CN116969930A - Thiazole ring-containing pyrazole carboxamide derivative and preparation method and application thereof - Google Patents

Thiazole ring-containing pyrazole carboxamide derivative and preparation method and application thereof Download PDF

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CN116969930A
CN116969930A CN202310819486.0A CN202310819486A CN116969930A CN 116969930 A CN116969930 A CN 116969930A CN 202310819486 A CN202310819486 A CN 202310819486A CN 116969930 A CN116969930 A CN 116969930A
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pyrazole
methyl
compound
thiazole
carboxylic acid
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吕献海
郭晓刚
李猛
常西浩
王丹丹
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Anhui Xitian Biotechnology Co ltd
Anhui Agricultural University AHAU
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Anhui Xitian Biotechnology Co ltd
Anhui Agricultural University AHAU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides

Abstract

The application provides a thiazole ring-containing pyrazole carboxamide derivative, and a preparation method and application thereof, and belongs to the technical field of bactericide preparation. The thiazole-ring-containing pyrazole amide derivatives prepared by chemical synthesis have antifungal activity, particularly have obvious antifungal activity on apple rot fungi, rape sclerotinia and trichoderma viride, provide a direction for further development of novel succinic dehydrogenase inhibitors, lay a foundation for preparing bactericides taking the thiazole-ring-containing pyrazole amide derivatives as main antifungal active ingredients, and have the characteristics of low reaction temperature, high safety performance, convenience in operation, high product purity and high yield.

Description

Thiazole ring-containing pyrazole carboxamide derivative and preparation method and application thereof
Technical Field
The application belongs to the technical field of bactericide preparation, and particularly relates to a thiazole ring-containing pyrazole carboxamide derivative, and a preparation method and application thereof.
Background
Succinate dehydrogenase inhibitors (SDHI) can inhibit the growth and proliferation of pathogenic fungi by disrupting mitochondrial citrate circulation and respiratory chain electron transport by disrupting the Succinate Dehydrogenase (SDH) that intercalates the inner mitochondrial membrane. During the past half century, practical exploration has demonstrated that SDHI has a unique mode of action, broad spectrum and excellent antifungal activity, which has been widely used to control fungal infections of cereals, vegetables and fruits. The development of succinate dehydrogenase inhibitors has never stopped since the first SDHI-like product Carboxin (Carboxin) was marketed in the 60 s of the 20 th century. To date, 24 succinate dehydrogenase inhibitors have been commercialized by the action committee for Fungicidal Resistance (FRAC), including oxathiin carboxin (1969), boscalid (2003), bixafen (2006), fluxapyroxad (2011), sedaxane (2011), penflufen (2012), flumenteram (2016) and inpyrruxam (2017). However, resistance to phytopathogenic fungi has become increasingly serious in recent years due to long-term unscientific and uncontrolled abuse of succinate dehydrogenase inhibitors. Therefore, there is an urgent need to develop lead compounds which are less toxic and have high antifungal activity.
Disclosure of Invention
In order to solve the technical problems, the application provides a pyrazole carboxamide derivative containing thiazole rings, and a preparation method and application thereof.
One of the technical schemes of the application is as follows:
a thiazole-containing pyrazole carboxamide derivative having the structural formula:
wherein R is 1 Is methyl or phenyl, R 2 Is hydrogen or chlorine, R 3 Is difluoromethyl, trifluoromethyl or methyl, R 4 Is o-tolyl group m-tolyl group p-tolyl group o-chlorophenyl group m-chlorophenyl group,P-chlorophenyl, naphthyl or isobutyl.
Further, the structural formula of the thiazole ring-containing pyrazole carboxamide derivative comprises:
one or any of the above.
The second technical scheme of the application is as follows:
the preparation method of the thiazole-ring-containing pyrazole carboxamide derivative comprises the following steps:
mixing pyrazole acid, an organic solvent, a condensing agent or a chlorinating agent to obtain a reaction system, adding a compound d into the reaction system for reaction, and extracting to obtain the thiazole ring-containing pyrazole carboxamide derivative;
the pyrazole acid is 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid or 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid;
the structural formula of the compound d is as follows:wherein R is 5 Is o-tolyl, m-tolyl, p-tolyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, naphthyl or isobutyl.
Further, the method specifically comprises the following steps:
dissolving 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid or 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid in piperidine, adding a chlorinating agent under ice bath, stirring for 5min, adding a compound d, reacting at 40 ℃ for 12H, extracting reaction liquid, and purifying to obtain the thiazole ring-containing pyrazole carboxamide derivative.
Further, the compound d is mixed with 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid or 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid in a molar ratio of 1:1.2, said compound d and POCl 3 The molar ratio of (2) is 1:10.
Further, the method specifically comprises the following steps:
mixing 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea Hexafluorophosphate (HATU) and N, N-dimethylformamide, adding a compound d to obtain a reaction system, dropwise adding an acid-binding agent under ice bath, stirring for 5min, reacting at 40 ℃ for 12H, extracting and purifying the reaction liquid to obtain the thiazole-ring-containing pyrazole carboxamide derivative, wherein the acid-binding agent is triethylamine.
Still further, the molar ratio of the compound d to 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid was 1:1.2, the molar equivalent ratio of the compound d to 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate was 1:2, and the molar equivalent ratio of the compound d to the acid-binding agent was 1:1.5.
Further, the preparation method of the compound d comprises the following steps: the preparation method comprises the steps of condensing 4, 5-dimethylthiazole and an aldehyde compound serving as raw materials, and sequentially carrying out addition reaction, oxidation reaction and reduction reaction to obtain the aldehyde compound, wherein the structural formula of the aldehyde compound is R 6 -CHO, wherein R 6 Is o-tolyl, m-tolyl, p-tolyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, naphthyl or isobutyl.
More specifically, the method comprises the following steps:
(1) Dissolving 4, 5-dimethylthiazole in tetrahydrofuran, dropwise adding n-butyllithium reagent at minus 78 ℃, stirring for 1h, adding aldehyde compound, stirring for 1h, reacting at 25 ℃ for 12h, cooling the obtained reaction liquid to room temperature (25+/-2 ℃) after the reaction is finished, adding a proper amount of saturated sodium chloride solution, drying the solvent under reduced pressure, extracting the reaction liquid by using ethyl acetate and saturated sodium chloride, retaining an organic phase, drying anhydrous sodium sulfate, drying under reduced pressure, purifying the obtained filter residue by a recrystallization method to obtain a compound b, wherein the flow is as follows:
wherein the molar equivalent ratio of the 4, 5-dimethylthiazole to the n-butyllithium is 1:1.2, and the molar equivalent ratio of the 4, 5-dimethylthiazole to the aldehyde compound is 1:3.
(2) Dissolving the compound b and manganese dioxide in dichloromethane, then reacting for 12 hours at 25 ℃, after the reaction is finished, carrying out suction filtration on diatomite, and carrying out reduced pressure spin-drying on the solvent to obtain a compound c, wherein the flow is as follows:
wherein the molar equivalent ratio of the compound b to the manganese dioxide is 1:10.
(3) Dissolving the compound c, ammonium acetate and sodium cyanoborohydride in methanol, reacting for 48 hours at 60 ℃, cooling the obtained reaction liquid to room temperature after the reaction is finished, performing reduced pressure spin-drying on the solvent, extracting the reaction liquid by using ethyl acetate, sodium hydroxide solution, ammonium chloride solution and saturated sodium chloride solution, retaining an organic phase, drying by using anhydrous sodium sulfate, performing reduced pressure spin-drying, and purifying the obtained filter residue by using a column chromatography to obtain a compound d, wherein the flow path is as follows:
wherein the molar equivalent ratio of the compound c to the ammonium acetate is 1:15, and the molar equivalent ratio of the compound c to the sodium cyanoborohydride is 1:4.
The third technical scheme of the application:
the thiazole ring-containing pyrazole carboxamide derivatives are applied to the preparation of antifungal medicaments.
Compared with the prior art, the application has the following advantages and technical effects:
the preparation method provided by the application has the characteristics of low reaction temperature, high safety performance, convenience in operation and high product purity and yield, and the prepared thiazole-ring-containing pyrazole carboxamide derivative has broad-spectrum antifungal activity.
The 24 thiazole-ring-containing pyrazole amide derivatives prepared by chemical synthesis have antifungal activity, particularly have obvious antifungal activity on apple rot fungi, rape sclerotinia and trichoderma viride, provide a direction for further development of novel succinic dehydrogenase inhibitors, and lay a foundation for preparing bactericides with the thiazole-ring-containing pyrazole amide derivatives as main antifungal active ingredients.
Detailed Description
Various exemplary embodiments of the application will now be described in detail, which should not be considered as limiting the application, but rather as more detailed descriptions of certain aspects, features and embodiments of the application.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the application. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the application described herein without departing from the scope or spirit of the application. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present application. The specification and examples of the present application are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
The application provides a preparation method of thiazole ring-containing pyrazole carboxamide derivatives, which comprises the following steps:
mixing pyrazole acid, an organic solvent, a condensing agent or a chlorinating agent to obtain a reaction system, adding a compound d into the reaction system for reaction, and extracting to obtain the thiazole ring-containing pyrazole carboxamide derivative;
the pyrazole acid is 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid or 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid;
the structural formula of the compound d is as follows:wherein R is 5 Is o-tolyl, m-tolyl, p-tolyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, naphthyl or isobutyl.
In some embodiments of the present application, the preparation method of the thiazole ring-containing pyrazole carboxamide derivative specifically includes the following steps:
dissolving 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid or 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid in piperidine, adding a chlorinating agent under ice bath, stirring for 5min, adding a compound d, reacting at 40 ℃ for 12H, extracting reaction liquid, and purifying to obtain the thiazole ring-containing pyrazole carboxamide derivative.
Preferably, the molar ratio of the compound d to 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid or 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 1:1.2, the compound d to POCl 3 The molar ratio of (2) is 1:10.
In some embodiments of the present application, the preparation method of the thiazole-ring-containing pyrazole carboxamide derivative specifically includes the following steps:
mixing 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea Hexafluorophosphate (HATU) and N, N-dimethylformamide, adding a compound d to obtain a reaction system, dropwise adding an acid-binding agent under ice bath, stirring for 5min, reacting at 40 ℃ for 12H, extracting and purifying the reaction liquid to obtain the thiazole-ring-containing pyrazole carboxamide derivative, wherein the acid-binding agent is triethylamine.
Preferably, the molar ratio of the compound d to the 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid is 1:1.2, the molar equivalent ratio of the compound d to the 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate is 1:2, and the molar equivalent ratio of the compound d to the acid binding agent is 1:1.5.
The preparation method of the compound d used in the embodiment of the application comprises the following steps: the preparation method comprises the steps of condensing 4, 5-dimethylthiazole and an aldehyde compound serving as raw materials, and sequentially carrying out addition reaction, oxidation reaction and reduction reaction to obtain the aldehyde compound, wherein the structural formula of the aldehyde compound is R 6 -CHO, wherein R 6 Is o-tolyl, m-tolyl, p-tolyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, naphthyl or isobutyl. More specifically, the method comprises the following steps:
(1) Dissolving 4, 5-dimethylthiazole in tetrahydrofuran, dropwise adding n-butyllithium reagent at minus 78 ℃, stirring for 1h, adding aldehyde compound, stirring for 1h, reacting at 25 ℃ for 12h, cooling the obtained reaction liquid to room temperature (25+/-2 ℃) after the reaction is finished, adding a proper amount of saturated sodium chloride solution, drying the solvent under reduced pressure, extracting the reaction liquid by using ethyl acetate and saturated sodium chloride, retaining an organic phase, drying anhydrous sodium sulfate, drying under reduced pressure, purifying the obtained filter residue by a recrystallization method to obtain a compound b, wherein the flow is as follows:
wherein the molar equivalent ratio of the 4, 5-dimethylthiazole to the n-butyllithium is 1:1.2, and the molar equivalent ratio of the 4, 5-dimethylthiazole to the aldehyde compound is 1:3.
(2) Dissolving the compound b and manganese dioxide in dichloromethane, then reacting for 12 hours at 25 ℃, after the reaction is finished, carrying out suction filtration on diatomite, and carrying out reduced pressure spin-drying on the solvent to obtain a compound c, wherein the flow is as follows:
wherein the molar equivalent ratio of the compound b to the manganese dioxide is 1:10.
(3) Dissolving the compound c, ammonium acetate and sodium cyanoborohydride in methanol, reacting for 48 hours at 60 ℃, cooling the obtained reaction liquid to room temperature after the reaction is finished, performing reduced pressure spin-drying on the solvent, extracting the reaction liquid by using ethyl acetate, sodium hydroxide solution, ammonium chloride solution and saturated sodium chloride solution, retaining an organic phase, drying by using anhydrous sodium sulfate, performing reduced pressure spin-drying, and purifying the obtained filter residue by using a column chromatography to obtain a compound d, wherein the flow path is as follows:
wherein the molar equivalent ratio of the compound c to the ammonium acetate is 1:15, and the molar equivalent ratio of the compound c to the sodium cyanoborohydride is 1:4.
The pyrazole acid used in the examples of the present application was 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, purchased from Shanghai Pichia pharmaceutical technologies Co., ltd.
The preparation method of the pyrazole acid 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid used in the embodiment of the application comprises the following steps:
dissolving 1-phenyl-3-methyl-5-pyrazolone in N, N-dimethylformamide, and dripping POCl at 0deg.C 3 Gradually heating to 90 ℃ for reaction for 4 hours, pouring the reaction solution into ice water, adding sodium hydroxide to adjust the pH value to be neutral, filtering to obtain yellow solid, dissolving the yellow solid and potassium permanganate in water, reacting for 5 hours at 80 ℃, filtering while the mixture is hot, adding concentrated hydrochloric acid into the filtrate to obtain turbid liquidStanding, suction filtering and drying to obtain the 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid.
In the embodiment of the application, the room temperature is 25+/-2 ℃.
The technical scheme of the application is further described by the following examples.
Example 1
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the flask and dissolved in 3mL of piperidine, and POCl was added dropwise in an ice bath (0deg.C) 3 (10 mmol) then stirred in an ice bath for 5min, added with (4, 5-dimethylthiazol-2-yl) (o-tolyl) methylamine (1 mmol) and then reacted at 40℃for 12h, after which the resulting reaction mixture was cooled to room temperature and 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give Compound 1 in a total yield of 59%.
Compound 1 was 3- (difluoromethyl) -N- ((4, 5-dimethylthiazol-2-yl) (o-tolyl) methyl) -1-methyl-1H-pyrazole-4-carboxamide (structural formula:): white powder, mp 152-153 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.88(s,1H),7.72(s,1H),7.24(s,1H),7.15(s,2H),7.12(d,J＝2.60Hz,1H),6.97(s,1H),6.57(d,J＝6.70Hz,1H),3.84(s,3H),2.46(s,3H),2.25(s,3H),2.24(s,3H). 13 C NMR(151MHz,CDCl 3 )δ165.4,160.4,147.8,143.9(t,J＝27.1Hz),138.6,136.0,134.2,130.7,128.0,127.1,126.8,126.3,116.1,110.9(t,J＝235.5Hz),52.6,39.3,19.3,14.5,11.1.HRMS(ESI)calculated for C 19 H 21 F 2 N 4 OS[M+H] + ,391.1399；found,391.1416.
example 2
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice bath 3 (10 mmol) after stirring for 5min in an ice bath, (4, 5-dimethylthiazol-2-yl) (m-methyl)Phenyl) methylamine (1 mmol) was then reacted at 40℃for 12h, after which the resulting reaction mixture was cooled to room temperature and 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give Compound 2 in a total yield of 65%.
Compound 2 was 3- (difluoromethyl) -N- ((4, 5-dimethylthiazol-2-yl) (m-tolyl) methyl) -1-methyl-1H-pyrazole-4-carboxamide (structural formula:): yellow powder, mp 191-192 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.91(s,1H),7.72(s,1H),7.22-7.18(m,3H),7.08(d,J＝7.7Hz,1H),6.98(s,1H),6.34(d,J＝6.6Hz,1H),3.90(s,3H),2.31(s,3H),2.28(s,6H). 13 C NMR(151MHz,CDCl 3 )δ165.3,160.3,147.7,143.8(t,J＝27.1Hz),140.3,138.5,134.3,128.8,128.6,127.8,126.9,124.1,116.4,111.0(t,J＝234.0Hz),55.5,39.4,21.3,14.6,11.1.C 19 H 21 F 2 N 4 OS[M+H] + ,391.1399；found,391.1396.
example 3
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice bath 3 (10 mmol) then stirred in an ice bath for 5min, added with (4, 5-dimethylthiazol-2-yl) (p-tolyl) methylamine (1 mmol) and then reacted at 40℃for 12h, after which the resulting reaction mixture was cooled to room temperature and 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give Compound 3 in a total yield of 63%.
Compound 3 is 3- (difluoromethyl) -N- ((4, 5-dimethylthiazol-2-yl) (p-tolyl) methyl) -1-methyl-1H-pyrazole-4-carboxamide (structural formula)): white powder, mp 181-182 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.87(s,1H),7.70(s,1H),7.28(d,J＝7.7Hz,2H),7.12(d,J＝7.7Hz,2H),6.96(t,J＝54.2Hz,1H),6.32(d,J＝6.6Hz,1H),3.88(s,3H),2.29(s,3H),2.27(s,6H). 13 C NMR(151MHz,CDCl 3 )δ165.4,160.3,147.7,143.8(t,J＝27.1Hz),137.7,137.5,134.2,129.4,127.0,126.8,116.4,111.0(t,J＝234.0Hz),55.3,39.4,21.0,14.5,11.1.HRMS(ESI)calculated for C 19 H 21 F 2 N 4 OS[M+H] + ,391.1399；found,391.1399.
example 4
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice bath 3 (10 mmol) then stirred in an ice bath for 5min, added with (o-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methylamine (1 mmol) and then reacted at 40℃for 12h, after the reaction was completed, the resulting reaction solution was cooled to room temperature and 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give Compound 4 in a total yield of 72%.
Compound 4 is 3- (difluoromethyl) -N- ((4, 5-dimethylthiazol-2-yl) (o-chlorophenyl) methyl) -1-methyl-1H-pyrazole-4-carboxamide (structural formula)): yellow powder, 72%; mp 202-203 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.93(s,1H),7.87(s,1H),7.44(d,J＝9.2Hz,1H),7.37(d,J＝9.0Hz,1H),7.24-7.21(m,2H),6.95(s,1H),6.77(d,J＝6.5Hz,1H),3.92(s,3H),2.28(s,3H),2.28(s,3H). 13 C NMR(151MHz,CDCl 3 )δ163.7,160.4,147.7,144.0(t,J＝27.2Hz),137.9,134.3,133.1,130.7,129.9,129.3,128.6,127.3,116.0,110.8(t,J＝235.3Hz),52.7,39.5,14.5,11.2.HRMS(ESI)calculated for C 18 H 18 ClF 2 N 4 OS[M+H] + ,411.0852；found,411.0836.
example 5
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice bath 3 (10 mmol) after stirring in an ice bath for 5min, (m-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methylamine (1 mmol) was added and then reacted at 40℃for 12h, after the reaction was completed, the resulting reaction solution was cooled to room temperature and 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give Compound 5 in a total yield of 70%.
Compound 5 is 3- (difluoromethyl) -N- ((4, 5-dimethylthiazol-2-yl) (m-chlorophenyl) methyl) -1-methyl-1H-pyrazole-4-carboxamide (structural formula)): white powder, mp 194-195 ℃;1H NMR (600 MHz, CDCl 3) delta 7.93 (s, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 7.31 (d, J=7.0 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 6.34 (d, J=6.6 Hz, 1H), 3.92 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H) 13C NMR (151 MHz, CDCl 3) delta 163.9,160.3,148.0,142.5,134.6,134.5,130.0,128.2,127.3,127.2,125.3,111.1 (t, J= 234.0 Hz), 54.9,39.4,14.5,11.1.HRMS (ESI) calculated for C18H18ClF2N4OS [ M+H]+,411.0852；found,411.0867.
Example 6
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice bath 3 (10 mmol) after stirring in an ice bath for 5min, (p-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methylamine (1 mmol) was added, then reacted at 40℃for 12h, after the reaction was completed, the resulting reaction solution was cooled to room temperature, and an appropriate amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure to give a residueThe compound 6 is obtained by column chromatography analysis and purification, and the total yield is 75%.
Compound 6 was 3- (difluoromethyl) -N- ((4, 5-dimethylthiazol-2-yl) (p-chlorophenyl) methyl) -1-methyl-1H-pyrazole-4-carboxamide (structural formula:): yellow powder, mp 118-119 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.87(s,1H),7.30(d,J＝8.5Hz,2H),7.25(d,J＝2.8Hz,2H),6.97(s,1H),6.31(d,J＝6.6Hz,1H),3.83(s,3H),2.25(s,3H),2.24(s,3H). 13 C NMR(151MHz,CDCl 3 )δ164.3,160.6,148.0,144.0(t,J＝27.1Hz),138.9,134.1,133.8,128.8,128.6,127.2,115.9,110.8(t,J＝237.0Hz),54.7,39.3,14.5,11.0.HRMS(ESI)calculated for C 18 H 17 ClF 2 N 4 OS[M+H] + ,411.0852；found,411.0861.
example 7
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice bath 3 (10 mmol) then stirred in an ice bath for 5 minutes, and (4, 5-dimethylthiazol-2-yl) (naphthalen-2-yl) methylamine (1 mmol) was added, then reacted at 40℃for 12 hours, after the reaction was completed, the resulting reaction solution was cooled to room temperature, and an appropriate amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give Compound 7 in a total yield of 67%.
Compound 7 was 3- (difluoromethyl) -N- ((4, 5-dimethylthiazol-2-yl) (naphthalen-1-yl) methyl) -1-methyl-1H-pyrazole-4-carboxamide (structural formula:): yellow powder, mp 84-85 ℃; 1 H NMR(600MHz,CDCl 3 )δ8.17(d,J＝8.4Hz,1H),7.94(s,1H),7.83(d,J＝8.0Hz,1H),7.76(d,J＝12.2Hz,2H),7.52(s,1H),7.48(d,J＝7.6Hz,1H),7.43(d,J＝7.1Hz,1H),7.37(d,J＝7.9Hz,1H),7.16(d,J＝7.0Hz,1H),7.01(s,1H),3.74(s,3H),2.24(s,3H),2.20(s,3H). 13 C NMR(151MHz,CDCl3)δ165.5,160.5,147.8,144.0(t,J＝27.1Hz),135.9,134.1,134.0,130.8,128.9,128.8,127.0,126.7,125.9,125.6,125.2,123.3,116.1,110.8(t,J＝235.5Hz),52.4,39.3,14.5,11.2.HRMS(ESI)calculated for C 22 H 21 F 2 N 4 OS[M+H] + ,427.1399；found,427.1404.
example 8
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice bath 3 (10 mmol) after stirring in an ice bath for 5min, 1- (4, 5-dimethylthiazol-2-yl) -2-methylpropan-1-amine (1 mmol) was added, then reacted at 40℃for 12h, after the reaction was completed, the resulting reaction solution was cooled to room temperature and a proper amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, dried under reduced pressure, and the resulting residue was purified by column chromatography to give Compound 8 in a total yield of 78%.
Compound 8 was 3- (difluoromethyl) -N- (1- (4, 5-dimethylthiazol-2-yl) -2-methylpropyl) -1-methyl-1H-pyrazole-4-carboxamide (structural formula:): yellow powder, mp 83-84 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.91(s,1H),7.09(s,1H),6.91(s,1H),5.18–5.14(m,1H),3.83(s,2H),2.31–2.27(m,1H),2.22(s,3H),2.21(s,3H),0.91(d,J＝3.4Hz,3H),0.90(d,J＝2.3Hz,3H). 13 C NMR(151MHz,CDCl3)δ165.6,160.8,147.8,143.3(t,J＝28.6Hz),134.6,125.4,116.3,111.2(t,J＝234.0Hz),56.4,39.3,33.3,19.1,17.4,14.5,11.0.HRMS(ESI)calculated for C 15 H 21 F 2 N 4 OS[M+H] + ,343.1399；found,343.1408
example 9
3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the reaction flask and dissolved in 3mL of piperidine, POC was added dropwise under ice-bathl 3 (10 mmol) after stirring in an ice bath for 5min, (4, 5-dimethylthiazol-2-yl) (o-tolyl) methylamine (1 mmol) was added, then reacted at 40℃for 12h, after which the resulting reaction mixture was cooled to room temperature and a suitable amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give Compound 9 in a total yield of 79%.
Compound 9 is N- ((4, 5-dimethylthiazol-2-yl) (o-tolyl) methyl) -1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxamide (structural formula:): yellow powder, mp 150-151 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.61(s,1H),7.53(d,J＝7.4Hz,1H),7.27–7.15(m,4H),3.98(s,3H),2.52(s,3H),2.24(s,3H),1.95(s,3H). 13 C NMR(151MHz,CDCl 3 )δ164.8,159.9,147.6,138.6(q,J＝36.2Hz),138.6,138.3,135.9,135.4,130.9,128.1,127.1,126.4,120.8(q,J＝271.8Hz),116.9,52.8,39.6,19.3,14.5,11.1.HRMS(ESI)calculated for C 19 H 20 F 3 N 4 OS[M+H] + ,409.1304；found,409.1310.
example 10
3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the reaction flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice-bath 3 (10 mmol) after stirring in an ice bath for 5min, (4, 5-dimethylthiazol-2-yl) (m-tolyl) methylamine (1 mmol) was added, then reacted at 40℃for 12h, after which the resulting reaction mixture was cooled to room temperature and a suitable amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give compound 10 in a total yield of 85%.
Compound 10 is N- ((4, 5-dimethylthiazol-2-yl) (m-tolyl) methyl) -1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxamide (structural formula:): yellow powder, mp 180-181 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.93(s,1H),7.66–7.62(m,1H),7.23–7.17(m,3H),7.08(d,J＝7.2Hz,1H),6.30(d,J＝6.4Hz,1H),3.94(s,3H),2.32(s,3H),2.29(s,3H),2.28(s,3H). 13 C NMR(151MHz,CDCl3)δ164.8,159.4,147.6,140.3,138.7(q,J＝36.2Hz),138.5,135.3,128.8,128.7,127.7,127.0,124.0,120.8(q,J＝270.2Hz),117.0,55.7,39.7,21.3,14.5,11.1.HRMS(ESI)calculated for C 19 H 20 F 3 N 4 NaOS[M+Na] + ,431.1126；found,431.1127.
example 11
3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the reaction flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice-bath 3 (10 mmol) after stirring in an ice bath for 5min, (4, 5-dimethylthiazol-2-yl) (p-tolyl) methylamine (1 mmol) was added, then reacted at 40℃for 12 hours, after which the resulting reaction solution was cooled to room temperature and a suitable amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give Compound 11 in a total yield of 83%.
Compound 11 was N- ((4, 5-dimethylthiazol-2-yl) (p-tolyl) methyl) -1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxamide (structural formula:): white powder, mp 203-204 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.91(s,1H),7.63(s,1H),7.27(d,J＝7.9Hz,2H),7.13(d,J＝7.8Hz,2H),6.29(d,J＝6.3Hz,1H),3.92(s,3H),2.30(s,3H),2.28(s,3H),2.27(s,3H). 13 C NMR(151MHz,CDCl 3 )δ164.9,159.4,147.6,138.6(q,J＝36.2Hz),137.8,137.5,135.3,129.4,127.0,120.9(q,J＝271.8Hz),117.0,55.5,39.6,21.0,14.5,11.1.HRMS(ESI)calculated for C 19 H 20 F 3 N 4 OS[M+H] + ,409.1304；found,409.1309.
example 12
3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the reaction flask and dissolved in 3mL of pyridine, and POCl was added dropwise under ice-bath 3 (10 mmol) then stirred in an ice bath for 5 minutes, and (o-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methylamine (1 mmol) was added, then reacted at 40℃for 12 hours, after the reaction was completed, the resulting reaction solution was cooled to room temperature, and an appropriate amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give compound 12 in a total yield of 81%.
Compound 12 is N- ((4, 5-dimethylthiazol-2-yl) (o-chlorophenyl) methyl) -1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxamide (structural formula:): yellow powder, mp 147-148 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.94(s,1H),7.84(s,1H),7.42(d,J＝5.8Hz,1H),7.38(d,J＝7.2Hz,1H),7.24–7.21(m,2H),6.73(d,J＝6.0Hz,1H),3.94(s,3H),2.28(s,3H),2.28(s,3H). 13 C NMR(151MHz,CDCl 3 )δ163.2,159.4,147.6,138.7(q,J＝37.7Hz),137.9,135.6,133.1,130.0,129.3,128.5,127.3,121.3(q,J＝270.2Hz),116.7,53.1,39.7,14.6,11.2.HRMS(ESI)calculated for C 18 H 17 ClF 3 N 4 OS[M+H] + ,429.0758；found,429.0767.
example 13
3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the reaction flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice-bath 3 (10 mmol) after stirring in an ice bath for 5 minutes, (m-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methylamine (1 mmol) was added, then reacted at 40℃for 12 hours, after the reaction was completed, the resulting reaction solution was cooled to room temperature, and an appropriate amount of10％ NaHCO 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give Compound 13 in a total yield of 79%.
Compound 13 was N- ((4, 5-dimethylthiazol-2-yl) (m-chlorophenyl) methyl) -1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxamide (structural formula:): white powder, mp 166-167 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.94(s,1H),7.74(s,1H),7.37(s,1H),7.30(d,J＝6.8Hz,1H),7.26(d,J＝7.9Hz,1H),6.29(d,J＝6.2Hz,1H),3.94(s,3H),2.29(s,3H),2.29(s,3H). 13 C NMR(151MHz,CDCl 3 )δ163.4,159.5,147.8,142.5,138.8(q,J＝37.7Hz),135.3,134.6,130.0,128.2,127.4,127.2,125.3,120.8(q,J＝270.2Hz),116.7,55.1,39.6,14.5,11.1.HRMS(ESI)calculated for C 18 H 17 ClF 3 N 4 OS[M+H] + ,429.0758；found,429.0773.
example 14
3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the reaction flask and dissolved in 3mL of pyridine, and POCl was added dropwise under ice-bath 3 (10 mmol) after stirring in an ice bath for 5min, (p-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methylamine (1 mmol) was added, then reacted at 40℃for 12h, after the reaction was completed, the resulting reaction solution was cooled to room temperature, and an appropriate amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the resulting residue was purified by column chromatography to give Compound 14 in 75% overall yield.
Compound 14 was N- ((4, 5-dimethylthiazol-2-yl) (p-chlorophenyl) methyl) -1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxamide (structural formula:): yellow powder, mp 182-183 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.92(s,1H),7.77–7.73(m,1H),7.33(d,J＝8.4Hz,2H),7.28(d,J＝8.5Hz,2H),6.28(s,1H),3.92(s,3H),2.28(s,6H). 13 C NMR(151MHz,CDCl 3 )δ163.8,159.5,147.8,139.0,135.2,133.9,128.9,128.5,127.4,125.4,120.8(q,J＝271.8Hz),119.9,116.7,55.0,39.6,14.4,11.1.HRMS(ESI)calculated for C 18 H 16 ClF 3 N 4 NaOS[M+Na] + ,451.0578；found,451.0580.
example 15
3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the reaction flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice-bath 3 (10 mmol) then stirred in an ice bath for 5 minutes, and (4, 5-dimethylthiazol-2-yl) (naphthalen-2-yl) methylamine (1 mmol) was added, then reacted at 40℃for 12 hours, after the reaction was completed, the resulting reaction solution was cooled to room temperature, and an appropriate amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the obtained residue was purified by column chromatography to give compound 15 in a total yield of 73%.
Compound 15 was N- ((4, 5-dimethylthiazol-2-yl) (naphthalen-1-yl) methyl) -1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxamide (structural formula:) Yellow powder, mp 201-202 ℃; 1 H NMR(600MHz,CDCl 3 )δ8.15(d,J＝8.4Hz,1H),7.98(d,J＝5.8Hz,1H),7.81(d,J＝7.8Hz,1H),7.75(d,J＝9.0Hz,2H),7.50(t,J＝7.5Hz,1H),7.46(t,J＝7.3Hz,1H),7.41(d,J＝7.0Hz,1H),7.34(t,J＝7.6Hz,1H),7.10(d,J＝6.6Hz,1H),3.69(s,3H),2.23(s,3H),2.17(s,3H). 13 C NMR(151MHz,CDCl 3 )δ165.2,159.7,147.7,139.3(q,J＝37.7Hz),135.9,134.7,134.0,130.8,128.9,128.8,127.1,126.7,125.9,125.6,125.2,123.2,120.8(q,J＝268.7Hz),116.2,52.6,39.3,14.3,11.1.HRMS(ESI)calculated for C 22 H 20 F 3 N 4 OS[M+H] + ,445.1304；found,445.1314.
example 16
3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) was added to the reaction flask and dissolved in 3mL of piperidine, and POCl was added dropwise under ice-bath 3 (10 mmol) after stirring in an ice bath for 5min, 1- (4, 5-dimethylthiazol-2-yl) -2-methylpropan-1-amine (1 mmol) was added, then reacted at 40℃for 12h, after the reaction was completed, the resulting reaction solution was cooled to room temperature and a proper amount of 10% NaHCO was added 3 The solution (5 mL) was extracted with ethyl acetate, dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, dried under reduced pressure, and the resulting residue was purified by column chromatography to give compound 16 in a total yield of 76%.
Compound 16 was N- (1- (4, 5-dimethylthiazol-2-yl) -2-methylpropyl) -1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxamide (structural formula:) Yellow powder, mp is 102-103 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.94(s,1H),6.87(d,J＝7.3Hz,1H),5.22-5.20(m,1H),3.93(s,3H),2.34–2.31(m,1H),2.29(s,3H),2.27(s,3H),0.96(s,3H),0.95(s,3H). 13 C NMR(151MHz,CDCl 3 )δ164.8,160.0,147.8,138.3(q,J＝37.7Hz),135.4,125.6,120.9(q,J＝270.2Hz),117.1,56.4,39.6,33.5,19.0,17.5,14.5,11.1.HRMS(ESI)calculated for C 15 H 20 F 3 N 4 OS[M+H] + ,361.1304；found,361.1291.
example 17
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (2 mmol) were added to the reaction flask and dissolved in N, N-dimethylformamide, followed by dropwise addition of an acid-binding agent (400. Mu.L) in an ice bath and stirring in an ice bath for 5 minutes, and (4, 5-dimethylthiazol-2-yl) (o-tolyl) methylamine (1 mmol) was added, followed by reaction at 40℃for 12 hours, after completion of the reaction, the resulting reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate and saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the resulting residue was purified by column chromatography to give compound 17 in an overall yield of 83%.
Compound 17 was 5-chloro-N- ((4, 5-dimethylthiazol-2-yl) (o-tolyl) methyl) -3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (structural formula:) Yellow powder, mp is 55-56 ℃;1H NMR (600 MHz, CDCl) 3 )δ7.73(s,1H),7.48(m,4H),7.32(s,1H),7.17(s,2H),6.62(s,1H),2.53(s,6H),2.29(s,3H),2.26(s,3H). 13 C NMR(151MHz,CDCl 3 )δ165.4,160.9,151.8,147.7,138.9,137.6,135.9,135.0,130.9,129.3,129.0,128.8,127.9,127.1,126.9,126.4,125.5,120.8,112.8,52.6,19.4,14.4,11.1.HRMS(ESI)calculated for C 24 H 24 ClN 4 OS[M+H] + ,451.1354；found,451.1362.
Example 18
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (2 mmol) were added to the reaction flask and dissolved in N, N-dimethylformamide, followed by dropwise addition of an acid-binding agent (400. Mu.L) in an ice bath and stirring in an ice bath for 5 minutes, and (4, 5-dimethylthiazol-2-yl) (m-tolyl) methylamine (1 mmol) was added, followed by reaction at 40℃for 12 hours, after completion of the reaction, the resulting reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate and saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the resulting residue was purified by column chromatography to give compound 18 in 86% total yield.
Compound 18 was 5-chloro-N- ((4, 5-dimethylthiazol-2-yl) (m-tolyl) methyl) -3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (structural formula:) White powder, mp 112-113 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.85(d,J＝6.0Hz,1H),7.51–7.48(m,4H),7.44(s,1H),7.23(d,J＝4.4Hz,2H),7.09(s,1H),6.37(d,J＝6.4Hz,1H),2.54(s,3H),2.33(s,3H),2.29(s,3H),2.28(s,3H). 13 CNMR(151MHz,CDCl 3 )δ165.2,160.9,151.8,147.6,140.7,138.5,137.6,129.1,128.8,128.8,128.7,127.8,127.0,126.5,125.5,124.1,112.8,55.5,21.4,14.4,11.1.HRMS(ESI)calculated for C 24 H 24 ClN 4 OS[M+H] + ,451.1354；found,451.1363.
example 19
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (2 mmol) were added to the reaction flask and dissolved in N, N-dimethylformamide, followed by dropwise addition of an acid-binding agent (400. Mu.L) in an ice bath and stirring in an ice bath for 5 minutes, and (4, 5-dimethylthiazol-2-yl) (p-tolyl) methylamine (1 mmol) was added, followed by reaction at 40℃for 12 hours, after completion of the reaction, the resulting reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate and saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the resulting residue was purified by column chromatography to give compound 19 in a total yield of 88%.
Compound 19 was 5-chloro-N- ((4, 5-dimethylthiazol-2-yl) (p-tolyl) methyl) -3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (structural formula:) White powder, mp 105-106 ℃;1H NMR (600 MHz, CDCl) 3 )δ7.84(d,J＝5.9Hz,1H),7.51–7.47(m,4H),7.44(s,1H),7.33(d,J＝7.8Hz,2H),7.15(d,J＝7.8Hz,2H),6.37(d,J＝6.3Hz,1H),2.54(s,3H),2.31(s,3H),2.28(s,3H),2.28(s,3H). 13 C NMR(151MHz,CDCl 3 )δ165.3,160.9,151.8,147.6,137.9,137.7,137.6,129.5,129.0,128.8,126.9,126.5,125.5,112.8,55.2,21.0,14.4,11.1.HRMS(ESI)calculated for C 24 H 24 ClN 4 OS[M+H] + ,451.1354；found,451.1357.
Example 20
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (2 mmol) were added to the reaction flask and dissolved in N, N-dimethylformamide, followed by dropwise addition of an acid-binding agent (400. Mu.L) in an ice bath and stirring in an ice bath for 5 minutes, and (o-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methylamine (1 mmol) was added, followed by reaction at 40℃for 12 hours, after completion of the reaction, the resulting reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate and saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the resulting residue was purified by column chromatography to give compound 20 in a total yield of 80%.
Compound 20 was 5-chloro-N- ((4, 5-dimethylthiazol-2-yl) (o-chlorophenyl) methyl) -3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (structural formula:) Yellow powder, mp is 63-64 ℃; 1 H NMR(600MHz,CDCl 3 )δ8.06(d,J＝5.9Hz,1H),7.49(m,4H),7.44(d,J＝6.8Hz,1H),7.38(d,J＝7.6Hz,1H),7.24–7.21(m,2H),6.80(d,J＝6.2Hz,1H),2.55(s,3H),2.27(s,6H). 13 C NMR(151MHz,CDCl 3 )δ163.7,160.8,151.9,147.5,138.2,137.6,133.1,130.1,129.2,129.1,128.8,128.8,127.3,127.1,126.6,125.5,112.6,53.1,14.6,11.1.HRMS(ESI)calculated for C 23 H 21 Cl 2 N 4 OS[M+H] + ,471.0808；found,471.0815.
example 21
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (2 mmol) were added to the reaction flask and dissolved in N, N-dimethylformamide, followed by dropwise addition of an acid-binding agent (400. Mu.L) in an ice bath and stirring in an ice bath for 5 minutes, addition of (m-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methylamine (1 mmol), then reaction was carried out at 40℃for 12 hours, after completion of the reaction, the resulting reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate and saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, dried under reduced pressure, and the resulting residue was purified by column chromatography analysis to give compound 21 in an overall yield of 83%.
Compound 21 was 5-chloro-N- ((4, 5-dimethylthiazol-2-yl) (m-chlorophenyl) methyl) -3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (structural formula:) White powder, mp is 125-126 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.97(d,J＝5.8Hz,1H),7.50-7.46(m,4H),7.45–7.41(m,2H),7.36(d,J＝7.3Hz,1H),7.28–7.25(m,2H),6.37(d,J＝6.1Hz,1H),2.54(s,3H),2.29(s,3H),2.28(s,3H). 13 CNMR(151MHz,CDCl 3 )δ163.8,161.0,151.8,147.8,142.9,137.5,134.6,130.0,129.1,128.9,128.2,127.4,127.2,126.6,125.5,125.4,112.5,54.9,14.6,11.1.HRMS(ESI)calculated for C 23 H 21 Cl 2 N 4 OS[M+H] + ,471.0808；found,471.0812.
example 22
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (2 mmol) were added to the reaction flask and dissolved in N, N-dimethylformamide, followed by dropwise addition of an acid-binding agent (400. Mu.L) in an ice bath and stirring in an ice bath for 5 minutes, addition of (p-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methylamine (1 mmol), then reaction was carried out at 40℃for 12 hours, after completion of the reaction, the resulting reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate and saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, dried under reduced pressure, and the resulting residue was purified by column chromatography analysis to give compound 22 in an overall yield of 87%.
Compound 22 was 5-chloro-N- ((4, 5-dimethylthiazol-2-yl) (p-chlorophenyl) methyl) -3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (structural formula:) White powder, mp 106-107 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.97(d,J＝5.6Hz,1H),7.50–7.47(m,4H),7.44(s,1H),7.39(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,2H),6.38(d,J＝6.0Hz,1H),2.55(s,3H),2.30(s,3H),2.29(s,3H). 13 C NMR(151MHz,CDCl 3 )δ164.2,161.0,151.8,147.7,139.4,137.5,133.9,129.1,129.0,128.9,128.9,128.6,127.3,126.6,125.5,112.5,54.8,14.6,11.2.HRMS(ESI)calculated for C 23 H 21 Cl 2 N 4 OS[M+H] + ,471.0808；found,471.0815.
example 23
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (2 mmol) were added to the reaction flask and dissolved in N, N-dimethylformamide, followed by dropwise addition of an acid-binding agent (400. Mu.L) in an ice bath and stirring in an ice bath for 5 minutes, and (4, 5-dimethylthiazol-2-yl) (naphthalen-2-yl) methylamine (1 mmol) was added, followed by reaction at 40℃for 12 hours, after completion of the reaction, the resulting reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate and saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, and dried under reduced pressure, and the resulting residue was purified by column chromatography to give compound 23 in a total yield of 65%.
Compound 23 was 5-chloro-N- ((4, 5-dimethylthiazol-2-yl) (naphthalen-1-yl) methyl) -3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (structural formula:) White powder, yield of 82%; mp 188-189 ℃; 1 H NMR(600MHz,CDCl 3 )δ8.25(d,J＝8.4Hz,1H),7.87(d,J＝8.0Hz,1H),7.82(d,J＝8.1Hz,1H),7.73(d,J＝6.3Hz,1H),7.54(d,J＝7.1Hz,2H),7.51-7.48(m,4H),7.44(t,J＝7.6Hz,2H),7.21(d,J＝6.7Hz,1H),2.54(s,3H),2.32(s,3H),2.27(s,3H). 13 C NMR(151MHz,CDCl 3 )δ165.4,161.0,151.8,147.8,137.5,136.1,134.2,130.8,129.0,129.0,128.9,128.8,127.0,126.6,126.5,125.8,125.7,125.5,125.3,123.4,112.7,52.8,14.7,14.4,11.2.HRMS(ESI)calculated for C 27 H 24 ClN 4 OS[M+H] + ,487.1354；found,487.1360.
example 24
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (1.2 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (2 mmol) were added to the reaction flask and dissolved in N, N-dimethylformamide, followed by dropwise addition of an acid-binding agent (400. Mu.L) in an ice bath and stirring in an ice bath for 5 minutes, 1- (4, 5-dimethylthiazol-2-yl) -2-methylpropan-1-amine (1 mmol) was added, then reacted at 40℃for 12 hours, after completion of the reaction, the resulting reaction solution was cooled to room temperature, the reaction solution was extracted with ethyl acetate and saturated sodium chloride, the organic phase was retained, dried over anhydrous sodium sulfate, dried under reduced pressure, and the resulting residue was purified by column chromatography to give compound 24 in a total yield of 65%.
Compound 24 was 5-chloro-N- (1- (4, 5-dimethylthiazol-2-yl) -2-methylpropyl) -3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (structural formula:) Yellow oily, yield 79%; 1 H NMR(600MHz,CDCl 3 )δ7.52–7.49(m,4H),7.45(m,1H),7.08(d,J＝8.2Hz,1H),5.31(m,1H),2.56(s,3H),2.40(m,1H),2.31(s,3H),2.29(s,3H),1.02(s,3H),1.01(s,3H). 13 C NMR(151MHz,CDCl 3 )δ165.0,161.3,151.7,147.8,137.6,129.0,128.8,126.1,125.5,125.5,113.0,56.0,33.6,19.1,17.9,14.6,14.4,11.1.HRMS(ESI)calculated for C 20 H 24 ClN 4 OS[M+H] + ,403.1354；found,487.1361.
performance testing
The in vitro inhibitory activities of the compounds 1 to 24 prepared in examples 1 to 24 on 9 test plant pathogenic fungi were determined by hypha linear growth rate method on Botrytis cinerea, alternaria tabaci (Alternaria alternata), alternaria wheat (Fusarium graminearum), mallotus canker (Valsa mali), pyricularia oryzae (Pyricularia oryzae), rhizoctonia cerealis (Physalospora piricola), sclerotinia brassicae (Sclerotinia scleotiorum), rhizoctonia solani (Rhizoctonia solani) and Trichoderma viride (Trichoderma viride).
Taking a 40mg/L boscalid solution as a positive control, taking a 5% DMS0 aqueous solution as a blank control, completely dissolving an accurately weighed compound to be tested in 5% 10mL DMSO solution (the concentration is 400 mg/L), and rapidly and uniformly mixing 10mL of the compound to be tested or the control solution with 90mL of sterile PDA culture medium at 50 ℃ to obtain a liquid medicine with the mass concentration of 40 mg/L; it was poured hot into sterilized petri dishes, 10mL each, and cooled for use. Inoculating plant pathogenic fungi to be tested (diameter of fungus cake is 6 mm) into the culture dish, and setting 3 parallel test groups; after culturing it in a constant temperature incubator at 26℃for 72 hours, colony diameter (mm) was measured by the crisscross method, and the hypha growth Inhibition Ratio (IR) was calculated according to the formula (1):
IR(％) ＝ [(d c - d o ) - (d s - d o )]/(d c - d o )×100 (1)
in the formula (1), d c Diameter of colony of blank group, d o For inoculation of colonies, diameter 0.6mm, d s The diameter of the colony after being treated by the thiazole ring-containing pyrazole carboxamide derivative is measured.
The results are shown in Table 1.
TABLE 1 in vitro bacteriostatic Activity (inhibition%) of thiazole ring-containing pyrazole carboxamide derivatives
Note that: a values are the mean Standard Deviation (SD) of triplicate; inactive; b p.o: pyricularia oryzae (Pyricularia oryzae); c s.s: sclerotinia scleotiorum (Sclerotinia sclerotiorum); d f.g: fusarium graminearum (Alternaria wheat); e r.s: rhizoctonia solani (Rhizoctonia solani); f v.m Valsa mali (apple rot pathogen); g botrytis cinerea (Botrytis cinerea); h p.p: physalospora piricola (Rhizoctonia cerealis); j alternaria solani (Alternaria tabaci); j t.v: trichoderma viride (Trichoderma viride).
As can be seen from the data in Table 1, thiazole ring-containing pyrazole amide derivatives have remarkable antifungal activity against selected fungi. Among all the target compounds, the in vitro antibacterial activity of most of the target compounds on 9 fungi exceeds 50%, wherein the antibacterial activity of the compound 6 is most prominent, and the inhibition rates on apple rot pathogen and sclerotinia rot pathogen are 91% and 81% respectively.
Preliminary structural activity relationship analysis of antifungal Activity of Compounds 1-24, it can be seen by comparing the antifungal Activity of Compounds 1-6, 9-14 and 17-22 in Table 1 that the same pyrazolecarboxylic acidUnder the radicals, the antifungal activity of the compound with electron donating substituents on the benzene ring is lower than that of the compound with electron withdrawing substituents on the benzene ring. The antifungal activity of the ortho-substituted benzene ring compound is lower than that of the para-or meta-electron donating substituted benzene ring compound. In addition, compounds 17-24 also exhibited the same structure activity relationship. On the other hand, by comparing the antifungal activity of compounds 7 and 8, 1 and 16, 23 and 24 in Table 1, it can be seen that in the case of the same pyrazolylcarboxylic acid group, R 1 The antifungal activity of the substituent compounds with smaller steric hindrance at the positions is lower than that of the substituent compounds with larger steric hindrance. Furthermore, by comparing the antifungal activity of compounds 1 and 9, 2 and 10, 3 and 11 in table 1, it can be seen that the antifungal activity of the trifluoromethylpyrazolamide compound is lower than that of the difluoromethylpyrazolamide compound at the same thiazole amine group. In addition, by comparing the antifungal activity data of compounds 17-24 and compounds 1-16, compounds 17-24 were found to have a better broad spectrum, indicating that the broad spectrum of compounds is greatly affected by the different substituents on the pyrazole ring.
In conclusion, 24 different derivatives are prepared by the method, and are used for antifungal activity identification of 9 tested plant pathogenic fungi of Botrytis cinerea, alternaria alternata, alternaria farnesis, alternaria mali, rhizoctonia cerealis, rhizoctonia solani and Trichoderma viride, and the result shows that most target compounds have medium to excellent in vitro antifungal activity on Alternaria mali, alternaria brassicae and Trichoderma viride. Among them, 5 compounds 6 (91%), 7 (89%), 9 (80%), 19 (84%), 23 (87%), and inhibition ratio to apple rot pathogen was equal to or higher than boscalid (81%); the inhibition rate of the compound 23 (83%) to rhizoctonia solani and trichoderma viride (80%) reaches 80%; in addition, compound 23 also shows broad-spectrum inhibitory activity against sclerotinia sclerotiorum (70%).
The 24 thiazole-ring-containing pyrazole amide derivatives prepared by chemical synthesis have antifungal activity, particularly have obvious antifungal activity on apple rot fungi, rape sclerotinia and trichoderma viride, provide a direction for further development of novel succinic dehydrogenase inhibitors, and lay a foundation for preparing bactericides with the thiazole-ring-containing pyrazole amide derivatives as main antifungal active ingredients.
The present application is not limited to the above-mentioned embodiments, and any changes or substitutions that can be easily understood by those skilled in the art within the technical scope of the present application are intended to be included in the scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims (8)

1. The thiazole-containing pyrazole carboxamide derivative is characterized by having the following structural formula:
wherein R is 1 Is methyl or phenyl, R 2 Is hydrogen or chlorine, R 3 Is difluoromethyl, trifluoromethyl or methyl, R 4 Is o-tolyl, m-tolyl, p-tolyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, naphthyl or isobutyl.
2. The thiazole-containing pyrazole carboxamide derivative according to claim 1, wherein the structural formula of the thiazole-containing pyrazole carboxamide derivative comprises:
one or any of the above.
3. A process for the preparation of thiazole-ring-containing pyrazole carboxamides derivatives according to any of claims 1 to 2, characterized by comprising the steps of:
mixing pyrazole acid, an organic solvent, a condensing agent or a chlorinating agent to obtain a reaction system, adding a compound d into the reaction system for reaction, and extracting to obtain the thiazole ring-containing pyrazole carboxamide derivative;
the pyrazole acid is 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid or 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid;
the structural formula of the compound d is as follows:wherein R is 5 Is o-tolyl, m-tolyl, p-tolyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, naphthyl or isobutyl.
4. The method for producing a thiazole ring-containing pyrazole carboxamide derivative according to claim 3, characterized by comprising the steps of:
dissolving 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid or 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid in piperidine, adding a chlorinating agent under ice bath, stirring for 5min, adding a compound d, reacting at 40 ℃ for 12H, extracting reaction liquid, and purifying to obtain the thiazole ring-containing pyrazole carboxamide derivative.
5. The process for producing thiazole-ring-containing pyrazole carboxamide derivative according to claim 4, wherein the molar ratio of the compound d to 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid or 3- (trifluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 1:1.2, the compound d to POCl 3 The molar ratio of (2) is 1:10.
6. The method for producing a thiazole ring-containing pyrazole carboxamide derivative according to claim 3, characterized by comprising the steps of:
mixing 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and N, N-dimethylformamide, adding a compound d to obtain a reaction system, dropwise adding an acid-binding agent in ice bath, stirring for 5min, reacting for 12H at 40 ℃, extracting and purifying the reaction liquid to obtain the thiazole-ring-containing pyrazole carboxamide derivative, wherein the acid-binding agent is triethylamine.
7. The process for producing a thiazole ring-containing pyrazole carboxamide derivative according to claim 6, characterized in that the molar ratio of the compound d to 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid is 1:1.2, the molar equivalent ratio of the compound d to 2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate is 1:2, and the molar equivalent ratio of the compound d to an acid-binding agent is 1:1.5.
8. Use of a thiazole ring-containing pyrazole carboxamide derivative according to any of claims 1 to 2 for the preparation of an antifungal medicament.
CN202310819486.0A 2023-07-06 2023-07-06 Thiazole ring-containing pyrazole carboxamide derivative and preparation method and application thereof Pending CN116969930A (en)

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