Preparation method and application of N-trifluoromethyl secondary amine compound

Abstract

The invention discloses a preparation method and application of an N-trifluoromethyl secondary amine compound, and belongs to the technical field of fine chemical engineering. The preparation method of the N-trifluoromethyl secondary amine compound provided by the invention comprises the following steps: taking isocyanide as a reaction substrate, and reacting under the action of iodine elementary substance, silver fluoride and tert-butyldimethylsilane to obtain the N-trifluoromethyl secondary amine compound. Compared with the prior art, the preparation method of the N-trifluoromethyl secondary amine compound has the advantages that use of irritant toxic gases such as fluorine gas, hydrogen fluoride gas and thiophosgene is avoided, experimental safety is effectively improved, reaction raw materials are easy to obtain, products are easy to separate, reaction conditions are mild, and the preparation method is suitable for industrial production. Therefore, the method is a novel method for preparing the N-trifluoromethyl secondary amine compound, which is safer, more efficient and milder.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical industry, and in particular relates to a preparation method of N-trifluoromethyl secondary amine compounds and application thereof. Background Art

[0002] The trifluoromethyl group connected to a heteroatom will give the compound special properties. In recent years, researchers have shown great interest in functional groups such as O-CF3 and S-CF3 formed by the trifluoromethyl group connected to a heteroatom. However, in comparison, there is still little research on the N-CF3 group. The main reason is the lack of reagents that can directly introduce the trifluoromethyl group into the amino nitrogen atom, and the poor stability of trifluoromethylamine, which easily causes fluorine elimination. Compared with methyl-substituted amino compounds, trifluoromethyl-substituted amino compounds can have higher lipophilicity and metabolic stability.

[0003] Up to now, there are few methods for synthesizing N-trifluoromethyl secondary amine compounds, and there are only a few examples, such as: a) In 1980, a study used isonitrile to synthesize N-trifluoromethyl secondary amine compounds under the conditions of fluorine gas and hydrogen fluoride; b) In 2022, a study prepared N-trifluoromethyl secondary amine by in-situ generation of difluoroimine intermediates through isothiocyanate, reacting with silane and silver fluoride, and was able to convert it into sulfonamide derivatives. The reaction formula of the above method is as follows:

[0004] a)Access to N-CF3 through isocyanide

[0005]

[0006] b)Access to N-CF3 through isothiocyanate

[0007]

[0008] Although the above methods can obtain N-trifluoromethyl secondary amine compounds, there are many limitations, such as method a) requires the use of fluorine gas and hydrogen fluoride gas, both of which are highly toxic gases, greatly reducing the safety of the synthesis; method b) requires the synthesis of isothiocyanates, which usually requires the use of highly toxic and irritating gases such as thiophosgene. The disadvantage of the above two methods is that the reactions involve the use of gases that are harmful to the human body and the environment. Therefore, in order to solve the use of the above toxic gases, it is necessary to develop a new method for preparing N-trifluoromethyl secondary amine compounds that is safer, more practical, milder and more efficient. Summary of the invention

[0009] In order to overcome at least one of the problems existing in the above-mentioned prior art, one of the objects of the present invention is to provide a method for preparing N-trifluoromethyl secondary amine compounds, which preparation method does not require the use of toxic and harmful gases such as fluorine gas, hydrogen fluoride or thiophosgene, and can prepare N-trifluoromethyl secondary amine compounds gently and efficiently.

[0010] A second object of the present invention is to provide an application of the above preparation method.

[0011] In order to achieve the above object, the technical solution adopted by the present invention is:

[0012] The first aspect of the present invention provides a method for preparing an N-trifluoromethyl secondary amine compound, comprising the following steps: using isonitrile as a reaction substrate, reacting under the action of elemental iodine, silver fluoride and tert-butyldimethylsilane to obtain the N-trifluoromethyl secondary amine compound.

[0013] Preferably, the reaction specifically includes: isonitrile generates an intermediate difluoroimine under the action of iodine and silver fluoride; tert-butyldimethylsilane generates a hydride ion under the action of silver fluoride; the intermediate difluoroimine generates an N-trifluoromethyl secondary amine compound under the action of hydride ions and silver fluoride. The reaction formula is as follows:

[0014]

[0015] Preferably, the reaction of isonitrile under the action of iodine and silver fluoride includes at least one of the following reactions: (1) isonitrile undergoes an oxidation reaction with iodine to generate diiodimine, and diiodimine undergoes a displacement reaction with silver fluoride to generate an intermediate difluoroimine; (2) isonitrile undergoes an oxidation reaction with iodine to generate diiodimine, diiodimine undergoes a displacement reaction with silver fluoride to generate fluoroiodimine, and fluoroiodimine undergoes a displacement reaction with silver fluoride to generate an intermediate difluoroimine. The reaction formula is shown below:

[0016] (1)

[0017] (2)

[0018] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the molar ratio of the isonitrile to the iodine element is 1:(0.5-2); more preferably 1:(1-1.5); and even more preferably 1:(1.05-1.2).

[0019] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the molar ratio of the isonitrile to the silver fluoride is 1:(5-10); more preferably 1:(5.5-9); and even more preferably 1:(6-8).

[0020] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the molar ratio of the isonitrile to the tert-butyldimethylsilane is 1:(1-2); more preferably 1:(1.2-1.8); and even more preferably 1:(1.3-1.5).

[0021] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the reaction temperature is 30 to 50°C; more preferably 32 to 48°C; and even more preferably 35 to 45°C.

[0022] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the reaction time is 2 to 6 hours; more preferably 2.5 to 5.5 hours; and even more preferably 3 to 5 hours.

[0023] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the reaction is carried out in a solvent.

[0024] Preferably, the solvent is selected from 1,4-dioxane.

[0025] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, a post-treatment step is further included after the reaction.

[0026] Preferably, the post-treatment step comprises: washing the product with ether, solid-liquid separation, and drying.

[0027] Preferably, the solid-liquid separation method is selected from filtration; further preferably, the filter medium used in the filtration is selected from diatomaceous earth.

[0028] Preferably, the drying method is selected from vacuum spin drying.

[0029] In some specific embodiments of the present invention, the structural formula of the N-trifluoromethyl secondary amine compound is as shown in formula (I):

[0030]

[0031] Wherein, R is a substituted or unsubstituted C1-C30 alkyl group, a substituted or unsubstituted C6-C30 aromatic ring, or a substituted or unsubstituted C6-C30 aromatic heterocycle; the substituted substituents are each independently selected from at least one of halogen, nitro, amino, cyano, hydroxyl, ester, sulfonyl, thiol, C1-C10 alkyl group, C1-C10 alkoxy group, C6-C60 aromatic ring, and C3-C60 aromatic heterocycle; the number of substitutions is from a single substitution to a maximum number of substitutions, and if the number of substitutions is greater than or equal to 2, two adjacent substituents may be connected to form a parallel ring; the substituents may be further substituted or not further substituted; the heteroatoms in the heterocycle include S, O, and N.

[0032] In some specific embodiments of the present invention, R is a monosubstituted phenyl, a polysubstituted phenyl, a biaryl, a benzoheterocyclic aromatic group, a disubstituted alkyl group at the ester group at the β-position of nitrogen, or a disubstituted alkyl group at the α-position of nitrogen, and the substituted substituents are each independently selected from at least one of halogen, nitro, amino, cyano, hydroxyl, ester, sulfonyl, thiol, C1-C10 alkyl, C1-C10 alkoxy, C6-C60 aromatic ring, and C3-C60 aromatic heterocycle; the substituents are further substituted or not further substituted; the heteroatoms in the heterocycle include S, O, and N.

[0033] In some specific embodiments of the present invention, the N-trifluoromethyl secondary amine compound is selected from any one of the following:

[0034]

[0035] The second aspect of the present invention provides an application of the preparation method described in the first aspect of the present invention in the preparation of N-trifluoromethyl secondary amine compounds, N-trifluoromethyl sulfonamide compounds or N-trifluoromethyl fluoroformamide compounds.

[0036] The beneficial effects of the present invention are as follows: compared with the prior art, the preparation method of the N-trifluoromethyl secondary amine compounds provided by the present invention avoids the use of irritating and toxic gases such as fluorine gas, hydrogen fluoride gas, and thiophosgene, effectively improving the safety of the experiment; and, the reaction raw materials of the present invention are easily available, the products are easily separated, and the reaction conditions are mild, so the present invention is a new method for preparing N-trifluoromethyl secondary amine compounds in a safer, more efficient and milder manner.

[0037] Specifically, compared with the prior art, the present invention has the following advantages:

[0038] 1. In the trifluoromethyl secondary amine compounds of the present invention, when R is an aryl group, the structure of the compound is relatively stable, and when R is an alkyl group, the structural stability of the compound is relatively poor. Therefore, hydrogen can be replaced by further reaction to prepare sulfonyl and fluoroformyl substituted derivatives to obtain compounds with better stability, thereby being able to prepare compounds with high value in medicine more simply, conveniently and quickly.

[0039] 2. The preparation method of the compound of the present invention is simple. The readily available aromatic isonitrile or alkyl isonitrile is used as the starting material. The target product can be obtained by reacting in the presence of silver fluoride, elemental iodine and tert-butyldimethylsilane. The reaction substrate has a wide range of applicability and can prepare a variety of 2-aryl-substituted N-trifluoromethyl secondary amine compounds. At the same time, the method has mild and safe reaction conditions, does not require high temperature or high pressure, is easy to operate and simple to post-process, and is an efficient method for synthesizing N-trifluoromethyl secondary amine compounds. DETAILED DESCRIPTION

[0040] The content of the present invention is further described in detail below through specific examples. It should also be understood that the following examples are only used to further illustrate the present invention and cannot be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the principles set forth in the present invention all belong to the scope of protection of the present invention. The specific process parameters and the like in the following examples are also only examples within a suitable range, that is, those skilled in the art can make a selection within a suitable range through the description herein, and are not limited to the specific data exemplified below. The raw materials, reagents or devices used in the following examples and comparative examples, unless otherwise specified, can all be obtained from conventional commercial sources, or can be obtained by existing known methods.

[0041] In an embodiment of the present invention, a method for preparing an N-trifluoromethyl secondary amine compound is provided, comprising the following steps: using isonitrile as a reaction substrate, reacting under the action of elemental iodine, silver fluoride and tert-butyldimethylsilane to obtain the N-trifluoromethyl secondary amine compound.

[0042] In some embodiments, the reaction specifically includes: isonitrile generates an intermediate difluoroimine under the action of iodine and silver fluoride; tert-butyldimethylsilane generates a hydride ion under the action of silver fluoride; the intermediate difluoroimine generates an N-trifluoromethyl secondary amine compound under the action of hydride ions and silver fluoride.

[0043] In some embodiments, the reaction of isonitrile under the action of iodine and silver fluoride includes at least one of the following reactions: (1) isonitrile undergoes an oxidation reaction with iodine to generate diiodoimine, and diiodoimine undergoes a displacement reaction with silver fluoride to generate an intermediate difluoroimine; (2) isonitrile undergoes an oxidation reaction with iodine to generate diiodoimine, and diiodoimine undergoes a displacement reaction with silver fluoride to generate fluoroiodoimine, and fluoroiodoimine undergoes a displacement reaction with silver fluoride to generate an intermediate difluoroimine.

[0044] In some embodiments, the reaction formula is as follows:

[0045]

[0046] The following is further described in conjunction with specific embodiments.

[0047] Example 1

[0048] Synthesis of compound 2a:

[0049] 1-isocyano-4-(methylsulfonyl)benzene (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a white solid with a yield of 82%.

[0050] Compound 2a is 4-(methylsulfonyl)-N-(trifluoromethyl)aniline, and its structure is shown below:

[0051]

[0052] Compound 2a was characterized by nuclear magnetic resonance and high resolution, and the results are as follows:

[0053] 1 H NMR (400MHz, Chloroform-d) δ7.86 (d, J = 8.7Hz, 2H), 7.07 (d, J = 8.4Hz, 2H), 5.90 (s, 1H), 3.04 (s, 3H).

[0054] 13 C NMR (126MHz, Chloroform-d) δ142.7, 133.9, 129.3, 120.7 (q, J = 257.3Hz), 116.4 (q, J = 2.3Hz), 44.8.

[0055] 19 F NMR (376MHz, Chloroform-d) δ-56.23 (d, J=4.6Hz).

[0056] HRMS(ESI):m / z calculated for C8H7F3NO2S - [MH] - ,238.0155;Found 238.0156.

[0057] Example 2

[0058] Synthesis of compound 2b:

[0059] 1-isocyano-4-nitrobenzene (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 95%.

[0060] Compound 2b is 4-nitro-N-(trifluoromethyl)aniline. Its structure is shown below:

[0061]

[0062] Compound 2b was characterized by nuclear magnetic resonance and high resolution, and the results are as follows:

[0063] 1 H NMR (400MHz, Acetonitrile-d3) δ8.08(d,J=9.2Hz,2H),7.46(s,1H),6.99(d,J=8.8Hz,2H).

[0064] 13 C NMR (101MHz, Acetonitrile-d3) δ145.3, 143.3, 126.5, 122.0 (q, J = 254.9Hz), 116.7 (q, J = 2.3Hz).

[0065] 19 F NMR (376MHz, Acetonitrile-d3) δ-57.13 (d, J=5.3Hz).

[0066] HRMS(FTMS-cAPCI):m / z calculated for C7H4N2O2F3 - [MH] - ,205.0230;Found205.0232.

[0067] Example 3

[0068] Synthesis of compound 2c:

[0069] 1-iodo-4-isocyanobenzene (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown liquid with a yield of 93%.

[0070] Compound 2c is 4-iodo-N-(trifluoromethyl)aniline. Its structure is shown below:

[0071]

[0072] Compound 2c was characterized by NMR and high resolution, and the results are as follows:

[0073] 1 H NMR (500MHz, Chloroform-d) δ7.59 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 5.24 (s, 1H).

[0074] 13 C NMR (126MHz, Chloroform-d) δ138.3, 137.4, 121.3 (q, J = 256.4Hz), 119.7 (q, J = 1.9Hz), 86.0.

[0075] 19 F NMR (376MHz, Chloroform-d) δ-56.00 (d, J=5.4Hz).

[0076] HRMS(FTMS-cAPCI):m / z calculated for C7H4NF3I - [MH] - ,285.9342;Found285.9346.Example 4

[0077] Synthesis of compound 2d:

[0078] Add (4-isocyanophenyl)(methyl)sulfane (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent to the Schlenk tube in sequence. After stirring for five minutes, dilute tert-butyldimethylsilane (0.7mmol, 1.4equiv) in 1.0mL 1,4-dioxane solvent and inject it into the tube through a syringe. After stirring at 40°C for 4h, add 10mL ether to dilute, filter through diatomaceous earth, and vacuum spin dry the solvent. Add 10mL ether to dissolve, filter through diatomaceous earth, and vacuum spin dry the solvent again to obtain the product as a brown liquid with a yield of 90%.

[0079] Compound 2d is 4-(methylthio)-N-(trifluoromethyl)aniline. Its structure is shown below:

[0080]

[0081] Compound 2d was characterized by NMR and high resolution, and the results are as follows:

[0082] 1 H NMR (400MHz, Chloroform-d) δ7.27–7.21(m,2H),6.96–6.89(m,2H),5.11(s,1H),2.46(s,3H).

[0083] 13 C NMR (126MHz, Chloroform-d) δ135.2, 132.7, 128.8, 121.6 (q, J = 256.0Hz), 119.1 (q, J = 2.0Hz), 16.9.

[0084] 19 F NMR (376MHz, Chloroform-d) δ-55.85 (d, J=5.4Hz).

[0085] HRMS(FTMS-cAPCI):m / z calculated for C8H7F3NS - [MH] - ,266.0260;Found266.0257.Example 5

[0086] Synthesis of compound 2e:

[0087] 1-(4-isocyanophenyl)cyclopentane-1-carbonitrile (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a yellow solid with a yield of 96%.

[0088] Compound 2e is 1-(4-((trifluoromethyl)amino)phenyl)cyclopentane-1-carbonitrile. Its structure is shown below:

[0089]

[0090] Compound 2e was characterized by NMR and high resolution, and the results are as follows:

[0091] 1 H NMR (400MHz, Chloroform-d) δ7.39–7.35(m,2H),6.97(d,J=7.8Hz,2H),5.36(s,1H),2.49–2.42(m,2H),2.08–1.99(m,4H),1.97–1.89(m,2H).

[0092] 13 C NMR (101MHz, Chloroform-d) δ137.2, 134.4, 127.2, 124.4, 121.4 (q, J = 256.4Hz), 117.9 (q, J = 2.2Hz), 47.1, 40.3, 24.1.

[0093] 19 F NMR(376MHz,Chloroform-d)δ-55.91.

[0094] HRMS(FTMS-cAPCI):m / z calculated for C 13 H 12 F3N2 - [MH] -,253.0958;Found253.0960.

[0095] Example 6

[0096] Synthesis of compound 2f:

[0097] 1-(benzyloxy)-4-isocyanobenzene (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 78%.

[0098] Compound 2f is 4-(benzyloxy)-N-(trifluoromethyl)aniline, and its structure is shown below:

[0099]

[0100] Compound 2f was characterized by NMR and high resolution, and the results are as follows:

[0101] 1 H NMR (400MHz, Chloroform-d) δ7.47–7.38(m,4H),7.36(d,J=6.9Hz,1H),7.03–6.92(m,4H),5.05(s,2H),4.87(s,1H).

[0102] 13 C NMR (126MHz, Chloroform-d) δ 155.8, 136.9, 130.5, 128.7, 128.1, 127.5, 122.0 (q, J = 255.6Hz), 122.0, 115.7, 70.4.

[0103] 19 F NMR (376MHz, Chloroform-d) δ-56.05 (d, J=6.0Hz).

[0104] HRMS(FTMS-cAPCI):m / z calculated for C 14 H11 F3NO - [MH] - ,266.0798;Found266.0798.

[0105] Example 7

[0106] Synthesis of compound 2g:

[0107] Add (4-isocyanophenyl)(phenyl)methanone (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent to the Schlenk tube in sequence. After stirring for five minutes, dilute tert-butyldimethylsilane (0.7mmol, 1.4equiv) in 1.0mL 1,4-dioxane solvent and inject it into the tube through a syringe. After stirring at 40°C for 4h, add 10mL ether to dilute, filter through diatomaceous earth, and vacuum spin dry the solvent. Add 10mL ether to dissolve, filter through diatomaceous earth, and vacuum spin dry the solvent again to obtain the product as a brown solid with a yield of 98%.

[0108] Compound 2g is phenyl(4-((trifluoromethyl)amino)phenyl)methanone, and its structure is shown below:

[0109]

[0110] Compound 2g was characterized by nuclear magnetic resonance and high resolution, and the results are as follows:

[0111] 1 H NMR (500MHz, Chloroform-d) δ7.78(dd,J=19.4,7.9Hz,4H),7.58(t,J=7.6Hz,1H),7.48(t,J=7.5Hz,2H),7.02(d,J=8.3Hz,2H),6.24(s,1H).

[0112] 13 C NMR (126MHz, Chloroform-d) δ196.0, 142.1, 137.8, 132.3, 132.2, 131.3, 129.8, 128.3, 121.0 (q, J = 256.7Hz), 115.7 (q, J = 2.2Hz).

[0113] 19F NMR (376MHz, Chloroform-d) δ-55.90 (d, J=4.8Hz).

[0114] ESI-MS: calculated for C 14 H 11 NOF3 + [M+H] + ,266.0787;Found 266.0782.

[0115] Example 8

[0116] Synthesis of compound 2h:

[0117] 4-isocyano-3-methylbenzonitrile (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 95%.

[0118] Compound 2h is 3-methyl-4-((trifluoromethyl)amino)benzonitrile. Its structure is shown below:

[0119]

[0120] Compound 2h was characterized by NMR and high resolution, and the results are as follows:

[0121] 1 H NMR (500MHz, Chloroform-d) δ7.48(d,J=8.5Hz,1H),7.44(s,1H),7.14(d,J=8.6Hz,1H),5.44(s,1H),2.26(s,3H).

[0122] 13 C NMR (126MHz, Chloroform-d) δ140.1, 134.3, 131.6, 125.4, 120.9 (q, J = 257.1Hz), 118.9, 115.6, 105.6, 17.3.

[0123] 19 F NMR (376MHz, Chloroform-d) δ-55.72 (d, J=4.4Hz).

[0124] HRMS(FTMS-cAPCI):m / z calculated for C9H6N2F3 - [MH] - ,199.0487;Found199.0489.Example 9

[0125] Synthesis of compound 2i:

[0126] 2-chloro-4-isocyanobenzonitrile (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 95%.

[0127] Compound 2i is 2-chloro-4-((trifluoromethyl)amino)benzonitrile. Its structure is shown below:

[0128]

[0129] Compound 2i was characterized by NMR and high resolution, and the results are as follows:

[0130] 1 H NMR (400MHz, Chloroform-d) δ7.58(d,J=8.5Hz,1H),7.07(d,J=2.2Hz,1H),6.90(dd,J=8.6,2.3Hz,1H),6.02(s,1H).

[0131] 13 C NMR (126MHz, Chloroform-d) δ 142.7, 138.4, 135.1, 120.3 (q, J = 257.9Hz), 117.0, 116.0, 114.6 (q, J = 2.1Hz), 106.4.

[0132] 19 F NMR (376MHz, Chloroform-d) δ-56.33 (d, J=4.5Hz).

[0133] HRMS(ESI):m / z calculated for C8H3N2F3Cl - [MH] - ,218.9942;Found 218.9949.

[0134] Example 10

[0135] Synthesis of compound 2j:

[0136] 2-fluoro-5-isocyanobenzonitrile (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 80%.

[0137] Compound 2j is 2-fluoro-5-((trifluoromethyl)amino)benzonitrile. Its structure is shown below:

[0138]

[0139] Compound 2j was characterized by NMR and high resolution, and the results are as follows:

[0140] 1 H NMR (400MHz, Chloroform-d) δ7.23 (dd, J=7.2, 4.1Hz, 2H), 7.18 (dd, J=10.0, 7.9Hz, 1H), 5.60 (s, 1H).

[0141] 13C NMR(126MHz,Chloroform-d)δ158.3(d,J=255.7Hz).,133.5,123.9(d,J=8.1Hz),121.1 (d, J = 2.4Hz), 120.1 (q, J = 257.1Hz), 116.6 (d, J = 21.0Hz), 112.5, 100.9 (d, J = 16.9Hz).

[0142] 19 F NMR (376MHz, Chloroform-d) δ -56.48 (d, J = 2.8Hz), -113.74 (dt, J = 8.9, 4.8Hz).

[0143] HRMS(ESI):m / z calculated for C8H3F4N2 - [MH] - ,203.0238;Found 203.0244.

[0144] Embodiment 11

[0145] Synthesis of compound 2k:

[0146] Add dimethyl 5-isocyanoisophthalate (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent to the Schlenk tube in sequence. After stirring for five minutes, dilute tert-butyldimethylsilane (0.7mmol, 1.4equiv) in 1.0mL 1,4-dioxane solvent and inject it into the tube through a syringe. After stirring at 40°C for 4h, add 10mL ether to dilute, filter through diatomaceous earth, and vacuum spin dry the solvent. Add 10mL ether to dissolve, filter through diatomaceous earth, and vacuum spin dry the solvent again to obtain the product as a brown solid with a yield of 98%.

[0147] Compound 2k is dimethyl 5-((trifluoromethyl)amino)isophthalate. Its structure is shown below:

[0148]

[0149] Compound 2k was characterized by NMR and high resolution, and the results are as follows:

[0150] 1H NMR (400MHz, Chloroform-d) δ8.34 (s, 1H), 7.90 (s, 2H), 6.21 (d, J = 5.7Hz, 1H), 3.95 (s, 6H).

[0151] 13 C NMR (126MHz, Chloroform-d) δ 166.1, 138.8, 131.7, 124.7, 122.2, 121.2 (q, J = 257.4Hz), 52.6.

[0152] 19 F NMR (376MHz, Chloroform-d) δ-56.07 (d, J=5.0Hz).

[0153] HRMS(ESI):m / z calculated for C 11 H 10 F3NO4Na + [M+Na] + ,300.0454;Found300.0464.Example 12

[0154] Synthesis of compound 2l:

[0155] 1,3-dibromo-5-isocyano-2-methylbenzene (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 94%.

[0156] Compound 21 is 3,5-dibromo-4-methyl-N-(trifluoromethyl)aniline. Its structure is shown below:

[0157]

[0158] Compound 2l was characterized by NMR and high resolution, and the results are as follows:

[0159] 1H NMR(400MHz,Chloroform-d)δ7.06(s,2H),5.07(s,1H),2.40(s,3H).

[0160] 13 C NMR (126MHz, Chloroform-d) δ135.7, 131.2, 124.4, 120.1, 120.0 (q, J = 256.8Hz), 21.8.

[0161] 19 F NMR (376MHz, Chloroform-d) δ-55.98 (d, J=5.1Hz).

[0162] HRMS(ESI):m / z calculated for C8H6Br2NF3[MH] - ,331.8665;Found 331.8664.

[0163] Example 13

[0164] Synthesis of compound 2m:

[0165] 2-bromo-6-isocyanonaphthalene (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I2 (0.55 mmol, 1.1 equiv) and 2.0 mL of 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4 hours, 10 mL of ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10 mL of ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 78%.

[0166] Compound 2m is 6-bromo-N-(trifluoromethyl)naphthalen-2-amine. Its structure is shown below:

[0167]

[0168] Compound 2m was characterized by NMR and high resolution, and the results are as follows:

[0169] 1H NMR(400MHz,Chloroform-d)δ7.93(d,J=1.9Hz,1H),7.68(d,J=8.8Hz,1H),7.59(d,J=8.7Hz,1H ),7.53(dd,J=8.8,2.0Hz,1H),7.32(d,J=2.1Hz,1H),7.11(dd,J=8.8,2.3Hz,1H),5.33(s,1H).

[0170] 13 C NMR (126MHz, Chloroform-d) δ 134.4, 131.3, 129.8, 129.1, 128.6, 127.6, 127.5, 120.4 (q, J = 256.6Hz), 118.3, 117.3, 112.1.

[0171] 19 F NMR (376MHz, Chloroform-d) δ-55.85 (d, J=5.4Hz).

[0172] HRMS(ESI):m / z calculated for C 11 H6BrNF3 - [MH] - ,287.9641;Found 287.9638.

[0173] Embodiment 14

[0174] Synthesis of compound 2n:

[0175] 6-isocyano-3,4-dihydronaphthalen-1(2H)-one (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a yellow solid with a yield of 94%.

[0176] Compound 2n is 6-((trifluoromethyl)amino)-3,4-dihydronaphthalen-1(2H)-one, and its structure is shown below:

[0177]

[0178] Compound 2n was characterized by NMR and high resolution, and the results are as follows:

[0179] 1 H NMR(500MHz,Chloroform-d)δ7.98(d,J=8.5Hz,1H),6.84(dd,J=8.6,2.3Hz,1H),6.79 (s,1H),6.09(s,1H),2.92(t,J=6.1Hz,2H),2.73–2.53(m,2H),2.11(p,J=6.4Hz,2H).

[0180] 13 C NMR (126MHz, Chloroform-d) δ197.6, 146.8, 142.5, 129.3, 127.3, 120.9 (q, J = 256.3Hz), 114.8 (dd, J = 6.1, 2.0Hz), 38.8, 30.0, 23.2.

[0181] 19 F NMR (376MHz, Chloroform-d) δ-55.76 (d, J=4.6Hz).

[0182] HRMS(ESI):m / z calculated for C 11 H 10 F3NO + [M+Na] + ,252.0607;Found252.060.Example 15

[0183] Synthesis of compound 2o:

[0184] 2-isocyano-9H-fluorene (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a light pink solid with a yield of 77%.

[0185] Compound 2o is N-(trifluoromethyl)-9H-fluoren-2-amine, and its structure is shown below:

[0186]

[0187] Compound 2o was characterized by NMR and high resolution, and the results are as follows:

[0188] 1 H NMR(400MHz,Chloroform-d)δ7.71(dd,J=11.3,7.8Hz,2H),7.37(t,J=7.5Hz,1H) ,7.32–7.24(m,1H),7.19(s,1H),6.98(d,J=8.1Hz,1H),5.15(s,1H),3.88(s,2H).

[0189] 13 C NMR(126MHz,Chloroform-d)δ144.9,142.8,141.2,137.5,136.3,126.9,126.4 ,125.0,121.8(q,J=255.9Hz),120.6,119.5,117.4,115.2(q,J=1.9Hz),37.0.

[0190] 19 F NMR (376MHz, Chloroform-d) δ-55.56 (d, J=5.5Hz).

[0191] HRMS(FTMS-cAPCI):m / z calculated for C 14 H9F3N - [MH] - ,248.0692;Found248.0692.Example 16

[0192] Synthesis of compound 2p:

[0193] 3-isocyanodibenzo[b,d]furan (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 79%.

[0194] Compound 2p is N-(trifluoromethyl)dibenzo[b,d]furan-3-amine, and its structure is shown below:

[0195]

[0196] Compound 2p was characterized by nuclear magnetic resonance and high resolution, and the results are as follows:

[0197] 1 H NMR (400MHz, Chloroform-d) δ7.88(dd,J=7.7,1.3Hz,1H),7.83(d,J=8.3Hz,1H),7.54(d,J=8.2Hz,1H),7.42(ddd,J =8.3,7.2,1.4Hz,1H),7.33(td,J=7.5,1.0Hz,1H),7.23(d,J=1.9Hz,1H),6.94(dd,J=8.4,2.0Hz,1H),5.34(s,1H).

[0198] 13 C NMR(126MHz,Chloroform-d)δ155.9,155.4,135.9,125.5,122.9,121.9,120.5(q, J=256.3Hz),120.2,119.1,118.8,112.6(q,J=1.8Hz),110.5,100.4(q,J=2.2Hz).

[0199] 19 F NMR (376MHz, Chloroform-d) δ-55.87 (d, J=5.3Hz).

[0200] HRMS(FTMS-cAPCI):m / z calculated for C7H3NF3I - [MH] - ,250.0485;Found250.0488.Example 17

[0201] Synthesis of compound 2q:

[0202] 2-isocyanodibenzo[b,d]thiophene (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 84%.

[0203] Compound 2q is N-(trifluoromethyl)dibenzo[b,d]thiophen-2-amine, and its structure is shown below:

[0204]

[0205] Compound 2q was characterized by nuclear magnetic resonance and high resolution, and the results are as follows:

[0206] 1 H NMR (400MHz, Chloroform-d) δ8.13–8.07(m,1H),7.87–7.82(m,1H),7.80–7.73(m,2H),7.51–7.42(m,2H),7.11(dd,J=8.5,2.2Hz,1H),5.24(s,1H).

[0207] 13 C NMR(126MHz,Chloroform-d)δ140.4,136.5,135.0,134.6,134.5,127.1,124.4,12 3.6, 122.9, 121.8 (q, J = 256.0Hz), 121.7, 118.9 (q, J = 1.7Hz), 111.6 (q, J = 2.0Hz).

[0208] 19F NMR (376MHz, Chloroform-d) δ-55.72 (d, J=5.0Hz).

[0209] HRMS(FTMS-cAPCI):m / z calculated for C 13 H7F3NO - [MH] - ,266.0260;Found266.0257.

[0210] Embodiment 18

[0211] Synthesis of compound 2r:

[0212] 5-isocyano-1-tosyl-1H-indole (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 73%.

[0213] Compound 2r is 1-tosyl-N-(trifluoromethyl)-1H-indol-5-amine, and its structure is shown below:

[0214]

[0215] Compound 2r was characterized by NMR and high resolution, and the results are as follows:

[0216] 1 H NMR(400MHz,Chloroform-d)δ7.90(d,J=8.8Hz,1H),7.77–7.70(m,2H),7.55(d,J=3.6Hz,1H),7.20(d,J =8.1Hz,2H),7.17(s,1H),6.96(dd,J=8.9,2.2Hz,1H),6.57(d,J=3.6Hz,1H),5.25(s,1H),2.32(s,3H).

[0217] 13C NMR(101MHz,Chloroform-d)δ144.1,134.0,132.3,130.6,130.4,128.9,126.4 ,125.7,120.8(q,J=255.6Hz),116.1,113.2,110.2(q,J=2.2Hz),107.9,20.5.

[0218] 19 F NMR (376MHz, Chloroform-d) δ-55.81 (d, J=5.3Hz).

[0219] HRMS(FTMS-cAPCI):m / z calculated for C 16 H 12 F3N2O2S - [MH] - ,353.0575;Found353.0577.

[0220] Embodiment 19

[0221] Synthesis of compound 2s:

[0222] Ethyl 5-isocyanobenzofuran-2-carboxylate (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (0.7mmol, 1.4equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added for dilution, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a brown solid with a yield of 90%.

[0223] Compound 2s is ethyl 5-((trifluoromethyl)amino)benzofuran-2-carboxylate, and its structure is shown below:

[0224]

[0225] Compound 2s was characterized by NMR and high resolution, and the results are as follows:

[0226] 1H NMR(400MHz,Chloroform-d)δ7.50(d,J=9.1Hz,1H),7.46(d,J=0.8Hz,1H),7.33(d,J=2.2Hz ,1H),7.10(dd,J=8.9,2.3Hz,1H),5.28(s,1H),4.44(q,J=7.1Hz,2H),1.42(t,J=7.2Hz,3H).

[0227] 13 C NMR (126MHz, Chloroform-d) δ159.5, 152.5, 146.6, 133.8, 127.7, 121.8 (q, J = 255.7Hz), 120.6, 113.6, 113.0, 112.3 (q, J = 1.7Hz), 61.7, 14.3.

[0228] 19 F NMR (376MHz, Chloroform-d) δ-56.11 (d, J=5.9Hz).

[0229] HRMS(FTMS-cAPCI):m / z calculated for C 12 H9F3NO3 - [MH] - ,272.0540;Found272.0540.

[0230] Embodiment 20

[0231] Synthesis of compound 2t:

[0232] 4-((4-isocyanophenyl)sulfonyl)-N-(trifluoromethyl)aniline (0.5mmol, 1.0equiv), silver fluoride (7.0mmol, 14.0equiv), I2 (1.1mmol, 2.2equiv) and 4.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (1.4mmol, 2.8equiv) was diluted in 2.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a yellow solid with a yield of 80%.

[0233] Compound 2t is 4,4'-sulfonylbis(N-(trifluoromethyl)aniline), and its structure is shown below:

[0234]

[0235] Compound 2t was characterized by NMR and high resolution, and the results are as follows:

[0236] 1 H NMR (400MHz, Acetonitrile-d3) δ7.76 (d, J = 8.9 Hz, 4H), 7.28 (s, 2H), 7.01 (d, J = 7.9 Hz, 4H).

[0237] 13 C NMR (126MHz, Acetonitrile-d3) δ143.5, 135.6, 129.7, 121.8 (q, J = 254.8Hz), 116.9 (q, J = 2.1Hz).

[0238] 19 F NMR (376MHz, Acetonitrile-d3) δ-57.00 (d, J=5.0Hz).

[0239] HRMS(Q-TOF EI):m / z calculated for C 14 H 11 F6N2O2S + [M+H] + ,385.0445;Found385.0444.

[0240] Embodiment 21

[0241] Synthesis of compound 2u:

[0242] Methyl(S)-2-isocyano-3-(1-tosyl-1H-indol-3-yl)propanoate (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (1.0mmol, 2.0equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a yellow liquid with a yield of 94%.

[0243] Compound 2u is methyl 1-tosyl-Na-(trifluoromethyl)-L-tryptophanate, and its structure is shown below:

[0244]

[0245] Compound 2u was characterized by NMR and high resolution, and the results are as follows:

[0246] 1 H NMR (400MHz, Chloroform-d) δ7.85(d,J=8.2Hz,1H),7.59(d,J=8.1Hz,2H),7.35(d,J=7.8Hz,1H),7.30(s,1H),7.19(t,J=7.1Hz,1H),7.13( d,J=7.7Hz,1H),7.08(d,J=8.1Hz,2H),3.93(dt,J=8.7,5.9Hz,1H),3.65(t,J=7.8Hz,1H),3.52(s,3H),2.99(d,J=5.8Hz,2H),2.20(s,3H).

[0247] 13 C NMR(101MHz,Chloroform-d)δ171.3,143.9,134.0,129.5,128.8,125.7,123.9,123.8, 122.3(q,J=255.6Hz),122.2,118.2,115.7,112.8,52.6(q,J=2.3Hz),51.7,28.1,20.5.

[0248] 19F NMR (376MHz, Chloroform-d) δ-57.69 (d, J=7.2Hz).

[0249] HRMS(FTMS-cAPCI):m / z calculated for C 20 H 21 O4N2SF3 + [M+H] + ,441.1090;Found441.1092.

[0250] Embodiment 22

[0251] Synthesis of compound 2v:

[0252] Methyl(S)-2-isocyano-3-(4-nitrophenyl)propanoate (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (1.0mmol, 2.0equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. Another 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a yellow solid with a yield of 95%.

[0253] Compound 2v is methyl(S)-3-(4-nitrophenyl)-2-((trifluoromethyl)amino)-propanoate, and its structure is shown below:

[0254]

[0255] Compound 2v was characterized by NMR and high resolution, and the results are as follows:

[0256] 1 H NMR (400MHz, Chloroform-d) δ8.17(d,J=8.7Hz,2H),7.35(d,J=8.7Hz,2H),4.11–4.02(m,1H),3.77(s,3H),3.12(qd,J=13.7,6.0Hz,2H).

[0257] 13C NMR (101MHz, Chloroform-d) δ170.9, 146.2, 142.3, 129.4, 122.6, 122.2 (q, J = 255.8Hz), 53.3 (q, J = 2.3Hz), 51.9, 38.2.

[0258] 19 F NMR (376MHz, Chloroform-d) δ-57.92 (d, J=7.3Hz).

[0259] HRMS(FTMS-cAPCI):m / z calculated for C 11 H5O4N2F3 - [M-3H] - ,289.0442;Found289.0442.

[0260] Embodiment 23

[0261] Synthesis of compound 2w:

[0262] Methyl(R)-3-(4-bromophenyl)-2-isocyanopropanoate (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (1.0mmol, 2.0equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a yellow liquid with a yield of 95%.

[0263] Compound 2w is methyl(R)-3-(4-bromophenyl)-2-((trifluoromethyl)amino)propanoate, and its structure is shown below:

[0264]

[0265] Compound 2w was characterized by NMR and high resolution, and the results are as follows:

[0266] 1H NMR (400MHz, Chloroform-d) δ7.42(d,J=8.4Hz,2H),7.04(d,J=8.4Hz,2H),4.00(dt,J=8.6,6.0Hz,1H),3.74(s,3H),2.98(d,J=5.9Hz,2H).

[0267] 13 C NMR (101MHz, Chloroform-d) δ171.3, 133.5, 130.6, 130.1, 122.3 (q, J = 255.7Hz), 120.2, 53.5 (q, J = 2.3Hz), 51.6, 37.9.

[0268] 19 F NMR (376MHz, Chloroform-d) δ-57.75 (d, J=7.4Hz).

[0269] HRMS(FTMS-cAPCI):m / z calculated for C 11 H5O2NBrF3 - [M-3H] - ,321.9696;Found321.9695.

[0270] Embodiment 24

[0271] Synthesis of compound 2x:

[0272] Add bis(4-cyanobenzyl)(R)-2-isocyanosuccinate (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent to the Schlenk tube in sequence. After stirring for five minutes, dilute tert-butyldimethylsilane (1.0mmol, 2.0equiv) in 1.0mL 1,4-dioxane solvent and inject it into the tube through a syringe. After stirring at 40°C for 4h, add 10mL ether to dilute, filter through diatomaceous earth, and vacuum spin dry the solvent. Add 10mL ether to dissolve, filter through diatomaceous earth, and vacuum spin dry the solvent again to obtain the product as a yellow liquid with a yield of 94%.

[0273] Compound 2x is bis(4-cyanobenzyl)(trifluoromethyl)-D-aspartate. Its structure is shown below:

[0274]

[0275] Compound 2x was characterized by NMR and high resolution, and the results are as follows:

[0276] 1 H NMR(500MHz,Chloroform-d)δ7.64(d,J=8.0Hz,4H),7.42(t,J=7.3Hz,4H),5.2 4(s,2H),5.15(d,J=3.9Hz,2H),4.14(dt,J=6.2,3.3Hz,2H),3.07–2.87(m,2H).

[0277] 13 C NMR(126MHz,Chloroform-d)δ170.6,169.7,140.4,140.0,132.5,132.4,128.5,1 28.4,123.2(q,J=255.6Hz),118.4,118.4,112.5,112.3,67.1,65.8,50.4,37.9.

[0278] 19 F NMR (376MHz, Chloroform-d) δ-57.82 (d, J=6.7Hz).

[0279] HRMS(FTMS-cAPCI):m / z calculated for C 21 H 17 O4N3F3 + [M+H] + ,432.1166,Found432.1160.

[0280] Embodiment 25

[0281] Synthesis of compound 2y:

[0282] 4-isocyano-1-tosylpiperidine (0.5mmol, 1.0equiv), silver fluoride (3.5mmol, 7.0equiv), I2 (0.55mmol, 1.1equiv) and 2.0mL 1,4-dioxane solvent were added to the Schlenk tube in sequence. After stirring for five minutes, tert-butyldimethylsilane (1.0mmol, 2.0equiv) was diluted in 1.0mL 1,4-dioxane solvent and injected into the tube through a syringe. After stirring at 40°C for 4h, 10mL ether was added to dilute, filtered through diatomaceous earth, and the solvent was dried under vacuum. 10mL ether was added to dissolve, filtered through diatomaceous earth, and the solvent was dried under vacuum again to obtain the product as a white solid with a yield of 97%.

[0283] Compound 2y is 1-tosyl-N-(trifluoromethyl)piperidin-4-amine, and its structure is shown below:

[0284]

[0285] Compound 2y was characterized by nuclear magnetic resonance and high resolution, and the results are as follows:

[0286] 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.3Hz,2H),7.32(d,J=8.3Hz,2H),3.76–3.59(m,2H),3.01–2.88(m,1H ),2.75(t,J=7.3Hz,1H),2.50–2.39(m,5H),1.97(dd,J=13.3,3.7Hz,2H),1.57(dtd,J=14.4,10.8,4.0Hz,2H).

[0287] 13 C NMR(101MHz,Chloroform-d)δ142.8,131.7,128.7,126.7,122.7(q,J=255.0Hz),46.6,43.8,31.4,20.5

[0288] 19 F NMR (376MHz, Chloroform-d) δ-55.67 (d, J=7.4Hz).

[0289] HRMS(FTMS-cAPCI):m / z calculated for C 13 H 17 O2N2F3 - [MH] - ,323.1036;Found323.1032.

[0290] In the above embodiments, in the N-trifluoromethyl secondary amine compounds, when R is an aromatic group, the structure of the compound is relatively stable, and when R is an alkyl group, the structural stability of the compound is relatively poor. Therefore, hydrogen can be replaced by further reaction to prepare N-trifluoromethylsulfonamide compounds and N-trifluoromethylfluoroformamide compounds to obtain compounds with better stability, thereby being able to prepare compounds with high value in medicine more simply, conveniently and quickly.

[0291] The preparation method of the compound in the embodiment of the present invention is simple, and the readily available aromatic isonitrile or alkyl isonitrile is used as a starting material, and the target product can be obtained by reaction in the presence of silver fluoride, elemental iodine, and tert-butyldimethylsilane. The reaction substrate has a wide range of applicability, and a variety of 2-aryl-substituted N-trifluoromethyl secondary amine compounds can be prepared. At the same time, the method has mild and safe reaction conditions, does not require high temperature or high pressure, is easy to operate, and has simple post-processing, and is a method for efficiently synthesizing N-trifluoromethyl secondary amine compounds.

[0292] In summary, the method for preparing N-trifluoromethyl secondary amine compounds provided by the present invention avoids the use of irritating and toxic gases such as fluorine gas, hydrogen fluoride gas, and thiophosgene compared to the prior art, effectively improving the safety of the experiment. In addition, the reaction raw materials of the present invention are easily available, the products are easy to separate, and the reaction conditions are mild. Therefore, it is a new method for preparing N-trifluoromethyl secondary amine compounds that is safer, more efficient, and milder.

Claims

1. A method for preparing N-trifluoromethyl secondary amine compounds, characterized in that: The following steps are involved: Isonitrile is used as a reaction substrate, and reacts under the action of elemental iodine, silver fluoride and tert-butyldimethylsilane to obtain the N-trifluoromethyl secondary amine compound.

2. The preparation method according to claim 1, characterized in that: The reaction specifically includes: isonitrile generates an intermediate difluoroimine under the action of iodine and silver fluoride; tert-butyldimethylsilane generates a hydride ion under the action of silver fluoride; and the intermediate difluoroimine generates an N-trifluoromethyl secondary amine compound under the action of hydride ions and silver fluoride.

3. The preparation method according to claim 2, characterized in that: The reaction of isonitrile under the action of iodine and silver fluoride includes at least one of the following reactions: (1) isonitrile undergoes an oxidation reaction with iodine to generate diiodoimine, and diiodoimine undergoes a displacement reaction with silver fluoride to generate an intermediate difluoroimine; (2) isonitrile undergoes an oxidation reaction with iodine to generate diiodoimine, and diiodoimine undergoes a displacement reaction with silver fluoride to generate fluoroiodoimine, and fluoroiodoimine undergoes a displacement reaction with silver fluoride to generate an intermediate difluoroimine.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of the isonitrile to the iodine element is 1:(0.5-2); and / or, the molar ratio of the isonitrile to the silver fluoride is 1:(5-10); And / or, the molar ratio of the isonitrile to the tert-butyldimethylsilane is 1:(1-2).

5. The preparation method according to claim 1, characterized in that: The reaction temperature is 30-50°C; And / or, the reaction time is 2 to 6 hours.

6. The preparation method according to claim 1, characterized in that: The reaction is carried out in a solvent; preferably, the solvent is selected from 1,4-dioxane.

7. The preparation method according to claim 1, characterized in that: The reaction further includes a post-treatment step; preferably, the post-treatment step includes: washing the product with ether, solid-liquid separation, and drying.

8. The preparation method according to claim 1, characterized in that: The structural formula of the N-trifluoromethyl secondary amine compound is shown in formula (I): Wherein, R is a substituted or unsubstituted C1-C30 alkyl group, a substituted or unsubstituted C6-C30 aromatic ring, or a substituted or unsubstituted C6-C30 aromatic heterocycle; the substituted substituents are each independently selected from at least one of halogen, nitro, amino, cyano, hydroxyl, ester, sulfonyl, thiol, C1-C10 alkyl group, C1-C10 alkoxy group, C6-C60 aromatic ring, and C3-C60 aromatic heterocycle; the number of substitutions is from a single substitution to a maximum number of substitutions, and if the number of substitutions is greater than or equal to 2, two adjacent substituents may be connected to form a parallel ring; the substituents may be further substituted or not further substituted; the heteroatoms in the heterocycle include S, O, and N.

9. The preparation method according to claim 1, characterized in that: The N-trifluoromethyl secondary amine compound is selected from any one of the following:

10. Use of the preparation method according to any one of claims 1 to 9 in the preparation of N-trifluoromethyl secondary amine compounds, N-trifluoromethyl sulfonamide compounds or N-trifluoromethyl fluoroformamide compounds.

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