CN113200924A - 4-amino-5-pyrimidine formamide compound and preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of bactericides, and particularly relates to a 4-amino-5-pyrimidine formamide compound and a preparation method and application thereof. The 4-amino-5-pyrimidine formamide compound provided by the invention shows certain activity on test strains (tomato early blight, wheat scab, rice blast, phytophthora capsici, sclerotium rolfsii, cucumber gray mold, rice sheath blight and castor wilt) under the dosage of 50mg/L, and the compound 2 and the compound 10 have good inhibitory activity on the rice blast bacteria, which can reach more than 90%, and have over 60% inhibitory activity on the sclerotium rolfsii, which indicates that the compound has the potential to be used as a bactericide.
Description
Technical Field
The invention relates to the technical field of bactericides, and in particular relates to a 4-amino-5-pyrimidine formamide compound and a preparation method and application thereof.
Background
The bactericide is a pesticide with important significance. Succinate Dehydrogenase (SDH) is present in the mitochondrial electron transport respiratory chain, and its role is to catalyze the transfer of electrons. The inhibition of the activity of SDH can indirectly block the tricarboxylic acid cycle, thereby achieving the purpose of bacteriostasis. Therefore, succinate dehydrogenase inhibitor (SDHI) fungicides have been developed. SDHI fungicides mostly have three components, namely an amide bond, an amine moiety, often a substituted phenyl group, which is linked to the N atom, and an acid moiety, often a five-or six-membered heterocyclic ring.
In the sixties of the twentieth century, the first SDHI bactericide carboxin was developed, and later in 1973, oxycarboxin was developed. It has good effect on rust of vegetables and grains.
Furametpyr was discovered and developed by Sumitomo chemical industries, Inc. in 1989. Furametpyr has good systemic property, excellent conduction and infiltration.
New SDHI-type fungicides have been developed since the new century. Comprises boscalid and fluxapyroxad which are pyridine amide bactericides of Basf company; bixafen and other bactericides of Bayer crop science companies can show the advantages of high activity, multiple applicable crops and the like, and are hot spots for research of bactericides.
Disclosure of Invention
The invention aims to provide a 4-amino-5-pyrimidine formamide compound which has better bactericidal activity. The structure of the compound is different from the reported compound, and the structure is novel.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a 4-amino-5-pyrimidine formamide compound which is characterized by having a structure shown in formula I
Wherein R is1And R2Independently is a hydrogen, methyl, ethyl, or halogen atom, R3Is a substituted hydrocarbon group or an alkoxycarbonylalkyl group having 4 to 5 carbon atoms, R4Is a substituted hydrocarbon group or an alkoxycarbonylalkyl group having 4 to 5 carbon atoms
The invention provides a preparation method of a 4-amino-5-pyrimidine formamide compound in the technical scheme, which comprises the following steps:
4-aminopyrimidine-5-carboxylic acid, N, N-dimethylformamide, a polypeptide condensation reagent 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP) and R1、R2、R3Substituted benzoxazinones or R4Mixing substituted tetra-substituted aniline, and carrying out a first substitution reaction to obtain the target 4-amino-5-pyrimidine formamide compound
The invention provides application of the 4-amino-5-pyrimidine formamide compound in the technical scheme as a bactericide.
The invention provides a 4-amino-5-pyrimidine formamide compound, which has certain inhibitory activity on early blight of tomato, gibberella cerealis and pyricularia oryzae at 50mg/L, can particularly have good inhibitory effect on pyricularia oryzae, and can reach more than 90%.
Detailed Description
The invention provides a 4-amino-5-pyrimidine formamide compound which has a structure shown in a formula I:
wherein R is1And R2Independently is a hydrogen, methyl, ethyl, or halogen atom, R3Is a substituted hydrocarbon group or an alkoxycarbonylalkyl group having 4 to 5 carbon atoms, R4Is a substituted hydrocarbon group or an alkoxycarbonylalkyl group having 4 to 5 carbon atoms
In the present invention, when said R is1Hydrogen, R2Hydrogen, R3When the compound is propargyl, the 4-amino-5-pyrimidine carboxamide compound is marked as compound 1;
when said R is1Hydrogen, R2Hydrogen, R3When the compound is propargyl, the 4-amino-5-pyrimidine carboxamide compound is marked as compound 2;
when said R is1Hydrogen, R2Hydrogen, R3When the aryl group is substituted by allyl, the 4-amino-5-pyrimidine carboxamide compound is represented as compound 3;
when said R is1Hydrogen, R2Methyl, R3When the compound is propargyl, the 4-amino-5-pyrimidine carboxamide compound is marked as compound 4;
when said R is1Hydrogen, R2Hydrogen, R3When the compound is methoxy ethyl, the 4-amino-5-pyrimidine formamide compound is marked as a compound 5;
when said R is1Fluorine, R2Fluorine, R3The 4-amino-5-pyrimidinecarboxamides are identified as compound 6;
when said R is4When the compound is propargyl, the 4-amino-5-pyrimidine carboxamide compound is marked as compound 7;
when said R is4When the compound is propargyl, the 4-amino-5-pyrimidinecarboxamides are depicted as compound 8.
When said R is4When the compound is allyl, the 4-amino-5-pyrimidine carboxamide compound is represented as compound 9
When said R is4When the compound is fluorine propyl, the 4-amino-5-pyrimidine formamide compound is marked as a compound 10
The invention provides a preparation method of a 4-amino-5-pyrimidine formamide compound in the technical scheme, which comprises the following steps:
4-aminopyrimidine-5-carboxylic acid, N, N-dimethylformamide, a polypeptide condensation reagent 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP) and R1、R2、R3Substituted benzoxazinones or R4And mixing the substituted tetra-substituted phenylamine, and carrying out a first substitution reaction to obtain the target 4-amino-5-pyrimidine formamide compound.
In the present invention, unless otherwise specified, all the starting materials required for the preparation are commercially available products well known to those skilled in the art.
The invention relates to a method for preparing 4-aminopyrimidine-5-carboxylic acid, N, N-dimethylformamide, a polypeptide condensation reagent 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP) and R1、R2、R3Substituted benzoxazinones or R4And mixing the substituted tetra-substituted aniline, and carrying out condensation reaction to obtain the target 4-amino-5-pyrimidine formamide compound. In the invention, the addition sequence of the components in the mixing process is preferably 4-aminopyrimidine-5-carboxylic acid, N, N-dimethylformamide, a polypeptide condensation reagent 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), and N, N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP) and R are added after mixing for 1h1、R2、R3Substituted benzoxazinones or R4Substituted tetra-substituted anilines. The mixing technique is a mixing process well known to those skilled in the art, and can be used to mix the components uniformly. In the present invention, with said R1、R2、R3When the substituted benzoxazinone intermediate is reacted, the ratio of the benzoxazinone intermediate to 4-aminopyrimidine-5-carboxylic acid, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and N, N-Diisopropylethylamine (DIPEA) is preferably 1:1.2:1.44:2.88, the temperature is preferably room temperature, and the time is preferably 12 h. In the present invention, with said R4Tetra-substitution during reaction of substituted tetra-substituted aniline intermediateThe ratio of the aniline intermediate to 4-aminopyrimidine-5-carboxylic acid, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and N, N-Diisopropylethylamine (DIPEA) is preferably 1:2:2.4:4.8, the temperature is preferably 50-60 ℃, and the time is preferably 24-32 h. After the above condensation reaction is completed, the present invention preferably adds the system to ice water under stirring so that the ratio of the total volume to the original volume after mixing is 5:1, then performs suction filtration and drying on the precipitated solid and performs extraction operation on the filtrate. The preferable drying mode of the invention is vacuum drying, the solvent used for extraction is preferably Ethyl Acetate (EA), the operation performed on the filtrate is preferably flash column chromatography separation by using 300-400-mesh silica gel as a stationary phase and using a mixed solution of dichloromethane and ethyl acetate with a volume ratio of 1:5 as a mobile phase.
The invention provides application of the 4-amino-5-pyrimidine formamide compound in the technical scheme as a bactericide. The method of applying the 4-amino-5-pyrimidine carboxamide compound as a bactericide in the present invention is not particularly limited, and a method known to those skilled in the art may be selected.
The following examples are provided to illustrate the 4-amino-5-pyrimidinecarboxamides of the present invention and their preparation and use in detail, but they should not be construed as limiting the scope of the present invention.
Example 1
334mg (2.4mmol,1.2eq) of 4-aminopyrimidine-5-carboxylic acid was charged in a 50mL round-bottomed flask, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and N, N-Dimethylformamide (DMF) were added, and stirred magnetically at room temperature for 1h to activate the carboxylic acid. After activation, 0.66mL of N, N-Diisopropylethylamine (DIPEA), 440mg (2.0mmol,1.0eq) of 4-propargyl-6-amino-7-fluoro-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one, and a catalytic amount of 4-Dimethylaminopyridine (DMAP) were added sequentially. After 8h at room temperature, the reaction was complete by TLC. Ice water was added to the system under stirring to precipitate a large amount of pale yellow solid, which was filtered with suction and washed with water, and dried under vacuum to give 430mg of pale yellow solid in 63.2% yield.
The structural characterization data of the 4-amino-5-pyrimidinecarboxamides described in example 1 are:1H NMR(400MHz,DMSO-d6) δ 10.28(s,1H),8.82(s,1H),8.51(s,1H),7.82(s,2H),7.37(d, J ═ 7.3Hz,1H),7.14(d, J ═ 10.5Hz,1H),4.77(s,2H),4.70(d, J ═ 2.0Hz,2H),3.33(t, J ═ 2.2Hz, 1H); the melting point was 241-243 ℃.
Example 2
167mg (1.2mmol,1.2eq) of 4-aminopyrimidine-5-carboxylic acid was charged in a 50mL round-bottomed flask, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and N, N-Dimethylformamide (DMF) were added, and stirred magnetically at room temperature for 1h to activate the carboxylic acid. After activation, 0.33mL of N, N-Diisopropylethylamine (DIPEA), 232mg (1.0mmol,1.0eq) of 4-alkynylbutyl-6-amino-7-fluoro-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one, and a catalytic amount of 4-Dimethylaminopyridine (DMAP) were added in that order. After 8h at room temperature, the reaction was complete by TLC. Ice water was added to the system under stirring to precipitate a large amount of pale yellow solid, which was filtered with suction and washed with water, and dried under vacuum to give 215mg of pale yellow solid with a yield of 61.0%.
The structural characterization data of the 4-amino-5-pyrimidinecarboxamides described in example 2 are:1H NMR(400MHz,CDCl3) δ 8.68(s,1H),8.64(s,1H),8.14(d, J ═ 7.5Hz,1H),7.85(s,1H),6.88(brs,2H),6.87(d, J ═ 10.7Hz,1H),4.66(q, J ═ 2.2Hz, 2H'), 4.64(s,2H),1.82(t, J ═ 2.3Hz, 3H); the melting point is 245-247 ℃.
Example 3
167mg (1.2mmol,1.2eq) of 4-aminopyrimidine-5-carboxylic acid was charged in a 50mL round-bottomed flask, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and N, N-Dimethylformamide (DMF) were added, and stirred magnetically at room temperature for 1h to activate the carboxylic acid. After activation, 0.33mL of N, N-Diisopropylethylamine (DIPEA), 222mg (1.0mmol,1.0eq) of 4-allyl-6-amino-7-fluoro-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one, and a catalytic amount of 4-Dimethylaminopyridine (DMAP) were added sequentially. After 8h at room temperature, the reaction was complete by TLC. Ice water was added to the system under stirring to precipitate a large amount of pale yellow solid, which was filtered with suction and washed with water, and dried under vacuum to give 215mg of pale yellow solid with a yield of 61.0%.
The structural characterization data of the 4-amino-5-pyrimidinecarboxamides described in example 3 are:1H NMR(400MHz,DMSO-d6) δ 10.18(s,1H),8.79(s,1H),8.50(s,1H),7.79(s,2H),7.20(d, J ═ 7.5Hz,1H),7.09(d, J ═ 10.9Hz,1H),5.86(ddt, J ═ 17.3,10.2,5.1Hz,1H),5.20-5.15(m,2H),4.77(s,2H),4.50(s, 2H); the melting point is 212-215 ℃.
Example 4
167mg (1.2mmol,1.2eq) of 4-aminopyrimidine-5-carboxylic acid was charged in a 50mL round-bottomed flask, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and N, N-Dimethylformamide (DMF) were added, and stirred magnetically at room temperature for 1h to activate the carboxylic acid. After activation, 0.33mL of N, N-Diisopropylethylamine (DIPEA), 232mg (1.0mmol,1.0eq) of 6-amino-7-fluoro-2-methyl-4-propargyl-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one, and a catalytic amount of 4-Dimethylaminopyridine (DMAP) were added in that order. After 8h at room temperature, the reaction was complete by TLC. Ice water was added to the system under stirring to precipitate a large amount of pale yellow solid, which was filtered and washed with water, and dried under vacuum to give 220mg of pale yellow solid with a yield of 62.4%.
The structural characterization data of the 4-amino-5-pyrimidinecarboxamides described in example 4 are:1H NMR(400MHz,CDCl3) δ 8.66(s,1H),8.64(s,1H),8.15(d, J ═ 7.4Hz,1H),7.86(s,1H),6.88(d, J ═ 10.8Hz,1H),6.87(brs,2H),4.79(dd, J ═ 17.7,2.5Hz,1H),4.67(q, J ═ 6.9Hz,1H),4.66(dd, J ═ 17.6,2.6Hz,1H),2.31(t, J ═ 2.5Hz 1H),1.59(d, J ═ 6.8Hz, 3H); its melting point is 237-240 ℃.
Example 5
208mg (1.5mmol,1.5eq) of 4-aminopyrimidine-5-carboxylic acid was charged in a 50mL round-bottomed flask, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and N, N-Dimethylformamide (DMF) were added, and stirred magnetically at room temperature for 1h to activate the carboxylic acid. After activation, N-Diisopropylethylamine (DIPEA)0.33mL, 4-alkynylbutyl-6-amino-7-fluoro-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one 233mg (1.0mmol,1.0eq), catalytic amount of 4-Dimethylaminopyridine (DMAP) were added sequentially. After 8h at room temperature, the reaction was complete by TLC. Ice water was added to the system under stirring to precipitate a large amount of pale yellow solid, which was filtered with suction and washed with water, and dried under vacuum to give 221mg of pale yellow solid with a yield of 62.4%.
The structural characterization data of the 4-amino-5-pyrimidinecarboxamides described in example 5 are:1H NMR(400MHz,CDCl3) δ 8.66(s,1H),8.63(s,1H),8.15(d, J ═ 7.6Hz,1H),7.85(s,1H),6.86(brs,2H),6.85(d, J ═ 10.7Hz,1H),4.62(s,2H),4.13(t, J ═ 5.4Hz,2H),3.70(t, J ═ 5.4Hz,2H),3.40(s, 3H); the melting point is 165-170 ℃.
Example 6
208mg (1.5mmol,1.2eq) of 4-aminopyrimidine-5-carboxylic acid was charged in a 50mL round-bottomed flask, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and N, N-Dimethylformamide (DMF) were added, and stirred magnetically at room temperature for 1h to activate the carboxylic acid. After activation, 0.33mL of N, N-Diisopropylethylamine (DIPEA), 256mg (1.0mmol,1.0eq) of 6-amino-2, 2, 7-trifluoro-4-propargyl-2H-benzo [ b ] [1,4] oxazin-3 (4H) one, and a catalytic amount of 4-Dimethylaminopyridine (DMAP) were sequentially added. After 8h at room temperature, the reaction was complete by TLC. Ice water was added to the system under stirring to precipitate a large amount of pale yellow solid, which was filtered and washed with water, and dried under vacuum to give 110mg of pale yellow solid with a yield of 29.0%.
The structural characterization data of the 4-amino-5-pyrimidinecarboxamides described in example 6 are:1H NMR(400MHz,CDCl3) δ 8.71(s,1H),8.64(s,1H),8.40(d, J ═ 7.2Hz,1H),8.19(s,1H),7.11(d, J ═ 10.1Hz,1H),6.90(brs,2H),4.83(d, J ═ 2.2Hz,2H),2.38(t, J ═ 2.4Hz, 1H); the melting point is 175-178 ℃.
Example 7
Synthesis of 4-amino-N- (5- (5- (2-propargyloxy) -4-chloro-2-fluorophenyl) pyrimidine-5-carboxamide in a 100mL round-bottomed flask to which 1112mg (1.5mmol,1.5eq) of 4-aminopyrimidine-5-carboxylic acid had been added 30mL of DMF was added with electromagnetic stirring, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) was added, the substrate was activated by stirring in an oil bath at 50 ℃ for 1h, then 0.49mL of N, N-Diisopropylethylamine (DIPEA), 199mg (1.0mmol,1.0eq) of 5- (2-propargyloxy) -4-chloro-2-fluoroaniline, a catalytic amount of 4-Dimethylaminopyridine (DMAP) were added in that order, the system darkens in color. After the temperature is raised to 60 ℃ and the reaction is carried out for 32 hours, little raw material is remained by TLC detection, and the reaction is stopped. Dropping the system into a 500mL beaker containing crushed ice under stirring, extracting the system, and then performing column chromatography by using 200-mesh 300-mesh silica gel as a stationary phase and using a mixed solution of V (EA) and V (DCM) 5:1 as a mobile phase to obtain 90mg of light yellow dry and comfortable solid, wherein the yield is 28.2 percent
The structural characterization data of the 4-amino-5-pyrimidinecarboxamides described in example 7 are:1H NMR(400MHz,CDCl3) δ 8.67(s,1H),8.66(s,1H),8.26(d, J ═ 7.1Hz,1H),8.04(s,1H),7.27(d, J ═ 10.7Hz,1H),6.87(brs,2H),4.83(d, J ═ 2.4Hz,1H),2.61(t, J ═ 2.4Hz, 1H); the melting point is 219-222 ℃.
Example 8
Synthesis of 4-amino-N- (5- (5- (2-alkynbutoxy) -4-chloro-2-fluorophenyl) pyrimidine-5-carboxamide in a 100mL round-bottomed flask to which had been added 1112mg (8.0mmol,2.0eq) of 4-aminopyrimidine-5-carboxylic acid, 50mL of DMF was added with electromagnetic stirring, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU)3648mg (9.6mmol,2.4eq) was added, the substrate was activated by oil bath at 50 ℃ and stirring for 1h, then 2.00mL of N, N-Diisopropylethylamine (DIPEA), 852mg (4.0mmol,1.0eq) of 5- (2-alkynbutoxy) -4-chloro-2-fluoroaniline, Catalytic amount of 4-Dimethylaminopyridine (DMAP) and the system becomes dark in color. After the temperature is raised to 60 ℃ and the reaction is carried out for 32 hours, little raw material is remained by TLC detection, and the reaction is stopped. Dropwise adding the system into a 500mL beaker containing crushed ice under stirring to ensure that the total volume of liquid after the ice is melted reaches 250mL, separating out a large amount of brown solid, performing suction filtration and water washing, drying to obtain black solid, dissolving the black solid by ethyl acetate under ultrasound, then performing column chromatography separation by using 200-plus-300-mesh silica gel as a stationary phase and using a mixed solution of V (DCM) 5:1 as a mobile phase to obtain 254mg of light yellow dry solid, wherein the yield is 18.4 percent
The structural characterization data of the 4-amino-5-pyrimidinecarboxamides described in example 8 are:1H NMR(400MHz,CDCl3) δ 8.65(s,1H),8.63(s,1H),8.18(d, J ═ 7.1Hz,1H),7.92(s,1H),7.23(d, J ═ 10.2Hz,1H),6.86(s,1H),4.76(d, J ═ 2.2Hz,1H),1.88(t, J ═ 2.1Hz, 3H); its melting point was 214-217 ℃.
Example 9
Synthesis of 4-amino-N- (5- (5- (2-alkynbutoxyl) -4-chloro-2-fluorophenyl) pyrimidine-5-carboxamide in a 100mL round bottom flask to which 556mg (4.0mmol,2.0eq) of 4-aminopyrimidine-5-carboxylic acid had been added 50mL of DMF was added with electromagnetic stirring, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) was added through an oil bath at 50 ℃ and stirred for 1h to activate the substrate, then 1.31mL of N, N-Diisopropylethylamine (DIPEA), 522mg (4mmol,1.0eq) of 5- (2-allyloxy) -4-chloro-2-fluoroaniline, a catalytic amount of 4-Dimethylaminopyridine (DMAP) were added in sequence, the system darkens in color. After the temperature is raised to 60 ℃ and the reaction is carried out for 32 hours, little raw material is remained by TLC detection, and the reaction is stopped. Adding dropwise the system into 500mL beaker containing crushed ice under stirring to make the total volume of the liquid reach 250mL after ice melting, performing suction filtration, washing with water, and drying to obtain 282mg of black solid with yield of 22.0%
The structural characterization data of the 4-amino-5-pyrimidinecarboxamides described in example 8 are:1H NMR(400MHz,CDCl3) δ 8.64(s,1H),8.63(s,1H),8.08(d, J ═ 7.1Hz,1H),7.91(s,1H),7.23(d, J ═ 10.2Hz,1H),6.85(brs,2H),6.08(ddt, J ═ 17.3,10.2,5.1Hz,1H),5.36-5.31(m,2H),4.65(d, J ═ 5.1Hz, 2H); the melting point is 204-205 ℃.
Example 10
Synthesis of 4-amino-N- (5- (5- (2-alkynbutoxyl) -4-chloro-2-fluorophenyl) pyrimidine-5-carboxamide 50mL of DMF was added to a 100mL round bottom flask to which 1112mg (8.0mmol,2.0eq) of 4-aminopyrimidine-5-carboxylic acid had been added, stirred magnetically, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) was added to activate the substrate by oil bath at 50 ℃ and stirring for 1h, then 2.00mL of N, N-Diisopropylethylamine (DIPEA), 968mg (4.0mmol,1.0eq) of 5- (2-fluoropropoxy) -4-chloro-2-fluoroaniline, a catalytic amount of 4-Dimethylaminopyridine (DMAP) were added in sequence, the system darkens in color. After the temperature is raised to 60 ℃ and the reaction is carried out for 32 hours, little raw material is remained by TLC detection, and the reaction is stopped. Dropwise adding the system into a 500mL beaker containing crushed ice under stirring to ensure that the total volume of liquid after the ice is melted reaches 250mL, separating out a large amount of brown solid, performing suction filtration and water washing, drying to obtain black solid, dissolving the black solid by ethyl acetate under ultrasound, then performing column chromatography by using 200-mesh and 300-mesh silica gel as a stationary phase and using a mixed solution of V (DCM) 5:1 as a mobile phase to obtain 225mg of light yellow dry solid, wherein the yield is 16.0 percent of the knot of the 4-amino-5-pyrimidine carboxamide compound described in the example 10The characterization data are:1H NMR(400MHz,CDCl3) δ 8.67(s,1H),8.64(s,1H),8.08(d, J ═ 6.8Hz,1H),7.91(s,1H),7.22(d, J ═ 9.4Hz,1H),6.85(brs,2H),4.70(dt, J ═ 47.2,5.3Hz,2H),4.13(dt, J ═ 53.1,6.01Hz,2H),2.29-2.14(m, 2H); the melting point was 195-198 ℃.
Application example
Preliminary biological activity measurements were performed on the 4-amino-5-pyrimidinecarboxamides prepared in examples 1 to 10:
TABLE 1 bacteriostatic Activity of pyrimidinecarboxamides
The compound shows over 40 percent of inhibitory activity on tomato early blight bacteria at 50mg/L, and compounds 2 and 4. The inhibition rate of the compound 10 to the gibberella zeae is over 40 percent. In addition, the compounds 9, 10 and 2 have good inhibitory activity on rice blast fungi, and the inhibitory activity can reach more than 90%. The inhibition rate of the compounds 2, 4 and 10 to the sclerotinia sclerotiorum is over 60 percent. For Rhizoctonia solani, compounds 2 and 10 showed an inhibition rate of more than 40%
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. A4-amino-5-pyrimidine carboxamide compound is characterized by having a structure shown in formula I:
wherein R is1And R2Independently is a hydrogen, methyl, ethyl, or halogen atom, R3Is a substituted hydrocarbyl or alkoxycarbonylalkyl group, R4Is a substituted hydrocarbyl or an alkoxycarbonylalkyl group.
2. The 4-amino-5-pyrimidinecarboxamides according to claim 1 wherein R is1And R2Is methyl or ethyl, and the halogen atom is fluorine atom.
3. 4-amino-5-pyrimidinecarboxamides according to claim 1 characterised in that said R is3Is a substituted hydrocarbon group having 2 to 4 carbon atoms or an alkoxycarbonylalkyl group having 4 to 5 carbon atoms.
4. 4-amino-5-pyrimidinecarboxamides according to claim 1 characterised in that said R is4Is a substituted hydrocarbon group having 2 to 4 carbon atoms or an alkoxycarbonylalkyl group having 4 to 5 carbon atoms.
5. A process for the preparation of a 4-amino-5-pyrimidinecarboxamide compound as claimed in any of claims 1 to 3, comprising the steps of:
4-aminopyrimidine-5-carboxylic acid, N, N-dimethylformamide, a polypeptide condensation reagent 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP) and R1、R2、R3Substituted benzoxazinones or R4And mixing the substituted tetra-substituted phenylamine, and carrying out a first substitution reaction to obtain the target 4-amino-5-pyrimidine formamide compound.
The R is1、R2、R3The substituted benzoxazinones have the structure shown in formula II:
the R is4Substituted tetra-substituted anilines have the structure shown in formula III:
6. the preparation method according to claim 4, wherein the temperature of the condensation with the compound having the structure of formula II is room temperature and the time is 8-24 h.
7. The process according to claim 4, wherein the condensation with the compound of formula III is carried out at a temperature of 30 to 60 ℃ for a period of 18 to 48 hours.
Use of a 4-amino-5-pyrimidinecarboxamide compound as claimed in any of claims 1 to 3 as a fungicide.
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| CN104292169A (en) * | 2013-07-19 | 2015-01-21 | 中国中化股份有限公司 | Substituted pyrimidinamine compound and use thereof |
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