Amino alkyl nitrile compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to an amino alkyl nitrile compound as well as a preparation method and application thereof. The N-fluorenyl imine compound and the cyclobutanone oxime compound are used as raw materials, alkali and an organic solvent are introduced at the same time, imino ring opening / free radical coupling is carried out, the amino alkyl nitrile compound is prepared, transition metal and a photooxidation reduction catalyst are not needed, and the amino alkyl nitrile compound is prepared in a green, efficient and sustainable mode. The preparation method provided by the invention is simple to operate and environment-friendly, the product is easy to purify, excellent functional group compatibility is achieved, the yield is generally high, and a gram-level reaction can be carried out to prepare a compound. The invention also provides the amino alkyl nitrile compound obtained by the preparation method in the scheme. The amino alkyl nitrile compound provided by the invention is low in cost and good in safety.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to an aminoalkyl nitrile compound and a preparation method and application thereof. Background Art

[0002] Aminoalkyl nitrile compounds are important structural units in organic synthetic chemistry and medicinal chemistry. Aminoalkyl nitrile structural units are widely present in a variety of active natural products and drug molecules. Their advantages make them play an irreplaceable role in medicinal chemistry. In addition, cyano, as an important functional group in organic synthesis, can be easily converted into compounds such as aldehydes, ketones, amides and carboxylic acids. Therefore, aminoalkyl nitrile compounds have attracted the attention and research of researchers.

[0003] Among the many aminoalkylnitrile derivatives, verapamil, as a calcium channel blocker, is used to treat hypertension, angina pectoris, arrhythmia, cerebrovascular disease and finger vasospasm; phenoxylate, as an antidiarrheal drug, is suitable for acute and chronic functional diarrhea and chronic enteritis; vildagliptin, as a DPP-4 enzyme inhibitor, is used to stimulate pancreatic beta cells to produce insulin, lower blood sugar concentration and treat diabetes; and pirilimide, as an opioid receptor agonist, is used to treat postoperative pain.

[0004] For many years, organic synthetic chemists have been looking for new and effective methods to construct aminocyanide compounds. However, the existing methods usually involve some harsh conditions, such as the use of toxic tin reagents (Bu3SnH / AIBN), which reduces the safety of the product; using transition metal (Pd, Ni, Cu, Fe, etc.) catalysis or photoredox / metal dual catalysis at high temperature, but most transition metal catalysts are also toxic. Summary of the invention

[0005] The object of the present invention is to provide an aminoalkyl nitrile compound and a preparation method and application thereof. The preparation method provided by the present invention can synthesize the aminoalkyl nitrile compound in a green way.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing an aminoalkyl nitrile compound, comprising the following steps:

[0008] The cyclobutanone oxime compound, the N-fluorenyl imine compound, the organic solvent and the base are mixed in a protective atmosphere to carry out a free radical coupling reaction to obtain the aminoalkyl nitrile compound.

[0009] Preferably, the cyclobutanone oxime compound includes one or more of cyclobutanone O-(4-nitrophenyl) oxime, oxetane-3-one O-(4-nitrophenyl) oxime, spiro[3.5]nonane-2-one O-(4-nitrophenyl) oxime, 3,3-diphenylcyclobutane-1-one O-(4-nitrophenyl) oxime and (E)-bicyclo[4.2.0]octa-1,3,5-triene-7-one O-(4-nitrophenyl) oxime.

[0010] Preferably, the N-fluorenyl imine compound includes one or more of N-benzyl-9H-fluorene-9-imine, N-(pyridin-3-ylmethyl)-9H-fluorene-9-imine, N-(thiophene-2-ylmethyl)-9H-fluorene-9-imine, N-(furan-2-ylmethyl)-9H-fluorene-9-imine, N-(2-(1-methyl-1H-indol-3-yl)ethyl)-9H-fluorene-9-imine, N-ethyl-9H-fluorene-9-imine, N-(cyclobutylmethyl)-9H-fluorene-9-imine and N-(cyclohexylmethyl)-9H-fluorene-9-imine.

[0011] Preferably, the molar ratio of the cyclobutanone oxime compound to the N-fluorenyl imine compound is 1:1-2.

[0012] Preferably, the molar ratio of the cyclobutanone oxime compound to the base is 1:1-2.

[0013] Preferably, the free radical coupling reaction is carried out under closed conditions; the free radical coupling reaction is carried out under stirring conditions; the temperature of the free radical coupling reaction is room temperature, and the reaction time is 1 to 12 hours.

[0014] Preferably, after the free radical coupling reaction, the free radical coupling reaction system is quenched and then post-treated; the post-treatment is: diluting the quenched reaction system and then sequentially performing extraction, organic phase washing, organic phase drying, solid-liquid separation, solvent removal and purification.

[0015] The present invention also provides an aminoalkyl nitrile compound obtained by the preparation method described in the above scheme, the structure of which is shown in Formula I:

[0016]

[0017] In formula I, R is an alkyl group, an aryl group or a heterocyclic group, and X is C, N or O.

[0018] Preferably, in Formula I, the alkyl group includes a straight-chain alkyl group, a branched-chain alkyl group or a cyclic alkyl group; the aryl group is a substituted phenyl group; and the heterocyclic group includes a furyl group, a pyridyl group, a thienyl group, a piperonyl group or a tryptamine group.

[0019] The present invention also provides the application of the aminoalkyl nitrile compounds described in the above scheme in the field of biomedicine.

[0020] The present invention provides a method for preparing an aminoalkyl nitrile compound. The present invention uses an N-fluorenyl imine compound and a cyclobutanone oxime compound as raw materials, introduces a base and an organic solvent at the same time, performs imine ring-opening / free radical coupling, and prepares an aminoalkyl nitrile compound, without requiring a transition metal and a photoredox catalyst, and is green, efficient, and sustainable in preparing an aminoalkyl nitrile compound. The preparation method provided by the present invention is simple to operate, environmentally friendly, and the product is easy to purify, has excellent functional group compatibility, and generally has a high yield, and can be used to prepare compounds by gram-level reaction.

[0021] The present invention also provides aminoalkyl nitrile compounds obtained by the preparation method described in the above scheme. The aminoalkyl nitrile compounds provided by the present invention have low cost, good safety and good functional group compatibility.

[0022] The present invention also provides the use of the aminoalkyl nitrile compound described in the above scheme in the field of biomedicine. The aminoalkyl nitrile compound provided by the present invention can be used in the field of biomedicine and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] 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.

[0024] Figure 1 The diagram is a preparation mechanism diagram of the aminoalkyl nitrile compounds of the present invention;

[0025] Figure 2 The present invention provides a process flow chart of the preparation method of aminoalkyl nitrile compounds. DETAILED DESCRIPTION

[0026] The present invention provides a method for preparing an aminoalkyl nitrile compound, comprising the following steps:

[0027] The cyclobutanone oxime compound, the N-fluorenyl imine compound, the organic solvent and the base are mixed in a protective atmosphere to carry out a free radical coupling reaction to obtain the aminoalkyl nitrile compound.

[0028] The present invention mixes a cyclobutanone oxime compound, an N-fluorenyl imine compound, an organic solvent and a base in a protective atmosphere (referred to as the first mixing). In the present invention, the cyclobutanone oxime compound preferably includes one or more of cyclobutanone O-(4-nitrophenyl) oxime, oxetane-3-one O-(4-nitrophenyl) oxime, spiro[3.5]nonane-2-one O-(4-nitrophenyl) oxime, 3,3-diphenylcyclobutane-1-one O-(4-nitrophenyl) oxime and (E)-bicyclo[4.2.0]octa-1,3,5-triene-7-one O-(4-nitrophenyl) oxime.

[0029] In the present invention, the N-fluorenyl imine compound preferably includes one or more of N-benzyl-9H-fluorene-9-imine, N-(pyridin-3-ylmethyl)-9H-fluorene-9-imine, N-(thiophene-2-ylmethyl)-9H-fluorene-9-imine, N-(furan-2-ylmethyl)-9H-fluorene-9-imine, N-(2-(1-methyl-1H-indol-3-yl)ethyl)-9H-fluorene-9-imine, N-ethyl-9H-fluorene-9-imine, N-(cyclobutylmethyl)-9H-fluorene-9-imine and N-(cyclohexylmethyl)-9H-fluorene-9-imine.

[0030] In the present invention, the molar ratio of the cyclobutanone oxime compound to the N-fluorenyl imine compound is preferably 1:1-2, specifically 1:1.2, 1:1.4, 1:1.6 or 1:1.8.

[0031] In the present invention, the organic solvent preferably includes one or more of nitrile, sulfoxide, furan, amide and benzene homologues; the nitrile is preferably acetonitrile; the acetonitrile is preferably anhydrous acetonitrile; the sulfoxide is preferably dimethyl sulfoxide (DMSO); the furan is preferably tetrahydrofuran (THF); the amide is preferably N,N-dimethylformamide (DMF); the benzene homologue is preferably toluene (PhCH3); the molar volume ratio of the cyclobutanone oxime compound to the organic solvent is preferably 1 mol:(10-20) mL, specifically 1 mol:12 mL, 1 mol:14 mL, 1 mol:16 mL or 1 mol:18 mL.

[0032] In the present invention, the base is preferably potassium tert-butoxide, NaN(SiMe3)2, KN(SiMe3)2 and NaO t One or more of Bu; the molar ratio of the cyclobutanone oxime compound to the base is preferably 1:1-2, specifically 1:1.2, 1:1.4, 1:1.6 or 1:1.8.

[0033] In the present invention, the protective atmosphere is preferably nitrogen.

[0034] In the present invention, the temperature of the first mixing is preferably room temperature; the first mixing is preferably: mixing the base, the N-fluorenyl imine compound and part of the organic solvent to obtain a premixed liquid, mixing the remaining part of the organic solvent and the cyclobutanone oxime compound to obtain a cyclobutanone oxime compound solution, and then adding the premixed liquid to the cyclobutanone oxime compound solution.

[0035] After the mixing, the present invention conducts a free radical coupling reaction on the obtained mixed solution to obtain the aminoalkyl nitrile compound. In the present invention, the free radical coupling reaction is carried out in a protective atmosphere; the protective atmosphere is preferably nitrogen; the free radical coupling reaction is preferably carried out in a closed condition; the free radical coupling reaction is preferably carried out under stirring conditions; the temperature of the free radical coupling reaction is preferably room temperature, and the reaction time is preferably 1 to 12 hours, specifically 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours or 12 hours. The preparation method provided by the present invention has mild reaction conditions, which is conducive to safe production. The specific reaction mechanism is as follows Figure 1 shown.

[0036] In the present invention, after the free radical coupling reaction, preferably the free radical coupling reaction system is quenched and then post-treated; the quenching agent is preferably saturated saline.

[0037] In the present invention, the post-treatment is preferably: diluting the quenched reaction system and then sequentially performing extraction, organic phase washing, organic phase drying, solid-liquid separation, solvent removal and purification.

[0038] In the present invention, the dilution reagent is preferably ethyl acetate; the dilution multiple is preferably 1 to 4 times, specifically 2 times.

[0039] In the present invention, the extraction reagent is preferably ethyl acetate.

[0040] In the present invention, the organic phase washing agent is preferably saturated saline; the washing times are preferably 3 or more, specifically 3 times.

[0041] In the present invention, the organic phase is preferably dried using anhydrous sodium sulfate.

[0042] In the present invention, the solid-liquid separation is preferably filtration.

[0043] In the present invention, the solvent removal is preferably performed by vacuum distillation; the temperature of the vacuum distillation is preferably 40-50°C, specifically 45°C, the vacuum degree is preferably 170-180Torr, specifically 175Torr, and the insulation distillation time is preferably 10-20min, specifically 15min.

[0044] In the present invention, the purification is preferably column chromatography; the column chromatography is preferably deactivated silica gel column chromatography; the solvent of the column chromatography is preferably petroleum ether-ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is preferably 1:8-10.

[0045] The process flow of the preparation method of aminoalkyl nitrile compounds provided by the present invention is as follows: Figure 2 As shown, the present invention conducts a free radical coupling reaction between a cyclobutanone oxime compound and an N-fluorenyl imine compound to obtain an aminoalkyl nitrile compound in one step, which has simple steps, convenient operation and good process stability.

[0046] The present invention also provides an aminoalkyl nitrile compound obtained by the preparation method described in the above scheme, the structure of which is shown in Formula I:

[0047]

[0048] In formula I, R is an alkyl group, an aryl group or a heterocyclic group, and X is C, N or O.

[0049] In the present invention, the alkyl group in Formula I preferably includes a straight-chain alkyl group, a branched-chain alkyl group or a cyclic alkyl group; the straight-chain alkyl group is preferably a C1-C5 straight-chain alkyl group; the C1-C5 straight-chain alkyl group is preferably a methyl group; the branched-chain alkyl group is preferably a C1-C5 branched-chain alkyl group; the C1-C5 branched-chain alkyl group is preferably an isopropyl group; the cyclic alkyl group is preferably a three-membered cycloalkyl group, a four-membered cycloalkyl group, a five-membered cycloalkyl group or a six-membered cycloalkyl group.

[0050] In the present invention, the aryl group in formula I is preferably a substituted phenyl group; the substituent of the substituted phenyl group is preferably an electron donating group or an electron withdrawing group; the electron donating group is preferably methyl, phenyl, tert-butyl or methoxy; the electron withdrawing group is preferably halogen, trifluoromethyl or naphthyl; the halogen is preferably F, Cl or Br; the substitution site of the substituent of the substituted phenyl group is preferably any site on the benzene ring.

[0051] In the present invention, the aryl group in Formula I is preferably o-methylphenyl or 1-naphthylphenyl.

[0052] In the present invention, the heterocyclic group in Formula I preferably includes furanyl, pyridyl, thienyl, piperonyl or tryptamine.

[0053] In the present invention, the aminoalkyl nitrile compound preferably includes 5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanenitrile, 5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)pentanenitrile, 5-((9H-fluorene-9-ylidene)amino)-5-(thiophen-2-yl)pentanenitrile, 5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanenitrile, 5-((9H-fluorene-9-ylidene)amino)-6-(1-methyl-1H-indol-3-yl)hexanenitrile, 5-((9H-fluorene-9-ylidene)amino)hexanenitrile, aminoalkyl nitrile compound 5-((9H -fluorene-9-ylidene)amino)-5-cyclobutylpentanenitrile, 5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanenitrile, 2-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethoxy)acetonitrile, 2-(1-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethyl)cyclohexyl)acetonitrile, 5-((9H-fluorene-9-ylidene)amino)-3,3,5-triphenylpentanenitrile, 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethoxy)acetonitrile and 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethyl)benzonitrile.

[0054] The present invention also provides the application of the aminoalkyl nitrile compounds described in the above scheme in the biomedical field.

[0055] The aminoalkyl nitrile compounds provided by the present invention are suitable for use in the biomedical field and have broad application prospects.

[0056] In order to further illustrate the present invention, the scheme of the present invention is described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be understood as limiting the protection scope of the present invention.

[0057] Example 1

[0058] This example prepares an aminoalkyl nitrile compound, 5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanenitrile, and the specific steps are as follows:

[0059] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-benzyl-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a cyclobutanone O-(4-nitrophenyl) oxime solution dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to the base is 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to N-benzyl-9H-fluorene-9-imine is 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl) oxime to acetonitrile is 1 mol:10 mL.

[0060] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50° C., vacuum degree 180 Torr, time 10 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0061] The aminoalkyl nitrile compound prepared in this example, 5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanenitrile, is denoted as compound 1, and its structure is shown in formula A:

[0062]

[0063] The hydrogen nuclear magnetic resonance spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanenitrile in this example is:

[0064] 1 H NMR(400MHz,Chloroform-d)δ7.84-7.81(m,1H),7.65(d,J=7.6Hz,1H),7.51(d,J=7.6Hz,1H),7.45(d,J=7.6Hz,1H),7.39-7.36(m,2H),7.30 (t,J=7.6,1H),7.26-7.20(m,4H),7.16-7.08(m,2H),5.50(t,J=6.0Hz,1H),2.23(t,J=7.2Hz,2H),2.16-2.04(m,2H),1.71-1.64(m,2H)ppm.

[0065] The carbon NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanenitrile in this example:

[0066] 13 C NMR(100MHz,Chloroform-d)δ161.5,143.0,142.5,139.9,137.6,130.4,130.3,130.0,127.6 ,127.3,127.0,126.4,126.1,125.7,121.7,119.4,118.7,118.3,62.8,38.0,21.3,16.2ppm.

[0067] In this example, 5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanenitrile was a colorless oily liquid with a yield of 95%. HRMS calculated for C 24H 21 N2 + :337.1699,found:337.1698[M+H] + .

[0068] Example 2

[0069] This example prepares an aminoalkyl nitrile compound, 5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)pentanenitrile, and the specific steps are as follows:

[0070] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-(pyridin-3-ylmethyl)-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a cyclobutanone O-(4-nitrophenyl) oxime solution dissolved in anhydrous acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to the base is 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to N-(pyridin-3-ylmethyl)-9H-fluorene-9-imine is 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl) oxime to acetonitrile is 1 mol:10 mL.

[0071] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 40° C., vacuum degree 180 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0072] The aminoalkyl nitrile compound prepared in this example, 5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)pentanenitrile, is denoted as compound 2, and has a structure as shown in formula B:

[0073]

[0074] The hydrogen nuclear magnetic resonance spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)pentanenitrile in this example is:

[0075] 1H NMR(400MHz,Chloroform-d)δ8.66(d,J=2.4Hz,1H),8.41(dd,J=4.8,1.6Hz,1H),7.80( d,J=7.2Hz,1H),7.75(d,J=8.0Hz,1H),7.65(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7. 46(d,J=7.2Hz,1H),7.34-7.28(m,2H),7.23(t,J=7.6Hz,1H),7.19-7.12(m,2H),5.57( dd,J=7.6,5.2Hz,1H),2.27(t,J=7.2Hz,2H),2.19-2.04(m,2H),1.73-1.64(m,2H)ppm.

[0076] The carbon NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)pentanenitrile in this example is:

[0077] 13 C NMR(100MHz,Chloroform-d)δ162.1,147.6,147.5,143.1,139.9,138.1,137.4,133.4,130.7,1 30.3,127.4,127.1,126.2,122.7,121.8,119.6,118.44,118.38,60.5,37.7,21.2,16.2ppm(one resonance was not observed due to overlappingpeaks).

[0078] In this example, 5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)pentanenitrile was a white oily liquid with a yield of 82%. HRMS calculated for C 23 H 20 N3 + :338.1652,found:338.1648[M+H] + .

[0079] Example 3

[0080] This example prepares an aminoalkyl nitrile compound, 5-((9H-fluorene-9-ylidene)amino)-5-(thiophen-2-yl)pentanenitrile, and the specific steps are as follows:

[0081] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-(thiophen-2-ylmethyl)-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a cyclobutanone O-(4-nitrophenyl) oxime solution dissolved in anhydrous acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to the base is 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to N-(thiophen-2-ylmethyl)-9H-fluorene-9-imine is 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl) oxime to acetonitrile is 1 mol:10 mL.

[0082] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 45° C., vacuum degree 175 Torr, time 15 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0083] The aminoalkyl nitrile compound prepared in this example, 5-((9H-fluorene-9-ylidene)amino)-5-(thiophen-2-yl)pentanenitrile, is denoted as compound 3, and its structure is shown in formula C:

[0084]

[0085] The hydrogen nuclear magnetic resonance spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-(thiophen-2-yl)pentanenitrile in this example is:

[0086] 1 H NMR(400MHz,Chloroform-d)δ7.80(d,J=7.2Hz,1H),7.69(d,J=7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.46(d,J=7.2Hz,1H),7.33-7.28(m,2H),7.22(t,J= 7.2Hz,1H),7.16-7.11(m,2H),6.91(s,1H),6.88-6.85(m,1H),5.82(t,J=6 .0Hz,1H),2.26(t,J=7.2Hz,2H),2.21-2.12(m,2H),1.76-1.68(m,2H)ppm.

[0087] The carbon NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-(thiophen-2-yl)pentanenitrile in this example is:

[0088] 13C NMR(100MHz,Chloroform-d)δ162.0,145.4,143.0,139.9,137.4,130.6,130.3,130.2,127.4 ,127.1,126.4,125.6,123.1,122.4,121.9,119.5,118.6,118.3,59.0,37.9,21.0,16.1ppm.

[0089] In this example, 5-((9H-fluorene-9-ylidene)amino)-5-(thiophen-2-yl)pentanenitrile was a white oily liquid with a yield of 96%. HRMS calculated for C 22 H 19 N2S + :343.1263,found:343.1266[M+H] + .

[0090] Example 4

[0091] This example prepares an aminoalkyl nitrile compound, 5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanenitrile, and the specific steps are as follows:

[0092] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-(furan-2-ylmethyl)-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a cyclobutanone O-(4-nitrophenyl) oxime solution dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to the base is 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to N-(furan-2-ylmethyl)-9H-fluorene-9-imine is 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl) oxime to acetonitrile is 1 mol:10 mL.

[0093] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50° C., vacuum degree 180 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0094] The aminoalkyl nitrile compound prepared in this example, 5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanenitrile, is denoted as compound 4, and has a structure as shown in formula D:

[0095]

[0096] The hydrogen nuclear magnetic resonance spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanenitrile in this example is:

[0097] 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=7.6Hz,1H),7.67(d,J=7.6Hz,1H),7.55( d,J=7.6Hz,1H),7.47(d,J=7.2Hz,1H),7.34-7.29(m,3H),7.21(td,J=7.6,1.2Hz ,1H),7.17-7.13(m,1H),6.21(dd,J=3.2,1.6Hz,1H),6.12(d,J=3.2Hz,1H),5.60 (t,J=6.0Hz,1H),2.30(t,J=7.2Hz,2H),2.23-2.18(m,2H),1.77-1.69(m,2H)ppm.

[0098] The carbon NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanenitrile in this example is:

[0099] 13 C NMR(100MHz,Chloroform-d)δ163.0,153.7,143.0,140.7,139.9,137.4,130.6,130.4,130.2 ,127.4,127.1,126.5,121.9,119.4,118.7,118.3,109.3,105.2,57.4,33.9,21.1,16.1ppm.

[0100] In this example, 5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanenitrile was a colorless oily liquid with a yield of 93%. HRMS calculated for C 22 H 19 N2O + :327.1492,found:327.1491[M+H] + .

[0101] Example 5

[0102] This example prepares an aminoalkyl nitrile compound, 5-((9H-fluorene-9-ylidene)amino)-6-(1-methyl-1H-indol-3-yl)hexanenitrile, and the specific steps are as follows:

[0103] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-(2-(1-methyl-1H-indol-3-yl)ethyl)-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a cyclobutanone O-(4-nitrophenyl)oxime solution dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of cyclobutanone O-(4-nitrophenyl)oxime to the base is 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl)oxime to N-(2-(1-methyl-1H-indol-3-yl)ethyl)-9H-fluorene-9-imine is 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl)oxime to acetonitrile is 1 mol:10 mL.

[0104] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring conditions for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 40° C., vacuum degree 170 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0105] The aminoalkyl nitrile compound prepared in this example, 5-((9H-fluorene-9-ylidene)amino)-6-(1-methyl-1H-indol-3-yl)hexanenitrile, is denoted as compound 5, and has a structure as shown in formula E:

[0106]

[0107] The nuclear magnetic resonance hydrogen spectrum of 5-((9H-fluorene-9-ylidene)amino)-6-(1-methyl-1H-indol-3-yl)hexanenitrile in this example is:

[0108] 1 H NMR(400MHz,Chloroform-d)δ7.79(d,J=7.2Hz,1H),7.65(d,J=7.6Hz,1H),7.57-7.54(m,2H) ,7.51(d,J=7.6Hz,1H),7.35(td,J=7.2,1.2Hz,1H),7.30-7.23(m,2H),7.17-7.11(m,2H),7. 05-7.00(m,2H),6.79(s,1H),4.81-4.75(m,1H),3.59(s,3H),3.15(dd,J=14.4,7.2Hz,1H),3 .04(dd,J=14.4,5.6Hz,1H),2.22(t,J=6.8Hz,2H),1.95-1.89(m,2H),1.73-1.59(m,2H)ppm.

[0109] The carbon NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-6-(1-methyl-1H-indol-3-yl)hexanenitrile in this example is:

[0110] 13 C NMR(100MHz,Chloroform-d)δ160.5,142.7,139.7,137.7,135.9,130.8,130.0,129.8,127.32,127.27,126.8,126 .5,126.0,121.7,120.5,119.2,118.8,118.2,117.9,117.8,110.0,108.2,59.8,34.2,31.5,30.8,21.7,16.2ppm.

[0111] In this example, 5-((9H-fluorene-9-ylidene)amino)-6-(1-methyl-1H-indol-3-yl)hexanenitrile was a colorless oily liquid with a yield of 72%. HRMS calculated for C 28 H 26 N3 + :404.2121,found:404.2124[M+H] + .

[0112] Example 6

[0113] This example prepares an aminoalkyl nitrile compound, 5-((9H-fluorene-9-ylidene)amino)capronitrile, and the specific steps are as follows:

[0114] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-ethyl-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a cyclobutanone O-(4-nitrophenyl) oxime solution dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to the base is 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to N-ethyl-9H-fluorene-9-imine is 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl) oxime to acetonitrile is 1 mol:10 mL.

[0115] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50° C., vacuum degree 180 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0116] The aminoalkyl nitrile compound prepared in this example, 5-((9H-fluorene-9-ylidene)amino)capronitrile, is denoted as compound 6, and its structure is shown in formula F:

[0117]

[0118] The nuclear magnetic resonance hydrogen spectrum of 5-((9H-fluorene-9-ylidene)amino)capronitrile in this example is:

[0119] 1 H NMR(400MHz,Chloroform-d)δ7.77(dd,J=7.6,1.2Hz,1H),7.73(t,J=7.6,1H),7.61(d,J=7.6Hz,1H),7.51(d,J=7.6Hz,1H),7.39-7.3 1(m,2H),7.25-7.20(m,2H),4.59-4.51(m,1H),2.31(t,J=7.2Hz,2H),1.95-1.79(m,2H),1.77-1.64(m,2H),1.34(d,J=6.4Hz,3H)ppm.

[0120] The carbon NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)capronitrile in this example:

[0121] 13 C NMR(100MHz,Chloroform-d)δ160.4,142.9,139.7,137.6,130.5,130.2,129.8,1 27.3,127.0,126.3,121.6,119.5,118.9,118.2,54.4,36.8,21.9,20.2,16.2ppm.

[0122] In this example, 5-((9H-fluorene-9-ylidene)amino)capronitrile was a colorless oily liquid with a yield of 96%. HRMS calculated for C 19 H 19 N2 + :275.1543,found:275.1542[M+H] + .

[0123] Example 7

[0124] This example prepares an aminoalkyl nitrile compound, namely, an aminoalkyl nitrile compound 5-((9H-fluorene-9-ylidene)amino)-5-cyclobutylpentanenitrile, and the specific steps are as follows:

[0125] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-(cyclobutylmethyl)-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a cyclobutanone O-(4-nitrophenyl) oxime solution dissolved in anhydrous acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to the base is 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to N-(cyclobutylmethyl)-9H-fluorene-9-imine is 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl) oxime to anhydrous acetonitrile is 1 mol:10 mL.

[0126] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 42° C., vacuum degree 172 Torr, time 15 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0127] The aminoalkyl nitrile compound prepared in this example, 5-((9H-fluorene-9-ylidene)amino)-5-cyclobutylpentanenitrile, is denoted as compound 7, and its structure is shown in formula G:

[0128]

[0129] The hydrogen nuclear magnetic resonance spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-cyclobutylpentanenitrile in this example is:

[0130] 1 H NMR(400MHz,Chloroform-d)δ7.91(d,J=7.6Hz,1H),7.74(d,J=7.2Hz,1H),7.59(d,J=7.6Hz,1H),7.50(d,J=7.2Hz,1H),7.35-7.29(m,2H),7.23 -7.18(m,2H),4.54(td,J=8.0,4.0Hz,1H),2.71-2.61(m,1H),2.20(t,J= 7.2Hz,2H),1.99-1.92(m,1H),1.85-1.67(m,7H),1.58-1.50(m,2H)ppm.

[0131] The carbon NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-cyclobutylpentanenitrile in this example:

[0132] 13C NMR(100MHz,Chloroform-d)δ160.3,143.1,139.5,137.7,131.3,130.0,129.7,127.2,126 .9,126.1,121.7,119.5,118.7,118.1,63.1,40.3,32.0,24.2,23.8,21.5,17.2,16.3ppm.

[0133] In this example, 5-((9H-fluorene-9-ylidene)amino)-5-cyclobutylpentanenitrile was a colorless oily liquid with a yield of 96%. HRMS calculated for C 22 H 23 N2 + :315.1856,found:315.1851[M+H] + .

[0134] Example 8

[0135] This example prepares an aminoalkyl nitrile compound, 5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanenitrile, and the specific steps are as follows:

[0136] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-(cyclohexylmethyl)-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a cyclobutanone O-(4-nitrophenyl) oxime solution dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to the base is 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl) oxime to N-(cyclohexylmethyl)-9H-fluorene-9-imine is 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl) oxime to acetonitrile is 1 mol:10 mL;

[0137] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50° C., vacuum degree 180 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0138] The aminoalkyl nitrile compound prepared in this example, 5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanenitrile, is denoted as compound 8, and its structure is shown in formula H:

[0139]

[0140] The hydrogen nuclear magnetic resonance spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanenitrile in this example is:

[0141] 1 H NMR (400MHz, Chloroform-d) δ7.84(d,J=7.6Hz,1H),7.74(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.52(d,J=7.2Hz,1H),7.37-7.31( m,2H),7.25-7.17(m,2H),4.33(q,J=6.4Hz,1H),2.23(t,J=7.2Hz,2H),1.91-1.81(m,3H),1.70-1.51(m,7H),1.20-1.01(m,5H)ppm.

[0142] The carbon NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanenitrile in this example is:

[0143] 13 C NMR(100MHz,Chloroform-d)δ160.0,143.1,139.5,137.6,131.2,130.0,129.7,127.2,126.9,126. 1,121.6,119.4,118.8,118.1,63.7,42.7,31.2,28.60,28.58,25.6,25.44,25.39,21.5,16.4ppm.

[0144] In this example, 5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanenitrile was a colorless oily liquid with a yield of 93%. HRMS calculated for C 24 H 27 N2 + :343.2169,found:343.2165[M+H] + .

[0145] Example 9

[0146] This example prepares an aminoalkyl nitrile compound, 2-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethoxy)acetonitrile, and the specific steps are as follows:

[0147] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-benzyl-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a solution of oxetane-3-one O-(4-nitrophenyl)oxime dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of oxetane-3-one O-(4-nitrophenyl)oxime to the base is 1:1, the molar ratio of oxetane-3-one O-(4-nitrophenyl)oxime to N-benzyl-9H-fluorene-9-imine is 1:2, and the molar volume ratio of oxetane-3-one O-(4-nitrophenyl)oxime to acetonitrile is 1 mol:10 mL.

[0148] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 40° C., vacuum degree 170 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:8.

[0149] The aminoalkyl nitrile compound prepared in this example, 2-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethoxy)acetonitrile, is denoted as compound 9, and has a structure as shown in formula J:

[0150]

[0151] The hydrogen nuclear magnetic resonance spectrum of 2-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethoxy)acetonitrile in this example is:

[0152] 1 H NMR (400MHz, Chloroform-d) δ7.85(d,J=7.2Hz,1H),7.69(d,J=7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.47(d,J=7.2Hz,1H),7.43(d,J=7.2Hz,2 H),7.35-7.22(m,5H),7.21-7.16(m,1H),7.11(td,J=7.6,1.2Hz,1H),5.72(dd,J=7.2,4.8Hz,1H),4.28-4.19(m,2H),4.06-3.99(m,2H)ppm.

[0153] The carbon NMR spectrum of 2-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethoxy)acetonitrile in this example is:

[0154] 13C NMR(100MHz,Chloroform-d)δ163.1,143.0,140.1,139.2,137.6,130.51,130.46,130.2,12 7.7,127.4,127.0,126.64,126.58,126.3,121.9,119.3,118.3,115.1,76.8,63.8,55.8ppm.

[0155] In this example, 2-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethoxy)acetonitrile was a colorless oil with a yield of 92%. HRMS calculated for C 23 H 19 N2O + :339.1492,found:339.1491[M+H] + .

[0156] Example 10

[0157] This example prepares an aminoalkyl nitrile compound, 2-(1-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethyl)cyclohexyl)acetonitrile, and the specific steps are as follows:

[0158] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-benzyl-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a solution of spiro[3.5]nonane-2-one O-(4-nitrophenyl)oxime dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of spiro[3.5]nonane-2-one O-(4-nitrophenyl)oxime to the base is 1:1, the molar ratio of spiro[3.5]nonane-2-one O-(4-nitrophenyl)oxime to N-benzyl-9H-fluorene-9-imine is 1:2, and the molar volume ratio of spiro[3.5]nonane-2-one O-(4-nitrophenyl)oxime to acetonitrile is 1 mol:10 mL.

[0159] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50° C., vacuum degree 180 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0160] The aminoalkyl nitrile compound prepared in this example, 2-(1-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethyl)cyclohexyl)acetonitrile, is denoted as compound 10, and its structure is shown in K:

[0161]

[0162] The hydrogen nuclear magnetic resonance spectrum of 2-(1-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethyl)cyclohexyl)acetonitrile in this example is:

[0163] 1 H NMR(400MHz,Chloroform-d)δ7.88(d,J=7.2Hz,1H),7.64(d,J=7.6Hz,1H),7.55(d,J=7.6H z,1H),7.50(d,J=7.2Hz,1H),7.37-7.34(m,3H),7.31-7.27(m,2H),7.23(t,J=7.6Hz,2H), 7.14-7.09(m,2H),5.60(dd,J=10.4,2.4Hz,1H),2.51-2.44(m,2H),2.28(d,J=16.4Hz,1H) ,2.04(dd,J=14.8,2.0Hz,1H),1.53-1.45(m,4H),1.43-1.36(m,4H),1.31-1.23(m,2H)ppm.

[0164] The carbon NMR spectrum of 2-(1-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethyl)cyclohexyl)acetonitrile in this example is:

[0165] 13 C NMR(100MHz,Chloroform-d)δ161.7,144.0,143.0,140.0,137.6,130.3,130.2,130.1,127.7,127.6,127.1 ,126.4,125.9,125.6,121.9,119.4,118.3,118.0,60.5,46.7,35.7,34.8,33.9,26.9,24.7,20.6,20.4ppm.

[0166] In this example, 2-(1-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethyl)cyclohexyl)acetonitrile was a colorless oily liquid with a yield of 90%. HRMS calculated for C 29 H 29 N2 + :405.2325,found:found:405.2323[M+H] + .

[0167] Embodiment 11

[0168] This example prepares an aminoalkyl nitrile compound, 5-((9H-fluorene-9-ylidene)amino)-3,3,5-triphenylpentanenitrile, and the specific steps are as follows:

[0169] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-benzyl-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a solution of 3,3-diphenylcyclobutane-1-one O-(4-nitrophenyl)oxime dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of 3,3-diphenylcyclobutane-1-one O-(4-nitrophenyl)oxime to the base is 1:1, the molar ratio of 3,3-diphenylcyclobutane-1-one O-(4-nitrophenyl)oxime to N-benzyl-9H-fluorene-9-imine is 1:2, and the molar volume ratio of 3,3-diphenylcyclobutane-1-one O-(4-nitrophenyl)oxime to acetonitrile is 1 mol:10 mL.

[0170] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50° C., vacuum degree 180 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0171] The aminoalkyl nitrile compound prepared in this example, 5-((9H-fluorene-9-ylidene)amino)-3,3,5-triphenylpentanenitrile, is denoted as compound 11, and its structure is shown in formula L:

[0172]

[0173] The hydrogen nuclear magnetic resonance spectrum of 5-((9H-fluorene-9-ylidene)amino)-3,3,5-triphenylpentanenitrile in this example is:

[0174] 1H NMR(600MHz,Chloroform-d)δ7.93(d,J=7.2Hz,1H),7.51-7.49(m,2H),7.38(t ,J=7.2Hz,1H),7.31(t,J=7.2Hz,1H),7.23-7.18(m,8H),7.17-7.15(m,3H),7.0 7-7.05(m,3H),6.92-6.91(m,2H),6.86-6.83(m,2H),4.96(dd,J=9.6,2.4Hz,1 H), 3.44-3.39 (m, 2H), 2.93 (d, J = 15.6Hz, 1H), 2.72 (dt, J = 13.8, 1.8Hz, 1H) ppm.

[0175] The carbon NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-3,3,5-triphenylpentanenitrile in this example is:

[0176] 13 C NMR(150MHz,Chloroform-d)δ162.1,146.1,143.5,143.2,142.6,140.0,137.5,130.2,130.1,127.6,127.5,127.3,12 6.71,126.67,126.3,126.2,126.03,125.99,125.7,125.6,121.9,119.0,118.3,117.7,61.2,48.3,47.8,28.9ppm(two resonanceswere not observed due to overlappingpeaks).

[0177] In this example, 5-((9H-fluorene-9-ylidene)amino)-3,3,5-triphenylpentanenitrile was a colorless oily liquid with a yield of 78%. HRMS calculated for C 36 H 29 N2 + :489.2325,found:489.2322[M+H] + .

[0178] Example 12

[0179] This example prepares an aminoalkyl nitrile compound, 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethoxy)acetonitrile, and the specific steps are as follows:

[0180] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-(cyclobutylmethyl)-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a solution of oxetane-3-one O-(4-nitrophenyl)oxime dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein the molar ratio of oxetane-3-one O-(4-nitrophenyl)oxime to the base is 1:1, the molar ratio of oxetane-3-one O-(4-nitrophenyl)oxime to N-(cyclobutylmethyl)-9H-fluorene-9-imine is 1:2, and the molar volume ratio of oxetane-3-one O-(4-nitrophenyl)oxime to acetonitrile is 1 mol:10 mL.

[0181] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring conditions for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50° C., vacuum degree 170 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0182] The aminoalkyl nitrile compound prepared in this example, 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethoxy)acetonitrile, is denoted as compound 12, and its structure is shown in formula M:

[0183]

[0184] The nuclear magnetic resonance hydrogen spectrum of 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethoxy)acetonitrile in this example is:

[0185] 1 H NMR(400MHz,Chloroform-d)δ7.93(d,J=7.6Hz,1H),7.76(d,J=7.6Hz,1H),7.60 (d,J=7.6Hz,1H),7.52(d,J=7.6Hz,1H),7.35(q,J=7.2Hz,2H),7.25-7.18(m,2H) ,4.79(td,J=7.2,4.0Hz,1H),4.22-4.11(m,2H),3.83(dd,J=9.2,4.0Hz,1H),3. 68(t,J=8.4Hz,1H),2.76-2.68(m,1H),2.00-1.79(m,5H),1.77-1.70(m,1H)ppm.

[0186] The carbon NMR spectrum of 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethoxy)acetonitrile in this example is:

[0187] 13 C NMR(100MHz,Chloroform-d)δ161.9,143.0,139.8,137.7,131.3,130.2,129.9,127.2, 126.9,126.5,121.8,119.3,118.2,115.1,73.1,63.3,55.7,37.3,24.1,23.4,17.6ppm.

[0188] In this example, 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethoxy)acetonitrile was a colorless oily liquid with a yield of 95%. HRMS calculated for C 21 H 21 N2O + :317.1648,found:found:317.1645[M+H] + .

[0189] Example 13

[0190] This example prepares an aminoalkyl nitrile compound, 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethyl)benzonitrile, and the specific steps are as follows:

[0191] (1) In a nitrogen atmosphere, potassium tert-butoxide and N-(cyclobutylmethyl)-9H-fluorene-9-imine are dissolved in anhydrous acetonitrile, and a solution of (E)-bicyclo[4.2.0]octa-1,3,5-triene-7-one O-(4-nitrophenyl)oxime dissolved in acetonitrile is added at room temperature to obtain a reaction system; wherein (E)-bicyclo[4.2.0]octa-1,3,5-triene-7-one O-(4-nitrophenyl)oxime is dissolved in acetonitrile to obtain a reaction system; The molar ratio of (E)-bicyclo[4.2.0]oct-1,3,5-triene-7-one O-(4-nitrophenyl)oxime to the base is 1:1, the molar ratio of (E)-bicyclo[4.2.0]oct-1,3,5-triene-7-one O-(4-nitrophenyl)oxime to N-(cyclobutylmethyl)-9H-fluorene-9-imine is 1:2, and the molar volume ratio of (E)-bicyclo[4.2.0]oct-1,3,5-triene-7-one O-(4-nitrophenyl)oxime to acetonitrile is 1 mol:10 mL.

[0192] (2) The reaction system of step (1) is sealed in a nitrogen atmosphere, reacted at room temperature under stirring for 2 hours, saturated brine is added to quench the reaction, extracted with ethyl acetate, the organic phase is washed with saturated brine three times, and then the organic phase is dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50° C., vacuum degree 180 Torr, time 20 min), the solvent is removed, and deactivated silica gel column chromatography is performed to obtain an aminoalkyl nitrile compound; wherein the solvent for the column chromatography is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:10.

[0193] The aminoalkyl nitrile compound prepared in this example, 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethyl)benzonitrile, is denoted as compound 13, and its structure is shown in formula N:

[0194]

[0195] The hydrogen nuclear magnetic resonance spectrum of 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethyl)benzonitrile in this example is:

[0196] 1 H NMR(400MHz,Chloroform-d)δ7.77(t,J=7.2Hz,2H),7.48(d,J=7.6Hz,1H),7.43(d,J=7.2Hz,1H),7 .39(d,J=7.6Hz,1H),7.30(t,J=7.2Hz,1H),7.23(q,J=6.8Hz,2H),7.16(d,J=4.4Hz,2H),7.10(t,J= 7.6Hz,1H),7.03-6.98(m,1H),4.89(td,J=8.4,3.2Hz,1H),3.27(dd,J=13.2,3.2Hz,1H),3.02(dd, J=13.2,9.2Hz,1H),2.81-2.71(m,1H),2.06-1.99(m,1H),1.94-1.79(m,4H),1.76-1.68(m,1H)ppm.

[0197] The carbon NMR spectrum of 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethyl)benzonitrile in this example:

[0198] 13C NMR(100MHz,Chloroform-d)δ160.4,142.7,142.6,139.5,137.6,131.5,131.24,131.16,130.1,129.8,129 .6,127.1,126.8,125.9,125.5,121.8,119.1,118.0,117.4,111.7,64.7,40.5,38.3,24.3,23.8,17.1ppm.

[0199] In this example, 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethyl)benzonitrile is a colorless oily liquid with a yield of 96%. HRMS calculated for C 26 H 23 N2 + :363.1856,found:363.1853[M+H] + .

[0200] It can be seen from the above examples that the preparation method provided by the present invention does not require transition metals and photoredox catalysts, is green, efficient, and sustainable for preparing aminoalkyl nitrile compounds. It is simple to operate, environmentally friendly, and the product is easy to purify. It has excellent functional group compatibility and high yield.

[0201] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing an aminoalkyl nitrile compound, characterized in that: The following steps are involved: The cyclobutanone oxime compound, the N-fluorenyl imine compound, the organic solvent and the base are mixed in a protective atmosphere to carry out a free radical coupling reaction to obtain the aminoalkyl nitrile compound.

2. The preparation method according to claim 1, characterized in that: The cyclobutanone oxime compound includes one or more of cyclobutanone O-(4-nitrophenyl) oxime, oxetane-3-one O-(4-nitrophenyl) oxime, spiro[3.5]nonane-2-one O-(4-nitrophenyl) oxime, 3,3-diphenylcyclobutane-1-one O-(4-nitrophenyl) oxime and (E)-bicyclo[4.2.0]octa-1,3,5-triene-7-one O-(4-nitrophenyl) oxime.

3. The preparation method according to claim 1, characterized in that: The N-fluorenyl imine compound includes one or more of N-benzyl-9H-fluorene-9-imine, N-(pyridin-3-ylmethyl)-9H-fluorene-9-imine, N-(thiophene-2-ylmethyl)-9H-fluorene-9-imine, N-(furan-2-ylmethyl)-9H-fluorene-9-imine, N-(2-(1-methyl-1H-indol-3-yl)ethyl)-9H-fluorene-9-imine, N-ethyl-9H-fluorene-9-imine, N-(cyclobutylmethyl)-9H-fluorene-9-imine and N-(cyclohexylmethyl)-9H-fluorene-9-imine.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of the cyclobutanone oxime compound to the N-fluorenyl imine compound is 1:1-2.

5. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the cyclobutanone oxime compound to the base is 1:1-2.

6. The preparation method according to any one of claims 1 to 3, characterized in that: The free radical coupling reaction is carried out under closed conditions; the free radical coupling reaction is carried out under stirring conditions; the temperature of the free radical coupling reaction is room temperature, and the reaction time is 1 to 12 hours.

7. The preparation method according to claim 1, characterized in that: After the free radical coupling reaction, the free radical coupling reaction system is quenched and then post-processed; the post-processing is: diluting the quenched reaction system and then sequentially performing extraction, organic phase washing, organic phase drying, solid-liquid separation, solvent removal and purification.

8. The aminoalkyl nitrile compound obtained by the preparation method according to any one of claims 1 to 7, characterized in that: The structure is shown in Formula I: In formula I, R is an alkyl group, an aryl group or a heterocyclic group, and X is C, N or O.

9. The aminoalkyl nitrile compound according to claim 8, characterized in that In formula I, the alkyl group includes a straight-chain alkyl group, a branched-chain alkyl group or a cyclic alkyl group; the aryl group is a substituted phenyl group; and the heterocyclic group includes a furyl group, a pyridyl group, a thienyl group, a piperonyl group or a tryptamine group.

10. Use of the aminoalkyl nitrile compound according to claim 9 in the field of biomedicine.

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