Alpha-tertiary primary amine direct deamination halogenation method, halogenated compound and application

Abstract

The invention discloses an alpha-tertiary primary amine direct deamination and halogenation method, a halogenated compound and application, and belongs to the technical field of organic synthesis.The alpha-tertiary primary amine direct deamination and halogenation method comprises the steps that alpha-tertiary primary amine, alkali, a halogenation reagent, a hydroxylamine compound and a solvent are mixed and heated for a deamination and functionalization reaction, and a halogenated compound is obtained; a halogenated compound containing a C (sp3)-X bond is generated, and X is chlorine, bromine or iodine. The method has the advantages of being wide in substrate range, mild in condition, simple and convenient to operate, easy to amplify and the like, can be widely applied to later-stage structure modification of drug molecules, and provides a novel efficient synthesis path for development of halogen-containing drug candidate compounds.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a deamination and halogenation method, in particular to a direct deamination and halogenation method for α-tertiary primary amines, a halogenated compound and an application thereof. Background Art

[0002] Primary amine compounds are a widely distributed and functionally diverse basic structural unit in organic synthesis and medicinal chemistry. Due to their abundant sources and high synthetic flexibility, they are widely used in important fields such as drug discovery, late-stage molecular functionalization, and structural diversity construction. The direct conversion of amine functional groups into alkyl halides not only provides a class of structurally diverse and easily accessible substrate sources, but also provides a new approach for the direct modification of drug molecules and the efficient late-stage transformation based on halogenated intermediates. However, due to the strong alkalinity and good nucleophilic ability of the amino group, coupled with the high bond energy of the CN bond, primary amines are prone to acid-base neutralization, addition, or substitution reactions without pretreatment, making them difficult to be directly replaced by other functional groups.

[0003] Currently, the C-N bond functionalization of primary amines is mainly achieved by pre-activation of primary amines, which requires the conversion of primary amines into diazonium salts, carbenes, electron-rich imines and isocyanides, etc. The direct deamination functionalization of primary amines is one of the long-term challenges in the field of organic synthesis. For example, the classic method for converting aromatic amines into aryl halides is to first convert the aromatic amines into diazonium salts, and then to achieve the corresponding conversion through the exothermic decomposition of the diazonium salts. However, the instability of aryl diazonium salts is often unpredictable, and once in contact with air, even in solution, it can lead to an explosion. In recent years, great progress has been made in the direct conversion of aryl halides from aromatic amines. The Ritter group (Mateos, J., Schulte, T., Behera, D. et al. Science 2024, 384, 446-452) achieved the deamination halogenation of aromatic amines through the generated transient aryl diazonium salt, effectively avoiding the safety hazards caused by the accumulation of diazonium salts in the traditional Sandmeyer reaction; The Cornella group (Ghiazza, C., Faber, T., Gómez-Palomino, A. & Cornella, J. Nature Chemistry 2021, 14, 78-84) developed a method for realizing the direct deamination chlorination of aromatic amines by using in-situ generated heteroaryl pyridinium salts. However, these methods are difficult to apply to the direct conversion of alkyl amines. The main reason is that the carbon cation obtained is prone to elimination or rearrangement side reactions, and the alkyl diazonium salt itself is unstable and difficult to participate in effective conversion. In order to solve such a problem, Wang et al. (Li, Y. et al. J Am Chem Soc 2023, 145, 2690-2697.) reported an ionic reaction system based on high-valent cobalt complexes, which can achieve the C-N bond activation of primary and secondary alkyl amines and perform halogenation conversion. However, due to the characteristics of carbon ion reactions, significant elimination side reactions still occur, which seriously reduce the yield and selectivity of the reaction. In addition, the Levin and Wang groups (Dherange, B. D. et al. Journal of the American Chemical Society 2022, 145, 17-24; Xue, J. H. et al. iScience 2023, 26, 106255) used anomeric amides as deamination reagents to achieve the direct deamination bromination of primary or secondary alkyl amines through free radicals. However, when trying to extend this strategy to deamination chlorination, significant challenges were encountered: compared to bromination reactions, only a few alkyl amines could achieve effective chlorination, and there were more serious hydrogenation byproducts, showing the challenge of realizing direct deamination chlorination.

[0004] In summary, although some systems have poor substrate applicability, chlorination reaction is difficult to achieve, etc. problems, aniline and alpha-primary or alpha-secondary alkylamine can realize direct denitrogenation halogenation under certain conditions, but the efficient conversion of widely existing alpha-tertiary alkylamine and aromatic amine into corresponding halogenated products is still a difficult synthetic obstacle to break through. In addition to the inherent difficulty of breaking the C-N bond, the large steric hindrance of alpha-tertiary alkylamine also makes such activation difficult, and the generation of tertiary carbon cation in the denitrogenation process is easy to cause elimination or rearrangement and other side reactions, thereby further increasing the complexity of the reaction. SUMMARY

[0005] The present application provides a kind of alpha-tertiary primary amine direct deamination halogenation method and halogenated compound, application, to overcome the defects of prior art.

[0006] To achieve the above object, the technical scheme adopted by the present application is as follows:

[0007] In a first aspect, the present application provides a kind of alpha-tertiary primary amine direct deamination halogenation method: alpha-tertiary primary amine is mixed with base, halogenation reagent, hydroxylamine compound and solvent, heated to carry out deamination functionalization reaction, and halogenated compound containing C (sp 3 )-X bond is generated, X is chlorine (Cl), bromine (Br) or iodine (I);

[0008] The structural formula of the alpha-tertiary primary amine is

[0009] In the formula, R 1 , R 2 and R 3 Each is independently selected from primary, secondary or tertiary alkyl and its derivative.

[0010] Alpha-tertiary primary amine can be a tertiary carbon connected with nitrogen containing aliphatic amine or aromatic amine, or an amine compound with high steric hindrance structure, specifically including but not limited to amine compounds with bridged ring structure, such as amine compounds with rigid three-dimensional skeleton of bicyclo [1.1.1] pentane, 2-azabicyclo [2.1.1] hexane, bicyclo [2.2.2] octane, cubane, adamantane, bridged [3.3.1] nonane, etc. The amine group is connected to the bridgehead carbon, bridging carbon or cyclic carbon. Through the method, the C-N bond can be efficiently broken and halogen can be introduced, so as to realize effective functionalization modification of high tension and high steric hindrance substrate.

[0011] In the reaction system, hydroxylamine compound acts as a nitrogen trapping agent to promote C-N bond breaking and complete halogen introduction process of free radical intermediate without introducing metal catalyst, so as to realize high selective synthesis of halogenated product.

[0012] Further, the base is an inorganic base or an organic base, preferably potassium carbonate.

[0013] Further, the halogenating reagent is carbon tetrachloride, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), chloramine-T, carbon tetrabromide or isopropyl iodide.

[0014] Further, the hydroxylamine compound is diphenylphosphinylhydroxylamine, 2,4-dinitrophenylhydroxylamine, an alkyl / aryl-substituted aryl of diphenylphosphinylhydroxylamine or a diaryl-substituted phosphinylhydroxylamine compound.

[0015] Further, the molar ratio of the α-tertiary primary amine, the base, the halogenating reagent and the hydroxylamine compound is 1.0:2.0-4.0:3.0-100:2.0-3.0.

[0016] Further, the solvent is a single organic solvent, a mixed organic solvent mixed by multiple organic solvents or a mixed solvent mixed by water and an organic solvent; and the organic solvent is trifluorotoluene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, trichloromethane or N,N-dimethylformamide.

[0017] Further, the heating temperature of the reaction is 40-70℃, and the reaction time is 6-18h.

[0018] Further, the reaction is carried out in air or an inert gas atmosphere, preferably in an inert gas atmosphere.

[0019] In a second aspect, the present application further provides a halogenated compound containing a C(sp 3 )-X bond prepared by the above-mentioned direct deamination halogenation method of α-tertiary primary amine.

[0020] In a third aspect, the present application further provides an application of the above-mentioned halogenated compound containing a C(sp 3 )-X bond in constructing a bioisostere structural unit of a drug molecule. 3 The halogenated compound containing a C(sp

[0021] The present application has the following beneficial effects:

[0022] I. The present application can realize the radical-mediated deamination halogenation conversion of alpha-tertiary primary amine, especially suitable for amine substrates with three-dimensional spatial skeleton or large steric structure. Specifically, the present application uses hydroxylamine compounds as nitrogen trapping agent, combined with appropriate halogenating reagent, can efficiently break the C(sp 3 )-N bond with large steric hindrance under mild conditions, and introduce chlorine, bromine or iodine, solving the bottleneck problem that traditional methods are difficult to break C-N bond at tertiary carbon center. The present method is suitable for BCP, cubane, 2-azabicyclo[2.1.1]hexane and other high-tension skeleton structures, expanding the application range of amine substrate deamination functionalization.

[0023] II. The reaction system of the present application has excellent functional group compatibility and reaction condition inclusiveness. Specifically, the present application can realize selective deamination halogenation under the coexistence of sensitive functional groups such as aromatic halogen, ether, ester, carboxylic acid, alcohol, olefin, alkyne, etc., without affecting the integrity of other functional groups, suitable for organic molecule conversion with high substrate complexity. At the same time, the present application can be carried out under inert gas or air atmosphere, and the solvent system is flexible, which can be selected from single organic solvent, mixed organic solvent or mixed solvent containing water, realizing simple operation, green and environmental protection under the premise of not affecting the yield and selectivity, suitable for popularization and application in conventional laboratory and industrial conditions.

[0024] III. The present application provides a halogenation reaction platform which is simple to operate and can be carried out in one pot.

[0025] IV. The method of the present application has good amplification potential and industrial application prospect. Specifically, the present method can be stably amplified to gram scale, and can maintain excellent selectivity and yield, with little side reaction, simple post-treatment, good process controllability and practical synthesis application potential, which is expected to be one of the key C-X bond construction strategies in drug synthesis, suitable for pilot and industrial amplification development.

[0026] V. The present application is suitable for end modification and structure optimization of drug molecules, and has important application prospect. Specifically, the present application is simple to operate, and can realize chlorination, bromination and iodination of various halogenation types in one pot reaction, which can be integrated with multi-step synthesis process, suitable for late-stage functional group modification of nitrogen-containing drug molecules and their derivatives. That is, by deamination halogenation treatment of alpha-tertiary primary amine sites in nitrogen-containing drug molecules, natural products, clinical drugs and lead compounds, halogen functional groups can be introduced under the premise of maintaining the integrity of the parent structure, realizing one-step molecular diversification modification, especially suitable for drug optimization, structure-activity relationship research and skeleton editing operation, with good practicability and expandability and significant application value in medical synthesis. DETAILED DESCRIPTION

[0027] The present application is further described below in combination with specific examples.

[0028] Example 1

[0029] This embodiment provides a method for direct deamination halogenation of a-tertiary primary amine, and the reaction equation is as follows:

[0030]

[0031] In a specific embodiment, the specific steps include:

[0032] (1) The compound shown in formula A1 (0.2 mmol, 44.2 mg) is added to a sealed tube with a stirrer, evacuated and filled with argon for 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv) are sequentially added; after sealing, it is placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0033] (2) After the reaction is completed, it is cooled to room temperature, and the reaction solution is directly wet-loaded and passed through a neutral alumina column to obtain the compound shown in formula 1 (44.7 mg, 93% yield).

[0034] In another specific embodiment, the specific steps include:

[0035] (1) The compound shown in formula A1 (0.2 mmol, 44.2 mg) is added to a sealed tube with a stirrer, evacuated and filled with argon for 3 times, and then K2CO3 (2.0 equiv), a mixed solvent of tetrahydrofuran and water (1:1 v / v, 0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv) are sequentially added; after sealing, it is placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0036] (2) After the reaction is completed, it is cooled to room temperature, and the reaction solution is directly wet-loaded and passed through a neutral alumina column to obtain the compound shown in formula 1 (42.7 mg, 89% yield).

[0037] In another specific embodiment, the specific steps include:

[0038] (1) The compound shown in formula A1 (0.2 mmol, 44.2 mg) is added to a sealed tube with a stirrer, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv) are sequentially added under air; after sealing, it is placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0039] (2) After the reaction is completed, cool to room temperature, and directly wet sample the reaction solution to obtain the compound shown in formula 1 (41.3 mg, 86% yield) by passing through a neutral alumina column.

[0040] The structure confirmation data of the product are as follows:

[0041] 1 H NMR (400 MHz, CDCI3) δ 7.00 (d, J = 7.4 Hz, 1 H), 6.66 (d, J = 7.5 Hz, 1 H), 6.62 (s, 1 H), 3.97 (t, J = 5.8 Hz, 2 H), 2.31 (s, 3 H), 2.18 (s, 3 H), 2.06-1.89 (m, 4 H), 1.62 (s, 6 H).

[0042] 13 C NMR (101 MHz, CDCI3) δ 156.9, 136.5, 130.3, 123.6, 120.8, 112.1, 70.6, 67.7, 42.7, 32.5, 25.5, 21.4, 15.7.

[0043] HRMS m / z (ESI) calcd for C 14 H 22 ClO + (M+H) + 241.1354, found 241.1354.

[0044] From the above data, it can be seen that the product structure is correct, which is the target product.

[0045] Example 2

[0046] This example provides a method for directly deaminating and halogenating an α-tertiary primary amine, and the reaction equation is as follows:

[0047]

[0048] The specific steps include:

[0049] (1) Put the compound shown in formula A2 (0.2 mmol, 93.7 mg) into a sealed tube with a stirrer, evacuate and fill with argon for 3 times, and then sequentially add K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv); after sealing, place on a preheated heating module at 50°C, and stir at 1400 rpm for 12 hours.

[0050] (2) After the reaction is completed, cool to room temperature, and directly wet sample the reaction solution to obtain the compound shown in formula 2 (73.2 mg, 76% yield) by passing through a neutral alumina column.

[0051] The structure confirmation data of the product are as follows:

[0052] 1 H NMR (400 MHz, CDCI3) δ 3.76 (s, 6H), 0.90 (s, 27H), 0.06 (s, 18H).

[0053] 13 C NMR (101 MHz, CDCI3) δ 75.7, 64.2, 25.9, 18.3, -5.4.

[0054] HRMS m / z (ESI) calcd for C 22 H 51 ClNaO3Si3 + (M+Na) + 505.2727, found 505.2723.

[0055] From the above data, it can be seen that the structure of the product is correct, which is the target product.

[0056] Example 3

[0057] This example provides a method for directly deaminating and halogenating an α-tertiary primary amine, and the reaction equation is as follows:

[0058]

[0059] (1) The compound shown in formula A3 (0.2 mmol, 60.2 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon for 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were sequentially added; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0060] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 3 (44.0 mg, 69% yield).

[0061] The structure confirmation data of the product are as follows:

[0062] 1 H NMR (400 MHz, CDCI3) δ 4.85 (t, J = 1.9 Hz, 2H), 4.42 (t, J = 1.9 Hz, 2H), 4.27 (s, 2H), 4.23 (s, 5H), 1.68 (s, 6H).

[0063] 13C NMR (101 MHz, CDC13) δ 171.1, 71.9, 71.4, 70.6, 70.2, 69.8, 66.3, 29.4.

[0064] HRMS m / z (ESI) calcd for C 15 H 17 ClFeNaO2 + (M+Na) + 343.0159, found 343.0162.

[0065] From the above data, the product structure is correct, which is the target product.

[0066] Example 4

[0067] This example provides a direct deamination halogenation method for a-tertiary primary amine, and the reaction equation is as follows:

[0068]

[0069] (1) The compound shown in formula A4 (0.35 mmol, 216.8 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module to 50°C, and stirred at 1400 rpm for 12 hours.

[0070] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 4 (155.7 mg, 70% yield).

[0071] The structure confirmation data of the product are as follows:

[0072] 1 H NMR (400MHz, CDC13) δ 7.14-7.03 (m, 4H), 3.96-3.83 (m, 4H), 2.83-2.75 (m, 2H), 2.59-2.52 (m, 2H), 2.12-2.04 (m, 2H), 1.65-1.53 (m, 2H), 1.33-1.25 (m, 10H), 1.12-1.04 (m, 42H), 0.90-0.85 (m, 3H).

[0073] 13C NMR (101 MHz, CDC13) δ 140.4, 139.2, 128.4, 128.3, 75.7, 66.5, 37.2, 35.6, 31.9, 31.6, 29.8, 29.5, 29.4, 29.3, 22.7, 18.1, 18.1, 14.1, 12.1.

[0074] HRMS m / z (EI) calcd for C 37 H 71 ClO2Si2 638.4681, found 638.4695.

[0075] From the above data, the product structure is correct, which is the target product.

[0076] Example 5

[0077] This example provides a method for direct deamination halogenation of a-tertiary primary amine, and the reaction equation is as follows:

[0078]

[0079] (1) The compound shown in formula A5 (0.2 mmol, 96.7 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module to 50°C, and stirred at 1400 rpm for 12 hours.

[0080] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 5 (49.3 mg, 51% yield).

[0081] The product structure confirmation data are as follows:

[0082] 1 H NMR (400 MHz, CDC13) δ 8.66-8.61 (m, 1H), 8.12-8.07 (m, 1H), 8.04-7.97 (m, 2H), 7.92 (d, J = 8.6 Hz, 1H), 7.84-7.77 (m, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.57-7.51 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.46 (s, 2H), 3.90 (s, 3H), 2.19 (d, J = 2.9 Hz, 6H), 2.14-2.07 (m, 3H), 1.84-1.78 (m, 6H), 1.73 (s, 6H).

[0083] 13 C NMR (101 MHz, CDC13) δ 166.2, 159.0, 141.6, 139.1, 136.1, 132.5, 131.2, 131.1, 129.7, 128.3, 126.5, 126.5, 126.0, 125.7, 125.5, 124.7, 112.2, 72.5, 66.4, 55.2, 40.7, 37.2, 37.1, 29.5, 29.1.

[0084] HRMS m / z (ESI) calcd for C 32 H 35 ClNaO3 + (M+Na) + 525.2167, found 525.2166.

[0085] From the above data, the product structure is correct, which is the target product.

[0086] Example 6

[0087] This example provides a method for direct deamination halogenation of a-tertiary primary amine, and the reaction equation is as follows:

[0088]

[0089] (1) The compound shown in formula A6 (0.2 mmol, 85.6 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0090] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 6 (55.3 mg, 62% yield).

[0091] The structure confirmation data of the product are as follows:

[0092] 1 H NMR (400 MHz, CDC13) δ 7.68-7.61 (m, 2H), 7.49-7.42 (m, 2H), 6.98 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.71-6.63 (m, 1H), 4.16 (s, 2H), 3.83 (s, 3H), 3.73 (s, 2H), 2.39 (s, 3H), 1.51 (s, 6H).

[0093] 13 C NMR (101 MHz, CDC13) δ 170.1, 168.2, 156.1, 139.3, 135.9, 133.9, 131.1, 130.8, 130.5, 129.1, 114.9, 112.2, 111.9, 101.2, 72.4, 66.1, 55.7, 30.2, 29.1, 13.3.

[0094] HRMS m / z (ESI) calcd for C 23 H 23 Cl2NNaO4 + (M+Na) + 470.0896, found 470.0890.

[0095] From the above data, the product structure is correct, which is the target product.

[0096] Example 7

[0097] This example provides a direct deamination halogenation method for a-tertiary primary amine, and the reaction equation is as follows:

[0098]

[0099] (1) The compound shown in formula A7 (0.1 mmol, 38.9 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module to 50°C, and stirred at 1400 rpm for 12 hours.

[0100] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded, and neutral alumina was passed through the column to obtain the compound shown in formula 7 (31.2 mg, 76% yield).

[0101] The product structure confirmation data are as follows:

[0102] 1H NMR (400 MHz, CDC13) δ 4.80 - 4.68 (m, 1H), 2.78 (s, 2H), 2.48 - 2.37 (m, 1H), 2.06 (dt, J = 19.2, 9.0 Hz, 1H), 1.97 - 1.87 (m, 1H), 1.84 - 1.75 (m, 3H), 1.72 (s, 6H), 1.68 - 1.61 (m, 2H), 1.58 - 1.46 (m, 3H), 1.45 - 1.15 (m, 8H), 1.10 - 0.91 (m, 2H), 0.86 (s, 6H), 0.76 - 0.66 (m, 1H).

[0103] 13 C NMR (101 MHz, CDC13) δ 169.0, 73.9, 66.2, 54.3, 51.4, 50.3, 47.7, 44.7, 36.7, 35.8, 35.7, 35.0, 33.9, 32.6, 32.5, 31.5, 30.8, 28.3, 27.4, 21.8, 20.5, 13.8, 12.2.

[0104] HRMS m / z (ESI) calcd for C 24 H 37 ClNaO3 + (M+Na) + 431.2323, found 431.2318.

[0105] From the above data, the product structure is correct, which is the target product.

[0106] Example 8

[0107] This example provides a method for direct deamination halogenation of a-tertiary primary amine, and the reaction equation is as follows:

[0108]

[0109] (1) The compound shown in formula A8 (0.1 mmol, 48.3 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0110] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 8 (35.2 mg, 70% yield).

[0111] The structure confirmation data of the product are as follows:

[0112] 1 H NMR (400 MHz, CDC13) δ 5.67 (s, 1H), 4.57-4.48 (m, 1H), 2.85-2.73 (m, 1H), 2.55-2.44 (m, 1H), 2.34 (s, 1H), 2.05 (s, 3H), 2.00-1.90 (m, 2H), 1.90-1.80 (m, 2H), 1.77-1.65 (m, 5H), 1.61 (s, 4H), 1.55-1.34 (m, 4H), 1.33 (s, 3H), 1.29-1.24 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H), 1.09-1.00 (m, 2H), 0.91 (s, 3H), 0.88 (s, 6H), 0.80 (d, J = 11.4 Hz, 1H).

[0113] 13 C NMR (101 MHz, CDC13) δ 199.8, 170.9, 168.3, 128.7, 80.6, 71.5, 61.8, 55.0, 47.0, 46.2, 45.4, 43.2, 38.8, 38.0, 37.0, 36.4, 36.3, 34.1, 32.7, 31.8, 28.1, 28.0, 26.5, 26.3, 23.6, 23.4, 21.3, 18.7, 17.4, 16.7, 16.4.

[0114] HRMS m / z (ESI) calcd for C 31 H 47 ClNaO3 + (M+Na) + 525.3106, found 525.3102.

[0115] From the above data, the product structure is correct, which is the target product.

[0116] Example 9

[0117] This example provides a method for directly deaminating and halogenating an α-tertiary primary amine, and the reaction equation is as follows:

[0118]

[0119] (1) The compound shown in formula A9 (0.2 mmol, 93.9 mg) was added to a sealed tube with a stir bar, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenylphosphoryl hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module at 50°C and stirred at 1400 rpm for 12 hours.

[0120] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 9 (88.3 mg, 90% yield).

[0121] The structure confirmation data of the product are as follows:

[0122] 1 H NMR (400 MHz, CDCl3) δ 5.23 (s, 1H), 4.57-4.44 (m, 1H), 2.36-2.12 (m, 4H), 2.09-1.87 (m, 6H), 1.71-1.50 (m, 8H), 1.46-1.20 (m, 5H), 1.16-1.09 (m, 2H), 1.07 (s, 6H), 0.99 (s, 3H), 0.95-0.91 (m, 3H), 0.90-0.86 (m, 8H), 0.86-0.82 (m, 2H).

[0123] 13 C NMR (101 MHz, CDCl3) δ 170.9, 137.8, 125.8, 80.9, 78.8, 61.2, 55.4, 47.6, 44.2, 42.3, 41.7, 40.1, 38.8, 38.4, 37.7, 36.9, 33.3, 33.1, 30.3, 28.1, 27.9, 23.6, 23.3, 23.3, 21.3, 20.7, 18.2, 17.7, 17.2, 16.7, 15.6.

[0124] HRMS m / z (ESI) calcd for C 31 H 49 ClNaO2 + (M+Na) + 511.3313, found 511.3321.

[0125] From the above data, it can be seen that the product structure is correct, which is the target product.

[0126] Example 10

[0127] This example provides a method for directly deaminating and halogenating an α-tertiary primary amine, and the reaction equation is as follows:

[0128]

[0129] (1) The compound shown in formula A10 (0.2 mmol, 28.2 mg) was added to a sealed tube with a stir bar, evacuated and filled with argon 3 times, and K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenylphosphoryl hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module to 50°C, and stirred at 1400 rpm for 12 hours.

[0130] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded, and neutral alumina was passed through the column to obtain the compound shown in formula 10 (20.7 mg, 65% yield).

[0131] The structure confirmation data of the product are as follows:

[0132] 1 H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 2.42 (s, 6H).

[0133] 13 C NMR (101 MHz, CDCl3) δ 168.1, 58.1, 52.1, 48.3, 36.0.

[0134] HRMS m / z (ESI) calcd for C7H9ClNaO2 + (M+Na) + 183.0183, found 183.0184.

[0135] From the above data, it can be seen that the product structure is correct, which is the target product.

[0136] The present embodiment also provides an application of a halogenated compound in constructing a bioisostere structural unit of a drug molecule, specifically, compound 10 is used to prepare BCP-Diflubenzuron, and the reaction equation is as follows:

[0137]

[0138] The specific steps are as follows:

[0139] Compound 10 methyl 3-chlorobicyclo[l. l. l]pentane- l -carboxylate (1.0 mmol, 1.0 equiv, 0.16 g) was dissolved in tetrahydrofuran (THF, 5 mL), followed by the addition of methanol (MeOH, 0.5 mL) and solid sodium hydroxide (NaOH, 1.1 mmol, 1.1 equiv, 44.0 mg). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction was quenched by the addition of 1 M aqueous hydrochloric acid solution. The aqueous phase was extracted with dichloromethane (DCM, 3 x 20 mL). After the combined organic phases were washed with water, dried over anhydrous sodium sulfate (Na2S04), filtered, and concentrated under reduced pressure. The resulting crude carboxylic acid was used directly in the next reaction without further purification.

[0140] The crude carboxylic acid was transferred to a Schlenk tube fitted with a PTFE screw cap, evacuated and filled with argon, and repeated three times. Subsequently, toluene (5 mL), triethylamine (Et3N, 3.0 mmol, 3.0 equiv, 0.30 g), and diphenyl phosphoryl azide (DPPA, 2.0 mmol, 2.0 equiv, 0.55 g) were added sequentially. After the reaction mixture was stirred at room temperature for 30 minutes, it was heated to 100 °C and maintained for 3 hours. After cooling to room temperature, 2,6-difluorobenzamide (3.0 mmol, 3.0 equiv, 0.47 g) was added under an argon atmosphere, and the reaction was heated to 100 °C overnight. After the reaction was completed, the reaction was quenched by the addition of water, and the aqueous phase was extracted with DCM (3 x 20 mL). After the combined organic phases were washed with water, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4: 1 v / v) to obtain the final product as a white solid (0.18 g, 60% overall yield for two steps).

[0141] The structure confirmation data of the product are as follows:

[0142] 1 H NMR (400 MHz, CDC13) δ 9.97 (s, 1H), 8.75 (s, 1H), 7.54-7.42 (m, 1H), 7.01 (t, J = 8.3 Hz, 2H), 2.34 (s, 6H).

[0143] 13 C NMR (101 MHz, CDC13) δ 162.0, 159.9 (dd, J = 255.0, 6.1 Hz), 153.0, 133.2 (t, J = 10.3 Hz), 112.6 (t, J = 18.9 Hz), 112.4-112.0 (m), 58.7, 46.9, 43.8.

[0144] 19F NMR (376 MHz, CDC13) δ -111.1.

[0145] HRMS m / z (ESI) calcd for C 13 H 11 ClF2N2NaO2 + (M+Na) + 323.0369, found 323.0373.

[0146] From the above data, it can be known that the structure of the product is correct, which is the target product.

[0147] The present embodiment also provides an application of the halogenated compound in constructing a bioisostere structural unit of a drug molecule. Specifically, the compound 10 is used to prepare BCP-Moclobemide, and the reaction equation is as follows:

[0148]

[0149] Compound 10 3-chlorobicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (0.2 mmol, 1.0 equiv, 32.0 mg) was dissolved in tetrahydrofuran (THF, 1 mL), and methanol (MeOH, 0.1 mL) and solid sodium hydroxide (NaOH, 0.22 mmol, 1.1 equiv, 8.8 mg) were added in sequence. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, 1M aqueous hydrochloric acid solution was added to quench the reaction. The aqueous phase was extracted with dichloromethane (DCM, 3x10 mL). After the organic phases were combined, they were washed with water, dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The obtained crude carboxylic acid was directly used in the next step reaction without further purification.

[0150] The obtained crude carboxylic acid was dissolved in DCM (0.5 mL) together with 4-(2-aminoethyl)morpholine (0.2 mmol, 1.0 equiv, 26.0 mg) and DMAP (0.02 mmol, 0.1 equiv, 2.4 mg), followed by the addition of EDCI (0.3 mmol, 1.5 equiv, 57.5 mg). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, water was added to quench the reaction, and the aqueous phase was extracted with DCM (3x10 mL). After the organic phases were combined, they were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM / methanol = 10:1 v / v) to obtain the final product as a white solid (47.1 mg, total yield of two steps 91%).

[0151] The structure confirmation data of the product are as follows:

[0152] 1H NMR (400 MHz, CDCI3) δ 6.11 (s, 1 H), 3.77-3.64 (m, 4 H), 3.39-3.27 (m, 2 H), 2.52-2.42 (m, 6 H), 2.39 (s, 6 H).

[0153] 13 C NMR (101 MHz, CDCI3) δ 167.0, 67.0, 57.6, 56.6, 53.3, 48.1, 37.7, 35.6.

[0154] HRMS m / z (ESI) calcd for C 12 H 19 ClN2NaO2 + (M+Na) + 281.1027, found 281.1027.

[0155] From the above data, the product structure is correct, which is the target product.

[0156] Example 11

[0157] This example provides a method for direct deamination halogenation of a-tertiary primary amine, and the reaction equation is as follows:

[0158]

[0159] (1) The compound shown in formula A11 (0.2 mmol, 33.8 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv) were sequentially added. After sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0160] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 11 (26.3 mg, 70% yield).

[0161] The structure confirmation data of the product are as follows:

[0162] 1 H NMR (400 MHz, CDCI3) δ 6.11 (s, 1 H), 3.77-3.64 (m, 4 H), 3.39-3.27 (m, 2 H), 2.52-2.42 (m, 6 H), 2.39 (s, 6 H).

[0163] 13C NMR (101 MHz, CDCI3) δ 174.8, 68.5, 51.8, 49.6, 49.5, 38.5, 33.8.

[0164] HRMS m / z (ESI) calcd for C9H 13 ClNaO2 + (M+Na) + 211.0496, found 211.0515.

[0165] From the above data, the product structure is correct, which is the target product.

[0166] Example 12

[0167] This example provides a method for direct deamination halogenation of a-tertiary primary amine, and the reaction equation is as follows:

[0168]

[0169] (1) The compound shown in formula A12 (0.2 mmol, 36.2 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module to 50°C, and stirred at 1400 rpm for 12 hours.

[0170] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 12 (30.4 mg, 75% yield).

[0171] The product structure confirmation data are as follows:

[0172] 1 H NMR (400 MHz, CDCI3) δ 3.64 (s, 3H), 2.15-2.02 (m, 6H), 2.02-1.91 (m, 6H).

[0173] 13 C NMR (101 MHz, CDCI3) δ 177.1, 66.2, 51.8, 37.5, 35.5, 30.4.

[0174] HRMS m / z (ESI) calcd for C 10 H 16 ClO2 + (M+H) + 203.0833, found 203.0835.

[0175] From the above data, it can be seen that the product structure is correct, which is the target product.

[0176] Example 13

[0177] This example provides a direct deamination halogenation method for α-tertiary primary amine, and the reaction equation is as follows:

[0178]

[0179] (1) The compound shown in formula A13 (0.2 mmol, 35.4 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module to 50°C, and stirred at 1400 rpm for 12 hours.

[0180] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 13 (23.5 mg, 60% yield).

[0181] The structure confirmation data of the product are as follows:

[0182] 1 H NMR (400 MHz, CDCl3) δ 4.27-4.20 (m, 3H), 4.20-4.13 (m, 3H), 3.71 (s, 3H).

[0183] 13 C NMR (101 MHz, CDCl3) δ 171.9, 72.0, 56.3, 54.0, 51.6, 45.9.

[0184] HRMS m / z (ESI) calcd for C 10 H9ClNaO2 + (M+Na) + 219.0183, found 219.0183.

[0185] From the above data, it can be seen that the product structure is correct, which is the target product.

[0186] Example 14

[0187] This example provides a direct deamination halogenation method for α-tertiary primary amine, and the reaction equation is as follows:

[0188]

[0189] (1) The compound represented by formula A14 (0.2 mmol, 53.7 mg) was added to a sealed tube with a stirrer. The tube was evacuated and filled with argon three times. K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv), and diphenylphosphonic acid hydroxylamine (2.2 equiv) were added in sequence. After sealing, the tube was placed on a heating block preheated to 50°C and stirred at 1400 rpm for 12 hours.

[0190] (2) After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column with neutral alumina to obtain the compound represented by formula 14 (44.3 mg, 80% yield).

[0191] The structural confirmation data of the product are as follows:

[0192] 1 H NMR (400MHz, CDCl3) δ5.40-5.31(m,1H),4.62-4.46(m,1H),2.25(d,J=8.2Hz,2H),2.10-2.02(m,6H),2.01-1.98(m,1H),1.97-1.90(m,6H),1. 89-1.74(m,3H),1.65-1.44(m,7H),1.43-1.18(m,6H),1.18-1.05(m,6 H),1.01(s,6H),0.91(d,J=6.4Hz,3H),0.89-0.82(m,6H),0.67(s,3H).

[0193] 13 C NMR (101MHz, CDCl3) δ176.0,139.6,122.7,73.8,66.4,56.7,56.2,50.0,42.3,39.7,39.5,38.0,37.4,37.0 ,36.6,36.2,35.8,35.6,31.9,31.9,30.3,28.2,28.0,27.7,24.3,23.8,22.8,22.5,21.0,19.3,18.7,11.8.

[0194] HRMS m / z(ESI)calcd.for C 36 H 57 ClNaO2 + (M+Na) + 579.3939,found 579.3941.

[0195] From the above data, it can be seen that the product structure is correct and is the target product.

[0196] Example 15

[0197] The present embodiment provides a method for direct deamination halogenation of a-tertiary primary amine, and the reaction equation is as follows:

[0198]

[0199] (1) The compound shown in formula A15 (0.1 mmol, 39.6 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon for 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were sequentially added. After sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0200] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 15 (19.4 mg, 47% yield).

[0201] The structure confirmation data of the product are as follows:

[0202] 1 H NMR (400 MHz, CDCl3) δ 5.79 (s, 1H), 5.73 (s, 1H), 2.43 (s, 6H), 2.40-2.24 (m, 3H), 2.20-1.99 (m, 3H), 1.96-1.81 (m, 2H), 1.75-1.68 (m, 3H), 1.62-1.41 (m, 3H), 1.38-1.22 (m, 3H), 1.19 (s, 3H), 1.13-1.01 (m, 2H), 1.01-0.90 (m, 1H), 0.71 (s, 3H).

[0203] 13 C NMR (101 MHz, CDCl3) δ 199.4, 172.9, 170.9, 123.9, 58.9, 56.9, 55.5, 53.8, 47.0, 44.4, 43.7, 38.6, 38.4, 35.8, 35.6, 33.9, 32.7, 31.9, 24.3, 23.4, 20.9, 17.3, 13.2.

[0204] HRMS m / z (ESI) calcd for C 25 H 34 ClNNaO2 + (M+Na) + 438.2170, found 438.2177.

[0205] From the above data, it can be seen that the product structure is correct, which is the target product.

[0206] Example 16

[0207] This example provides a method for direct deamination halogenation of an alpha-tertiary primary amine, the reaction equation is as follows:

[0208]

[0209] (1) The compound shown in formula A16 (0.1 mmol, 37.3 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0210] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 16 (27.0 mg, 69% yield).

[0211] The structure confirmation data of the product are as follows:

[0212] 1 H NMR (400 MHz, CDCl3) δ 7.63-7.51 (m, 4H), 7.41-7.28 (m, 6H), 6.95 (s, 1H), 3.16 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 7.1 Hz, 2H), 2.42 (s, 6H).

[0213] 13 C NMR (101 MHz, CDCl3) δ 171.6, 162.3, 145.6, 134.8, 132.3, 128.7, 128.6, 128.6, 128.2, 127.8, 126.4, 58.8, 46.9, 44.3, 33.0, 23.6.

[0214] HRMS m / z (ESI) calcd for C 23 H 21 ClN2NaO2 + (M+Na) + 415.1184, found 415.1181.

[0215] From the above data, it can be seen that the structure of the product is correct, which is the target product.

[0216] Example 17

[0217] This example provides a method for direct deamination halogenation of an alpha-tertiary primary amine, the reaction equation is as follows:

[0218]

[0219] (1) Into a sealed tube with a stir bar, the compound shown in formula A17 (0.1 mmol, 39.0 mg) was added, evacuated and filled with argon for 3 times, K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenylphosphoryl hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a heating module preheated to 50 °C, stirred at 1400 rpm for 12 hours.

[0220] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded, and neutral alumina was passed through the column to obtain the compound shown in formula 17 (39.9 mg, 97% yield).

[0221] The structure confirmation data of the product are as follows:

[0222] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.3 Hz, 2H), 7.44 (t, J = 7.8 Hz, 4H), 7.35 (t, J = 7.2 Hz, 2H), 7.28 (t, J = 7.0 Hz, 1H), 6.57-6.42 (m, 4H), 4.44 (s, 1H), 3.62 (s, 3H), 2.87 (d, J = 6.9 Hz, 1H), 2.81-2.72 (m, 1H), 2.67-2.58 (m, 1H), 2.00 (d, J = 7.2 Hz, 1H).

[0223] 13 C NMR (101 MHz, CDCl3) δ 154.0, 143.5, 138.3, 137.5, 133.8, 130.2, 128.8, 128.2, 127.5, 126.1, 120.6, 113.9, 75.4, 68.3, 62.5, 55.3, 52.0, 48.0.

[0224] HRMS m / z (ESI) calcd for C 24 H 22 Cl2NO + (M+H) + 410.1073, found 410.1073.

[0225] From the above data, it can be seen that the product structure is correct, which is the target product.

[0226] Example 18

[0227] This example provides a method for directly deaminating and halogenating an α-tertiary primary amine, and the reaction equation is as follows:

[0228]

[0229] (1) Into a sealed tube with a stir bar, the compound shown in Formula A18 (0.098 mmol, 39.7 mg) was added, evacuated and filled with argon 3 times, K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenylphosphoryl hydroxylamine (2.2 equiv) were added in sequence; after sealing, it was placed on a heating module preheated to 50 °C, and stirred at 1400 rpm for 12 hours.

[0230] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded, and neutral alumina was passed through the column to obtain the compound shown in Formula 18 (37.2 mg, 90% yield).

[0231] The structure confirmation data of the product are as follows:

[0232] 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 1.8 Hz, 1H), 7.94-7.84 (m, 3H), 7.72-7.64 (m, 1H), 7.55-7.47 (m, 2H), 7.32-7.19 (m, 7H), 7.15-7.06 (m, 1H), 6.94 (t, J = 7.6 Hz, 2H), 5.26 (s, 1H), 3.14-3.04 (m, 1H), 2.81-2.69 (m, 2H), 2.21-2.13 (m, 1H).

[0233] 13 C NMR (101 MHz, CDCl3) δ 174.5, 136.8, 135.6, 134.4, 133.2, 132.9, 130.2, 128.2, 128.2, 127.9, 127.7, 127.6, 127.5, 127.4, 126.6, 126.2, 126.2, 126.1, 70.3, 69.2, 62.0, 53.0, 48.0.

[0234] HRMS m / z (ESI) calcd for C 28 H 22 ClNNaO + (M+Na) + 446.1283, found 446.1285.

[0235] From the above data, it can be seen that the structure of the product is correct, which is the target product.

[0236] Example 19

[0237] The present embodiment provides a method for direct deamination halogenation of a-tertiary primary amine, and the reaction equation is as follows:

[0238]

[0239] (1) The compound shown in formula A19 (0.053 mmol, 20.8 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon for 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv) were sequentially added; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0240] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 19 (14.2 mg, 66% yield).

[0241] The structure confirmation data of the product are as follows:

[0242] 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.89-7.75 (m, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.17-7.03 (m, 8H), 6.96 (t, J = 7.5 Hz, 2H), 5.27 (s, 1H), 2.92-2.81 (m, 1H), 2.80-2.71 (m, 1H), 2.68 (d, J = 7.2 Hz, 1H), 2.26 (d, J = 7.9 Hz, 1H).

[0243] 13 C NMR (101 MHz, CDCl3) δ 173.4, 151.3, 149.0, 138.4, 135.3, 131.2, 130.1, 128.2, 128.2, 127.6, 127.6, 127.1, 123.6, 70.9, 66.0, 61.2, 53.2, 47.8.

[0244] HRMS m / z (ESI) calcd for C 23 H 18 Cl2N2NaO + (M+Na) + 431.0688, found 431.0693.

[0245] From the above data, it can be seen that the product structure is correct, which is the target product.

[0246] Example 20

[0247] The present embodiment provides a method for direct deamination halogenation of alpha-tertiary primary amine, and the reaction equation is as follows:

[0248]

[0249] (1) The compound shown in formula A20 (0.079 mmol, 30.2 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon for 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv) were sequentially added; after sealing, it was placed on a heating module preheated to 50°C, and stirred at 1400 rpm for 12 hours.

[0250] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 20 (14.8 mg, 46% yield).

[0251] The structure confirmation data of the product are as follows:

[0252] 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.9 Hz, 2H), 7.45-7.32 (m, 3H), 7.24-7.18 (m, 2H), 7.18-7.10 (m, 2H), 7.02-6.94 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.78-6.64 (m, 2H), 5.09 (s, 1H), 3.74 (s, 3H), 3.06-2.91 (m, 1H), 2.67 (d, J = 5.4 Hz, 2H), 2.13 (d, J = 7.8 Hz, 1H).

[0253] 13 C NMR (101 MHz, CDCl3) δ 174.3, 159.4, 138.2, 136.7, 135.7, 130.1, 129.3, 128.2, 128.1, 128.0, 127.8, 127.4, 119.1, 113.0, 112.8, 70.1, 69.0, 61.7, 55.1, 53.0, 47.9.

[0254] HRMS m / z (ESI) calcd for C 25 H 22 ClNNaO2 + (M+Na) + 426.1231, found 426.1235.

[0255] From the above data, it can be seen that the product structure is correct, which is the target product. From the above data, it can be seen that the product structure is correct, which is the target product.

[0256] Example 21

[0257] This example provides a method for direct deamination halogenation of a-tertiary primary amine, the reaction equation is as follows:

[0258]

[0259] (1) The compound shown in formula A21 (0.085 mmol, 37.3 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrachloride (20.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0260] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 21 (23.8 mg, 61% yield).

[0261] The structure confirmation data of the product are as follows:

[0262] 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.4 Hz, 2H), 7.47-7.33 (m, 3H), 7.32-7.17 (m, 5H), 7.12-6.92 (m, 4H), 5.09 (s, 1H), 3.05-2.91 (m, 1H), 2.77-2.62 (m, 2H), 2.13 (d, J = 7.8 Hz, 1H).

[0263] 13 C NMR (101 MHz, CDCl3) δ 174.6, 148.4, 136.4, 135.6, 135.4, 130.4, 128.2, 128.1, 128.1, 128.1, 127.9, 127.6, 121.6, 120.8, 119.1, 69.4, 69.0, 61.6, 52.8, 47.9.

[0264] 19 F NMR (376 MHz, CDCl3) δ -57.7.

[0265] HRMS m / z (ESI) calcd for C 25 H 19 ClF3NNaO2 + (M+Na) + 480.0949, found 480.0947.

[0266] From the above data, it can be seen that the product structure is correct, which is the target product.

[0267] Example 22

[0268] This example provides a method for direct deamination halogenation of an α-tertiary primary amine, and the reaction equation is as follows:

[0269]

[0270] (1) The compound shown in formula A22 (0.2 mmol, 33.5 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrabromide (5.0 equiv) and diphenyl phosphorohydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0271] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 22 (40.0 mg, 87% yield).

[0272] The structure confirmation data of the product are as follows:

[0273] 1 H NMR (400 MHz, CDCl3) δ 2.37-2.15 (m, 8H), 1.80 (s, 1H), 1.76-1.67 (m, 4H), 1.65-1.52 (m, 2H).

[0274] 13 C NMR (101 MHz, CDCl3) δ 70.3, 63.2, 56.6, 47.6, 43.4, 34.0, 33.0.

[0275] HRMS m / z (ESI) calcd for C 10 H 15 BrNaO + (M+Na) + 253.0198, found 253.0207.

[0276] From the above data, it can be seen that the product structure is correct, which is the target product.

[0277] Example 23

[0278] This example provides a method for direct deamination halogenation of an α-tertiary primary amine, and the reaction equation is as follows:

[0279]

[0280] (1) The compound shown in formula A23 (0.2 mmol, 33.5 mg) was added to a sealed tube with a stir bar, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), isopropyl iodide (5.0 equiv) and diphenylphosphoryl hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module at 50°C and stirred at 1400 rpm for 12 hours.

[0281] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 23 (49.3 mg, 88% yield).

[0282] The structure confirmation data of the product are as follows:

[0283] 1 H NMR (400 MHz, CDCl3) δ 2.59-2.52 (m, 2H), 2.51-2.39 (m, 4H), 2.15-2.07 (m, 2H), 1.94 (s, 1H), 1.86-1.68 (m, 4H), 1.71-1.60 (m, 2H).

[0284] 13 C NMR (101 MHz, CDCl3) δ 69.7, 59.7, 50.6, 45.3, 43.4, 34.1, 33.6.

[0285] HRMS m / z (ESI) calcd for C 10 H 15 INaO + (M+Na) + 301.0060, found 301.0054.

[0286] From the above data, it can be seen that the product structure is correct, which is the target product.

[0287] Example 24

[0288] This example provides a method for directly deaminating and halogenating an α-tertiary primary amine, and the reaction equation is as follows:

[0289]

[0290] (1) The compound shown in formula A24 (0.2 mmol, 28.2 mg) was added to a sealed tube with a stir bar, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrabromide (5.0 equiv) and diphenylphosphoryl hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module at 50°C and stirred at 1400 rpm for 12 hours.

[0291] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 24 (17.1 mg, 42% yield).

[0292] The structure confirmation data of the product are as follows:

[0293] 1 H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 2.50 (s, 6H).

[0294] 13 C NMR (101 MHz, CDCl3) δ 167.8, 59.2, 52.2, 39.5, 36.3.

[0295] HRMS m / z (ESI) calcd for C7H9BrNaO2 + (M+Na) + 226.9678, found 226.9678.

[0296] From the above data, it can be seen that the structure of the product is correct, which is the target product.

[0297] Example 25

[0298] This example provides a method for directly deaminating and halogenating an α-tertiary primary amine, and the reaction equation is as follows:

[0299]

[0300] (1) The compound shown in formula A25 (0.2 mmol, 28.2 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon for 3 times, and K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), isopropyl iodide (5.0 equiv) and diphenyl phosphinyl hydroxylamine (2.2 equiv) were sequentially added; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0301] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 25 (35.7 mg, 71% yield).

[0302] The structure confirmation data of the product are as follows:

[0303] 1 H NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 2.56 (s, 6H).

[0304] 13C NMR (101 MHz, CDC13) δ 167.1, 60.6, 52.1, 46.0, 5.7.

[0305] HRMS m / z (ESI) calcd for C7H 10 IO2 + (M+H) + 252.9720, found 252.9720.

[0306] From the above data, the product structure is correct, which is the target product.

[0307] Example 26

[0308] This example provides a direct deamination halogenation method for an alpha-tertiary primary amine, and the reaction equation is as follows:

[0309]

[0310] (1) The compound shown in formula A26 (0.1 mmol, 53.7 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), isopropyl iodide (5.0 equiv) and diphenyl phosphine hydroxylamine (2.2 equiv) were added in turn; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0311] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 26 (53.2 mg, 82% yield).

[0312] The product structure confirmation data are as follows:

[0313] 1 H NMR (400 MHz, CDC13) δ 5.35 (d, J = 5.0 Hz, 1H), 4.61-4.45 (m, 1H), 2.54-2.36 (m, 6H), 2.24 (d, J = 8.2 Hz, 2H), 1.96-1.88 (m, 6H), 1.89-1.71 (m, 4H), 1.63-1.42 (m, 7H), 1.41-1.18 (m, 6H), 1.18-1.05 (m, 6H), 1.01 (s, 6H), 0.91 (d, J = 6.4 Hz, 3H), 0.89-0.81 (m, 6H), 0.67 (s, 3H).

[0314] 13C NMR (101 MHz, CDC13) δ 176.2, 139.6, 122.7, 73.8, 56.7, 56.2, 50.0, 43.4, 42.3, 39.9, 39.7, 39.5, 38.0, 36.9, 36.6, 36.2, 35.8, 35.5, 31.9, 31.9, 31.8, 28.2, 28.0, 27.7, 24.3, 23.8, 22.8, 22.5, 21.0, 19.3, 18.7, 11.8.

[0315] HRMS m / z (ESI) calcd for C 36 H 58 IO2 + (M+H) + 649.3476, found 649.3471.

[0316] From the above data, the product structure is correct, which is the target product.

[0317] Example 27

[0318] This example provides a method for directly deaminating a tertiary primary amine to a halide, and the reaction equation is as follows:

[0319]

[0320] (1) The compound shown in formula A27 (0.1 mmol, 37.3 mg) was added to a sealed tube with a stirrer, evacuated and filled with argon 3 times, and then K2CO3 (2.0 equiv), trifluorotoluene (0.2 M), carbon tetrabromide (5.0 equiv), and diphenyl phosphorohydroxylamine (2.2 equiv) were added in sequence; after sealing, it was placed on a preheated heating module at 50°C, and stirred at 1400 rpm for 12 hours.

[0321] (2) After the reaction was completed, it was cooled to room temperature, and the reaction solution was directly wet-loaded and passed through a column of neutral alumina to obtain the compound shown in formula 27 (36.3 mg, 83% yield).

[0322] The product structure confirmation data are as follows:

[0323] 1 H NMR (400MHz, CDC13) δ 7.65-7.48 (m, 4H), 7.43-7.28 (m, 6H), 7.01 (s, 1H), 3.15 (t, J = 7.1 Hz, 2H), 2.69 (t, J = 7.1 Hz, 2H), 2.47 (s, 6H).

[0324] 13C NMR (101 MHz, CDC13) δ 171.4, 162.2, 145.6, 134.8, 132.2, 128.7, 128.6, 128.6, 128.2, 127.8, 126.4, 59.9, 46.8, 33.9, 33.0, 23.6.

[0325] HRMS m / z (ESI) calcd for C 23 H 22 BrN2O2 + (M+H) + 437.0859, found 437.0862.

[0326] From the above data, the product structure is correct, which is the target product.

[0327] In the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by a person skilled in the art. And the reagents, materials and operation steps used herein are all widely used reagents, materials and conventional steps in the corresponding field.

[0328] Finally, it should be noted that: the above only for the preferred embodiments of the present application, and not for the purpose of limiting the present application, although the present application is described in detail with reference to the foregoing embodiments, for those skilled in the art, it still can be modified, or part of the technical features of the equivalent replacement of the technical solutions recorded in the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for direct deamination and halogenation of α-tertiary primary amines, characterized in that: The α-tertiary primary amine is mixed with a base, a halogenating agent, a hydroxylamine compound and a solvent, and heated to perform a deamine functionalization reaction to generate a C(sp 3 )-X bond halogenated compounds, X is chlorine, bromine or iodine; The structural formula of the α-tertiary primary amine is Where R 1 、R 2 and R 3 Each is independently selected from primary, secondary or tertiary alkyl groups and their derivatives.

2. The method for direct deamination and halogenation of α-tertiary primary amines according to claim 1, wherein: The base is an inorganic base or an organic base.

3. The method for direct deamination and halogenation of α-tertiary primary amines according to claim 1, wherein: The halogenating agent is carbon tetrachloride, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, chloramine-T, carbon tetrabromide or isopropyl iodide.

4. The method for direct deamination and halogenation of α-tertiary primary amines according to claim 1, wherein: The hydroxylamine compound is diphenylphosphonohydroxylamine, 2,4-dinitrophenylhydroxylamine, a hydroxylamine compound in which the aryl group of diphenylphosphonohydroxylamine is substituted with an alkyl group or an alkyl group or diaryl-substituted phosphonohydroxylamine compound.

5. The method for direct deamination and halogenation of α-tertiary primary amines according to claim 1, wherein: The molar ratio of the α-tertiary primary amine, the base, the halogenating agent and the hydroxylamine compound is 1.0:2.0-4.0:3.0-100:2.0-3.

0.

6. The method for direct deamination and halogenation of α-tertiary primary amines according to claim 1, wherein: The solvent is a single organic solvent, a mixed organic solvent of multiple organic solvents, or a mixed solvent of water and an organic solvent; The organic solvent is trifluorotoluene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, chloroform or N,N-dimethylformamide.

7. The method for direct deamination and halogenation of α-tertiary primary amines according to claim 1, wherein: The heating temperature of the reaction is 40-70° C., and the reaction time is 6-18 hours.

8. The method for direct deamination and halogenation of α-tertiary primary amines according to claim 1, wherein: The reaction is carried out in air or an inert gas atmosphere.

9. The C(sp 3 )-X bond halogenated compounds.

10. The C(sp)-containing compound according to claim 9. 3 Application of halogenated compounds with )-X bonds in constructing bioisosteric structural units in drug molecules.

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