Monofluorinated cyclopropane compound and preparation method and application thereof

Abstract

The application discloses a monofluorinated cyclopropane compound and a preparation method and application thereof. The method is characterized in that, under the action of a metal salt catalyst, a reducing agent and an optional additive, dibromofluoromethane is used as a fluorine source, and is reacted with an olefin containing various functional groups at 10-60 DEG C in a closed state for 0.5-48 hours, and the target product is obtained through post-treatment. The reaction condition is mild, and a strong alkali or an extreme environment is not needed. The substrate has strong universality, and can be compatible with alkyl, aryl, heteroaryl, ester, carboxylic acid, borate and other groups, and the late-stage modification of a complex drug molecule is successfully realized. The examples show that the yield of a key intermediate is up to 99%. The bioactivity test shows that the inhibition rate of a representative compound on the mycelium growth of Botrytis cinerea is up to 81.92% (200 mg / L), the potted plant control efficiency on cucumber downy mildew is up to 91.41% (500 mg / L), and the compound can be used as a pathogenic bacterium inhibitor for pesticide development, and has significant industrial application potential.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a monofluorocyclopropane compound, its preparation method, and its application. Background Technology

[0002] Fluorine atoms possess unique chemical properties such as high electronegativity, strong lipophilicity, and low polarizability, which can improve the bioavailability and bioselectivity of drug molecules in vivo, thus making them widely used in new drug development. However, due to limitations in synthetic methods, fluorine-containing compounds generally exist in structural forms such as fluorobenzene, fluoroalkyl groups, and trifluoromethyl groups, while those with fluorocyclopropane as the structural unit are less common. Furthermore, the cyclopropyl framework is frequently used in drug molecule design, particularly in drugs for anti-infection, cardiovascular, respiratory, and mental disorders. Therefore, combining fluorine atoms with cyclopropane for the development of bioactive molecules holds significant application potential. One of the earliest fluorocyclopropane drug molecules is the quinolone antibacterial drug sitafloxacin. Studies have found that introducing fluorine atoms onto cyclopropane reduces its cytotoxicity compared to the non-fluorine structure (J. Med. Chem. 1994, 37, 3344). In 2025, Pfizer announced PF-07293893, a clinical candidate drug with a fluorinated cyclopropane structure for the treatment of heart failure, which had completed Phase I clinical trials and demonstrated good selectivity and in vivo efficacy (C&EN, 2025, 103, 9). The introduction of the fluorinated cyclopropane structure into this molecule via a commercially available monofluorocyclopropane carboxylic acid limited further optimization and screening of related bioactive molecules (Org. Process Res. Dev. 2026, 30, 189). In the foreseeable future, the development of correspondingly simple and rapid preparation methods will make it possible to introduce more complex and variable fluorinated cyclopropane structures, thus providing a highly valuable and precise controllable means for lead compound optimization.

[0003] Given the importance of the fluorocyclopropane skeleton, developing a strategy that can introduce this structure under simple conditions is particularly important. Traditional synthetic routes typically involve multiple steps and often require relatively harsh reaction conditions. Among them, the reaction types can be divided into the following categories: (1) the addition reaction of fluorocarbene to alkenes, which generally uses dihalofluoromethane as the carbene precursor and requires the use of organometallic reagents or strong bases for dehalogenation (Tetrahedron Lett. 1975, 16, 1819; Tetrahedron Lett. 1971, 12, 3869); (2) the addition of carbene to fluoroalkenes, which requires the introduction of fluorine atoms into the alkene beforehand, increasing the steps and challenges of synthesis (Chem. Pharm. Bull. 1992, 40, 3189); (3) the ring-closing reaction initiated by Mike addition, which uses electron-withdrawing alkenes as the acceptor of Mike addition reaction (Org. Lett. 2012, 14, 2270); (4) the direct fluorination reaction using cyclopropane compounds as raw materials (Tetrahedron Lett. 2003, 44, 8518). The methods described above for synthesizing monofluorocyclopropane compounds often require special substrates, limiting their applicability and making them unsuitable for the later introduction of fluorocyclopropane structures into lead compounds. In 2013, Professor Hu Jinbo's research group at the Chinese Academy of Sciences disclosed a patented method for synthesizing monofluorocyclopropane structures, using a special monofluoromethylphenyl sulfoxide imide as the fluorocyclopropane synthon and the organometallic reagent bis(trimethylsilyl)aminolithium as the base, with relatively demanding reaction conditions (CN103373911).

[0004] Given the common problems of long reaction steps, complex conditions, and narrow substrate range in the above methods, it is essential to develop a general and mild synthetic route for monofluorocyclopropane compounds. Summary of the Invention

[0005] To address the above problems, the present invention aims to provide a monofluorocyclopropane compound, its preparation method, and its application.

[0006] The specific technical solution is as follows:

[0007] A method for preparing monofluorocyclopropane compounds includes the following steps: mixing an olefin compound of formula I with dibromofluoromethane, a metal salt catalyst, a reducing agent, and an organic solvent; carrying out a cyclization reaction under closed stirring at a temperature of 10-60°C; and post-processing the resulting reaction solution to obtain compound II. The reaction equation is as follows:

[0008]

[0009] In Formulas I and II, the substituents R1 and R2 are each independently hydrogen, C1~C1.10 Straight-chain or branched aliphatic alkyl groups, substituted or unsubstituted C6~C 14 aryl, substituted or unsubstituted C4-C 14 The substitution refers to having one or more substituents selected from the group consisting of heteroaryl, C2-C6 acyl, C1-C6 aminoacyl, C1-C6 amide, C1-C6 ester, formic acid, or boron group; the substitution refers to having one or more substituents selected from the group consisting of halogen, C1-C6 amide, C1-C6 ester, formic acid, or boron group. 10 Alkyl, C1-C 10 Alkoxy, carbonyl, sulfone, or dioxonyl; halogens are F, Cl, or Br.

[0010] Preferably, R1 and R2 are each independently selected from the following groups:

[0011] (1) Hydrogen;

[0012] (2) C1~C10 straight-chain or branched aliphatic alkyl groups: preferably C1~C6 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; more preferably C1~C4 alkyl groups, such as methyl, ethyl, isopropyl or tert-butyl.

[0013] (3) Substituted or unsubstituted C6~C14 aryl groups: preferably phenyl or naphthyl; more preferably phenyl. Examples include, but are not limited to: unsubstituted aryl groups: phenyl, 1-naphthyl; substituted aryl groups: for example, phenyl groups substituted with fluorine, chlorine, methyl, methoxy, trifluoromethyl, acetyl (-COCH3), methanesulfonyl (-SO2CH3) or 1,3-dioxolane-2-yl, specifically such as 4-fluorophenyl, 3-chlorophenyl, 4-methylphenyl (p-tolyl), 4-methoxyphenyl, 3,5-di(trifluoromethyl)phenyl, 4-acetylphenyl, 4-(methanesulfonyl)phenyl, or 3,4-methylenedioxyphenyl (piperyl), etc.

[0014] (4) Substituted or unsubstituted C4~C14 heteroaryl groups: The heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, preferably 5-membered or 6-membered heteroaryl groups, such as furanyl, thiophene, pyrrole, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophene, or indoleyl. Examples include, but are not limited to: unsubstituted heteroaryl groups: 2-furanyl, 3-thiophene, 2-pyridinyl; substituted heteroaryl groups: for example, heteroaryl groups substituted by methyl, chlorine, or methoxy, specifically 5-methyl-2-furanyl, 5-chloro-2-thiophene, 6-methoxy-2-pyridinyl, etc.

[0015] (5) Acyl group of C2~C6: preferably acetyl (-COCH3), propionyl (-COC2H5), butyryl or benzoyl (-COPh); more preferably acetyl, benzoyl or pentamethylbenzoyl;

[0016] (6) C1~C6 aminoacyl groups (i.e., mono- or di-substituted derivatives of carbamoyl groups): for example, formamido (-NHCHO), acetamido (-NHCOCH3), N-methylaminoacyl (-N(CH3)CHO), or N,N-dimethylaminoacyl (-N(CH3)2), N-methylbenzamido (-N(CH3)COPh); preferably acetamido (-NHCOCH3);

[0017] (7) Amide group of C1~C6: for example N,N-dimethylaminoformyl (-CON(CH3)2), N-ethylaminoformyl (-CONHC2H5) or N-anilineformyl (-CONHPh); preferably N,N-dimethylaminoformyl (-CON(CH3)2);

[0018] (8) Ester groups of C1 to C6: preferably methoxycarbonyl (-COOCH3), ethoxycarbonyl (-COOC2H5), isopropoxycarbonyl or phenoxycarbonyl (-COOPh); more preferably methoxycarbonyl or ethoxycarbonyl;

[0019] (9) Formic acid group: i.e. -COOH;

[0020] (10) Boron group: preferably borate ester, such as pinacol boronic acid ester (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl).

[0021] More preferably, R1 and R2 are each independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 2-furanyl, 2-pyridyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, -COOH or pinacol boronic acid ester.

[0022] Furthermore, the above reaction also includes an additive, which is zinc chloride, zinc bromide, zinc iodide, sodium bromide or sodium iodide, preferably zinc bromide.

[0023] Furthermore, the metal salt catalyst is nickel chloride, cobalt bromide, nickel chloride with ethylene glycol dimethyl ether, nickel bromide, nickel bromide with ethylene glycol dimethyl ether, nickel iodide, nickel acetylacetone, nickel nitrate, nickel acetate, bis(1,5-cyclooctadiene) nickel, bis(triphenylphosphine) nickel chloride, or tetra(triphenylphosphine) nickel, preferably nickel chloride with ethylene glycol dimethyl ether or nickel bromide with ethylene glycol dimethyl ether.

[0024] Furthermore, the reducing agent is manganese, zinc, iron, or magnesium, preferably manganese.

[0025] Further, the organic solvent is one or a mixture of several of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, trifluorotoluene, tetrahydrofuran, diethyl ether, dichloromethane, and acetonitrile, preferably one or a mixture of N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran; more preferably N,N-dimethylacetamide.

[0026] Further, the molar ratio of the olefin compound shown in Formula I to dibromofluoromethane, the metal salt catalyst, the reducing agent, and the additive is 1:0.5~5:0.01~0.2:0.5~5:1~5, more preferably 1:1~3:0.05~0.2:1~3:1~3; and even more preferably 1:1~1.5:0.05~0.1:1.2~3:1~2.

[0027] Preferably, the reaction temperature is 15-40℃ and the reaction time is 6-24 hours.

[0028] More specifically, the method described in this invention is recommended to be performed according to the following steps:

[0029] The compound of formula I was added to a sealed reaction vessel with dibromofluoromethane, ethylene glycol dimethyl ether nickel bromide, manganese, zinc bromide, and N,N-dimethylacetamide. The mixture was stirred at 15–40 °C for 6–24 hours to carry out a cyclization reaction. The resulting reaction solution was diluted with an organic solvent (such as ethyl acetate or dichloromethane) and water and extracted. The organic phases were combined, washed three times with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography using petroleum ether and ethyl acetate as eluents. The eluent containing the product was collected, and the solvent was removed by evaporation of the eluent to obtain the monofluorocyclopropane compound of formula II. The molar ratio of the compound of formula I, dibromofluoromethane, ethylene glycol dimethyl ether nickel bromide, manganese, and zinc bromide was 1:1–1.5:0.05–0.1:1.2–3:1–2.

[0030] A monofluorocyclopropane compound prepared by the above preparation method.

[0031] An application of a monofluorocyclopropane compound, wherein the application is in the preparation of a pathogen inhibitor.

[0032] The beneficial effects of this invention are as follows:

[0033] The method provided by this invention breaks through the limitations of traditional monofluorocyclopropane synthesis and has significant advantages: mild reaction conditions, no need for strong bases or extreme environments, and can be carried out efficiently at 10~60℃; extremely broad substrate versatility, applicable to alkenes containing various functional groups such as alkyl, aryl, heteroaryl, ester, carboxylic acid, and borate esters, and has been successfully applied to the late-stage modification of complex drug molecules; excellent stereoselectivity and controllable product configuration; simple and efficient process, using inexpensive and readily available dibromofluoromethane as the fluorine source, combined with a low-toxicity metal catalyst and reducing agent, and convenient post-processing; outstanding application value, with examples demonstrating a synthesis yield of up to 99% for key intermediates of fluorine-containing drugs, providing a flexible and efficient new strategy for introducing fluorocyclopropane structures for drug development, and has great industrialization potential. Detailed Implementation

[0034] The specific embodiments of the present invention will be described in detail below with reference to examples. It should be understood that the specific embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0035] Example 1

[0036]

[0037] Under N2 protection, N-methyl-N-(1-phenylvinyl)acetamide (87.5 mg, 0.5 mmol), ethylene glycol dimethyl ether nickel bromide (15.4 mg, 0.05 mmol), zinc bromide (225.2 mg, 1.0 mmol), manganese powder (82.4 mg, 1.5 mmol), and N,N-dimethylacetamide (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 30°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (75.0 mg, 73% yield).

[0038] 1 H NMR (400 MHz, Chloroform-d) δ = 7.38 – 7.23 (m, 3H), 7.20 – 6.88(m, 2H), 5.09 – 4.72 (m, 1H), 3.12 (s, 3H), 2.04 (s, 3H), 1.95 – 1.80 (m,1H), 1.75 – 1.54 (m,1H). 13C NMR (101 MHz, Chloroform-d) δ = 174.3, 139.9,129.2 (2C), 127.2 (2C), 123.2, 78.5 (d, J = 235.7 Hz), 45.7 (d, J = 9.2 Hz),34.5, 24.6, 21.38 (d, J = 4.6 Hz). 19 F NMR (376 MHz, Chloroform-d) δ = -203.3.

[0039] Example 2

[0040]

[0041] Under N2 protection, N-methyl-N-(1-(4-(trifluoromethyl)phenyl)vinyl)acetamide (121.6 mg, 0.5 mmol), nickel chloride (6.5 mg, 0.05 mmol), zinc bromide (225.2 mg, 1.0 mmol), manganese powder (82.4 mg, 1.5 mmol), and tetrahydrofuran (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 30°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (78.4 mg, 57% yield).

[0042] 1 H NMR (400 MHz, Chloroform-d) δ = 7.64 – 7.56 (m, 2H), 7.29 – 6.99(m, 2H), 5.14 – 4.76 (m, 1H), 3.18 – 3.13(m, 3H), 2.18 – 2.03 (m, 3H), 1.92 –1.61 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ = 174.1, 144.2, 129.7 (q, J =32.3 Hz), 126.3 (q, J = 3.2 Hz, 2C), 124.0 (q, J = 271.9 Hz), 123.6 (2C),78.5 (d, J = 235.4 Hz), 45.7 (d, J = 9.0 Hz), 27.7, 25.1, 21.3 (d, J = 6.5Hz).19 F NMR (376 MHz, Chloroform-d) δ = -62.6, -201.8.

[0043] Example 3

[0044]

[0045] Under N2 protection, 2-(1-(p-tolyl)vinyl)isoindoline-1,3-dione (131.6 mg, 0.5 mmol), ethylene glycol dimethyl ether nickel chloride (11.0 mg, 0.05 mmol), zinc bromide (225.2 mg, 1.0 mmol), zinc powder (82.4 mg, 1.5 mmol), and N,N-dimethylformamide (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 30°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (128.5 mg, 87% yield).

[0046] 1 H NMR (400 MHz, Chloroform-d) δ = 7.85 – 7.82 (m, 2H), 7.72 – 7.67(m, 2H), 7.60 – 7.39 (m, 2H), 7.17 – 7.11 (m, 2H), 5.21 – 5.01 (m, 1H), 2.29(s, 3H), 2.03 – 1.92 (m, 1H), 1.84 – 1.65 (m, 1H). 13 C NMR (101 MHz,Chloroform-d) δ = 167.7 (2C), 138.3 (2C), 134.2 (2C), 131.7, 130.5, 129.6(2C), 128.3 (2C), 123.5 (2C), 73.8 (d, J = 232.3 Hz), 36.2 (d, J = 9.2 Hz), 21.2, 20.1 (d, J = 10.4 Hz). 19 F NMR (376 MHz, Chloroform-d) δ = -210.8.

[0047] Example 4

[0048]

[0049] Under N2 protection, 2-(1-phenylvinyl)pyridine (90.6 mg, 0.5 mmol), cobalt bromide (10.9 mg, 0.05 mmol), zinc chloride (136.3 mg, 1.0 mmol), iron powder (83.8 mg, 1.5 mmol), and N-methylpyrrolidone (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 30°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (72.5 mg, 68% yield).

[0050] 1 H NMR (400 MHz, Chloroform-d) δ = 8.45 (ddd, J = 4.9, 1.9, 1.0 Hz, 1H), 7.46 – 7.32 (m, 6H), 7.00 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 6.75 (dt, J =8.0, 1.1 Hz, 1H), 5.28 (ddd, J = 65.9, 6.1, 3.2 Hz, 1H), 1.98 (dt, J = 12.7,6.2 Hz, 1H), 1.78 (ddd, J = 23.3, 6.3, 3.2 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ = 162.2 (d, J = 2.7 Hz), 149.0, 137.0 (d, J = 3.3 Hz), 135.9,132.0 (2C), 128.8 (2C), 127.7, 121.9, 120.7, 77.8 (d, J = 231.3 Hz), 35.5 (d, J = 10.4 Hz), 23.0 (d, J = 7.8 Hz). 19 F NMR (376 MHz, Chloroform-d) δ = -205.2, dr > 20:1.

[0051] Example 5

[0052]

[0053] Under N2 protection, N,N-diphenylmethylacrylamide (118.6 mg, 0.5 mmol), nickel acetate (8.8 mg, 0.05 mmol), zinc bromide (112.6 mg, 0.5 mmol), manganese powder (82.4 mg, 1.5 mmol), and N,N-dimethylacetamide (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 30°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (71.4 mg, 53% yield).

[0054] 1 H NMR (400 MHz, Chloroform-d) δ = 7.29 – 7.25 (m, 4H), 7.18 – 7.10(m, 6H), 4.82 (ddt, J = 65.6, 5.2, 1.9 Hz, 1H), 1.48 – 1.41 (m, 1H), 0.92 (s,3H), 0.79 (dddd, J = 21.5, 7.0, 3.4, 1.5 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ = 172.9, 143.3 (2C), 129.3 (4C), 127.6 (4C), 126.9 (2C), 76.6 (d, J = 230.9 Hz), 26.2 (d, J = 11.0 Hz), 21.6 – 21.5 (m), 14.5 – 14.4 (m). 19 F NMR (376 MHz, Chloroform-d) δ = -217.1.

[0055] Example 6

[0056]

[0057] Under N2 protection, 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxoboronane (115.1 mg, 0.5 mmol), bis(triphenylphosphine) nickel dichloride (32.7 mg, 0.05 mmol), zinc iodide (319.2 mg, 1.0 mmol), magnesium powder (36.5 mg, 1.5 mmol), and acetonitrile (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 30°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (57.7 mg, 44% yield).

[0058] 1 H NMR (400 MHz, Chloroform-d) δ = 7.29 – 7.14 (m, 5H), 4.93 – 4.65(m, 1H), 1.81 – 1.41 (m, 1H), 1.34 – 1.28 (m, 1H), 1.25 (s, 3H), 1.21 (s,3H), 1.19 (s, 3H), 1.18 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ = 137.6 (d,J = 4.8 Hz), 130.5 (2C), 128.2 (2C), 126.2, 84.0, 75.3 (d, J = 225.8 Hz), 25.0, 24.9, 24.8, 24.8, 24.6, 24.6, 16.3 (d, J = 8.9 Hz). 19 F NMR (376 MHz, Chloroform-d) δ = -212.4.

[0059] Example 7

[0060]

[0061] Under N2 protection, 2-methyl-1-(2,3,4,5,6-pentamethylphenyl)prop-2-en-1-one (108.1 mg, 0.5 mmol), ethylene glycol dimethyl ether nickel bromide (7.7 mg, 0.025 mmol), zinc bromide (33.8 mg, 0.15 mmol), manganese powder (82.4 mg, 1.5 mmol), and N,N-dimethylacetamide (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 40°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (80.7 mg, 65% yield).

[0062] 1 H NMR (400 MHz, Chloroform-d) δ = 4.91 (ddd, J = 66.1, 6.5, 3.6 Hz,1H), 2.24 (s, 3H), 2.19 (s, 6H), 2.10 (s, 3H), 2.09 (s, 3H), 1.79 – 1.72 (m,1H), 1.31 (s, 3H), 1.28 – 1.20 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ =212.2 (d, J = 2.1 Hz), 138.7, 135.5, 133.2, 133.1, 127.4, 127.3, 79.6 (d, J =233.7 Hz), 32.5 (d, J = 10.2 Hz), 24.5 – 24.4 (m), 17.5, 17.4, 16.8, 16.1(2C), 13.1 – 12.9 (m). 19 F NMR (376 MHz, Chloroform-d) δ = -212.2.

[0063] Example 8

[0064]

[0065] Under N2 protection, 2-(3-bromobenzyl)-1-(2,3,4,5,6-pentamethylphenyl)prop-2-en-1-one (185.7 mg, 0.5 mmol), ethylene glycol dimethyl ether nickel bromide (15.4 mg, 0.05 mmol), manganese powder (82.4 mg, 1.5 mmol), and N,N-dimethylacetamide (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (115.2 mg, 0.6 mmol) was added dropwise. After reacting at 15°C for 6 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (125.0 mg, 62% yield).

[0066] 1 H NMR (400 MHz, Chloroform-d) δ = 7.24 – 7.21 (m, 1H), 7.00 – 6.94(m, 2H), 6.67 (s, 1H), 5.13 – 4.93 (m, 1H), 3.03 – 2.90 (m, 2H), 2.24 (s,3H), 2.14 (s, 3H), 2.07 (s, 3H), 1.84 (s, 3H), 1.80 (dd, J = 13.6, 6.7 Hz,1H), 1.76 (s, 3H), 1.54 – 1.46 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ =210.2 (d, J = 2.2 Hz), 141.1, 138.1, 136.1, 133.2, 133.2, 132.6, 129.4,129.4, 129.2, 128.2, 127.8, 121.9, 79.5 (d, J = 234.7 Hz), 38.5 (d, J = 9.7Hz), 32.8 (d, J = 5.9 Hz), 24.5 (d, J = 6.8 Hz), 17.6, 17.4, 16.9, 16.1,16.0. 19 F NMR (376 MHz, Chloroform-d) δ = -207.1, dr > 20:1.

[0067] Example 9

[0068]

[0069] Under N2 protection, diphenylmethacrylate (119.1 mg, 0.5 mmol), ethylene glycol dimethyl ether nickel bromide (15.4 mg, 0.05 mmol), zinc bromide (225.2 mg, 1.0 mmol), manganese powder (82.4 mg, 1.5 mmol), and N,N-dimethylacetamide (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 25°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (81.1 mg, 60% yield).

[0070] 1 H NMR (400 MHz, Chloroform-d) δ = 7.34 – 7.32 (m, 8H), 7.30 – 7.28(m, 2H), 6.87 (s, 1H), 4.83 (dddd, J = 63.6, 7.7, 3.5, 1.6 Hz, 1H), 2.26 –2.17 (m, 1H), 1.53 – 1.42 (m, 1H), 1.38 – 1.26 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ = 170.4, 140.0, 140.0, 128.7 (4C), 128.2 (2C), 127.2 (2C), 127.2 (2C), 77.5 (d, J = 3.0 Hz), 73.6 (d, J = 228.1 Hz), 20.4 (d, J = 12.4Hz), 14.9 (d, J = 8.6 Hz).

[0071] Example 10

[0072]

[0073] Under N2 protection, methyl 2-(2,2-difluorobenzo[d][1,3]dioxane-5-yl)acrylate (1.21 g, 5 mmol), ethylene glycol dimethyl ether nickel bromide (0.15 g, 0.5 mmol), zinc bromide (2.25 g, 10 mmol), manganese powder (0.82 g, 15 mmol), and N,N-dimethylacetamide (50 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (1.44 g, 7.5 mmol) was added dropwise. After reacting at 30°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product (1.10 g, 80% yield) was obtained by rapid column chromatography.

[0074] 1 H NMR (400 MHz, Chloroform-d) δ = 7.12 – 6.99 (m, 3H), 5.08 (ddd, J= 65.0, 6.2, 3.6 Hz, 1H, major), 4.83 (ddd, J = 64.5, 6.4, 3.9 Hz, 1H, minor), 3.71 (s, 3H, minor), 3.65 (s, 3H, major), 2.41 (ddd, J = 22.4, 7.3,3.9 Hz, 1H, minor), 1.92 (dt, J = 13.6, 6.5 Hz, 1H, major), 1.69 (ddd, J =22.0, 6.8, 3.6 Hz, 1H, major), 1.47 (ddd, J = 11.6, 7.4, 6.5 Hz, 1H, minor). 13 C NMR (101 MHz, Chloroform-d) δ = 171.9 (d, J = 2.6 Hz), 143.7, 143.5, 131.8 (t, J = 255.4 Hz), 129.3 (d, J = 2.9 Hz), 127.0, 113.0 (d, J = 3.2 Hz),109.3, 75.6 (d, J = 232.8 Hz), 52.9 (d, J = 2.4 Hz), 33.3 (d, J = 11.2 Hz), 21.7 (d, J = 7.7 Hz). 19F NMR (376 MHz, Chloroform-d) δ = -49.8, -206.7(major), -212.6 (minor), dr = 6.4:1.

[0075] Example 11

[0076]

[0077] Under N2 protection, methyl (Z)-2-(5-fluoro-2-methyl-1-(4-methylenesulfinylbenzyl)-1H-inden-3-yl)acrylate (191.2 mg, 0.5 mmol), ethylene glycol dimethyl ether nickel bromide (15.4 mg, 0.05 mmol), zinc bromide (225.2 mg, 1.0 mmol), manganese powder (82.4 mg, 1.5 mmol), and N,N-dimethylacetamide (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 25°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (173.0 mg, 83.5% yield).

[0078] 1 H NMR (400 MHz, Chloroform-d) δ = 7.47 (d, J = 8.2 Hz, 2H), 7.40 (dd, J = 8.4, 5.2 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.19 (s, 1H), 6.87 (dd,J = 9.0, 2.5 Hz, 1H), 6.60 (td, J = 8.9, 2.5 Hz, 1H), 5.22 (ddd, J = 64.8,6.3, 3.7 Hz, 1H), 3.67 (s, 3H), 2.55 (s, 3H), 2.23 (s, 3H), 2.03 (dq, J =15.2, 8.7, 7.5 Hz, 1H), 1.63 – 1.55 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ= 171.7 (d, J = 2.2 Hz), 163.2 (d, J = 245.5 Hz), 146.8 (d, J = 8.8 Hz),142.5, 140.1, 139.4, 133.0, 130.6 (d, J = 2.0 Hz), 130.0 (2C), 130.0, 129.8,126.0 (2C), 123.8 (d, J = 8.9 Hz), 110.5 (d, J = 23.2 Hz), 106.1 (d, J = 24.1Hz), 75.7 (d, J = 234.3 Hz), 52.9 (d, J = 2.6 Hz), 25.3 (d, J = 11.7 Hz),20.8, 15.5, 11.5. 19 F NMR (376 MHz, Chloroform-d) δ = -113.9, -206.8.

[0079] Example 12

[0080]

[0081] Under N2 protection, ethyl 2-phenylacrylate (88.1 mg, 0.5 mmol), ethylene glycol dimethyl ether nickel bromide (15.4 mg, 0.05 mmol), zinc bromide (225.2 mg, 1.0 mmol), manganese powder (82.4 mg, 1.5 mmol), and N,N-dimethylacetamide (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 30°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (94.7 mg, 91% yield).

[0082] Example 13

[0083]

[0084] Under N2 protection, 2-phenylacrylic acid (74.1 mg, 0.5 mmol), ethylene glycol dimethyl ether nickel bromide (15.4 mg, 0.05 mmol), zinc bromide (225.2 mg, 1.0 mmol), manganese powder (82.4 mg, 1.5 mmol), and N,N-dimethylacetamide (5 mL) were added to a Schlenk reaction tube. Dibromofluoromethane (144 mg, 0.75 mmol) was added dropwise. After reacting at 30°C for 24 hours, the reaction was quenched with saturated saline solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by rapid column chromatography (74.8 mg, 83% yield).

[0085] Example 14

[0086]

[0087] At 0°C, trifluoroacetic acid (0.1 mL) was added dropwise to a solution of 2-fluorocyclopropane-1-carboxylic acid diphenyl methyl ester (54.1 mg, 0.2 mmol) in dichloromethane (2 mL). The reaction mixture was slowly heated to room temperature and stirred overnight. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted three times with methyl tert-butyl ether (30 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then obtained by rapid column chromatography (17.5 mg, 84% yield).

[0088] Example 15

[0089]

[0090] Under nitrogen protection, dibromofluoromethane (1.5 mmol) was added dropwise to a stirred solution of ethylene glycol dimethyl ether nickel bromide (30.8 mg 0.10 mmol), methyl 2-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)acrylate (1 mmol), zinc bromide (2.0 mmol), and manganese powder (3.0 mmol) in DMA (10 mL). The mixture was stirred at 30°C for 36 hours, followed by quenching in saturated brine. The mixture was extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, dried, and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give methyl 1-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-2-fluorocyclopropane-1-carboxylate (0.178 g, 65% yield).

[0091] Under N2 protection, methyl 1-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-2-fluorocyclopropane-1-carboxylate (0.274 g, 1 mmol), tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate (0.341 g, 1.2 mmol), and tetrahydrofuran (2 mL) were added to a Schlenk reaction tube, followed by dropwise addition of hexamethyldisilamide lithium (0.335 g, 2 mmol). The reaction was carried out at 30°C for 15 hours. After the reaction was completed, the mixture was quenched with saturated saline solution and extracted six times with dichloromethane (20 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product (0.52 g, 99% yield) was obtained by rapid column chromatography.

[0092] 1 H NMR (400 MHz, Chloroform-d) δ = 8.17 – 7.99 (m, 3H), 7.76 (s, 1H), 7.64 – 7.55 (m, 2H), 7.47 (q, J = 7.7, 6.9 Hz, 1H), 7.25 – 7.17 (m, 2H), 7.14– 7.07 (m, 1H), 5.20 (ddd, J = 65.3, 6.0, 3.4 Hz, 1H), 2.27 (s, 3H), 2.05 (dt, J = 13.7, 6.4 Hz, 1H), 1.66 (ddd, J = 22.5, 6.5, 3.6 Hz, 1H), 1.59 (s,9H). 13 C NMR (101 MHz, Chloroform-d) δ = 169.3 (d, J = 2.4 Hz), 165.4, 155.6,148.4, 144.3, 144.2, 141.0, 139.6, 132.8, 132.2, 131.7 (t, J = 257.6 Hz),129.9, 129.2, 128.4 (d, J = 3.2 Hz), 128.2, 127.7, 127.4, 113.2, 112.9,110.4, 81.2, 75.8 (d, J = 232.9 Hz), 35.0 (d, J = 10.8 Hz), 28.2 (3C), 22.3 (d, J = 7.7 Hz), 19.2. 19 F NMR (376 MHz, Chloroform-d) δ = -49.4, -206.8.

[0093] Example 16

[0094]

[0095] Under nitrogen protection, dibromofluoromethane (1.5 mmol) was added dropwise to a stirred solution of ethylene glycol dimethyl ether nickel bromide (30.8 mg + 0.10 mmol), methyl 2-[2-((6-trifluoromethylpyridin-2-yl)oxymethyl)phenyl]acrylate (1 mmol), zinc bromide (2.0 mmol), and manganese powder (3.0 mmol) in DMA (10 mL). The mixture was stirred at 30°C for 36 hours, and then quenched in saturated brine. The mixture was extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, dried, and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give methyl 2-fluoro-1-[2-((6-trifluoromethylpyridin-2-yl)oxymethyl)phenyl]cyclopropane-1-carboxylic acid (0.299 g, 81% yield).

[0096] 1 H NMR (400 MHz, Chloroform-d) δ = 7.70 - 7.66 (t, J = 7.9 Hz, 1H), 7.56 - 7.55 (d, J = 7.4 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.25 - 7.24 (d, J = 7.4Hz, 1H), 6.90 - 6.87 (d, J = 8.4 Hz, 1H), 5.60 - 5.46 (m, 2H), 5.27 - 5.02(m, 1H), 3.66 - 3.57 (d, J = 37.6 Hz, 3H), 2.55 - 1.92 (m, 1H), 1.80 – 1.72(m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ = 172.1, 163.4, 145.4 (q, J = 34.8Hz), 139.6, 137.6, 132.3, 132.1, 132.1, 129.7, 128.3, 121.4 (q, J = 273.7Hz), 114.7, 113.5 (d, J = 3.4 Hz), 76.84 (d, J =231.1 Hz), 65.7, 52.63, 33.79 (d, J = 11.1 Hz), 22.0 (d, J = 7.9 Hz). 19F NMR (376 MHz, Chloroform-d) δ = -68.30, -214.05.

[0097] Example 17

[0098] The bioactivity of methyl 2-fluoro-1-[2-((6-trifluoromethylpyridin-2-yl)oxymethyl)phenyl]cyclopropane-1-carboxylate, an analogue of azoxystrobin, was tested to inhibit the growth of botrytis cinerea mycelium in tomatoes and downy mildew in cucumbers.

[0099] (1) Determination of the inhibitory activity of in vitro mycelial growth of the pathogenic fungus *Gycnidium monnieri* in tomatoes

[0100] Experimental procedure: Using the mycelial growth rate method, the test compound and the control agent were dissolved in DMSO and diluted to prepare three concentration gradient PDA plates containing the drug at 200 mg / L, 20 mg / L and 2 mg / L respectively. The solvent control group was added with the same volume of DMSO, and the water control group was added with only Tween aqueous solution.

[0101] The tested pathogens were punched into 5 mm diameter mycelial discs, which were then transferred to the center of each drug-containing plate and incubated at 25 ℃ in the dark. After the blank control colonies had fully grown on the plate, the diameter of each treatment colony was measured, and the mycelial growth inhibition rate was calculated.

[0102] Mycelial growth inhibition rate (%) = [(diameter of blank control colony - diameter of drug-treated colony) ÷ diameter of blank control colony] × 100%.

[0103] The experimental results are shown in Table 1.

[0104] Table 1. Summary of the inhibition rates of azoxystrobin analogues against Botrytis cinerea mycelia of tomato.

[0105]

[0106] In vitro activity conclusions:

[0107] Within the experimental dose range of 2 to 200 mg / L, the compound 2-fluoro-1-[2-((6-trifluoromethylpyridin-2-yl)oxymethyl)phenyl]cyclopropane-1-carboxylic acid methyl ester of the present invention exhibited excellent mycelial inhibitory activity against Botrytis cinerea, the causal agent of tomato mold: the inhibition rate reached 81.92% at a concentration of 200 mg / L and 61.25% at a concentration of 20 mg / L.

[0108] (2) In vivo control efficacy test of cucumber downy mildew in potted plants

[0109] Experimental Procedure: Each pesticide was diluted with a 0.1% Tween aqueous solution, with three supply concentrations: 500 mg / L, 250 mg / L, and 125 mg / L. DMSO was diluted 50 times and sprayed, while a control (CK) of only Tween solution was applied. Cucumber seedlings were sprayed with the pesticides, and artificially inoculated with cucumber downy mildew 24 hours later. The experimental period was 12 days. After the disease stabilized, the disease index was assessed by grade, and the control effect was calculated.

[0110] Efficacy (%) = [(CK disease index − drug-treated disease index) ÷ CK disease index] × 100%

[0111] The experimental results are shown in Table 2.

[0112] Table 2. Summary of the effects of azoxystrobin analogues on cucumber downy mildew.

[0113]

[0114] Conclusion on potted plant efficacy:

[0115] At a high dose of 500 mg / L, the compound 2-fluoro-1-[2-((6-trifluoromethylpyridin-2-yl)oxymethyl)phenyl]cyclopropane-1-carboxylic acid methyl ester of this invention achieved a control efficacy of 91.41% against cucumber downy mildew, demonstrating excellent in vivo fungicidal and control activity. The control efficacy decreased significantly with decreasing concentration: only 46.34% at 250 mg / L and only 18.44% at 125 mg / L.

Claims

1. A method for preparing monofluorocyclopropane compounds, characterized in that, Includes the following steps: An olefin compound of Formula I was mixed with dibromofluoromethane, a metal salt catalyst, a reducing agent, and an organic solvent, and a cyclization reaction was carried out under closed stirring at 10-60°C for 0.5-48 hours. The resulting reaction solution was then post-treated to obtain compound II. In Formulas I and II, the substituents R1 and R2 are each independently selected from hydrogen, C1~C1. 10 Straight-chain or branched aliphatic alkyl groups, substituted or unsubstituted C6~C 14 Aryl, substituted or unsubstituted C4-C 14 The substitution refers to having one or more substituents selected from the group consisting of heteroaryl, C2-C6 acyl, C1-C6 aminoacyl, C1-C6 amide, C1-C6 ester, formic acid, or boron group; the substitution refers to having one or more substituents selected from the group consisting of halogen, C1-C6 amide, C1-C6 ester, formic acid, or boron group. 10 Alkyl, C1-C 10 Alkoxy, carbonyl, sulfone, or dioxonyl; halogens are F, Cl, or Br.

2. The preparation method according to claim 1, characterized in that, It also contains additives, such as zinc chloride, zinc bromide, zinc iodide, sodium bromide, or sodium iodide.

3. The preparation method according to claim 1 or 2, characterized in that, The metal salt catalysts are nickel chloride, cobalt bromide, nickel chloride with ethylene glycol dimethyl ether, nickel bromide, nickel bromide with ethylene glycol dimethyl ether, nickel iodide, nickel acetylacetone, nickel nitrate, nickel acetate, bis(1,5-cyclooctadiene) nickel, bis(triphenylphosphine) dichloride, or tetra(triphenylphosphine) nickel.

4. The preparation method according to claim 1 or 2, characterized in that, The reducing agent is manganese, zinc, iron, or magnesium.

5. The preparation method according to claim 1 or 2, characterized in that, The organic solvent is one or a mixture of several of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, trifluorotoluene, tetrahydrofuran, diethyl ether, dichloromethane, and acetonitrile.

6. The preparation method according to claim 2, characterized in that, The molar ratio of the olefin compound shown in Formula I to dibromofluoromethane, metal salt catalyst, reducing agent, and additive is 1:0.5~5:0.01~0.2:0.5~5:1~5.

7. The preparation method according to claim 1, characterized in that, The reaction temperature is 15-40℃, and the reaction time is 6-24 hours.

8. A monofluorocyclopropane compound prepared by the method of claim 1 or 2.

9. An application of a monofluorocyclopropane compound as described in claim 8, characterized in that, The application is in the preparation of pathogen inhibitors.

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