Synthesis method of amine compound

Abstract

The invention provides a preparation method of an amine compound, and relates to synthesis and application of organic compounds, and the method comprises the following steps: carrying out coordination mediation effect on a deoxidizing reagent, alcohol and metal copper, and carrying out nucleophilic substitution reaction on the deoxidizing reagent and the amine compound to obtain various alkyl and alkylamine compounds. The preparation method comprises the following specific steps: adding an alcohol compound and an amine compound into a reaction tube, adding a copper catalyst, a deoxidizing reagent and a solvent into the reaction tube, and fully stirring for complete reaction to prepare various aminated products. The invention aims to develop a general synthesis method for efficiently obtaining various alkylamine and arylamine compounds by utilizing a cheap transition metal copper catalyst to react with commercially available raw materials such as alcohol, amine and a deoxidizing reagent. The synthesis method uses transition metal copper for catalysis, is efficient in reaction and diversified in product structure, and has the advantages of simplicity in operation, concise steps, high atom utilization rate, relatively stable chemical properties, low cost, easiness in purification and the like.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis and application of organic compounds, and in particular to a method for synthesizing amine compounds. Background Art

[0002] Amine compounds are products of one or more hydrogen atoms in the ammonia molecule being replaced by hydrocarbon groups. Amine compounds are widely present in the biological world and have extremely important physiological and biological activities. For example, proteins, nucleic acids, hormones, antibiotics and alkaloids are all derivatives of amines. Most drugs used clinically are also amines or amine derivatives. Amine compounds occupy an important position in the development of medicinal chemistry and life sciences. Therefore, the efficient construction of carbon-nitrogen bonds has always been one of the core research areas of organic synthetic chemistry.

[0003] Deoxygenation amination is one of the important methods for efficiently constructing amine compounds, such as Buchwald-Hartwig coupling, Ullman-Goldberg coupling and Chan-Evans-Lam coupling reactions, but the construction of C(sp3)-N bonds in the pharmaceutical field still faces huge challenges. In 2023, Wang Yi's research group successfully developed a nickel-catalyzed alkyl electrophilic C(sp3)-N coupling reaction. Using pre-prepared amine sources and alkyl halides as raw materials, aliphatic amines can be quickly synthesized under the action of nickel catalysts and equivalent zinc powder. In 2024, David W.C. MacMillan's research group at the Merck Catalysis Center at Princeton University in the United States developed a photocopper-catalyzed nitrogen-carbene deoxygenation amination strategy to achieve the synthesis of various amine compounds. Although this strategy provides a new route for the efficient synthesis of C(sp3)-N bonds, it requires the use of expensive and multi-step synthesis of nitrogen-carbene precursors and photocatalysts.

[0004] Alcohol is a natural resource with a very abundant content in nature. The direct and selective conversion of alcohol hydroxyl groups is particularly important in the field of organic synthesis, especially the deoxidation reaction of alcohols by cutting the CO bond. This method can convert alcohols or polyol compounds into amine compounds. At present, there are two common methods for alcohol deoxygenation: one is an indirect deoxidation strategy of converting alcohols into active intermediates and then reducing them, and the other is a metal-catalyzed direct deoxidation strategy. The metal-catalyzed deoxidation reaction of the prior art usually utilizes alcohol compounds to be converted into amine compounds, which requires the catalytic action of nickel, palladium, copper, etc. Its main technical route is to convert alcohol compounds into aldehyde / ketone compounds, which are then condensed with amine compounds to form imine compounds, and finally catalytically hydrogenated into amine compounds under the action of a catalyst. The reaction process requires pre-activation of alcohol compounds, cumbersome steps, and huge energy consumption.

[0005] The above prior art shows that the current use of transition metals to catalyze alcohol deoxygenation amination reactions has at least the following defects, such as the inevitable use of equivalent reducing agents or expensive catalysts, the need to pre-activate the reactants, cumbersome reaction steps, and complex reaction principles. Based on the defects of the prior art, the present invention discloses a more efficient and convenient, safe operation, easy-to-obtain catalyst, and no need for pre-activation alcohol deoxygenation amination reaction strategy, which can greatly reduce energy loss and environmental pollution. Summary of the invention

[0006] 1. Technical issues to be resolved

[0007] In view of the above problems, the present invention provides a method for synthesizing amine compounds, which can achieve efficient alcohol deoxygenation amination reaction with the help of a copper catalyst. The method has the advantages of simple operation, efficient reaction, diverse product structures, high atom utilization, relatively stable chemical properties, low cost, easy purification, etc. It has a wider substrate range and functional group applicability, and can achieve efficient conversion from alcohol compounds to amine compounds in one step.

[0008] (II) Technical solution

[0009] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0010] The synthetic method of amine compounds comprises the following specific steps:

[0011] Adding an alcohol compound as shown in Formula 1 and an amine compound as shown in Formula 2 into a reaction tube, and then adding a copper catalyst, a deoxidation agent and a solvent into the reaction tube, and after sufficient stirring and complete reaction, an amination product as shown in Formula 3 can be obtained;

[0012] The reaction equation is as follows:

[0013]

[0014] Wherein, Formula 1 is an alkyl alcohol compound, R 1 , R 2 , R 3 is any one or a combination of hydrogen, heteroaryl, halogen, alkyl, carbonyl, ether bond, ester, carboxyl, aldehyde, cyano, alkenyl, alkynyl, and imine, R 1 , R 2 , R 3 The groups represented may be identical or non-identical or completely different.

[0015] Wherein, Formula 2 is a heteroarylamine compound or an alkylamine compound, and R is any one or a combination of hydrogen atom, heteroaryl group, halogen, hydroxyl, ether bond, ester group, nitro group, amine group, carboxyl group, aldehyde group, cyano group, alkenyl group, alkynyl group, and imine.

[0016] The reaction mechanism of this reaction is:

[0017]

[0018] In the reaction equation and reaction mechanism:

[0019] R 1 , R 2 , R 3 represents any one or a combination of hydrogen atom, heteroaryl, halogen, alkyl, carbonyl, ether bond, ester group, carboxyl, aldehyde group, cyano group, alkenyl, alkynyl, and imine, R 1 , R 2 , R 3 The groups represented may be identical or non-identical or completely different.

[0020] R includes, but is not limited to, any one or a combination of hydrogen atom, heteroaryl group, halogen, hydroxyl group, ether bond, ester group, nitro group, amine group, carboxyl group, aldehyde group, cyano group, alkenyl group, alkynyl group, and imine.

[0021] (III) Beneficial effects

[0022] The present invention provides a method for synthesizing amine compounds. Compared with the prior art, the method has the following beneficial effects:

[0023] 1. The preparation method of the amine compounds of the present invention is to obtain various alkylamines and arylamine compounds by the coordination mediation of the deoxygenation reagent with the alcohol and the metal copper, and then undergoing SN2 nucleophilic substitution reaction with the amine compound. The present invention aims to develop a general synthesis method that uses an inexpensive transition metal copper catalyst to react with commercially available alcohols, amines, deoxygenation reagents and other raw materials to efficiently obtain various alkylamines and arylamine compounds. The synthesis method of the present invention is catalyzed by transition metal copper, has efficient reaction, simple principle, and diverse product structures. It has the advantages of simple operation, concise steps, high atomic utilization, relatively stable chemical properties, low cost, and easy purification;

[0024] 2. The preparation method of the present invention can produce excellent catalytic effect by using only copper catalyst and no equivalent reducing agent in the catalytic process. The operation method of the present invention is simple, and the ideal product can be synthesized without pre-activating the raw materials, so it is easy to realize batch synthesis;

[0025] 3. The preparation method of the present invention is applicable to primary, secondary and tertiary alcohols and various amine substrates, has a wide range of substrate applicability, has good compatibility of reaction substrate functional groups, and can be used for the synthesis of natural drug molecules;

[0026] 4. In view of the core role of organic amine compounds in many fields such as drug development and materials science, the present invention has developed a highly efficient, environmentally friendly and highly selective copper-catalyzed alcohol deoxygenation amination reaction system, which has significant strategic significance for promoting scientific and technological progress in related fields. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] 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 or the description of the prior art 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.

[0028] Figure 1 For Example 1 of the present invention 1 H NMR spectrum;

[0029] Figure 2 For Example 2 of the present invention 1 H NMR spectrum;

[0030] Figure 3 For Example 3 of the present invention 1 H NMR spectrum;

[0031] Figure 4 For Example 4 of the present invention 1 H NMR spectrum;

[0032] Figure 5 For Example 5 of the present invention 1 H NMR spectrum;

[0033] Figure 6 For Example 6 of the present invention 1 H NMR spectrum;

[0034] Figure 7 For Example 7 of the present invention 1 H NMR spectrum;

[0035] Figure 8 For Example 8 of the present invention 1 H NMR spectrum. DETAILED DESCRIPTION

[0036] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] The present invention discloses a method for synthesizing amine compounds, wherein a deoxygenating agent is mediated by coordination with an alcohol and metal copper, and then undergoes an SN2 nucleophilic substitution reaction with the amine compound to obtain various alkylamine and arylamine compounds. The present invention aims to develop a general synthesis method that uses a cheap transition metal copper catalyst to react with commercially available alcohols, amines, deoxygenating agents and other raw materials to efficiently obtain various alkylamine and arylamine compounds.

[0038] The synthetic method of amine compounds comprises the following specific steps:

[0039] Adding an alcohol compound as shown in Formula 1 and an amine compound as shown in Formula 2 into a reaction tube, and then adding a copper catalyst, a deoxidation agent and a solvent into the reaction tube, and after sufficient stirring and complete reaction, an amination product as shown in Formula 3 can be obtained;

[0040] The reaction equation is as follows:

[0041]

[0042] Wherein, Formula 1 is an alkyl alcohol compound, R 1 , R 2 , R 3 is any one or a combination of hydrogen, heteroaryl, halogen, alkyl, carbonyl, ether bond, ester, carboxyl, aldehyde, cyano, alkenyl, alkynyl, and imine, R 1 , R 2 , R 3 The groups represented may be identical or non-identical or completely different.

[0043] Wherein, Formula 2 is a heteroarylamine compound or an alkylamine compound, and R is any one or a combination of hydrogen atom, heteroaryl group, halogen, hydroxyl, ether bond, ester group, nitro group, amine group, carboxyl group, aldehyde group, cyano group, alkenyl group, alkynyl group, and imine.

[0044] The reaction mechanism of this reaction is:

[0045]

[0046] Among them, R 1 , R 2 , R 3represents any one or a combination of hydrogen atom, heteroaryl, halogen, alkyl, carbonyl, ether bond, ester group, carboxyl, aldehyde group, cyano group, alkenyl, alkynyl, and imine, R 1 , R 2 , R 3 The groups represented may be identical or non-identical or completely different.

[0047] R includes, but is not limited to, any one or a combination of hydrogen atom, heteroaryl group, halogen, hydroxyl group, ether bond, ester group, nitro group, amine group, carboxyl group, aldehyde group, cyano group, alkenyl group, alkynyl group, and imine.

[0048] In some specific embodiments, the copper catalyst is a combination of one or more of cuprous chloride, cuprous bromide, cuprous iodide, 2-thiophene cuprous, cuprous trifluoromethanesulfonate, cuprous oxide, cuprous cyanide, cuprous thiocyanate, cuprous acetate, cupric chloride, cupric bromide, cupric iodide, cupric trifluoromethanesulfonate, cupric oxide, cupric acetate, cupric sulfate, and basic cupric carbonate.

[0049] In some specific embodiments, the amount of copper catalyst used is 5-100 mol %.

[0050] In some specific embodiments, the deoxygenation agent is selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), propylphosphonic anhydride (T3P), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (HBTU), hexafluorophosphate-1-[bis(dimethylamino)methyl]-3-ethyl-1H-1,2,3-triazole (HCTU), diphenylphosphoryl chloride (DPP-Cl), diphenylphosphoryl azide (DPPA), thiodimethylphosphoryl azide (MPTA), and bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl). One or more combinations thereof.

[0051] In some specific embodiments, the solvent is selected from one or more combinations of dichloromethane (DCM), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile (MeCN), ethyl acetate (EA), n-hexane (Hexane), ether (Ethor), acetone (Atcone), carbon tetrachloride (CCl4), toluene (Tolane), pyridine (Pydine), dimethyl sulfoxide (DMSO), and N,N-dimethylacetamide (DMAc).

[0052] In some specific embodiments, the mass ratio of the alcohol compound, the amine compound, the copper catalyst, and the deoxidation agent is 1:(1.0-3.0):(0.1-3.0):(1.0-5.0).

[0053] In some specific embodiments, the mixture of the alcohol compound, the amine compound, and the deoxygenation agent is diluted to 0.1M-0.3M using a solvent.

[0054] In some specific embodiments, the reaction temperature is 25-80°C.

[0055] In some specific embodiments, the reaction time is 0.5-4 h.

[0056] In some specific embodiments, during the preparation of the product, an inert gas protection is used or the reaction is carried out in air.

[0057] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with the accompanying drawings and specific implementation methods.

[0058] Embodiment 1:

[0059] The synthetic method of N-phenethylaniline is specifically as follows:

[0060] Depend on Figure 1 As shown in the reaction formula below, 0.1mmol of alcohol compound is added to an 8mL chemical reaction tube, 0.12mmol of aniline, cuprous chloride (0.2equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and dichloromethane (1mL) are added to the reaction tube in sequence, and the reaction tube is moved to a 60°C oil bath pot for reaction for 1 hour, during which TLC is used for reaction monitoring. After the reaction is complete, the reactant is transferred to a 50mL single-necked flask, and the solvent is removed using a rotary evaporator. The crude product is purified by silica gel column chromatography, and the eluent is petroleum ether and ethyl acetate in a volume ratio (10:1-2:1).

[0061] The reaction formula is:

[0062]

[0063] The reaction product is: N-phenylethylaniline

[0064]

[0065] 2H), 3.40 (t, J=7.0Hz, 3H), 2.91 (t, J=7.0Hz, 2H). 13 C NMR (101MHz, CDCl3): δ148.0,139.3,129.3,128.8,128.6,126.4,117.5,113.0,45.1,35.5.HRMS (ESI-TOF): calculated for C 14 H 16 N[M+H]+ :198.1277,found:198.1275.

[0066] Embodiment 2:

[0067] The synthesis method of N,N-dibenzylcycloheptylamine is specifically as follows:

[0068] Depend on Figure 2 As shown in the reaction formula below, 0.1mmol of alcohol compound is added to an 8mL chemical reaction tube, 0.12mmol of benzylamine, cuprous chloride (0.2equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and dichloromethane (1mL) are added to the reaction tube in sequence, and the reaction tube is moved to a 60°C oil bath pot for reaction for 1 hour, during which TLC is used for reaction monitoring. After the reaction is complete, the reactant is transferred to a 50mL single-necked flask and the solvent is removed using a rotary evaporator. The crude product is purified by silica gel column chromatography, and the eluent is petroleum ether and ethyl acetate in a volume ratio (50:1-10:1).

[0069] The reaction formula is:

[0070]

[0071] The reaction product is: N,N-dibenzylcycloheptylamine

[0072]

[0073] 2H),1.43(dt,J=10.4,4.6Hz,4H),1.36–1.18(m,2H). 13 C NMR (101MHz, CDCl3): δ141.1,128.5,128.1,126.5,59.0,53.8,30.1,28.2,25.9.HRMS (ESI-TOF): calculated forC 21 H 28 N[M+H]+:294.2222,found:294.2222.

[0074] Embodiment 3:

[0075] The synthetic method of N-phenylcyclooctylamine is specifically as follows:

[0076] Depend on Figure 3As shown in the reaction formula below, 0.1mmol of alcohol compound is added to an 8mL chemical reaction tube, 0.12mmol of aniline, cuprous chloride (0.2equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and dichloromethane (1mL) are added to the reaction tube in sequence, and the reaction tube is moved to a 60°C oil bath pot for reaction for 1 hour, during which TLC is used for reaction monitoring. After the reaction is complete, the reactant is transferred to a 50mL single-necked flask, and the solvent is removed using a rotary evaporator. The crude product is purified by silica gel column chromatography, and the eluent is petroleum ether and ethyl acetate in a volume ratio (10:1-2:1).

[0077] The reaction formula is:

[0078]

[0079] Reaction product: N-phenylcyclooctylamine

[0080]

[0081] 1.89(td,J=10.8,8.9,3.7Hz,2H),1.76–1.69(m,2H),1.62–1.51(m,10H). 13 C NMR (101MHz, CDCl3): δ147.3,129.3,116.8,113.4,52.6,32.7,27.2,26.0,24.1.HRMS (ESI-TOF): calculated for C 14 H 22 N[M+H] + :204.1747,found:204.1748.

[0082] Embodiment 4:

[0083] The synthesis method of N-(4,4-difluorocyclohexyl)aniline is specifically as follows:

[0084] Depend on Figure 4 As shown in the reaction formula below, 0.1mmol of alcohol compound is added to an 8mL chemical reaction tube, 0.12mmol of aniline, cuprous chloride (0.2equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and dichloromethane (1mL) are added to the reaction tube in sequence, and the reaction tube is moved to a 60°C oil bath pot for reaction for 1 hour, during which TLC is used for reaction monitoring. After the reaction is complete, the reactant is transferred to a 50mL single-necked flask, and the solvent is removed using a rotary evaporator. The crude product is purified by silica gel column chromatography, and the eluent is petroleum ether and ethyl acetate in a volume ratio (10:1-2:1).

[0085] The reaction formula is:

[0086]

[0087] Reaction product: N-(4,4-difluorocyclohexyl)aniline

[0088]

[0089] 1.52 (q, J = 11.6, 10.4 Hz, 2H). 13 C NMR (101MHz,CDCl3): 13 C NMR (101MHz, CDCl3) δ147.0, 129.5, 123.0 (t, J = 239Hz), 117.6, 113.3, 49.6, 32.1 (t, J = 25Hz), 28.9 (d, J = 5Hz). 19 F NMR (376MHz, CDCl3): δ-95.19 (d, J = 236.3Hz), -99.78 (d, J = 241.6Hz). HRMS (ESI-TOF): calculated for C 12 H 16 F2N[M+H] + :212.1245,found:212.1246.

[0090] Embodiment 5:

[0091] N-(4-(Benzo[d][1,3]dioxolan-5-yl)butan-2-yl)aniline, specifically:

[0092] Depend on Figure 5 As shown in the reaction formula below, 0.1mmol of alcohol compound is added to an 8mL chemical reaction tube, 0.12mmol of aniline, cuprous chloride (0.2equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and dichloromethane (1mL) are added to the reaction tube in sequence, and the reaction tube is moved to a 60°C oil bath pot for reaction for 1 hour, during which TLC is used for reaction monitoring. After the reaction is complete, the reactant is transferred to a 50mL single-necked flask, and the solvent is removed using a rotary evaporator. The crude product is purified by silica gel column chromatography, and the eluent is petroleum ether and ethyl acetate in a volume ratio (10:1-2:1).

[0093] The reaction formula is:

[0094]

[0095] Reaction product: N-(4-(Benzo[d][1,3]dioxolan-5-yl)butan-2-yl)aniline

[0096] MHz, CDCl3): δ7.14(dd,J=8.5,7.4Hz,2H),6.71(d,J=7.9Hz,1H),6.69–6.63(m,2H),6.60(dd,J=7.9,1.7Hz,1H),6.54–6.51(m,2H) ,5.89(s,2H),3.46(q,J=6.3Hz,1H),2.63(t,J=7.8Hz,2H),1.81(dd,J=14.2,6.6Hz,1H),1.74–1.67(m,1H),1.19(d,J=6.3Hz,3H). 13 C NMR (101MHz, CDCl3): δ147.6,147.6,145.7,135.9,129.4,121.2,117.0,113.3,108.9,108.2,100.8,47.9,39.1,32.3,20.9.HRMS(ESI-TOF): calculated forC 17 H 20 NO2[M+H] + :270.1489,found:270.1488.

[0097] Embodiment 6:

[0098] The synthetic method of N-(tert-butyl)naphthalene-1-amine is specifically as follows:

[0099] Depend on Figure 6 As shown in the reaction formula below, 0.1mmol of alcohol compound is added to an 8mL chemical reaction tube, 0.12mmol of naphthylamine, cuprous chloride (0.2equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and dichloromethane (1mL) are added to the reaction tube in sequence, and the reaction tube is moved to a 60°C oil bath pot for reaction for 1 hour, during which TLC is used for reaction monitoring. After the reaction is complete, the reactant is transferred to a 50mL single-necked flask, and the solvent is removed using a rotary evaporator. The crude product is purified by silica gel column chromatography, and the eluent is petroleum ether and ethyl acetate in a volume ratio (10:1-2:1).

[0100] The reaction formula is:

[0101]

[0102] Reaction product: N-(tert-butyl)naphthalene-1-amine

[0103]

[0104] Hz,1H),3.70(s,1H),1.47(s,9H). 13 C NMR (101MHz, CDCl3): δ141.8,134.7,128.8,126.1,125.5,124.7,120.4,117.9,110.1,51.7,30.0.HRMS (ESI-TOF): calculated forC 14 H 18 N[M+H] + :200.1434,found:200.1437.

[0105] Embodiment 7:

[0106] The synthesis method of N-(tert-butyl)-9H-fluorene-1-amine is specifically as follows:

[0107] Depend on Figure 7 As shown in the reaction formula below, 0.1mmol of alcohol compound is added to an 8mL chemical reaction tube, 0.12mmol of naphthylamine, cuprous chloride (0.2equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and dichloromethane (1mL) are added to the reaction tube in sequence, and the reaction tube is moved to a 60°C oil bath pot for reaction for 1 hour, during which TLC is used for reaction monitoring. After the reaction is complete, the reactant is transferred to a 50mL single-necked flask, and the solvent is removed using a rotary evaporator. The crude product is purified by silica gel column chromatography, and the eluent is petroleum ether and ethyl acetate in a volume ratio (10:1-2:1).

[0108] The reaction formula is:

[0109]

[0110] Reaction product: N-(tert-butyl)-9H-fluoren-1-amine

[0111]

[0112] 1H),3.81(s,2H),2.82(s,1H),1.37(s,9H). 13 C NMR (101MHz, CDCl3): δ144.63,142.39,126.61,125.05,124.71,120.23,118.63,117.04,114.44,51.97,36.97,30.16.HRMS (ESI-TOF): calculated for C 17 H 20N[M+H]+:238.1590,found:238.1592.

[0113] Embodiment 8:

[0114] The synthesis method of 4-chloro-N-(1,1,1-trifluoro-2-methylprop-2-yl)aniline is specifically as follows:

[0115] Depend on Figure 8 As shown in the reaction formula below, 0.1mmol of alcohol compound is added to an 8mL chemical reaction tube, 0.12mmol of aniline, cuprous chloride (0.2equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and dichloromethane (1mL) are added to the reaction tube in sequence, and the reaction tube is moved to a 60°C oil bath pot for reaction for 1 hour, during which TLC is used for reaction monitoring. After the reaction is complete, the reactant is transferred to a 50mL single-necked flask, and the solvent is removed using a rotary evaporator. The crude product is purified by silica gel column chromatography, and the eluent is petroleum ether and ethyl acetate in a volume ratio (10:1-2:1).

[0116] The reaction formula is:

[0117]

[0118] Reaction product: Chloro-N-(1,1,1-trifluoro-2-methylprop-2-yl)aniline

[0119]

[0120] Hz,2H),3.47(s,1H),1.43–1.42(m,6H).13C NMR (101MHz, CDCl3): δ142.33, 128.83, 127.37 (q, J = 285Hz), 127.01, 122.76 (d, J = 1Hz), 58.0 0(q,J=27Hz),22.58.19FNMR(376MHz,Chloroform-d):δ-79.52.HRMS(ESI-TOF):calculated for C 10 H 12 ClF3N[M+H]+:238.0605,found:238.0607.

[0121] In summary, compared with the prior art, the present invention has the following beneficial effects:

[0122] 1. The preparation method of the amine compounds of the present invention is to obtain various alkylamines and arylamine compounds by the coordination mediation of the deoxygenation reagent with the alcohol and the metal copper, and then undergoing SN2 nucleophilic substitution reaction with the amine compound. The present invention aims to develop a general synthesis method that uses an inexpensive transition metal copper catalyst to react with commercially available alcohols, amines, deoxygenation reagents and other raw materials to efficiently obtain various alkylamines and arylamine compounds. The synthesis method of the present invention is catalyzed by transition metal copper, has efficient reaction, simple principle, and diverse product structures. It has the advantages of simple operation, concise steps, high atomic utilization, relatively stable chemical properties, low cost, and easy purification;

[0123] 2. The preparation method of the present invention can produce excellent catalytic effect by using only copper catalyst and no equivalent reducing agent in the catalytic process. The operation method of the present invention is simple, and the ideal product can be synthesized without pre-activating the raw materials, so it is easy to realize batch synthesis;

[0124] 3. The preparation method of the present invention is applicable to primary, secondary and tertiary alcohols and various amine substrates, has a wide range of substrate applicability, has good compatibility of reaction substrate functional groups, and can be used for the synthesis of natural drug molecules;

[0125] 4. In view of the core role of organic amine compounds in many fields such as drug development and materials science, the present invention has developed a highly efficient, environmentally friendly and highly selective copper-catalyzed alcohol deoxygenation amination reaction system, which has significant strategic significance for promoting scientific and technological progress in related fields.

[0126] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0127] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing an amine compound, characterized in that: The specific steps are: Adding an alcohol compound as shown in Formula 1 and an amine compound as shown in Formula 2 into a reaction tube, and then adding a copper catalyst, a deoxidation agent and a solvent into the reaction tube, and after sufficient stirring and complete reaction, an amination product as shown in Formula 3 can be obtained; The reaction equation is as follows: Wherein, Formula 1 is an alkyl alcohol compound, R 1 , R 2 , R 3 is any one or a combination of hydrogen, heteroaryl, halogen, alkyl, carbonyl, ether bond, ester, carboxyl, aldehyde, cyano, alkenyl, alkynyl, and imine, R 1 , R 2 , R 3 The groups represented may be identical or non-identical or completely different; Formula 2 is a heteroarylamine compound or an alkylamine compound, and R is any one or a combination of hydrogen atom, heteroaryl group, halogen, hydroxyl, ether bond, ester group, nitro group, amine group, carboxyl group, aldehyde group, cyano group, alkenyl group, alkynyl group, and imine.

2. The method for synthesizing an amine compound according to claim 1, characterized in that: The copper catalyst is selected from one or more combinations of cuprous chloride, cuprous bromide, cuprous iodide, 2-thiophene cuprous, cuprous trifluoromethanesulfonate, cuprous oxide, cuprous cyanide, cuprous thiocyanate, cuprous acetate, cupric chloride, cupric bromide, cupric iodide, cupric trifluoromethanesulfonate, cupric oxide, cupric acetate, cupric sulfate, and basic cupric carbonate.

3. The method for synthesizing an amine compound according to claim 1, characterized in that: The copper catalyst is used in an amount of 5-100 mol%.

4. The method for synthesizing an amine compound according to claim 1, wherein: The deoxygenation agent is selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), propylphosphonic anhydride (T3P), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (HBTU), hexafluorophosphate-1-[bis(dimethylamino)methyl]-3-ethyl-1H-1,2,3-triazole (HCTU), diphenylphosphoryl chloride (DPP-Cl), diphenylphosphoryl azide (DPPA), thiodimethylphosphoryl azide (MPTA), and bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl). One or more combinations thereof.

5. The method for synthesizing an amine compound according to claim 1, characterized in that: The solvent is selected from one or more combinations of dichloromethane (DCM), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile (MeCN), ethyl acetate (EA), n-hexane (Hexane), ether (Ethor), acetone (Atcone), carbon tetrachloride (CCl4), toluene (Tolane), pyridine (Pydine), dimethyl sulfoxide (DMSO), and N,N-dimethylacetamide (DMAc).

6. The method for synthesizing an amine compound according to claim 1, wherein: The mass ratio of the alcohol compound, the amine compound, the copper catalyst and the deoxidation agent is 1:(1.0-3.0):(0.1-3.0):(1.0-5.0).

7. The method for synthesizing an amine compound according to claim 1, characterized in that: The solvent is used to dilute the mixture of the alcohol compound, the amine compound and the deoxygenation agent to 0.1M-0.3M.

8. The method for synthesizing an amine compound according to claim 1, wherein: The reaction temperature is 25-80°C.

9. The method for synthesizing an amine compound according to claim 1, characterized in that: The reaction time is 0.5-4h.

10. The method for synthesizing an amine compound according to claim 1, characterized in that: During the preparation of the product, an inert gas protection or reaction in air is used.

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