CN112390725B - Preparation method of amide compound - Google Patents

Preparation method of amide compound Download PDF

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CN112390725B
CN112390725B CN201910756573.XA CN201910756573A CN112390725B CN 112390725 B CN112390725 B CN 112390725B CN 201910756573 A CN201910756573 A CN 201910756573A CN 112390725 B CN112390725 B CN 112390725B
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alkyl
cycloalkyl
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methyl
acid
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CN112390725A (en
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王刚
王徵
连伟祥
郝泽生
金守征
关云飞
杨辉斌
李斌
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Shenyang Sinochem Agrochemicals R&D Co Ltd
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Abstract

A method for preparing benzamide compounds shown as a general formula (I) relates to an application of oxime carboxylate compounds as bactericides, and the reaction formula is as follows:

Description

Preparation method of amide compound
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of an amide compound.
Background
The amide compounds have certain bactericidal activity, and CN104649973A discloses that the compounds shown in the following general formula have good bactericidal activity on rice sheath blight disease.
Figure GDA0003259218960000011
CN104649973A discloses a preparation method of two amide compounds simultaneously: reacting a 3-difluoromethyl pyrazole acyl chloride compound with substituted aniline under an alkaline condition to obtain a target product; reacting hydroxybenzamide compounds with bromopentane under an alkaline condition to obtain a target product. However, the two methods have the key process problems of high price of reaction raw materials, more three wastes in reaction, difficult treatment, low yield and the like. So far, technicians are dedicated to continuously research and develop new, more advanced, more reasonable and more environment-friendly preparation methods so as to obtain high-efficiency and safe bactericides with better quality and lower price.
Disclosure of Invention
One of the purposes of the invention is to provide a novel method for preparing amide compounds with lower cost and more environmental protection.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of amide compounds (shown in a general formula I) comprises the steps of carrying out condensation reaction on acyl halide (II) and substituted oxime carboxylate (III) in a proper solvent to obtain the amide compounds shown in the general formula I; the reaction formula is as follows:
Figure GDA0003259218960000012
in the formula:
R1selected from the group consisting of a phenyl ring, a 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms or a 5 or 6 membered heterocyclic ring wherein the hydrogen on the phenyl ring or heterocyclic ring may be replaced by one or more of the same or different R5Substitution;
R2is selected from H or C1-C12Alkyl groups of (a);
R3is selected from C1-C12Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Cycloalkyl of (C)1-C6Alkyl radical, C3-C6Halogenocycloalkyl or C3-C6Cycloalkyl of (C)3-C6Cycloalkyl groups of (a);
R4is selected from C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Cycloalkyl of (C)1-C6Alkyl radical, C3-C6Halogenocycloalkyl of (A), C1-C6Alkoxy radical C of1-C6Alkyl of (C)1-C6Of (2)Alkoxy radicals C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)3-C6Cycloalkoxy of (A), C3-C6Halogenocycloalkoxy of (A), C3-C6Cycloalkyl of (C)1-C6An alkoxy group of (a) a phenyl ring, a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms or a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms, wherein hydrogen on the phenyl ring or the heterocyclic ring may be replaced by one or more identical or different R5Substitution;
R5selected from halogen, nitro, cyano, C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Halogenocycloalkyl of (A), C1-C6Alkoxy radical C of1-C6Alkyl of (C)1-C6Halogenoalkoxy group C of1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)3-C6Cycloalkoxy of (A), C3-C6Halogenocycloalkoxy or C3-C6Cycloalkyl of (C)1-C6Alkoxy group of (a);
l represents a leaving group.
In a further aspect of the present invention,
the charging molar ratio of the acyl halide compound shown in the general formula (II) to the substituted oxime carboxylate (III) is 1: 0.8 to 1.5, and carrying out condensation reaction in a proper solvent at the temperature of between 10 ℃ below zero and the boiling point of the proper solvent for 0.5 to 8 hours to obtain the amide compound shown in the general formula I. (amount of solvent added)
The solvent is selected from dichloromethane, chloroform, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, butanone, N-dimethylformamide or dimethyl sulfoxide.
In a still further aspect of the present invention,
the charging molar ratio of the acyl halide compound shown in the general formula (II) to the substituted oxime carboxylate (III) is 1: 0.8 to 1.5, and carrying out condensation reaction in a proper solvent at the temperature of between 10 ℃ below zero and the boiling point range of the proper solvent and under the pressure of between 0.1MPa and 0.01MPa for 0.5 to 8 hours to obtain the amide compound shown in the general formula I.
In particular to
The charging molar ratio of the acyl halide compound shown in the general formula (II) to the substituted oxime carboxylate (III) is 1: 0.8 to 1.5, adding proper acid into proper solvent at the temperature of between 10 ℃ below zero and the boiling point of the proper solvent and under the pressure of between 0.1MPa below zero and 0.01MPa below zero, and carrying out condensation reaction for 0.5 to 8 hours to obtain the amide compound shown in the general formula I.
The acid is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid.
The charging molar ratio of the acyl halide compound shown in the general formula (II) to the substituted oxime carboxylate (III) is 1: 0.9 to 1.2, adding proper acid in proper solvent in the absence of acid-binding agent, at the temperature of between 20 ℃ and the boiling point range and under the pressure of between-0.05 MPa and-0.01 MPa, and carrying out condensation reaction for 0.5 to 4 hours to obtain the amide compound; wherein the solvent is selected from toluene or acetonitrile; the acid is selected from hydrochloric acid, sulfuric acid or p-methanesulfonic acid, and the feeding molar ratio of the acid to the substituted oxime carboxylate (III) is 0.01-0.5: 1.
an oxime carboxylate compound for preparing amide compounds shown as a general formula I is shown as a general formula III:
Figure GDA0003259218960000031
in the formula:
R2is selected from H or C1-C12Alkyl groups of (a);
R3is selected from C1-C12Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Cycloalkyl of (C)1-C6Alkyl radical, C3-C6Halogenocycloalkyl or C3-C6Cycloalkyl of (C)3-C6Cycloalkyl groups of (a);
R4is selected from C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Cycloalkyl of (C)1-C6Alkyl radical, C3-C6Halogenocycloalkyl of (A), C1-C6Alkoxy radical C of1-C6Alkyl of (C)1-C6Halogenoalkoxy group C of1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)3-C6Cycloalkoxy of (A), C3-C6Halogenocycloalkoxy of (A), C3-C6Cycloalkyl of (C)1-C6An alkoxy group of (a) a phenyl ring, a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms or a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms, wherein hydrogen on the phenyl ring or the heterocyclic ring may be replaced by one or more identical or different R5Substitution;
R5selected from halogen, nitro, cyano, C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Halogenocycloalkyl of (A), C1-C6Alkoxy radical C of1-C6Alkyl of (C)1-C6Halogenoalkoxy group C of1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)3-C6Cycloalkoxy of (A), C3-C6Halogenocycloalkoxy or C3-C6Cycloalkyl of (C)1-C6Alkoxy group of (2).
Further, in the formula:
R2is selected from H or C1-C6Alkyl groups of (a);
R3is selected from C1-C8Alkyl groups of (a);
R4selected from the group consisting of a benzene ring, a 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms, wherein the hydrogen on the benzene ring or the heterocyclic ring isBy one or more R, which may be the same or different5Substitution;
R5selected from halogen, nitro, cyano, C1-C3Alkyl or C1-C3A haloalkyl group of (a).
More particularly, in the formula:
R2is selected from H or C1-C3Alkyl groups of (a);
R3is selected from C1-C6Alkyl groups of (a);
R4selected from benzene, furan, thiophene, pyrrole, pyrazole, oxazole, isoxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine, benzoxazole, benzothiazole, quinoxaline, quinazoline, the hydrogen of the above ring can be replaced by one or more same or different R5Substitution;
R5selected from fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C3Alkyl or C1-C3A haloalkyl group of (a).
Table 1 Structure and physical Properties of part of the Compounds of formula III
Figure GDA0003259218960000032
Figure GDA0003259218960000041
Figure GDA0003259218960000051
Figure GDA0003259218960000061
Figure GDA0003259218960000071
The invention has the advantages that:
in the preparation process, acyl halide (II) and substituted oxime carboxylate (III) are selected to carry out condensation reaction in a proper solvent to prepare the amide compound shown in the general formula I, compared with the original reaction of acyl chloride and amine, the use of aniline which is high in price and difficult in raw material obtaining is avoided, and the obvious cost reduction effect is achieved (the cost of the route provided by the invention is about 100 ten thousand yuan, and the cost of the method according to the existing reaction of acyl chloride and amine is about 200 ten thousand yuan), the use of an acid binding agent is avoided, the pollution to the environment is reduced, and the safety of the reaction is improved.
Meanwhile, the amide compound prepared by the invention has high bactericidal activity, and the carboxylic oxime ester compound shown in the general formula III related in the preparation process can also be used for preparing amide bactericides.
Detailed Description
The following synthetic examples may be used to further illustrate the invention, but are not meant to limit the invention.
Example 1
Synthesis of 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-benzoyl oxime (Table 1 Compounds III-68)
(1) Synthesis of 2- [ (dimethylamino) methylene ] -1, 3-cyclohexanedione
Figure GDA0003259218960000081
Methanol (200.0g), dimethylamine solution (112.8g, 40%) and 1, 3-cyclohexanedione (56.0g) were added to a three-necked flask with a mechanical stirring device, stirred at room temperature for 30min, cooled to 0-10 ℃, and formaldehyde solution (88.3g, 37%) was slowly dropped and stirred for 5h to give 2- [ (dimethylamino) methylene ] -1, 3-cyclohexanedione, which was used directly in the next step.
(2) Synthesis of 2-methyl-1, 3-cyclohexanedione
Figure GDA0003259218960000082
Transferring the reaction solution to a high-pressure reaction kettle, adding a palladium-carbon catalyst (5.6g, 10 percent), and reacting for 8 hours under the conditions of 2MPa and 30 ℃. The reaction mixture was taken out, the catalyst was filtered off, 200g of water were added, methanol was distilled off, and the pH was adjusted to 6 with concentrated hydrochloric acid. A large amount of solid is separated out, filtered by suction and dried to obtain 51.7g of 2-methyl-1, 3-cyclohexanedione, and the yield is as follows: 80% (calculated by 1, 3-cyclohexanedione), and the purity of the product is 97.5% by liquid phase detection.
(3) Synthesis of 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one
Figure GDA0003259218960000083
2-methyl-1, 3-cyclohexanedione (12.9g), toluene (200mL), 2-pentanol (72.1g), p-toluenesulfonic acid monohydrate (2.0g) were added to a three-necked flask with a water-dividing device, and the mixture was heated to reflux temperature for 4 hours. Cooling to room temperature, adding NaHCO3(11.2g) saturated aqueous solution, and the layers were separated. And carrying out decompression desolventizing on the oil layer. 18.1g of intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one was obtained in yield: 90% (calculated as 2-methyl-1, 3-cyclohexanedione).
(4) Synthesis of 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one oxime
Figure GDA0003259218960000084
2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one (19.6g), hydroxylamine hydrochloride (13.9g), sodium acetate (32.8g), anhydrous methanol (200mL), and water (20mL) were added to a reaction flask, and the mixture was heated to 80 ℃ for reaction for 4 hours. The reaction mixture was cooled to below 10 ℃ and 200mL of water was added. At this time, a large amount of solid is separated out, filtration is carried out, and a filter cake is rinsed by ice water and dried. To obtain 11.6g of intermediate 2-methyl-3- (2-pentoxy) cyclohex-2-en-1-one oxime with the quantitative content of 98 percent and the yield: 54% (calculated as 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one).
(5) Synthesis of 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-benzoyl oxime
Figure GDA0003259218960000091
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one oxime (21.1g), triethylamine (10.1g), and toluene (200mL) were added to a reaction flask, to which benzoyl chloride (14.1g) was added dropwise, followed by stirring at room temperature for 3 hours after completion of dropwise addition. The reaction solution was cooled to room temperature, and water (100mL) was added thereto, followed by stirring at this temperature for 30min and then separation. The oil layer is desolventized to obtain 31.2g of intermediate 2-methyl-3- (2-pentoxy) cyclohex-2-en-1-one-O-benzoyl oxime, and the yield is as follows: 99% (calculated as 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one oxime).
Example 2
Synthesis of 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-pivaloyl oxime (Table 1 Compounds III-67)
Figure GDA0003259218960000092
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one oxime (21.1g), triethylamine (10.1g), and toluene (200mL) were added to a reaction flask, pivaloyl chloride (12.1g) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours after dropwise addition. The reaction solution was cooled to room temperature, and water (100mL) was added thereto, followed by stirring at this temperature for 30min and then separation. Desolventizing the oil layer to obtain 28.4g of intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-pivaloyl oxime, yield: 96% (calculated as 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one oxime).
Example 3
Synthesis of 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-acetyloxime (Table 1 Compounds III-65)
Figure GDA0003259218960000093
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one oxime (21.1g), triethylamine (10.1g), and toluene (200mL) were added to a reaction flask, to which acetyl chloride (7.9g) was added dropwise, followed by stirring at room temperature for 3 hours after completion of the addition. The reaction solution was cooled to room temperature, and water (100mL) was added thereto, followed by stirring at this temperature for 30min and then separation. The oil layer is desolventized to obtain 24.8g of intermediate 2-methyl-3- (2-pentoxy) cyclohex-2-en-1-one-O-acetyloxime, and the yield is as follows: 98% (calculated as 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one oxime).
Example 4
Synthesis of 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O- (1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid) oxime (Table 1, Compounds III-87)
Figure GDA0003259218960000094
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one oxime (21.1g), triethylamine (10.1g), and toluene (200mL) were charged into a reaction flask, and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride (19.5g) was added dropwise thereto, followed by stirring at room temperature for 1 hour after completion of the dropwise addition. The reaction solution was cooled to room temperature, and water (100mL) was added thereto, followed by stirring at this temperature for 30min and then separation. The oil layer was desolventized to give 36.0g of intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O- (1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid) oxime, yield: 97% (calculated on 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one oxime).
Example 5
Synthesis of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide (Compound I-315 of Table 2)
Figure GDA0003259218960000101
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-benzoyl oxime (31.5g, synthesis procedure see example 1) was added to the reaction flask, a toluene solution (100mL) of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbonyl chloride (20.4g) was added to the reaction initially and rapidly dropwise, methanesulfonic acid (1.0g) was added, the reaction was slowly warmed to 110 ℃ and evacuated to-0.04 MPa and reacted at this temperature for 4H. The reaction was cooled to room temperature, and then water (100mL) and an aqueous solution of NaOH (16.8g, 33%) were added thereto, and the mixture was stirred at this temperature for 30min and then the layers were separated. The oil layer was desolventized, and the residue was recrystallized from methanol water to give 25.9g of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide, yield: 73.8 percent.
Example 6
Synthesis of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide (Compound I-315 of Table 2)
Figure GDA0003259218960000102
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-pivaloyl oxime (29.5g, synthesis procedure see example 2) was added to a reaction flask, a toluene solution (100mL) of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbonyl chloride (20.4g) was added to the reaction initially and rapidly dropwise, methanesulfonic acid (1.0g) was added, the reaction was slowly warmed to 110 ℃ and evacuated to-0.04 MPa, and reacted at this temperature for 4H. The reaction was cooled to room temperature, and then water (100mL) and an aqueous solution of NaOH (16.8g, 33%) were added thereto, and the mixture was stirred at this temperature for 30min and then the layers were separated. The oil layer was desolventized, and the residue was recrystallized from methanol water to give 18.4g of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide in yield: 52.4 percent.
Example 7
Synthesis of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide (Compound I-315 of Table 2)
Figure GDA0003259218960000111
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-acetyloxime (25.3g, synthesis procedure see example 3) was added to the reaction flask, to this reaction was started the quick dropwise addition of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbonyl chloride (20.4g) in toluene (100mL), methanesulfonic acid (1.0g) was added, the reaction was slowly warmed to 110 ℃ and evacuated to-0.04 MPa and reacted at this temperature for 4H. The reaction was cooled to room temperature, and then water (100mL) and an aqueous solution of NaOH (16.8g, 33%) were added thereto, and the mixture was stirred at this temperature for 30min and then the layers were separated. The oil layer was desolventized, and the residue was recrystallized from methanol water to give 16.9g of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide in yield: 48.1 percent.
Example 8
Synthesis of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide (Compound I-315 of Table 2)
Figure GDA0003259218960000112
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O- (1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid) oxime (36.0g, synthesis procedure see example 4) was added to a reaction flask, 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid chloride (19.5g) in toluene (100mL) was initially added quickly to the reaction, methanesulfonic acid (1.0g) was added, the reaction was slowly warmed to 100 ℃ and evacuated to-0.03 MPa and reacted at this temperature for 2H, followed by 2H reaction with removal of vacuum. The reaction solution was cooled to room temperature, and then an aqueous solution (120mL) of NaOH (8.8g) was added thereto, and the mixture was stirred at this temperature for 30min and then the layers were separated. The aqueous layer was back-extracted with toluene (50mL) to synthesize an oil layer and desolventized to give an oily product. The product was recrystallized from 2 times the weight of the oily product in methanol water (85%) to give 20.7g of a solid product in 56% yield.
Example 9
Synthesis of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide (Compound I-315 of Table 2)
Figure GDA0003259218960000113
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-benzoyl oxime (31.5g, synthesis procedure see example 1) was added to the reaction flask, a toluene solution (100mL) of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbonyl chloride (20.4g) was added to the reaction initially and rapidly dropwise, methanesulfonic acid (1.0g) was added, the reaction was slowly warmed to 80 ℃ and evacuated to-0.05 MPa, and reacted at this temperature for 4H. The reaction solution was cooled to room temperature, and 100mL of water and an aqueous solution of NaOH (16.8g, 33%) were added thereto, and the mixture was stirred at this temperature for 30min and then the layers were separated. The oil layer was desolventized, and the residue was recrystallized from methanol water to give 21.8g of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide in yield: 62.1 percent.
Example 10
Synthesis of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide (Compound I-315 of Table 2)
Figure GDA0003259218960000121
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-benzoyl oxime (31.5g, synthesis procedure see example 1) was added to the reaction flask, a toluene solution (100mL) of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbonyl chloride (20.4g) was added to the reaction initially and rapidly dropwise, methanesulfonic acid (1.0g) was added, the reaction was slowly warmed to 80 ℃ and evacuated to-0.01 MPa, and reacted at this temperature for 4H. The reaction was cooled to room temperature, and then water (100mL) and an aqueous solution of NaOH (16.8g, 33%) were added thereto, and the mixture was stirred at this temperature for 30min and then the layers were separated. The oil layer was desolventized, and the residue was recrystallized from methanol water to give 19.3g of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide in yield: 55.0 percent.
Example 11
Synthesis of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide (Compound I-315 of Table 2)
Figure GDA0003259218960000122
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-benzoyl oxime (31.5g, synthesis procedure see example 1) was added to the reaction flask, to this reaction was started the rapid dropwise addition of a solution of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbonyl chloride (20.4g) in acetonitrile (100mL), methanesulfonic acid (1.0g) was added, the reaction was slowly warmed to 110 ℃ and evacuated to-0.04 MPa and reacted at this temperature for 4H. The reaction was cooled to room temperature, most of the acetonitrile was evaporated and dissolved in toluene, and then water (100mL) and an aqueous solution of NaOH (16.8g, 33%) were added, and the mixture was stirred at this temperature for 30min and then the layers were separated. The oil layer was desolventized, and the residue was recrystallized from methanol water to give 25.3g of 3- (difluoromethyl) -1-methyl-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide, yield: 72.1 percent.
Example 12
Synthesis of 1, 3-dimethyl-5-chloro-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide (Compound I-317 of Table 2)
Figure GDA0003259218960000123
The intermediate 2-methyl-3- (2-pentyloxy) cyclohex-2-en-1-one-O-benzoyl oxime (24.8g, synthesis procedure see example 1) was added to the reaction flask, a toluene solution (100mL) of 1, 3-dimethyl-5-chloro-1H-pyrazole-4-carbonyl chloride (15.2g) was added quickly dropwise to the reaction, methanesulfonic acid (0.8g) was added, the reaction was slowly warmed to 110 ℃ and evacuated to-0.04 MPa, and reacted at this temperature for 4H. The reaction was cooled to room temperature, and then water (100mL) and an aqueous solution of NaOH (16.8g, 33%) were added thereto, and the mixture was stirred at this temperature for 30min and then the layers were separated. The oil layer was desolventized, and the residue was recrystallized from methanol water to give 18.2g of 1, 3-dimethyl-5-chloro-N- (2-methyl-3- (2-pentyloxy) phenyl) -1H-pyrazole-4-carboxamide in yield: 66.1 percent.
Example 13
Synthesis of 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one-O-benzoyl oxime (Compound III-100, Table 1)
(1) Synthesis of 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one
Figure GDA0003259218960000131
To three with water diversion devices2-methyl-1, 3-cyclohexanedione (12.9g), toluene (200mL), 2-hexanol (83.6g), and p-toluenesulfonic acid monohydrate (2.0g) were charged into a flask, and the mixture was heated to reflux temperature and reacted for 4 hours. Cooling to room temperature, adding NaHCO3(11.2g) saturated aqueous solution, and the layers were separated. And carrying out decompression desolventizing on the oil layer. 16.2g of intermediate 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one was obtained in yield: 75.3% (calculated as 2-methyl-1, 3-cyclohexanedione).
(2) Synthesis of 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one oxime
Figure GDA0003259218960000132
2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one (21.0g), hydroxylamine hydrochloride (13.9g), sodium acetate (32.8g), anhydrous methanol (200mL), and water (20mL) were added to a reaction flask, and the mixture was heated to 80 ℃ for reaction for 4 hours. The reaction mixture was cooled to below 10 ℃ and 200mL of water was added. At this time, a large amount of solid is separated out, filtration is carried out, and a filter cake is rinsed by ice water and dried. 10.8g of intermediate 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one oxime is obtained, the quantitative content is 98%, and the yield is as follows: 48% (calculated as 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one).
(3) Synthesis of 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one-O-benzoyl oxime
Figure GDA0003259218960000133
The intermediate 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one oxime (22.5g), triethylamine (10.1g), and toluene (200mL) were added to a reaction flask, benzoyl chloride (14.1g) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours after completion of dropwise addition. The reaction solution was cooled to room temperature, and water (100mL) was added thereto, followed by stirring at this temperature for 30min and then separation. The oil layer is desolventized to obtain 30.8g of intermediate 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one-O-benzoyl oxime, and the yield is as follows: 94% (calculated as 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one oxime).
Example 14
Synthesis of 1, 3-dimethyl-5-chloro-N- (2-methyl-3- (2-hexyloxy) phenyl) -1H-pyrazole-4-carboxamide (Compound I-353 of Table 2)
Figure GDA0003259218960000141
The intermediate 2-methyl-3- (2-hexyloxy) cyclohex-2-en-1-one-O-benzoyl oxime (26.0g, synthesis procedure see example 13) was added to the reaction flask, a toluene solution (100mL) of 1, 3-dimethyl-5-chloro-1H-pyrazole-4-carbonyl chloride (15.2g) was added quickly to the reaction, methanesulfonic acid (0.8g) was added, the reaction was slowly warmed to 110 ℃ and evacuated to-0.04 MPa, and reacted at this temperature for 4H. The reaction was cooled to room temperature, and then water (100mL) and an aqueous solution of NaOH (16.8g, 33%) were added thereto, and the mixture was stirred at this temperature for 30min and then the layers were separated. The oil layer was desolventized, and the residue was recrystallized from methanol water to give 18.6g of 1, 3-dimethyl-5-chloro-N- (2-methyl-3- (2-hexyloxy) phenyl) -1H-pyrazole-4-carboxamide in yield: 64.8 percent.
The amide compounds shown in the general formula (I) can be prepared by the method provided by the invention, and the structures of part of the compounds shown in the general formula (I) are listed in Table 2.
TABLE 2 Structure of part of the compounds of the general formula (I)
Figure GDA0003259218960000142
Figure GDA0003259218960000143
Figure GDA0003259218960000151
Figure GDA0003259218960000161
Figure GDA0003259218960000171
Figure GDA0003259218960000181
Figure GDA0003259218960000191
Figure GDA0003259218960000201
Figure GDA0003259218960000211
Figure GDA0003259218960000221
Figure GDA0003259218960000231
Figure GDA0003259218960000241
Figure GDA0003259218960000251
Figure GDA0003259218960000261
Figure GDA0003259218960000271
Figure GDA0003259218960000281
Figure GDA0003259218960000291
Figure GDA0003259218960000301
It is another object of the present invention to provide intermediates (substituted oxime carboxylate (III)) useful in the preparation of fungicides of formula I. Therefore, the invention also comprises an oxime carboxylate compound (III) for preparing the amide compound shown as the general formula I. The amide compound of the general formula I can be used as a bactericide. It should be understood that various changes and modifications may be made within the scope of the present invention as defined by the claims.

Claims (10)

1. A preparation method of an amide compound is characterized in that: carrying out condensation reaction on acyl halide II and substituted carboxylic oxime ester III in a proper solvent to obtain an amide compound shown as a general formula I; the reaction formula is as follows:
Figure FDA0003259218950000011
in the formula:
R1selected from the group consisting of a phenyl ring, a 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms or a 5 or 6 membered heterocyclic ring wherein the hydrogen on the phenyl ring or heterocyclic ring may be replaced by one or more of the same or different R5Substitution;
R2is selected from H or C1-C12Alkyl groups of (a);
R3is selected from C1-C12Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Cycloalkyl of (C)1-C6Alkyl radical, C3-C6Halogenocycloalkyl or C3-C6Cycloalkyl of (C)3-C6Cycloalkyl groups of (a);
R4is selected from C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Cycloalkyl of (C)1-C6Alkyl radical, C3-C6Halogenocycloalkyl of (A), C1-C6Alkoxy radical C of1-C6Alkyl of (C)1-C6Halogenoalkoxy group C of1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)3-C6Cycloalkoxy of (A), C3-C6Halogenocycloalkoxy of (A), C3-C6Cycloalkyl of (C)1-C6An alkoxy group of (a) a phenyl ring, a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms or a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms, wherein hydrogen on the phenyl ring or the heterocyclic ring may be replaced by one or more identical or different R5Substitution;
R5selected from halogen, nitro, cyano, C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Halogenocycloalkyl of (A), C1-C6Alkoxy radical C of1-C6Alkyl of (C)1-C6Halogenoalkoxy group C of1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)3-C6Cycloalkoxy of (A), C3-C6Halogenocycloalkoxy or C3-C6Cycloalkyl of (C)1-C6Alkoxy group of (a);
l is halogen.
2. The method of claim 1, wherein:
the charging molar ratio of the acyl halide compound shown in the general formula II to the substituted oxime carboxylate shown in the general formula III is 1: 0.8 to 1.5, and carrying out condensation reaction in a proper solvent at the temperature of between 10 ℃ below zero and the boiling point of the proper solvent for 0.5 to 8 hours to obtain the amide compound shown in the general formula I.
3. The production method according to claim 1 or 2, characterized in that:
the solvent is selected from dichloromethane, chloroform, carbon tetrachloride, hexane, benzene, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, butanone, N-dimethylformamide or dimethyl sulfoxide.
4. The method of claim 2, wherein:
the charging molar ratio of the acyl halide compound shown in the general formula II to the substituted oxime carboxylate shown in the general formula III is 1: 0.8 to 1.5, and carrying out condensation reaction in a proper solvent at the temperature of between 10 ℃ below zero and the boiling point range of the proper solvent and under the pressure of between 0.1MPa and 0.01MPa for 0.5 to 8 hours to obtain the amide compound shown in the general formula I.
5. The method of claim 4, wherein:
the charging molar ratio of the acyl halide compound shown in the general formula II to the substituted oxime carboxylate shown in the general formula III is 1: 0.8 to 1.5, adding proper acid into proper solvent at the temperature of between 10 ℃ below zero and the boiling point of the proper solvent and under the pressure of between 0.1MPa below zero and 0.01MPa below zero, and carrying out condensation reaction for 0.5 to 8 hours to obtain the amide compound shown in the general formula I.
6. The method of claim 5, wherein:
the acid is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid.
7. The method of claim 4, wherein:
the charging molar ratio of the acyl halide compound shown in the general formula II to the substituted oxime carboxylate shown in the general formula III is 1: 0.9 to 1.2, adding proper acid in proper solvent in the absence of acid-binding agent, at the temperature of between 20 ℃ and the boiling point range and under the pressure of between-0.05 MPa and-0.01 MPa, and carrying out condensation reaction for 0.5 to 4 hours to obtain the amide compound; wherein the solvent is selected from toluene or acetonitrile; the acid is selected from hydrochloric acid, sulfuric acid or p-methanesulfonic acid, and the charging molar ratio of the acid to the substituted oxime carboxylate shown in the general formula III is 0.01-0.5: 1.
8. a method of manufacturing as claimed in any one of claims 1, 2, 4, 5, wherein: the oxime carboxylate compound is shown as a general formula III:
Figure FDA0003259218950000021
in the formula:
R2is selected from H or C1-C12Alkyl groups of (a);
R3is selected from C1-C12Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Cycloalkyl of (C)1-C6Alkyl radical, C3-C6Halogenocycloalkyl or C3-C6Cycloalkyl of (C)3-C6Cycloalkyl groups of (a);
R4is selected from C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Cycloalkyl of (C)1-C6Alkyl radical, C3-C6Halogenocycloalkyl of (A), C1-C6Alkoxy radical C of1-C6Alkyl of (C)1-C6Halogenoalkoxy group C of1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)3-C6Cycloalkoxy of (A), C3-C6Halogenocycloalkoxy of (A), C3-C6Cycloalkanes ofRadical C1-C6An alkoxy group of (a) a phenyl ring, a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms or a 5-or 6-membered heterocyclic ring having 1 to 3 heteroatoms, wherein hydrogen on the phenyl ring or the heterocyclic ring may be replaced by one or more identical or different R5Substitution;
R5selected from halogen, nitro, cyano, C1-C6Alkyl of (C)1-C6Halogenoalkyl of, C3-C6Cycloalkyl of, C3-C6Halogenocycloalkyl of (A), C1-C6Alkoxy radical C of1-C6Alkyl of (C)1-C6Halogenoalkoxy group C of1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Halogenoalkoxy of (C)3-C6Cycloalkoxy of (A), C3-C6Halogenocycloalkoxy or C3-C6Cycloalkyl of (C)1-C6Alkoxy group of (2).
9. The method of claim 8, wherein: in the formula:
R2is selected from H or C1-C6Alkyl groups of (a);
R3is selected from C1-C8Alkyl groups of (a);
R4selected from the group consisting of a phenyl ring, a 5 or 6 membered heterocyclic ring having 1 to 3 heteroatoms, wherein hydrogen on the phenyl ring or the heterocyclic ring may be replaced by one or more R which may be the same or different5Substitution;
R5selected from halogen, nitro, cyano, C1-C3Alkyl or C1-C3A haloalkyl group of (a).
10. The method of claim 9, wherein: in the formula:
R2is selected from H or C1-C3Alkyl groups of (a);
R3is selected from C1-C6Alkyl groups of (a);
R4selected from benzene, furan, thiophene, pyrrole, pyrazole, oxazole, isoxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine, benzoxazole, benzothiazole, quinoxaline, quinazoline, the hydrogen of the above ring can be replaced by one or more same or different R5Substitution;
R5selected from fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C3Alkyl or C1-C3A haloalkyl group of (a).
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