JP3954127B2 - Cyclic amide derivatives and herbicides - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a specific novel cyclic amide derivative and a herbicide for paddy rice containing this as an active ingredient.
[0002]
[Prior art]
Heretofore, some cyclic amide derivatives having herbicidal activity have been known. For example, cyclic amide derivatives described in JP-A-3-204855, cyclic urea derivatives described in JP-A-3-176475, 2- (2-oxo-3) described in JP-A-5-221972. -Pyrrolin-1-yl) isobutyric acid derivative, 2-oxo-3-pyrroline derivative described in JP-A-5-221973 and 1,3-oxazine-4-described in JP-A-4-89485 It is described that ON derivatives and the like are effective as herbicides.
[0003]
[Problems to be solved by the invention]
In recent years, there has been a strong demand for a herbicide having a selective action that kills only weeds without causing harm to the crops even when applied to effective crops and weeds simultaneously.
[0004]
In addition, it is desired to develop a drug that can be used at a low dose in order to prevent the drug from remaining excessively in the environment.
[0005]
[Means for Solving the Problems]
In order to achieve the above-mentioned object, the present inventors synthesized a large number of cyclic amide derivatives and examined various usefulness thereof. As a result, the present inventors have found that the cyclic amide derivatives we have synthesized have excellent herbicides and selectivity suitable for the above purpose, and have completed the present invention. That is, the present invention provides { 1-[(2-cyclopropylcarbonyl) -substituted isopropyl] -2-oxo-3- [X-substituted phenyl (X represents a hydrogen atom or a fluorine atom bonded to the 2-position)]-4. The present invention relates to a novel cyclic amide derivative having a structure of -methyl} -substituted 3-pyrroline and a herbicide for paddy rice containing the same as an active ingredient.
[0006]
[Chemical 1]
{Wherein, -A-B- is a group _{-N-CH (CH 3) -} , group _{-N-N (CH 3) -} , group -N-O-, group _{-C = C (CH 3) -} , Represents a group —N—CH ₂ — or —C═C (CH ₃ ) —O—, wherein X is the same or different and is a hydrogen atom, halogen atom, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, methylenedi An oxy group, an alkylthio group, an alkylsulfonyl group, a phenoxy group, an alkoxycarbonyl group, an acyl group, a nitro group, a hydroxy group, a cyano group, or a dimethylamino group, m represents an integer of 1 or 2, and n represents 1 to 3 R ¹ represents the formula
[Chemical 2]
[Wherein Y is the same or different, hydrogen atom, halogen atom, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, methylenedioxy group, alkylthio group, alkylsulfonyl group, phenoxy group, alkoxycarbonyl group, phenyl A group, an alkoxycarbonylalkyl group, an acyl group, a nitro group, a hydroxy group, a cyano group or a dimethylamino group, k represents an integer of 1 to 5, and R ² represents a formula
[Chemical 3]
[Wherein, Y and k represent the same meaning as described above, Z represents a sulfur atom, an oxygen atom, or a formula —NR ⁴ (wherein R ⁴ represents a hydrogen atom, an alkyl group, or a haloalkyl group); D is a nitrogen atom or a formula —CR ⁵ (wherein R ⁵ is a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, an alkylsulfonyl group, a phenyl group, an alkoxycarbonyl group, an acyl group) Represents a group, a nitro group, a hydroxy group, a cyano group, or a dimethylamino group. R ³ represents an alkyl group, an alkoxy group, a haloalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group, a cycloalkyl group (the group may be substituted with a halogen atom or an alkyl group), cycloalkylalkyl Represents a group, a halocycloalkylalkyl group, a cycloalkenyl group, an alkoxyalkyl group, or a formula —R ² (wherein R ² has the same meaning as described above). ].
Provided that when —A—B— represents a group —C═C (CH ₃ ) — or a group —N—CH ₂ —, R ¹ represents the formula
[Formula 4]
[Wherein, Y, k and R ² represent the same meaning as described above. However, when R ¹ is a phenyl group having a substituent of Yk (Y and k are as defined above), n represents the integer 3. R ³ represents a haloalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group, a cycloalkyl group (which may be substituted with a halogen atom or an alkyl group), a cycloalkylalkyl group, a halocycloalkylalkyl A group, a cycloalkenyl group, an alkoxyalkyl group or a formula —R ² (wherein R ² represents the same meaning as described above), and —A—B— represents a group —C═C (CH ₃ ) —O. In the case of-, m and n both represent the integer 1, and R ¹ represents the formula -CONHR ² (wherein R ² represents the same meaning as described above). } And herbicides containing this as an active ingredient.
[0010]
In the present specification, the alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an n-butyl group. , Isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, isoamyl group, neopentyl group, n-hexyl group, isohexyl group, 3,3-dimethylbutyl group and the like.
[0011]
An alkoxy group, an alkylthio group, an alkoxycarbonyl group, an acyl group, and an alkylsulfonyl group are an alkyloxy group, an alkylthio group, an alkyloxycarbonyl group, an alkylcarbonyl group, and an alkylsulfonyl group, respectively, in which the alkyl portion has the above-mentioned meaning.
[0012]
A halogen atom shows a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
[0013]
The haloalkyl group refers to an alkyl group substituted with a halogen atom, and examples thereof include a difluoromethyl group, a trifluoromethyl group, and a pentafluoroethyl group.
[0014]
A cycloalkyl group shows a C3-C7 cycloalkyl group, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group etc. can be mentioned.
[0015]
The haloalkoxy group is a haloalkyloxy group in which the haloalkyl moiety has the above meaning, and examples thereof include a difluoromethoxy group, a trifluoromethoxy group, and a pentafluoroethoxy group.
[0016]
The alkenyl group represents a straight or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include a vinyl group, a propenyl group, an isopropenyl group, a butenyl group, a pentenyl group, and a hexenyl group.
[0017]
A haloalkenyl group refers to an alkenyl group substituted with a halogen atom.
The alkynyl group is a straight or branched alkynyl group having 2 to 6 carbon atoms, and includes, for example, ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, 3,3-dimethyl-1 -Butynyl group, 4-methyl-1- pentynyl group, 3-methyl-1-pentynyl group and the like can be mentioned.
[0019]
DETAILED DESCRIPTION OF THE INVENTION
Next, this invention compound represented by general formula [I] is described in Tables 1-12. The compound number is referred to in the following description.
[0020]
[Table 1]
[0021]
[Table 2]
[0022]
[Table 3]
[0023]
[Table 4]
[0024]
[Table 5]
[0025]
[Table 6]
[0026]
[Table 7]
[0027]
[Table 8]
[0028]
[Table 9]
[0029]
[Table 10]
[0030]
[Table 11]
[0031]
[Table 12]
[0032]
Next, although this invention compound shown by general formula [I] can be manufactured according to the manufacturing method shown below, for example, it is not limited to these methods.
[0033]
<Production method 1>
[0034]
Embedded image
(Wherein, X, m and R ² represent the same meaning as described above.)
[0035]
First, 2-aminoisobutyric acid represented by the formula [II-1] is reacted in the presence of benzyl alcohol and p-toluenesulfonic acid to give 2-aminoisobutyric acid benzyl ester represented by the formula [II-2]. Can be manufactured.
[0036]
Examples of the solvent include chlorine-containing hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbons such as n-hexane, benzene and toluene, and aliphatics such as acetone and methyl ethyl ketone. Ketones, alcohols such as methanol and ethanol, or aprotic polar solvents such as acetonitrile, N, N-dimethylformamide (DMF), and N, N-dimethylacetamide (DMAC) can be used (hereinafter referred to as production). Method 1-1 referred to as solvent). The above reaction is carried out at a temperature ranging from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours.
[0037]
Next, the resulting 2-aminoisobutyric acid benzyl ester represented by the formula [II-2] is reacted with monochloroacetone in the presence of a base to produce a compound represented by the formula [II-3]. <Described in Example (a)>.
[0038]
Examples of the base include organic amines such as triethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, picoline, quinoline, or sodium hydride, sodium hydroxide, potassium hydroxide, carbonic acid. Inorganic bases such as sodium, potassium carbonate, sodium hydrogen carbonate and the like can be used (hereinafter referred to as production method 1 base). As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in a nitrogen atmosphere at a temperature ranging from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0039]
Next, the compound represented by the general formula [II-4] can be produced by reacting the obtained compound represented by the formula [II-3] with a substituted phenylacetic chloride in the presence of a base. Described in Example (b)>.
[0040]
As the base, those described above (Production method 1 base) can be used in the same manner. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range of −15 ° C. to 60 ° C. and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0041]
Next, the compound represented by the general formula [II-4] can be produced by intramolecular condensation cyclization in the presence of a base to produce the compound represented by the general formula [II-5].
[0042]
As the base, for example, metal alkoxides such as sodium methoxide and sodium ethoxide, or organic amines such as triethylamine, DBU, pyridine, picoline and quinoline can be used. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from the temperature under ice cooling to the boiling point of the solvent, and is completed in 0.5 to 10 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it is purified by recrystallization or column chromatography.
[0043]
Next, the compound represented by the general formula [II-6] can be obtained by alkaline hydrolysis of the compound represented by the general formula [II-5] <described in Example (c)>.
[0044]
Examples of the base that can be used include sodium hydroxide and potassium hydroxide. As the solvent, for example, a water-soluble solvent that does not undergo hydrolysis such as dioxane, methanol, ethanol, or water can be used. The reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 0.5 to 10 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it can be purified by recrystallization or column chromatography.
[0045]
Next, after reacting the compound represented by the general formula [II-6] with a peptidizing agent in the presence or absence of a base, the compound represented by the general formula [II-7] or a salt thereof The compound of the present invention represented by the general formula [II] can be produced by reacting with <described in Example (d)>.
[0046]
Examples of peptidizing agents include 2-chloro-1-methylpyridinium iodide, diphenylphosphoryl azide, triphenylphosphine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, carbonyldiimidazole or 1,3- Examples include dicyclohexylcarbodiimide. As the base, for example, organic amines such as triethylamine, DBU, pyridine, picoline, quinoline and the like can be used. Examples of the solvent include chlorine-containing hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbons such as n-hexane, benzene and toluene, and aliphatics such as acetone and methyl ethyl ketone. Ketones or aprotic polar solvents such as acetonitrile, DMF, and DMAC can be used (hereinafter referred to as production method 1-2 solvent). The above reaction is carried out in the temperature range from −10 ° C. to the boiling point of the solvent and is completed in 0.5 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it is purified by recrystallization or column chromatography.
[0047]
<Production method 2>
[0048]
Embedded image
(Wherein, X, m and R ² are as defined above, Q is a hydrogen atom or a methyl group.)
[0049]
First, 2-aminoisobutyric acid ethyl ester hydrochloride represented by the formula [III-1] is reacted with methyl vinyl ketone or acrolein in the presence of a base to produce a compound represented by the general formula [III-2]. <Described in Example (e)>.
[0050]
As the base, those described above (Production method 1 base) can be used in the same manner. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in a nitrogen atmosphere at a temperature ranging from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0051]
Next, the compound represented by the general formula [III-2] is reacted with the compound represented by the general formula [III-3] to obtain a compound represented by the general formula [III-4]. Can be manufactured.
[0052]
As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0053]
Next, the obtained compound represented by the general formula [III-4] is reacted in the presence of a base, followed by a dehydration reaction to produce a compound represented by the general formula [III-5]. <As described in Example (f)>.
[0054]
As the base, those described above (Production method 1 base) can be used in the same manner. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from the temperature under ice cooling to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0055]
Next, the compound represented by the general formula [III-5] can be catalytically reduced in the presence of a catalyst to produce the compound represented by the general formula [III-6] <Example ( described in g)>.
[0056]
Examples of the catalyst include palladium carbon and Raney nickel. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbons such as n-hexane, benzene and toluene, aliphatic ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, or acetonitrile, DMF, An aprotic polar solvent such as DMAC can be used (hereinafter referred to as production method 2-1 solvent). The above reaction is carried out in the temperature range from the temperature under ice cooling to the boiling point of the solvent, and is completed in 0.5 to 10 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it is purified by recrystallization or column chromatography.
[0057]
Next, the compound represented by the general formula [III-7] can be obtained by alkaline hydrolysis of the compound represented by the general formula [III-6] <described in Example (h)>.
[0058]
Examples of the base that can be used include sodium hydroxide and potassium hydroxide. As the solvent, for example, a water-soluble solvent that does not undergo hydrolysis such as dioxane, methanol, ethanol, or water can be used. The reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 0.5 to 10 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it can be purified by recrystallization or column chromatography.
[0059]
Next, the compound represented by the general formula [III-7] is reacted with a peptidizing agent in the presence or absence of a base and then reacted with a compound represented by the general formula [III-8]. The compound of the present invention represented by the general formula [III] can be produced <described in Example (i)>.
[0060]
As the peptidizing agent, the one used in Example 1 can be used in the same manner. As the base, for example, organic amines such as triethylamine, DBU, pyridine, picoline, quinoline and the like can be used. As the solvent, those described in the above (Production Method 1-2 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 0.5 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it is purified by recrystallization or column chromatography.
[0061]
<Production method 3>
[0062]
Embedded image
(Wherein X, Y, m and k represent the same meaning as described above.)
[0063]
The amine compound represented by the general formula [IV-1] can be reacted with methyl vinyl ketone to produce the compound represented by the general formula [IV-2].
[0064]
This reaction can be carried out without a solvent <described in Example (j)>, but the above-mentioned (Production Method 1-1 solvent) can be similarly used as a solvent. The above reaction is carried out in a nitrogen atmosphere at a temperature ranging from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0065]
Next, the compound represented by the general formula [IV-2] is reacted with the compound represented by the general formula [IV-3] to obtain a compound represented by the general formula [IV-4]. Can be manufactured <described in Example (k)>.
[0066]
As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0067]
Next, the resulting compound represented by the general formula [IV-4] is reacted in the presence of a base, followed by a dehydration reaction to produce a compound represented by the general formula [IV-5]. <As described in Example (k)>.
[0068]
As the base, those described above (Production method 1 base) can be used in the same manner. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from ice-cold temperature to 60 ° C. and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0069]
Next, the compound represented by the general formula [IV-5] thus obtained is subjected to catalytic reduction in the presence of a catalyst to produce the compound of the present invention represented by the general formula [IV] <Example ( described in l)>.
[0070]
Examples of the catalyst include palladium carbon and Raney nickel. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from the temperature under ice cooling to the boiling point of the solvent, and is completed in 0.5 to 10 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it is purified by recrystallization or column chromatography.
[0071]
<Production Method 4>
[0072]
Embedded image
(Wherein X, Y, m and k represent the same meaning as described above.)
[0073]
The compound represented by the general formula [V-1] can be reacted with methyl chlorocarbonate to produce the compound represented by the general formula [V-2] <described in Example (m)>.
[0074]
As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in a nitrogen atmosphere at a temperature ranging from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0075]
Next, the compound represented by the general formula [V-3] is reacted with methyl iodide in the presence of a base to produce the compound represented by the general formula [V-3]. <Described in Example (n)>.
[0076]
Examples of the base that can be used include inorganic bases such as sodium, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, or organic amines such as triethylamine, DBU, pyridine, picoline, and quinoline. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0077]
Next, the compound represented by the general formula [V-3] can be hydrolyzed in the presence of an acid to produce the compound represented by the general formula [V-4]. Described in Example (o)>.
[0078]
For example, sulfuric acid or hydrochloric acid can be used as the acid. As the solvent, for example, alcohols such as water, methanol and ethanol can be used. The above reaction is carried out in the range of room temperature to boiling point, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0079]
Next, the compound represented by the general formula [V-5] can be produced by reacting the compound represented by the general formula [V-4] with chloroacetyl chloride in the presence of a base. <Described in Example (p)>.
[0080]
As the base, those described above (Production method 1 base) can be used in the same manner. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from the temperature under ice cooling to the boiling point of the solvent, and is completed in 0.5 to 10 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it is purified by recrystallization or column chromatography.
[0081]
Next, the obtained compound represented by the general formula [V-5] is reacted with the compound represented by the general formula [V-6] in the presence of a base to obtain the general formula [V-7]. <Described in Example (q)> can be produced.
[0082]
As the base, those described above (Production method 1 base) can be used in the same manner. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0083]
Next, the compound represented by the general formula [V-8] can be obtained by subjecting the obtained compound represented by the general formula [V-7] to alkaline hydrolysis <Example (r) Description>.
[0084]
Examples of the base that can be used include sodium hydroxide and potassium hydroxide. As the solvent, for example, a water-soluble solvent that does not undergo hydrolysis such as dioxane, methanol, ethanol, or water can be used. The reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 0.5 to 10 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it can be purified by recrystallization or column chromatography.
[0085]
Next, the compound represented by the general formula [V-9] can be produced by reacting the compound represented by the general formula [V-8] with lithium aluminum hydride <Example (s )>.
[0086]
As the solvent, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbons such as n-hexane, benzene and toluene can be used. The above reaction is carried out in a temperature range from room temperature to the boiling point of the solvent under a nitrogen atmosphere, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0087]
Next, the compound of the present invention represented by the general formula [V] can be produced by reacting the obtained compound represented by the general formula [V-9] with phosgene in the presence of a base. Described in Example (t)>.
[0088]
As the base, those described above (manufacturing method 1 base) can be used similarly. As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from the temperature under ice cooling to the boiling point of the solvent, and is completed in 0.5 to 10 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it is purified by recrystallization or column chromatography.
[0089]
<Production method 5>
[0090]
Embedded image
(Wherein X, Y, m, n and k represent the same meaning as described above, and L ¹ and L ² represent a halogen atom.)
[0091]
Reacting a hydroxyamine derivative represented by the general formula [VI-1] with an isocyanate compound represented by the general formula [VI-2] to produce a compound represented by the general formula [VI-3]. Yes <described in Example (u)>.
[0092]
As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0093]
Next, the obtained compound represented by the general formula [VI-3] is reacted with a dihalide represented by the general formula [VI-4] in the presence of a base to represent the general formula [VI]. The compounds of the present invention can be prepared <described in Example (v) and Example (w)>.
[0094]
As the base, those described above (Production method 1 base) can be used in the same manner. As the solvent, water or the above-mentioned (Production Method 1-1 solvent) can be similarly used. The above reaction is carried out in the temperature range from the temperature under ice cooling to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0095]
<Production method 6>
[0096]
Embedded image
(Wherein X, m and R ³ represent the same meaning as described above.)
[0097]
An aldehyde compound represented by the general formula [VII-1] is reacted with a Grignard compound represented by the general formula [VII-2] or a lithium compound represented by [VII-3] to give a general formula [VII-4]. The compound represented by this can be manufactured <described in Example (x)>.
[0098]
As the solvent, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane can be used. The above reaction is carried out in a nitrogen atmosphere at a temperature ranging from −30 ° C. to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0099]
Next, the compound represented by the general formula [VII-4] obtained is reacted with dimethyl sulfoxide (DMSO) and oxalyl chloride in the presence of a base to produce the compound of the present invention represented by the general formula [VII]. <Described in Example (x)>.
[0100]
As the base, those described above (Production method 1 base) can be used in the same manner. As the solvent, for example, chlorinated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride can be used. The above reaction is carried out in the temperature range from −70 ° C. to the boiling point, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0101]
<Production method 7>
[0102]
Embedded image
(Wherein X, m, Y, k, L ¹ and L ² represent the same meaning as described above.)
[0103]
A compound represented by the general formula [VIII-3] can be produced by reacting a compound represented by the general formula [VIII-1] with a compound represented by the general formula [VIII-2] < Described in Example (y)>.
[0104]
As the solvent, those described in the above (Production method 1-1 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0105]
Next, the obtained compound represented by the general formula [VIII-3] is reacted with a dihalide represented by the general formula [VIII-4] in the presence of a base to represent the general formula [VIII]. The compounds of the present invention can be prepared <described in Example (y)>.
[0106]
As the base, those described above (Production method 1 base) can be used in the same manner. As the solvent, water or the above-mentioned (Production Method 1-1 solvent) can be similarly used. The above reaction is carried out in the temperature range from the temperature under ice cooling to the boiling point of the solvent, and is completed in 1 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method.
[0107]
<Production method 8>
[0108]
Embedded image
(Wherein X, Y, m and k represent the same meaning as described above.)
[0109]
The compound represented by the general formula [IX-1] is reacted with a peptidizing agent in the presence or absence of a base and then reacted with the compound represented by the general formula [IX-2] or a salt thereof. The compound of the present invention represented by the general formula [IX] can be produced. <Described in Example (z)>
As the peptidizing agent, the one used in Example 1 can be used in the same manner. As the base, for example, organic amines such as triethylamine, DBU, pyridine, picoline, quinoline and the like can be used. As the solvent, those described in the above (Production Method 1-2 solvent) can be used in the same manner. The above reaction is carried out in the temperature range from room temperature to the boiling point of the solvent, and is completed in 0.5 to 24 hours. The target compound can be obtained from the reaction solution by a conventional method. If necessary, it is purified by recrystallization or column chromatography.
[0110]
【Example】
Next, an Example is given and the manufacturing method, formulation method, and use of this invention compound are demonstrated concretely. In addition, the synthesis example of the intermediate body or precursor of this invention compound is also described collectively.
[0111]
<Example of Production Method 1>
[0112]
(A) Preparation of benzyl 2- (2-oxopropylamino) isobutyrate (Compound [II-3]) 84.4 g (0.437 mol) of benzyl 2-aminoisobutyrate was dissolved in 400 ml of DMF, and 88.4 g (0 .874 mol) and 60.6 g (0.655 mol) of chloroacetone were added, and the mixture was stirred at 90 ° C. for 2 hours. After allowing to cool, the reaction mixture was poured into water and extracted twice with ether. The product was treated by a conventional method to obtain 89.1 g (yield 82%) of the desired product.
[0113]
(B) Production of benzyl 2- [N- (2-oxopropyl) -N-phenylacetylamino] isobutyrate (Compound [II-4]) 89.1 g of benzyl 2- (2-oxopropylamino) isobutyrate ( 0.357 mol) was dissolved in 500 ml of acetone, and 59.3 g (0.429 mol) of potassium carbonate was added thereto. To this solution, 60.8 g (0.393 mol) of phenylacetic acid chloride was added dropwise at -10 ° C. After completion of the dropwise addition, the mixture was stirred at -10 ° C for 1 hour and then allowed to stand overnight at room temperature. The solvent was distilled off, ether was added to the residue, washed well with water, and treated by a conventional method to obtain 114.5 g (yield 87%) of the desired product.
[0114]
(C) Preparation of 2- (4-methyl-2-oxo-3-phenyl-3-pyrrolin-1-yl) isobutyric acid (compound [II-6]) 2- [N- (2-oxopropyl)- 114.5 g (0.312 mol) of benzyl N-phenylacetylamino] isobutyrate was dissolved in 500 ml of ethanol, 17.7 g (0.312 mol) of 95% sodium methoxide powder was added thereto, and the mixture was allowed to stand overnight at room temperature. To the reaction solution, 18.7 g (0.468 mol) of sodium hydroxide and 150 ml of water were added and heated under reflux for 1 hour. After distilling off ethanol, the residue was poured into ice water and extracted with ethyl acetate. The aqueous layer was taken and adjusted to pH 2-3 with hydrochloric acid. The precipitated crystals were separated by filtration, washed well with water, and then washed with isopropyl ether to obtain 47.1 g (yield 58%) of the desired product.
[0115]
(D) N- (5-chloro-4-trifluoromethylthiazol-2-yl) -2- (4-methyl-2-oxo-3-phenyl-3-pyrrolin-1-yl) -isobutyric acid amide ( Preparation of the present compound No. 1) 2- (4-Methyl-2-oxo-3-phenyl-3-pyrrolin-1-yl) isobutyric acid 1.0 g (3.9 mmol) was dissolved in 30 ml of acetonitrile, and 2- 1.08 g (4.2 mmol) of chloro-1-methylpyridinium iodide and 1.17 g (11.6 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 0.5 hour. To this reaction solution, an acetonitrile solution of 0.79 g (3.9 mmol) of 2-amino-5-chloro-4-trifluoromethylthiazole and 0.39 g (3.9 mmol) of triethylamine was dropped at room temperature, and then heated under reflux. For 17 hours. After completion of the reaction, the reaction solution was allowed to cool and acetonitrile was distilled off. The residue was poured into water and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1 → 2: 1) to obtain 0.60 g (yield 34%) of the desired product having a melting point of 217-219 ° C. Obtained.
[0116]
<Example of Production Method 2>
[0117]
(E) Preparation of ethyl 2- (3-oxobutylamino) isobutyrate (compound [III-2]) 30 ml of acetonitrile was added to 5.00 g (29.8 mmol) of ethyl 2-aminoisobutyrate and stirred. To the mixture, 3.02 g (29.8 mmol) of triethylamine was added and stirred for 30 minutes. Next, 2.19 g (31.3 mmol) of methyl vinyl ketone was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 24 hours. Ether was added to remove insoluble matters, and the filtrate was concentrated under reduced pressure to obtain 6.00 g (yield 100%) of the desired product.
[0118]
(F) Preparation of ethyl 2- (4-methyl-3-phenyl-2-oxo-1,2,3,6-tetrahydropyrimidin-1-yl) isobutyrate (compound [III-5]) 2- (3 -Oxobutylamino) ethyl isobutyrate (6.00 g, 29.8 mmol) was dissolved in dichloromethane (20 ml), and phenyl isocyanate (3.55 g, 29.8 mmol) was added dropwise thereto and stirred for 30 minutes. The solvent was distilled off, the residue was dissolved in 30 ml of ethanol, and 25% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 8, followed by stirring overnight. Saturated aqueous ammonium chloride solution was added for neutralization, and then the solvent was concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The residue was dissolved in 20 ml of benzene, further added with a dean star (glass apparatus for dehydration reaction), and heated to reflux for 12 hours. After cooling to room temperature, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to give 2.93 g of the desired product. (Yield 33%) was obtained.
[0119]
(G) Preparation of ethyl 2- (4-methyl-3-phenyl-2-oxoperhydropyrimidin-1-yl) isobutyrate (Compound [III-6]) 2- (4-Methyl-3-phenyl-2) -Oxo-1,2,3,6-tetrahydropyrimidin-1-yl) ethyl isobutyrate 2.75 g (9.09 mmol) was dissolved in 20 ml of ethanol, and 0.20 g of 10% palladium carbon was added under a nitrogen atmosphere. Thereafter, catalytic reduction reaction was performed with hydrogen gas. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to give the intended product 1 having a refractive index (20 ° C.) of 1.5249. Obtained .44 g (52% yield).
[0120]
(H) Preparation of 2- (4-methyl-3-phenyl-2-oxoperhydropyrimidin-1-yl) isobutyric acid (Compound [III-7]) 2- (4-Methyl-3-phenyl-2-) 1.27 g (4.17 mmol) of ethyl oxoperhydropyrimidin-1-yl) isobutyrate was dissolved in 15 ml of ethanol, added with 3.35 g (20.9 mmol) of 25% sodium hydroxide and heated to reflux for 1 hour. After cooling, the solvent was concentrated under reduced pressure, and the residue was dissolved in 20 ml of water and adjusted to pH 1 with concentrated hydrochloric acid. The precipitated crystals were separated by filtration to obtain 0.87 g (yield 75%) of the desired product having a melting point of 200 to 202 ° C.
[0121]
(I) N- (5-chloro-4-trifluoromethylthiazol-2-yl) -2- (4-methyl-2-oxo-3-phenylperhydropyrimidin-1-yl) isobutyric acid amide (invention) Preparation of Compound No. 72) 0.50 g (1.8 mmol) of 2- (4-methyl-2-oxo-3-phenyl-perhydropyrimidin-1-yl) isobutyric acid was dissolved in 20 ml of acetonitrile, and triethylamine 0 After dropwise addition of .82 g (8.2 mmol), 0.51 g (2.0 mmol) of 2-chloro-1-methylpyridinium iodide was further added and stirred for 1 hour. Thereafter, 0.18 g (1.8 mmol) of triethylamine and 0.34 g (1.8 mmol) of 2-amino-5-chloro-4-trifluoromethylthiazole were added, and the mixture was allowed to stand overnight at room temperature. The solvent was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, and then dried with anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 0.51 g (yield 61%) of the desired product having a melting point of 87 to 90 ° C.
[0122]
<Example of Production Method 3>
[0123]
(J) Preparation of N- (3,5-dichloro-α, α-dimethylbenzyl) -N- (3-oxobutyl) amine (compound [IV-2]) 3,5-dichloro-α, α-dimethylbenzyl To 10 g (49 mmol) of amine, 3.4 g (49 mmol) of methyl vinyl ketone was added and left under a nitrogen atmosphere for 24 hours to obtain 13.4 g (yield 100%) of the desired product.
[0124]
(K) 1- (3,5-dichloro-α, α-dimethylbenzyl) -4-methyl-3-phenyl-1,2,3,6-tetrahydropyrimidin-2-one (precursor number 4; Table 15) 6.58 g (24 mmol) of N- (3,5-dichloro-α, α-dimethylbenzyl) -N- (3-oxobutyl) amine obtained in Preparation Example (j) in 100 ml of dichloromethane was dissolved. Then, 2.86 g (24 mmol) of phenyl isocyanate was added dropwise at room temperature, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of ethanol, adjusted to pH 8 by dropwise addition of 25% aqueous sodium hydroxide solution, and stirred overnight. After neutralization by adding an aqueous ammonium chloride solution, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate and treated in a conventional manner, and then the solvent was distilled off under reduced pressure. Further, this residue was dissolved in 50 ml of benzene, subjected to Dean Stark and heated to reflux for 10 hours to carry out a dehydration reaction. After completion of the reaction, the reaction mixture is allowed to cool, and the reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give the desired product having a melting point of 147 to 148 ° C. 88 g (yield 32.4%) was obtained.
Table 15 shows specific examples of the precursors obtained by performing the same operation as in (k).
[0125]
[Table 15]
[0126]
(L) Preparation of 1- (3,5-dichloro-α, α-dimethylbenzyl) -4-methyl-2-oxo-3-phenylperhydropyrimidine (the present compound No. 81) (Dichloro-α, α-dimethylbenzyl) -4-methyl-2-oxo-3-phenyl-1,2,3,6-tetrahydropyrimidine (0.62 g, 1.7 mmol) was dissolved in 40 ml of methanol, and the reaction was conducted under a nitrogen atmosphere. After adding 0.1 g of 10% palladium carbon, catalytic reduction reaction was performed with hydrogen gas. After the reaction, palladium on carbon was filtered off, and methanol was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1), and had a melting point of 111 to 113 ° C. 0.22 g (34% yield) of the product was obtained.
[0127]
<Example of Production Method 4>
[0128]
(M) Preparation of 1-acetyl-2-methoxycarbonyl-2-phenylhydrazine (Compound [V-2]) 13.2 g (754 mmol) of 1-acetyl-2-phenylhydrazine was dissolved in 500 ml of toluene and heated under reflux. Then, 71.3 g (754 mmol) of methyl chlorocarbonate was gradually added dropwise. After completion of the dropwise addition, the mixture was further refluxed for 2 hours. After completion of the reaction, the solvent was distilled off, and the precipitated crystals were washed with isopropyl alcohol and n-hexane to obtain 148.2 g (yield 94.4%) of the desired product.
[0129]
(N) Preparation of 1-acetyl-1-methyl-2-methoxycarbonyl-2-phenylhydrazine (compound [V-3]) 1-acetyl-2-methoxycarbonyl-2-phenyl obtained in Example (m) 70 g (336 mmol) of hydrazine was dissolved in 500 ml of DMF, added dropwise to a DMF suspension of 14.8 g (370 mmol) of 60% sodium hydride, and then stirred at room temperature for 1 hour. Methyl iodide 47.7g (336mmol) was dripped at this reaction liquid, and it stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, washed with 2N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, treated in the usual manner, and 54.0 g of the desired product (yield 72.4%). Got.
[0130]
(O) Preparation of 1-methyl-2-methoxycarbonyl-2-phenylhydrazine (Compound [V-4]) 1-acetyl-1-methyl-2-methoxycarbonyl-2-phenyl obtained in Example (n) Hydrazine (54 g, 243 mmol) was suspended in 10% sulfuric acid (300 ml) and heated to reflux for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water, adjusted to neutral with a 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The product was treated by a conventional method to obtain 22.7 g (yield 52.0%) of the desired product.
[0131]
(P) Preparation of 1-chloroacetyl-1-methyl-2-methoxycarbonyl-2-phenylhydrazine (compound [V-5]) 1-methyl-2-methoxycarbonyl-2- obtained in Example (o) 25.5 g (141 mmol) of phenylhydrazine was dissolved in 200 ml of dichloromethane, 14.3 g (141 mmol) of triethylamine was added, and 16.0 g (141 mmol) of chloroacetyl chloride was gradually added dropwise under ice cooling, followed by stirring at room temperature for 3 hours. did. After completion of the reaction, the reaction mixture was poured into ice water, extracted with dichloromethane, and treated in a conventional manner. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 31.2 g of the desired product (yield 86.2%).
[0132]
(Q) Preparation Example 1- (3,5-Dichloro-α, α-dimethylbenzylaminoacetyl) -1-methyl-2-methoxycarbonyl-2-phenylhydrazine (Compound [V-7]) 6.9 g (27 mmol) of 1-chloroacetyl-1-methyl-2-methoxycarbonyl-2-phenylhydrazine obtained in 1 above was dissolved in 100 ml of DMF, and 2.74 g (27 mmol) of triethylamine and 3,5-dichloro-α, α -Dimethylbenzylamine 5.51g (27 mmol) was added, and it stirred at 70 degreeC for 11 hours. After completion of the reaction, it was poured into water and extracted with ethyl acetate. The product was treated by a conventional method to obtain 9.5 g (yield 83%) of the desired product.
[0133]
(R) Preparation of 1- (3,5-dichloro-α, α-dimethylbenzylaminoacetyl) -1-methyl-2-phenylhydrazine (compound [V-8]) 1- obtained in Example (q) 9.5 g (22 mmol) of (3,5-dichloro-α, α-dimethylbenzylaminoacetyl) -1-methyl-2-methoxycarbonyl-2-phenylhydrazine was dissolved in methanol / water (50 ml / 50 ml) and iced. Under cooling, 0.88 g (22 mmol) of sodium hydroxide was added, followed by stirring at room temperature for 24 hours. After completion of the reaction, methanol was distilled off, acidified with 2N hydrochloric acid, alkalified with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1 → 1: 2), and 1.77 g of the desired product having a melting point of 127 to 128 ° C. (yield 22.0%) )
[0134]
(S) Preparation of 1- [2- (3,5-dichloro-α, α-dimethylbenzylamino) ethyl] -1-methyl-2-phenylhydrazine (Compound [V-9]) Lithium aluminum hydride 0.31 g 1- (3,5-dichloro-α, α-dimethylbenzylaminoacetyl) -1-methyl-2-phenylhydrazine 1 obtained in Example (r) was added to a tetrahydrofuran suspension to which (8.2 mmol) was added. A solution of 0.5 g (4.1 mmol) in 50 ml of tetrahydrofuran was added dropwise at room temperature, and the mixture was stirred for 4 hours while heating under reflux. After completion of the reaction, the reaction solution was allowed to cool, water was gradually added, the mixture was filtered, and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 0.89 g of the desired product (yield 62%).
[0135]
(T) Preparation of 4- (3,5-dichloro-α, α-dimethylbenzyl) -1-methyl-3-oxo-2-phenylperhydro-1,2,4-triazine (Compound No. 102 of the present invention) Diphosgene 0.79g (4.0mmol) was dripped at the dichloromethane suspension of activated carbon, and it stirred at room temperature for 1 hour. The reaction solution was filtered off, and the filtrate was filtered with 0.7 g (2.0 mmol) of 1- [2- (3,5-dichloro-α, α-dimethylbenzylamino) ethyl] -1-methyl-2-phenylhydrazine. And 1.21 g (12.0 mmol) of triethylamine was added dropwise to a dichloromethane solution, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water, extracted with dichloromethane, and treated in a conventional manner. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain 0.29 g (yield 38%) of the desired product having a melting point of 102 to 103 ° C.
[0136]
<Example of Production Method 5>
[0137]
(U) Preparation of 1- (3,5-dichloro-α, α-dimethylbenzyl) -3-hydroxy-3-phenylurea (compound [VI-3]) 1.2 g (11.0 mmol) of N-phenylhydroxyamine ) Was dissolved in 30 ml of benzene, and 3.84 g (17.0 mmol) of 3,5-dichloro-α, α-dimethylbenzyl isocyanate was added dropwise, followed by stirring at room temperature for 1 hour. The precipitated crystals were separated by filtration and washed with n-hexane to obtain 3.01 g (yield 52.4%) of the desired product.
[0138]
(V) Preparation of 4- (3,5-dichloro-α, α-dimethylbenzyl) -3-oxo-2-phenyl-1,2,4-oxadiazolidine (Compound No. 115 of the present invention) 0.96 g (2.8 mmol) of 5-dichloro-α, α-dimethylbenzyl) -3-hydroxy-3-phenylurea was dissolved in 20 ml of DMF, and this was dissolved in 0.25 g (6.1 mmol) of 60% sodium hydride. After dropwise addition to the DMF suspension, the mixture was stirred at room temperature for 1 hour. To this reaction solution, a DMF solution of 0.42 g (3.2 mmol) of chlorobromomethane was added dropwise and stirred at 50 ° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, and treated by a conventional method. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 → 8: 1) to obtain 70 mg (yield 7.1%) of the desired product having a melting point of 102 to 103 ° C.
[0139]
(W) Preparation of 4- (3,5-dichloro-α, α-dimethylbenzyl) -3-oxo-2-phenylperhydro-1,2,4-oxadiazine (Compound No. 116 of the present invention) 1- (3 , 5-dichloro-α, α-dimethylbenzyl) -3-hydroxy-3-phenylurea (1.0 g, 2.9 mmol) was dissolved in 20 ml of DMF, and this was dissolved in 0.25 g (6.3 mmol) of 60% sodium hydride. Was added dropwise to the DMF suspension and stirred at room temperature for 1 hour. To this reaction solution, a DMF solution of 0.62 g (4.4 mmol) of 1-chloro-2-bromoethane was added dropwise and stirred at 80 ° C. for 6 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, and treated by a conventional method. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 → 4: 1) to obtain 0.15 g (yield 14%) of the desired product having a melting point of 125 to 127 ° C.
[0140]
<Example of Production Method 6>
[0141]
(X) Preparation of 1- [1-methyl-1- (2-thenoyl) ethyl] -4-methyl-2-oxo-3-phenyl-3-pyrroline (Compound No. 130 of the present invention) 2-Oxo-3-phenyl-3-pyrrolin-1-yl) isobutyraldehyde 2.0 g (8.2 mmol) was dissolved in 50 ml of tetrahydrofuran, and 2.7 g (17 mmol) of 2-bromothiophene at room temperature under a nitrogen atmosphere. And a solution prepared from 0.5 g (21 mmol) of magnesium was added dropwise. After standing overnight, the reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. Treatment in a conventional manner yielded 2.5 g of an oil. Next, to a solution of 1.1 g (8.7 mmol) of oxalyl chloride in 30 ml of dichloromethane was added dropwise a solution of 0.7 g (9.0 mmol) of dimethylsulfoxide in 1 ml of dichloromethane at −60 ° C., and the mixture was stirred at −60 ° C. for 5 minutes. . Subsequently, a 20 ml dichloromethane solution of the above oil was added dropwise at -60 ° C. After dropping, the mixture was stirred for 30 minutes, and 4.0 g (40 mmol) of triethylamine was further added dropwise. After dropping, the temperature was gradually returned to room temperature, and then the solvent was distilled off and extracted with ethyl acetate. It processed by the conventional method and obtained 0.5 g (yield 19%) of target objects with melting | fusing point 188-191 degreeC.
[0142]
<Example of Production Method 7>
[0143]
(Y) Production of 1- (3-chloro-α, α-dimethylbenzyl) -3-phenyl-1,3-perhydrodiazepin-2-one (present compound number 209) 1.69 g of α, α-dimethylbenzylamine and 10 ml of isopropyl ether were added, 1.19 g of phenyl isocyanate was added at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the precipitated crystals were collected by filtration to obtain 2.70 g of 1- (3-chloro-α, α-dimethylbenzyl) -3-phenylurea (yield 94%).
[0144]
Next, 2.0 g of the obtained 1- (3-chloro-α, α-dimethylbenzyl) -3-phenylurea, 15 ml of DMF, and 60% sodium hydride were placed in a reaction flask and stirred at room temperature for 30 minutes. 1,8-dichlorobutane 0.88 g was added and stirred at room temperature for 1 hour. The mixture was further stirred at 90 ° C. for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain 0.90 g of the desired product (yield 38 %).
[0145]
<Example of Production Method 8>
[0146]
(Z) N- (thiazol-2-yl) -2- [6-methyl-4-oxo-5- (2-fluoro-phenyl) -2,3-dihydro-4H-1,3-oxazine-3- L] Preparation of isobutyric acid amide (Compound No. 218 of the present invention) 2- (6-Methyl-4-oxo-5-phenyl-2,3-dihydro-4H-1,3-oxazin-3-yl) isobutyric acid 1 40 ml of acetonitrile was added to 0.000 g (3.41 mmol), 1.38 g (13.6 mmol) of triethylamine was added dropwise thereto, and 0.96 g (3.75 mmol) of 2-chloro-1-methylpyridinium iodide was further added. Stir for 1 hour. Thereafter, 0.34 g (3.41 mmol) of triethylamine and 0.34 g (3.41 mmol) of 2-aminothiazole were added, and the mixture was allowed to stand overnight at room temperature. The solvent was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, and then dried with anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 0.84 g of the desired product having a melting point of 163 to 164 ° C. (yield 66%).
[0147]
The herbicide of the present invention comprises a cyclic amide derivative represented by the general formula [I] as an active ingredient.
[0148]
In order to use the compound of the present invention as a herbicide, the compound of the present invention may be used as such, but it contains a carrier, surfactant, dispersant or auxiliary agent generally used for formulation, It can also be used in the form of wettable powders, emulsions, fine granules or granules.
[0149]
Examples of carriers used for formulation include talc, bentonite, clay, kaolin, diatomaceous earth, white carbon, vermiculite, calcium carbonate, slaked lime, silica sand, ammonium sulfate, urea and other solid carriers, isopropyl alcohol, xylene, cyclohexane, methylnaphthalene, etc. Liquid carriers and the like.
[0150]
Surfactants and dispersants include, for example, alkylbenzene sulfonic acid metal salts, dinaphthylmethane disulfonic acid metal salts, alcohol sulfate esters, alkylaryl sulfonate formalin condensates, lignin sulfonates, polyoxyethylene glycol ethers, Examples thereof include oxyethylene alkyl aryl ether and polyoxyethylene sorbitan monoalkylate. Examples of the auxiliary agent include carboxymethyl cellulose, polyethylene glycol, gum arabic and the like. In use, dilute to an appropriate concentration and spray or apply directly.
[0151]
The herbicide of the present invention can be used by foliage application, soil application or water surface application. The blending ratio of the active ingredient is appropriately selected as necessary, but in the case of powder or granule, it is appropriately selected from the range of 0.05 to 20% (weight), preferably 0.1 to 10% (weight). It is good. In the case of emulsions and wettable powders, the content is suitably selected from the range of 0.5 to 50% (weight), preferably 1 to 30% (weight).
[0152]
The application rate of the herbicide of the present invention varies depending on the type of compound used, the target weed, the tendency to occur, the environmental conditions and the dosage form to be used, but when used as it is like powders and granules, as an active ingredient It is preferable to appropriately select from the range of 0.1 g to 1 kg, preferably 1 g to 500 g per 10 ares. When used in a liquid state as in the case of emulsions and wettable powders, it is appropriate to select from the range of 0.1 to 50,000 ppm, preferably 10 to 10,000 ppm.
[0153]
Moreover, you may mix the compound of this invention with an insecticide, a fungicide, another herbicide, a plant growth regulator, a fertilizer, etc. as needed.
[0154]
Next, the preparation method will be specifically described with reference to typical preparation examples. The types and compounding ratios of the compounds and additives are not limited to these and can be changed in a wide range. In the following description, “parts” means parts by weight.
[0155]
<Formulation Example 1> 10 parts of the wettable powder compound (129), 0.5 parts of polyoxyethylene octylphenyl ether, 0.5 parts of β-naphthalenesulfonic acid formalin condensate sodium salt, 20 parts of diatomaceous earth, clay 69 parts are mixed and ground to obtain a wettable powder.
<Formulation Example 2> 10 parts of the wettable powder compound (81), 0.5 parts of polyoxyethylene octylphenyl ether, 0.5 parts of β-naphthalenesulfonic acid formalin condensate sodium salt, 20 parts of diatomaceous earth, white 5 parts of carbon and 64 parts of clay are mixed and ground to obtain a wettable powder.
<Formulation example 3> 10 parts of the wettable powder compound (84), 0.5 parts of polyoxyethylene octylphenyl ether, 0.5 parts of β-naphthalenesulfonic acid formalin condensate sodium salt, 20 parts of diatomaceous earth, white 5 parts of carbon and 64 parts of calcium carbonate are mixed and ground to obtain a wettable powder.
<Formulation Example 4> 30 parts of the emulsion compound (85) were mixed with 60 parts of an equal amount mixture of xylene and isophorone, 10 parts of a mixture of surfactant polyoxyethylene sorbitan alkylate, polyoxyethylene alkylaryl polymer and alkylaryl sulfonate. In addition, an emulsion is obtained by thoroughly stirring them.
<Formulation Example 5> 10 parts of the granule compound (207), 80 parts of a bulking agent obtained by mixing talc and bentonite in a ratio of 1: 3, 5 parts of white carbon, surfactant polyoxyethylene sorbitan alkylate, poly 10 parts of water was added to 5 parts of a mixture of oxyethylene alkylaryl polymer and alkylaryl sulfonate, and kneaded well into a paste to extrude it through a sieve hole with a diameter of 0.7 mm and dried to a length of 0.5 to 1 mm. Cut into pieces to obtain granules.
[0156]
Next, effects of the compound of the present invention will be described with reference to test examples.
[0157]
<Test Example 1> Herbicidal effect test by paddy paddy treatment Filled with 100 cm ² plastic pot with paddy soil, and after seeding, seeds of Tainubie (Ec), Konagi (Mo) and Firefly (Sc) were sown. Water was flooded to a depth of 3 cm. The next day, the wettable powder prepared according to Formulation Example 1 was diluted with water and dropped onto the water surface. The application rate was 100 g per 10 ares of active ingredient. Then, it grew in the greenhouse and investigated the herbicidal effect according to the criteria of Table 16 on the 21st day after the treatment. The results are shown in Tables 17-21.
[0158]
[Table 16]
[0159]
[Table 17]
[0160]
[Table 18]
[0161]
[Table 19]
[0162]
[Table 20]
[0163]
[Table 21]
[0164]
<Test Example 2> Herbicidal effect test by upland soil treatment 120 cm ² Plastic pot was filled with sand and seeded with various seeds of fly (Ec), barnyard (Di), Aobaille (Am), and Kogomegatsuri (Ci). . The wettable powder prepared according to Formulation Example 1 was diluted with water, and 100 l per 10 ares were uniformly sprayed on the soil surface with a small sprayer so that the active ingredient per 10 ares was 100 g. Then, it grew in the greenhouse and investigated the herbicidal effect according to the criteria of Table 16 on the 21st day of treatment. The results are shown in Tables 22 to 26.
[0165]
[Table 22]
[0166]
[Table 23]
[0167]
[Table 24]
[0168]
[Table 25]
[0169]
[Table 26]
[0170]
<Test example 3> Herbicidal effect test by upland foliage treatment 120 cm ² Plastic pot is filled with sand, seedlings of fly (Ec), barnyard (Di), Aobaille (Am), Kogomegatsuri (Ci) are seeded, and in the greenhouse After 2 weeks of growth, the wettable powder prepared in accordance with Formulation Example 1 is diluted with water, and 100 l per 10 ares are added to the whole from above the plant body with a small sprayer so that the active ingredient per 10 ares is 100 g. The foliage was sprayed. Then, it grew in the greenhouse and investigated the herbicidal effect according to the standard of Table 16 on the 14th day of treatment. The results are shown in Tables 27 to 28.
[0171]
[Table 27]
[0172]
[Table 28]
[0173]
<Test Example 4> Crop selectivity test by paddy paddy treatment Paddy soil is filled in a 100 cm ² plastic pot, and after cutting, various children of Tainubie (Ec), Konagi (Mo), and Firefly (Sc) are set to 0. The seedlings were sown to a depth of 5 cm, and two rice plants (Or) at the second leaf stage were transplanted at a transplantation depth of 2 cm and submerged at a depth of 3 cm. On the next day, a predetermined active ingredient amount (ai, g / 10a) of a wettable powder prepared according to Formulation Example 1 was diluted with water and dropped onto the water surface. Then, it grew in the greenhouse and investigated the herbicidal effect according to the standard of Table 16 on the 28th day after the treatment. The results are shown in Table 29 to Table 34.
[0174]
[Table 29]
[0175]
[Table 30]
[0176]
[Table 31]
[0177]
[Table 32]
[0178]
[Table 33]
[0179]
[Table 34]
[0180]
<Test Example 5> Crop selectivity test by upland soil treatment 600 cm ² Plastic pot is filled with sand, rice (Or), wheat (Tr), edible shrimp (Ec), barb (Di), enokorogusa (Se), Johnson Various seeds of glass (So) were seeded and covered with soil. On the next day, the predetermined active ingredient amount (ai, g / 10a) of the wettable powder prepared according to Formulation Example 1 was diluted with water and uniformly sprayed on the soil surface with a spraying amount of 100 l per 10 ares using a small sprayer. . Then, it grew in the greenhouse and investigated the herbicidal effect according to the criteria of Table 16 on the 21st day after the treatment. The test results are shown in Table 35.
[0181]
[Table 35]
[0182]
<Test Example 6> Crop selectivity test by upland soil treatment 600 cm ² Plastic pot is filled with sand, soybean (Gl), cotton (Go), beet (Be), edible shrimp (Ec), barb (Di), enokorogusa (Se), various kinds of Johnson glass (So) were seeded and covered with soil. On the next day, the predetermined active ingredient amount (ai, g / 10a) of the wettable powder prepared according to Formulation Example 1 was diluted with water and uniformly sprayed on the soil surface with a spraying amount of 100 l per 10 ares using a small sprayer. . Then, it grew in the greenhouse and investigated the herbicidal effect according to the criteria of Table 16 on the 21st day after the treatment. Test results are shown in Tables 36-37.
[0183]
[Table 36]
[0184]
[Table 37]
[0185]
<Test Example 7> Crop selectivity test by upland foliage treatment 600 cm ² Plastic pot is filled with sand, soybean (Gl), cotton (Go), beet (Be), edible shrimp (Ec), barb (Di), enokorogusa Various seeds of (Se) and Johnson glass (So) were seeded and covered with soil, and grown in a greenhouse for 2 weeks. Thereafter, the predetermined active ingredient amount (ai, g / 10a) of the wettable powder prepared according to Formulation Example 1 was diluted with water and uniformly sprayed on the soil surface with a spraying amount of 100 l per 10 ares using a small sprayer. . Then, it grew in the greenhouse and investigated the herbicidal effect according to the criteria of Table 16 on the 14th day after the treatment. The test results are shown in Table 38.
[0186]
[Table 38]
[0187]
【The invention's effect】
The compound of the present invention represented by the general formula [I] is a low-dose control of annual weeds such as Tainubie, Tamagayatsu, Kogi, etc., and perennial weeds such as Urikawa, Omodaka, Mitsugayatsuri, Krogwei, Firefly, and Heramodaka. can do. At the same time, it has high safety against rice. In addition, various weeds that are problematic in the field, such as grasses such as barnyard millet, barnyard grass, green foxtail, hornbill, Johnson grass, hornbill, wild oats, perennials and annuals, such as humus geese, yellow mussels, cygnus crickets, red crocodiles, etc. It shows excellent herbicidal activity in soil treatment and foliage treatment against broad-leaved weeds such as family weeds, euphorbiaceae, abalone, shiroza, chickweed, etc., and can suppress the occurrence of weeds over a wide period of growth period before weeds emerged . And it has high safety against crops, and especially high safety against rice, wheat, barley, corn, grain sorghum, soybean, cotton and beet.

Claims (2)

General formula
(Wherein X represents a hydrogen atom or a fluorine atom) . A herbicide for paddy rice containing the cyclic amide derivative according to claim 1 as an active ingredient.