A chiral α-(trichloromethyl)amine compound and its preparation method

Abstract

The present invention discloses a chiral α-(trichloromethyl)amine compound and a preparation method thereof. The structural formula of the compound is #imgabs0#R 1 which is at least one of an aryl group and a heterocycle; PG is one of benzoyl group, tert-butoxycarbonyl group, fluorenylmethoxycarbonyl group, benzyloxycarbonyl group and p-toluenesulfonyl group. The preparation method includes: in the presence of a transition metal catalyst, an additive and a chiral ligand, in an organic solvent, N,O-acetal and arylboric anhydride are used as reaction substrates to carry out a reaction to obtain the chiral α-(trichloromethyl)amine compound; the structural formula of N,O-acetal is #imgabs1#PG is one of benzoyl group, tert-butoxycarbonyl group, fluorenylmethoxycarbonyl group, benzyloxycarbonyl group and p-toluenesulfonyl group; the structural formula of arylboric anhydride is (R 1 -BO)3, R 1 is at least one of an aryl group and a heterocycle.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a chiral α-(trichloromethyl)amine compound and a preparation method thereof. Background Art

[0002] Chiral amines are common in natural and synthetic bioactive compounds. As a branch of such compounds, chiral α-(trichloromethyl)amine compounds have attracted the interest of many organic and medicinal chemists. Since the trichloromethyl group has unique pharmaceutical activities and low toxicity (Bioorg. Med. Chem., 2009, 17, 4313–4322), the selective synthesis of chiral α-(trichloromethyl)amines has attracted great attention in the fields of medicinal chemistry and synthetic chemistry.

[0003] On the one hand, the incorporation of α-(trichloromethyl)amine can improve the metabolism of target candidate drugs and enhance their biological properties. In addition, the α-(trichloromethyl)amine structure is also a very valuable synthetic intermediate, and it is often used as a synthetic precursor for α-amino acids, 2,2-dichloroazoles, 3,3-dichloropyridines, and trichloromethylated heterocyclic compounds. Although the α-(trichloromethyl)amine structure has such important application values, its stereoselective synthesis has not been well explored. The earliest report on α-(trichloromethyl)amine compounds was the addition reaction of trichloroacetic acid and imine achieved by Lukasiewicz et al. in 1964 (Tetrahedron., 1964, 20, 1–12), and the yield of α-(trichloromethyl)amine obtained by this method was relatively low. In 2009, Tehrani et al. synthesized α,β-unsaturated α-(trichloromethyl)amine through the petasi-type reaction of 2,2,2-trichloroethylamine and styryl or phenethyl trifluoroborate promoted by Lewis acid (Tetrahedron., 2009, 65, 1957–1966). None of the above-reported α-(trichloromethyl)amines achieved their enantioselectivity, and there are still few reports on the stereoselective synthesis of α-(trichloromethyl)amine compounds. In 1990, Steglich et al. synthesized chiral trichloromethylamine derivatives through chiral enamine catalysis (Synthesis., 1990, 9, 750), but its reaction conditions were relatively harsh and one-step synthesis could not be achieved. Therefore, it is particularly important to invent a more efficient synthesis method for chiral α-(trichloromethyl)amine.

[0004] The Chinese patent application document with the publication number CN101857559A discloses a chiral α-(trichloromethyl)amine compound and its preparation method. It is a potential synthetic building block for bioactive molecules and can be used as an important intermediate to synthesize chiral chlorine-containing amine compounds, such as 2,2-dichloroaziridine. Its preparation method has mild process conditions, easily available raw materials, and the prepared α-(trichloromethyl)amine has high optical purity, which is convenient for industrial implementation and is expected to be widely used in the fields of asymmetric synthesis and pharmaceutical research and development. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a chiral α-(trichloromethyl)amine compound and its preparation method that are simple to operate and can be synthesized on a large scale.

[0006] The present invention solves the above technical problems through the following technical means:

[0007] A chiral α-(trichloromethyl)amine compound, the structural formula of which is shown as follows:

[0008]

[0009] Among them, R 1 is at least one of an aryl substituent and a heterocyclic substituent;

[0010] The PG is one of benzoyl (abbreviation: Bz), tert-butoxycarbonyl (abbreviation: Boc), fluorenylmethoxycarbonyl (abbreviation: Fmoc), benzyloxycarbonyl (abbreviation: Cbz), and p-toluenesulfonyl (abbreviation: Ts).

[0011] Preferably, the aryl substituent is at least one of phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethoxyphenyl, p-methylphenyl, β-naphthyl, m-methylphenyl, and p-tert-butylphenyl; the heterocyclic substituent is at least one of 2-thienyl and 2-pyridyl.

[0012] Preferably, the R 1 is at least one of phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethoxyphenyl, p-methylphenyl, β-naphthyl, 2-thienyl, m-methylphenyl, and p-tert-butylphenyl.

[0013] Preferably, the chiral α-(trichloromethyl)amine compound has a structural formula of

[0014] One of them.

[0015] The present invention also provides a method for preparing the chiral α-(trichloromethyl)amine compound, comprising the following steps: in the presence of a transition metal catalyst, an additive and a chiral ligand, in an organic solvent, N,O-acetal and arylboronic anhydride are used as reaction substrates to carry out a reaction to obtain the chiral α-(trichloromethyl)amine compound; wherein, the structural formula of the N,O-acetal is shown as formula 1 below, and the structural formula of the arylboronic anhydride is shown as formula 2 below:

[0016]

[0017] In formula 2, R 1 is at least one of an aryl substituent and a heterocyclic substituent;

[0018] In formula 1, PG is one of benzoyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl and p-toluenesulfonyl.

[0019] Preferably, in formula 2, the R 1 is at least one of phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethoxyphenyl, p-methylphenyl, β-naphthyl, 2-thienyl, m-methylphenyl and p-tert-butylphenyl; in formula 1, the PG is fluorenylmethoxycarbonyl.

[0020] Preferably, the reaction time is 6-12 h and the temperature is 20°C-100°C.

[0021] Preferably, the chiral ligand is one of (S)-4-tert-butyl-2-(2-pyridyl)oxazoline, (S)-4-isopropyl-2-(2-pyridyl)oxazoline, (S)-4-tert-butyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline, (S)-4-phenyl-2-(6-phenylpyridin-2-yl)-4,5-dihydrooxazoline; the organic solvent is one of 1,2-dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran; the transition metal catalyst is one of palladium trifluoroacetate, palladium acetate, palladium chloride, bis(dibenzylideneacetone)palladium; the additive is one of silver hexafluoroantimonate, silver tetrafluoroborate, ammonium hexafluorophosphate.

[0022] Preferably, the chiral ligand is (S)-4-tert-butyl-2-(2-pyridyl)oxazoline.

[0023] Preferably, the organic solvent is 1,2-dichloroethane or dichloromethane.

[0024] Preferably, the molar ratio of the N,O-acetal to the arylboronic anhydride is 1:1-10.

[0025] Preferably, the molar amount of the transition metal catalyst is 2%-10% of the molar amount of the N,O-acetal; the molar amount of the chiral ligand is 5%-20% of the molar amount of the N,O-acetal; the molar amount of the additive is 10%-40% of the molar amount of the N,O-acetal.

[0026] Preferably, for the preparation method of the chiral α-(trichloromethyl)amine compound, the reaction equation is as follows:

[0027]

[0028] The advantages of the present invention are as follows: For the preparation method of the chiral α-(trichloromethyl)amine compound of the present invention, a metal palladium salt and a chiral ligand form a complex, silver hexafluoroantimonate, etc. are used as additives, and general organic reagents such as 1,2-dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran, etc. are used as solvents. It has high catalytic efficiency, good enantioselectivity, is easy for large-scale production, and can be used for the development of chiral drug molecules; the preparation method of the present invention has a high yield and good optical selectivity, and can obtain optically pure chiral α-(trichloromethyl)amine compounds, which can be applied in the preparation of chiral ligand skeletons and can also be used as important intermediates of bioactive molecules.

[0029] This preparation method is simple and easy to operate. The one-step synthesis greatly reduces the synthesis cost and synthesis cycle. The reaction conditions are mild, and the atom economy is high. The reaction can occur in the air; the molar amount of the catalyst used in the preparation method of the present invention is only 2%-10% of the raw materials, and the catalytic efficiency and enantioselectivity are good; the method involved in the present invention is easy for large-scale production, and the yield and enantioselectivity can be well maintained after scaling up. Description of the Drawings

[0030] Figure 1 1H NMR spectrum of the product prepared in Example 4 of the present invention;

[0031] Figure 2 13C NMR spectrum of the product prepared in Example 4 of the present invention;

[0032] Figure 3 19F NMR spectrum of the product prepared in Example 4 of the present invention;

[0033] Figure 4 HPLC chart of the product prepared in Example 4 of the present invention;

[0034] Figure 5 1H NMR spectrum of the product prepared in Example 5 of the present invention;

[0035] Figure 6 13C NMR spectrum of the product prepared in Example 5 of the present invention;

[0036] Figure 7 HPLC chromatogram of the product prepared in Example 5 of the present invention;

[0037] Figure 8 1H NMR spectrum of the product prepared in Example 6 of the present invention;

[0038] Figure 9 13C NMR spectrum of the product prepared in Example 6 of the present invention;

[0039] Figure 10 HPLC chromatogram of the product prepared in Example 6 of the present invention;

[0040] Figure 11 1H NMR spectrum of the product prepared in Example 7 of the present invention;

[0041] Figure 12 13C NMR spectrum of the product prepared in Example 7 of the present invention;

[0042] Figure 13 HPLC chromatogram of the product prepared in Example 7 of the present invention. Detailed implementation manners

[0043] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0044] The test materials, reagents, etc. used in the following embodiments can be obtained from commercial channels without special instructions.

[0045] For those not specifying specific techniques or conditions in the embodiments, they can all be carried out according to the techniques or conditions described in the literature in this field or according to the product specifications.

[0046] Example 1

[0047] Preparation of N,O-acetal compound

[0048] Refer to the reported method in the literature to synthesize N,O-acetal compound (Org. Lett., 2018, 20, 7137 - 7140). The preparation method includes the following steps:

[0049]

[0050] Under nitrogen conditions, trichloroacetaldehyde (15 mmol) and acetic acid (60 μL) were successively added to a solution of Fmoc (fluorenylmethyloxycarbonyl)-protected ammonia (10 mmol) in ethyl acetate (100 mL). The mixture was heated under reflux for 16 hours, and the solvent was concentrated under vacuum. The resulting product was recrystallized with dichloromethane and directly used for the next step. Under nitrogen conditions, pyridine (1 mmol) was added to a solution of the resulting product (10 mmol) in acetic anhydride (20 mL). The mixture was stirred at room temperature for 12 hours, and the resulting product was concentrated under vacuum at 70 °C. The final product was obtained by column chromatography separation.

[0051] Example 2

[0052] Preparation of arylboric anhydride compounds

[0053] The arylboric anhydride compounds were synthesized according to the reported method in the literature (Chem. Sci., 2017, 8, 6071–6075). The preparation method includes the following steps:

[0054]

[0055] Phenylboronic acid (10 mmol) was dissolved in toluene (50 mL) solution, and the mixture was heated under reflux for 8 hours using a Dean-Stark apparatus. The solvent was removed by rotary evaporation to obtain the final product.

[0056] Other arylboric anhydride compounds used in the examples of the present invention were all prepared according to the above method.

[0057] Example 3

[0058]

[0059] A preparation method of chiral α-(trichloromethyl)amine compounds includes the following steps: In an air atmosphere, compound 1 (0.1 mmol), compound 2a (0.2 mmol), palladium trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol), and silver hexafluoroantimonate (0.02 mmol) were added to a reaction flask with a clean magnetic stir bar. Then, organic solvent 1,2-dichloroethane (1 mL) was added, and the mixture was placed in an oil bath at 70 °C and reacted for 12 hours. The reaction process was monitored by TLC. After the reaction was completed, it was cooled to room temperature, and the solvent was evaporated to dryness using a rotary evaporator. The white solid 3a was obtained by column chromatography separation and purification, with a yield of 86%.

[0060]

[0061] The corresponding NMR data of the white solid 3a are as follows: 11H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz, 2H), 7.58 (dd, J = 7.8, 3.9 Hz, 2H), 7.51 (t, J = 4.0 Hz, 2H), 7.43–7.37 (m, 5H), 7.30 (q, J = 7.0 Hz, 2H), 5.89 (d, J = 10.3 Hz, 1H), 5.65 (d, J = 10.3 Hz, 1H), 4.59 (dd, J = 10.9, 6.8 Hz, 1H), 4.38 (dd, J = 10.8, 7.0 Hz, 1H), 4.24 (t, J = 6.8 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 155.31, 143.57, 141.34, 134.74, 129.33, 129.28, 128.25, 127.81, 127.12, 127.10, 125.06, 124.93, 120.06, 101.61, 69.09, 67.38, 47.15.

[0062] Example 4

[0063]

[0064] A method for preparing a chiral α-(trichloromethyl)amine compound, comprising the following steps: In an air atmosphere, compound 1 (0.1 mmol), compound 2b (0.2 mmol), palladium trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol) and silver hexafluoroantimonate (0.02 mmol) were added to a reaction flask with a clean magnetic stir bar, and then organic solvent 1,2-dichloroethane (1 mL) was added, and the mixture was placed in an oil bath at 70 °C and reacted for 12 hours. The reaction process was monitored by TLC. After the reaction was completed, it was cooled to room temperature, the solvent was evaporated to dryness using a rotary evaporator, and the product was separated and purified by column chromatography to obtain white solid 3b with a yield of 78%.

[0065]

[0066] The 1H NMR spectrum of white solid 3b is as Figure 1 shown, and the 13C NMR spectrum is as Figure 2 shown, and the 19F NMR spectrum is as Figure 3 shown. The corresponding NMR data are as follows: 11H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 6.7 Hz, 2H), 7.48 (dd, J = 8.4, 5.1 Hz, 1H), 7.40 (td, J = 7.5, 2.2 Hz, 3H), 7.30 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 8.5 Hz, 2H), 5.85 (d, J = 10.2 Hz, 1H), 5.63 (d, J = 10.0 Hz, 1H), 4.64–4.57 (m, 1H), 4.40 (dd, J = 10.9, 6.5 Hz, 1H), 4.23 (t, J = 6.6 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 163.93, 162.28, 155.26, 143.53, 143.51, 141.36, 131.16, 131.11, 130.68, 127.84, 127.11, 125.00, 124.89, 120.08, 115.37, 115.22, 101.42, 68.50, 67.36, 47.16.

[0067] Figure 4 The HPLC chromatogram of the product 3b prepared in this example, where the upper figure is the racemic sample and the lower figure is the chiral sample. It can be seen from Figure 4 that the ee value of 3b is 97%.

[0068] Example 5

[0069]

[0070] A preparation method of a chiral α-(trichloromethyl)amine compound, comprising the following steps: In an air atmosphere, compound 1 (0.1 mmol), compound 2c (0.2 mmol), palladium trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol) and silver hexafluoroantimonate (0.02 mmol) are added to a reaction flask with a clean magnetic stirrer, then organic solvent 1,2-dichloroethane (1 mL) is added, and the mixture is placed in an oil bath at 70 °C and reacted for 12 hours. The reaction process is monitored by TLC. After the reaction is completed, it is cooled to room temperature, the solvent is evaporated to dryness using a rotary evaporator, and the product is separated and purified by column chromatography to obtain a light yellow solid 3c with a yield of 67%;

[0071]

[0072] The 1H NMR spectrum of the light yellow solid 3c is as shown in Figure 5 and the 13C NMR spectrum is as shown in Figure 6 The corresponding NMR data are as follows: 11H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.2 Hz, 2H), 7.46–7.39 (m, 4H), 7.37 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 5.96 (d, J = 10.1 Hz, 1H), 5.64 (d, J = 10.2 Hz, 1H), 4.61 (dd, J = 10.8, 6.5 Hz, 1H), 4.46–4.39 (m, 1H), 4.23 (t, J = 6.6 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 155.29, 143.51, 141.37, 135.38, 133.28, 130.67, 128.49, 127.86, 127.14, 125.01, 124.90, 120.10, 101.17, 68.59, 67.38, 47.16.

[0073] Figure 7 The HPLC chromatogram of the product 3c prepared in this example; among them, the upper figure is the racemic sample, and the lower figure is the chiral sample. It can be seen from Figure 7 that the ee value of 3c is 96%.

[0074] Example 6

[0075]

[0076] A method for preparing a chiral α-(trichloromethyl)amine compound, comprising the following steps: In an air atmosphere, compound 1 (0.1 mmol), compound 2d (0.2 mmol), palladium trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol) and silver hexafluoroantimonate (0.02 mmol) were added to a reaction flask with a clean magnetic stirrer, and then organic solvent 1,2-dichloroethane (1 mL) was added, and the mixture was placed in an oil bath at 70 °C and reacted for 12 hours. The reaction process was monitored by TLC. After the reaction was completed, it was cooled to room temperature, the solvent was evaporated to dryness using a rotary evaporator, and the product was separated and purified by column chromatography to obtain a pale yellow solid 3d with a yield of 50%;

[0077]

[0078] The 1H NMR spectrum of the pale yellow solid 3d is as shown in Figure 8 shown, and the 13C NMR spectrum is as shown in Figure 9 shown. The corresponding NMR data are as follows: 11H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.64–7.47 (m, 4H), 7.45–7.34 (m, 4H), 7.30 (d, J = 7.4 Hz, 2H), 5.87 (d, J = 10.2 Hz, 1H), 5.61 (d, J = 10.2 Hz, 1H), 4.60 (dd, J = 10.7, 6.4 Hz, 1H), 4.48–4.34 (m, 1H), 4.22 (t, J = 6.7 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 155.24, 143.49, 141.36, 133.80, 131.44, 130.93, 127.85, 127.12, 124.98, 124.88, 123.64, 120.08, 100.99, 68.65, 67.36, 47.16.

[0079] Figure 10 HPLC chromatogram of the product 3d prepared in this example; among them, the upper figure is the racemic sample, and the lower figure is the chiral sample. As Figure 10 can be seen, the ee value of 3d is 97%.

[0080] Example 7

[0081]

[0082] A preparation method of a chiral α-(trichloromethyl)amine compound, comprising the following steps: in an air atmosphere, add compound 1 (0.1 mmol), compound 2e (0.2 mmol), palladium trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol) and silver hexafluoroantimonate (0.02 mmol) into a reaction flask with a clean magnetic stirrer, then add organic solvent 1,2-dichloroethane (1 mL), and place it in an oil bath at 70 °C for reaction for 12 hours. Monitor the reaction process by TLC. After the reaction is completed, cool to room temperature, spin-dry the solvent using a rotary evaporator, and separate and purify by column chromatography to obtain white solid 3e with a yield of 78%;

[0083]

[0084] The 1H NMR spectrum of white solid 3e is as shown in Figure 11 shown, and the 13C NMR spectrum is as shown in Figure 12 shown. The corresponding NMR data are as follows: 11H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 6.4 Hz, 2H), 7.41 (t, J = 7.3 Hz, 4H), 7.31 (q, J = 7.2 Hz, 2H), 7.21 (d, J = 7.7 Hz, 2H), 5.96 (d, J = 10.4 Hz, 1H), 5.65 (d, J = 10.3 Hz, 1H), 4.59 (dd, J = 10.9, 6.9 Hz, 1H), 4.38 (dd, J = 10.8, 7.0 Hz, 1H), 4.24 (t, J = 6.8 Hz, 1H), 2.39 (s, 3H). 13 13C NMR (151 MHz, CDCl3) δ 155.35, 143.62, 141.36, 139.28, 131.83, 129.20, 128.96, 127.82, 127.80, 127.13, 127.11, 125.09, 124.97, 120.07, 120.06, 101.92, 68.95, 67.39, 47.17.

[0085] Figure 13 The HPLC chromatogram of the product 3e prepared in this example; among them, the upper figure is the racemic sample and the lower figure is the chiral sample. It can be seen from Figure 13 that the ee value of 3e is 98%.

[0086] Example 8

[0087]

[0088] A method for preparing a chiral α-(trichloromethyl)amine compound, comprising the following steps: In an air atmosphere, add compound 1 (0.1 mmol), compound 2f (0.2 mmol), palladium trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol) and silver hexafluoroantimonate (0.02 mmol) into a reaction flask with a clean magnetic stirrer, then add organic solvent 1,2-dichloroethane (1 mL), and place it in an oil bath at 70 °C for reaction for 12 hours. Monitor the reaction process by TLC. After the reaction is completed, cool to room temperature, spin-dry the solvent using a rotary evaporator, and separate and purify by column chromatography to obtain white solid 3f with a yield of 61% and an ee value of 96%;

[0089]

[0090] The NMR data of white solid 3f are as follows: 11H NMR (600 MHz, CDCl3) δ 7.79–7.74 (m, 2H), 7.60–7.51 (m, 4H), 7.40 (tt, J = 6.9, 2.9 Hz, 2H), 7.33–7.21 (m, 5H), 5.86 (d, J = 10.2 Hz, 1H), 5.66 (d, J = 10.1 Hz, 1H), 4.61 (ddd, J = 9.8, 6.4, 2.4 Hz, 1H), 4.47–4.38 (m, 1H), 4.23 (td, J = 6.6, 2.3 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 155.23, 149.73, 143.49, 143.46, 141.37, 133.38, 130.89, 127.84, 127.10, 124.97, 124.87, 121.23, 120.48, 120.07, 119.52, 101.04, 68.46, 67.34, 47.18.

[0091] Example 9

[0092]

[0093] A method for preparing a chiral α-(trichloromethyl)amine compound, comprising the following steps: In an air atmosphere, compound 1 (0.1 mmol), compound 2g (0.2 mmol), palladium (II) trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol) and silver hexafluoroantimonate (0.02 mmol) were added to a reaction flask equipped with a clean magnetic stir bar, and then organic solvent 1,2-dichloroethane (1 mL) was added. The mixture was placed in an oil bath at 70 °C and reacted for 12 hours. The reaction progress was monitored by TLC. After the reaction was completed, it was cooled to room temperature, the solvent was removed by rotary evaporation, and the product was purified by column chromatography to obtain white solid 3g with a yield of 66% and an ee value of 99%.

[0094]

[0095] The NMR data of white solid 3g are as follows: 11H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.87 (d, J = 8.8 Hz, 4H), 7.76 (t, J = 7.7 Hz, 3H), 7.58 (ddd, J = 29.5, 19.0, 7.8 Hz, 6H), 7.39 (dt, J = 14.9, 7.5 Hz, 3H), 7.29 (t, J = 7.6 Hz, 2H), 6.02 (d, J = 10.2 Hz, 1H), 5.84 (d, J = 10.4 Hz, 1H), 4.61 (t, J = 9.1 Hz, 1H), 4.47–4.35 (m, 1H), 4.24 (t, J = 6.8 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 155.36, 143.56, 141.35, 141.34, 133.41, 132.64, 132.14, 129.39, 128.31, 127.97, 127.79, 127.68, 127.10, 126.99, 126.63, 126.06, 125.02, 124.92, 120.04, 101.69, 69.33, 67.37, 47.19.

[0096] Example 10

[0097]

[0098] A method for preparing a chiral α-(trichloromethyl)amine compound, comprising the following steps: In an air atmosphere, compound 1 (0.1 mmol), compound 2h (0.2 mmol), palladium trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol) and silver hexafluoroantimonate (0.02 mmol) were added to a reaction flask with a clean magnetic stirrer, and then organic solvent 1,2-dichloroethane (1 mL) was added. The mixture was placed in an oil bath at 70 °C and reacted for 12 hours. The reaction process was monitored by TLC. After the reaction was completed, it was cooled to room temperature, the solvent was evaporated to dryness using a rotary evaporator, and the product was separated and purified by column chromatography to obtain white solid 3h with a yield of 74% and an ee value of 97%.

[0099]

[0100] The NMR data of white solid 3h are as follows: 11H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 2H), 7.63–7.56 (m, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.31 (d, J = 19.4 Hz, 5H), 7.23 (d, J = 7.5 Hz, 1H), 5.94 (d, J = 10.2 Hz, 1H), 5.64 (d, J = 10.3 Hz, 1H), 4.63–4.57 (m, 1H), 4.42–4.34 (m, 1H), 4.25 (t, J = 6.8 Hz, 1H), 2.40 (s, 3H). 13 13C NMR (151 MHz, CDCl3) δ 155.38, 143.61, 141.36, 137.99, 134.71, 130.14, 130.05, 128.16, 127.83, 127.81, 127.14, 127.12, 126.31, 125.10, 124.97, 120.07, 101.72, 69.16, 67.39, 47.17, 21.54.

[0101] Example 11

[0102]

[0103] A method for preparing a chiral α-(trichloromethyl)amine compound, comprising the following steps: In an air atmosphere, compound 1 (0.1 mmol), compound 2i (0.2 mmol), palladium (II) trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol) and silver hexafluoroantimonate (0.02 mmol) were added to a reaction flask with a clean magnetic stir bar, and then organic solvent 1,2-dichloroethane (1 mL) was added. The mixture was placed in an oil bath at 70 °C and reacted for 12 hours. The reaction progress was monitored by TLC. After the reaction was completed, it was cooled to room temperature, the solvent was removed by rotary evaporation, and the product was purified by column chromatography to obtain white solid 3i with a yield of 56% and an ee value of 94%.

[0104]

[0105] The NMR data of white solid 3i are as follows: 11H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.59 (dd, J = 7.7, 2.8 Hz, 2H), 7.41 (p, J = 7.8 Hz, 6H), 7.30 (q, J = 7.4 Hz, 2H), 5.89 (d, J = 10.4 Hz, 1H), 5.64 (d, J = 10.4 Hz, 1H), 4.58 (dd, J = 10.8, 6.9 Hz, 1H), 4.35 (dd, J = 10.9, 7.0 Hz, 1H), 4.24 (t, J = 6.9 Hz, 1H), 1.34 (s, 8H). 13 13C NMR (151 MHz, CDCl3) δ 155.32, 152.29, 143.60, 141.34, 131.73, 128.96, 127.80, 127.77, 127.11, 127.09, 125.20, 125.10, 124.97, 120.04, 101.92, 68.82, 67.37, 47.16, 34.69, 31.27.

[0106] Example 12

[0107]

[0108] A method for preparing a chiral α-(trichloromethyl)amine compound, comprising the following steps: In an air atmosphere, compound 1 (0.1 mmol), compound 2j (0.2 mmol), palladium trifluoroacetate (0.005 mmol), chiral ligand (S)-4-tert-butyl-2-(2-pyridyl)oxazoline (0.012 mmol) and silver hexafluoroantimonate (0.02 mmol) were added to a reaction flask with a clean magnetic stirrer, then organic solvent 1,2-dichloroethane (1 mL) was added, and the mixture was placed in an oil bath at 70 °C and reacted for 12 hours. The reaction process was monitored by TLC. After the reaction was completed, it was cooled to room temperature, the solvent was evaporated to dryness using a rotary evaporator, and the product was separated and purified by column chromatography to obtain a yellow solid 3j with a yield of 44% and an ee value of 94%;

[0109]

[0110] The NMR data of the yellow solid 3j are as follows: 11H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.37 (d, J = 5.1 Hz, 1H), 7.34–7.29 (m, 2H), 7.27 (d, J = 3.4 Hz, 1H), 7.03 (t, J = 4.5 Hz, 1H), 5.96 (d, J = 10.2 Hz, 1H), 5.74 (d, J = 10.4 Hz, 1H), 4.59 (dd, J = 10.8, 6.7 Hz, 1H), 4.41 (dd, J = 10.8, 7.0 Hz, 1H), 4.25 (t, J = 7.0 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 155.15, 143.52, 143.51, 141.35, 136.98, 129.39, 127.84, 127.82, 127.14, 127.12, 126.76, 126.58, 125.07, 124.96, 120.08, 101.23, 67.51, 65.82, 47.12.

[0111] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a chiral α-(trichloromethyl)amine compound, characterized in that: The structural formula of the chiral α-(trichloromethyl)amine compound is as shown in the following formula: Among them, R 1 is one of an aryl substituent and a heterocyclic substituent; The PG is 9-fluorenylmethoxycarbonyl; The preparation method includes the following steps: in the presence of a transition metal catalyst, an additive and a chiral ligand, in an organic solvent, N,O-acetal and arylboronic anhydride are used as reaction substrates to carry out a reaction to obtain the chiral α-(trichloromethyl)amine compound; wherein, the structural formula of the N,O-acetal is as shown in Formula 1 below, and the structural formula of the arylboronic anhydride is as shown in Formula 2 below: In Formula 2, R 1 is one of an aryl substituent and a heterocyclic substituent; In Formula 1, PG is 9-fluorenylmethoxycarbonyl; The aryl substituent is one of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethoxyphenyl, 4-methylphenyl, β-naphthyl, 3-methylphenyl and 4-tert-butylphenyl; the heterocyclic substituent is one of 2-thienyl and 2-pyridyl; The chiral ligand is one of (S)-4-tert-butyl-2-(2-pyridyl)oxazoline and (S)-4-isopropyl-2-(2-pyridyl)oxazoline; the transition metal catalyst is one of palladium(III) trifluoroacetate and palladium acetate; the additive is one of silver hexafluoroantimonate and silver tetrafluoroborate.

2. The preparation method of the chiral α-(trichloromethyl)amine compound according to claim 1, wherein: The structural formula of the chiral α-(trichloromethyl)amine compound is , , , , , , , , , one of them.

3. The preparation method of the chiral α-(trichloromethyl)amine compound according to claim 1, characterized in that: The time of the reaction is 6 - 12 h, and the temperature is 20 o °C to 100 o °C.

4. The preparation method of the chiral α-(trichloromethyl)amine compound according to claim 1, wherein: The organic solvent is one of 1,2-dichloroethane, dichloromethane, acetonitrile and tetrahydrofuran.

5. The preparation method of the chiral α-(trichloromethyl)amine compound according to claim 1, characterized in that: The molar ratio of the N,O-acetal to the arylboronic anhydride is 1:1-10.

6. The preparation method of the chiral α-(trichloromethyl)amine compound according to any one of claims 1-5, characterized in that: The molar amount of the transition metal catalyst used is 2%-10% of the molar amount of the N,O-acetal used; the molar amount of the chiral ligand used is 5%-20% of the molar amount of the N,O-acetal used; the molar amount of the additive used is 10%-40% of the molar amount of the N,O-acetal used.

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