CN113831328A - 6- (benzo 1,3 dioxygen pentacyl) -4 phenyl pyrimidine amide derivative and preparation method and application thereof - Google Patents
6- (benzo 1,3 dioxygen pentacyl) -4 phenyl pyrimidine amide derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN113831328A CN113831328A CN202111168127.0A CN202111168127A CN113831328A CN 113831328 A CN113831328 A CN 113831328A CN 202111168127 A CN202111168127 A CN 202111168127A CN 113831328 A CN113831328 A CN 113831328A
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- Prior art keywords
- benzo
- reaction
- washing
- general formula
- dioxopentacyl
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- 125000005605 benzo group Chemical group 0.000 title claims abstract description 44
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 229910001882 dioxygen Inorganic materials 0.000 title claims abstract description 5
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- -1 6- (benzo 1, 3-dioxolanyl) -4-phenyl pyrimidine Chemical compound 0.000 claims abstract description 26
- 230000000694 effects Effects 0.000 claims abstract description 18
- 241000233866 Fungi Species 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 216
- 238000006243 chemical reaction Methods 0.000 claims description 78
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 76
- 238000005406 washing Methods 0.000 claims description 65
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- 239000007787 solid Substances 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 43
- 239000012153 distilled water Substances 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 238000001035 drying Methods 0.000 claims description 38
- 239000003208 petroleum Substances 0.000 claims description 38
- 125000001424 substituent group Chemical group 0.000 claims description 23
- BMHMKWXYXFBWMI-UHFFFAOYSA-N 3,4-Methylenedioxyacetophenone Chemical compound CC(=O)C1=CC=C2OCOC2=C1 BMHMKWXYXFBWMI-UHFFFAOYSA-N 0.000 claims description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 21
- 238000004440 column chromatography Methods 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 21
- 230000002829 reductive effect Effects 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- 229920006395 saturated elastomer Polymers 0.000 claims description 21
- 239000000741 silica gel Substances 0.000 claims description 21
- 229910002027 silica gel Inorganic materials 0.000 claims description 21
- 238000004809 thin layer chromatography Methods 0.000 claims description 19
- 239000002244 precipitate Substances 0.000 claims description 17
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 16
- IATXFPUBPMZBPH-UHFFFAOYSA-N (n'-carbamoylcarbamimidoyl)azanium;sulfate Chemical compound OS(O)(=O)=O.NC(N)=NC(N)=O.NC(N)=NC(N)=O IATXFPUBPMZBPH-UHFFFAOYSA-N 0.000 claims description 13
- SQSPRWMERUQXNE-UHFFFAOYSA-N Guanylurea Chemical compound NC(=N)NC(N)=O SQSPRWMERUQXNE-UHFFFAOYSA-N 0.000 claims description 13
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 8
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 6
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims description 6
- 230000003032 phytopathogenic effect Effects 0.000 claims description 5
- 238000012544 monitoring process Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 3
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- 239000000203 mixture Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- XNEUMNKLWSLQOH-UHFFFAOYSA-N 4-phenylpyrimidine-2-carboxamide Chemical class NC(=O)C1=NC=CC(C=2C=CC=CC=2)=N1 XNEUMNKLWSLQOH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
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- 125000000623 heterocyclic group Chemical group 0.000 abstract description 3
- 230000000854 inhibitional effect Effects 0.000 abstract description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 58
- 239000000243 solution Substances 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 239000000843 powder Substances 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
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- WYEMLYFITZORAB-UHFFFAOYSA-N boscalid Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1NC(=O)C1=CC=CN=C1Cl WYEMLYFITZORAB-UHFFFAOYSA-N 0.000 description 15
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- 229940118790 boscalid Drugs 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
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- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 2
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- 230000009036 growth inhibition Effects 0.000 description 1
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- 239000003446 ligand Substances 0.000 description 1
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- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
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- 239000012452 mother liquor Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
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- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
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- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
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- WOSNCVAPUOFXEH-UHFFFAOYSA-N thifluzamide Chemical compound S1C(C)=NC(C(F)(F)F)=C1C(=O)NC1=C(Br)C=C(OC(F)(F)F)C=C1Br WOSNCVAPUOFXEH-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The invention discloses a 6- (benzo 1,3 dioxygen five-ring group) -4 phenyl pyrimidine amide derivative, a preparation method and an application thereof, wherein the derivative has a general formula I:
wherein, R is independently selected from H, halogen, alkyl and alkoxy; the nitrogenous heterocyclic 6- (benzo 1, 3-dioxolanyl) -4-phenyl pyrimidine amide derivative has good fungal bioactivity inhibition, and biological activity research shows that the compound has obvious inhibition effect on fungi such as sclerotinia sclerotiorum, alternaria solani, fusarium graminearum and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis and pesticides, and particularly relates to a 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivative, and a preparation method and application thereof.
Background
Plant diseases cause huge losses to agricultural and under-forest resources, and the use of bactericides is the most economical and effective method for preventing and treating plant diseases. Therefore, antifungal pesticides play an important role in reducing the enormous losses of plant diseases to agricultural production. The use of agricultural chemicals not only causes pollution to the ecological environment, but also easily causes plant germs, pests, weeds and the like to have drug resistance by using a single agricultural chemical variety for a long time, and in order to effectively treat the pests, it is necessary to develop a new agricultural chemical variety having a novel action mechanism (targeting action). Therefore, there is an urgent need to develop novel antifungal agents having better therapeutic effects on plant pathogenic bacteria.
Heterocyclic compounds have attracted a great deal of interest in the development of medicines and pesticides because of their outstanding physicochemical and pharmaceutical properties. Pyrimidine compounds have a variety of biological activities, such as antitumor, antibacterial, antifungal, insecticidal, herbicidal, and the like, and thus are receiving increasing attention. Many pyrimidines are being developed as commercial drugs such as lamivudine, raltegravir, imatinib, etc. In addition, amide bonds are also a key component of many drugs or pesticides, such as fluoropyram, penflufen, bixafen, fluxapyroxad, and the like. In particular, aromatic carboxamides such as thifluzamide, isopyrazam, benodanil, etc. have attracted much attention due to their commercialization as crop protection agents.
Therefore, a pyrimidine unit structure is introduced during compound design, and a drug guide with excellent antifungal activity is searched, so that the method has good theoretical and practical significance for researching and developing novel antifungal pesticide and preventing and treating agricultural and forestry crop diseases and insect pests.
Disclosure of Invention
This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.
The present invention has been made keeping in mind the above and/or other problems occurring in the prior art.
Accordingly, it is an object of the present invention to overcome the deficiencies of the prior art and to provide a class of 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivatives having activity against phytopathogenic fungi.
In order to solve the technical problems, the invention provides the following technical scheme: a class of 6- (benzo 1,3 dioxolanyl) -4-phenylpyrimidine amide derivatives having activity against phytopathogenic fungi, said derivatives having the general formula I:
wherein, R is respectively selected from H, halogen, alkyl and alkoxy.
As a preferable embodiment of the 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivative of the present invention, wherein: the derivatives are compounds from I-a to I-o:
the invention aims to overcome the defects in the prior art and provide a preparation method of 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivatives with anti-plant pathogenic fungi activity.
In order to solve the technical problems, the invention provides the following technical scheme: a process for the preparation of 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivatives comprising,
the 3, 4-methylene dioxy acetophenone and benzaldehyde with different substituents are subjected to aldol condensation reaction to generate ketene with different substituents, namely the ketene with the structure shown in the general formula II:
reacting acetophenone with different substituents and N-guanylurea sulfate to obtain 6- (benzo 1,3 dioxy pentacyl) -4 (substituted phenyl) pyrimidine amide I:
as a preferable embodiment of the method for preparing the 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivative of the present invention, wherein: comprises the steps of (a) preparing a mixture of a plurality of raw materials,
adding benzaldehyde and 3,4- (methylenedioxy) acetophenone with different substituents into absolute ethyl alcohol, adding sodium hydroxide at room temperature, stirring and reacting for 3-5 h, monitoring by thin-layer chromatography, filtering a precipitate, washing with petroleum ether, and drying to obtain a general formula II structure with different substituents, wherein the general formula II structure is a yellow solid, and the yield is 85-92%;
adding guanylurea N-sulfate and general formula II with different substituents into absolute ethyl alcohol, adding sodium hydroxide at room temperature, gradually heating to 78 ℃, stirring and reacting for 3-7 hours, monitoring the reaction process by adopting a thin-layer chromatography, adding distilled water after the reaction is finished, extracting for 2-3 times by using dichloromethane, washing for 2-3 times by using distilled water, washing for 1 time by using saturated sodium bicarbonate, washing for 1 time by using saturated salt, drying by using anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on a crude product by using 200-300-mesh silica gel, and purifying by using petroleum ether/ethyl acetate in a volume ratio of 100:1-2:1 to obtain a powdery solid of general formula I.
As a preferable embodiment of the method for preparing the 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivative of the present invention, wherein: the molar ratio of the benzaldehyde to the 3,4- (methylenedioxy) acetophenone is 1: 1.
As a preferable embodiment of the method for preparing the 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivative of the present invention, wherein: the molar ratio of the general formula II with different substituents to the N-guanylurea sulfate is 1: 2-1: 6.
As a preferable embodiment of the method for preparing the 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivative of the present invention, wherein: the substituent of the general formula II with different substituents is any one of 3 fluorophenyl, 2 furyl, 4 trifluoromethylphenyl, 3 methoxyphenyl, 4 fluorophenyl, 4 methylphenyl, 4 cyanophenyl, 2,5 dimethoxyphenyl, 4 chlorophenyl, 4 bromophenyl, 2 fluorophenyl, 3,4,5 trimethoxyphenyl, 3,4 difluorophenyl, phenyl and 2,4 difluorophenyl.
Another object of the present invention is to overcome the disadvantages of the prior art and to provide a class of 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivatives having activity against phytopathogenic fungi for use against phytopathogenic fungi.
The invention has the beneficial effects that:
the nitrogenous heterocyclic 6- (benzo 1, 3-dioxolanyl) -4-phenyl pyrimidine amide derivative has good fungal bioactivity inhibition, and biological activity research shows that the compound has obvious inhibition effect on fungi such as sclerotinia sclerotiorum, alternaria solani, fusarium graminearum and the like.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without inventive exercise. Wherein:
FIG. 1 is a graph comparing the effect of treating Fusarium graminearum with different concentrations of Boscalid on PDA medium in the examples of the invention.
FIG. 2 is a molecular docking diagram of I-j and boscalid of the present invention, wherein a.I-j; bosscalid.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, specific embodiments thereof are described in detail below with reference to examples of the specification.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Furthermore, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivatives I-a to I-o with the structure shown in the general formula I have good antifungal activity.
Wherein, R corresponding to I-a to I-o is respectively selected from H, halogen, alkyl and alkoxy.
The invention relates to a preparation method of 6- (benzo 1,3 dioxygen pentacyl) -4 phenyl pyrimidine amide derivatives I-a to I-o with the structure shown in the general formula I, which is characterized by comprising the following steps:
1) the 3, 4-methylene dioxy acetophenone and benzaldehyde with different substituents are subjected to aldol condensation reaction to generate ketene with different substituents, namely the ketene with the structure shown in the general formula II:
2) acetophenone with different substituents reacts with N-guanylurea sulfate to prepare the 6- (benzo 1,3 dioxy five ring group) -4 (substituted phenyl) pyrimidine amide derivative I.
Example 1
Synthesis of 6- (benzo 1,3 dioxopentacyclyl) -4 (2-fluorophenyl) -pyrimidinamide I-a
In step (1), in a round-bottom flask, 3-fluorobenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 4h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 3-fluoro substituent group with the structure shown in the general formula II and a yellow solid.
In step (2), the 3-fluoro substituent of formula II (1.0mmol) and the guanylurea N-sulfate (2.0mmol) are added to 15ml of anhydrous ethanol and sodium hydroxide (NaOH, 4.0mmol) is added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 3 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, finally drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, finally performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-a with the yield of 55.7%.
Light yellow powder solid；mp＝213.1-214.0℃；Yield:55.7％；1H NMR(600 MHz,DMSO-d6)δ6.16(s,2H),7.13(d,J＝8.2Hz,1H),7.43(td,J＝8.5,2.6Hz, 1H),7.63(td,J＝8.1,6.0Hz,1H),7.88(d,J＝1.7Hz,1H),7.90(dd,J＝8.2,1.8Hz, 1H),8.09–8.13(m,2H),8.14(s,1H),8.54(s,2H),9.63(s,1H).13C NMR(151 MHz,DMSO-d6)δ101.88,102.03,102.33,107.47,108.74,113.93,114.08,117.63, 122.21,123.47,131.00,131.05,131.79,148.33,149.85,155.23,164.26,164.92.
Example 2
Synthesis of 6- (benzo 1,3 dioxopentacyl) -4 (2-furyl) -pyrimidinamides I-b
Further, in step (1), in a round-bottom flask, furfural (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 3h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the furan substituent group with the structure shown in the general formula II and yellow solid.
In step (2), formula II (1.0mmol) of the furan substituent and guanylurea N-sulfate (2.0mmol) were added to 15ml of anhydrous ethanol and sodium hydroxide (NaOH, 4.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 3 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, finally drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, finally performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-b with the yield of 49.7%.
Yellow powder solid；mp＝247.1-248.5℃；Yield:49.7％；1H NMR(600MHz, DMSO-d6)δ6.15(s,2H),6.77(dd,J＝3.4,1.6Hz,1H),7.10(d,J＝8.2Hz,1H), 7.53(d,J＝3.4Hz,1H),7.78(d,J＝1.6Hz,1H),7.82(dd,J＝8.2,1.6Hz,1H),7.84(s, 1H),8.00-8.03(m,1H),8.65(s,2H),9.54(s,1H).13C NMR(151MHz,DMSO-d6)δ 40.53,102.30,103.69,107.43,109.03,113.30,114.11,122.64,130.49,146.77,148.58, 150.58,151.22,155.28,155.85,158.86,164.58.
Example 3
Synthesis of 6- (benzo 1,3 dioxopentacyl) -4 (4-trifluoromethylphenyl) -pyrimidinamides I-c
Further, in step (1), in a round-bottom flask, 4-trifluoromethylbenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 4-trifluoromethyl substituent with the structure shown in the general formula II and yellow solid.
In step (2), 4-trifluoromethyl substituted formula II (1.0mmol) and N-guanylurea sulfate (2.0mmol) were added to 15ml of absolute ethanol and sodium hydroxide (NaOH, 4.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 3 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-c with the yield of 68.5%.
Yellow powder solid；mp＝153.4-154.3℃；Yield:68.5％；1H NMR(600MHz, DMSO-d6)δ6.16(s,2H),7.13(d,J＝8.2Hz,1H),7.87(s,1H),7.90(d,J＝8.3Hz, 1H),7.95(d,J＝8.1Hz,2H),8.18(s,1H),8.46(d,J＝8.0Hz,2H),8.50(s,1H),9.68(s, 1H).13C NMR(151MHz,DMSO-d6)δ40.53,102.06,102.28,107.45,108.77, 122.24,125.94,128.21,131.72,148.35,149.91,164.34,165.08.
Example 4
Synthesis of 6- (benzo 1,3 dioxopentacyl) -4 (3-methoxyphenyl) -pyrimidinamide I-d
Further, in step (1), 3-methoxybenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol in a round-bottom flask, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 3-methoxyl substituent general formula II structure, yellow solid.
In step (2), 3-methoxy substituted formula II (1.0mmol) and N-guanylurea sulfate (2.0mmol) were added to 15ml of anhydrous ethanol and sodium hydroxide (NaOH, 4.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 3 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-d with the yield of 51.5%.
Light yellow powder solid；mp＝185.1-187.2℃；Yield:51.5％；1H NMR(600 MHz,DMSO-d6)δ3.87(s,3H),6.15(s,2H),7.12(d,J＝8.2Hz,1H),7.16(dd,J＝ 8.1,2.3Hz,1H),7.49(t,J＝7.9Hz,1H),7.78(s,1H),7.83(d,J＝7.6Hz,1H),7.87(d, J＝1.4Hz,1H),7.88-7.91(m,1H),8.07(s,1H),8.63(s,2H),9.57(s,1H).13C NMR (151MHz,DMSO-d6)δ55.79,102.29,106.02,107.70,109.01,113.09,117.23,120.02, 122.80,130.48,130.69,138.18,148.57,150.52,155.34,158.91,160.20,164.74,164.79.
Example 5
Synthesis of 6- (benzo 1,3 dioxopentacyclyl) -4 (4-fluorophenyl) -pyrimidinamide I-e
Further, in step (1), in a round-bottom flask, 4-fluorobenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 4-fluoro substituent general formula II structure, yellow solid.
In step (2), the 4-fluoro substituent of formula II (1.0mmol) and the guanylurea N-sulfate (4.0mmol) are added to 15ml of anhydrous ethanol and sodium hydroxide (NaOH, 8.0mmol) is added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 3 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, finally drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, finally performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-e with the yield of 59.3%.
Light yellow powder solid；mp＝193.2-195.4℃；Yield:59.3％；1H NMR(600 MHz,DMSO-d6)δ6.12(s,2H),6.69(s,2H),7.06(d,J＝8.1Hz,1H),7.35(t,J＝8.8 Hz,2H),7.67(s,1H),7.82(d,J＝1.7Hz,1H),7.85(dd,J＝8.1,1.8Hz,1H),8.30(dd, J＝8.8,5.6Hz,2H),9.59(s,1H).13C NMR(151MHz,DMSO-d6)δ101.51,102.01, 107.42,107.82,108.49,108.73,115.25,115.83,115.97,122.11,129.75,129.81,131.91, 148.31,149.77,163.25,164.00,164.25,164.68.
Example 6
Synthesis of 6- (benzo 1,3 dioxopentacyl) -4 (4-methylphenyl) -pyrimidinamides I-f
Further, in step (1), in a round-bottom flask, 4-methylbenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 3h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain 4-methyl substituent general formula II structure, yellow solid.
In step (2), 4-methyl substituted formula II (1.0mmol) and N-guanylurea sulfate (2.0mmol) were added to 15ml of anhydrous ethanol and sodium hydroxide (NaOH, 4.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 4 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-f with the yield of 78.6%.
Light yellow powder solid；mp＝198.7-199.8℃；Yield:78.6％；1H NMR(600 MHz,DMSO-d6)δ2.09(s,3H),6.14(s,2H),6.71(s,1H),7.09(d,J＝41.0Hz,2H), 7.70(d,J＝14.3Hz,1H),7.80(s,1H),7.86(s,1H),8.21(d,J＝8.2Hz,2H),8.51(s, 2H),9.61(s,1H).13C NMR(151MHz,DMSO)δ21.48,102.32,105.52,107.65, 109.06,122.71,127.37,127.66,129.98,133.93,141.74,142.94,148.58,150.47,155.35, 158.97,164.60.
Example 7
Synthesis of 6- (benzo 1,3 dioxopentacyl) -4 (4-cyanophenyl) -pyrimidinamides I-g
Further, in step (1), in a round-bottom flask, 4-cyanobenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 4-cyano substituent general formula II structure, yellow solid.
In step (2), 4-cyano substituted formula II (1.0mmol) and N-guanylurea sulfate (6.0mmol) were added to 15ml of anhydrous ethanol and sodium hydroxide (NaOH, 12.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 5 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, finally drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, finally performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-g with the yield of 52.3%.
Yellow powder solid；mp＝232.6-233.5℃；Yield:52.3％；1H NMR(400MHz, DMSO-d6)δ6.16(s,2H),7.13(d,J＝8.2Hz,1H),7.87(s,1H),7.90(d,J＝8.2Hz, 1H),8.08(d,J＝8.1Hz,2H),8.20(s,1H),8.44(d,J＝8.1Hz,2H),8.65(s,2H),9.69 (s,1H).13C NMR(151MHz,DMSO-d6)δ102.37,106.74,107.70,109.10,113.84, 118.99,122.96,128.50,130.45,133.33,140.98,148.64,150.74,155.16,159.05,163.22, 165.24.
Example 8
Synthesis of 6- (benzo 1, 3-dioxopentacyclyl) -4(2, 5-dimethylphenyl) -pyrimidinamide I-h
Further, in step (1), in a round-bottom flask, 2, 5-dimethylbenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 2, 5-dimethyl substituent general formula II structure, yellow solid.
In step (2), 2, 5-dimethyl substituted amidinourea of formula II (1.0mmol) and N-sulphatoenurea (6.0mmol) were added to 15ml absolute ethanol and sodium hydroxide (NaOH, 12.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 7 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain a powdery solid I-h with the yield of 79.2%.
White powder solid；mp＝109.8-110.6℃；Yield:79.2％；1H NMR(600MHz, DMSO-d6)δ3.76(s,3H),3.81(s,3H),6.11(s,2H),6.63(s,1H),7.04(d,J＝7.1Hz, 1H),7.10(d,J＝9.0Hz,1H),7.36(d,J＝3.2Hz,1H),7.48(s,1H),7.61(d,J＝1.7Hz, 1H),7.65(dd,J＝8.2,1.8Hz,1H),8.32(s,2H),9.54(s,1H).13C NMR(151MHz, DMSO-d6)δ55.78,56.38,101.18,102.44,105.92,107.12,107.98,108.45,111.92, 112.20,114.35,115.70,118.99,146.75,147.46,150.08,153.86.
Example 9
Synthesis of 6- (benzo 1, 3-dioxopentacyclyl) -4 (4-chlorophenyl) -pyrimidinamide I-I
Further, in step (1), in a round-bottomed flask, 4-chlorobenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 3.5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 4-chlorine substituent general formula II structure, yellow solid.
In step (2), the 4-chloro-substituted compound of formula II (1.0mmol) and the guanylurea N-sulfate (4.0mmol) were added to 15ml of anhydrous ethanol and sodium hydroxide (NaOH, 8.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 7 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain a powdery solid I-I with the yield of 71.2%.
White powder solid；mp＝210.7-211.4℃；Yield:71.2％；1H NMR(600MHz, DMSO-d6)δ6.12(s,2H),6.71(s,2H),7.05(d,J＝8.2Hz,1H),7.58(d,J＝8.5Hz, 2H),7.69(s,1H),7.81(s,1H),7.85(d,J＝8.7Hz,1H),8.26(d,J＝8.5Hz,2H),8.53 (s,2H).13C NMR(151MHz,DMSO-d6)δ40.54,101.63,102.03,107.43,108.75, 122.16,129.08,129.23,129.54,131.84,135.60,136.70,148.32,149.82,163.81,164.82.
Example 10
Synthesis of 6- (benzo 1,3 dioxopentacyclyl) -4 (4-bromophenyl) -pyrimidinamide I-j
Further, in step (1), in a round-bottom flask, 4-bromobenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 4-bromine substituent general formula II structure, yellow solid.
In step (2), the 4-bromo substituent of formula II (1.0mmol) and the guanylurea N-sulfate (6.0mmol) are added to 15ml of absolute ethanol and sodium hydroxide (NaOH, 12.0mmol) is added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 5 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain a powdery solid I-j with the yield of 78.5%.
Light yellow powder solid；mp＝223.1-224.5℃；Yield:78.5％；1H NMR(600 MHz,DMSO-d6)δ6.14(d,J＝21.8Hz,2H),6.72(s,1H),7.10(s,1H),7.67-7.75(m, 1H),7.81(s,1H),7.86(s,1H),8.12(s,1H),8.20(dd,J＝15.4,8.2Hz,2H),8.54(s, 2H),9.61(s,1H).13C NMR(151MHz,DMSO-d6)δ101.63,102.02,107.43,108.75, 122.16,129.08,129.23,131.84,135.60,136.70,149.82,164.27,164.82.
Example 11
Synthesis of 6- (benzo 1,3 dioxopentacyclyl) -4 (2-fluorophenyl) -pyrimidinamide I-k
Further, in step (1), in a round-bottom flask, 2-fluorobenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 4.5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 2-fluoro substituent general formula II structure, yellow solid.
In step (2), 2-fluoro substituent of formula II (1.0mmol) and N-guanylurea sulfate (4.0mmol) are added to 15ml of anhydrous ethanol and sodium hydroxide (NaOH, 8.0mmol) is added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 4 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain a powdery solid I-k with the yield of 71.3%.
Light yellow powder solid；mp＝143.8-144.7℃；Yield:71.3％；1H NMR(600 MHz,DMSO-d6)δ6.15(s,2H),7.11(d,J＝8.2Hz,1H),7.39–7.47(m,2H),7.61 (s,1H),7.77(s,1H),7.81(d,J＝7.1Hz,1H),7.86(s,1H),7.99(t,J＝7.2Hz,1H), 8.55(s,2H),9.64(s,1H).13C NMR(151MHz,DMSO-d6)δ101.59,102.04,102.34, 105.89,107.45,107.66,108.72,109.04,117.02,118.46,122.20,122.81,124.91,130.50, 148.31,148.60,150.63,155.20,158.91,162.81,164.93,164.95.
Example 12
Synthesis of 6- (benzo 1,3 dioxopentacyl) -4(3,4, 5-trimethoxyphenyl) -pyrimidinamide I-l
Further, in step (1), in a round-bottom flask, 3,4, 5-trimethoxybenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 4h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 3,4, 5-trimethoxy substituent with a structure shown in a general formula II and a yellow solid.
In step (2), formula II (1.0mmol) of the 3,4, 5-trimethoxy substituent and guanylurea N-sulfate (6.0mmol) were added to 15ml of anhydrous ethanol, and sodium hydroxide (NaOH, 12.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 7 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-l with the yield of 79.6%.
White powder solid；mp＝250.1-251.2℃；Yield:79.6％；1H NMR(600MHz, DMSO-d6)δ3.76(s,3H),3.92(s,6H),6.16(s,2H),7.13(dd,J＝8.1,2.0Hz,1H), 7.56(s,2H),7.84-7.90(m,1H),8.04(s,1H),8.65(s,2H),9.56(s,1H).13C NMR(151 MHz,DMSO-d6)δ56.25,56.60,60.59,101.67,102.00,102.45,104.95,106.15, 107.50,107.88,108.70,122.17,124.82,132.00,133.40,148.27,149.70,153.47.
Example 13
Synthesis of 6- (benzo 1,3 dioxopentacyclyl) -4(3, 4-difluorophenyl) -pyrimidinamides I-m
Further, in step (1), in a round-bottom flask, 3, 4-difluorobenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 3, 4-difluoro substituent general formula II structure, yellow solid.
In step (2), the 3, 4-difluoro-substituted compound of formula II (1.0mmol) and N-guanylurea sulfate (2.0mmol) were added to 15mL of anhydrous ethanol and sodium hydroxide (NaOH, 4.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 4 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-m with the yield of 76.9%.
Light powder solid；mp＝207.3-208.9℃；Yield:76.9％；1H NMR(600MHz, DMSO-d6)δ6.11(s,2H),7.08(d,J＝8.2Hz,1H),7.59(q,J＝9.0Hz,1H),7.78(s, 1H),7.84(dd,J＝8.2,1.9Hz,1H),8.04(s,1H),8.11(d,J＝6.8Hz,1H),8.27(d,J＝ 11.4Hz,1H),8.56(s,2H),9.59(s,1H).13C NMR(151MHz,DMSO-d6)δ102.03, 102.33,107.44,107.65,108.73,109.04,122.20,122.81,148.59,155.21,158.91,164.20, 164.95.
Example 14
Synthesis of 6- (benzo 1,3 dioxopentacyl) -4 phenyl-pyrimidinamides I-n
Further, in step (1), in a round-bottom flask, benzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the hydrogen substituent general formula II structure, yellow solid.
In step (2), the hydrogen-substituted compound of formula II (1.0mmol) and N-guanylurea sulfate (2.0mmol) were added to 15ml of anhydrous ethanol, and sodium hydroxide (NaOH, 4.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 3 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-n with the yield of 63.6%.
Light yellow powder solid；mp＝219.2-220.1℃；Yield:63.6％；1H NMR(600 MHz,DMSO-d6)δ6.15(s,2H),7.11(d,J＝8.2Hz,1H),7.58(d,J＝2.2Hz,1H), 7.89(dd,J＝8.2,1.8Hz,1H),7.99(d,J＝7.9Hz,2H),8.08(s,1H),8.25(dd,J＝6.5, 3.2Hz,2H),8.35(s,2H),9.58(s,1H),10.03(s,1H).13C NMR(151MHz,DMSO-d6) δ102.28,105.92,107.65,109.00,122.75,127.71,129.36,130.69,131.66,136.73, 148.57,150.51,155.37,158.98,164.75,164.98.
Example 15
Synthesis of 6- (benzo 1, 3-dioxolanyl) -4(2, 4-difluorophenyl) -pyrimidinamides I-o
Further, in step (1), in a round-bottom flask, 2, 4-difluorobenzaldehyde (10.0mmol) and 3,4- (methylenedioxy) acetophenone (10.0mmol) were added to 20ml of anhydrous ethanol, and sodium hydroxide (NaOH, 20.0mmol) was added at room temperature. The reaction was stirred for 5h and monitored by thin layer chromatography. After completion, the precipitate was filtered and washed with petroleum ether. Drying to obtain the 2, 4-difluoro substituent general formula II structure, yellow solid.
In step (2), 2, 4-difluoro-substituted compound of formula II (1.0mmol) and N-guanylurea sulfate (2.0mmol) were added to 15mL of anhydrous ethanol and sodium hydroxide (NaOH, 4.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 4 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain powdery solid I-o with the yield of 56.5%.
Yellow powder solid；mp＝210.5-211.7℃；Yield:56.5％；1H NMR(600MHz, DMSO-d6)δ6.15(s,2H),7.11(d,J＝8.1Hz,1H),7.33(t,J＝7.1Hz,1H),7.50(t,J ＝10.4Hz,1H),7.76(s,1H),7.81(d,J＝8.1Hz,1H),7.85(s,1H),8.05-8.13(m,1H), 8.42(s,2H),9.64(s,1H).13C NMR(151MHz,DMSO-d6)δ102.34,105.65,107.50, 109.10,122.81,130.44,132.81,132.89,148.62,155.20,158.83.
Example 16
Optimization of the preparation method of the 6- (benzo 1, 3-dioxopentacyl) -4(2, 5-dimethylphenyl) -pyrimidine amide derivative:
test 1: in step (2), 2, 5-dimethyl substituted amidinourea of formula II (1.0mmol) and N-sulphatoenurea (2.0mmol) were added to 15ml absolute ethanol and sodium hydroxide (NaOH, 4.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 7 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain a powdery solid I-h with the yield of 52.3%.
Test 2: in step (2), 2, 5-dimethyl substituted amidinourea of formula II (1.0mmol) and N-sulphatoenurea (4.0mmol) were added to 15ml absolute ethanol and sodium hydroxide (NaOH, 8.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 7 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain a powdery solid I-h with the yield of 68.0%.
Test 3: in step (2), 2, 5-dimethyl substituted amidinourea of formula II (1.0mmol) and N-sulphatoenurea (6.0mmol) were added to 15ml absolute ethanol and sodium hydroxide (NaOH, 12.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 7 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain a powdery solid I-h with the yield of 79.2%.
Test 4: in step (2), 2, 5-dimethyl substituted amidinourea of formula II (1.0mmol) and N-sulphatoenurea (6.0mmol) were added to 15ml absolute ethanol and sodium hydroxide (NaOH, 12.0mmol) was added at room temperature. The temperature was then gradually increased to 78 ℃ and the reaction was stirred at 78 ℃ for 3 h. After the reaction is finished, adding 30mL of distilled water after the reaction is finished, extracting with dichloromethane for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on the crude product with silica gel (200-mesh and 300-mesh), and purifying petroleum ether (60-90 ℃) and ethyl acetate (100: 1-2: 1) to obtain a powdery solid I-h with the yield of 63.7%.
TABLE 1 yield of 6- (benzo 1,3 dioxopentacyl) -4(2, 5-dimethylphenyl) -pyrimidinamide under different conditions
Example 17
In vitro antifungal activity screening:
screening strains: sclerotinia sclerotiorum (ACCC 30096), botrytis cinerea (ACCC 36027), fusarium oxysporum (ACCC 37985), rhizoctonia solani (ACCC 38870), colletotrichum capsici (ACCC 37623), early blight solani (ACCC 36110) and fusarium graminearum (ACCC 38871), and all the test strains are purchased from the China center for agricultural microbial culture collection (ACCC).
The test method comprises the following steps: seven crop pathogenic fungi were tested for in vitro bactericidal activity, and the commercial SDHI fungicide boscalid was selected as a positive control to evaluate the utility value of the constructed molecule as a potential fungicide candidate. The in vitro fungal inhibition of the target compounds was tested by the hyphal inhibition growth method. The target compound was dissolved in DMSO to prepare a mother liquor at a concentration of 10 g/L. The stock solution was added to PDA medium at a concentration of 20mg/L of the target compound in the medium. Pure DMSO without the target compound was added to PDA medium as a blank control and boscalid as a positive control. Fresh culture dishes with a diameter of 5mm were taken from the edge of the PDA-cultured fungal colony and inoculated on the above three PDA media. Each treatment was repeated 3 times and the average of the bactericidal effect was taken. Their relative inhibition I (%) was calculated according to the following formula: i (%) [ (C-T)/(C-5) ] × 100, where I is the inhibition, C is the blank colony diameter control (mm), and T is the treated colony diameter (mm). For the effective compounds, the corresponding EC50 values were calculated from the concentration-dependent curve, and the in vitro antifungal activity of the compounds is shown in table 1.
TABLE 2 common Sieve antifungal Activity
As shown in Table 2, the synthesized compounds have different inhibiting effects on Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium oxysporum, Rhizoctonia solani, Colletotrichum capsici, Alternaria solani and Fusarium graminearum, part of the compounds show excellent antifungal activity, and part of the compounds effectively inhibit the growth of the Fusarium graminearum and the Alternaria solani. Most compounds show moderate to good fungicidal activity against tomato gray mold, sclerotinia sclerotiorum, tomato early blight and fusarium graminearum. In the series of compounds, the inhibition rates of the compounds I-a, I-b and I-j on the early blight bacteria of tomato are 96.0%, 98.0% and 90.7%, and are obviously better than that of a positive control boscalid (85.9%).
In the inhibition test of botrytis cinerea, the inhibition rate (84.2%) of only the compound I-b is lower than that of the positive control boscalid (81.7%). In the control of cucumber fusarium wilt and rice sheath blight bacteria, the antifungal activity of most compounds is superior to that of boscalid (24.3 percent and 24.8 percent) of positive control, but the total antibacterial effect is not ideal. In the case of fusarium graminearum, the antifungal activity of the compounds I-a, I-b, I-j and I-k (81.8%, 80.4%, 84.0% and 87.4%) is more than 80%, and is equivalent to the bacteriostatic effect of boscalid (84.6%) which is a positive control.
To evaluate the antifungal efficacy, compounds with a fungal inhibition rate of more than 80% at a concentration of 20mg/L were further examined to obtain their median effective concentration (EC50) values, with specific values as in table 3.
Table 3 part compound EC50
FIG. 1 treatment of Fusarium graminearum with different concentrations of Boscalid on PDA medium: (a)5.000(b) 1.250(c)0.325(d)0.078(e)0.020 and (f)0 mg/L; compounds I-j: (g)5.000(h)1.250 (i)0.325(j)0.078(k) 0.020; and (L)0 mg/L; a compound I-a: (m)5.000(n)1.250 (o)0.325(p)0.078(q) 0.020; and (r)0mg/L (4 days at 28 ℃).
As shown in FIG. 1, the growth diameter of Fusarium graminearum gradually decreased with the increase of the concentration of the compound, and it can be seen visually that the growth inhibition of Fusarium graminearum by the compound is linear concentration.
As also shown in Table 3, most of the compounds had EC50 values of less than 1.0 mg/L.
Notably, for sclerotinia sclerotiorum, compound I-j exhibited excellent bactericidal activity with an EC50 value of 0.146 mg/L. In the control of tomato early blight, the compound I-b shows excellent activity, the EC50 value of the compound is 0.199mg/L, and the compound I-b is equivalent to the inhibition effect of positive control boscalid (EC50 is 0.158 mg/L).
Example 16
Succinate Dehydrogenase (SDH) inhibitory activity screening:
screening strains: the test strain (tomato early blight) was purchased from China agricultural microorganism (ACCC) public network.
The test method comprises the following steps: further, Succinate Dehydrogenase (SDH) inhibitory activity of a part of the compounds was performed.
The specific method comprises the following steps:
and (3) enzyme extraction: the inoculation amount of the early blight of tomato is 0.05OD 600nm, and the early blight of tomato is cultured on a shaker (180rpm, 28 ℃) for 5 days and cultured in a PDA culture medium. The hyphae were collected and disrupted in liquid nitrogen with a mortar and pestle. The resulting powder was resuspended to 10% w/v in mitochondrial extraction buffer. (mitochondrial extraction buffer: 10mM KH2PO4, pH 7.2, 10mM KCl, 10mM MgCl2, 0.5M sucrose, 0.2mM EDTA, 2mM PMSF) the extract was clarified by centrifugation (5000g, 4 ℃, 10min, 2 times), and the intact mitochondria were centrifuged at 10000g for 20 minutes at 4 ℃ and resuspended in the same buffer. The mitochondrial suspension was concentrated to a concentration of 10mg/mL and stored at-80 ℃ until use. SDH activity remains stable for several months.
Detection of enzyme inhibitory Activity: ubiquinone/dcpip. mitochondrial suspension was diluted 1/3 with extraction buffer and preactivated for 30min at 30 ℃ in the presence of 10mM succinic acid. ubiquinone/DCPIP activity inhibition assay: mu.L of pre-activated mitochondria was added to 200. mu.L of assay buffer containing 140. mu.M Dichlorophenol (DCPIP) and 1mM 2, 3-dimethoxy-5-methyl-1, 4-benzoquinone (Q0).
Detection buffer (50mM phosphate-sodium, pH 7.2, 250mM sucrose, 10mM succinate). The range of drug concentration is 0.285-72.861 μ M, 4 × dilution multiple step method (5 drug concentrations + DMSO control). In a 96-well plate, pre-equilibration at reaction temperature (30 ℃) for 10min, 10. mu.L of pre-activated extracted mitochondrial suspension was added for reaction. DCPIP inhibition was monitored at 595nm at 30 ℃. The half inhibitory concentration (IC50) was calculated as the absorbance slope (OD/min) using a data processing system (IBM SPSS Statistics 25). The results of SDH enzyme activity inhibition by some compounds are shown in Table 3.
TABLE 3
Further tested for SDH inhibitory activity of a part of the compounds, we can see from Table 3 that the IC50 values of I-a and I-b are 1.224 μ M and 2.096 μ M, which are obviously superior to the positive control boscalid (IC)503.399 μ M). However, I-j exhibited inferior inhibitory activity compared to boscalid.
Example 17
The crystal structure diagram of SDH was obtained from the protein database (pdb code: 2 FBW). I-j and bosscalid energy minimization was accomplished by Discovery Studio 2016 software. Molecular docking of Compounds I-j and boscalid to SDH was also accomplished by Discovery Studio 2016 software. The ligand Carboxin (P/CBE 144) was removed and all water molecules were removed from the crystalline complex. Finally, the docking work of the compounds I-j and boscalid is carried out. The docking results are shown in figure 2.
As can be seen from FIG. 2, the different groups of compounds I-b are involved in the interaction with the SDH enzyme. For example, the pyrimidine group forms a pi-sigma hydrophobic interaction with the ILE-40, the piperonyl ring forms a pi-cation and a pi-alkyl interaction with the amino acid residues Ser-39 and ILE-218, respectively, and the 4-bromo substituted phenyl ring group forms a pi-alkyl interaction with the amino acid residue ILE-40, on the other hand. Thus, the groups of the compound I-j play an important role in the combination with SDH, and further, the synergistic effect among different groups of the compound I-j is illustrated. In addition, comparison with the positive control, boscalind, also further indicates that I-j and boscalind act on the same binding site. The molecular docking result also provides a new idea for developing a novel SDH inhibitor.
Therefore, from structural analysis, the compounds all contain a pyrimidine ring and a benzo 1,3 dioxypentacene ring, wherein the compound I-j with 4-bromine has the strongest anti-sclerotinia oleifera activity. The results show that the compounds have potential value in developing antifungal pesticides.
The invention reports that the antifungal mechanism of the nitrogen heterocyclic ring-containing 6- (benzo 1,3 dioxopentacyclyl) -4 phenylpyrimidine amide derivative is to inhibit SDH enzyme activity for the first time, and SDH enzyme activity test results show that part of compounds have strong enzyme inhibition effect, and the structure is a brand-new structure as an SDH enzyme inhibitor. The nitrogenous heterocyclic 6- (benzo 1, 3-dioxolanyl) -4-phenyl pyrimidine amide derivative has good fungal bioactivity inhibition, and biological activity research shows that the compound has obvious inhibition effect on fungi such as sclerotinia sclerotiorum, alternaria solani, fusarium graminearum and the like.
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.
Claims (8)
1. A6- (benzo 1,3 dioxygen five ring group) -4 phenyl pyrimidine amide derivative with anti-plant pathogenic fungi activity is characterized in that: the derivatives have the general formula I:
wherein, R is respectively selected from H, halogen, alkyl and alkoxy.
2. The 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidinamide derivative of claim 1, wherein: the derivatives are compounds from I-a to I-o:
I-a：
I-b：
I-c：
I-d：
I-e：
I-f：
I-g：
I-h：
I-i：
I-j：
I-k：
I-l：
I-m：
I-n：
I-o：
3. a process for preparing a 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivative according to claim 1 or 2, characterized in that: comprises the steps of (a) preparing a mixture of a plurality of raw materials,
the 3, 4-methylene dioxy acetophenone and benzaldehyde with different substituents are subjected to aldol condensation reaction to generate ketene with different substituents, namely the ketene with the structure shown in the general formula II:
reacting acetophenone with different substituents and N-guanylurea sulfate to obtain 6- (benzo 1,3 dioxy pentacyl) -4 (substituted phenyl) pyrimidine amide I:
4. a process for preparing a 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivative according to claim 3, wherein: comprises the steps of (a) preparing a mixture of a plurality of raw materials,
adding benzaldehyde and 3,4- (methylenedioxy) acetophenone with different substituents into absolute ethyl alcohol, adding sodium hydroxide at room temperature, stirring and reacting for 3-5 h, monitoring by thin-layer chromatography, filtering a precipitate, washing with petroleum ether, and drying to obtain a general formula II structure with different substituents, wherein the general formula II structure is a yellow solid, and the yield is 85-92%;
adding guanylurea N-sulfate and general formula II with different substituents into absolute ethyl alcohol, adding sodium hydroxide at room temperature, gradually heating to 78 ℃, stirring and reacting for 3-7 hours, monitoring the reaction process by adopting a thin-layer chromatography, adding distilled water after the reaction is finished, extracting for 2-3 times by using dichloromethane, washing for 2-3 times by using distilled water, washing for 1 time by using saturated sodium bicarbonate, washing for 1 time by using saturated salt, drying by using anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, performing column chromatography on a crude product by using 200-300-mesh silica gel, and purifying by using petroleum ether/ethyl acetate in a volume ratio of 100:1-2:1 to obtain a powdery solid of general formula I.
5. A process for preparing 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivatives as claimed in claim 4, wherein: the molar ratio of benzaldehyde to 3,4- (methylenedioxy) acetophenone was 1: 1.
6. A process for preparing 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivatives as claimed in claim 4, wherein: the molar ratio of the general formula II with different substituents to the N-guanylurea sulfate is 1: 2-1: 6.
7. A process for preparing 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivatives as claimed in claim 6, wherein: the substituent of the general formula II with different substituents is any one of 3 fluorophenyl, 2 furyl, 4 trifluoromethylphenyl, 3 methoxyphenyl, 4 fluorophenyl, 4 methylphenyl, 4 cyanophenyl, 2,5 dimethoxyphenyl, 4 chlorophenyl, 4 bromophenyl, 2 fluorophenyl, 3,4,5 trimethoxyphenyl, 3,4 difluorophenyl, phenyl and 2,4 difluorophenyl.
8. The use of 6- (benzo 1,3 dioxopentacyl) -4 phenylpyrimidine amide derivatives according to claim 1 for combating phytopathogenic fungi.
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