represented by the general formula (I) described above, more preferable compounds as the acetonitrile compounds of the present invention include the following compounds or salts thereof, or optical isomers thereof.

  Moreover, among the acetonitrile compounds represented by the general formula (I) described above, more preferable compounds as the acetonitrile compounds of the present invention include the following optical isomer compounds or salts thereof.

<Method for producing acetonitrile compound of the present invention>
The acetonitrile compound of the present invention can be synthesized, for example, according to the following production scheme 1. In the following production schemes 1 to 3, Y represents an atom or group having a leaving ability, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom. ^{R 1, R 2, X,} m and n are the same as ^{R 1, R 2, X,} m and n in the general formula (I).

The compound represented by general formula (I), which is an acetonitrile compound of the present invention, represents, for example, the phenol moiety of the compound represented by general formula (XI) or (IX) represented by general formula (X) as described above. (Step A or D). From the compound represented by the general formula (XI), a compound (Ia) represented by the general formula (I) in which R ¹ is a hydrogen atom is obtained, and from the compound represented by the general formula (IX), R A compound in which ¹ is represented by any general formula (I) is obtained.

Compound (Ia) is a compound (I) in which R ¹ is an arbitrary compound (I) by substituting R ¹ for the hydrogen atom of the hydroxy group using compound YR ¹ represented by formula (VII). (Step C). Here, Y in Y—R ¹ usually represents a halogen atom, but is not particularly limited as long as it is an atom or an atomic group having a leaving ability. Moreover, the compound shown by the formula (VII) used as a raw material can be suitably selected and used according to the target compound. In addition, there are compounds well known in the field of organic chemistry, and there are some which are available as reagents (for example, from Tokyo Chemical Industry Co., Ltd.).

Furthermore, the compound (Ia) represented by the general formula (I) in which R ¹ is a hydrogen atom includes the compound represented by the formula (IV) and the general formula (V
It can also be obtained by condensing the compound represented by (Step B).
Hereinafter, steps A to D will be described in detail.

[Process A]
In the production scheme 1, the step A is a reaction of the compound represented by the formula (XI) with the compound represented by the formula (X).
This is a step of obtaining the acetonitrile compound of the present invention represented by Ia). The reaction can be performed in the presence of a solvent, a base, and a catalyst as necessary.
In the reaction of Step A, the ratio of the compound represented by the formula (XI) and the compound represented by the formula (X) is not particularly limited and can be appropriately selected from a wide range. do it.

  The reaction of Step A is usually performed in an inert solvent. Solvents used in the reaction of Step A are, for example, aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene; esters such as ethyl acetate, butyl acetate or ethyl propionate; diethyl ether, tetrahydrofuran or 1,4-dioxane Ethers such as; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane; such as methyl alcohol, ethyl alcohol or tert-butyl alcohol Aliphatic alcohols; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-di Amides such as chill-2-imidazolidinone; dimethyl sulfoxide; water, or a mixed solvent thereof. Of these, N, N-dimethylformamide, tetrahydrofuran or acetone is preferred.

Examples of the base used in the reaction of Step A include triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2,2,2] octane, or 1,8-diazabicyclo [5, Organic tertiary amines such as 4,0] -7-undecene; alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium tert-butoxide; sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate And alkali metal carbonates such as sodium hydroxide and potassium hydroxide; alkali metal hydrides such as sodium hydride and potassium hydride. Of these, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or potassium hydroxide are preferred.
The amount of the base used is not particularly limited and can be appropriately selected from a wide range, but it may be usually a stoichiometric amount or more than that, preferably about 1 to 7 times more than the stoichiometric amount. do it. In addition, when using organic bases, such as a triethylamine and a pyridine, these can also be used in large excess as a solvent.

  In addition, the reaction rate can be increased by using a catalyst such as potassium iodide, sodium iodide or a phase transfer catalyst in the reaction of Step A.

The reaction temperature in Step A is in the range of −50 ° C. to the reflux temperature in the reaction system, preferably 0 ° C. to 100 ° C. The reaction in Step A can be performed under reduced pressure or pressurized conditions, but is usually performed under normal pressure conditions. The reaction time of step A varies depending on the reaction temperature and reaction substrate, but is usually in the range of 30 minutes to 24 hours.
After completion of the reaction, the target compound can be obtained from the reaction solution by ordinary post-treatment. For example, the reaction solution can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water and extracting the solvent, and then distilling off the solvent. If necessary, the obtained target compound can be purified by operations such as chromatography, recrystallization or distillation.
In Step A, the compound represented by the formula (XI) used as a raw material can be produced according to, for example, Production Scheme 2 described later. Moreover, a well-known compound may be used and it can also synthesize | combine according to the method as described in Japanese translations of PCT publication No. 2002-534494.
The compound represented by the formula (X) includes a compound well known in the field of organic chemistry, and can be obtained as a reagent from, for example, Tokyo Chemical Industry Co., Ltd.

[Process B]
As shown in Preparation Scheme 1 above, the acetonitrile compound represented by the formula (Ia) can also be synthesized according to Step B. In step B, the amine compound represented by the formula (IV) or a salt thereof and the carboxylic acid compound represented by the formula (V) or a carboxyl-activated derivative thereof are reacted in the presence of a solvent and a base, if necessary. In this step, the compound of the present invention represented by the formula (Ia) is obtained.
In Step B, the ratio of the amine compound represented by the formula (IV) or a salt thereof and the carboxylic acid compound represented by the formula (V) or the carboxyl-activated derivative thereof is not particularly limited and can be appropriately selected from a wide range. Usually, an equimolar ratio or the vicinity thereof may be used.

  The carboxylic acid compound represented by the formula (V) has a chiral center. By using the carboxylic acid compound represented by the formula (V) of the optically active substance, the optically active substance of the formula (Ia) can be obtained. Obtainable. For example, by using a carboxylic acid compound represented by the R-form formula (V), a compound represented by the R-form formula (Ia) can be obtained, while the S-form represented by the formula (V). It is considered that the compound represented by the formula (Ia) in the S form can be obtained by using the carboxylic acid compound.

The carboxyl activated derivative of the carboxylic acid compound represented by the formula (V) is a derivative obtained by converting the carboxyl group of the compound represented by the formula (V) into an activated carboxyl group, and represented by the formula (V) by a condensing agent. And derivatives of carboxylic acid compounds in which the carboxyl group of the compound is activated.
Here, the activated carboxyl group includes acid halides such as acid chlorides, anhydrides such as acid anhydrides with O-alkyl carbonate, p-nitrophenyl ester or N-hydroxysuccinimide ester. Can do.
The condensing agents are dicyclohexylcarbodiimide, carbonyldiimidazole, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, O-benzotriazol-1-yl-N, N, N ′, N′-bis. (Pentamethylene) uronium hexafluorophosphate, O-benzotriazol-1-yl-N, N, N ′, N′-bis (tetramethylene) uronium hexafluorophosphate, O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate can be mentioned.

Step B is usually performed in an inert solvent. Examples of the solvent used in Step B include aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene; esters such as ethyl acetate, butyl acetate or ethyl propionate; diethyl ether, tetrahydrofuran or 1,4-dioxane Ethers; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane; nitriles such as acetonitrile; N, N-dimethylformamide; Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone; dimethyl sulfoxide or a mixed solvent thereof. Preferably, N, N-dimethylformamide or tetrahydrofuran is used.

Examples of the base used in Step B include triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2,2,2] octane, or 1,8-diazabicyclo [5,4, Organic tertiary amines such as 0] -7-undecene; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide And alkali metal hydrides such as sodium hydride or potassium hydride. Of these, triethylamine, diisopropylethylamine, pyridine and the like are preferable.
The amount of the base used is not particularly limited and can be appropriately selected from a wide range. Usually, the stoichiometric amount or an excess thereof may be used, and preferably an excess amount of about 1 to 8 times the stoichiometric amount. do it. In addition, when using organic bases, such as a triethylamine and a pyridine, these can also be used in large excess as a solvent.

The reaction temperature in Step B is in the range of −50 ° C. to the reflux temperature in the reaction system, preferably 0 ° C. to 100 ° C. The reaction in Step B can be performed under reduced pressure or pressurized conditions, but is usually performed under normal pressure conditions. The reaction time in Step B varies depending on the reaction temperature and reaction substrate, but is usually in the range of 30 minutes to 24 hours.
After completion of the reaction, the target compound can be obtained from the reaction solution by ordinary post-treatment. For example, the reaction solution can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water and extracting the solvent, and then distilling off the solvent. If necessary, the obtained target compound can be purified by operations such as chromatography, recrystallization or distillation.

  In Step B, the amine compound represented by the formula (IV) used as a raw material or a salt thereof is a known compound, and can be synthesized according to the method described in, for example, JP-T-2003-515566. Further, a specific production example is shown in Reference Production Example 2 described later.

The carboxylic acid compound represented by the formula (V) used as a raw material in the process B is also known as a known compound. For example, “Organic Syntheses”, 1945, Vol. 25, p. , “Organic Syntheses Collective Volume I”, 1941, P
.336, “Organic Syntheses Collective Volume III” 1955, P.538, “Organic Syntheses Collective Volume IV” 1963, P.110, “Journal of Organic Chemistry” (Journal of Organic Chemistry) ", 1968, Vol. 33, P. 2565," Journal of Organic Chemistry ", 1978, Vol. 43, P. 2702, International Patent Publication No. WO 2004/058685 Pamphlet, JP 2003-533502 A, “Journal of the American Chemical Society”, 1961, 83, P.2755, “Synthetic” It can be manufactured according to the method described in “Synthetic Communications”, 1988, Vol. 18, P. 2141. Moreover, the specific manufacture example of the compound represented by Formula (V) was shown to the below-mentioned reference manufacture example 3.

The optical isomer of the carboxylic acid compound represented by the formula (V) is also known as a known compound. For example, JP 55-47643 A; International Publication No. WO 95/23139 Pamphlet; Letters), 1990, Vol. 31, No. 9, p1249; JP 2003-226666 A; JP 9-322797 A; JP 5-320102 A; Synthesis, 1990, p 575, etc. Can be produced according to the method described in 1. above. Specific production examples of optical isomers of the carboxylic acid compound represented by the formula (V) are shown in Reference Production Examples 4 to 7 described later.

[Process C]
As shown in Preparation Scheme 1 above, Step C reacts a compound of formula (Ia) with a compound of formula (VII) to give an acetonitrile compound of formula (I). It is a process. The reaction can be carried out in the presence of a solvent, a base and a phase transfer catalyst as necessary.
The ratio of use of the compound represented by the formula (Ia) and the compound represented by the formula (VII) is not particularly limited and can be appropriately selected from a wide range. Usually, the equimolar ratio or the vicinity thereof may be used.

  The reaction of Step C is usually performed in an inert solvent. Examples of the solvent used in the reaction of Step C include aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene; esters such as ethyl acetate, butyl acetate or ethyl propionate; diethyl ether, tetrahydrofuran or 1,4- Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane; methyl alcohol, ethyl alcohol or tert-butyl alcohol Aliphatic alcohols; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1, Amides such as 3-dimethyl-2-imidazolidinone; dimethyl sulfoxide; water or a mixed solvent thereof. Preferred are N, N-dimethylformamide, tetrahydrofuran, or a mixed solvent of methylene chloride and water.

Examples of the base used in Step C include triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2,2,2] octane, or 1,8-diazabicyclo [5,4, Organic tertiary amines such as 0] -7-undecene; alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium tert-butoxide; alkalis such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate Mention may be made of metal carbonates; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkali metal hydrides such as sodium hydride or potassium hydride. Of these, triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or potassium hydroxide are preferred.
The amount of the above base used is not particularly limited and can be appropriately selected from a wide range. Usually, the stoichiometric amount or an excess thereof may be used, and preferably about 1 to 5 times the stoichiometric amount. It can be an amount. In addition, when using organic bases, such as a triethylamine and a pyridine, these can also be used in large excess as a solvent.

  Although it is not always necessary to use a phase transfer catalyst in the reaction of Step C, the reaction may be performed in the presence of a phase transfer catalyst. Examples of the phase transfer catalyst used include tetrabutylammonium bromide and benzyltriethylammonium chloride. The amount of the phase transfer catalyst used is not particularly limited and can be appropriately selected from a wide range. Usually, it may be 0.0001 to 1 times the stoichiometric amount, preferably 0.01 to 1 stoichiometric amount. What is necessary is just about twice the amount.

The reaction temperature in Step C is in the range of −50 ° C. to the reflux temperature in the reaction system, preferably 0 ° C. to 100 ° C. The reaction in Step C can be performed under reduced pressure or pressurized conditions, but is usually performed under normal pressure conditions. The reaction time in Step C varies depending on the reaction temperature and reaction substrate, but is usually in the range of 30 minutes to 24 hours.
After completion of the reaction, the target compound can be obtained from the reaction solution by ordinary post-treatment. For example, the reaction solution can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water and extracting the solvent, and then distilling off the solvent. If necessary, the obtained target compound can be purified by operations such as chromatography, recrystallization or distillation.

[Process D]
As shown in the above-mentioned production scheme 1, the compound represented by the general formula (I) can also be produced according to Step D.
Step D is a step in which the compound represented by the formula (IX) is reacted with the compound represented by the formula (X) to obtain the compound of the present invention represented by the formula (I). The reaction can be carried out in the presence of a solvent, a base and a catalyst as necessary.
The use ratio of the compound represented by the formula (IX) and the compound represented by the formula (X) is not particularly limited and can be appropriately selected from a wide range.

  The reaction of Step D is usually performed in an inert solvent. Examples of the solvent used in the reaction of Step D include aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene; esters such as ethyl acetate, butyl acetate or ethyl propionate; diethyl ether, tetrahydrofuran or 1,4- Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane; methyl alcohol, ethyl alcohol or tert-butyl alcohol Aliphatic alcohols; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1, Amides such as 3-dimethyl-2-imidazolidinone; dimethyl sulfoxide; water or a mixed solvent thereof. Among these, N, N-dimethylformamide, tetrahydrofuran, acetone or a mixed solvent of water and methylene chloride is preferable.

Examples of the base used in Step D include triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2,2,2] octane, or 1,8-diazabicyclo [5,4, Organic tertiary amines such as 0] -7-undecene; alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium tert-butoxide; alkalis such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate Mention may be made of metal carbonates; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkali metal hydrides such as sodium hydride or potassium hydride. Of these, potassium carbonate, sodium hydride, triethylamine, diisopropylethylamine, pyridine, sodium hydroxide or potassium hydroxide are preferable.
The amount of the above base used is not particularly limited and can be appropriately selected from a wide range, but it may be usually a stoichiometric amount or an excess thereof, preferably about 1 to 7 times the stoichiometric amount. It can be an amount. In addition, when using organic bases, such as a triethylamine and a pyridine, these can also be used in large excess as a solvent.

  Although it is not always necessary to use a catalyst in the reaction of Step D, the reaction may be performed in the presence of a catalyst. Examples of the catalyst used include iodide salts such as potassium iodide or sodium iodide, and phase transfer catalysts such as tetrabutylammonium bromide or benzyltriethylammonium chloride. The amount of the catalyst used is not particularly limited and can be appropriately selected from a wide range, but is usually 0.0001 to 1 times the stoichiometric amount, preferably 0.01 to 1 times the stoichiometric amount. It should be about.

The reaction temperature in Step D is in the range of −50 ° C. to the reflux temperature in the reaction system, preferably 0 ° C. to 100 ° C. The reaction in Step D can be performed under reduced pressure or pressurized conditions, but is usually performed under normal pressure conditions. The reaction time in Step D varies depending on the reaction temperature and reaction substrate, but is usually in the range of 30 minutes to 24 hours.
After completion of the reaction, the target compound can be obtained from the reaction solution by ordinary post-treatment. For example, the reaction solution can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water and extracting the solvent, and then distilling off the solvent. If necessary, the obtained target compound can be purified by operations such as chromatography, recrystallization or distillation.

  In Step D, the compound represented by the formula (IX) used as a raw material can be synthesized, for example, according to Production Scheme 3 described later. Moreover, a well-known compound can also be used and it can also synthesize | combine according to the method as described in Japanese translations of PCT publication No. 2003-533502.

  As described above, the compound represented by the formula (XI), which is the raw material used in Step A, can be produced according to the following production scheme 2. Hereinafter, Steps 1 to 3 in Production Scheme 2 will be described.

[Step 1]
In Step 1 in the above production scheme 2, the benzyl group is deprotected from the compound represented by the formula (VI) in the presence of a solvent and an acid as necessary to obtain the compound represented by the formula (XI). It is a process. The benzyl group is an example of a protecting group, and may be another protecting group.

The reaction of step 1 is usually performed in an inert solvent. Examples of the solvent used in Step 1 include aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene; esters such as ethyl acetate, butyl acetate or ethyl propionate; diethyl ether, tetrahydrofuran or 1,4-dioxane Ethers; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane; fats such as methyl alcohol, ethyl alcohol or tert-butyl alcohol Alcohols; ketones such as acetone or methyl ethyl ketone; nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-di Amides such as chill-2-imidazolidinone; dimethylsulfoxide; acetic acid; water or a mixed solvent thereof. Preferably, acetic acid, acetonitrile, methylene chloride or the like is used.

  Examples of the acid used in the reaction of Step 1 include hydrobromic acid, hydroiodic acid, trifluoroacetic acid, aluminum chloride, boron tribromide, and boron trichloride. Preferred is hydrobromic acid. The amount of the acid used is not particularly limited and can be appropriately selected from a wide range. Usually, the stoichiometric amount or an excess thereof may be used, and preferably about 1 to 5 times the stoichiometric amount. It can be an amount. In addition, when using organic acids, such as a trifluoroacetic acid, these can also be used in large excess and can be used as a solvent.

The reaction temperature in Step 1 is in the range of −50 ° C. to the reflux temperature in the reaction system, preferably 0 ° C. to 120 ° C. The reaction in Step 1 can be carried out under reduced pressure or pressurized conditions, but is usually carried out under normal pressure conditions. The reaction time in step 1 varies depending on the reaction temperature and reaction substrate, but is usually in the range of 30 minutes to 24 hours.
After completion of the reaction, the target compound can be obtained from the reaction solution by ordinary post-treatment. For example, the reaction solution can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water and extracting the solvent, and then distilling off the solvent. If necessary, the obtained target compound can be purified by operations such as chromatography, recrystallization or distillation.

[Step 2]
The compound (VI) used as a raw material in the above step 1 can be obtained according to step 2 as shown in production scheme 2. In the above production scheme, Step 2 is represented by Formula (VI) by reacting an amine compound represented by Formula (II) or a salt thereof with a carboxylic acid compound represented by Formula (V) or a carboxyl-activated derivative thereof. This is a step of obtaining a compound. The reaction can be carried out in the presence of a solvent and a base as necessary. Moreover, the benzyl group of the compound represented by the formula (II) is a group used as a protecting group, and other protecting groups may be used.
Moreover, it is thought that the optical isomer (R form or S form) of the formula (VI) can be obtained by using the optical isomer (R form or S form) of the formula (V).

  In the reaction of Step 2, the use ratio of the amine compound represented by the formula (II) or a salt thereof and the carboxylic acid compound represented by the formula (V) or a carboxyl activated derivative thereof is not particularly limited, and is appropriately selected from a wide range. Although it can be selected, it is usually sufficient to use the equimolar ratio or the vicinity thereof.

The reaction of step 2 can be performed in the same manner as the reaction of step B.
That is, the type of the carboxyl-activated derivative of the carboxylic acid compound represented by the formula (V); the type and amount of the reaction solvent used and the base; reaction conditions such as reaction temperature, reaction pressure and reaction time, post-treatment and purification method Etc., and can be selected in the same manner as in the reaction of Step B.

The amine compound represented by the formula (II) or a salt thereof used as a raw material in the reaction of Step 2 is also known as a known compound, and is synthesized, for example, according to the method described in JP-A-2002-356465. be able to. Further, a specific production example is shown in Reference Production Example 1 described later.
Further, the carboxylic acid compound represented by the formula (V) used as a raw material in the reaction of Step 2 can be obtained in the same manner as described in Step B.

[Step 3]
On the other hand, compound (XI), which is a raw material used in Step A, can also be produced according to Step 3 as shown in Production Scheme 2. In step 3, the amine compound represented by the formula (III) or a salt thereof and the carboxylic acid compound represented by the formula (V) or a carboxyl-activated derivative thereof are reacted in the presence of a solvent and a base as necessary. And obtaining a compound represented by formula (XI).
In the reaction of Step 3, the ratio of the amine compound represented by formula (III) or a salt thereof and the carboxylic acid compound represented by formula (V) or a carboxyl-activated derivative thereof is not particularly limited, and is appropriately selected from a wide range. Although it can be selected, it is usually sufficient to use the equimolar ratio or the vicinity thereof.

The reaction in Step 3 can be performed in the same manner as the reaction in Step B.
That is, the type of the carboxyl-activated derivative of the carboxylic acid compound represented by the formula (V); the type and amount of the reaction solvent used and the base; reaction conditions such as reaction temperature, reaction pressure and reaction time, post-treatment and purification method Etc., and can be selected in the same manner as in the reaction of Step B.
Moreover, it is thought that the optical isomer (R form or S form) of the formula (XI) can be obtained by using the optical isomer (R form or S form) of the formula (V).

In Step 3, the amine compound represented by the formula (III) used as a raw material or a salt thereof is also known as a known compound. For example, “Bulletin of the Chemical Society Japan” 1990, 63, p. 1252, “Journal of the American Chemical Society”, 1950, 72, p. 2781, Journal of Pharmaceutical Sciences, 1963, 83, P.1035, Journal of Pharmaceutical Sciences, 1969, Vol. 89, P.230, Japanese Patent Publication No. 49-13777, “Organic Syntheses Collective Volume I”, 1941, P.107, “Journal Of Organic Chemistry ", 197 Year, Vol 41, are synthesized according to the method described in P.2502.
In step 3, the compound represented by formula (V) used as a raw material can be obtained in the same manner as described in step B.

[Step 4]
The compound represented by the formula (IX) which is the raw material of the above-mentioned Step D can be produced, for example, according to the following production scheme 3.

[Step 4]
Step 4 in the production scheme 3 is a step of deprotecting the benzyl group from the compound represented by the formula (VIII) to obtain the compound represented by the formula (IX). The reaction can be performed in the presence of a solvent and an acid, if necessary. The benzyl group is used as a protecting group, and other protecting groups can be appropriately used instead of the benzyl group.

The reaction in step 4 can be performed in the same manner as the reaction in step 1 above.
That is, the type of the solvent used in the reaction of Step 4 and the conditions such as the acid and its amount, reaction temperature, reaction pressure, reaction time, post-treatment and purification method can be selected in the same manner as in the reaction of Step 1. .

[Step 5]
As shown in Production Scheme 3, the compound represented by Formula (VIII), which is the raw material of Step 4, can be produced according to Step 5. Step 5 is a step of reacting a compound represented by the formula (VI) with a compound represented by the formula (VII) to obtain a compound represented by the formula (VIII). The reaction can be carried out in the presence of a solvent, a base and a phase transfer catalyst as necessary.
In the reaction of Step 5, the use ratio of the compound represented by the formula (VI) and the compound represented by the formula (VII) is not particularly limited and can be appropriately selected from a wide range. do it.

The reaction of step 5 can be performed in the same manner as the reaction of step C described above.
That is, the type of solvent used in the reaction of Step 5, the type and amount of base, the type and amount of phase transfer catalyst, reaction conditions such as reaction temperature, reaction pressure and reaction time, post-treatment and purification methods are the same as in Step C. Can be selected as well.
The compound represented by the formula (VI) used as a raw material in Step 5 can be produced according to Step 2 described above.

[Fungicide of the present invention]
Of the acetonitrile compounds of the present invention represented by the general formula (I) described above (hereinafter, also simply referred to as “compound (I)”), preferred compounds have a bactericidal activity. The fungicide containing the acetonitrile compound of the present invention is hereinafter referred to as “the fungicide of the present invention”.

  The disinfectant of the present invention can have the same composition as that of a normal disinfectant except that it contains compound (I). That is, the fungicide of the present invention may contain components generally used for formulation as an agricultural chemical auxiliary. In addition to the adjuvant, other sterilizing components may be included as active ingredients.

The content of the compound (I) in the fungicide of the present invention is usually arbitrarily selected from the range of 0.1 to 90 parts by weight. Compound (I) is preferably contained as an active ingredient in the fungicide of the present invention.
In addition, examples of the component as an agricultural chemical auxiliary contained in the bactericide of the present invention include 1) a carrier, 2) a surfactant, and 3) other auxiliary agents.

The carrier contained in the fungicide of the present invention may be either a solid carrier or a liquid carrier as long as it can be used for agricultural and horticultural medicines, and is not limited to a specific one.
Examples of solid carriers include animal and vegetable powders such as starch, activated carbon, soybean flour, wheat flour, wood flour, fish flour, and milk powder, talc, kaolin, bentonite, zeolite, diatomaceous earth, white carbon, clay, alumina, calcium carbonate, potassium chloride, Examples thereof include mineral powders such as ammonium sulfate.
Examples of the liquid carrier include water, alcohols such as isopropyl alcohol and ethylene glycol, ketones such as cyclohexanone and methyl ethyl ketone, ethers such as propylene glycol monomethyl ether and diethylene glycol mono-n-butyl ether, and aliphatic carbonization such as kerosene and light oil. Hydrogens, xylenes, trimethylbenzenes, tetramethylbenzenes, aromatic hydrocarbons such as methylnaphthalene, solvent naphtha, amides such as N-methyl-2-pyrrolidone, esters such as glycerol esters of fatty acids, soybean oil, rapeseed And vegetable oils such as oil. Two or more of these carriers can be used in combination.

Examples of the surfactant contained in the bactericide of the present invention include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. Is mentioned.
Examples of the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene styryl phenyl ether, polyoxyethylene alkyl ester, polyoxyethylene sorbitan alkylate, and polyoxyethylene phenyl ether polymer. , Polyoxyethylene alkylene aryl phenyl ether, polyoxyethylene alkylene glycol, polyoxyethylene polyoxypropylene block polymer, and the like.
Examples of the anionic surfactant include lignin sulfonate, alkylaryl sulfonate, dialkyl sulfosuccinate, polyoxyethylene alkylaryl ether sulfate, alkylnaphthalene sulfonate, polyoxyethylene styryl phenyl ether sulfate, and the like. Can be mentioned.
Examples of the cationic surfactant include alkylamine salts.
Examples of amphoteric surfactants include quaternary ammonium salt alkylbetaines and amine oxides.
The surfactant that can be used for formulation is not limited to these. Two or more surfactants can be used in combination.

Other adjuvants contained in the bactericidal agent of the present invention include binders, thickeners, sticking agents, antiseptics, antifungal agents, solvents, stabilizers for agrochemical active ingredients, antioxidants, UV inhibitors, crystals Examples thereof include, but are not limited to, precipitation inhibitors, antifoaming agents, physical property improvers, and colorants.
The binder, thickener, and sticking agent are not particularly limited. For example, starch, dextrin, cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl starch. , Pullulan, sodium alginate, ammonium alginate, propylene glycol ester alginate, guar gum, locust bean gum, gum arabic, xanthan gum, gelatin, casein, polyvinyl alcohol, polyethylene oxide, polyethylene glycol, ethylene / propylene block polymer, sodium polyacrylate, polyvinyl Examples include pyrrolidone.

The disinfectant of the present invention is in accordance with a general formulation method according to the intended dosage form, except that the acetonitrile compound of the present invention (compound (I)) is blended (preferably contained as an active ingredient). Can be manufactured.
The dosage form of the disinfectant of the present invention includes emulsions, suspensions, powders, granules, tablets, wettable powders, aqueous solvents, liquids, flowable powders, granular wettable powders, aerosols, pastes, oils, and emulsions. It can be made into dosage forms of various forms such as an agent.

  It described more concretely about the manufacturing method of the fungicide of this invention in the below-mentioned formulation example. Of course, the fungicide of the present invention is not limited to these formulation examples, and other various additives can be mixed in any ratio, and other fungicides can be mixed in any ratio. Can also be formulated.

The disinfectant of the present invention can be used in the same manner as a normal disinfectant.
That is, the bactericidal agent of the present invention can be used as it is or diluted to a predetermined concentration with a diluent such as water.
Moreover, as an application method of the bactericidal agent (including the dilution thereof) of the present invention, spraying (for example, spraying, misting, atomizing, dusting, dusting, water surface application, box application, etc.), soil application (for example, mixing, Irrigation, etc.), surface application (for example, application, powder coating, coating, etc.), immersion and the like.
The application amount of the fungicide of the present invention is not particularly limited, the concentration of the active ingredient in the fungicide, the form of the preparation, the target disease or crop type, the degree of damage caused by the disease, the place of application, the application method, the application time, the mixed use It is appropriately selected from a wide range according to various conditions such as the amount and type of drugs and fertilizer used in combination. As a guide, about 0.001 to 100 g, preferably about 0.01 to 50 g of the compound of the present invention is usually applied per 100 m ² .

When the disinfectant of the present invention is an emulsion, wettable powder or flowable agent, it may be used after diluted with water. The application concentration is about 0.1 to 1000 ppm by mass, preferably about 1 to 500 ppm by mass, but is not limited thereto.
On the other hand, granules, powders and the like are usually applied as they are without dilution.

  Needless to say, the fungicide of the present invention alone is sufficiently effective, but if necessary, other fertilizers, agricultural chemicals such as insecticides, acaricides, nematicides, fungicides, antivirals. It can be used in combination with agents, attractants, herbicides, plant growth regulators, synergists, etc.

The disinfectant of the present invention has a feature of “high therapeutic effect” as described later. Therefore, in addition to being able to be applied preventively before the plant disease occurs, it can also be applied therapeutically after the plant disease has occurred, thereby making the characteristics of the fungicide of the present invention more effective. Demonstrated.
Moreover, the disinfectant of the present invention has a feature of “high rain resistance effect” as will be described later. Therefore, in addition to being able to be applied inside the facility, it can also be applied outdoors, whereby the characteristics of the fungicide of the present invention are more effectively exhibited.
Further, the disinfectant of the present invention has a feature of “high safety against chemical damage” as will be described later. Therefore, it can be applied with peace of mind without fear of the risk of phytotoxicity, whereby the characteristics of the fungicide of the present invention are more effectively exhibited.

The bactericidal agent of the present invention has the following control effect as a bactericidal agent.
Firstly, the fungicide of the present invention is lower than conventional fungicides, particularly against cucumber downy mildew, tomato blight, potato blight, and grape downy mildew which are important diseases of agricultural and horticultural crops. High control effect at dose
Secondly, the fungicide of the present invention is particularly effective against cucumber downy mildew, tomato blight, potato blight, grape downy mildew, and the like, with a lower therapeutic amount and higher therapeutic effect than conventional fungicides. It is useful as an agricultural and horticultural fungicide.
Thirdly, the fungicide of the present invention has a higher rain-resistance effect at a lower dose than conventional fungicides, particularly against cucumber downy mildew, tomato blight and potato blight, and even grape downy mildew. It is useful as an agricultural and horticultural fungicide.
Fourthly, the fungicide of the present invention can be used by spraying foliage, applying soil, etc. against diseases of agricultural and horticultural crops.
Fifth, the fungicide of the present invention does not cause phytotoxicity on useful crops.

The fungicides of the present invention containing the acetonitrile compound of the present invention can be applied to the control of the following plant diseases, for example. However, plant diseases to which the fungicide of the present invention can be applied are not limited to these.
Plant diseases that can be controlled by the fungicide of the present invention include, for example, rice blast (Pyric
ularia grisea), sesame leaf blight (Cochliobolus miyabeanus), coat blight (Thanatephorus cucumeris), stupid seedling (Gibberella fujikuroi), seedling blight (Fusarium fungus, Rhizopus fungus, Pythium fungus, Trichoderma viride), rice koji disease (Claviceps virens), wheat red mold (Gibberella zeae, Fusarium avenaceum, Fusarium culmorum, Monographella nivale), snow rot (Pythium, Typhula, Monographella nivalis, Myriosclerotinia borealis), naked smut (Ustilago nuda) Namahusa smut (Tilletia controversa), eye disease (Pseudocercosporella)
herpotrichoides), leaf blight (Septoria tritici), blight (Phaeosphaeria nodorum), citrus black spot (Diaporthe citri), small black spot (Diaporthe medusa, Alternaria citri), common scab (Elsinoe fawcettii), brown rot (Phytophthora citrophthra), green mold (Penicillium digitatum), blue mold (Penicillium italicum), apple monilinia (Monilinia)
mali), black spot disease (Venturia inaequalis), spotted leaf disease (Alternaria mali), black spot disease (Mycosphaerella pomi), soot spot disease (Gloeodes pomigena), soot spot disease (Zygophiala jamaicensis), ring rot disease (Botryosphaeria berengeriana), brown Spot disease (Diplocarpon mali), red spot disease (Gymnosporangium yamadae), rot disease (Valsa ceratosperma) pear black spot disease (Venturia nashicola), red star disease (Gymnosporangium asiaticum), ring rot (Botryosphaeria berengeriana), body rot (Phomukuri disease) ), Peach streak (Taphrina deformans), ash scab (Monilinia fructicola, Monilinia fructigena), black scab (Cladosporium carpophilum), homopsis rot (Phomopsis sp.), Sweet scab (Monilinia fructicola, Monilinia fructigena) ), Larvae nuclear disease (Monilinia kusanoi), ume black rot (Cladosporium carpophilum), grape black rot (Elsinoe ampelina), late rot (Colletotrichum acutatum, Glomerella cingulata), brown spot (Pseudocercospora vitis), Vinegar disease (Phomopsis viticola), oyster horn Deciduous leaf disease (Cercospora kaki), circle star leaf disease (Mycosphaerella nawae), tea ring spot disease (Pestalotiopsis longiseta, Pestalotiopsis theae), brown circle disease (Pseudocercospora ocellata, Cercospora chaae), rice bran disease (Exobasidium vexans) Disease (Exobasidium reticulatum), cucumber vine blight (Mycosphaerella melonis), vine split disease (Fusarium oxysporum), black spot disease (Cladosporium cucumerinum), brown spot disease (Corynespora cassiicola), tomato leaf mold disease (Fulvia fulva), Ring rot (Alternaria solani), eggplant brown rot (Phomopsis vexans), scab (Mycovellosiella nattrassii), cruciferous vegetable white rust (Albugo macrospora), vitiligo (Cercosporella brassicae, Pseudocercosporella capsellae), onion Gray rot (Botrytis allii), Strawberry potato (Mycosphaerella fragariae), Potato summer plague (Alternaria solani), Dice stalk (Phytophthora sojae), Purpura (Cercospora kikuchii), Azuki bean stalk (Phytophthora) vignae) Peanut brown spot (Mycosphaerella arachidis), sugar beet brown spot (Cercospora beticola), leaf rot (Thanatephorus cucumeris), buckwheat curbularia leaf blight (Curvularia fungus), dollar spot (Sclerotinia homoeocarpa), hermint spo Examples include leaf blight (Cochliobolus), rose scab (Diplocarpon rosae), and chrysanthemum rust (Puccinia horiana).

Furthermore, downy mildew of various crops (Peronospora, Pseudoperonospora, Plasmopara, Bremia), plague (Phytophthora), powdery mildew (Erysiphe, Blumeria, Sphaerotheca, Podosphaerea, Phyllactinia, Uncinula, Oidiopsis), rust (Puccinia, Uromyces, Physopella), anthrax (Glomerella, Colletotrichum, Gloeosporium), black spot (Alternaria), gray mold (Botrytis cinerea), sclerotia (nucleus) Sclerotinia sclerotiorum), white rot (Rosellinia necatrix), purple white rot (Helicobasidium mompa), white scab (Sclerotium rolfsii), other various soil diseases (Fusarium, Rhizoctonia, Pythium, Aphanomyces, Phoma, Diseases such as Verticillium bacteria and Plasmodiophora brassicae).
Among these, preferably, cucumber downy mildew, tomato plague, potato plague, grape downy mildew, vegetables caused by downy mildew or pathogenic fungi, field crops, fruit trees, downy mildew, plague .

  The usefulness (control effect on diseases) of the fungicide of the present invention is specifically shown by Test Examples 1 to 6 described later.

Hereinafter, the present invention will be specifically described with reference to Examples (Synthesis and Formulation Examples of Compounds) and Test Examples, but the present invention is not limited to these ranges.
[Example 1]
Preparation of N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide (Compound No. 18)

  a) In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 1.00 g (6.0 mmol) of 4-hydroxy-3-methoxy-β-phenethylamine, N, N— 15 ml of dimethylformamide, 3.10 g (24.0 mmol) of diisopropylethylamine and 1.12 g (6.0 mmol) of 4-chloromandelic acid were added. After adding 3.19 g (7.2 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 9 hours. The resulting reaction mixture was acidified with 1N hydrochloric acid, and further extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The resulting crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a chloroform-methanol mixture (solvent volume ratio chloroform: methanol = 50: 1) as a developing solvent, and N- 1.3 g of [2- (4-hydroxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide was obtained as a pale yellow oil (yield 65%).

  b) In a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., 1.18 g (8.6 mmol) of potassium carbonate, 15 ml of N, N-dimethylformamide and N- [2- (4-Hydroxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide (2.23 g, 6.6 mmol) was added. After adding 1.19 g (9.9 mmol) of bromoacetonitrile at room temperature, the mixture was stirred at room temperature for 5 hours. The resulting reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and N- [2 There was obtained 2.47 g of (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide as a pale yellow oil (yield 100%).

[Example 2]
Preparation of N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-methylphenyl) acetamide (Compound No. 63)

a) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 4.4 g (17.0 mmol) of 4-benzyloxy-3-methoxy-β-phenethylamine, N, N -40 ml of dimethylformamide, 8.8 g (68.0 mmol) of diisopropylethylamine and 3.4 g (20.4 mmol) of 4-methylmandelic acid were added. After adding 9.0 g (20.4 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 6 hours.
Water was added to the resulting reaction mixture, followed by further extraction with ethyl acetate. The obtained organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [ 4.1 g of 2- (4-benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-methylphenyl) acetamide was obtained as a pale yellow oil (yield 59%).

b) N- [2- (4-Benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2-in in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 2.04 g (5.0 mmol) of (4-methylphenyl) acetamide, 10 ml of methylene chloride, 0.16 g (0.5 mmol) of tetra-n-butylammonium bromide and 0.89 g (7.5 mmol) of propargyl bromide were added. After adding 1.2 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 6 hours under reflux with heating.
The resulting reaction mixture was acidified with 3N hydrochloric acid, and further extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [ 2.0 g of 2- (4-benzyloxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-methylphenyl) acetamide was obtained as a pale yellow oil (yield 91 %).

c) In a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., N- [2- (4-benzyloxy-3-methoxyphenyl) ethyl] -2- (prop- 2-Inyloxy) -2- (4-methylphenyl) acetamide 1.95 g (4.5 mmol) and 10 ml of acetic acid were added. After adding 0.84 g (5.0 mmol) of 48% aqueous hydrobromic acid solution at room temperature, the mixture was stirred at 80 ° C. for 2.5 hours.
The resulting reaction mixture was neutralized and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed liquid (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [2 -(4-Hydroxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-methylphenyl) acetamide (1.27 g) was obtained as a pale yellow oil (yield 79%). .

d) N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -2- (prop-2) in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -Inyloxy) -2- (4-methylphenyl) acetamide 1.27 g (3.6 mmol), methylene chloride 8 ml, tetra-n-butylammonium bromide 0.12 g (0.4 mmol) and chloroacetonitrile 0.41 g (5. 4 mmol). After adding 0.8 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 6 hours with heating under reflux.
The resulting reaction mixture was acidified and further extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [ 1.2 g of 2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-methylphenyl) acetamide was obtained as a pale yellow oil (yield 86 %).

Example 3
Preparation of N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-bromophenyl) acetamide (Compound No. 39)

a) 1.2 g (4.09 mmol) of 4-benzyloxy-3-methoxy-β-phenethylamine hydrochloride in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., N , 20 ml of N-dimethylformamide, 2.64 g (20.45 mmol) of diisopropylethylamine and 4-bromomandelic acid (4.09 mmol). After adding 2.17 g (4.91 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 4 hours.
Water was added to the obtained reaction mixture, and ethyl acetate was further added for extraction treatment. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 8: 1) as a developing solvent, and N- [ 1.6 g of 2- (4-benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-bromophenyl) acetamide was obtained as a pale yellow oil (yield 83%).

b) In a 100 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., N- [2- (4-benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2 -(4-Bromophenyl) acetamide 1.6 g (3.4 mmol), methylene chloride 25 ml, tetra-n-butylammonium bromide 0.11 g (0.34 mmol) and propargyl bromide 0.81 g (6.8 mmol) were added. . After adding 1.0 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 7 hours with heating under reflux.
The resulting reaction mixture was acidified with hydrochloric acid, and further extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixture (solvent volume ratio toluene: acetone = 20: 1) as a developing solvent, and N- [2 There was obtained 1.7 g of-(4-benzyloxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-bromophenyl) acetamide as a pale yellow oil (yield 93% ).

c) N- [2- (4-benzyloxy-3-methoxyphenyl) ethyl] -2- (prop-2) in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C -Inyloxy) -2- (4-bromophenyl) acetamide 1.7 g (3.35 mmol) and acetic acid 10 ml were added. After adding 0.71 g (4.19 mol) of 48% aqueous hydrobromic acid solution at room temperature, the mixture was stirred at 80 ° C. for 2 hours.
The resulting reaction mixture was neutralized and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [ 1.20 g of 2- (4-hydroxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-bromophenyl) acetamide was obtained as a pale yellow oil (yield 86% ).

d) N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -2- (prop) at room temperature in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -2-ynyloxy) -2- (4-bromophenyl) acetamide 1.20 g (2.87 mmol), N, N-dimethylformamide 15 ml, potassium carbonate 0.52 g (3.73 mmol), bromoacetonitrile 0.52 g (4 .31 mmol) and 0.10 g (0.57 mmol) of potassium iodide were added, and the mixture was stirred at room temperature for 6 hours.
Water was added to the resulting reaction mixture, followed by further extraction with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: silica gel 60H manufactured by Merck & Co., Inc.) using chloroform as a developing solvent, and N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] 0.7 g of -2- (prop-2-ynyloxy) -2- (4-bromophenyl) acetamide was obtained as a pale yellow oil (yield 54%).

Example 4
Preparation of N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-ethylphenyl) acetamide (Compound No. 76)

a) 2.44 g (8.33 mmol) of 4-benzyloxy-3-methoxy-β-phenethylamine hydrochloride in a 100 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., N, 35 ml of N-dimethylformamide, 1.50 g (8.33 mmol) of 4-ethylmandelic acid and 5.37 g (41.65 mmol) of diisopropylethylamine were added. After adding 4.42 g (10.00 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 4 hours.
Water was added to the obtained reaction mixture, and ethyl acetate was further added for extraction treatment. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: silica gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 7: 1) as a developing solvent, and N- [ 2.10 g of 2- (4-benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-ethylphenyl) acetamide was obtained as a pale yellow oil (yield 89%).

b) N- [2- (4-Benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2 in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C -(4-ethylphenyl) acetamide 3.1 g (7.4 mmol), methylene chloride 25 ml, tetra-n-butylammonium bromide 0.37 g (1.11 mmol) and propargyl bromide 2.64 g (22.2 mmol) were added. . After adding 2.0 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 4 hours with heating under reflux.
The resulting reaction mixture was acidified and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 25: 1) as a developing solvent, and N- [ 3.0 g of 2- (4-benzyloxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-ethylphenyl) acetamide was obtained as a pale yellow oil (yield 89 %).

c) In a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., N- [2- (4-benzyloxy-3-methoxyphenyl) ethyl] -2- (prop- 2-Inyloxy) -2- (4-ethylphenyl) acetamide (3.0 g, 6.56 mmol) and acetic acid (20 ml) were added. A 48% aqueous hydrobromic acid solution (1.41 g, 8.20 mmol) was added at room temperature, and the mixture was stirred at 80 ° C. for 1.5 hours.
The resulting reaction mixture was neutralized and then extracted by adding ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 15: 1) as a developing solvent, and N- [ There was obtained 1.55 g of 2- (4-hydroxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-ethylphenyl) acetamide as a pale yellow oil (yield 64%). ).

d) N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -2- (prop-) at room temperature in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 2-Inyloxy) -2- (4-ethylphenyl) acetamide 1.55 g (4.22 mmol), N, N-dimethylformamide 15 ml, potassium carbonate 1.16 g (8.44 mmol), bromoacetonitrile 1.16 g (9. 71 mmol) and 0.14 g (0.84 mmol) of potassium iodide were added and stirred at room temperature for 6 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The resulting crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using chloroform as the developing solvent, and N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl]- 1.0 g of 2- (prop-2-ynyloxy) -2- (4-ethylphenyl) acetamide was obtained as a pale yellow oil (yield 58%).

Example 5
Method for producing N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (acetyloxy) -2- (4-chlorophenyl) acetamide (Compound No. 32)

In a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -2-acetyloxy-2- 1.1 g (2.9 mmol) of (4-chlorophenyl) acetamide, 10 ml of N, N-dimethylformamide, 0.80 g (5.8 mmol) of potassium carbonate, 0.70 g (5.8 mmol) of bromoacetonitrile, and 0.81 of potassium iodide. 10 g (0.58 mmol) was added and stirred at room temperature for 4 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixture (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [2 1.07 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (acetyloxy) -2- (4-chlorophenyl) acetamide was obtained as a pale yellow oil (yield 88%).

Example 6
Method for producing N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-trifluoromethylphenyl) acetamide (Compound No. 142)

a) In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 1.16 g (4.5 mmol) of 4-benzyloxy-3-methoxy-β-phenethylamine, N, N— 15 ml of dimethylformamide and 0.99 g (4.5 mmol) of 4-trifluoromethylmandelic acid and 2.03 g (15.8 mmol) of diisopropylethylamine were added. After adding 2.39 g (5.4 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 4 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 7: 1) as a developing solvent, and N- [2 1.48 g of (4-benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-trifluoromethylphenyl) acetamide was obtained as a pale yellow oil (yield 70%).

b) N- [2- (4-Benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2-in in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 1.48 g (3.2 mmol) of (4-trifluoromethylphenyl) acetamide and 10 ml of acetic acid were added. After adding 0.70 g (4.2 mmol) of 48% aqueous hydrobromic acid solution at room temperature, the mixture was stirred at 80 ° C. for 2 hours.
The resulting reaction mixture was neutralized and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and N- [2 0.69 g of-(4-hydroxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-trifluoromethylphenyl) acetamide was obtained as a pale yellow oil (yield 58%).

c) N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -2-hydroxy-2 at room temperature in a 30 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -(4-trifluoromethylphenyl) acetamide 0.69 g (1.9 mmol), N, N-dimethylformamide 8 ml, potassium carbonate 0.79 g (5.7 mmol), bromoacetonitrile 0.46 g (3.8 mmol) and iodine 0.06 g (0.38 mmol) of potassium halide was added and stirred at room temperature for 2.5 hours.
1N Hydrochloric acid was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The resulting crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 6: 1) as a developing solvent, and N- [2 0.70 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-trifluoromethylphenyl) acetamide was obtained as a pale yellow oil (yield 92%).

d) N- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2-in in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. Add 0.7 g (1.7 mmol) of (4-trifluoromethylphenyl) acetamide, 10 ml of methylene chloride, 0.11 g (0.34 mmol) of tetra-n-butylammonium bromide and 0.40 g (3.4 mmol) of propargyl bromide. It was. After adding 0.4 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 3 hours under reflux with heating.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixture (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [2 0.65 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-trifluoromethylphenyl) acetamide was obtained as a pale yellow oil (yield) 84%).

Example 7
Method for producing N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chlorophenyl) acetamide (Compound No. 16)

a) 8.4 g (28.7 mmol) of 4-benzyloxy-3-methoxy-β-phenethylamine hydrochloride in a 500 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., N, 70 ml of N-dimethylformamide, 5.35 g (28.7 mmol) of 4-chloromandelic acid and 14.8 g (114.8 mmol) of diisopropylethylamine were added. After adding 15.2 g (34.4 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 6 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixture (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [2 10.14 g of-(4-benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide was obtained as a pale yellow oil (yield 83%).

b) N- [2- (4-Benzyloxy-3-methoxyphenyl) ethyl] -2-hydroxy-2-in in a 200 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 10.14 g (23.8 mmol) of (4-chlorophenyl) acetamide and 50 ml of acetic acid were added. After adding 5.22 g (30.9 mmol) of 48% aqueous hydrobromic acid solution at room temperature, the mixture was stirred at 80 ° C. for 2 hours.
The resulting reaction mixture was neutralized and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-ethyl acetate mixed solution (solvent volume ratio toluene: ethyl acetate = 3: 1) as a developing solvent. 5.24 g of [2- (4-hydroxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide was obtained as a pale yellow oil (yield 66%).

c) N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] -2-hydroxy-2 at room temperature in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -(4-Chlorophenyl) acetamide 1.21 g (3.6 mmol), N, N-dimethylformamide 12 ml, potassium carbonate 1.0 g (7.2 mmol), bromoacetonitrile 0.86 g (7.2 mmol) and potassium iodide 0 .12 g (0.72 mmol) was added and stirred at room temperature for 5 hours.
1N Hydrochloric acid was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and N- [2 1.16 g of (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide was obtained as a pale yellow oil (yield 85%).

d) N- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2-in in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. (4-Chlorophenyl) acetamide 0.85 g (2.3 mmol), methylene chloride 10 ml, tetra-n-butylammonium bromide 0.08 g (0.23 mmol) and propargyl bromide 0.55 g (4.6 mmol) were added. After adding 0.6 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 1.5 hours under reflux with heating.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixture (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [2 0.83 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chlorophenyl) acetamide was obtained as white crystals (yield 87%). mp63-65 ℃.

Example 8
Method for producing N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (but-2-ynyloxy) -2- (4-chlorophenyl) acetamide (Compound No. 25)

In a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4 -Chlorophenyl) acetamide 0.85 g (2.3 mmol), methylene chloride 10 ml, tetra-n-butylammonium bromide 0.08 g (0.23 mmol) and 1-bromo-2-butyne 0.61 g (4.6 mmol) It was. After adding 0.6 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 1.5 hours under reflux with heating.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixture (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and N- [2 0.84 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (but-2-ynyloxy) -2- (4-chlorophenyl) acetamide was obtained as a pale yellow oil (yield 86%) .

Example 9
Method for producing N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (indan-5-yl) acetamide (Compound No. 184)

a) 0.54 g of 4-cyanomethoxy-3-methoxy-β-phenethylamine in a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. (2.
62 mmol), 8 ml of N, N-dimethylformamide, 0.56 g (2.62 mmol) of indan-5-yl-2-hydroxyacetic acid and 1.35 g (10.5 mmol) of diisopropylethylamine were added. After adding 1.39 g (3.14 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 5 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and N- [2 0.83 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (indan-5-yl) acetamide was obtained as a pale yellow oil (yield 83%).

b) N- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2-in in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. (Indan-5-yl) acetamide 0.80 g (2.11 mmol), methylene chloride 10 ml, tetra-n-butylammonium bromide 0.20 g (0.63 mmol) and propargyl bromide 0.38 g (3.16 mmol) were added. . After adding 0.5 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 4 hours under reflux with heating.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 7: 1) as a developing solvent, and N- [2 There were obtained 0.75 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (indan-5-yl) acetamide as a pale yellow oil (yield 85 %).

Example 10
Method for producing N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chloro-3-methylphenyl) acetamide (Compound No. 116)

a) In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 0.93 g (4.5 mmol) of 4-cyanomethoxy-3-methoxy-β-phenethylamine, N, N— 15 ml of dimethylformamide, 0.9 g (4.5 mmol) of 4-chloro-3-methylmandelic acid and 2.32 g (18.0 mmol) of diisopropylethylamine were added. After adding 2.38 g (5.4 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 5 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and N- [2 0.76 g of (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chloro-3-methylphenyl) acetamide was obtained as a pale yellow oil (43% yield).

b) N- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2-in in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. (4-Chloro-3-methylphenyl) acetamide 0.76 g (2.0 mmol), methylene chloride 13 ml, tetra-n-butylammonium bromide 0.13 g (0.4 mmol) and propargyl bromide 0.47 g (4.0 mmol) Put. After adding 0.5 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 1.5 hours with heating under reflux.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 7: 1) as a developing solvent, and N- [2 0.61 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chloro-3-methylphenyl) acetamide was obtained as a pale yellow oil ( Yield 73%).

Example 11
Method for producing N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (3,4-dichlorophenyl) acetamide (Compound No. 88)

a) In a 30 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 0.65 g (3.2 mmol) of 4-cyanomethoxy-3-methoxy-β-phenethylamine, N, N— 12 ml of dimethylformamide, 0.71 g (3.2 mmol) of 3,4-dichloromandelic acid and 1.65 g (12.8 mmol) of diisopropylethylamine were added. After adding 1.70 g (3.84 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 5 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and N- [2 0.78 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (3,4-dichlorophenyl) acetamide was obtained as a pale yellow oil (yield 60%).

b) N- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2-in in a 30 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 0.24 g (0.5 mmol) of (3,4-dichlorophenyl) acetamide, 10 ml of methylene chloride, 0.02 g (0.05 mmol) of tetra-n-butylammonium bromide and 0.12 g (1.0 mmol) of propargyl bromide were added. . After adding 0.5 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 3 hours with heating under reflux.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 7: 1) as a developing solvent, and N- [2 0.15 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (3,4-dichlorophenyl) acetamide was obtained as a pale yellow oil (yield 65 %).

Example 12
Method for producing N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chlorophenyl) acetamide (Compound No. 16)

a) In a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 1.78 g (8.6 mmol) of 4-cyanomethoxy-3-methoxy-β-phenethylamine, N, N— 20 ml of dimethylformamide, 1.5 g (8.0 mmol) of 4-chloromandelic acid and 4.1 g (32.0 mmol) of diisopropylethylamine were added. After adding benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate 4.3 g (9.6 mmol) at room temperature, the mixture was stirred at room temperature for 5 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and N- [2 There were obtained 2.91 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide as a pale yellow oil (yield 97%).

b) N- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2-in in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. (4-Chlorophenyl) acetamide 1.5 g (4.0 mmol), methylene chloride 15 ml, tetra-n-butylammonium bromide 0.26 g (0.8 mmol) and propargyl bromide 0.95 g (8.0 mmol) were added. After adding 1.0 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 2 hours with heating under reflux.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 7: 1) as a developing solvent, and N- [2 There were obtained 1.55 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chlorophenyl) acetamide as white crystals (yield 94%). mp63-65 ℃.

Example 13
Method for producing N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -3- (4-chlorophenyl) propionamide (Compound No. 36)

a) In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 1.49 g (7.25 mmol) of 4-cyanomethoxy-3-methoxy-β-phenethylamine, N, N— 15 ml of dimethylformamide and 1.45 g (7.25 mmol) of 3- (4-chlorophenyl) -2-hydroxypropionic acid and 3.74 g (29 mmol) of diisopropylethylamine were added. After adding 3.85 g (8.70 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 2 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and N- [2 1.62 g of-(4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-3- (4-chlorophenyl) propionamide was obtained as a pale yellow oil (57% yield).

b) N- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-3-in in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 1.60 g (4.12 mmol) of (4-chlorophenyl) propionamide, 12 ml of methylene chloride, 0.40 g (1.24 mmol) of tetra-n-butylammonium bromide and 0.74 g (6.18 mmol) of propargyl bromide were added. After adding 1.0 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 5 hours under heating to reflux.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and N- [2 -(4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -3- (4-chlorophenyl) propionamide 1.37 g was obtained as a pale yellow oil (yield 78% ).

Example 14
Process for producing R-(-)-N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chlorophenyl) acetamide (Compound No. 199 )

a) 0.69 g of 4-cyanomethoxy-3-methoxy-β-phenethylamine in a 100 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C.
(3.3 mmol), 10 ml of N, N-dimethylformamide, R-(−)-4-chloromandelic acid (α _D ²³ = −125.92 ° (C = 0.98, EtOH)) 0.56 g (3 0.0 mmol) and 1.55 g (12.0 mmol) of diisopropylethylamine. After adding 1.59 g (3.6 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 6 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and RN- 0.56 g of [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide was obtained as a pale yellow oil (yield 50%).

b) RN- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxyl in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. Add 0.56 g (1.5 mmol) of -2- (4-chlorophenyl) acetamide, 10 ml of methylene chloride, 0.10 g (0.3 mmol) of tetra-n-butylammonium bromide and 0.36 g (3.0 mmol) of propargyl bromide It was. After adding 0.4 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 2 hours under heating to reflux.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent. -(-)-N- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chlorophenyl) acetamide (0.56 g) as a pale yellow oil (Yield 90%). α _D ²⁴ = −53.73 ° (C = 1.01, EtOH)

Example 15
Method for producing S-(+)-N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chlorophenyl) acetamide (Compound No. 200) )

a) In a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 0.92 g (4.4 mmol) of 4-cyanomethoxy-3-methoxy-β-phenethylamine, N, N -Dimethylformamide 10 ml, S-(+)-4-chloromandelic acid (α _D ²⁴ = + 134.29 ° (C = 1.42, EtOH)) 0.75 g (4.0 mmol) and diisopropylethylamine 2.0 g ( 16.0 mmol). After adding 2.12 g (4.8 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 3 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The resulting crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and S—N— 1.50 g of [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-chlorophenyl) acetamide was obtained as a pale yellow oil (yield 100%).

b) In a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., S—N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy Add 1.50 g (4.0 mmol) of -2- (4-chlorophenyl) acetamide, 10 ml of methylene chloride, 0.27 g (0.8 mmol) of tetra-n-butylammonium bromide and 0.95 g (8.0 mmol) of propargyl bromide. It was. After adding 1.0 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 3 hours under reflux with heating.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and S- 1.46 g of (+)-N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-chlorophenyl) acetamide as a pale yellow oil Obtained (yield 88%). α _D ²⁴ = + 67.19 ° (C = 1.01, EtOH)

Example 16
Method for producing R-(−)-N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-bromophenyl) acetamide (Compound No. 201)

a) In a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 0.65 g (3.2 mmol) of 4-cyanomethoxy-3-methoxy-β-phenethylamine, N, N -Dimethylformamide 10 ml, R-(−)-4-bromomandelic acid (α _D ²⁴ = −112.07 ° (C = 1.424, EtOH)) 0.69 g (3.0 mmol) and 1.55 g of diisopropylethylamine (12.0 mmol) was added. After adding 1.59 g (3.6 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 5 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and RN- 0.83 g of [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-bromophenyl) acetamide was obtained as a pale yellow oil (yield 66%).

b) RN- [2- (4-Cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxyl in a 50 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -2- (4-Bromophenyl) acetamide 0.83 g (2.0 mmol), methylene chloride 10 ml, tetra-n-butylammonium bromide 0.13 g (0.4 mm)
ol) and propargyl bromide 0.48 g (4.0 mmol). After adding 0.5 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 2 hours under heating to reflux.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and R- 0.85 g of (−)-N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-bromophenyl) acetamide was added to a pale yellow oil. (Yield 83%). α _D ²³ = -60.70 ° (C = 1.02, EtOH)

Example 17
Method for producing S-(+)-N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-bromophenyl) acetamide (Compound No. 202)

a) In a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 0.65 g (3.2 mmol) of 4-cyanomethoxy-3-methoxy-β-phenethylamine, N, N -Dimethylformamide 10 ml, S-(+)-4-bromomandelic acid (α _D ²⁵ = + 112.83 ° (C = 1.42, EtOH)) 0.69 g (3.0 mmol) and 1.55 g diisopropylethylamine ( 12.0 mmol). After adding 1.59 g (3.6 mmol) of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate at room temperature, the mixture was stirred at room temperature for 5 hours.
Water was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The resulting crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and S—N— 0.96 g of [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy-2- (4-bromophenyl) acetamide was obtained as a pale yellow oil (yield 76%).

b) In a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., S—N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2-hydroxy 0.96 g (2.3 mmol) of -2- (4-bromophenyl) acetamide, 10 ml of methylene chloride, 0.15 g (0.46 mmol) of tetra-n-butylammonium bromide and 0.55 g (4.6 mmol) of propargyl bromide I put it in. After adding 0.6 ml of 30% aqueous sodium hydroxide solution at room temperature, the mixture was stirred for 2 hours while heating under reflux.
The resulting reaction mixture was acidified and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and S- 0.94 g of (+)-N- [2- (4-cyanomethoxy-3-methoxyphenyl) ethyl] -2- (prop-2-ynyloxy) -2- (4-bromophenyl) acetamide was pale yellow oil (Yield 90%). α _D ²⁴ = + 60.15 ° (C = 1.01, EtOH)

[Reference Production Example 1]
Method for producing 4-benzyloxy-3-methoxy-β-phenethylamine

a) 29.6 g (0.215 mol) of potassium carbonate, 250 ml of N, N-dimethylformamide and 25 g of vanillin (0.165 mol) in a 1 l four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. ) After adding 29.6 g (0.173 mol) of benzyl bromide at room temperature, the mixture was stirred at 60 ° C. for 3 hours.
The insoluble matter of the obtained reaction mixture was filtered, and water and ethyl acetate were added to the filtrate for extraction. The ethyl acetate layer was washed with water, then with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was washed with hexane to obtain 38.8 g of 4-benzyloxy-3-methoxybenzaldehyde as a white crystal (yield 97%).

b) 14.6 g (0.24 mol) of nitromethane, 300 ml of acetic acid and 4-benzyloxy-3-methoxybenzaldehyde 38 at room temperature in a 11 l 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 0.8 g (0.16 mol) was added. N-Butylamine 12.8g (0.176mol) was dripped at room temperature, and it stirred under heating-refluxing for 2 hours.
Ice water was added to the resulting reaction mixture. The crystals were filtered, and the crystals were washed twice with water and dried to obtain 37.1 g of 1-benzyloxy-2-methoxy-4- (2-nitrovinyl) benzene as a yellow crystal (yield 81%).

c) In a 2 l 4-neck flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C, 14.8 g (0.39 mol) of lithium aluminum hydride and 500 ml of tetrahydrofuran were placed at room temperature. At room temperature, 37.1 g (0.13 mol) of 1-benzyloxy-2-methoxy-4- (2-nitrovinyl) benzene was added little by little, and the mixture was stirred for 7 hours with heating under reflux. After cooling the obtained reaction mixture, an aqueous sodium hydroxide solution was added dropwise, and the insoluble material was filtered through celite. The solvent was distilled off from the obtained filtrate under reduced pressure of a vacuum pump. The residue was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump to obtain 27.4 g of 4-benzyloxy-3-methoxy-β-phenethylamine. Obtained as a light brown oil (82% yield).

[Reference Production Example 2]
Process for producing 4-cyanomethoxy-3-methoxy-β-phenethylamine

a) 25.4 g (0.139 mol) of 4-hydroxy-3-methoxyphenylacetic acid and 500 ml of tetrahydrofuran were placed in a 2 l four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. Under ice-cooling, 11.1 g (0.292 mol) of lithium aluminum hydride was added in 5 portions, followed by stirring under reflux for 7 hours.
A saturated ammonium chloride solution was added to the obtained reaction mixture, and the insoluble material was filtered through celite. The solvent was distilled off from the filtrate under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 5: 1) as a developing solvent, and 2- (4 There were obtained 20.2 g of (hydroxy-3-methoxy) phenethyl alcohol as a pale yellow oil (yield 87%).

b) 2- (4-Hydroxy-3-methoxy) phenethyl alcohol 18.9 g (112 mmol), N, N in a 500 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. -120 ml of dimethylformamide, 23.2 g (168 mmol) of potassium carbonate, 22.8 g (190 mmol) of bromoacetonitrile and 1.9 g (11.2 mmol) of potassium iodide were added and stirred at room temperature for 7 hours.
1N Hydrochloric acid was added to the obtained reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The resulting crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-acetone mixed solution (solvent volume ratio toluene: acetone = 10: 1) as a developing solvent, and 2- (4 There was obtained 23.3 g of (cyanomethoxy-3-methoxy) phenethyl alcohol as a pale yellow oil (yield 100%).

c) 23.3 g (112 mmol) of 2- (4-cyanomethoxy-3-methoxy) phenethyl alcohol at room temperature in a 500 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., 150 ml of toluene And 16.0 g (134 mmol) of thionyl chloride were added and stirred at 80 ° C. for 1 hour.
The solvent was distilled off from the obtained reaction mixture under reduced pressure of a vacuum pump. The obtained crude product was purified by chromatography on silica gel (trade name: Silica Gel 60H, manufactured by Merck & Co., Inc.) using a toluene-ethyl acetate mixed solution (solvent volume ratio toluene: ethyl acetate = 25: 1) as a developing solvent. 20.7 g of (4-cyanomethoxy-3-methoxy) phenethyl chloride was obtained as a pale yellow oil (yield 82%).

d) 28.9 g (156 mmol) of potassium phthalimide, 140 ml of N, N-dimethylformamide and 2- (4-cyano) at room temperature in a 500 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 20.7 g (92 mmol) of methoxy-3-methoxy) phenethyl chloride was added and stirred at 80 ° C. for 10 hours.
Water was added to the resulting reaction mixture, and the precipitated crystals were filtered and washed with ethyl acetate to obtain 27.7 g of N- [2- (4-cyanomethoxy-3-methoxy) phenethyl] phthalimide as white crystals ( Yield 90%).

e) 27.7 g (82 mmol) of N- [2- (4-cyanomethoxy-3-methoxy) phenethyl] phthalimide at room temperature in a 500 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. ), 180 ml of methanol and 12.3 g (246 mmol) of hydrazine hydrate were added and stirred at room temperature for 4 hours. 3N hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours.
After filtering the obtained reaction mixture, the solvent was distilled off from the filtrate under reduced pressure of a vacuum pump. The residue was made alkaline with 3N aqueous sodium hydroxide solution, extracted four times with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. 13.0 g of 4-cyanomethoxy-3-methoxy-β-phenethylamine was obtained as a light brown oil (yield 76%).

[Reference Production Example 3]
Method for producing 4-methylmandelic acid

a) 19.5 g (348 mmol) of potassium hydroxide and 65 ml of water were placed in a 500 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. Under ice cooling, 7.4 g (174 mmol) of lithium chloride, 65 ml of dioxane, 10.4 g (87 mmol) of 4-methylbenzaldehyde and 22.1 g (87 mmol) of bromoform were added. The mixture was stirred for 10 hours under ice-cooling and then for 24 hours at room temperature. 36% hydrochloric acid was added to the obtained reaction mixture, and the mixture was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was washed with hexane to obtain 11.1 g of 4-methylmandelic acid as a white crystal (yield 77%).

[Reference Production Example 4]
Method for producing R-(−)-4-chloromandelic acid

a) In a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 8.21 g (44 mmol) of DL-4-chloromandelic acid and 2.62 g (29.5 mmol) of L-alanine And 13 ml of water were added. The reaction mixture was heated to 70 ° C. and then cooled to room temperature. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration, and the crystals were washed with cold water to obtain 2.49 g of an R-(−)-4-chloromandelic acid-L-alanine complex (yield 31% ). α _D ²⁵ = −76.28 ° (C = 1.01, H ₂ O)

b) 2.48 g (9.0 mmol) of R-(−)-4-chloromandelic acid-L-alanine complex in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. Then, 15 ml of 1N hydrochloric acid was added and stirred at room temperature for 30 minutes. Ether was added to the reaction mixture, and the mixture was further stirred at room temperature for 30 minutes. After completion of the reaction, an ether layer was obtained. The obtained ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump to obtain R-(-)- 1.50 g of 4-chloromandelic acid was obtained as white crystals (yield 89%). α _D ²³ = −125.92 ° (C = 0.98, EtOH)

[Reference Production Example 5]
Method for producing S-(+)-4-chloromandelic acid

a) 200 ml equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C
In a four-necked flask, 18.65 g (100 mmol) of DL-4-chloromandelic acid, 5.96 g (67.0 mmol) of D-alanine and 30 ml of water were added. The reaction mixture was heated to 70 ° C. and then cooled to room temperature. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration, and the crystals were washed with cold water to obtain 9.81 g of a S-(+)-4-chloromandelic acid-D-alanine complex (yield 53% ). α _D ²³ = + 44.73 ° (C = 1.01, H ₂ O)

b) S-(+)-4-chloromandelic acid-D-alanine complex (α _D ²³ = + 44.73) in a 200 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. (C = 1.01, H ₂ O)) 9.81 g (35.6 mmol) and 1N hydrochloric acid 50 ml were added, and the mixture was stirred at room temperature for 30 minutes. Ether was added to the reaction mixture, and the mixture was further stirred at room temperature for 30 minutes. After completion of the reaction, an ether layer was obtained. The obtained ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump to remove S-(+)- This gave 6.01 g of 4-chloromandelic acid as white crystals (yield 91%). α _D ²³ = + 71.84 ° (C = 1.41, EtOH)

c) S-(+)-4-chloromandelic acid (α _D ²³ = + 71.84 ° (C = 1.C) in a 300 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 41, EtOH)) 6.01 g (32.2 mmol), S-(−)-α-methylbenzylamine 3.90 g (32.2 mmol) and 100 ml of ethyl alcohol were added. The mixture was heated under reflux for 30 minutes and allowed to stand at room temperature for 10 hours. The precipitated crystals were collected by filtration and washed with cold ethyl alcohol to obtain white crystals. The obtained crystals were recrystallized twice from ethyl alcohol to obtain 4.71 g of S-(+)-4-chloromandelic acid-S-(-)-α-methylbenzylamine complex (yield). 48%). α _D ²³ = + 47.92 ° (C = 0.626, MeOH)

d) S-(+)-4-chloromandelic acid-S-(-)-α-methylbenzylamine complex in a 500 ml 4-neck flask equipped with stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C (Α _D ²³ = + 47.92 ° (C = 0.626, MeOH)) 4.71 g (15.3 mmol), 1N hydrochloric acid 40 ml and ether 100 ml were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, liquid separation was performed to obtain an ether layer. The obtained ether layer was washed with 1N hydrochloric acid, further washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure of a vacuum pump to obtain 2.62 g of S-(+)-4-chloromandelic acid as white crystals (yield 92%). α _D ²⁴ = + 134.29 ° (C = 1.42, EtOH)

[Reference Production Example 6]
Method for producing R-(-)-4-bromomandelic acid

a) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 16.1 g (69.7 mmol) of DL-4-bromomandelic acid and 4.17 g (46. 8 mmol) and 30 ml of water were added. The reaction mixture was heated to 70 ° C. and then cooled to room temperature. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration, and the crystals were washed with cold water to obtain 8.72 g of R-(−)-4-bromomandelic acid-L-alanine complex (yield 39% ). α _D ²⁵ = −88.02 ° (C = 1.00, H ₂ O)

b) 200 ml equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C
In a four-necked flask, 8.67 g of R-(−)-4-bromomandelic acid-L-alanine complex (α _D ²⁵ = −88.02 ° (C = 1.00, H ₂ O)) (27 0.1 mmol) and 40 ml of 1N hydrochloric acid were added, and the mixture was stirred at room temperature for 30 minutes. Ether was added to the reaction mixture, and the mixture was further stirred at room temperature for 30 minutes. After completion of the reaction, an ether layer was obtained. The obtained ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump to obtain R-(-)- 4.67 g of 4-bromomandelic acid was obtained as white crystals (yield 91%). α _D ²⁵ = −107.71 ° (C = 1.43, EtOH)

c) R-(−)-4-bromomandelic acid (α _D ²⁵ = −107.71 ° (C = 1) in a 200 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. .43, EtOH)) 5.67 g (24.5 mmol), R-(+)-α-methylbenzylamine 2.97 g (24.5 mmol) and 120 ml of ethyl alcohol were added. The mixture was heated under reflux for 30 minutes and allowed to stand at room temperature for 10 hours, and then the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethyl alcohol to obtain 6.52 g of R-(−)-4-bromomandelic acid-R-(+)-α-methylbenzylamine complex as white crystals ( Yield 75%). α _D ²³ = −43.67 ° (C = 0.632, MeOH)

d) R-(−)-4-bromomandelic acid-R-(+)-α-methylbenzylamine complex in a 300 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. (Α _D ²³ = −43.67 ° (C = 0.632, MeOH)) 6.47 g (18.4 mmol), 1N hydrochloric acid 40 ml and ether 100 ml were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, liquid separation was performed to obtain an ether layer. The obtained ether layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure of a vacuum pump to obtain 4.0 g of R-(−)-4-bromomandelic acid as white crystals (yield 94%). α _D ²⁴ = −112.07 ° (C = 1.42, EtOH)

[Reference Production Example 7]
Method for producing S-(+)-4-bromomandelic acid

a) In a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 21.0 g (91.0 mmol) of DL-4-bromomandelic acid and 5.4 g of D-alanine (61. 0 mmol) and 30 ml of water were added. The reaction mixture was heated to 80 ° C. and then cooled to room temperature. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration and washed with water. The obtained crystals were recrystallized from water to obtain 6.92 g of S-(+)-4-bromomandelic acid-D-alanine complex (yield 35%). α _D ²³ = + 63.49 ° (C = 1.01, H ₂ O)

b) 6.87 g (21.5 mmol) of S-(+)-4-bromomandelic acid-D-alanine complex in a 200 ml 4-neck flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. Then, 40 ml of 1N hydrochloric acid was added and stirred at room temperature for 30 minutes. Ether was added to the reaction mixture, and the mixture was further stirred at room temperature for 30 minutes. After completion of the reaction, an ether layer was obtained. The obtained ether layer was washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. -(+)-4-Bromomandelic acid (4.55 g) was obtained as white crystals (yield 92%). α _D ²³ = + 98.59 ° (C = 1.43,
EtOH)

c) S-(+)-4-bromomandelic acid (α _D ²³ = + 98.59 ° (C = 1.C) in a 200 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C. 43, EtOH)) 4.45 g (19.3 mmol), S-(−)-α-methylbenzylamine 2.32 g (19.3 mmol) and 100 ml of ethyl alcohol were added. The mixture was heated under reflux for 30 minutes and allowed to stand at room temperature for 10 hours, and then the precipitated crystals were collected by filtration. The obtained crystals were recrystallized twice from ethyl alcohol to obtain 4.31 g of S-(+)-4-bromomandelic acid-S-(-)-α-methylbenzylamine complex as white crystals. (Yield 63%). α _D ²⁴ = + 42.94 ° (C = 0.62, MeOH)

d) S-(+)-4-bromomandelic acid-S-(-)-α-methylbenzylamine complex in a 300 ml 4-neck flask equipped with stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C (Α _D ²⁴ = + 42.94 ° (C = 0.62, MeOH)) 4.31 g (12.2 mmol), 1N hydrochloric acid 30 ml and ether 80 ml were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, liquid separation was performed to obtain an ether layer. The obtained ether layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure of a vacuum pump to obtain 2.49 g of S-(+)-4-bromomandelic acid as white crystals (yield 88%). α _D ²⁵ = + 112.83 ° (C = 1.42, EtOH)

Next, formulation examples of the bactericide of the present invention are shown. “Parts” in formulation examples represents parts by weight.
Additives and addition ratios of formulation examples shown below are not limited to these formulation examples, and can be changed in a wide range.

[Formulation Example 1] Emulsion Compound No. 39 (10 parts) was dissolved in Solvesso 150 (45 parts) and N-methyl-2-pyrrolidone (35 parts). To the obtained solution, Solpol 3005X (manufactured by Toho Chemical Industry Co., Ltd.) (10 parts) was added and mixed by stirring to obtain a 10% emulsion.
Further, each emulsion was obtained in the same manner as in Formulation Example 1, except that each compound shown in Table 1 was used instead of the compound of Compound No. 39.

[Formulation Example 2] Wetting agent Compound No. 16 (20 parts) was mixed with sodium lauryl sulfate (2 parts), sodium lignin sulfonate (4 parts), white carbon (20 parts) and clay (54 parts). The mixture was stirred and mixed with a juice mixer to obtain a 20% wettable powder.
Furthermore, each wettable powder was obtained by the same method except that each compound shown in Table 1 was used instead of the compound of Compound No. 16.

[Formulation Example 3] Granules Compound No. 76 (5 parts), sodium dodecylbenzenesulfonate (2 parts), carboxymethylcellulose (2 parts), sodium lauryl sulfate (2 parts), bentonite (10 parts) and clay (79 parts) was added and mixed with sufficient stirring. An appropriate amount of water was added and the mixture was further stirred and granulated with a granulator. The resulting granulated product was dried by ventilation to obtain a 5% granule.
Furthermore, each granule was obtained by the same method except having used each compound of Table 1 instead of the compound of the compound number 76. FIG.

[Formulation Example 4] Powder A compound of Compound No. 184 (1 part) was dissolved in soybean oil (2 parts). White carbon (5 parts), acidic isopropyl phosphate (PAP) (0.3 parts) and clay (91.7 parts) were added to the obtained solution, and the mixture was stirred and mixed with a juice mixer to obtain a 1% powder.
Furthermore, each powder agent was obtained by the same method except using each compound shown in Table 1 instead of the compound of Compound No. 184.

[Formulation Example 5] Flowable agent Compound No. 88 (20 parts), polyoxyethylene alkyl ether, sodium dialkylsulfosuccinate and proxel GXL (1,2-benzisothiazolin-3-one), Part and 0.2 part water (20 parts) were mixed. The obtained mixture was wet-ground using a dyno mill. The obtained pulverized product was mixed with water (60 parts) containing 8 parts and 0.32 parts of propylene glycol and xanthan gum, respectively, to obtain a flowable agent which was a 20% suspension in water.
Furthermore, each flowable agent was obtained by the same method except having used each compound of Table 1 instead of the compound of Compound No. 88.

[Formulation Example 6] Granule wettable powder Compound No. 102 (20 parts), sodium lauryl sulfate (2 parts), sodium alkylnaphthalene sulfonate (3 parts), dextrin (5 parts), white carbon (20 parts) , Clay (50 parts) was added and mixed with sufficient stirring. An appropriate amount of water was added and the mixture was further stirred and granulated with a granulator. The resulting granulated product was dried by ventilation to obtain a 20% granular wettable powder.
Furthermore, each granule wettable powder was obtained by the same method except having used each compound of Table 1 instead of the compound of the compound number 102. FIG.

Next, test examples of the bactericide of the present invention are shown.
[Test Example 1] Cucumber downy mildew control effect test Prepared according to Formulation Example 2 to a 1.5-leaf stage cucumber (variety: Sagamihanjiro) grown in a plastic pot with a diameter of 6 cm in a greenhouse. 10 ml of a diluted liquid of wettable powder (1.6 ppm) was sprayed (stem and leaf spray) per pot. On the other hand, zoosporangium of cucumber downy mildew (Pseudoperonospora cubensis) was formed on cucumber leaves cultivated in another pot.
The obtained zoosporangium was inoculated on the next day after the spraying treatment to the cucumber sprayed with the drug. This cucumber was allowed to stand in an inoculation box at 20 ° C. (relative humidity = 100%) for 24 hours, and then further left in an artificial weather chamber at 24 ° C. to promote disease.
Five days after the inoculation, the lesion area ratio (%) of cucumber downy mildew on the first leaf was investigated to obtain the lesion area ratio from each repeated section, and the control value (%) was further calculated by the following formula 1. Calculated.
Control value (%) = [1− (average lesion area ratio of sprayed area / average lesion area ratio of non-scattered area)] × 100 (Equation 1)
The calculated control value was converted into an evaluation value according to the criteria shown in Table 3 below.

  This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The results are shown in the column of “Evaluation value of control effect” in Table 4.

In addition, the degree of phytotoxicity to cucumber leaves was investigated according to the following criteria.
Survey index of the degree of phytotoxicity (evaluated in 6 levels)
5: Excitement 4: Acupuncture 3: Many 2: Slight 1: Slightly 0: None The above investigation index of the degree of phytotoxicity was also applied to Test Example 2 and Test Example 3. The results are shown in the column of “Drug damage” in Table 4. Comparative compounds B to G in Table 4 represent the following compounds. These comparative compounds are compounds described in JP-T-2003-533502. These comparative compounds are also used in Test Examples 2, 4, 5, and 6.

[Test Example 2] Tomato plague control effect test Hydration prepared in accordance with Formulation Example 2 on 5-6 leaf tomatoes (cultivar: Toko K) grown in a plastic pot with a diameter of 6 cm in a greenhouse. 10 ml of a diluted solution of the agent (1.6 ppm) was sprayed per one pot (stem and leaf spray). On the other hand, zoospores were germinated from the zoosporangium of the tomato blight fungus (Phytophthora infestans) formed on the potato slices.
The tomatoes sprayed with the zoospores were inoculated on the day after the drug treatment. After leaving it in a 20 ° C. inoculation box (relative humidity = 100%) for 24 hours, it was left still in a 20 ° C. artificial weather chamber to promote disease. Five days after the inoculation, the lesion area ratio (%) of the tomato plague on the first to fifth leaves was examined, and the average value was obtained.
From the obtained average value, the control value (%) was calculated according to the above formula 1. Furthermore, according to said Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. These results are shown in Table 5.

[Test Example 3] Potato plague control effect test A wettable powder prepared according to Formulation Example 2 in 7-8 leaf potatoes (variety: Baron) cultivated in a plastic pot having a diameter of 9 cm in a greenhouse. 10 ml of a diluted liquid (100 ppm) was sprayed (stem and leaf spray) per pot. On the other hand, zoospores were germinated from zoosporangium of potato phytopathogens formed on potato slices. The zoospores were inoculated into the potatoes sprayed with the drug the day after the drug treatment. After leaving it in a 20 ° C. inoculation box (relative humidity = 100%) for 24 hours, the disease was promoted in an artificial climate room at 20 ° C. Five days after the inoculation, the lesion area ratio (%) of the potato plague on the first to sixth leaves was examined, and the average value was obtained. From the obtained average value, the control value (%) was calculated by the above formula 1. From the calculated control value, according to the above Table 3, the control value was converted into an evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. These results are shown in Table 6.

[Test Example 4] Cucumber downy mildew treatment effect test Cultivated in a plastic pot with a diameter of 6 cm in a greenhouse, cultivated in a separate pot in advance at 1.5 leaf stage cucumber (variety: Sagamihanjiro) Pseudoperonospora cubensis zoosporangia formed on the cucumber leaves were inoculated.
It was allowed to stand for 24 hours in a 20 ° C. inoculation box (relative humidity = 100%). Into the cucumber pot after inoculation, 10 ml of a diluting liquid (1.6 ppm) prepared in accordance with Formulation Example 2 was sprayed (stem and leaf spray) per pot. After spraying the drug, the cucumber urged the onset in a 24 ° C. artificial climate room.
Five days after the inoculation, the lesion area ratio (%) of cucumber downy mildew on the first leaf was investigated, and the average value was obtained. From the obtained average value, the control value (%) was calculated by the above formula 1. And according to said Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. These results are shown in Table 7.
Comparative compound A in Table 7 represents the following compound. Comparative compound A is a compound described in JP-T-2003-533002. This comparative compound A is also used as a comparative compound in Test Example 5, Test Example 6 and Test Example 7.

[Test Example 5] Tomato Blight Treatment Effect Test Tomato blight fungus previously formed on potato slices in 5-6 leaf tomatoes (variety: Toko K) grown in a plastic pot with a diameter of 6 cm in a greenhouse. The zoospore was germinated from the zoospore sac of (Phytophthora infestans), and the zoospore was inoculated. This was left to stand in an inoculation box at 20 ° C. (relative humidity = 100%) for 24 hours. In the pot after the inoculation, 10 ml of a wettable powder diluted solution (6.3 ppm) prepared according to Formulation Example 2 was sprayed per one pot (foliage spray).
After spraying the drug, the tomato was urged to attack in an artificial weather room at 20 ° C. Five days after the inoculation, the lesion area ratio (%) of the tomato plague on the first to fifth leaves was investigated, and the average value was obtained. From the obtained average value, the control value (%) was calculated by the above formula 1. And according to said Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. These results are shown in Table 8.

[Test Example 6] Cucumber downy mildew rain resistance test Prepared according to Formulation Example 2 in a 1.5-leaf cucumber (cultivar: Sagamihanjiro) grown in a plastic pot with a diameter of 6 cm in a greenhouse. The diluted liquid (25 ppm) of the wettable powder was sprayed (pot spray) on one pot. Three hours after the chemical treatment, the chemical-treated cucumber was subjected to the rain treatment with an artificial rain apparatus at an intensity of 20 mm / hour for 2 hours (accumulated precipitation 40 mm).
Twenty-four hours after the drug treatment, zoosporangium of Pseudoperonospora cubis formed in advance on another cucumber leaf was inoculated into the cucumber sprayed with the drug. This was allowed to stand in an inoculation box at 20 ° C. (relative humidity = 100%) for 24 hours, and then the disease was further promoted in a climate chamber at 24 ° C.
Five days after the inoculation, the lesion area ratio (%) of cucumber downy mildew on the first leaf was investigated, and the average value was obtained. From the obtained average value, the control value (%) was calculated by the above formula 1. And according to said Table 3, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. These results are shown in Table 9.

[Test Example 7] Test of phytotoxicity on cucumber fruit To a fruit (fruit enlargement stage) of cucumber (variety: Yoshinari) cultivated in a vinyl greenhouse, a dilute liquid (150 ppm) prepared in accordance with Formulation Example 2 was added. 5 ml was sprayed per fruit. Observation was made over time from the next day of the chemical treatment, and after 14 days of spraying, the degree of phytotoxicity of all cucumber fruits was determined according to the above criteria. This test was carried out in a double regime of 10 fruits per ward per chemical solution concentration. These results are shown in Table 10. Comparative compound H in Table 10 represents the following compound. The comparative compound H is a compound described in JP-T-8-511772.

Claims (10)

Formula (I)

(In general formula (I),
R ¹ represents a hydrogen atom; a chain or cycloalkyl group optionally having a halogen atom, an alkoxy group or a cyano group; an alkenyl group optionally having a halogen atom; and optionally having a halogen atom. An alkynyl group; or an alkylcarbonyl group,
R ² represents a hydrogen atom or an alkyl group,
m represents an integer of 0 to 2,
X is a halogen atom; an alkoxy group or a chain or cycloalkyl group optionally having a halogen atom; an alkenyl group optionally having a halogen atom: an alkynyl group optionally having a halogen atom; A chain or a cycloalkoxy group which may have a halogen atom; an alkenyloxy group which may have a halogen atom; an alkynyloxy group which may have a halogen atom; An alkylthio group, an alkylsulfinyl group or an alkylsulfonyl group; a phenyl group; a phenoxy group; a cyano group; a nitro group; a formyl group; a carboxyl group; an alkylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, and an alkynyloxycarbonyl group. Selected carbonyl ; 1 or an amino group which may have a two alkyl groups; a benzyl group; or the following general formula (II)

(In the general formula (II), R ³ represents a hydrogen atom or an alkyl group, and R ⁴ represents an alkyl group, an alkenyl group, or an alkynyl group.)
A substituent represented by
n represents an integer of 0 to 5,
when n is 2 or more, each X may be the same or different;
Two Xs may be bonded to two adjacent carbons of the phenyl ring carbon, respectively, and the two Xs together may represent an alkylenedioxy group or an alkylene group. )
Or a salt thereof. The compound or a salt thereof according to claim 1, wherein R ² in the general formula (I) represents a hydrogen atom.   M in the said general formula (I) shows 0, The compound or its salt of Claim 1 or 2 characterized by the above-mentioned.   M in the said general formula (I) shows 1 or 2, The compound or its salt of Claim 1 or 2 characterized by the above-mentioned. The R ¹ in the general formula (I) represents an unsubstituted chain alkyl group, alkenyl group, alkynyl group, or cyanoalkyl group, according to any one of claims 1 to 4. Compound or salt thereof. N in the general formula (I) represents 1 or 2,
X in the general formula (I) is a halogen atom; an alkoxy group or an alkyl group optionally having a halogen atom; a chain alkoxy group or a cycloalkoxy group optionally having a halogen atom; an alkenyloxy group; an alkynyl An oxy group, an alkylthio group, a hydroxy group, or a cyano group, or when two Xs are bonded to two adjacent carbons of the phenyl ring carbon, respectively, the two Xs are taken together to form an alkylenedioxy group Or an alkylene group,
When n is 2, each X is the same or different, The compound or its salt as described in any one of Claims 1-5 characterized by the above-mentioned. At least one compound selected from the compounds represented by the following formulas or a salt thereof.

  The compound or salt thereof according to any one of claims 1 to 7, which is an optical isomer. At least one compound selected from the compounds represented by the following formulas or a salt thereof.

  An agricultural and horticultural fungicide containing the compound according to any one of claims 1 to 9 or a salt thereof.