An aminoalkyl nitrile compound, its preparation method and application

Abstract

This invention belongs to the field of organic synthesis technology, specifically relating to an aminoalkyl nitrile compound, its preparation method, and its applications. Using N-fluorenylimine and cyclobutanone oxime compounds as raw materials, and simultaneously introducing a base and organic solvent, this invention facilitates imine ring-opening / radical coupling to prepare aminoalkyl nitrile compounds. This method requires no transition metals or photoredox catalysts, making it a green, efficient, and sustainable method for preparing aminoalkyl nitrile compounds. The preparation method provided by this invention is simple to operate, environmentally friendly, and the product is easily purified. It exhibits excellent functional group compatibility, generally high yields, and can be used for gram-scale compound preparation. This invention also provides aminoalkyl nitrile compounds obtained by the above-described preparation method. The aminoalkyl nitrile compounds provided by this invention are low in cost and have good safety.

Description

Technical Field

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

[0002] Aminoalkyl nitrile compounds are important structural units in organic synthesis and medicinal chemistry. These units are widely found in various bioactive natural products and drug molecules, and their advantages make them irreplaceable in medicinal chemistry. Furthermore, the cyano group, as an important functional group in organic synthesis, can be readily converted into aldehydes, ketones, amides, and carboxylic acids, thus attracting considerable attention and research from 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; diphenhydramine, as an antidiarrheal, is suitable for acute and chronic functional diarrhea and chronic enteritis; vildagliptin, as a DPP-4 enzyme inhibitor, is used to stimulate pancreatic β-cells to produce insulin, lower blood glucose levels, and treat diabetes; and piperonitrile amide, as an opioid receptor agonist, is used to treat postoperative pain.

[0004] For many years, organic synthetic chemists have been searching for new and effective methods to construct aminocyanide compounds. However, current methods often involve harsh conditions, such as the use of toxic tin reagents (Bu3SnH / AIBN), which reduces the safety of the products; and the use of transition metal (Pd, Ni, Cu, Fe, etc.) catalysis or photo-redox / metal dual catalysis at high temperatures, but most transition metal catalysts are also toxic. Summary of the Invention

[0005] The purpose of this invention is to provide an aminoalkyl nitrile compound, its preparation method, and its application. The preparation method provided by this invention enables the green synthesis of aminoalkyl nitrile compounds.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] This invention provides a method for preparing aminoalkyl nitrile compounds, comprising the following steps:

[0008] The cyclobutanone oxime compound, N-fluorenylimine compound, organic solvent and base were mixed in a protective atmosphere and subjected to 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, oxepane-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]octyl-1,3,5-trien-7-one O-(4-nitrophenyl)oxime.

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

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

[0012] Preferably, the molar ratio of the cyclobutanone oxime compound to the base is 1:1 to 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, the free radical coupling reaction further includes quenching the free radical coupling reaction system and then performing post-treatment; the post-treatment is as follows: diluting the quenched reaction system and then sequentially performing extraction, organic phase washing, organic phase drying, solid-liquid separation, solvent removal, and purification.

[0015] This invention also provides an aminoalkyl nitrile compound obtained by the preparation method described above, with the structure shown in Formula I:

[0016]

[0017] In Formula I, R is an alkyl, aryl, or 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 alkyl group, or a cyclic alkyl group; the aryl group is a substituted phenyl group; and the heterocyclic group includes furanyl, pyridyl, thiophenyl, piperyl, or tryptamine.

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

[0020] This invention provides a method for preparing aminoalkyl nitrile compounds. Using N-fluorenylimine compounds and cyclobutanone oxime compounds as raw materials, and simultaneously introducing a base and an organic solvent, this invention facilitates imine ring-opening / radical coupling to prepare aminoalkyl nitrile compounds. This method is green, efficient, and sustainable, requiring no transition metals or photoredox catalysts. The preparation method provided by this invention is simple to operate, environmentally friendly, and the products are easily purified. It exhibits excellent functional group compatibility, generally high yields, and can be used for gram-scale compound preparation.

[0021] This invention also provides aminoalkyl nitrile compounds prepared by the above-described method. The aminoalkyl nitrile compounds provided by this invention are low in cost, have good safety, and exhibit good functional group compatibility.

[0022] This invention also provides the application of the aminoalkyl nitrile compounds described above in the biomedical field. The aminoalkyl nitrile compounds provided by this invention can be used in the biomedical field and have broad application prospects. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

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

[0025] Figure 2 The process flow diagram illustrates the preparation method of aminoalkyl nitrile compounds provided by this invention. Detailed Implementation

[0026] This invention provides a method for preparing aminoalkyl nitrile compounds, comprising the following steps:

[0027] The cyclobutanone oxime compound, N-fluorenylimine compound, organic solvent and base were mixed in a protective atmosphere and subjected to a free radical coupling reaction to obtain the aminoalkyl nitrile compound.

[0028] In this invention, a cyclobutanone oxime compound, an N-fluorenylimine compound, an organic solvent, and a base are mixed in a protective atmosphere (referred to as the first mixture). In this invention, the cyclobutanone oxime compound preferably includes one or more of the following: cyclobutanone O-(4-nitrophenyl)oxime, oxepane-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]octyl-1,3,5-trien-7-one O-(4-nitrophenyl)oxime.

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

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

[0031] In this 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 this invention, the alkali 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 to 2, specifically 1:1.2, 1:1.4, 1:1.6 or 1:1.8.

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

[0034] In this invention, the temperature of the first mixing is preferably room temperature; the first mixing is preferably: mixing an alkali, an N-fluorenylimine compound and a portion of an organic solvent to obtain a premix, mixing the remaining portion of the organic solvent and a cyclobutanone oxime compound to obtain a cyclobutanone oxime compound solution, and then adding the premix to the cyclobutanone oxime compound solution.

[0035] After mixing, the resulting mixture is subjected to a free radical coupling reaction to obtain the aminoalkyl nitrile compound. In this invention, the free radical coupling reaction is carried out under a protective atmosphere; preferably, the protective atmosphere is nitrogen; the free radical coupling reaction is preferably carried out under closed conditions; 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 1–12 h, specifically 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, or 12 h. The preparation method provided by this invention has mild reaction conditions, which is conducive to safe production. The specific reaction mechanism is as follows: Figure 1 As shown.

[0036] In this invention, the free radical coupling reaction preferably includes a post-treatment process after quenching the free radical coupling reaction system; the quenching reagent is preferably saturated saline solution.

[0037] In this invention, the post-processing is preferably performed by 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 this invention, the diluent is preferably ethyl acetate; the dilution factor is preferably 1 to 4 times, specifically 2 times.

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

[0040] In this invention, the reagent used for washing the organic phase is preferably saturated saline solution; the number of washing cycles is preferably three or more, specifically three times.

[0041] In this invention, the drying of the organic phase is preferably carried out using anhydrous sodium sulfate.

[0042] In this invention, the solid-liquid separation is preferably performed by filtration.

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

[0044] In this invention, the purification is preferably performed by column chromatography; the column chromatography is preferably performed by inactivated silica gel column chromatography; the solvent for the column chromatography is preferably petroleum ether-ethyl acetate; and the volume ratio of petroleum ether to ethyl acetate is preferably 1:8 to 10.

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

[0046] This invention also provides an aminoalkyl nitrile compound obtained by the preparation method described above, with the structure shown in Formula I:

[0047]

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

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

[0050] In this 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 this invention, the aryl group in Formula I is preferably o-methylphenyl or 1-naphthylphenyl.

[0052] In this invention, the heterocyclic group in Formula I preferably includes furanyl, pyridyl, thiophene, piperyl or tryptamine.

[0053] In this invention, the aminoalkyl nitrile compounds preferably include 5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanilide, 5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)pentanilide, 5-((9H-fluorene-9-ylidene)amino)-5-(thiophen-2-yl)pentanilide, 5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanilide, 5-((9H-fluorene-9-ylidene)amino)-6-(1-methyl-1H-indol-3-yl)hexanolyl, 5-((9H-fluorene-9-ylidene)amino)hexanolyl, and aminoalkyl nitrile compounds 5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanilide. One of the following: 5-((9H-fluorene-9-ylidene)amino)-5-cyclobutylpentanonitrile, 5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanonitrile, 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-triphenylpentanonitrile, 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 above in the biomedical field.

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

[0056] To further illustrate the present invention, the following detailed description of the invention's solutions, in conjunction with the accompanying drawings and embodiments, is provided, but should not be construed as limiting the scope of protection of the present invention.

[0057] Example 1

[0058] This embodiment prepares an aminoalkyl nitrile compound—5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanilide—using the following specific steps:

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

[0060] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50℃, vacuum degree 180 Torr, time 10 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0061] The aminoalkyl nitrile compound prepared in this embodiment—5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanilide, denoted as compound 1, has the structure shown in formula A:

[0062]

[0063] The 1H NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-phenylpentanilide in this example:

[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-phenylpentanilide 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-phenylpentanilonitrile was a colorless oily liquid with a yield of 95%. HRMS calculation for C 24H 21 N2 + :337.1699,found:337.1698[M+H] + .

[0068] Example 2

[0069] This embodiment prepares an aminoalkyl nitrile compound—5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)pentanilonitrile, 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 were dissolved in anhydrous acetonitrile. At room temperature, a solution of cyclobutanone O-(4-nitrophenyl)oxime dissolved in anhydrous acetonitrile was added to obtain a reaction system. The molar ratio of cyclobutanone O-(4-nitrophenyl)oxime to the base was 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl)oxime to N-(pyridin-3-ylmethyl)-9H-fluorene-9-imine was 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl)oxime to acetonitrile was 1 mol: 10 mL.

[0071] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 40℃, vacuum degree 180 Torr, time 20 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0072] The aminoalkyl nitrile compound prepared in this embodiment—5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)pentanilonitrile, denoted as compound 2, has the structure shown in formula B:

[0073]

[0074] The 1H NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-(pyridin-3-yl)valerate in this example is as follows:

[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)valerate in this example:

[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)valerate was a white oily liquid with a yield of 82%. HRMS calculation for C 23 H 20 N3 + :338.1652,found:338.1648[M+H] + .

[0079] Example 3

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

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

[0082] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 45℃, vacuum degree 175 Torr, time 15 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0083] The aminoalkyl nitrile compound prepared in this embodiment—5-((9H-fluorene-9-ylidene)amino)-5-(thiophene-2-yl)pentanilide, denoted as compound 3, has the structure shown in formula C:

[0084]

[0085] The 1H NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-(thiophene-2-yl)pentanilide in this example:

[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-(thiophene-2-yl)valerate in this example:

[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-(thiophene-2-yl)pentanonitrile was a white oily liquid with a yield of 96%. HRMS calculation for C 22 H 19 N2S + :343.1263,found:343.1266[M+H] + .

[0090] Example 4

[0091] This embodiment prepares an aminoalkyl nitrile compound—5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanilonitrile, 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 were dissolved in anhydrous acetonitrile. At room temperature, a solution of cyclobutanone O-(4-nitrophenyl)oxime dissolved in acetonitrile was added to obtain a reaction system. The molar ratio of cyclobutanone O-(4-nitrophenyl)oxime to the base was 1:1, the molar ratio of cyclobutanone O-(4-nitrophenyl)oxime to N-(furan-2-ylmethyl)-9H-fluorene-9-imine was 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl)oxime to acetonitrile was 1 mol: 10 mL.

[0093] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50℃, vacuum degree 180 Torr, time 20 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0094] The aminoalkyl nitrile compound prepared in this embodiment—5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanilonitrile, denoted as compound 4, has the structure shown in formula D:

[0095]

[0096] The 1H NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-(furan-2-yl)pentanonitrile in this example is as follows:

[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)pentanonitrile in this example:

[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)pentanilonitrile was a colorless oily liquid with a yield of 93%. HRMS calculation for C 22 H 19 N2O + :327.1492,found:327.1491[M+H] + .

[0101] Example 5

[0102] This embodiment prepares an aminoalkyl nitrile compound—5-((9H-fluorene-9-ylidene)amino)-6-(1-methyl-1H-indol-3-yl)hexanonitrile, 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 were dissolved in anhydrous acetonitrile. At room temperature, a solution of cyclobutanone O-(4-nitrophenyl)oxime dissolved in acetonitrile was added to obtain a reaction system. The molar ratio of cyclobutanone O-(4-nitrophenyl)oxime to the base was 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 was 1:2, and the molar volume ratio of cyclobutanone O-(4-nitrophenyl)oxime to acetonitrile was 1 mol: 10 mL.

[0104] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 40℃, vacuum degree 170 Torr, time 20 min) to remove the solvent. The solvent was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

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

[0106]

[0107] The 1H NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-6-(1-methyl-1H-indol-3-yl)hexanonitrile in this example:

[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)hexanonitrile in this example:

[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 calculation for C 28 H 26 N3 + :404.2121,found:404.2124[M+H] + .

[0112] Example 6

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

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

[0115] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50℃, vacuum degree 180 Torr, time 20 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0116] The aminoalkyl nitrile compound prepared in this embodiment—5-((9H-fluorene-9-ylidene)amino)hexanonitrile, denoted as compound 6, has the structure shown in formula F:

[0117]

[0118] The 1H NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)hexanonitrile in this example:

[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)hexanonitrile 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)hexanonitrile was a colorless oily liquid with a yield of 96%, calculated using HRMS calculations for C. 19 H 19 N2 + :275.1543,found:275.1542[M+H] + .

[0123] Example 7

[0124] This embodiment prepares an aminoalkyl nitrile compound—5-((9H-fluorene-9-ylidene)amino)-5-cyclobutylpentanonitrile—the specific steps of which are as follows:

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

[0126] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 42℃, vacuum degree 172 Torr, time 15 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0127] The aminoalkyl nitrile compound prepared in this embodiment—5-((9H-fluorene-9-ylidene)amino)-5-cyclobutylpentanilide, denoted as compound 7, has the structure shown in formula G:

[0128]

[0129] The 1H NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-cyclobutylpentanilonitrile in this example:

[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-cyclobutylpentanilonitrile 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-cyclobutylpentanilide was a colorless oily liquid with a yield of 96%. HRMS calculation for C 22 H 23 N2 + :315.1856,found:315.1851[M+H] + .

[0134] Example 8

[0135] This embodiment prepares an aminoalkyl nitrile compound—5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanilonitrile—using the following specific steps:

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

[0137] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50℃, vacuum degree 180 Torr, time 20 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0138] The aminoalkyl nitrile compound prepared in this embodiment—5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanilide, denoted as compound 8, has the structure shown in formula H:

[0139]

[0140] The 1H NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-5-cyclohexylpentanilide in this example:

[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-cyclohexylpentanilide in this example:

[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-cyclohexylpentanilonitrile was a colorless oily liquid with a yield of 93%. HRMS calculation for C 24 H 27 N2 + :343.2169,found:343.2165[M+H] + .

[0145] Example 9

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

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

[0148] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 40℃, vacuum degree 170 Torr, time 20 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:8.

[0149] The aminoalkyl nitrile compound prepared in this embodiment—2-(2-((9H-fluorene-9-ylidene)amino)-2-phenethoxy)acetonitrile, denoted as compound 9, has the structure shown in formula J:

[0150]

[0151] The 1H NMR spectrum of 2-(2-((9H-fluorene-9-ylidene)amino)-2-phenethoxy)acetonitrile in this example is as follows:

[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-phenethoxy)acetonitrile in this example:

[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-phenethoxy)acetonitrile was a colorless oil with a yield of 92%. HRMS calculation for C 23 H 19 N2O + :339.1492,found:339.1491[M+H] + .

[0156] Example 10

[0157] This embodiment 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 were dissolved in anhydrous acetonitrile. At room temperature, a solution of spiro[3.5]nonane-2-one O-(4-nitrophenyl)oxime dissolved in acetonitrile was added to obtain a reaction system. The molar ratio of spiro[3.5]nonane-2-one O-(4-nitrophenyl)oxime to the base was 1:1, the molar ratio of spiro[3.5]nonane-2-one O-(4-nitrophenyl)oxime to N-benzyl-9H-fluorene-9-imine was 1:2, and the molar volume ratio of spiro[3.5]nonane-2-one O-(4-nitrophenyl)oxime to acetonitrile was 1 mol: 10 mL.

[0159] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50℃, vacuum degree 180 Torr, time 20 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0160] The aminoalkyl nitrile compound prepared in this embodiment—2-(1-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethyl)cyclohexyl)acetonitrile, denoted as compound 10, has the structure shown in K:

[0161]

[0162] The 1H NMR spectrum of 2-(1-(2-((9H-fluorene-9-ylidene)amino)-2-phenylethyl)cyclohexyl)acetonitrile in this example:

[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:

[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 calculation for C 29 H 29 N2 + :405.2325,found:found:405.2323[M+H] + .

[0167] Example 11

[0168] This embodiment prepares an aminoalkyl nitrile compound—5-((9H-fluorene-9-ylidene)amino)-3,3,5-triphenylpentanilonitrile—through the following specific steps:

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

[0170] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50℃, vacuum degree 180 Torr, time 20 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0171] The aminoalkyl nitrile compound prepared in this embodiment—5-((9H-fluorene-9-ylidene)amino)-3,3,5-triphenylpentanilide, denoted as compound 11, has the structure shown in formula L:

[0172]

[0173] The 1H NMR spectrum of 5-((9H-fluorene-9-ylidene)amino)-3,3,5-triphenylpentanilide in this example:

[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-triphenylpentanilide in this example:

[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-triphenylpentanilonitrile was a colorless oily liquid with a yield of 78%. HRMS calculation for C 36 H 29 N2 + :489.2325,found:489.2322[M+H] + .

[0178] Example 12

[0179] This embodiment 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 were dissolved in anhydrous acetonitrile. At room temperature, a solution of oxetane-3-one O-(4-nitrophenyl)oxime dissolved in acetonitrile was added to obtain a reaction system. The molar ratio of oxetane-3-one O-(4-nitrophenyl)oxime to the base was 1:1, the molar ratio of oxetane-3-one O-(4-nitrophenyl)oxime to N-(cyclobutylmethyl)-9H-fluorene-9-imine was 1:2, and the molar volume ratio of oxetane-3-one O-(4-nitrophenyl)oxime to acetonitrile was 1 mol: 10 mL.

[0181] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50℃, vacuum degree 170 Torr, time 20 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0182] The aminoalkyl nitrile compound prepared in this embodiment—2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethoxy)acetonitrile, denoted as compound 12, has the structure shown in formula M:

[0183]

[0184] The 1H NMR spectrum of 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethoxy)acetonitrile in this example:

[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:

[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 calculation for C 21 H 21 N2O + :317.1648,found:found:317.1645[M+H] + .

[0189] Example 13

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

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

[0192] (2) The reaction system of step (1) was sealed in a nitrogen atmosphere and reacted at room temperature with stirring for 2 hours. The reaction was quenched by adding saturated brine, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was then dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure (temperature 50℃, vacuum degree 180 Torr, time 20 min) to remove the solvent. The aminoalkyl nitrile compound was obtained by deactivated silica gel column chromatography. The solvent for column chromatography was petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 1:10.

[0193] The aminoalkyl nitrile compound prepared in this embodiment—2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethyl)benzonitrile, denoted as compound 13, has the structure shown in formula N:

[0194]

[0195] The 1H NMR spectrum of 2-(2-((9H-fluorene-9-ylidene)amino)-2-cyclobutylethyl)benzonitrile in this example:

[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 was a colorless oily liquid with a yield of 96%. HRMS calculation for C 26 H 23 N2 + :363.1856,found:363.1853[M+H] + .

[0200] As can be seen from the above embodiments, the preparation method provided by the present invention does not require transition metals and photo-redox catalysts, is green, efficient, and sustainable for the preparation of aminoalkyl nitrile compounds, is simple to operate, environmentally friendly, the product is easy to purify, has excellent functional group compatibility, and has a high yield.

[0201] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for producing an aminoalkylnitrile compound, characterized by, Includes the following steps: Cyclobutanone oxime compounds, N-fluorenylimine compounds, organic solvents, and bases were mixed in a protective atmosphere and subjected to a free radical coupling reaction to obtain the aminoalkyl nitrile compounds; The cyclobutanone oxime compounds are selected from one or more of cyclobutanone O-(4-nitrophenyl)oxime, oxacyclobutane-3-one O-(4-nitrophenyl)oxime, spiro[3.5]nonane-2-one O-(4-nitrophenyl)oxime and 3,3-diphenylcyclobutane-1-one O-(4-nitrophenyl)oxime; The N-fluorenylimine compounds are selected from one or more of N-benzyl-9H-fluoren-9-imine, N-(pyridin-3-ylmethyl)-9H-fluoren-9-imine, N-(thiophen-2-ylmethyl)-9H-fluoren-9-imine, N-(furan-2-ylmethyl)-9H-fluoren-9-imine, N-(2-(1-methyl-1H-indol-3-yl)ethyl)-9H-fluoren-9-imine, N-ethyl-9H-fluoren-9-imine, N-(cyclobutylmethyl)-9H-fluoren-9-imine, and N-(cyclohexylmethyl)-9H-fluoren-9-imine; The reaction formula is as follows: 。 2. The production method according to claim 1, characterized by, The molar ratio of the cyclobutanone oxime compound to the N-fluorenylimine compound is 1:1~2.

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

4. The method of claim 1, wherein, 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 1~12 h.

5. The preparation method according to claim 1, characterized in that, The free radical coupling reaction further includes quenching the free radical coupling reaction system and then performing post-treatment; the post-treatment is as follows: diluting the quenched reaction system and then sequentially performing extraction, organic phase washing, organic phase drying, solid-liquid separation, solvent removal and purification.

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