Alkyl nitrile compound containing fluoroalkyl N-acylhydrazone structural unit as well as preparation method and application of alkyl nitrile compound

Abstract

The invention discloses an alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis. The preparation method of the alkyl nitrile compound containing the fluoroalkyl N-acylhydrazone structural unit comprises the following steps: mixing fluoroalkyl N-acylhydrazone, cyclobutanone oxime ester, ferric salt and a solvent, and carrying out coupling reaction to obtain the alkyl nitrile compound containing the fluoroalkyl N-acylhydrazone structural unit. According to the invention, fluoroalkyl is introduced into the alkyl nitrile compound, so that the chemical, physical and biological properties of the alkyl nitrile compound, such as acid-base property, bioavailability, metabolic stability, fat solubility and protein binding capacity, can be changed, and the technical effect of the alkyl nitrile compound in subsequent application is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and more particularly relates to an alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit, and a preparation method and application thereof. Background Art

[0002] The cyano group is a common reactive group. Alkanes containing cyano groups, also known as alkylnitrile compounds, play a crucial role in modern organic synthesis and medicine. As a class of biologically active nitrogen-containing compounds, alkylnitrile building blocks are present in many biologically active natural products and pharmaceutical molecules.

[0003] As precursors of cyanoalkyl radicals, reactions involving cyclobutanone oxime derivatives are becoming a novel and practical method for synthesizing alkyl nitrile compounds. The reaction principle for the synthesis of alkyl nitrile compounds using cyclobutanone oxime derivatives is as follows: under certain conditions, the N-O bond in a cyclobutanone oxime derivative, such as a cyclobutanone oxime ester, undergoes homolytic cleavage to produce a cyclobutylimine radical. This radical then cleaves through the carbon ring to form a distal cyano-substituted alkyl radical, namely a γ-cyanoalkyl radical. This radical then undergoes coupling reactions with various compounds to form structurally diverse alkyl nitrile compounds.

[0004] The formation of carbon-carbon bonds is one of the important reactions in the synthesis of alkyl nitrile compounds. The free radical coupling reaction involving cyclobutanone oxime derivatives can be used to construct carbon-carbon bonds of the following types: C(sp 3 )-C(sp 3 )、C(sp 3 )-C(sp 2 ) and C(sp 3 )-C(sp) carbon-carbon bond formation. Currently, C(sp 3 ) and C(sp 2 ) forms carbon-carbon bonds, which plays an important role in the free radical coupling reaction of cyclobutanone oxime derivatives. 3 )-C(sp 2 Nitrogen-containing compounds with carbon-carbon bonds primarily include aromatic heterocyclic nitrogen oxides, quinoxalinone compounds, quinoline and isoquinoline derivatives, and aniline derivatives. The coupling reaction of open-chain imine compounds containing carbon-nitrogen double bonds with cyclobutanone oxime derivatives has not been reported. Therefore, developing a method for obtaining novel alkyl nitrile compounds by coupling open-chain imine compounds containing carbon-nitrogen double bonds with cyclobutanone oxime derivatives is of great significance. Summary of the Invention

[0005] The present invention aims to provide an alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit, and a preparation method and application thereof, so as to solve the problems existing in the above-mentioned prior art, enrich the types of alkyl nitrile compounds, and expand the application fields of alkyl nitrile compounds.

[0006] To achieve the above object, the present invention provides the following solutions:

[0007] One of the technical solutions of the present invention is to provide an alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit, having the following structure:

[0008]

[0009] Among them, R f is -CF2H or -CF3; R is phenyl, 4-methylphenyl, 4-methoxyphenyl or isopropyl.

[0010] The second technical solution of the present invention is to provide a method for preparing the alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit, comprising the following steps:

[0011] Mixing a fluoroalkyl N-acylhydrazone, a cyclobutanone oxime ester, an iron salt, and a solvent and performing a coupling reaction to obtain an alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit;

[0012] The structural formula of the fluoroalkyl N-acylhydrazone is: Among them, R f is -CF2H or -CF3; R is phenyl, 4-methylphenyl, 4-methoxyphenyl or isopropyl.

[0013] The reaction formula for preparing the alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit of the present invention is:

[0014] Among them, R f is -CF2H or -CF3; R is phenyl, 4-methylphenyl, 4-methoxyphenyl or isopropyl.

[0015] Difluoromethyl and trifluoromethyl are fluorinated alkyl groups. Introducing difluoro / trifluoromethyl groups into organic compounds can alter the chemical and physical properties of the parent compound and increase its biological activity. The present invention introduces fluoroalkyl groups, including difluoromethyl and trifluoromethyl groups, into alkyl nitrile compounds to alter their chemical, physical, and biological properties, such as acidity and alkalinity, bioavailability, metabolic stability, lipid solubility, and protein binding, thereby enhancing the technical effectiveness of the alkyl nitrile compounds in subsequent applications.

[0016] Preferably, the iron salt is a ferric salt; the ferric salt includes ferric bromide, ferric trifluoromethanesulfonate or ferric chloride; and the solvent includes methanol, ethanol, 1,4-dioxane or dimethyl sulfoxide.

[0017] Preferably, the molar ratio of the fluoroalkyl N-acylhydrazone, cyclobutanone oxime ester and iron salt is 1:1.5-2.5:0.05-0.2; the amount ratio of the cyclobutanone oxime ester and solvent is 1.5-2.5 mmol:10 mL.

[0018] Preferably, the coupling reaction temperature is 65-100° C., and the coupling reaction time is 8-48 h.

[0019] More preferably, the coupling reaction temperature is 80-90° C., and the coupling reaction time is 12-32 h.

[0020] More preferably, the coupling reaction time is 14 to 24 hours.

[0021] Preferably, the coupling reaction further includes a post-treatment step; the post-treatment step includes: quenching and column chromatography separation in sequence; the reagent used for quenching includes a saturated sodium bicarbonate solution; the eluent used for column chromatography separation includes petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is 5 to 3:1.

[0022] The third technical solution of the present invention: provides the use of the alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit in the preparation of antiviral, antitumor, antimalarial, bactericidal and / or cathepsin inhibitor drugs.

[0023] The alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit obtained in the present invention can change the acidity and alkalinity of the drug during the preparation of the drug, thereby increasing its bioavailability, metabolic stability and pharmacokinetic properties, making it more conducive to the absorption of the drug by the organism and improving the efficacy.

[0024] The fourth technical solution of the present invention: provides the use of the alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit in the preparation of pesticides.

[0025] Preferably, the pesticide comprises an insecticide.

[0026] The fluoroalkyl N-acylhydrazones used in the present invention belong to the class of N-acylhydrazone compounds. These compounds are not only stable and readily available imine equivalents, widely used in the preparation of nitrogen-containing organic compounds in organic synthesis, but also possess excellent biological activity. For example, N-acylhydrazone compounds can be used as carbonic anhydrase II inhibitors. Furthermore, N-acylhydrazone compounds can be used as raw materials for the preparation of drugs and pesticides with antiviral, antitumor, antimalarial, and bactericidal properties. Furthermore, alkylnitrile compounds also possess excellent pharmaceutical activity. Therefore, the alkylnitrile compounds containing fluoroalkyl N-acylhydrazone structural units prepared in the present invention also possess the aforementioned properties. Furthermore, the introduction of fluoroalkyl groups into drug molecules can alter the drug's acidity and alkalinity, increasing its bioavailability, metabolic stability, and pharmacokinetic properties, further facilitating its absorption by organisms and improving its efficacy. Therefore, the alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit prepared by the present invention can be used to prepare antiviral, antitumor, antimalarial, bactericidal and / or cathepsin inhibitor drugs and pesticides, and exerts excellent effects.

[0027] The present invention discloses the following technical effects:

[0028] 1. The present invention provides for the first time a method for synthesizing a ketoacylhydrazone compound containing a fluoroalkyl group, and discloses for the first time a new method for synthesizing an alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit by a free radical coupling reaction using cyclobutanone oxime ester and a fluoroalkyl N-acylhydrazone as raw materials.

[0029] 2. The fluoroalkyl N-acylhydrazones used in the reaction of the present invention are inexpensive, readily available, and stable. Cyclobutanone oxime esters are relatively stable and can be easily prepared from cyclobutanone and hydroxylamine derivatives. The raw materials used in the present invention are simple, inexpensive, readily available, and stable, providing great potential for further industrialization of the method.

[0030] 3. 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.

[0031] 4. The alkyl nitrile compound containing fluoroalkyl N-acylhydrazone structural unit synthesized by the present invention is 1 H NMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection showed that the obtained product was of high purity.

[0032] 5. The alkylnitrile compound containing a fluoroalkyl N-acylhydrazone structural unit of the present invention can be used to prepare antiviral, antitumor, antimalarial, bactericidal and cathepsin inhibitor drugs or pesticides, and exhibits excellent effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1The N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide synthesized in Example 1 1 H NMR spectrum;

[0034] Figure 2 The N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide synthesized in Example 1 13 C NMR spectrum;

[0035] Figure 3 The N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide synthesized in Example 1 19 F NMR spectrum;

[0036] Figure 4 This is a high-resolution mass spectrometry monitoring diagram of N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide synthesized in Example 1;

[0037] Figure 5 N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzoic acid hydrazide synthesized in Example 2 1 HNMR spectrum;

[0038] Figure 6 N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzoic acid hydrazide synthesized in Example 2 13 C NMR spectrum;

[0039] Figure 7 N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzoic acid hydrazide synthesized in Example 2 19 F NMR spectrum;

[0040] Figure 8 This is a high-resolution mass spectrometry monitoring diagram of N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzohydrazide synthesized in Example 2;

[0041] Figure 9 N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide synthesized in Example 3 1 H NMR spectrum;

[0042] Figure 10 N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide synthesized in Example 3 13 C NMR spectrum;

[0043] Figure 11 N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide synthesized in Example 319 F NMR spectrum;

[0044] Figure 12 This is a high-resolution mass spectrometry monitoring diagram of N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide synthesized in Example 3;

[0045] Figure 13 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide synthesized in Example 4 1 HNMR spectrum;

[0046] Figure 14 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide synthesized in Example 4 13 CNMR images;

[0047] Figure 15 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide synthesized in Example 4 19 FNMR spectra;

[0048] Figure 16 This is a high-resolution mass spectrometry monitoring diagram of N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide synthesized in Example 4;

[0049] Figure 17 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzoylhydrazide synthesized in Example 5 1 HNMR spectrum;

[0050] Figure 18 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzoylhydrazide synthesized in Example 5 13 C NMR spectrum;

[0051] Figure 19 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzoylhydrazide synthesized in Example 5 19 F NMR spectrum;

[0052] Figure 20 This is a high-resolution mass spectrometry monitoring chart of N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzohydrazide synthesized in Example 5. DETAILED DESCRIPTION

[0053] 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 rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0054] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. The intermediate value within any stated value or stated range, and each smaller range between any other stated value or intermediate value within the stated range, is also encompassed within the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0055] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice 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 any conflict with any incorporated document, the contents of this specification shall prevail.

[0056] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be illustrative only.

[0057] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0058] The present invention synthesizes an alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit, which is different from the structure of previously reported alkyl nitrile compounds. The present invention provides for the first time a method for synthesizing a ketoacylhydrazone compound containing a fluoroalkyl group, and discloses for the first time a new method for synthesizing an alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit by a free radical coupling reaction using cyclobutanone oxime ester and a fluoroalkyl N-acylhydrazone as raw materials. The method has the characteristics of high purity of the obtained product, stable and easily available raw materials used in the preparation, and mild preparation conditions.

[0059] The N'-(2,2-difluoroethylidene)benzohydrazide, N'-(2,2-difluoroethylidene)-4-methoxybenzohydrazide and N'-(2,2-difluoroethylidene)isobutyrohydrazide used in the following examples and comparative examples were prepared according to the article (TandemAddition / Cyclization / Halogenation Reaction ofDifluoromethylatedN-AcylhydrazoneswithAllyltrimethylsilanes, J.Org.Chem.2023,88,17356-17367.); the N'-(2,2,2-trifluoroethylidene)benzohydrazide and 4-methyl-N'-(2,2,2-trifluoroethylidene)benzohydrazide used were prepared according to the article (One-potpreparation of trifluoromethylated homoallylic N-acylhydrazines orα-methylene-γ-lactams from acylhydrazines,trifluoroacetaldehyde methylhemiacetal,allyl bromide and Other raw materials were commercially available unless otherwise specified.

[0060] The room temperature involved in the present invention is based on 25±3°C.

[0061] Example 1

[0062] Synthesis of N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide:

[0063] The synthetic route is as follows:

[0064]

[0065] The specific synthesis process is as follows:

[0066] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 80°C with stirring. Monitor the reaction by TLC, and the reaction is complete after 12 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (38.7 mg) as a white solid with a yield of 73%.

[0067] The N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide synthesized above was subjected to 1 H NMR, 13 CNMR, 19 F NMR and high-resolution mass spectrometry detection, the test results are as follows Figures 1 to 4 As shown, the characterization data of the corresponding products are:

[0068] 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),7.78(d,J=7.2Hz,2H),7.59(t,J=7.3Hz,1H),7.50(t,J=7.4H z, 2H), 6.41 (t, J = 50.0Hz, 1H), 2.64 (t, J = 7.6Hz, 2H), 2.58 (t, J = 7.2Hz, 2H), 1.81 (p, J = 7.2Hz, 2H).

[0069] 13 C NMR (150MHz, DMSO-d6) δ165.9, 148.9, 133.9, 132.2, 128.9, 128.7, 120.6, 115.9 (t, J = 236.1Hz), 23.4, 21.7, 16.8.

[0070] 19 F NMR (376MHz, DMSO-d6): δ-117.2 (d, J=54.9Hz).

[0071] HRMS(ESI)m / z:calcd for C 13 H 14F2N3O[M+H]+266.1099,found:266.1099.

[0072] Figure 1 The N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide synthesized in Example 1 1 H NMR spectrum; Figure 2 The N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide synthesized in Example 1 13 C NMR spectrum; Figure 3 The N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide synthesized in Example 1 19 F NMR spectrum; Figure 4 This is a high-resolution mass spectrometry monitoring diagram of N'-(5-cyano-1,1-difluoropentane-2-methylene)benzoylhydrazide synthesized in Example 1. Figures 1 to 4 It can be seen that the N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide obtained in this example is a pure target compound.

[0073] Example 2

[0074] Synthesis of N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzoic acid hydrazide

[0075] The synthetic route is as follows:

[0076]

[0077] The specific synthesis process is as follows:

[0078] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)-4-methoxybenzohydrazide (0.2 mmol, 45.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 80°C with stirring. Monitor the reaction by TLC, which indicates completion after 14 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate (10 mL), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzohydrazide (33.6 mg) as a white solid with a yield of 57%.

[0079] The synthesis of N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzoic acid hydrazide was carried out. 1 H NMR, 13 C NMR, 19 The results of F NMR and high-resolution mass spectrometry are as follows Figures 5 to 8 As shown, the characterization data of the corresponding products are:

[0080] 1 H NMR (400MHz, CDCl3) δ9.71 (s, 1H), 7.85 (d, J = 8.8Hz, 2H), 6.94 (d, J = 8.8Hz, 2H), 6.18 (t, J = 5 5.6Hz, 1H), 3.86 (s, 3H), 2.69 (t, J = 8.0Hz, 2H), 2.51 (t, J = 6.8Hz, 2H), 2.04 (p, J = 7.2Hz, 2H).

[0081] 13 C NMR (150MHz, CDCl3) δ 163.04, 138.6, 130.9, 128.8, 124.0, 119.1, 115.3 (t, J = 236.6Hz) 113.8, 55.5, 22.2, 21.6, 17.2.

[0082] 19 F NMR (376MHz, CDCl3): δ-117.1 (d, J=54.9Hz).

[0083] HRMS(ESI)m / z:calcd for C 14 H 16 F2N3O2[M+H]+296.1205,found:296.1205.

[0084] Figure 5 N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzoic acid hydrazide synthesized in Example 2 1 HNMR spectrum; Figure 6 N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzoic acid hydrazide synthesized in Example 2 13 C NMR spectrum; Figure 7 N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzoic acid hydrazide synthesized in Example 2 19 F NMR spectrum; Figure 8 This is a high-resolution mass spectrometry monitoring diagram of N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzoic acid hydrazide synthesized in Example 2. Figures 5 to 8It can be seen that the N'-(5-cyano-1,1-difluoropentane-2-methylene)-4-methoxybenzohydrazide obtained in this example is a pure target compound.

[0085] Example 3

[0086] Synthesis of N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide

[0087] The synthetic route is as follows:

[0088]

[0089] The specific synthesis process is as follows:

[0090] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)isobutyrylhydrazide (0.2 mmol, 32.8 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 80°C with stirring. Monitor the reaction by TLC; completion is achieved after 8 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide (24.0 mg) as a white solid with a yield of 52%.

[0091] The N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide synthesized above was subjected to 1 H NMR, 13 CNMR, 19 F NMR and high-resolution mass spectrometry detection, the test results are as follows Figures 9-12 As shown, the characterization data of the corresponding products are:

[0092] 1 H NMR (400MHz, CDCl3) δ10.68(s,1H),6.04(t,J=55.2Hz,1H),3.46-3.39(m,1H),2.64(s,2H),2.55(s,2H),1.98-1.96(m,2H),1.15(d,J=5.3Hz,6H).

[0093] 13C NMR (151MHz, CDCl3) δ 182.2, 144.4 (t, J = 29.9Hz), 118.8, 115.3 (t, J = 237.2Hz), 30.1, 22.6, 21.7, 18.7, 17.0.

[0094] 19 F NMR (376MHz, CDCl3): δ-116.9 (d, J=55.3Hz).

[0095] HRMS(ESI)m / z:calcd for C10H16F2N3O[M+H]+232.1256,found:232.1258.

[0096] Figure 9 N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide synthesized in Example 3 1 H NMR spectrum; Figure 10 N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide synthesized in Example 3 13 C NMR spectrum; Figure 11 N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide synthesized in Example 3 19 F NMR spectrum; Figure 12 This is a high-resolution mass spectrometry monitoring diagram of N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide synthesized in Example 3. Figures 9-12 It can be seen that the N'-(5-cyano-1,1-difluoropentane-2-methylene)isobutyrylhydrazide obtained in this example is a pure target compound.

[0097] Example 4

[0098] Synthesis of N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide

[0099] The synthetic route is as follows:

[0100]

[0101] The specific synthesis process is as follows:

[0102] To a 10 mL pressure tube, add N'-(2,2,2-trifluoroethylidene)benzohydrazide (0.2 mmol, 43.2 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 80°C with stirring. Monitor the reaction by TLC; completion is achieved after 8 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=5:1, v / v) to obtain N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzohydrazide (44.1 mg) as a white solid with a yield of 78%.

[0103] The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide synthesized above was subjected to 1 HNMR, 13 CNMR, 19 F NMR and high-resolution mass spectrometry detection, the test results are as follows Figures 13-16 As shown, the characterization data of the corresponding products are:

[0104] 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),7.78(d,J=7.0Hz,2H),7.60(t,J=7.1Hz,1H),7.5 1(t,J=7.2Hz,2H),2.71(t,J=7.2Hz,2H),2.59(t,J=7.2Hz,2H),1.81(p,J=7.6Hz,2H).

[0105] 13 C NMR (150MHz, DMSO-d6) δ165.9, 156.2, 133.6, 132.4, 129.1, 128.7, 121.6 (q, J = 273.6Hz), 120.4, 24.5, 21.5, 16.6.

[0106] 19 F NMR (376MHz, DMSO-d6): δ–68.13.

[0107] HRMS(ESI)m / z:calcd for C 13 H 13 F3N3O[M+H]+284.1005,found:284.1002.

[0108] Figure 13 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide synthesized in Example 4 1 HNMR spectrum; Figure 14 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide synthesized in Example 4 13 C NMR spectrum; Figure 15 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide synthesized in Example 4 19 F NMR spectrum; Figure 16 This is a high-resolution mass spectrometry monitoring diagram of N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzoylhydrazide synthesized in Example 4. Figures 13-16 It can be seen that the N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)benzohydrazide obtained in this example is a pure target compound.

[0109] Example 5

[0110] Synthesis of N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzohydrazide

[0111] The synthetic route is as follows:

[0112]

[0113] The specific synthesis process is as follows:

[0114] To a 10 mL pressure tube, add 4-methyl-N'-(2,2,2-trifluoroethylidene)benzohydrazide (0.2 mmol, 46.0 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 80°C with stirring. Monitor the reaction by TLC; completion is achieved after 8 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate (10 mL), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzohydrazide (41.0 mg) as a white solid with a yield of 69%.

[0115] The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzoylhydrazide synthesized above was subjected to1 HNMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection, the test results are as follows Figures 17-20 As shown, the characterization data of the corresponding products are:

[0116] 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),7.71(d,J=7.6Hz,2H),7.31(d,J=8.0Hz,2H) ,2.71(t,J=7.2Hz,2H),2.60(t,J=7.1Hz,2H),2.36(s,3H),1.81(p,J=6.8Hz,2H).

[0117] 13 C NMR (151MHz, Acetone-d6) δ160.8, 142.6, 130.2, 130.2, 128.7, 128.7, 121.5 (q, J = 272.8Hz), 119.1, 23.8, 21.4, 20.6, 16.2.

[0118] 19 F NMR (376MHz, DMSO-d6): δ–68.17.

[0119] HRMS(ESI)m / z:calcd for C 14 H 15 F3N3O[M+H]+298.1162,found:298.1166.

[0120] Figure 17 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzoylhydrazide synthesized in Example 5 1 HNMR spectrum; Figure 18 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzoylhydrazide synthesized in Example 5 13 C NMR spectrum; Figure 19 The N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzoylhydrazide synthesized in Example 5 19 F NMR spectrum; Figure 20 This is a high-resolution mass spectrometry monitoring diagram of N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzoylhydrazide synthesized in Example 5. Figures 17-20 It can be seen that the N'-(5-cyano-1,1,1-trifluoropentane-2-methylene)-4-methylbenzohydrazide obtained in this example is a pure target compound.

[0121] Example 6

[0122] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), iron trifluoromethanesulfonate (0.02 mmol, 4.1 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 65°C with stirring. Monitor the reaction by TLC; completion is achieved after 24 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate (10 mL), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (21.2 mg) as a white solid with a yield of 40%.

[0123] Example 7

[0124] In a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric chloride (0.02 mmol, 2.5 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 65°C with stirring. Monitor the reaction by TLC; completion is achieved after 24 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (22.8 mg) as a white solid with a yield of 43%.

[0125] Example 8

[0126] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 65°C with stirring. Monitor the reaction by TLC; completion is achieved after 24 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate (10 mL), the organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (33.4 mg) as a white solid with a yield of 63%.

[0127] Example 9

[0128] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.01 mmol, 2.9 mg, 0.05 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 65°C with stirring. Monitor the reaction by TLC; completion is achieved after 32 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then rapidly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (3a): white solid, 27 mg, yield 51%.

[0129] Example 10

[0130] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.03 mmol, 8.8 mg, 0.15 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 65°C with stirring. Monitor the reaction by TLC; completion is achieved after 24 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (32.9 mg) as a white solid with a yield of 62%.

[0131] Example 11

[0132] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of ethanol and seal the pressure tube. Heat the mixture at 65°C with stirring. Monitor the reaction by TLC; completion is achieved after 24 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (25.4 mg) as a white solid with a yield of 48%.

[0133] Example 12

[0134] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of 1,4-dioxane solvent and seal the pressure tube. Heat the mixture at 65°C with stirring. Monitor the reaction by TLC; completion is achieved after 24 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (29.1 mg) as a white solid with a yield of 55%.

[0135] Example 13

[0136] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 100°C with stirring. Monitor the reaction by TLC, which indicates completion after 8 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (32.9 mg) as a white solid with a yield of 62%.

[0137] Example 14

[0138] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.3 mmol, 56.7 mg, 1.5 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 80°C with stirring. Monitor the reaction by TLC; completion is achieved after 12 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (28.1 mg) as a white solid with a yield of 52%.

[0139] Example 15

[0140] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.5 mmol, 94.5 mg, 2.5 equiv.). Then, add 2 mL of methanol and seal the pressure tube. Heat the mixture at 80°C with stirring. Monitor the reaction by TLC; completion is achieved after 12 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (32.9 mg) as a white solid with a yield of 62%.

[0141] Comparative Example 1

[0142] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of N,N-dimethylformamide and seal the pressure tube. Heat the mixture at 65°C with stirring. Monitor the reaction by TLC; completion is achieved after 24 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (19.6 mg) as a white solid with a yield of 37%.

[0143] Comparative Example 2

[0144] To a 10 mL pressure tube, add N'-(2,2-difluoroethylidene)benzohydrazide (0.2 mmol, 39.6 mg, 1.0 equiv.), ferric bromide (0.02 mmol, 5.9 mg, 0.1 equiv.), and cyclobutanone oxime (0.4 mmol, 75.6 mg, 2 equiv.). Then, add 2 mL of acetonitrile and seal the pressure tube. Heat the mixture at 65°C with stirring. Monitor the reaction by TLC; completion is achieved after 24 h. Then, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined and concentrated, and then quickly separated by column chromatography using a mixed eluent of petroleum ether (PE) and ethyl acetate (PA) (PE:EA=3:1, v / v) to obtain N'-(5-cyano-1,1-difluoropentane-2-methylene)benzohydrazide (16.4 mg) as a white solid with a yield of 31%.

[0145] By comparing Example 8 with Comparative Examples 1 and 2, it can be seen that the change in solvent type has a significant effect on the yield. The solvent type selected in the present invention can significantly increase the yield of the product.

[0146] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0147] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. An alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit, characterized in that: It has the following structure: Among them, R f It is -CF2H or -CF3; R is phenyl, 4-methylphenyl, 4-methoxyphenyl or isopropyl.

2. The method for preparing the alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit according to claim 1, characterized in that: The steps include: Mixing fluoroalkyl N-acylhydrazone, cyclobutanone oxime ester, iron salt and solvent and subjecting them to coupling reaction to obtain the alkyl nitrile compound containing the fluoroalkyl N-acylhydrazone structural unit; The structural formula of the fluoroalkyl N-acylhydrazone is: Among them, R f It is -CF2H or -CF3; R is phenyl, 4-methylphenyl, 4-methoxyphenyl or isopropyl.

3. The preparation method according to claim 2, characterized in that: The iron salt is a trivalent iron salt; the solvent includes methanol, ethanol, 1,4-dioxane or dimethyl sulfoxide.

4. The preparation method according to claim 2, characterized in that: The molar ratio of the fluoroalkyl N-acylhydrazone, cyclobutanone oxime ester and iron salt is 1:1.5-2.5:0.05-0.2; the dosage ratio of the cyclobutanone oxime ester and the solvent is 1.5-2.5mmol:10mL.

5. The preparation method according to claim 2, characterized in that: The coupling reaction temperature is 65-100° C., and the coupling reaction time is 8-48 hours.

6. The preparation method according to claim 2, characterized in that: The coupling reaction temperature is 80-90° C., and the coupling reaction time is 12-32 hours.

7. The preparation method according to claim 2, characterized in that: The coupling reaction time is 14 to 24 hours.

8. The preparation method according to claim 2, characterized in that: The coupling reaction further includes a post-processing step; the post-processing step includes: quenching and column chromatography separation in sequence.

9. Use of the alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit according to claim 1 in the preparation of antiviral, antitumor, antimalarial, bactericidal and / or cathepsin inhibitor drugs.

10. Use of the alkyl nitrile compound containing a fluoroalkyl N-acylhydrazone structural unit according to claim 1 in the preparation of pesticides.

Images