Synthesis method of fluoroalkyl N-acylhydrazone compound containing diphenyl phosphine oxide structural unit

Abstract

The invention discloses a synthesis method of a fluoroalkyl N-acylhydrazone compound containing a diphenyl phosphine oxide structural unit, and relates to the technical field of organic synthesis. Fluoroalkyl N-acylhydrazone and diphenylphosphine oxide are mixed in an organic solvent system, an oxidizing agent and metal salt are added, and the fluoroalkyl N-acylhydrazone compound containing the diphenylphosphine oxide structural unit is synthesized through a cross dehydrogenation coupling reaction. The diphenylphosphine oxide structural unit is introduced into a fluoroalkyl N-acylhydrazone molecule for the first time, the fluoroalkyl N-acylhydrazone compound containing the diphenylphosphine oxide structural unit is synthesized through a cross dehydrogenation coupling reaction, and the synthesis method has the advantages that reaction conditions are mild, raw materials are stable and easy to obtain, operation is easy, and the reaction yield is high.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit. Background Art

[0002] Organophosphine compounds are an important class of compounds that are commonly found in natural products and biologically active molecules and are widely used as medicines, pesticides, and veterinary drugs. In organic synthesis, these compounds are often used as ligands for organic catalysts and transition metal catalysis. At the same time, organophosphine compounds also play an important role in materials science. (Reference: DrugDiscovery Today.2019,24,916-929, Med.Drug Discovery.2020,8,No.100063; Toxicol.Sci.2018.162,24-35.Basic Res.J.Agric.Sci.Rev.2012,1,43-57; Chem.Rev.2024,124,8657,8739, Chem.Soc.Rev.2024,53 ,6735,6778; Chem.Soc.Rev.2016,45,5296-5310.Angew.Chem.Int.Ed.2018,57,10450-10467.)

[0003] In the past few decades, people have conducted in-depth research on phosphorus-containing drugs, and many phosphorus-containing drugs have been successfully commercialized (J.Med.Chem.2020,63,7081-7107). However, among these approved phosphorus-containing drugs, most contain a charged phosphonate group, phosphoramide group or phosphonate group, while uncharged tertiary phosphines, phosphinates and phosphine oxides are rare. Recently, it has been found that organic phosphine oxides, especially diaryl phosphine oxides, exhibit good drug activity and material properties. For example, diaryl phosphine oxide compounds with the following chemical structures A to E:

[0004]

[0005] Studies have shown that alkynyl diphenylphosphine oxide compound A can be used as a progesterone receptor (PR) antagonist. In the rat progesterone sensitivity test, its activity and selectivity are much higher than the marketed mifepristone (reference: Steroids. 2006, 71, 949-954.); compound B, benzyl diphenylphosphine oxide, as an inhibitor of Kv1.5 potassium ion channel, can be used to treat atrial fibrillation (reference: Bioorg. Med. Chem. Lett. 2013, 23, 706-710); compound C is a methionine aminopeptidase 2 (MetAP2) inhibitor (reference: WO 2016 / 100778, 2016); Compound D is an α-dicarbonyl analog of human protease I inhibitor, which can be used to treat pathological and physiological lesions such as stroke, Alzheimer's disease, muscular atrophy, motor neuron damage and muscle atrophy ((reference: J.Med.Chem.1998,41,3912-3916); Compound E, i.e. Fosenazide, is a neurological drug with a strong inhibitory effect on adrenaline and 5-hydroxytryptamine (serotonin) (Med.Drug Discovery.2020,8,No.100063.).

[0006] So far, synthesizers have developed various methods to synthesize a large number of organophosphine compounds and successfully achieved the construction of CP bonds. (Related review references: Chem. Rev. 2004, 104, 6177-6215; Chem. Soc. Rev. 2012, 41, 2095; Sci. Bull. 2019, 64, 337; Curr. Org. Synth. 2021, 18, 377-387; Org. Biomol. Chem. 2022, 20, 498.) Among these reported methods, the cross-dehydrogenative coupling reaction (CDC) of C(sp2)-H in molecules such as alkanes, alkenes, aromatics, heteroaromatics, imines and aldehyde hydrazones and P(O)-H in diarylphosphine oxide molecules under transition metal catalysis or promotion, oxidant oxidation, photoinduction and electrochemical conditions is one of the powerful measures to construct CP bonds. (Related review articles: Org. Biomol. Chem. 2022, 20, 498 and Chemistry of Heterocyclic Compounds. 2023, 59 (4 / 5), 193-200, etc.) In contrast, the cross-dehydrogenation coupling reaction of C(sp)-H in alkyne molecules and P(O)-H in diarylphosphine oxide molecules has been less studied (Dalton Trans. 2020, 49, 3001-3006).

[0007] Among the numerous organophosphine compounds, α-imidophosphine compounds containing PCN structural fragments often exhibit important biological activities such as antibacterial, anti-inflammatory, anti-Alzheimer's, anti-parasitic, anti-hepatitis, anti-proliferation, anti-influenza, anti-HIV, anti-malaria, metabolic regulation, enzyme inhibitors, etc. (J. Med. Chem. 2011, 54, 5955-5980; Drug Discovery Today. 2019, 24, 916-929, etc.) and good material properties. For example, the above-mentioned compound F, i.e., a phosphinate containing an α-imido group, is a very good flame retardant (Org. Chem. Front. 2024, 11, 270-276).

[0008] Trifluoromethyl is a common fluorine-containing group. The introduction of trifluoromethyl into organic compounds can significantly change the chemical, physical and biological properties of the parent compound, such as acidity, bioavailability, metabolic stability, lipid solubility and protein binding ability. Therefore, trifluoromethyl compounds have been widely used in the fields of medicine, pesticides and materials science. In recent years, chemists and pharmaceutical workers have devoted themselves to the study of difluoromethyl compounds. This is because difluoromethyl has weak acidity and can serve as a lipophilic hydrogen bond donor and a bioisostere of some functional groups (such as methyl, methoxy, hydroxyl, amino and thiol), which can effectively promote the absorption of drug molecules and improve drug efficacy. Therefore, difluoromethyl-substituted compounds are also used in the design and development of new drugs and pesticides. In view of the important application value of the aforementioned diarylphosphine oxide compounds and the characteristics of the fluorine-containing group, the introduction of fluoroalkyl groups into diarylphosphine oxide compounds will increase or give these compounds new biological activities or material properties. Therefore, exploring new and efficient synthetic methods to prepare diarylphosphine oxide compounds containing fluoroalkyl groups has very important theoretical significance and practical application value.

[0009] On the other hand, N-acylhydrazone, as an imine equivalent that is easy to store, stable and readily available, is widely used in the preparation of nitrogen-containing organic compounds in organic synthesis (Angew.Chem.Int.Ed.2005,44,5176). At the same time, this type of compound itself also has biological activity (J.Med.Chem.2012,55,7525; ACS Omega 2022,7,705-715) and material properties, and can be used as medicine (Curr.Med.Chem.2006,13,167-198; Bioorg.Med.Chem.Lett.2018,28,2797-2806.) and functional materials (New J.Chem.2018,42,14111-14119). In addition, N-acylhydrazone is also a raw material for preparing some functional molecules with excellent activity. For example, as the hydride of N-acylhydrazone, hydrazide generally has antiviral, antitumor, antimalarial, bactericidal and other biological activities, especially some hydrazide compounds containing trifluoromethyl have been shown to have anticancer effects (Bioorg.Med.Chem.2009,19,83; Bioorg.Med.Chem.2009,17,6158.). At present, hydrazide compounds have been widely used in pesticides, medicines and functional materials (Chin.J.Org.Chem.2017,37,925~935). In contrast, the reactions involving difluoromethyl N-acylhydrazone have been less studied (J.Org.Chem.2023,88(24),17356-17367). Although many reactions involving N-acylhydrazones including trifluoromethyl N-acylhydrazone have been reported, the cross-dehydrogenative coupling reaction involving N-acylhydrazones including difluoro / trifluoromethyl N-acylhydrazones and the synthesis of fluoroalkyl N-acylhydrazones containing diphenylphosphine oxide structural units have not been reported so far. Summary of the invention

[0010] The purpose of the present invention is to provide a method for synthesizing a fluoroalkyl N-acylhydrazone containing a diphenylphosphine oxide structural unit to solve the problems existing in the above-mentioned prior art.

[0011] To achieve the above object, the present invention provides the following solutions:

[0012] The present invention provides a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit, which has a general structure shown in Formula I:

[0013]

[0014] Among them, R f is CF2H or CF3; Ar is any one of phenyl, 3-chlorophenyl and 4-nitrophenyl.

[0015] The present invention also provides a method for preparing the above-mentioned fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit, comprising the following steps:

[0016] Mixing a fluoroalkyl N-acylhydrazone and diphenylphosphine oxide in an organic solvent system, adding an oxidant and a metal salt, and synthesizing the fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit through a cross-dehydrogenation coupling reaction;

[0017] The general structural formula of the fluoroalkyl N-acylhydrazone is shown in Formula II:

[0018]

[0019] Among them, R f is CF2H or CF3; Ar is any one of phenyl, 3-chlorophenyl and 4-nitrophenyl.

[0020] In the present invention, the fluoroalkyl N-acylhydrazone is preferably difluoromethyl N-acylhydrazone or trifluoromethyl N-acylhydrazone, and its structural formula is as follows:

[0021]

[0022] Furthermore, the oxidant includes tert-butyl perbenzoate (TBPB), benzoyl peroxide (BPO), tert-butyl hydroperoxide ( t Any one of BuOOH) and potassium persulfate (K2S2O8). Preferably, tert-butyl perbenzoate (TBPB) is used.

[0023] Furthermore, the metal salt includes any one of AgOAc, CuSO4 and Cu(OAc)2.

[0024] Furthermore, the metal salt is copper acetate (Cu(OAc)2); the molar ratio of the fluoroalkyl N-acylhydrazone, diphenylphosphine oxide, oxidant and copper acetate is 1.0:(3.0-4.0):(0-1.0):(0.25-1.0). The most preferred ratio is 1:3.5:0.5:0.5.

[0025] Further, the organic solvent includes any one of tetrahydrofuran (THF), 1,4-dioxane, toluene and 1,2-dichloroethane (DCE), and 1,4-dioxane is more preferred.

[0026] Furthermore, the reaction temperature of the cross-dehydrogenation coupling reaction is 40°C-60°C, and the reaction time is 5 to 24 hours; more preferably, the reaction temperature is 60°C, and the reaction time is 5 to 10 hours.

[0027] Furthermore, after the cross-dehydrogenation coupling reaction is completed, the method further comprises the steps of adding a saturated sodium thiosulfate solution to the reaction solution and performing column chromatography separation.

[0028] Furthermore, the eluent used for column chromatography separation is a mixture of petroleum ether (PE) and ethyl acetate (EA), preferably in a volume ratio of (5-3):1.

[0029] In the present invention, the reaction route of the synthesis method of the fluoroalkyl N-acylhydrazone compound containing the diphenylphosphine oxide structural unit is:

[0030]

[0031] The method comprises the following steps: adding fluoroalkyl N-acylhydrazone, metal salt, oxidant and diphenylphosphine oxide to a reaction container, and then adding an organic solvent. The mixed solution is placed at 60° C. and stirred and heated. The reaction is monitored by TLC. After the fluoroalkyl N-acylhydrazone is completely reacted, a saturated sodium thiosulfate solution is added to the reaction solution to quench the reaction, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=(5-3):1) to obtain the target product.

[0032] In view of the importance of fluorine-containing group compounds, the inventor team designed and synthesized N-acylhydrazone containing trifluoromethyl for the first time, and successfully synthesized a series of nitrogen-containing compounds containing trifluoromethyl through various reactions such as addition, substitution and cyclization involving trifluoromethyl N-acylhydrazone, thus proving that trifluoromethyl N-acylhydrazone is an excellent synthetic building block for synthesizing nitrogen-containing compounds containing trifluoromethyl (Tetrahedron.2024,154,133870).

[0033] The present invention also provides the use of the fluoroalkyl N-acylhydrazone compound containing the diphenylphosphine oxide structural unit in the preparation of antiviral, antitumor, antimalarial, bactericidal and other drugs and pesticides.

[0034] N-acylhydrazone compounds can not only be used as stable and readily available imine equivalents, but are also widely used in the preparation of nitrogen-containing organic compounds in organic synthesis, and this type of compound itself also has good biological activity. For example, N-acylhydrazone can be used as a carbonic anhydrase II inhibitor (ACS Omega.2022,7,705-715). At the same time, N-acylhydrazone compounds can be used as raw materials for preparing drugs and pesticides with antiviral, antitumor, antimalarial, bactericidal, etc. In addition, diarylphosphine oxide also has good drug activity. Therefore, the fluoroalkyl N-acylhydrazone compounds containing diphenylphosphine oxide structural units prepared by the present invention also have the above properties. Because the fluoroalkyl group is introduced into the drug molecule, the acidity and alkalinity of the drug can be changed, its bioavailability and metabolic stability can be increased, etc., which is more conducive to the absorption of the drug by the organism and improves the efficacy. Therefore, the fluoroalkyl N-acylhydrazone compounds containing diphenylphosphine oxide structural units also have the above activity.

[0035] The present invention discloses the following technical effects:

[0036] (1) The fluoroalkyl N-acylhydrazone compound containing diphenylphosphine oxide structural units of the present invention can be used to prepare antiviral, antitumor, antimalarial, bactericidal and other drugs and pesticides.

[0037] (2) The present invention discloses for the first time a new method for synthesizing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit by using diphenylphosphine oxide and a fluoroalkyl N-acylhydrazone as raw materials through a cross-dehydrogenation coupling reaction.

[0038] (3) The present invention uses fluoroalkyl N-acylhydrazone for the construction of CP bond for the first time. The fluoroalkyl N-acylhydrazone used in the reaction is cheap, readily available and stable; diphenylphosphine oxide is a common commercially available phosphine oxide compound. Therefore, these advantages of the raw material provide great possibilities for the further industrialization of the method.

[0039] (4) The synthesis method provided by the present invention has the characteristics of mild reaction conditions, stable and easily available raw materials, simple operation and high reaction yield.

[0040] (5) The fluoroalkyl N-acylhydrazone compound containing diphenylphosphine oxide structural unit synthesized by the present invention is 1 H NMR, 13 CNMR, 19 F NMR, 31 P NMR high-resolution mass spectrometry detection, the product is a pure target compound with high product purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0042] Figure 1 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzoylhydrazide (3a) synthesized in Example 1 1 HNMR spectra;

[0043] Figure 2 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzoylhydrazide (3a) synthesized in Example 1 13 CNMR images;

[0044] Figure 3 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzoylhydrazide (3a) synthesized in Example 1 19 FNMR images;

[0045] Figure 4 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzoylhydrazide (3a) synthesized in Example 1 31 PNMR images;

[0046] Figure 5 This is a high-resolution mass spectrometry monitoring diagram of N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzoylhydrazide (3a) synthesized in Example 1;

[0047] Figure 6 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-3-chlorobenzoylhydrazide (3b) synthesized in Example 2 1 H NMR spectra;

[0048] Figure 7 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-3-chlorobenzoylhydrazide (3b) synthesized in Example 2 13 C NMR spectra;

[0049] Figure 8 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-3-chlorobenzoylhydrazide (3b) synthesized in Example 2 19 F NMR spectra;

[0050] Fig. 9The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-3-chlorobenzoylhydrazide (3b) synthesized in Example 2 31 P NMR spectra;

[0051] Fig.10 This is a high-resolution mass spectrometry monitoring diagram of N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-3-chlorobenzoylhydrazide (3b) synthesized in Example 2;

[0052] Fig.11 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-4-nitrobenzoylhydrazide (3c) synthesized in Example 3 1 HNMR spectra;

[0053] Fig.12 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-4-nitrobenzoylhydrazide (3c) synthesized in Example 3 13 CNMR images;

[0054] Fig.13 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-4-nitrobenzoylhydrazide (3c) synthesized in Example 3 19 FNMR images;

[0055] Fig.14 The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-4-nitrobenzoylhydrazide (3c) synthesized in Example 3 31 P NMR spectra;

[0056] Fig.15 This is a high-resolution mass spectrometry monitoring diagram of N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-4-nitrobenzoylhydrazide (3c) synthesized in Example 3;

[0057] Fig.16 The N'-[1-(diphenylphosphinoyl)-2,2,2-trifluoroethylidene]benzoylhydrazide (3d) synthesized in Example 4 1 H NMR spectra;

[0058] Fig.17 The N'-[1-(diphenylphosphinoyl)-2,2,2-trifluoroethylidene]benzoylhydrazide (3d) synthesized in Example 4 13 C NMR spectra;

[0059] Fig.18 The N'-[1-(diphenylphosphinoyl)-2,2,2-trifluoroethylidene]benzoylhydrazide (3d) synthesized in Example 4 19 F NMR spectra;

[0060] Fig.19 The N'-[1-(diphenylphosphinoyl)-2,2,2-trifluoroethylidene]benzoylhydrazide (3d) synthesized in Example 4 31 P NMR spectra;

[0061] Fig. 20 This is a high-resolution mass spectrum monitoring chart of N'-[1-(diphenylphosphinoyl)-2,2,2-trifluoroethylidene]benzohydrazide (3d) synthesized in Example 4. DETAILED DESCRIPTION

[0062] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0063] It should be understood that the terms described in the present invention are only for describing a particular embodiment and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0064] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0065] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

[0066] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0067] Unless otherwise specified, the room temperature in the present invention is 25±3°C.

[0068] The raw materials used in the examples of the present invention were synthesized from literature or purchased from the market. Difluoromethyl acylhydrazone was prepared according to (J. Org. Chem. 2022, 87, 498.); trifluoromethyl acylhydrazone was prepared according to (J. Fluorine Chem. 2016.10.018.).

[0069] The technical solution of the present invention is further illustrated by the following embodiments.

[0070] Example 1

[0071] Synthesis of N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzoylhydrazide (3a)

[0072] The synthetic route is as follows:

[0073]

[0074] The specific synthesis process is as follows:

[0075] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), tert-butyl peroxybenzoate (TBPB) (0.05mmol, 9.7mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture at 60℃ and heat with stirring. Monitor the reaction by TLC. The reaction is complete after 10 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 32.0 mg, yield 80%.

[0076] The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzoylhydrazide (3a) synthesized above was 1 H NMR, 13 CNMR, 19 FNMR, 31 P NMR, high-resolution mass spectrometry (such as Figure 1-5 As shown), it can be concluded that the product is a pure target compound. The characterization data of the corresponding product are:

[0077] 1H NMR (400MHz, CDCl3) δ7.99(d,J=7.6Hz,2H),7.84-7.79(m,4H),7.68(t,J=7.6Hz,2H),7.59-7.55(m,5H),7.49(t,J=7.6Hz,2H),6.37(td,J H-F =54.8,J H-P =12.0 Hz, 1H);

[0078] 13 C NMR (150MHz, CDCl3): δ163.6,139.1,133.6(d,J C-P =3.0Hz),133.0,132.1(d,J C-P =11.4Hz),131.5,129.0,128.9,128.7,127.9,115.9(td,J C-F =238.8Hz,J C-P =17.4Hz);

[0079] 19 F NMR(376MHz, CDCl3): δ-109.58(dd,J F-H =54.5Hz,J F-P =4.5Hz);

[0080] 31 P NMR (162MHz, CDCl3): δ31.33;

[0081] HRMS(ESI)m / z:calcd for C 21 H 18 F2N2O2P[M+H] + 399.1069, found:399.1071.

[0082] Example 2

[0083] Synthesis of N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-3-chlorobenzoylhydrazide (3b)

[0084] The synthetic route is as follows:

[0085]

[0086] The specific synthesis process is as follows:

[0087] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylidene)-3-chlorobenzoyl hydrazide (0.1mmol, 23.2mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), tert-butyl peroxybenzoate (TBPB) (0.05mmol, 9.7mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture at 60℃ and stir and heat. Monitor the reaction by TLC. The reaction is complete after 10 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-3-chlorobenzohydrazide (3b): white solid, 30.3 mg, yield 70%.

[0088] The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-3-chlorobenzoylhydrazide (3b) synthesized above was 1 HNMR, 13 CNMR, 19 F NMR, 31 P NMR, high-resolution mass spectrometry (such as Figure 6-10 As shown), it can be concluded that the product is a pure target compound. The characterization data of the corresponding product are:

[0089] 1 H NMR (400MHz, CDCl3) δ8.01(s,1H),7.84-7.79(m,5H),7.68(t,J=7.2Hz,2H),7.58-7.53(m,5H),7.42(t,J=8.0Hz,1H),6.35(td,J H-F =54.8,J H-P =12.0 Hz, 1H);

[0090] 13 C NMR (150MHz, CDCl3) δ162.4,135.3,133.7(d,J C-P =2.8Hz),133.3,133.0,132.1(d,J C-P =11.4Hz),130.2,129.0(d,J C-P =13.0Hz),128.6,128.5,127.8,125.5,115.7(td,J C-F=239.1Hz,J C-P =17.5Hz);

[0091] 19 F NMR(376MHz,CDCl3)δ-109.73(dd,J F-H =53.8Hz,J F-P =4.5Hz);

[0092] 31 P NMR (162MHz, CDCl3): δ31.72;

[0093] HRMS(ESI)m / z:calcd for C 21 H 17 ClF2N2O2P[M+H] + 433.0679,found:433.0679.

[0094] Example 3

[0095] Synthesis of N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-4-nitrobenzoylhydrazide (3c)

[0096] The synthetic route is as follows:

[0097]

[0098] The specific synthesis process is as follows:

[0099] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylidene)-4-nitrobenzoyl hydrazide (0.1mmol, 24.3mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), tert-butyl peroxybenzoate (TBPB) (0.05mmol, 9.7mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture under stirring and heating at 60℃. Monitor the reaction by TLC, and the reaction is complete after 10 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=3:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-4-nitrobenzohydrazide (3c): white solid, 39.0 mg, yield 88%.

[0100] The N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]-4-nitrobenzoylhydrazide (3c) synthesized above was 1 HNMR, 13 CNMR, 19 F NMR, 31 P NMR, high-resolution mass spectrometry (such as Figure 11-15 The results show that the product is a pure target compound. The characterization data of the corresponding product are:

[0101] 1 H NMR (400MHz, CDCl3) δ8.33(d,J=8.8Hz,2H),8.16(d,J=8.2Hz,2H),7.84-7.79(m,4H),7.70(t,J=7.2Hz,2H),7.62-7.57(m,4H),6.35(td,J H-F =55.6,J H-P =14.5Hz,1H);

[0102] 13 C NMR (150MHz, CDCl3) δ161.6,150.3,141.2,136.9,133.9(d,J C-P =2.8Hz),132.1(d,J C-P =11.4Hz),129.1(d,J C-P =13.2Hz),128.2,127.5,124.0.115.6(td,J C-F =237.1Hz,J C-P =

[0103] 15.1Hz);

[0104] 19 F NMR(376MHz,CDCl3)δ-109.87(dd,J F-H =54.5Hz,J F-P =4.5Hz);

[0105] 31 P NMR (162MHz, CDCl3): δ32.70;

[0106] HRMS(ESI)m / z:calcd for C 21 H 17 F2N3O4P[M+H] + 444.0919, found:444.0920.

[0107] Example 4

[0108] Synthesis of N'-[1-(Diphenylphosphinoyl)-2,2,2-trifluoroethylidene]benzoylhydrazide (3d)

[0109] The synthetic route is as follows:

[0110]

[0111] The specific synthesis process is as follows:

[0112] Take a 10mL Shrek reaction tube, add N'-2,2,2-trifluoroethyl)benzoyl hydrazide (0.1mmol, 21.6mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), tert-butyl peroxybenzoate (TBPB) (0.05mmol, 9.7mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture at 60℃ and heat with stirring. Monitor the reaction by TLC. The reaction is complete after 5 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=5:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2,2-trifluoroethylidene]benzohydrazide (3d): white solid, 34.1 mg, yield 82%.

[0113] The N'-[1-(diphenylphosphinoyl)-2,2,2-trifluoroethylidene]benzoylhydrazide (3d) synthesized above was 1 H NMR, 13 C NMR, 19 F NMR, 31 P NMR, high-resolution mass spectrometry (such as Figure 16-20 The results show that the product is a pure target compound. The characterization data of the corresponding product are:

[0114] 1 H NMR (600MHz, CDCl3): δ8.01(d,J=7.8Hz,2H),7.82(d,J=7.8Hz,2H),7.80(d,J =7.8Hz,2H),7.71(t,J=6.6Hz,2H),7.61-7.57(m,5H),7.50(t,J=7.8Hz,2H);

[0115] 13 C NMR (150MHz, CDCl3): δ163.5,134.1(d,JC-P =2.9Hz),133.2,132.2(d,J C-P =11.3Hz),131.5,129.3(d,J C-P =13.1Hz),129.1,128.3,127.6,120.4(dq,J=274.5Hz,J=28.5Hz);

[0116] 19 F NMR (376MHz, CDCl3): δ-61.05;

[0117] 31 P NMR (162MHz, CDCl3): δ29.60;

[0118] HRMS(ESI)m / z:calcd for C 21 H 16 F3N2NaO2P[M+Na] + 439.0794,found:439.0812.

[0119] Example 5

[0120] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), benzoyl peroxide (BPO) (0.05mmol, 12.1mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture under stirring and heating at 60℃. Monitor the reaction by TLC, and the reaction is complete after 12 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 29.2 mg, yield 73%.

[0121] Example 6

[0122] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), benzoyl peroxide (BPO) (0.05mmol, 12.1mg, 0.5equiv.) and diphenylphosphine oxide (0.4mmol, 80.8mg, 4.0equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture under stirring and heating at 60℃. Monitor the reaction by TLC, and the reaction is complete after 12 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 24.5 mg, yield 61%.

[0123] Example 7

[0124] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), benzoyl peroxide (BPO) (0.05mmol, 12.1mg, 0.5equiv.) and diphenylphosphine oxide (0.3mmol, 60.6mg, 3.0equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture under 60℃ and stir and heat. Monitor the reaction by TLC. The reaction is complete after 12 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 21.6 mg, yield 54%.

[0125] Example 8

[0126] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), benzoyl peroxide (BPO) (0.05mmol, 12.1mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of tetrahydrofuran solvent. Place the mixture under 60℃ and stir and heat. Monitor the reaction by TLC. The reaction is complete after 12 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 26.0 mg, yield 65%.

[0127] Example 9

[0128] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), benzoyl peroxide (BPO) (0.05mmol, 12.1mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent toluene. Place the mixture under 60℃ and stir and heat. Monitor the reaction by TLC. The reaction is complete after 12 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 24.0 mg, yield 60%.

[0129] Example 10

[0130] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), benzoyl peroxide (BPO) (0.05mmol, 12.1mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,2-dichloroethane. Place the mixture under 60℃ and stir and heat. Monitor the reaction by TLC. The reaction is complete after 12 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 22.0 mg, yield 55%.

[0131] Embodiment 11

[0132] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoyl hydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), potassium persulfate (K2S2O8) (0.05mmol, 13.5mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture at 60℃ and heat with stirring. Monitor the reaction by TLC. The reaction is complete after 24 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 21.2 mg, yield 53%.

[0133] Example 12

[0134] Take a 10mL Shrek reaction tube and add N'-(2,2-difluoroethylene)benzoyl hydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), tert-butyl hydroperoxide ( tBuOOH) (0.05mmol, 13.2mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then 3mL of 1,4-dioxane solvent was added. The mixture was stirred and heated at 60°C. The reaction was monitored by TLC and the reaction was complete after 24 hours. Then, 5mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10mL×3). The organic phases were combined, concentrated, and quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 18.8mg, yield 47%.

[0135] Embodiment 13

[0136] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture under 60℃ and stir and heat. Monitor the reaction by TLC. The reaction is complete after 18 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 22.8 mg, yield 57%.

[0137] Embodiment 14

[0138] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), tert-butyl peroxybenzoate (TBPB) (0.05mmol, 9.7mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture under stirring and heating at 40℃. The reaction was monitored by TLC. After 24 hours, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined and concentrated, and then rapidly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 23.1 mg, yield 58%.

[0139] Comparative Example 1

[0140] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), benzoyl peroxide (BPO) (0.05mmol, 12.1mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of acetonitrile solvent. Place the mixture at 60℃ and stir and heat. Monitor the reaction by TLC. The reaction is complete after 12 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 8.4 mg, yield 21%.

[0141] Comparative Example 2

[0142] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), benzoyl peroxide (BPO) (0.05mmol, 12.1mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of methanol solvent. Place the mixture under 60℃ and stir and heat. Monitor the reaction by TLC. The reaction is complete after 12 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 15.6 mg, yield 39%.

[0143] It can be seen from Comparative Examples 1 and 2 that the change in solvent type has a significant effect on the yield.

[0144] Comparative Example 3

[0145] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper sulfate (0.05mmol, 8.0mg, 0.5equiv.), tert-butyl peroxybenzoate (TBPB) (0.05mmol, 9.7mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture at 60℃ and heat with stirring. Monitor the reaction by TLC. The reaction is complete after 24 hours. Then, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 17.9 mg, yield 45%.

[0146] Compared with Example 1, when only copper acetate was changed to an equimolar amount of copper sulfate, the yield was significantly reduced.

[0147] Comparative Example 4

[0148] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), silver acetate (0.05mmol, 8.3mg, 0.5equiv.), tert-butyl peroxybenzoate (TBPB) (0.05mmol, 9.7mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Heat the mixture at 60℃ with stirring. The reaction was monitored by TLC. After 24 hours, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined and concentrated, and then rapidly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 14.7 mg, yield 37%.

[0149] Compared with Example 1, when only copper acetate was changed to an equimolar amount of silver acetate, the yield was significantly reduced.

[0150] Comparative Example 5

[0151] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), tert-butyl peroxybenzoate (TBPB) (0.05mmol, 9.7mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Heat the mixture at 60℃ with stirring. The reaction was monitored by TLC. After 24 hours, 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined and concentrated, and then rapidly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 2.4 mg, yield 6%.

[0152] Compared with Example 1, without adding copper acetate, the yield is significantly reduced.

[0153] Comparative Example 6

[0154] Take a 10mL Shrek reaction tube, add N'-(2,2-difluoroethylene)benzoylhydrazide (0.1mmol, 19.8mg, 1.0equiv.), copper acetate (0.05mmol, 9.1mg, 0.5equiv.), tert-butyl peroxybenzoate (TBPB) (0.05mmol, 9.7mg, 0.5equiv.) and diphenylphosphine oxide (0.35mmol, 70.7mg, 3.5equiv.), and then add 3mL of solvent 1,4-dioxane. Place the mixture under reflux and stir and heat. The reaction was monitored by TLC. After 6 hours, the reaction was complete. 5 mL of saturated sodium thiosulfate solution was added to the reaction solution to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined and concentrated, and then rapidly separated by column chromatography using a mixed eluent of petroleum ether and ethyl acetate (PE:EA=4:1) to obtain N'-[1-(diphenylphosphinoyl)-2,2-difluoroethylidene]benzohydrazide (3a): white solid, 18.7 mg, yield 47%.

[0155] Compared with Example 1, when the reaction temperature was changed to reflux, the yield decreased significantly.

[0156] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit, characterized in that: It has the general structure shown in Formula I: Among them, R f is CF2H or CF3; Ar is any one of phenyl, 3-chlorophenyl and 4-nitrophenyl.

2. The method for preparing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit according to claim 1, characterized in that: The following steps are involved: Mixing a fluoroalkyl N-acylhydrazone and diphenylphosphine oxide in an organic solvent system, adding an oxidant and a metal salt, and synthesizing the fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit through a cross-dehydrogenation coupling reaction; The general structural formula of the fluoroalkyl N-acylhydrazone is shown in Formula II: Among them, R f is CF2H or CF3; Ar is any one of phenyl, 3-chlorophenyl and 4-nitrophenyl.

3. The method for preparing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit according to claim 2, characterized in that: The oxidant includes any one of tert-butyl perbenzoate, benzoyl peroxide, tert-butyl hydroperoxide and potassium persulfate.

4. The method for preparing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit according to claim 2, characterized in that: The metal salt includes any one of AgOAc, CuSO4 and Cu(OAc)2.

5. The method for preparing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit according to claim 4, characterized in that: The metal salt is copper acetate; the molar ratio of the fluoroalkyl N-acylhydrazone, diphenylphosphine oxide, oxidant and copper acetate is 1.0:(3.0-4.0):(0-1.0):(0.25-1.0).

6. The method for preparing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit according to claim 2, characterized in that: The organic solvent includes any one of tetrahydrofuran, 1,4-dioxane and 1,2-dichloroethane.

7. The method for preparing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit according to claim 2, characterized in that: The reaction temperature of the cross-dehydrogenation coupling reaction is 40° C.-60° C., and the reaction time is 5 to 24 hours.

8. The method for preparing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit according to claim 2, characterized in that: After the cross-dehydrogenation coupling reaction is completed, the method further includes adding a saturated sodium thiosulfate solution to the reaction solution and performing column chromatography separation.

9. The method for preparing a fluoroalkyl N-acylhydrazone compound containing a diphenylphosphine oxide structural unit according to claim 8, characterized in that: The eluent used for the column chromatography separation is a mixture of petroleum ether and ethyl acetate.

10. Use of the fluoroalkyl N-acylhydrazone compound containing diphenylphosphine oxide structural units according to claim 1 in the preparation of antiviral, antitumor, antimalarial, bactericidal drugs or pesticides.

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