CN115557887A - Synthesis of trifluoromethyl pyridine derivative based on Ugi reaction and biological activity research of trifluoromethyl pyridine derivative - Google Patents
Synthesis of trifluoromethyl pyridine derivative based on Ugi reaction and biological activity research of trifluoromethyl pyridine derivative Download PDFInfo
- Publication number
- CN115557887A CN115557887A CN202211409135.4A CN202211409135A CN115557887A CN 115557887 A CN115557887 A CN 115557887A CN 202211409135 A CN202211409135 A CN 202211409135A CN 115557887 A CN115557887 A CN 115557887A
- Authority
- CN
- China
- Prior art keywords
- reaction
- pyridine derivative
- trifluoromethyl pyridine
- trifluoromethylpyridine
- heated
- 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.)
- Pending
Links
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical class FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000006058 Ugi-reaction Methods 0.000 title claims description 6
- 230000004071 biological effect Effects 0.000 title abstract description 4
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000011160 research Methods 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- HXRMCZBDTDCCOP-UHFFFAOYSA-N 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=C(C(F)(F)F)C=C1Cl HXRMCZBDTDCCOP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001412 amines Chemical class 0.000 claims abstract description 5
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 4
- -1 isonitrile compound Chemical class 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000010992 reflux Methods 0.000 claims abstract description 3
- 238000000926 separation method Methods 0.000 claims abstract description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000002474 experimental method Methods 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 241000221696 Sclerotinia sclerotiorum Species 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 241000233866 Fungi Species 0.000 claims description 4
- 241000813090 Rhizoctonia solani Species 0.000 claims description 4
- 241000222199 Colletotrichum Species 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 241000123650 Botrytis cinerea Species 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000001311 chemical methods and process Methods 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 150000002527 isonitriles Chemical class 0.000 claims description 2
- 125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 241001465180 Botrytis Species 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 244000061456 Solanum tuberosum Species 0.000 description 7
- 235000002595 Solanum tuberosum Nutrition 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 235000012015 potatoes Nutrition 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 239000005740 Boscalid Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- WYEMLYFITZORAB-UHFFFAOYSA-N boscalid Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1NC(=O)C1=CC=CN=C1Cl WYEMLYFITZORAB-UHFFFAOYSA-N 0.000 description 2
- 229940118790 boscalid Drugs 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 1
- NYCGGAQICCWUCI-UHFFFAOYSA-N 3-bromo-2-iodopyridine Chemical compound BrC1=CC=CN=C1I NYCGGAQICCWUCI-UHFFFAOYSA-N 0.000 description 1
- XDCOYBQVEVSNNB-UHFFFAOYSA-N 4-[(7-naphthalen-2-yl-1-benzothiophen-2-yl)methylamino]butanoic acid Chemical compound OC(=O)CCCNCc1cc2cccc(-c3ccc4ccccc4c3)c2s1 XDCOYBQVEVSNNB-UHFFFAOYSA-N 0.000 description 1
- 244000024469 Cucumis prophetarum Species 0.000 description 1
- 235000010071 Cucumis prophetarum Nutrition 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthetic method and a biological activity test for synthesizing a trifluoromethyl pyridine derivative, belonging to the field of pharmaceutical chemistry. The method comprises the following steps: adding a raw material 3-chloro-5-trifluoromethylpyridine-2-formic acid into 8ml of methanol solvent, sequentially adding amine and aldehyde, finally adding an isonitrile compound, and stirring at the rotation speed of 400-1200rpm at room temperature until the reaction is terminated. Unreacted or incomplete reaction was heated to 55 ℃ and stirred overnight or heated to 75 ℃ reflux point and observed. After the reaction is finished, concentrating the reaction solution by using a rotary evaporator, and then carrying out silica gel column chromatography separation to obtain a target product. The synthetic method of the trifluoromethyl pyridine derivative provided by the invention has the characteristics of being scientific and reasonable, simple, good in atom economy, mild in condition, high in chemical selectivity and the like. The reaction equation is as followsThe following:
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a synthetic means and a biological activity test for synthesizing a trifluoromethyl pyridine derivative.
Background
Trifluoromethylpyridine is a biologically active fragment formed by connecting trifluoromethyl and a pyridine ring, and has unique properties including a hydrogen-like simulation effect, an electronic effect and a fat-soluble permeation effect. These properties can greatly affect the conformation, biomolecule affinity and drug metabolism of the compound, and make them have low toxicity, and have many resistance effects, such as herbicidal activity, insecticidal activity, antifungal activity and antiviral activity, so that various pesticide compounds containing TFMP fragments are found and marketed, and play an important role in crop protection research.
So far, trifluoromethyl pyridine intermediate is synthesized by methods such as exchanging with chloro and fluoro, constructing pyridine ring with trifluoromethyl building block, and substituting trifluoromethyl for bromoiodopyridine, so as to carry out the next synthesis. The synthesis method of the derivatives is complex, the change is single, and the conditions are harsh; and the reported oxidizing agent of the trifluoromethyl pyridine derivative has the problems of high toxicity, more waste and the like, so that the development of the synthesis method of the trifluoromethyl pyridine derivative has great significance.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the above-mentioned deficiencies of the prior art, the present invention provides a method for synthesizing a trifluoromethylpyridine derivative based on Ugi reaction, as a supplement to the existing method for synthesizing a trifluoromethylpyridine derivative.
The technical scheme is as follows: in order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method for synthesizing a trifluoromethylpyridine derivative based on Ugi reaction, wherein the trifluoromethylpyridine derivative has a structure shown as a formula I:
R 1 selected from phenyl, benzyl, p-tolyl, o-nitrophenyl, 4-chlorophenyl, 4-fluorophenyl, and the like; r 2 Selected from p-methoxyphenyl, phenyl, p-nitrophenyl, furyl, thienyl, p-methylphenyl, etc.; r 3 Selected from tert-butyl, phenyl, cyclohexyl; the method is characterized in that a raw material of 3-chloro-5-trifluoromethylpyridine-2-formic acid is added into 8ml of methanol solvent, amine and aldehyde are sequentially added, and an isonitrile compound is finally added, and the mixture is stirred at the rotating speed of 400-1200rpm at room temperature until the reaction is finishedAnd (4) stopping. Unreacted or incomplete reaction was heated to 55 ℃ and stirred overnight or to 75 ℃ and the reflux point was observed. After the reaction is finished, concentrating the reaction solution by using a rotary evaporator, and then carrying out silica gel column chromatography separation to obtain the target product. The chemical process is shown in a reaction formula II:
the mol ratio of the 3-chloro-5-trifluoromethyl pyridine-2-formic acid to the amine to the aldehyde to the isonitrile is 1.2: 1: 1.2. The solvent is methanol, the reaction temperature is room temperature or 55 ℃, and the reaction time is 24 hours.
The invention has the beneficial effects that: the synthetic method of the trifluoromethyl pyridine derivative provided by the invention is scientific and reasonable, provides a new way for synthesizing the trifluoromethyl pyridine derivative based on the Ugi reaction, obtains the trifluoromethyl pyridine derivative with various substituents, and is characterized by simple synthetic method, good atom economy, mild conditions and high chemical selectivity.
Drawings
FIG. 1 is a chemical reaction formula for preparing a trifluoromethylpyridine derivative;
FIG. 2 is an NMR spectrum of Compound 5a prepared in example 1;
FIG. 3 is an NMR spectrum of Compound 5b prepared in example 2;
FIG. 4 is an NMR spectrum of compound 5c prepared in example 3;
FIG. 5 is an NMR spectrum of compound 5d prepared in example 3;
FIG. 6 is an NMR spectrum of compound 5e prepared in example 3;
Detailed Description
The invention is described in further detail below with reference to the figures and specific examples.
The test methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Example 1
To a 20mL reaction flask were added 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid 1a (0.24mmol, 54.1mg), aniline 2a (0.24mmol, 22.4 mg), p-methoxybenzaldehyde 3a (0.2mmol, 27.2mg), tert-butylisonitrile 4a (0.24mmol, 20.0 mg) and methanol (8 mL), and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the solvent was removed using a rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography (200-300 mesh silica gel) (petroleum ether/ethyl acetate = 3/1), and the solvent was removed using a rotary evaporator to obtain the objective product 5a with a yield of 76%.
Spectral analysis data 5a
1 H NMR(400MHz，CDCl 3 )δ8.53(s，1H)，7.72(s，1H)，7.21-7.07(m，4H)，7.00(d，J＝7.6Hz，3H)，6.82-6.68(m，2H)，6.14(s，1H)，5.95(s，1H)，3.75(s，3H)，1.40(s，9H). 13 C NMR(101MHz，CDCl 3 )δ168.0，165.8，159.7，156.5，143.5(q，J CF ＝4.0Hz)，137.8，134.2(q，J CF ＝3.6Hz)，131.7，130.4，128.6，128.4，128.2，127.1(q，J CF ＝33.7Hz)，125.7，122.1(q，J CF ＝271.5Hz)，113.8，64.9，55.2，51.7，28.6. 19 F NMR(565MHz，CDCl 3 )δ-62.55.
Example 2
The same conditions as in example 1 were used except that 3b was used instead of 3a in example 1, and the results of the experiment are shown in Table 1.
Spectrogram analysis data 5b
1 H NMR(400MHz，CDCl 3 )δ8.54(s，1H)，7.73(s，1H)，7.31-7.27(m，2H)，7.24(d，J＝5.7Hz，3H)，7.16(s，2H)，7.00(d，J＝7.7Hz，3H)，6.16(s，1H)，5.98(s，1H)，1.42(s，9H). 13 C NMR(101MHz，CDCl 3 )167.7，165.8，156.5，143.5(q，J CF ＝4.0Hz)，138.0，134.2(q，J CF ＝3.7Hz)，133.8，130.3，128.6，128.6，128.5，128.4(2C)，128.3，127.0(q，J CF ＝33.8Hz)，122.1(q，J CF ＝273.4Hz)，65.8，51.8，28.6. 19 F NMR(565MHz，CDCl 3 )δ-62.55.
Example 3
3a in example 1 was replaced with 3c, and the experimental results are shown in Table 1, except that the conditions were the same as in example 1.
Spectrogram analysis data 5c
1 H NMR(400MHz，CDCl 3 )δ8.51(s，1H)，7.70(s，1H)，7.29(s，1H)，7.21-7.11(m，2H)，7.05-6.95(m，3H)，6.40-6.34(m，2H)，6.31(s，1H)，6.18(dd，J＝3.3，1.7Hz，1H)，1.39(s，9H). 13 C NMR(101MHz，CDCl 3 )δ165.7，165.5，156.1，146.9，143.6(q，J CF ＝3.9Hz)，142.8，137.7，134.3(q，J CF ＝3.6Hz)，129.5，128.6，128.6(2C)，128.4，127.1(q，J CF ＝33.6Hz)，122.1(q，J CF ＝271.6Hz)，112.7，110.7，59.1，51.8，28.6. 19 F NMR(565MHz，CDCl 3 )δ-62.58.
Example 4
The experiment results are shown in Table 1, except that 4b is used instead of 4a in example 3 and the conditions are the same as in example 3.
Spectrogram analysis data 5d
1 H NMR(400MHz，CDCl 3 )δ8.54(s，1H)，7.73(s，1H)，7.33(s，1H)，7.25-7.11(m，2H)，7.05(s，3H)，6.41(s，2H)，6.29(d，J＝8.2Hz，1H)，6.22(d，J＝3.1Hz，1H)，3.89(dq，J＝9.9，5.3，4.8Hz，1H)，2.06-1.90(m，2H)，1.78-1.65(m，2H)，1.61(dt，J＝13.4，3.9Hz，1H)，1.38(qd，J＝11.5，6.2Hz，2H)，1.21(dq，J＝25.5，13.1，11.5Hz，4H). 13 C NMR(101MHz，CDCl 3 )δ165.8，165.4，156.1，146.8，143.6(q，J CF ＝4.0Hz)，143.0，137.7，134.3(q，J CF ＝3.6Hz)，129.6，128.7，128.6，128.4，127.1(q，J CF ＝33.6Hz)，122.1(q，J CF ＝271.5Hz)，112.8，110.7，58.6，48.9，32.8，25.5，24.7(d，J＝6.0Hz). 19 F NMR(565MHz，CDCl 3 )δ-62.55.
Example 5
3a in example 1 was replaced with 3d and 4a in example 1 was replaced with 4c, and the experimental results are shown in Table 1, except that the conditions were the same as in example 1.
Spectrogram analysis data 5e
1 H NMR(400MHz，CDCl 3 )δ8.56(s，1H)，8.01(s，1H)，7.76(s，1H)，7.55(d，J＝7.8Hz，2H)，7.32(t，J＝7.5Hz，2H)，7.22(d，J＝7.7Hz，3H)，7.12(d，J＝7.4Hz，1H)，7.05(dd，J＝13.0，8.3Hz，5H)，6.48(s，1H)，2.45(d，J＝2.1Hz，1H)，2.31(d，J＝2.1Hz，3H). 13 C NMR(101MHz，CDCl 3 )δ167.1，166.2，156.3，143.5(q，J CF ＝3.8Hz)，138.9，137.7(d，J＝2.9Hz)，134.3(q，J CF ＝3.9Hz)，130.9，130.5，130.4，129.9，129.4，128.9，128.7，128.6，128.3，127.1(q，J CF ＝33.5Hz)，124.4，122.1(q，J CF ＝271.3Hz)，120.1，65.7，21.2. 19 F NMR(377MHz，CDCl 3 )δ-62.54.
Example 6
The compounds 5a-e prepared in examples 1-5 were subjected to a bioactivity test experiment, which was as follows:
the plant fungi used in the experiment are strains stored in a laboratory at 4 ℃, such as Botrytis cinerea, sclerotinia sclerotiorum, colletotrichum cucumis and Rhizoctonia solani. The adopted culture medium is a potato agar glucose culture medium (PDA for short). The PDA culture medium formula comprises: 200g of potato (peeled), 20g of glucose, 15g of agar and 1000mL of distilled water, and the preparation method comprises the following steps: cleaning and peeling potatoes, weighing 200g of potatoes, cutting the potatoes into small pieces, adding water, boiling the potatoes thoroughly (boiling for 20-30 minutes and being capable of being punctured by a glass rod), filtering the potatoes in a beaker by eight layers of gauze, adding 15-20g of agar according to experimental requirements, adding 20g of glucose, stirring the mixture evenly, slightly cooling the mixture after the mixture is fully dissolved, supplementing water to 1000mL, sterilizing the mixture for 15 minutes at 121 ℃ after split charging, and cooling the mixture for later use.
The experimental method comprises the following steps: a growth rate method is used.
(1) Firstly, 2 plant fungi are cultured on a PDA flat plate at 25 ℃ for about 3-6 days for later use;
(2) Heating PDA culture medium to melt, cooling to 45-50 deg.C, adding 250 μ L of 10g/L compound (1 a) to be tested to obtain culture medium containing 50mg/L medicinal liquid, and respectively cooling in culture dish, and using boscalid as positive control;
(3) Using a puncher to punch a round bacterial cake (the diameter is 0.50 cm) at the edge of each bacterial strain hypha cultured for 6d (the growth condition is as consistent as possible), then using an inoculating needle to pick the bacterial cake to the center of a drug-containing flat plate, and then placing the culture dish in an incubator (28 ℃) for culture;
(4) Observing and measuring the growth condition of hyphae at different time after treatment, measuring the diameter by adopting a cross method, processing data and calculating the inhibition rate;
(5) Inhibition (%) = (control hypha diameter-treated hypha diameter)/(control hypha diameter-0.5) × 100;
(6) Each treatment was repeated 3 times.
The test results are shown in Table 2.
TABLE 1
TABLE 2
The results of the bactericidal activity measurements of the experimental groups 5a-e and the control boscalid are shown in table 2. As can be seen from the results in Table 2, at a concentration of 50mg/L, the compounds 5a-e showed different degrees of bacteriostatic activity against 4 plant fungi, and some of the compounds had certain inhibitory activity against Sclerotinia sclerotiorum and Rhizoctonia solani; wherein the inhibition rate of the compound 5d on sclerotinia sclerotiorum is 90.7%, and the inhibition rate of part of compounds on rice sheath blight germ is more than 30%.
Claims (5)
1. A preparation method for synthesizing a trifluoromethylpyridine derivative based on Ugi reaction, wherein the trifluoromethylpyridine derivative has a structure shown as formula I:
R 1 selected from phenyl, benzyl, p-tolyl, o-nitrophenyl, 4-chlorophenyl, 4-fluorophenyl, and the like; r 2 Selected from p-methoxyphenyl, phenyl, p-nitrophenyl, furyl, thienyl, p-methylphenyl, etc.; r 3 Selected from tert-butyl, phenyl, cyclohexyl; the method is characterized in that a raw material 3-chloro-5-trifluoromethylpyridine-2-formic acid is added into 8ml of methanol solvent, amine and aldehyde are sequentially added, and an isonitrile compound is finally added and stirred at the rotating speed of 400-1200rpm at room temperature until the reaction is finished. Unreacted or incomplete reaction was heated to 55 ℃ and stirred overnight or heated to 75 ℃ reflux point and observed. After the reaction is finished, concentrating the reaction solution by using a rotary evaporator, and then carrying out silica gel column chromatography separation to obtain a target product. The chemical process is shown in a reaction formula II:
2. the preparation method of claim 1, wherein the molar ratio of the 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid to the amine to the aldehyde to the isonitrile is 1.2: 1: 1.2.
3. The method of claim 1, wherein: the solvent is methanol, the reaction temperature is room temperature or 55 ℃, and the reaction time is 24 hours.
4. The fungi tested in the experiment were characterized by: including Botrytis cinerea, sclerotinia sclerotiorum, colletotrichum cucumerinum and Rhizoctonia solani.
5. The use of a compound according to claim 1 for the preparation of a medicament against the fungi Botrytis fragilis, sclerotinia sclerotiorum, colletotrichum cucumeri and Rhizoctonia solani.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211409135.4A CN115557887A (en) | 2022-11-10 | 2022-11-10 | Synthesis of trifluoromethyl pyridine derivative based on Ugi reaction and biological activity research of trifluoromethyl pyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211409135.4A CN115557887A (en) | 2022-11-10 | 2022-11-10 | Synthesis of trifluoromethyl pyridine derivative based on Ugi reaction and biological activity research of trifluoromethyl pyridine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115557887A true CN115557887A (en) | 2023-01-03 |
Family
ID=84770267
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211409135.4A Pending CN115557887A (en) | 2022-11-10 | 2022-11-10 | Synthesis of trifluoromethyl pyridine derivative based on Ugi reaction and biological activity research of trifluoromethyl pyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115557887A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1448810A (en) * | 1974-04-02 | 1976-09-08 | Ciba Geigy Ag | Fungicidal n-substituted furoic amide derivatives |
| CN110372622A (en) * | 2018-04-13 | 2019-10-25 | 南京农业大学 | Phenyl acetanides containing chiral oxazoline and the purposes as disinfectant use in agriculture |
-
2022
- 2022-11-10 CN CN202211409135.4A patent/CN115557887A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1448810A (en) * | 1974-04-02 | 1976-09-08 | Ciba Geigy Ag | Fungicidal n-substituted furoic amide derivatives |
| CN110372622A (en) * | 2018-04-13 | 2019-10-25 | 南京农业大学 | Phenyl acetanides containing chiral oxazoline and the purposes as disinfectant use in agriculture |
Non-Patent Citations (2)
| Title |
|---|
| ANDRÉS BORJA-MIRANDA等: "Synthesis of Polysubstituted Isoindolinones via Radical Cyclization of 1, 3-Dicarbonyl Ugi-4CR Adducts Using Tetrabutylammonium Persulfate and TEMPO", 《J. ORG. CHEM.》, vol. 86, pages 929 * |
| JI-YING QIU等: "A Facile Synthesis of Indole Derivatives by a Palladium- Catalyzed Process Initiated from Ugi Adducts and their Antifungal Activities", 《CHEMISTRYSELECT》, vol. 6, pages 12921 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109810062B (en) | Phenylimidazole derivative, synthesis method thereof and application of phenylimidazole derivative in pesticide | |
| CN114436911A (en) | Preparation method and application of camphorsulfonyl benzylamine compound | |
| CN109824742B (en) | Trehalase inhibitor and preparation method thereof | |
| CN111763199B (en) | 2-thienyl quinolinone derivative and preparation method and application thereof | |
| CN111747943B (en) | 3- (2-furan methylene) quinolinone compound and preparation method and application thereof | |
| CN115557887A (en) | Synthesis of trifluoromethyl pyridine derivative based on Ugi reaction and biological activity research of trifluoromethyl pyridine derivative | |
| CN109942427B (en) | Monoterpene phenol derivative, and synthesis method and application thereof in pesticide | |
| CN111718336B (en) | Quinolinone Schiff base compound and preparation method and application thereof | |
| CN111196785B (en) | Triazole derivative and preparation method and application thereof | |
| CN111499554B (en) | Phenyl pyrrole compound and application of bactericidal activity thereof | |
| CN104326918B (en) | Fluoro- 4- hydroxyls -5- nitros -1- phenyl butanone of compound 3- and preparation method thereof and agricultural biological activity | |
| CN111039904B (en) | 2-cyano-3-furan substituted ethyl valerate compound and application thereof | |
| CN111018826B (en) | 2-cyano-5-oxo-ethyl valerate compound and application thereof | |
| CN115611756B (en) | Preparation method and application of alpha-substituted glycine derivative | |
| CN111393348A (en) | Nitrogen-substituted phenylpyrrole compound and application thereof in plant sterilization | |
| CN114957124B (en) | 3- (trifluoromethyl) -pyrazole-4-carboxylic ester derivative and preparation method and application thereof | |
| CN114957123B (en) | 3- (difluoromethyl) -pyrazole-4-carboxylic ester derivative and preparation method and application thereof | |
| CN111072643B (en) | 4, 5-dihydropyrazole compound and application thereof in pesticide | |
| CN111704607B (en) | Quinolinone compound and preparation method and application thereof | |
| CN104326919B (en) | Phenyl butanone of 5 nitro of compound 2 hydroxyl, 3 fluorine 1 and preparation method thereof and agricultural biological activity | |
| CN112939939B (en) | 2- (4-chlorophenyl) pyridine compound and application thereof in pesticides | |
| CN110981864B (en) | N- (4-fluorophenyl) -4, 5-dihydropyrazole compound and application thereof in pesticide | |
| CN116813572B (en) | Preparation method of camphoric acid formylhydrazine compound, product and application thereof | |
| CN115925680B (en) | Trifluoromethyl-containing pyridine compound and preparation method and application thereof | |
| CN111004196B (en) | 2-cyano-5-oxo-valeramide compound and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |