CN115124475A - Pyrimidine derivative and preparation method and application thereof - Google Patents
Pyrimidine derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN115124475A CN115124475A CN202210813917.8A CN202210813917A CN115124475A CN 115124475 A CN115124475 A CN 115124475A CN 202210813917 A CN202210813917 A CN 202210813917A CN 115124475 A CN115124475 A CN 115124475A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- methyl
- oxy
- pyrimidin
- benzoate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 27
- 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 39
- 241000700605 Viruses Species 0.000 claims abstract description 18
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 3
- -1 hydrogen radicals Chemical class 0.000 claims description 157
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 120
- 238000000034 method Methods 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
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 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 14
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 claims description 14
- 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 13
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- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 8
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 8
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 5
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- LVOYSBZJJWPUBD-UHFFFAOYSA-N 6-(trifluoromethyl)-1h-pyrimidin-4-one Chemical class OC1=CC(C(F)(F)F)=NC=N1 LVOYSBZJJWPUBD-UHFFFAOYSA-N 0.000 claims description 4
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- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 claims description 3
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
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- 230000002779 inactivation Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100000225 lethality Toxicity 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
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003032 phytopathogenic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 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
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 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
-
- 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
-
- 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 as a formula I:
wherein R is 1 Selected from hydrogen radicals, methyl radicals; r 2 Selected from hydrogen radical, methyl, allyl, substituted or unsubstituted benzyl, substituted or unsubstitutedA thiazolyl group. The invention synthesizes a series of pyrimidine derivatives by structurally modifying active pyrimidine structures. The activity test of the synthesized pyrimidine derivatives against phytopathogen proves that the pyrimidine derivatives prepared by the invention have good activity of inhibiting phytopathogen (bacteria and fungi) and resisting virus, and can be used for preparing medicaments for sterilizing and resisting virus.
Description
Technical Field
The invention relates to the technical field of pesticide synthesis, in particular to a pyrimidine derivative and a preparation method and application thereof.
Background
The 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 by people in recent years.
In 2012, Taher et al (Taher a.t., Abou-Seri S m. molecules,2012,17, 9868-: wherein, the two compounds have higher antibacterial activity to gram positive bacteria staphylococcus aureus and bacillus subtilis, the MIC values are 1.17,2.34 and 0.19 respectively, and 1.17 mu g/mL, which is superior to the control drug of armoxi (1.25,150 mu g/mL); in addition, one compound had broad-spectrum bactericidal activity, with the highest bacteriostatic activity against candida albicans, with a MIC of 2.34 μ g/mL, even higher than that of the control drug amphotericin B (MIC of 3.00 μ g/mL).
In 2015, a series of novel pyrimidine ring-containing pyrazole oxime ether derivatives are designed and synthesized by using the principle of biological isostere, namely organic chemistry 2015,35,100-108. in the Yanagi, and antibacterial activity evaluation is carried out on all target compounds, so that the results prove that most compounds have certain inhibitory activity on apple ring rot fungi, and the inhibitory rates of the two compounds on the apple ring rot fungi are 49.2% and 50.0% respectively at 50 mu g/m L.
In 2015, Wu (Wu W., Chen Q., Tai A., et al, bioorganic and Medicinal Chemistry Letters,2015,25,2243- 50 Is 246.48 ug/mL is better than the control drug ningnanmycin (301.83 ug/mL).
Wuning Jie (Wuning Jie, Chenglong, Wang Jian, et al. organic chemistry, 2019,39, 852) 860.) reported in 2019 that substituted aniline as a raw material was subjected to a series of reactions such as diazotization, arylation, methylation and the like to synthesize target compounds, wherein the lethality rates to armyworms of one compound at concentrations of 500, 100 and 20mg/L were respectively 100, 100 and 80%.
In 2019, a series of 1,3, 4-thiadiazolo [3,2-a ] pyrimidone mesoionic derivatives are reported in organic chemistry, 2019,39, 2287. sup. 2294. about.Liudeng, Ganhuo, etc., wherein the inhibition rate of one compound on rice bacterial stripe virus is 70.91% and 53.34% when the concentration of one compound is 50 mug/mL, and the inhibition rate is superior to that of a control medicament, namely thiabendazole copper (47.76%, 23.45%).
In conclusion, the pyrimidine has a unique structure, has resource advantages in the research and application of medicines, is widely applied in medicines, has a small amount of commercialized medicaments in the aspect of pesticides, and has no related report of pyrimidine derivatives with resistance to plant pathogenic bacteria, fungi and viruses at present.
Disclosure of Invention
The invention mainly aims to provide a pyrimidine derivative with plant pathogenic bacteria, fungi and viruses resistance, and a preparation method and application thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
one of the technical schemes of the invention is as follows: a pyrimidine derivative is provided, and the structural general formula of the pyrimidine derivative is shown as formula I:
wherein R is 1 Selected from hydrogen radicals, methyl radicals; r 2 Selected from hydrogen radicals, methyl, allyl, substituted or unsubstituted benzyl, substituted or unsubstituted thiazolyl.
Preferably, the pyrimidine derivatives are 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;
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 methyl- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
(6-chloropyridin-3-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
allyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
(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;
m.2-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
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;
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 allyl- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) 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) taking trifluoroacetyl ethyl acetate and formamidine hydrochloride or acetamidine hydrochloride as raw materials, ethanol as a solvent and DBU as an acid-binding agent, and refluxing to prepare intermediate-substituted 4-hydroxy-6-trifluoromethyl pyrimidine; then using acetonitrile as solvent, and using substituted 4-hydroxy-6-trifluoromethyl pyrimidine 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 substituted 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine or 4-chloro-6- (trifluoromethyl) 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) refluxing methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate or methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate with KOH and tetrahydrofuran to prepare 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) pyrimidine-4-yl) oxy) benzoic acid or 4- ((6- (trifluoromethyl) pyrimidine-4-yl) oxy) benzoic acid is used as raw material, K 2 CO 3 The pyrimidine derivative is prepared by taking DMF as a solvent as a catalyst.
Preferably, the ethyl trifluoroacetoacetate and the formamidine hydrochloride or the acetamidine hydrochloride in the step (1) are reacted in an absolute ethyl alcohol solvent, and the chlorinating agent in the step (1) is POCl 3 The solvent is also acetonitrile 3 。
The step (1) of the invention comprises two steps of reaction, the second step is POCl 3 The hydroxyl 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 step (3) of the present invention is as follows:
preferably, the reaction of step (4) is carried out under ice bath conditions.
The reaction process of step (4) of the present invention is as follows:
the third technical scheme of the invention is as follows: provides the application of the pyrimidine derivative in preparing anti-plant pathogenic bacteria and/or anti-plant virus medicines. The term "phytopathogen" as used herein refers to a phytopathogenic bacterium and/or fungus.
The invention has the beneficial effects that:
the invention synthesizes a series of pyrimidine derivatives by structurally modifying active pyrimidine structures. The activity test of the synthesized pyrimidine derivative against phytopathogen proves that the pyrimidine derivative prepared by the invention has good activity of inhibiting phytopathogen (bacteria and fungi) and resisting virus, and can be used for preparing medicaments for sterilizing and resisting virus.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description 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.
Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, 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 open-ended terms that mean including, but not limited to. In addition, the meaning of "and/or" appearing throughout includes three juxtapositions, exemplified by "A and/or B" including either A or B or both A and B.
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):
a100 mL round-bottomed flask was charged with 5.0g (27.16mmol) of ethyl trifluoroacetoacetate, 5.37g (35.30mmol) of DBU (1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene) and 30mL ethanol (CH) 3 CH 2 OH) stirring at room temperature for 15min, adding 3.85g (40.74mmol) acetamidine hydrochloride, heating to 85 deg.C, reflux heating, and tracking by TLCReaction (petroleum ether: ethyl acetate ═ 3:1, V/V). After the reaction is stopped, 30mL of purified water is added after the vacuum concentration, the ethyl acetate is used for extraction, the organic layer is taken and concentrated under the vacuum, and the white solid 2-methyl-6- (trifluoromethyl) pyrimidine-4-hydroxyl is obtained after the drying. In a 100mL round-bottom flask, 4.0g (24.38mmol) of 2-methyl-6- (trifluoromethyl) pyrimidin-4-yl group was added and dissolved in 30mL of acetonitrile, and 9.34g of POCl was slowly dropped using an isopiestic dropping funnel under ice-bath conditions 3 (60.94mmol), after the dropwise addition, placing the mixture in an oil bath kettle, heating to 90 ℃ for reflux reaction for 30min, stopping the reaction, cooling the reaction solution, dropwise adding 0.32g (2.4mmol) of N, N-diisopropylethylamine into the reaction system, continuously heating to 90 ℃ for reflux reaction, and tracking the reaction by TLC (petroleum ether: ethyl acetate: 3:1, V/V). After the reaction is completed, the mixture is concentrated under reduced pressure, 60mL of ice water is added under the ice bath condition, the pH value is adjusted to 9 by using 50% NaOH, dichloromethane is used for extraction, an organic layer is taken, and the extract is concentrated under reduced pressure to obtain brown oil (intermediate 1) for later use. Yield: 45 percent.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
a50 mL round-bottomed flask was charged with 2.00g (10.18mmol) of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1), 1.86g (12.21mmol) of methyl p-hydroxybenzoate, and cesium carbonate (Cs) 2 CO 3 )4.97g (15.26mmol) and 20mL of acetone were stirred at room temperature and followed by TLC (petroleum ether: ethyl acetate: 5:1, V/V). After the reaction was stopped, concentrated under reduced pressure, added 40mL of distilled water, extracted three times with ethyl acetate, combined organic layers, concentrated under reduced pressure to give a crude product of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2), yield: 65 percent.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
a100 mL three-necked round bottom flask was charged with methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2)2.0g (6.41mmol), KOH 0.72g (12.81mmol), and 40mL tetrahydrofuran in that order, heated to 70 ℃ for reflux, and the reaction was monitored by TLC (ethyl acetate). After the reaction is stopped, cooling to room temperature, adjusting pH to 1 by using hydrochloric acid under an ice bath condition, separating out white solid, performing suction filtration, and drying to obtain 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3) with yield: and 69 percent.
(4) Preparation of 2, 4-dichlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I1):
in a 100mL single-neck flask were added 0.5g (1.68mmol) of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3) and K in that order 2 CO 3 0.31g (2.3mmol) and 40mL DMF, stirring for 0.5-1 h under ice bath conditions, adding 0.30g (1.52mmol) of 2, 4-dichlorobenzyl chloride, tracking the reaction by TLC (petroleum ether: ethyl acetate ═ 3:1, V/V), stopping the reaction, pouring the reaction mixture into 100mL water, precipitating a white precipitate, clarifying the solution, performing suction filtration to obtain a crude product, and purifying by column chromatography (petroleum ether: ethyl acetate ═ 15:1, V/V) to obtain a white solid (target compound I1), yield: 50 percent.
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):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 2-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I2):
the procedure was as in step (4) of example 1, except for replacing 2, 4-dichlorobenzyl chloride with an equimolar amount of 2-fluorobenzyl chloride. Yield: 65 percent.
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):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 2-methylbenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I3):
the procedure of step (4) in example 1 was followed, except for replacing 2, 4-dichlorobenzyl chloride with an equimolar amount of 2-methylbenzyl chloride. Yield: 54 percent.
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):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 2-chlorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I4):
the procedure was as in step (4) of example 1, except for replacing 2, 4-dichlorobenzyl chloride 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):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 4-nitrobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I5):
the procedure was as in step (4) of example 1, except for replacing 2, 4-dichlorobenzyl chloride with an equimolar amount of 4-nitrobenzyl chloride. Yield: 42 percent.
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):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 2-chloro-6-fluorobenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I6):
the procedure of step (4) in example 1 was followed, except for replacing 2, 4-dichlorobenzyl chloride with an equimolar amount of 2-chloro-6-fluorobenzyl chloride. Yield: 45 percent.
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):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3-methoxybenzyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I7):
the procedure is as in step (4) of example 1, except that 2, 4-dichlorobenzyl chloride is replaced with an equimolar amount of 3-methoxybenzyl chloride. Yield: 50 percent.
Example 8
The preparation method of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I8) is as follows:
(1) preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I8):
the procedure was as in step (4) in example 1, except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of methyl iodide. Yield: 57 percent.
Example 9
The preparation method of (6-chloropyridin-3-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I9) was as follows:
(1) preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of (6-chloropyridin-3-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I9):
the procedure of step (4) in example 1 was followed, except for replacing 2, 4-dichlorobenzyl chloride with an equimolar amount of 2-chloro-5- (chloromethyl) pyridine. Yield: 49 percent.
Example 10
The preparation method of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) allyl benzoate (target compound I10) is as follows:
(1) preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of allyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I10):
the procedure of (4) in example 1 was followed, except for replacing 2, 4-dichlorobenzyl chloride with an equimolar amount of 3-chloroprop-1-ene. Yield: 41 percent.
Example 11
The preparation method of (2-chlorothiazol-5-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I11) was as follows:
(1) preparation of 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine (intermediate 1):
as in step (1) of example 1.
(2) Preparation of methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of (2-chlorothiazol-5-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I11):
the procedure was as in step (4) of example 1, except for replacing 2, 4-dichlorobenzyl chloride with an equimolar amount of 2-chloro-5- (chloromethyl) thiazole. Yield: 62 percent.
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):
as in step (1) of 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):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 2, 4-dichlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I12):
as in step (4) of example 1. Yield: 71 percent.
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):
as in step (1) of 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):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 2-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I13):
as in step (4) of example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-fluorobenzyl chloride. Yield: 71 percent.
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):
as in step (1) of 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):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 2-methylbenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I14):
as in step (4) of example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-methylbenzyl chloride. Yield: 66 percent.
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):
as in step (1) of 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):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 2-chlorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I15):
as in step (4) of example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chlorobenzyl chloride. Yield: and 63 percent.
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):
as in step (1) of 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):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 4-nitrobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I16):
as in step (4) of example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 4-nitrobenzyl chloride. Yield: 68 percent.
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):
as in step (1) of 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):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 2-chloro-6-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I17):
as in step (4) of example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chloro-6-fluorobenzyl chloride. Yield: 73 percent.
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):
as in step (1) of example 1. Except that acetamidine hydrochloride was replaced by an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 3-methoxybenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I18):
as in step (4) of example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 3-methoxybenzyl chloride. Yield: and 55 percent.
Example 19
The preparation method of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I19) is as follows:
(1) preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
as in step (1) of 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):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I19):
as in step (4) of example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of methyl iodide. Yield: 82 percent.
Example 20
The preparation method of (6-chloropyridin-3-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I20) was as follows:
(1) preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
as in step (1) of 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):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of (6-chloropyridin-3-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I20):
as in step (4) in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chloro-5- (chloromethyl) pyridine. Yield: and 47 percent.
Example 21
The preparation method of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) allyl benzoate (target compound I21) is as follows:
(1) preparation of 4-chloro-6- (trifluoromethyl) pyrimidine (intermediate 1):
as in step (1) of 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):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of allyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I21):
as in step (4) of example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 3-chloroprop-1-ene. Yield: and 43 percent.
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):
as in step (1) of example 1. Except that acetamidine hydrochloride was replaced by an equimolar amount of formamidine hydrochloride.
(2) Preparation of methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoic acid (intermediate 3):
as in step (3) of example 1.
(4) Preparation of (2-chlorothiazol-5-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate (target compound I22):
as in step (4) in example 1. Except that 2, 4-dichlorobenzyl chloride was replaced with an equimolar amount of 2-chloro-5- (chloromethyl) thiazole. Yield: 57 percent.
The physicochemical properties and mass spectrum data of the pyrimidine derivatives synthesized in the above examples are shown in Table 1, and the hydrogen nuclear magnetic resonance 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 the example Compounds I1-I22
TABLE 2 NMR data for target compounds I1-I22
Test example 1
Anti-phytopathogenic bacteria test:
(1) test method
A96-well plate method is adopted, the in-vitro inhibitory activity of a target compound on melon bacterial fruit blotch (Ac), tomato ralstonia solanacearum (Rs), rice bacterial leaf blight (Xoo), potato soft rot (Pcb) and mango bacterial black spot (Xcm) is tested under the concentration of 200 mug/mL and 100 mug/mL, the control agents are Bismerthiazol (BT) and benziothiazolinone (TC), and the specific operation steps are as follows:
preparing a bacterial liquid: selecting a single colony in a liquid culture medium (different bacteria adopt different culture media), placing the single colony in a shaking table at 28 ℃ and 180r/min for culturing until the logarithmic growth phase, taking two tubes of 2mL bacteria liquid, centrifuging for 5min under the condition that the rotating speed is 6000rpm, removing the culture medium liquid, adding 2mL sterile water, uniformly mixing the bacteria and the water, taking one tube for measuring under the wavelength of 600nm of an ultraviolet spectrophotometer, adjusting the absorbance value to be 0.6, and storing the other tube for later use. Preparing a liquid medicine: 1mg of test drug was dissolved in 100. mu.L DMSO and the final concentrations were made up to 200. mu.g/mL and 100. mu.g/mL of drug-containing medium in liquid medium (different media for different bacteria). 190 mu L of drug-containing culture medium and 10 mu L of prepared bacterial liquid are added into a 96-well plate, the negative control is culture medium with bacteria and without liquid, the positive control is commercial medicament of thiabendazole and bismerthiazol, and the culture medium with the bacteria and without the bacteria is used as blank control. Placing the 96-well plate in a shaker at 28 deg.C and 180r/min for culturing until the negative control OD value is 0.6-0.8, and measuring the OD of all bacteria liquid with microplate reader 600nm Values were determined and the inhibition of test bacteria by the test drug was calculated using SPSS. 3 replicates were set for each treatment and 3 replicates for each experiment. The inhibition rate was calculated as follows:
correcting OD 600 Value-bacteria-containing Medium OD 600 Sterile Medium OD 600
Inhibition ratio (%) (control medium OD after correction) 600 Corrected drug-containing Medium OD 600 ) Corrected OD value of control medium liquid is multiplied by 100%.
(2) Results of biological Activity test against plant pathogenic bacteria
TABLE 3 bacteriostatic activity (% inhibition) of the compounds prepared in example I1-20 a
Remarking: a average three replicates; b bismerthiazol and thiediazole copper (20% wettable powder) were used as positive controls
As can be seen from Table 3, at 200. mu.g/mL, the inhibition rates of the target compounds I1, I12, I18 and I22 on Ac (bacterial leaf blight of melon) were 81.8, 86.7, 83.5 and 84.4%, respectively, which were better than those of the control drugs TC (47.6%) and BT (37.0%), and the inhibition rates of the compounds I3 and I20 on Pcb (potato soft rot) were 76.2 and 80.0%, respectively, which were better than those of the control drugs TC (45.6%) and BT (45.8%), and the inhibition rates of the compounds I6, I10 and I11 on Xoo (bacterial blight of rice) were 89.7, 81.4 and 85.2%, respectively, which were better than those of the control drugs TC (56.6%) and BT (51.2%).
Test example 2
Anti-plant pathogenic fungi activity test:
(1) test method
In vitro activity evaluation is carried out on twelve plant pathogenic fungi, namely, cabbage black spot pathogen (AB), strawberry fusarium moniliforme (FF), cucumber Fusarium Oxysporum (FO), pepper Colletotrichum (CT), Phytophthora Capsici (PC), pectorale blight (CG), rice sheath blight pathogen (RS), wheat scab (FG), soybean Phytophthora Sojae (PS), tobacco black shank pathogen (PP), tomato gray mold pathogen (BC) and Peronophythora Litchi (PL), by adopting a hypha growth rate method, and the commercial agent azoxystrobin is used as a positive control. The method comprises the following specific steps:
dissolving 3mg of test drug in 300 mu L of DMSO, adding 200 mu L of liquid medicine into 1980 mu L of melted PDA culture medium to prepare a drug-containing culture medium with a final concentration of 100 mu g/mL, uniformly pouring the drug-containing culture medium into three sterilized culture dishes, beating a 4.00mm fungus cake from fungus colonies after the fungus cake is solidified, placing the fungus cake at the center of the drug-containing culture dish, sealing a sealing film, placing a negative control medium which is a culture medium with bacteria and without liquid medicine, placing a positive control medium which is a commercial medicament carbendazim in an incubator at 28 ℃ for culturing for 2-6 days, measuring the diameter of the fungus colonies by adopting a cross method, and calculating the inhibition rate of the test drug on the test fungus by using SPSS. 3 replicates were set for each treatment and 3 replicates for each experiment. The inhibition 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 the drug-treated colony;
0.4: the diameter of the fungus cake;
i, inhibition rate.
PDA culture medium: 200g of potato, 20g of glucose, 20g of agar and 1000mL of distilled water
Cutting peeled potatoes into blocks, putting the cut potatoes into 800mL of distilled water, boiling until the potatoes are cut up, filtering the cut potatoes with gauze, boiling the filtrate, 20g of glucose and 20g of agar again, uniformly mixing the filtrate, and adding the distilled water to a constant volume of 1000 mL.
(2) Results of biological Activity test against plant pathogenic fungi
TABLE 4 bacteriostatic activity (% inhibition) of the compounds prepared in example I1-20 a
Remarking: a average three replicates; b azoxystrobin (Azoxystrobin) was used as a positive control
Under the concentration of 100 mu g/mL, most target compounds have good inhibition effect on PL (peronophythora litchi), wherein the inhibition rates of the compound I9 and the compound I16 on PL are 81.5% and 87.3% respectively, which are close to azoxystrobin (86.3%), and the compounds I11, I17, I19 and I20 are worthy of attention, and have remarkable antifungal activity on PL, the inhibition rates of the compounds I11, I17, I19 and I20 are 90.1, 93.8, 96.3 and 96.0% respectively, which are all superior to azoxystrobin (86.3%).
Test example 3
Anti-tobacco mosaic virus activity test:
(1) test method
A. Virus purification
A Zhoxueping method (Zhou, X.P.; Xu, Z.X.; Xu, J.; Li, D.B.J.south Chin.Agric.Univ.1995,16,74-79.) is adopted, and the upper leaves of the host Nicotiana tabacum.L plant are selected and inoculated for more than 3 weeks, a TMV system infects the upper leaves of the host Nicotiana tabacum.L plant, the upper leaves are homogenized in a phosphate buffer solution, the upper leaves are filtered by a double-layer gauze, the upper leaves are centrifuged at 8000r/min, the upper leaves are treated by polyethylene glycol for 2 times, the upper leaves are centrifuged, and the precipitate is suspended by the phosphate buffer solution to obtain a refined liquid of the TMV. The whole experiment was carried out at 4 ℃. The TMV refined liquid used in the present invention was determined to have a virus concentration of 6X 10 -3 mg/mL。
B. In vivo therapeutic effect of agents on TMV infection
In vivo treatment of infections with agents: selecting folium Xinliangye of 5-6 leaf stage with consistent growth, topping, spreading emery to the whole leaf, dipping virus juice (6 × 10) with a row pen -3 mg/mL) whole leaf virus, air-dried naturally and washed with clear water. After the leaves are dry, lightly applying the medicament on the left half leaf by using a writing brush, applying a solvent with the concentration corresponding to the solvent on the right half leaf as a reference, recording the number of the scorched spots after 6-7 days, and calculating the inhibition rate according to the formula (1).
C. In vivo protection of agents against TMV infection
In vivo protection of agents against TMV infection: selecting the heart-leaf tobacco with consistent growth and 5-6 leaf stage, topping, lightly applying the medicament on the left half leaf with a writing brush, and applying the solvent with the concentration corresponding to the solvent on the right half leaf as a control. Spreading emery powder to the whole leaf 24h later, and dipping virus juice (6 × 10) with a spread pen -3 mg/mL) of the whole leaf, washing with clear water, recording the number of dead spots after 6-7 days, and calculating the inhibition rate according to the formula (1).
D. In vivo inactivation of TMV infection by agents
Mixing the medicament and virus juice with the same volume, inactivating for 30min, dipping the mixed solution of the medicament and virus with a row pen, manually rubbing and inoculating on the left half of the leaf scattered with carborundum, and supporting the lower part of the leaf with a flat wood plate. Sterile water is mixed with the viral juice to inoculate the right half leaf. 3 plants are set for each medicament treatment, each plant has 5-6 leaves, then the plants are put in a light incubator for moisture preservation and culture, the temperature is controlled to be 23 +/-1 ℃, after the light is 10000Lux, the number of the generated scorched spots is observed and recorded after 6-7d, and the inhibition rate is calculated according to the formula (1).
Wherein the average number of half-leaf dry spots without the application of the medicament and the average number of half-leaf dry spots with the application of the medicament are the average of three times of repetition of each group.
(2) The results of the bioactivity test against tobacco mosaic virus are shown in table 5.
TABLE 5 therapeutic, protective and inactivating activity of tobacco mosaic virus of compounds prepared in examples I1-20 a
Remarking: a average three replicates; b ningnanmycin was used as a positive control.
Under the condition that the concentration is 500 mu g/mL, the antiviral activity of the target compound I1-I22 is tested by a half-leaf spot method, and part of compounds have certain inhibition effect on TMV virus. Among them, the inhibitory effects of compounds I2, I10, I12, I13, I17 and I19 were 70.1, 76.3, 64.1, 66.1, 71.3 and 64.2%, respectively, superior to that of the control drug ningnanmycin (54.0%) in terms of therapeutic activity, and the inhibitory effects of compounds I6, I8, I11, I13, I17 and I19 were 65.7, 66.4, 62.1, 65.5, 62.7 and 61.6%, respectively, superior to that of ningnanmycin (58.6%) in terms of protective activity.
The experimental activity data show that the pyrimidine derivative has a certain inhibiting effect on plant germs, and part of target compounds have excellent activity on resisting the plant germs and viruses, can be used as potential plant germ and virus resisting medicines, and have a good application prospect.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention may be made by those skilled in the art without departing from the spirit of the present invention, which is defined by the claims.
Claims (4)
1. A pyrimidine derivative is characterized in that the structural general formula is shown as formula I:
wherein R is 1 Selected from hydrogen radicals, methyl radicals; r 2 Selected from hydrogen radicals, methyl, allyl, substituted or unsubstituted benzyl, substituted or unsubstituted thiazolyl.
2. A process for the preparation of a pyrimidine derivative according to claim 1, wherein the pyrimidine derivative is 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;
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 methyl- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
(6-chloropyridin-3-yl) methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
allyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
(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;
m.2-fluorobenzyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
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;
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 allyl- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
(2-chlorothiazol-5-yl) methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate;
3. a process for the preparation of a pyrimidine derivative according to claim 1, comprising the steps of:
(1) using ethyl trifluoroacetoacetate and formamidine hydrochloride or acetamidine hydrochloride as raw materials, ethanol as a solvent, and DBU as an acid-binding agent, and refluxingPreparing an intermediate substituted 4-hydroxy-6-trifluoromethylpyrimidine; then using acetonitrile as solvent, and using substituted 4-hydroxy 6-trifluoromethyl pyrimidine 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 substituted 4-chloro-2-methyl-6- (trifluoromethyl) pyrimidine or 4-chloro-6- (trifluoromethyl) 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) refluxing methyl 4- ((2-methyl-6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate or methyl 4- ((6- (trifluoromethyl) pyrimidin-4-yl) oxy) benzoate with KOH and tetrahydrofuran to prepare 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) pyrimidine-4-yl) oxy) benzoic acid or 4- ((6- (trifluoromethyl) pyrimidine-4-yl) oxy) benzoic acid is used as a raw material, K 2 CO 3 The pyrimidine derivative is prepared by taking DMF as a solvent as a catalyst.
4. Use of a pyrimidine derivative as claimed in claim 1 in the manufacture of a medicament against phytopathogens and/or plant viruses.
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