CN115124475B - Pyrimidine derivative and preparation method and application thereof - Google Patents
Pyrimidine derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN115124475B CN115124475B CN202210813917.8A CN202210813917A CN115124475B CN 115124475 B CN115124475 B CN 115124475B CN 202210813917 A CN202210813917 A CN 202210813917A CN 115124475 B CN115124475 B CN 115124475B
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- China
- Prior art keywords
- trifluoromethyl
- pyrimidin
- oxy
- methyl
- benzoate
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- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims description 117
- 239000003814 drug Substances 0.000 claims abstract description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 36
- 241000700605 Viruses Species 0.000 claims abstract description 17
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims abstract description 9
- 244000000005 bacterial plant pathogen Species 0.000 claims abstract description 7
- -1 2, 4-dichlorobenzyl Chemical group 0.000 claims description 147
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 110
- 150000001875 compounds Chemical class 0.000 claims description 72
- 230000001580 bacterial effect Effects 0.000 claims description 20
- XHSBUHCCIKEGNY-UHFFFAOYSA-N 4-[6-(trifluoromethyl)pyrimidin-4-yl]oxybenzoic acid Chemical compound OC(=O)c1ccc(Oc2cc(ncn2)C(F)(F)F)cc1 XHSBUHCCIKEGNY-UHFFFAOYSA-N 0.000 claims description 17
- JYLBKMNTQSEPJM-UHFFFAOYSA-N 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine Chemical class CC1=NC(Cl)=CC(C(F)(F)F)=N1 JYLBKMNTQSEPJM-UHFFFAOYSA-N 0.000 claims description 16
- YXWLDPBASXYLJO-UHFFFAOYSA-N CC1=NC(=CC(=N1)OC1=CC=C(C(=O)O)C=C1)C(F)(F)F Chemical compound CC1=NC(=CC(=N1)OC1=CC=C(C(=O)O)C=C1)C(F)(F)F YXWLDPBASXYLJO-UHFFFAOYSA-N 0.000 claims description 16
- TYSPDLZOMUDHQZ-UHFFFAOYSA-N 4-chloro-6-(trifluoromethyl)pyrimidine Chemical class FC(F)(F)C1=CC(Cl)=NC=N1 TYSPDLZOMUDHQZ-UHFFFAOYSA-N 0.000 claims description 15
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 claims description 15
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- JNPZQRQPIHJYNM-UHFFFAOYSA-N carbendazim Chemical compound C1=C[CH]C2=NC(NC(=O)OC)=NC2=C1 JNPZQRQPIHJYNM-UHFFFAOYSA-N 0.000 description 1
- 239000006013 carbendazim Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
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- 238000004611 spectroscopical analysis Methods 0.000 description 1
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- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000004563 wettable powder Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- 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
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a pyrimidine derivative, which has a structural general formula shown in formula I:wherein R is 1 Selected from the group consisting of hydrogen radicals, methyl radicals; r is R 2 Selected from the group consisting of hydrogen, methyl, allyl, substituted or unsubstituted benzyl, substituted or unsubstituted thiazolyl. The invention synthesizes a series of pyrimidine derivatives by structural modification of active pyrimidine structure. The pyrimidine derivative prepared by the invention has good plant pathogenic bacteria (bacteria, fungi) inhibiting and antiviral activities, and can be used for preparing medicines for sterilizing and resisting viruses.
Description
Technical Field
The invention relates to the technical field of pesticide synthesis, in particular to a pyrimidine derivative, a preparation method and application thereof.
Background
Pyrimidine derivatives are nitrogen-containing heterocyclic compounds, are important chemical intermediates, play an important role in the design and synthesis of novel heterocyclic compounds, have certain research and application values, and are increasingly researched in recent years.
In 2012, taher et al (Taher a.t., abou-series S m.molecules,2012,17,9868-9886.) synthesized several 6-aryl-5-cyanothiouracil derivatives and studied for their antibacterial, antifungal and anticancer activity, and antibacterial evaluation showed that: wherein, the two compounds have higher antibacterial activity on gram positive bacteria staphylococcus aureus and bacillus subtilis, and the MIC values of the two compounds are 1.17,2.34 and 0.19,1.17 mug/mL respectively, which are superior to that of a control drug amoxicillin (1.25,150 mug/mL); in addition, one compound has a broad spectrum of bactericidal activity, with the highest antibacterial activity against candida albicans, with a MIC of 2.34 μg/mL, even higher than that of the control drug amphotericin B (mic=3.00 μg/mL).
In 2015, yang Ya (Yang Ya, lin Dayong, fu Cuirong, et al, organic chemistry, 2015,35,100-108.) a series of novel pyrimidine ring-containing pyrazoloxime ether derivatives were designed and synthesized by applying the bioisosteric principle, and antibacterial activity evaluation was performed on all target compounds, and the results prove that most of the compounds have certain inhibitory activity on the alternaria mali, and the inhibitory rates of the two compounds on the alternaria mali are 49.2% and 50.0% respectively at 50 μg/m L.
Wu (Wu W., chen Q., tai A., et al bioorganic and Medicinal Chemistry Letters,2015,25,2243-2246.) reported a series of pyrimidine group-containing 1,3, 4-oxadiazole derivatives, which were tested for antiviral activity, and the results showed that the compounds had better activity against tobacco mosaic virus and their EC' s 50 246.48. Mu.g/mL, is superior to the control agent Ningnanmycin (301.83. Mu.g/mL).
Wu Ningjie in 2019 (Wu Ningjie, cheng Long, wangjian, et al, organic chemistry, 2019,39,852-860.) reported that 4-aryl pyrimidine derivatives were synthesized from substituted anilines as raw materials by a series of reactions such as diazotization, arylation, methylation, and the like, wherein the mortality rate of one compound to armyworms was 100, 80% when the concentration was 500, 100, 20mg/L, respectively.
What is described in 2019 (what is described in Liu Deng, gan Xiuhai, et al. Organic chemistry, 2019,39,2287-2294.) a series of 1,3, 4-thiadiazolo [3,2-a ] pyrimidinone mesoionic derivatives were reported, wherein the inhibition rate of one compound on bacterial blight of rice was 70.91% and the inhibition rate on bacterial banaba of rice was 53.34% at a concentration of 50 μg/mL, both being superior to the control agent thiabendazole (47.76%, 23.45%).
In summary, the pyrimidine structure is unique, has resource advantages in the research and application of medicaments, is widely applied in medicaments, has a small amount of commercial medicaments in the aspect of pesticides, but has no report on pyrimidine derivatives with plant pathogenic bacteria, fungi and viruses resistance at present.
Disclosure of Invention
The main object of the present invention is to provide pyrimidine derivatives having resistance against plant pathogenic bacteria, fungi and viruses, and a process for their preparation and use.
In order to achieve the above purpose, the present invention provides the following technical solutions:
one of the technical schemes of the invention is as follows: providing a pyrimidine derivative, wherein the structural general formula of the pyrimidine derivative is shown as formula I:
wherein R is 1 Selected from the group consisting of hydrogen radicals, methyl radicals; r is R 2 Selected from the group consisting of hydrogen, methyl, allyl, substituted or unsubstituted benzyl, substituted or unsubstituted thiazolyl.
Preferably, the pyrimidine derivative is specifically as follows:
2, 4-dichlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
2-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
2-methylbenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
2-chlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
e.4-nitrobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
f.2-chloro-6-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
g.3-methoxybenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
h.4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid methyl ester;
I. (6-chloropyridin-3-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
j.4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid allyl ester;
K. (2-chlorothiazol-5-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
l.2, 4-dichlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
2-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
n.2-methylbenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
o.2-chlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
p.4-nitrobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
q.2-chloro-6-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
r.3-methoxybenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
s.4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid methyl ester;
(6-chloropyridin-3-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
u.4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) allyl benzoate;
(2-chlorothiazol-5-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
the second technical scheme of the invention is as follows: the preparation method of the pyrimidine derivative comprises the following steps:
(1) Ethyl trifluoroacetoacetate and formamidine hydrochloride or acetamidine hydrochloride are used as raw materials, ethanol is used as a solvent, DBU is used as an acid binding agent, and intermediate substituted 4-hydroxy-6-trifluoromethyl pyrimidine is prepared by reflux; then using acetonitrile as solvent, substituted 4-hydroxy 6-trifluoromethyl pyrimidine is passed through POCl 3 After chlorination, substituted 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine or 4-chloro-6- (trifluoromethyl) pyrimidine is obtained;
(2) Using acetone as a solvent and cesium carbonate as a catalyst, and reacting the substituted 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine or 4-chloro-6- (trifluoromethyl) pyrimidine with methyl paraben to prepare methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate or methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
(3) Methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate or methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate was reacted with KOH, tetrahydrofuran under reflux to produce 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid or 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid;
(4) 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid or 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid as raw material, K 2 CO 3 The pyrimidine derivative is prepared by using DMF as a solvent and a catalyst.
Preferably, the ethyl trifluoroacetoacetate and formamidine hydrochloride or acetamidine hydrochloride in the step (1) are reacted in absolute ethanol solvent, and the chloridizing reagent in the step (1) is POCl 3 The solvent is acetonitrile 3 。
The step (1) of the invention comprises two steps of reactions, and the second step is carried out by POCl 3 The hydroxy group is chlorinated, and the reaction process is as follows:
preferably, the reaction of step (2) is carried out in an acetone solvent.
The reaction process of the step (2) of the invention is as follows:
the reaction process of the step (3) of the invention is as follows:
preferably, the reaction of step (4) is carried out under ice bath conditions.
The reaction process of the step (4) of the invention is as follows:
the third technical scheme of the invention: provides the application of the pyrimidine derivative in preparing medicines for resisting plant pathogenic bacteria and/or plant viruses. The term "phytopathogenic bacteria" here refers to phytopathogenic bacteria and/or fungi.
The beneficial effects of the invention are as follows:
the invention synthesizes a series of pyrimidine derivatives by structural modification of active pyrimidine structure. The pyrimidine derivative prepared by the invention has good plant pathogenic bacteria (bacteria, fungi) inhibiting and antiviral activities, and can be used for preparing medicines for sterilizing and resisting viruses.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to. In addition, the meaning of "and/or" as it appears throughout includes three parallel schemes, for example "A and/or B", including the A scheme, or the B scheme, or the scheme where A and B are satisfied simultaneously.
Example 1
The preparation method of 2, 4-dichlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I1) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
into a 100mL round bottom flask was charged 5.0g (27.16 mmol) of ethyl trifluoroacetoacetate, 5.37g (35.30 mmol) of DBU (1, 8-diazabicyclo [ 5.4.0)]Undec-7-ene) and 30mL ethanol (CH 3 CH 2 OH) was stirred at room temperature for 15min, after which 3.85g (40.74 mmol) acetamidine hydrochloride was added, heated to 85℃and then heated under reflux with TLC tracking (petroleum ether: ethyl acetate=3:1, V/V). After stopping the reaction, concentrating under reduced pressure, adding 30mL of purified water, extracting with ethyl acetate, concentrating the organic layer under reduced pressure, and drying to obtain white solid 2-methyl-6- (trifluoromethyl) pyrimidine-4-hydroxy. In a 100mL round bottom flask4.0g (24.38 mmol) of 2-methyl-6- (trifluoromethyl) pyrimidine-4-hydroxy was added and 30mL of acetonitrile was added for dissolution, and under ice-bath conditions, 9.34g of POCl was slowly added dropwise using a constant pressure dropping funnel 3 (60.94 mmol) was placed in an oil bath to heat up to 90 ℃ for reflux reaction for 30min after the dropwise addition, the reaction was stopped, and after the reaction solution cooled, 0.32g (2.4 mmol) of N, N-diisopropylethylamine was added dropwise into the reaction system, the temperature was continuously raised to 90 ℃ for reflux reaction, and TLC followed by reaction (petroleum ether: ethyl acetate=3:1, V/V). After completion of the reaction, the mixture was concentrated under reduced pressure, 60mL of ice water was added under ice-bath conditions, pH was adjusted to 9 with 50% NaOH, extraction was performed with methylene chloride, and the organic layer was taken and the extract was concentrated under reduced pressure to give a brown oil (intermediate 1) for use. Yield: 45%.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
in a 50mL round bottom flask was added in order 2.00g (10.18 mmol) of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1), 1.86g (12.21 mmol) of methylparaben, cesium carbonate (Cs 2 CO 3 ) 4.97g (15.26 mmol) and 20mL of acetone, the reaction was stirred at room temperature and followed by TLC (Petroleum ether: ethyl acetate=5:1, V/V). After stopping the reaction, the reaction mixture was concentrated under reduced pressure, 40mL of distilled water was added, extracted three times with ethyl acetate, the organic layers were combined, and concentrated under reduced pressure to give a crude product methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2), yield: 65%.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
to a 100mL three-necked round bottom flask was successively added 2.0g (6.41 mmol) of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2), 0.72g (12.81 mmol) of KOH and 40mL of tetrahydrofuran, heated to 70℃and reacted under reflux, followed by TLC monitoring the reaction (ethyl acetate). After stopping the reaction, cooling to room temperature, adjusting the pH=1 by using hydrochloric acid under ice bath condition, precipitating white solid, carrying out suction filtration and drying to obtain 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3), and obtaining the yield: 69%.
(4) Preparation of 2, 4-dichlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I1):
into a 100mL one-necked flask, 0.5g (1.68 mmol) of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3) and K were successively added 2 CO 3 0.31g (2.3 mmol) and 40mL DMF, after stirring for 0.5-1h under ice bath conditions, 0.30g (1.52 mmol) of 2, 4-dichlorobenzyl chloride is added, TLC is used for tracking the reaction (petroleum ether: ethyl acetate=3:1, V/V), after stopping the reaction, the mixture is poured into 100mL of water, white precipitate is separated out, after the solution is clear, the crude product is obtained by suction filtration, and the white solid (target compound I1) is obtained after separation and purification by column chromatography (petroleum ether: ethyl acetate=15:1, V/V), the yield is: 50%.
Example 2
The preparation method of 2-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I2) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 2-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I2):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-fluorobenzyl chloride. Yield: 65%.
Example 3
The preparation method of 2-methylbenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I3) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 2-methylbenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I3):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-methylbenzyl chloride. Yield: 54%.
Example 4
The preparation method of 2-chlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I4) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 2-chlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I4):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chlorobenzyl chloride. Yield: 67%.
Example 5
The preparation method of 4-nitrobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I5) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 4-nitrobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I5):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 4-nitrobenzyl chloride. Yield: 42%.
Example 6
The preparation method of 2-chloro-6-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I6) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 2-chloro-6-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I6):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chloro-6-fluorobenzyl chloride. Yield: 45%.
Example 7
The preparation method of 3-methoxybenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I7) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 3-methoxybenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I7):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 3-methoxybenzyl chloride. Yield: 50%.
Example 8
The preparation method of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid methyl ester (target compound I8) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I8):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of methyl iodide. Yield: 57%.
Example 9
The preparation method of (6-chloropyridin-3-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I9) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of (6-chloropyridin-3-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I9):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chloro-5- (chloromethyl) pyridine. Yield: 49%.
Example 10
The preparation method of allyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I10) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of allyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I10):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 3-chloroprop-1-ene. Yield: 41%.
Example 11
The preparation method of (2-chlorothiazol-5-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I11) is as follows:
(1) Preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of (2-chlorothiazol-5-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I11):
step (4) as in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chloro-5- (chloromethyl) thiazole. Yield: 62%.
Example 12
The preparation method of 2, 4-dichlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I12) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 2, 4-dichlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I12):
step (4) as in example 1. Yield: 71%.
Example 13
The preparation method of 2-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I13) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 2-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I13):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-fluorobenzyl chloride. Yield: 71%.
Example 14
The preparation method of 2-methylbenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I14) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 2-methylbenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I14):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-methylbenzyl chloride. Yield: 66%.
Example 15
The preparation method of 2-chlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I15) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 2-chlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I15):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chlorobenzyl chloride. Yield: 63%.
Example 16
The preparation method of 4-nitrobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I16) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 4-nitrobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I16):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 4-nitrobenzyl chloride. Yield: 68%.
Example 17
The preparation method of 2-chloro-6-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I17) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 2-chloro-6-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I17):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chloro-6-fluorobenzyl chloride. Yield: 73%.
Example 18
The preparation method of 3-methoxybenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I18) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of 3-methoxybenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I18):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 3-methoxybenzyl chloride. Yield: 55%.
Example 19
The preparation method of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid methyl ester (target compound I19) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I19):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of methyl iodide. Yield: 82%.
Example 20
The preparation method of (6-chloropyridin-3-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I20) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of (6-chloropyridin-3-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I20):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chloro-5- (chloromethyl) pyridine. Yield: 47%.
Example 21
The preparation method of the allyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I21) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of allyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I21):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 3-chloroprop-1-ene. Yield: 43%.
Example 22
The preparation method of (2-chlorothiazol-5-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I22) is as follows:
(1) Preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
step (1) as in example 1. Except that acetamidine hydrochloride was replaced with an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
step (2) as in example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
step (3) as in example 1.
(4) Preparation of (2-chlorothiazol-5-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I22):
step (4) as in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chloro-5- (chloromethyl) thiazole. Yield: 57%.
Physical and chemical properties and mass spectrum data of pyrimidine derivatives synthesized in the above examples are shown in Table 1, and nuclear magnetic resonance hydrogen spectrum [ ] 1 H NMR), carbon spectrum [ ] 13 C NMR) and fluorine Spectroscopy 19 F NMR) data are shown in table 2.
TABLE 1 physicochemical Properties of Compounds I1 to I22
TABLE 2 Hydrogen nuclear magnetic resonance, carbon and fluorine spectra data for target compounds I1-I22
Test example 1
Anti-phytopathogenic bacteria test:
(1) Test method
The in vitro inhibition activities of the target compounds on melon bacterial fruit blotch germs (Ac), tomato bacterial wilt germs (Rs), rice bacterial blight germs (Xoo), potato soft rot germs (Pcb) and mango bacterial black blotch germs (Xcm) are tested by adopting a 96-well plate method at the concentrations of 200 mug/mL and 100 mug/mL, and the specific operation steps are as follows:
preparing bacterial liquid: selecting a single colony in a liquid culture medium (different bacteria adopt different culture mediums), culturing in a shaking table at 28 ℃ and 180r/min to logarithmic phase, centrifuging 2mL of bacterial liquid of two tubes at 6000rpm for 5min, removing the culture medium liquid, adding 2mL of sterile water to mix the bacterial cells with the water uniformly, measuring one tube at 600nm wavelength of an ultraviolet spectrophotometer, adjusting the absorbance value to 0.6, and preserving the other tube for later use. Preparing a liquid medicine: 1mg of the test drug was dissolved in 100. Mu.L of DMSO and its final concentration was formulated with liquid medium (different medium for different bacteria) to 200. Mu.g/mL and 100. Mu.g/mL of drug-containing medium. 190 mu L of the culture medium containing the medicine and 10 mu L of the prepared bacterial liquid are added into a 96-well plate, the negative control is the culture medium with the medicine added and without the medicine liquid, the positive control is the commercial medicines of thiabendazole and metconazole, and the culture medium with the medicine added and without the medicine liquid is used as a blank control. Culturing 96-well plate at 28deg.C in 180r/min shaking table until OD value of negative control is 0.6-0.8, and performing enzyme labeling on OD of all bacterial solutions 600nm The values were determined and the inhibition of the test bacteria by the test drug was calculated using SPSS. 3 replicates were set for each treatment, 3 replicates for each trial. The inhibition rate was calculated as follows:
correcting OD 600 Value = fungus-containing medium OD 600 Sterile Medium OD 600
Inhibition (%) = (after correction control medium bacterial liquid OD 600 Correction of the OD of the drug-containing Medium 600 ) After correction, the OD value of the control culture medium is multiplied by 100%.
(2) Results of biological Activity test against plant pathogenic bacteria
TABLE 3 antibacterial Activity (% inhibition) of the Compounds prepared in examples I1-20 a
Remarks: a average three replicates; b use of metconazole and copper thiabendazole (20% wettable powder) as positive controls
As can be seen from Table 3, at 200. Mu.g/mL, the inhibition rates of the objective compounds I1, I12, I18, I22 on Ac (melon bacterial fruit blotch) were 81.8, 86.7, 83.5 and 84.4%, respectively, which were superior to the control drugs TC (47.6%) and BT (37.0%), the inhibition rates of the compounds I3 and I20 on Pcb (potato soft rot) were 76.2, 80.0%, which were superior to the control drugs TC (45.6%) and BT (45.8%), the inhibition rates of the compounds I6, I10 and I11 on Xoo (rice bacterial blight) were 89.7, 81.4 and 85.2%, which were superior to the control drugs TC (56.6%) and BT (51.2%), respectively.
Test example 2
Test of Activity against phytopathogenic fungi:
(1) Test method
The in vitro activity evaluation of twelve plant pathogenic fungi including white vegetable black spot pathogen (AB), strawberry moniliforme fusarium (FF), cucumber fusarium wilt pathogen (FO), pepper anthracnose pathogen (CT), phytophthora Capsici (PC), mango jelly cell pathogen (CG), rice sheath blight pathogen (RS), wheat gibberella (FG), soybean phytophthora Parasitica (PS), tobacco black shank pathogen (PP), tomato gray mold pathogen (BC) and litchi downy mildew (PL) is carried out by adopting a hypha growth rate method, and the commercial medicament azoxystrobin is used as a positive control. The method comprises the following specific steps:
3mg of test drug is dissolved in 300 mu L of DMSO, 200 mu L of liquid medicine is taken and added into 1980 mu L of melted PDA nutrient medium, so that the solution is prepared into a drug-containing nutrient medium with the final concentration of 100 mu g/mL, the drug-containing nutrient medium is uniformly poured into three sterilized culture dishes, after the drug-containing nutrient medium is solidified, a bacterial cake with the thickness of 4.00mm is beaten out of bacterial colonies of fungi, the fungi are placed in the center of the drug-containing culture dishes, a sealing film is sealed, a negative control is a nutrient medium added with bacteria and not added with liquid medicine, a positive control is commercial medicament carbendazim, the fungi-containing culture dishes are placed in a 28 ℃ incubator for 2-6 d, the bacterial colony diameter is measured by adopting a cross method, and the inhibition rate of the test drug on test fungi is calculated by using SPSS. 3 replicates were set for each treatment, 3 replicates for each trial. The inhibition rate was calculated as follows:
inhibition ratio I (%) = (C tur -T tur )/(C tur -0.4)×100
C tur Control colony diameter, i.e., DMSO-treated colony diameter;
T tur diameter of colonies treated with the agent;
0.4: the diameter of the fungus cake;
i, inhibition rate.
PDA medium: 200g of potato, 20g of glucose, 20g of agar and 1000mL of distilled water
Cutting peeled potato, boiling in 800mL distilled water until potato is crushed, filtering with gauze, mixing filtrate with 20g glucose and 20g agar, boiling again, mixing, and adding distilled water to 1000mL.
(2) Results of biological Activity test against plant pathogenic fungi
TABLE 4 antibacterial Activity (% inhibition) of Compounds prepared in examples I1-20 a
Remarks: a average three replicates; b azoxystrobin (Azoxystrobin) was used as a positive control
At a concentration of 100 mug/mL, most of the target compounds have good inhibition effect on PL (phytophthora litchii), wherein the inhibition rates of the compound I9 and the compound I16 on PL are respectively 81.5 and 87.3 percent and are close to azoxystrobin (86.3 percent), and the compounds I11, I17, I19 and I20 are remarkable in antifungal activity on PL, and the values of the compounds are respectively 90.1, 93.8, 96.3 and 96.0 percent and are better than that of azoxystrobin (86.3 percent).
Test example 3
Testing of anti-tobacco mosaic virus activity:
(1) Test method
A. Virus purification
Adopting a Zhou Xue flat method (Zhou, X.P.; xu, Z.X.; xu, J.; li, D.B.J. south Chin. Agric. Univ.1995,16, 74-79.;), selecting upper leaves of a host Nicotiana tabacum.L plant infected by a TMV system for more than 3 weeks, homogenizing in a phosphate buffer, filtering by double-layer gauze, centrifuging at 8000r/min, treating by polyethylene glycol for 2 times, centrifuging again, suspending the precipitate by the phosphate buffer, and obtaining the TMV refined extract. The whole experiment was carried out at 4 ℃. The virus concentration of the TMV refined extract used in the invention was determined to be 6X 10 -3 mg/mL。
B. In vivo therapeutic effects of agents on TMV infection
In vivo therapeutic effects of agents on infection: selecting 5-6 leaf stage with consistent growth vigor, topping, spreading Carborundum on whole leaf, dipping virus juice (6×10) with a gang pen -3 mg/mL) whole leaf inoculated virus, naturally air-dried and rinsed with clear water. After the leaves are dried, the left half She Qing is lightly coated with Shi Yaoji by using a writing brush, the right half She Tushi is used as a comparison, the number of dead spots is recorded after 6-7d, and the inhibition rate is calculated according to a formula (1).
C. In vivo protection of TMV infection by agents
In vivo protection of TMV infection by agents: the heart leaf cigarettes with 5-6 leaf periods and consistent growth vigor are selected for topping, the left half She Qing of the brush pen is lightly coated with Shi Yaoji, and the right half She Tushi of the brush pen is used as a comparison with the solvent with the concentration corresponding to the solvent. After 24h, the whole leaves were sprinkled with silicon carbide and the virus juice was dipped with a volleyball (6X 10) -3 mg/mL), the whole leaf inoculated virus is washed by clean water, the number of dead spots is recorded after 6-7d, and the inhibition rate is calculated according to the formula (1).
D. In vivo inactivation of TMV infection by agents
Mixing the medicament with the virus juice with the same volume, inactivating for 30min, dipping the mixed liquid of the medicament and the virus by a gang pen, manually rubbing and inoculating the mixed liquid on the left half leaf of the leaf scattered with silicon carbide, and supporting the lower part of the leaf by a flat wood plate. The right half leaf is inoculated by mixing sterilized water with virus juice. 3 plants are arranged for each medicament treatment, 5-6 leaves of each plant are placed in an illumination incubator for moist culture, the temperature is controlled to be 23+/-1 ℃, the number of generated dead spots is observed and recorded after illumination is performed for 10000Lux and 6-7d, and the inhibition rate is calculated according to a formula (1).
Wherein the average number of dead spots of half leaves without the applied agent and the number of dead spots of half leaves with the applied agent are the average number of three replicates of each group.
(2) The results of the biological activity test against tobacco mosaic virus are shown in Table 5.
TABLE 5 treatment, protection and inactivation Activity of Compounds prepared in examples I1-20 against tobacco mosaic Virus a
Remarks: a average three replicates; b ningnanmycin was used as a positive control.
Under the condition of 500 mug/mL concentration, the half leaf spot method is adopted to test the antiviral activity of target compounds I1-I22, and part of the compounds have certain inhibiting effect on TMV viruses. Wherein, in terms of therapeutic activity, the inhibition of the compounds I2, I10, I12, I13, I17 and I19 is respectively 70.1, 76.3, 64.1, 66.1, 71.3 and 64.2%, which is superior to that of the control drug ningnanmycin (54.0%), and in terms of protective activity, the inhibition of the compounds I6, I8, I11, I13, I17 and I19 is respectively 65.7, 66.4, 62.1, 65.5, 62.7 and 61.6%, which is superior to that of the control drug ningnanmycin (58.6%).
The experimental activity data show that the pyrimidine derivative has a certain inhibition effect on plant pathogens, wherein part of target compounds show excellent activity against plant pathogens and viruses, can be used as potential plant pathogens and virus resistant drugs, and has good application prospects.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the scope of protection defined by the claims of the present invention without departing from the spirit of the design of the present invention.
Claims (3)
1. Pyrimidine derivative is characterized in that the structural general formula is shown in formula I:
the compound shown in the formula I is specifically as follows:
2, 4-dichlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
2-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
2-methylbenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
2-chlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
e.4-nitrobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
f.2-chloro-6-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
g.3-methoxybenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
I. (6-chloropyridin-3-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
j.4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid allyl ester;
K. (2-chlorothiazol-5-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
l.2, 4-dichlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
2-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
n.2-methylbenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
o.2-chlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
p.4-nitrobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
q.2-chloro-6-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
r.3-methoxybenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
(6-chloropyridin-3-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
u.4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) allyl benzoate;
(2-chlorothiazol-5-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate.
2. A process for the preparation of pyrimidine derivatives according to claim 1, comprising the steps of:
(1) Ethyl trifluoroacetoacetate and formamidine hydrochloride or acetamidine hydrochloride are used as raw materials, ethanol is used as a solvent, DBU is used as an acid binding agent, and intermediate substituted 4-hydroxy-6-trifluoromethyl pyrimidine is prepared by reflux; then using acetonitrile as solvent, substituted 4-hydroxy 6-trifluoromethyl pyrimidine is passed through POCl 3 After chlorination, substituted 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine or 4-chloro-6- (trifluoromethyl) pyrimidine is obtained;
(2) Using acetone as a solvent and cesium carbonate as a catalyst, and reacting the substituted 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine or 4-chloro-6- (trifluoromethyl) pyrimidine with methyl paraben to prepare methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate or methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
(3) Methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate or methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate was reacted with KOH, tetrahydrofuran under reflux to produce 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid or 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid;
(4) 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid or 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid as raw material, K 2 CO 3 The pyrimidine derivative is prepared by using DMF as a solvent and a catalyst.
3. The use of pyrimidine derivatives according to claim 1 for the preparation of a medicament against plant pathogenic bacteria, which are melon bacterial fruit blotch, tomato bacterial wilt, rice bacterial blight, potato soft rot, mango bacterial black blotch, cabbage black blotch, strawberry moniliforme, cucumber fusarium, pepper anthracnose, phytophthora capsici, mango jelly, rice sheath blight, wheat scab, soybean phytophthora, tobacco black shank, tomato gray mold or litchi downy mildew, and/or against plant viruses, which are tobacco mosaic virus resistant.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5215990A (en) * | 1990-08-10 | 1993-06-01 | Hoechst Aktiengesellschaft | Substituted pyrimidine derivatives, a process for the preparation thereof and the use thereof as reagents |
| TW200409634A (en) * | 2001-12-07 | 2004-06-16 | Astrazeneca Ab | Novel compounds |
| WO2007109783A2 (en) * | 2006-03-23 | 2007-09-27 | Janssen Pharmaceutica, N.V. | Substituted pyrimidine kinase inhibitors |
| WO2021209366A1 (en) * | 2020-04-16 | 2021-10-21 | Bayer Aktiengesellschaft | Active compound combinations and fungicide compositions comprising those |
| CN114516844A (en) * | 2022-01-18 | 2022-05-20 | 贵州大学 | Quinoxaline derivative, preparation method and application |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110317177B (en) * | 2019-07-30 | 2022-05-17 | 常州大学 | Preparation method of pyrimidine salicylic acid oxime ester compound and application of pyrimidine salicylic acid oxime ester compound as herbicide |
-
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- 2022-07-11 CN CN202210813917.8A patent/CN115124475B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5215990A (en) * | 1990-08-10 | 1993-06-01 | Hoechst Aktiengesellschaft | Substituted pyrimidine derivatives, a process for the preparation thereof and the use thereof as reagents |
| TW200409634A (en) * | 2001-12-07 | 2004-06-16 | Astrazeneca Ab | Novel compounds |
| WO2007109783A2 (en) * | 2006-03-23 | 2007-09-27 | Janssen Pharmaceutica, N.V. | Substituted pyrimidine kinase inhibitors |
| WO2021209366A1 (en) * | 2020-04-16 | 2021-10-21 | Bayer Aktiengesellschaft | Active compound combinations and fungicide compositions comprising those |
| CN114516844A (en) * | 2022-01-18 | 2022-05-20 | 贵州大学 | Quinoxaline derivative, preparation method and application |
Non-Patent Citations (4)
| Title |
|---|
| Nianjuan Pan，et al..Novel Pyrimidine Derivatives Bearing a 1,3,4-Thiadiazole Skeleton: Design, Synthesis, and Antifungal Activity.《Frontiers in Chemistry》.2022,第10卷第922813页. * |
| Xuetong Yu,et al..Synthesis and Antifungal and Insecticidal Activities of Novel N-Phenylbenzamide Derivatives Bearing a Trifluoromethylpyrimidine Moiety.《Hindawi》.2021,第2021卷第1-8页. * |
| 具有杀菌活性的嘧啶类衍生物的研究进展;陈美航 等;《农药》;第56卷(第7期);第474-476页 * |
| 新型嘧啶、喹喔啉衍生物的设计合成及生物活性研究;唐雪梅;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》(第02期);B016-3597 * |
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