Chiral alpha-trifluoromethyl amine derivative and synthesis method thereof

Abstract

The synthesis method comprises the following steps: in the presence of a nickel catalyst, a ligand, a reducing agent, an additive and an organic solvent, reacting a compound I with a compound II to obtain a compound III; the compound I is an alpha-amino-trifluoromethyl acetate derivative, and the compound II is aryl halide or a derivative thereof. The invention relates to a nickel-catalyzed asymmetric reductive arylation reaction of alpha-amino-trifluoromethyl acetate. A chiral alpha-trifluoromethyl amine derivative is prepared by taking nickel as a catalyst, taking a nitrogen-containing heterocyclic ring or a derivative thereof as a ligand, taking zinc powder as a reducing agent, taking anhydrous magnesium chloride as an additive and taking DMF (Dimethyl Formamide) and THF (Tetrahydrofuran) as solvents. The method provided by the invention has the advantages of cheap catalyst metal, good functional group compatibility, simple operation, and high yield and stereoselectivity. A new synthetic route is provided for synthesis of the chiral alpha-trifluoromethylamine derivative, and the method has potential application value in organic synthesis.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and more specifically, to a chiral α-trifluoromethylamine derivative and a method for synthesizing the same. Background Art

[0002] As an innovative bioisostere of the traditional amide bond, α-trifluoromethylamine is a very important amide substitute and has become the "golden structural unit" of innovative drug design, showing broad prospects and applications in the fields of antiviral drugs, CNS disease therapeutics, and anti-tumor drugs. The stereochemical properties of α-trifluoromethylamine not only significantly affect the biological activity of molecules but also are directly related to the ultimate efficacy of drugs. This structure-activity relationship makes the stereochemical control of this group a key consideration in the drug optimization process.

[0003] Chiral α-trifluoromethylamine derivatives have important research and application values, and people have been working on developing simple methods for synthesizing this compound. In recent years, the methods reported in the literature for synthesizing chiral α-trifluoromethylamine derivatives mainly include the following:

[0004] The group of Jun-An Ma used a chiral phosphoric acid derivative as a Brønsted acid catalyst in a three-component reaction. Through the in-situ formation of an imine from trifluoroacetaldehyde methyl hemiacetal and aniline, and its reaction with indole, a chiral molecule containing a trifluoromethyl group was efficiently constructed to synthesize a chiral α-trifluoromethylamine derivative (Scheme 1), see reference: Zhang, G.-W.; Wang, L.; Nie, J.; Ma, J.-A. Chiral Acid-Mediated Enantioselective Organocatalytic Three-Component Reaction for the Construction of Trifluoromethyl-Containing Molecules. Adv. Synth. Catal. 2008, 350, 1457-1463.

[0005]

[0006] Cahard et al. first reported the asymmetric transfer hydrogenation of trifluoromethyl imines. Through a simple combination system of dichloro(p-cymene)ruthenium(II) dimer, chiral amino alcohol and isopropyl alcohol, the in-situ generation of a bifunctional catalyst for the transfer hydrogenation of trifluoromethyl ketimine was successfully achieved (Scheme 2), see reference: Dai, X.; Cahard, D. Enantioselective Synthesis of α-Trifluoromethyl Arylmethylamines by Ruthenium-Catalyzed Trasnfer Hydrogenation Reaction. Adv. Synth. Catal. 2014, 356, 1317-1328.

[0007]

[0008] Punna et al. achieved stereodivergent control of the trifluoromethylation reaction of N-sulfinylimines by selecting different base systems: organic superbase or organometallic base, and were able to selectively obtain either diastereoisomer. This study used an organic superbase system (such as P4-tBu) or an organometallic base system (such as KHMDS), which could promote the stereodivergent trifluoromethylation reaction of fluoroform with N-sulfinylimines, and finally obtained a high yield and high enantioselectivity (Scheme 2), see reference: Punna, N.; Saito, T.; Kosobokov, M.; Tokunaga, E.; Sumii, Y.; Shibata, N. Stereodivergent trifluoromethylation of N-sulfinylimines by fluoroform with either organic-superbase or organometallic-base. Chem. Commun. 2018, 54, 4294-4297.

[0009]

[0010] Among the above several methods for synthesizing chiral α-trifluoromethylamines, noble metal catalysts are expensive, aryl nucleophiles are limited, chiral auxiliary agents are very expensive themselves, and the dosage is large, which reduces the synthesis efficiency, etc. Therefore, it is of great significance to find a method for synthesizing chiral α-trifluoromethylamine derivatives with easily available and cheaper raw materials and simple operation. Summary of the Invention

[0011] To solve the above technical problems, the object of the present invention is to provide a chiral α-trifluoromethylamine derivative and its synthesis method. The chiral α-trifluoromethylamine derivative is prepared under the catalysis of a nickel catalyst, and has the advantages of cheap catalyst metal, good functional group compatibility, simple operation, high yield and high stereoselectivity.

[0012] The object of the present invention is achieved by the following technical solutions:

[0013] In the first aspect, the present invention provides a synthesis method of a chiral α-trifluoromethylamine derivative, which includes the following steps: in the presence of a nickel catalyst, a ligand, a reducing agent, an additive and a first organic solvent, reacting compound Ⅰ with compound Ⅱ to obtain compound Ⅲ;

[0014] The structural formulas of the compound Ⅰ, compound Ⅱ and compound Ⅲ are shown as follows:

[0015]

[0016] Among them, R1 includes any one of pyrrolecarbonyl, benzoyl, thiophenecarbonyl (all are protecting groups);

[0017] R includes any one of an ester group, H, an aldehyde group, a methoxy group, a halogen, a carbonyl group, a cyano group, a sulfone group, a trifluoromethyl group, a phosphate ester, a sulfonamide;

[0018] X is selected from Br or I, preferably Br.

[0019] As some specific embodiments of the present invention, the nickel catalyst includes nickel metal or a nickel compound, and the nickel compound is selected from at least one of nickel acetate, nickel bromide, nickel chloride.

[0020] As some specific embodiments of the present invention, the ligand includes a nitrogen-containing heterocycle or its derivative, and the nitrogen-containing heterocycle is selected from at least one of pyridine, quinine, carbazole.

[0021] Preferably, the ligand includes compound L1, and the structural formula of compound L1 is shown as follows:

[0022]

[0023] As some specific embodiments of the present invention, the reducing agent is selected from at least one of zinc, manganese, triethylamine. Preferably zinc powder.

[0024] As some specific embodiments of the present invention, the additive includes at least one of magnesium chloride, magnesium bromide, zinc chloride. Preferably anhydrous magnesium chloride.

[0025] As some specific embodiments of the present invention, the first organic solvent is selected from at least one of N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, and acetonitrile. Preferably, it is a mixed solvent of DMF and THF, and the volume ratio of DMF to THF is 1:1.

[0026] As some specific embodiments of the present invention, the molar ratio of compound I, compound II, ligand, reducing agent, additive, and nickel catalyst is 1:2.5 - 3:0.1 - 0.15:3.0 - 3.2:2 - 2.2:0.05 - 0.15.

[0027] As some specific embodiments of the present invention, compound I is α-amino-trifluoromethyl acetate or its derivative, and compound II is aryl halide or its derivative. Preferably, compound II uses aryl bromide.

[0028] As some specific embodiments of the present invention, the preparation method of compound I includes the following steps:

[0029] A1. React compound IV with compound V by heating in a second organic solvent, concentrate under reduced pressure after cooling, and purify to obtain compound VI;

[0030] A2. React compound VI with pyridine in acetic anhydride, concentrate under reduced pressure to remove unreacted acetic anhydride and pyridine, and obtain the product after purification;

[0031] The structural formulas of compound IV, compound V, and compound VI are shown as follows:

[0032]

[0033] Among them, Ar is selected from any one of them.

[0034] As some specific embodiments of the present invention, in step A1, it includes at least one of the following technical features:

[0035] One, the second organic solvent includes 1,4-dioxane;

[0036] Two, the molar ratio of compound IV to compound V is 1:1 - 2;

[0037] Three, the heating reaction is carried out under a nitrogen atmosphere, the temperature of the heating reaction is 110°C - 130°C, and the time is 1.5 - 2.5 h;

[0038] Four, the purification is carried out by recrystallization with dichloromethane or silica gel column chromatography.

[0039] As some specific embodiments of the present invention, in step A2, it includes at least one of the following technical features:

[0040] (1) The molar ratio of the compound VI to pyridine is 8:1 to 12:1;

[0041] (2) The reaction is carried out under an argon atmosphere, the reaction temperature is 20 to 30 °C, and the time is 10 to 14 h;

[0042] (3) The temperature of the reduced pressure concentration is 60 to 80 °C;

[0043] (4) The purification includes purification by a silica gel chromatography column.

[0044] As some specific embodiments of the present invention, the reaction equation is:

[0045]

[0046] Wherein,

[0047] As some specific embodiments of the present invention, the synthesis method specifically includes the following steps:

[0048] S1. Mix the compound I, compound II, ligand, catalyst, reducing agent, and additive in a first organic solvent, stir to make the reducing agent evenly suspended, and continue the reaction;

[0049] S2. After the reaction is completed, quench with saturated sodium chloride solution, extract the aqueous phase with ethyl acetate, combine the organic phases, dry and concentrate, and obtain the product after separation and purification.

[0050] As some specific embodiments of the present invention, in step S1, first add the compound I, compound II, ligand, catalyst, reducing agent, and additive into a reaction tube, transfer the reaction tube to a nitrogen glove box, inject the first organic solvent, seal it, and then transfer it out of the glove box.

[0051] As some specific embodiments of the present invention, in step S1, the reaction temperature is -10 to 10 °C, and the time is 24 to 48 h, preferably 0 °C and 36 h.

[0052] As some specific embodiments of the present invention, in step S2, the drying is carried out using anhydrous magnesium sulfate; the separation and purification are carried out by silica gel column chromatography.

[0053] As some specific embodiments of the present invention, the reaction equation is as follows:

[0054]

[0055] Wherein, the compound L1 is

[0056] In a second aspect, the present invention provides a chiral α-trifluoromethylamine derivative, which is prepared by using the synthesis method described in any one of the above.

[0057] Compared with the prior art, the present invention has the following beneficial effects:

[0058] 1) In the reaction of the present invention, α-amino-trifluoromethyl acetate and aryl bromide are used as substrates, and under the action of a catalyst, a ligand, a reducing agent, and an additive, the reaction is carried out at 0 °C for 36 hours to obtain a chiral α-trifluoromethylamine derivative; the metal of the catalyst in the present invention is relatively inexpensive, has good functional group compatibility, the raw materials are simple and easy to obtain, the reaction is a one-step reaction, the operation steps are simple, the operation is safe, the yield and stereoselectivity are relatively high, and the substrate applicability is wide;

[0059] 2) The method of the present invention is simple and feasible, has a low cost, and is suitable for popularization and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] By reading the following detailed description of non-limiting embodiments with reference to the accompanying drawings, other features, objects, and advantages of the present invention will become more apparent:

[0061] Figure 1 It is the X-ray crystal structure diagram of compound 2 prepared in Example 2;

[0062] Figure 2 It is the hydrogen spectrum of compound 1 prepared in Example 1;

[0063] Figure 3 It is the carbon spectrum of compound 1 prepared in Example 1;

[0064] Figure 4 It is the fluorine spectrum of compound 1 prepared in Example 1;

[0065] Figure 5 It is the hydrogen spectrum of compound 2 prepared in Example 2;

[0066] Figure 6 It is the carbon spectrum of compound 2 prepared in Example 2;

[0067] Figure 7 It is the fluorine spectrum of compound 2 prepared in Example 2;

[0068] Figure 8 It is the hydrogen spectrum of compound 3 prepared in Example 3;

[0069] Figure 9 It is the carbon spectrum of compound 3 prepared in Example 3;

[0070] Figure 10 It is the fluorine spectrum of compound 3 prepared in Example 3;

[0071] Figure 11 It is the hydrogen spectrum of compound 4 prepared in Example 4;

[0072] Figure 12 13C NMR spectrum of compound 4 prepared in Example 4;

[0073] Figure 13 19F NMR spectrum of compound 4 prepared in Example 4;

[0074] Figure 14 1H NMR spectrum of compound 5 prepared in Example 5;

[0075] Figure 15 13C NMR spectrum of compound 5 prepared in Example 5;

[0076] Figure 16 19F NMR spectrum of compound 5 prepared in Example 5;

[0077] Figure 17 1H NMR spectrum of compound 6 prepared in Example 6;

[0078] Figure 18 13C NMR spectrum of compound 6 prepared in Example 6;

[0079] Figure 19 19F NMR spectrum of compound 6 prepared in Example 6;

[0080] Figure 20 1H NMR spectrum of compound 7 prepared in Example 7;

[0081] Figure 21 13C NMR spectrum of compound 7 prepared in Example 7;

[0082] Figure 22 19F NMR spectrum of compound 7 prepared in Example 7;

[0083] Figure 23 1H NMR spectrum of compound 8 prepared in Example 8;

[0084] Figure 24 13C NMR spectrum of compound 8 prepared in Example 8;

[0085] Figure 25 19F NMR spectrum of compound 8 prepared in Example 8;

[0086] Figure 26 Exemplary reaction equation of the synthesis method of the present invention;

[0087] Figure 27 1H NMR spectrum of pyrrolecarbonyl-protected α-amino-trifluoromethyl acetate prepared in Example 1;

[0088] Figure 28 13C NMR spectrum of pyrrolecarbonyl-protected α-amino-trifluoromethyl acetate prepared in Example 1;

[0089] Figure 29 19F NMR spectrum of the pyrrolecarbonyl - protected α - amino - trifluoro - methylacetate prepared in Example 1. Detailed Description of the Embodiments

[0090] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made. These all belong to the protection scope of the present invention.

[0091] Using compound I (α - amino - trifluoro - methylacetate derivative) and compound II (aryl halide or its derivative) as reaction raw materials, nickel as a catalyst, nitrogen - containing heterocyclic or its derivative as a ligand, zinc powder as a reducing agent, anhydrous magnesium chloride as an additive, and DMF and THF as solvents to prepare chiral α - trifluoromethylamine derivatives. The reaction equation is as Figure 26 shown. Among them, R1 includes any one of pyrrolecarbonyl, benzoyl, and thiophenecarbonyl (all are protecting groups); R includes any one of ester group, H, aldehyde group, methoxy group, halogen, carbonyl group, cyano group, sulfone group, trifluoromethyl group, phosphate group, and sulfonamide group.

[0092] Example 1

[0093] In this example, a chiral α - trifluoromethylamine derivative was synthesized using pyrrolecarbonyl - protected α - amino - trifluoro - methylacetate and methyl 4 - bromobenzoate as raw materials.

[0094] 1. The pyrrolecarbonyl - protected α - amino - trifluoro - methylacetate was prepared by the following method:

[0095]

[0096] The hemi - acetal (compound 9, 20 mmol, 2.88 g, 1.0 equivalent) and pyrrole - 2 - carboxamide (compound 12, 30 mmol, 3.30 g, 1.5 equivalents) were dissolved in 1,4 - dioxane (40 mL), heated to 120 °C under a nitrogen atmosphere and stirred for 2 hours, and then cooled to room temperature. The mixture was concentrated under reduced pressure to obtain a white solid, which was purified by recrystallization from dichloromethane or silica gel column chromatography to obtain trifluoromethylated 1,1 - amino alcohol (compound 10, 10.8 mmol, 1.70 g, yield 54%).

[0097] In a dry round-bottom flask, trifluoromethylated 1,1-amino alcohol solid (Compound 10, 2.32 g, 14.8 mmol, 1.0 equiv) and pyridine (119 mg, 1.5 mmol, 0.10 equiv) were dissolved in acetic anhydride (40.0 mL), and the mixture was stirred at room temperature for 12 h under an argon atmosphere. The resulting colorless solution was concentrated under reduced pressure at 70 °C until unreacted acetic anhydride and pyridine were completely removed. The residue was purified by silica gel column chromatography to give pyrrolidinecarbonyl-protected α-amino-trifluoromethyl acetate (Compound 11, 2.9 g, yield 82%). The prepared product was characterized as follows:

[0098] 1 H NMR (600 MHz, Chloroform-d) δ 9.85 (s, br, 1H), 7.20 (dq, JH-H = 10.3, JH-F = 5.2 Hz, 1H), 7.05 (s, br, 1H), 6.72 (s, br, 1H), 6.49 (d, J = 10.4 Hz, 1H), 6.28 (s, br, 1H), 2.15 (s, 3H).( Figure 27 )

[0099] 13 C NMR (151 MHz, Chloroform-d) δ 167.9, 159.6, 123.9, 123.7, 121.9 (q, J = 281.0 Hz), 111.4, 110.4, 69.7 (q, J = 37.1 Hz), 20.4;( Figure 28 )

[0100] 19 F NMR (565 MHz, Chloroform-d) δ -79.75 (d, J = 5.2 Hz).( Figure 29 )

[0101] HRMS (ESI) calcd for C9H10F3N2O3 [M+H]+: 251.0638; Found: 251.0642.

[0102] 2. The specific synthesis steps of the chiral α-trifluoromethylamine derivative are as follows:

[0103] To the reaction tube dried in an oven and equipped with a magnetic stir bar, zinc powder (0.6 mmol, 3.0 equiv), methyl 4-bromobenzoate (0.4 mmol, 2.0 equiv), anhydrous magnesium chloride (0.40 mmol, 2.0 equiv), ligand L1 (0.02 mmol, 0.1 equiv), nickel(II) acetate tetrahydrate (0.02 mmol, 0.1 equiv), and pyrrolylcarbonyl-protected α-amino-trifluoroacetate (0.2 mmol, 1.0 equiv, prepared by the same method as in Example 1) were added successively. The reaction tube was transferred to a nitrogen glove box, and a DMF:THF mixed solvent (1.5 mL, v1:v2 = 1:1) was injected. After sealing, it was removed from the glove box. The reaction mixture was vigorously stirred to suspend the reducing agent uniformly, and the reaction was continued at 0 °C for 36 hours. After the reaction was completed, it was quenched with saturated sodium chloride solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and finally purified by flash column chromatography on silica gel to obtain the target product, and the white solid product compound 1 was obtained with a yield of 80% - 85% and an er value of 95:5.

[0104] The structural formula of ligand L1 (Shanghai Anyinuo Biomedical Technology Co., Ltd., AYN1152) is as follows:

[0105]

[0106] 3. Characterize the product compound 1 synthesized in this example:

[0107] 1 H NMR (600 MHz, Chloroform-d) δ 9.75 (s, br, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 6.95 (s, br, 1H), 6.75 (s, br, 1H), 6.60 (d, J = 9.4 Hz, 1H), 6.26 (s, br, 1H), 5.94 (dq, J H-H = 9.4 Hz, J H-F = 8.1 Hz, 1H), 3.92 (s, 3H); ( Figure 2 )

[0108] 13 C NMR (151 MHz, Chloroform-d) δ 166.4, 160.4, 137.7, 131.0, 130.2, 128.0, 124.4 (q, J = 281.1 Hz), 124.3, 123.0, 110.6, 110.2, 54.0 (q, J = 31.3 Hz), 52.3; ( Figure 3 )

[0109] 19 F NMR(565 MHz, Chloroform-d) δ -73.09 (d, J=8.1 Hz).( Figure 4 )

[0110] HRMS(ESI) calcd for C 15 H 14 F3N2O3 [M+H] + : 327.0951;Found: 327.0945.

[0111] HPLC(OD-H, hexane / isopropanol=80 / 20 (v / v%), flow 1.0 mL / min, UV detection at 254 nm) retention time=6.63 min (minor) and 10.33 min (major). 95:5 er

[0112] [α] D 20 = -15 (c=0.1, CHCl3, 95:5 e.r.).

[0113] The structural formula of the chiral α-trifluoromethylamine derivative (Compound 1) synthesized in this example is:

[0114]

[0115] Example 2

[0116] The synthesis method of this example is basically the same as that of Example 1, except that the raw materials used for synthesizing the chiral α-trifluoromethylamine derivative are different. In this example, the chiral α-trifluoromethylamine derivative is synthesized using pyrrolidinecarbonyl-protected α-amino-trifluoromethyl acetate and p-bromoacetophenone as raw materials.

[0117] The specific synthesis steps are as follows:

[0118] To a reaction tube dried in an oven and equipped with a magnetic stir bar, zinc powder (0.6 mmol, 3.0 equiv), p-bromoacetophenone (0.4 mmol, 2.0 equiv), magnesium chloride (0.40 mmol, 2.0 equiv), ligand L1 (0.02 mmol, 0.1 equiv), nickel(II) acetate tetrahydrate (0.02 mmol, 0.1 equiv), and pyrrolecarbonyl-protected α-amino-trifluoroacetate (0.2 mmol, 1.0 equiv) were added successively. The reaction tube was transferred to a nitrogen glove box, and a DMF:THF mixed solvent (1.5 mL, v1:v2 = 1:1) was injected. After sealing, it was removed from the glove box. The reaction mixture was vigorously stirred to suspend the reducing agent evenly and reacted at 0 °C for 36 h. After completion of the reaction, it was quenched with saturated sodium chloride solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and finally purified by flash column chromatography on silica gel to obtain the target product, i.e., a white solid compound 2, with a yield of 65% - 70% and an er value of 95:5.

[0119] The product compound 2 synthesized by the method of this example was characterized as follows:

[0120] 1H NMR (600 MHz, Chloroform-d) δ 9.67 (s, br, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 6.96 (s, br, 1H), 6.75 (s, br, 1H), 6.62 (d, J = 9.3 Hz, 1H), 6.26 (s, br, 1H), 5.94 (dq, JH-H = 9.3 Hz, JH-F = 7.5 Hz, 1H), 2.60 (s, 3H); ( Figure 5 )

[0121] 13C NMR (151 MHz, Chloroform-d) δ 197.5, 160.4, 137.9, 137.6, 128.9, 128.2, 124.4 (q, J = 281.7 Hz), 124.3, 123.0, 110.6, 110.3, 54.0 (q, J = 31.5 Hz), 26.7; ( Figure 6 )

[0122] 19F NMR (565 MHz, Chloroform-d) δ -73.0 (d, J = 7.5 Hz). ( Figure 7 )

[0123] HRMS (ESI) calcd for C15H14F3N2O2 [M+H]+: 311.1002; Found: 311.0998.

[0124] HPLC (OD-H, hexane / isopropanol = 80 / 20 (v / v%), flow 1.0 mL / min, UV detection at 254 nm) retention time = 7.77 min (minor) and 12.42 min (major). 95:5 e.r.

[0125] [α]D20 = -29 (c = 0.1, CHCl3, 95:5 e.r.).

[0126] The structural formula of the chiral α-trifluoromethylamine derivative (Compound 2) synthesized in this example is:

[0127]

[0128] Example 3

[0129] The synthesis method of this example is basically the same as the previous example, except that the raw materials used for synthesizing the chiral α-trifluoromethylamine derivative are not completely the same. In this example, the chiral α-trifluoromethylamine derivative is synthesized using pyrrolecarbonyl-protected α-amino-trifluoromethyl acetate and p-bromobenzaldehyde as raw materials.

[0130] The specific synthesis steps are as follows:

[0131] Add zinc powder (0.6 mmol, 3.0 equiv), p-bromobenzaldehyde (0.4 mmol, 2.0 equiv), magnesium chloride (0.40 mmol, 2.0 equiv), ligand L1 (0.02 mmol, 0.1 equiv), nickel acetate tetrahydrate (0.02 mmol, 0.1 equiv), and pyrrolecarbonyl-protected α-amino-trifluoromethyl acetate (0.2 mmol, 1.0 equiv) successively into a reaction tube dried in an oven and equipped with a magnetic stirrer. Transfer the reaction tube to a nitrogen glove box, inject the DMF:THF mixed solvent (1.5 mL, v1:v2 = 1:1), seal it, and then remove it from the glove box. Stir the reaction mixture vigorously to make the reducing agent evenly suspended, and continue the reaction at 0 °C for 36 hours. After the reaction is completed, quench it with saturated sodium chloride solution, and extract the aqueous phase with ethyl acetate three times. Combine the organic phases, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and finally separate and purify by flash column chromatography on silica gel to obtain the target product, that is, a white solid compound 3 with a yield of 43% - 50% and an e.r. value of 94:6.

[0132] Characterize the product compound 3 synthesized by the method of this example:

[0133] 11H NMR (600 MHz, Chloroform-d) δ 10.04 (s, 1H), 9.44 (s, br, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.9 Hz, 2H), 6.98 (s, br, 1H), 6.74 (s, br, 1H), 6.48 (d, J = 9.4 Hz, 1H), 6.29 (s, br, 1H), 5.96 (dq, J H-H = 9.4 Hz, J H-F = 8.1 Hz, 1H); ( Figure 8 )

[0134] 13 13C NMR (151 MHz, Chloroform-d) δ 191.5, 160.3, 139.3, 136.8, 130.2, 128.6, 124.3 (q, J = 281.7 Hz), 124.2, 123.0, 110.6, 110.3, 54.1 (q, J = 31.6 Hz); ( Figure 9 )

[0135] 19 19F NMR (565 MHz, Chloroform-d) δ -72.96 (d, J = 8.1 Hz). ( Figure 10 )

[0136] HRMS (ESI) calcd for C 14 H 12 F3N2O [M+H] + : 297.0846; Found: 297.0846.

[0137] HPLC (OD-H, hexane / isopropanol = 80 / 20 (v / v%), flow 1.0 mL / min, UV detection at 254 nm) retention time = 7.52 min (minor) and 9.19 min (major). 94:6 er

[0138] [α] D 20 = -164 (c = 0.1, CHCl3, 94:6 e.r.).

[0139] The structural formula of the chiral α-trifluoromethylamine derivative (Compound 3) synthesized in this example is:

[0140]

[0141] Example 4

[0142] The synthesis method of this example is basically the same as that of the foregoing example, except that the raw materials for synthesizing the chiral α-trifluoromethylamine derivative are different. In this example, the chiral α-trifluoromethylamine derivative is synthesized using pyrrolecarbonyl-protected α-amino-trifluoromethyl acetate and p-bromobenzonitrile as raw materials.

[0143] The specific synthesis steps are as follows:

[0144] Zinc powder (0.6 mmol, 3.0 equiv), p-bromobenzonitrile (0.4 mmol, 2.0 equiv), magnesium chloride (0.40 mmol, 2.0 equiv), ligand L1 (0.02 mmol, 0.1 equiv), nickel acetate tetrahydrate (0.02 mmol, 0.1 equiv), and pyrrolecarbonyl-protected α-amino-trifluoromethyl acetate (0.2 mmol, 1.0 equiv) were successively added to a reaction tube dried in an oven and equipped with a magnetic stir bar. The reaction tube was transferred to a nitrogen glove box, and a DMF:THF mixed solvent (1.5 mL, v1:v2 = 1:1) was injected. After sealing, the reaction tube was removed from the glove box. The reaction mixture was vigorously stirred to evenly suspend the reducing agent, and the reaction was continued at 0 °C for 36 hours. After the reaction was completed, it was quenched with saturated sodium chloride solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and finally purified by flash column chromatography on silica gel to obtain the target product, i.e., a white solid compound 4, with a yield of 70% - 75% and an er value of 94:6.

[0145] The product compound 4 synthesized by the method of this example was characterized:

[0146] 1 H NMR (600 MHz, Chloroform-d) δ 9.62 (s, br, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 6.97 (s, br, 1H), 6.76 (s, br, 1H), 6.64 (d, J = 9.3 Hz, 1H), 6.26 (s, br, 1H), 5.93 (dq, J H-H = 9.3 Hz, J H-F = 7.5 Hz, 1H); ( Figure 11 )

[0147] 13 C NMR (151 MHz, Chloroform-d) δ 171.3, 138.1, 132.7, 128.7, 124.4 (q, J = 281.7 Hz), 124.1, 123.1, 118.0, 113.4, 110.7, 110.4, 54.0 (q, J = 31.7 Hz); (Figure 12 )

[0148] 19 F NMR (565 MHz, Chloroform-d) δ -72.9 (d, J = 7.5 Hz).( Figure 13 )

[0149] HRMS (ESI) calcd for C 14 H 11 F3N3O [M+H] + : 294.0849; Found: 294.0849.

[0150] HPLC (OD-H, hexane / isopropanol = 80 / 20 (v / v%), flow 1.0 mL / min, UV detection at 254 nm) retention time = 7.28 min (minor) and 8.25 min (major). 94:6 er

[0151] [α] D 20 = -38 (c = 0.1, CHCl3, 94:6 e.r.).

[0152] The structural formula of the chiral α-trifluoromethylamine derivative (Compound 4) synthesized in this example is:

[0153]

[0154] Example 5

[0155] The synthesis method of this example is basically the same as that of the previous example, except that the raw materials used for synthesizing the chiral α-trifluoromethylamine derivative are not completely the same. In this example, the chiral α-trifluoromethylamine derivative is synthesized using pyrrolecarbonyl-protected α-amino-trifluoromethyl acetate and 4-trifluoromethylbromobenzene as raw materials.

[0156] The specific synthesis steps are as follows:

[0157] To a reaction tube that was dried in an oven and equipped with a magnetic stir bar, zinc powder (0.6 mmol, 3.0 equiv), 4-bromobenzotrifluoride (0.4 mmol, 2.0 equiv), magnesium chloride (0.40 mmol, 2.0 equiv), ligand L1 (0.02 mmol, 0.1 equiv), nickel(II) acetate tetrahydrate (0.02 mmol, 0.1 equiv), and pyrrolidine-1-carbonyl-protected α-amino-α-(trifluoromethyl)acetic acid ester (0.2 mmol, 1.0 equiv) were added successively. The reaction tube was transferred to a nitrogen glove box, and a DMF:THF mixed solvent (1.5 mL, v1:v2 = 1:1) was injected. After sealing, it was removed from the glove box. The reaction mixture was vigorously stirred to evenly suspend the reducing agent, and the reaction was continued at 0 °C for 36 hours. After completion of the reaction, it was quenched with saturated sodium chloride solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and finally purified by flash column chromatography on silica gel to obtain the target product, namely, white solid compound 5, with a yield of 75% - 80% and an er value of 95:5.

[0158] The product compound 5 synthesized by the method of this example was characterized as follows:

[0159] 1 H NMR (600 MHz, Chloroform-d) δ 9.84 (s, br, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 6.93 (s, br, 1H), 6.76 (s, br, 1H), 6.62 (d, J = 9.3 Hz, 1H), 6.26 (s, br, 1H), 5.95 (dq, J H-H = 9.3 Hz, J H-F = 8.3 Hz, 1H); ( Figure 14 )

[0160] 13 C NMR (151 MHz, Chloroform-d) δ 160.4, 136.9, 131.5 (q, J = 31.9 Hz), 128.4, 126.0, 124.3 (q, J = 281.7 Hz), 124.2, 123.7 (q, J = 281.7 Hz), 123.1, 110.7, 110.3, 54.0 (q, J = 31.6, Hz); ( Figure 15 )

[0161] 19 F NMR (565 MHz, Chloroform-d) δ -62.90, -73.13 (d, J = 8.3 Hz). ( Figure 16 )

[0162] HRMS(ESI)calcd for C 14 H 11 F6N2O[M+H] + : 337.0763; Found: 337.0769.

[0163] HPLC(ID, hexane / isopropanol = 80 / 20 (v / v%), flow 1.0 mL / min, UV detection at 254 nm) retention time = 5.85 min (major) and 6.72 min (minor). 95:5 er

[0164] [α] D 20 = -50 (c = 0.1, CHCl3, 95:5 e.r.).

[0165] The structural formula of the chiral α-trifluoromethylamine derivative (Compound 5) synthesized in this example is:

[0166]

[0167] Example 6

[0168] The synthesis method of this example is basically the same as that of the previous example, except that the raw materials used for synthesizing the chiral α-trifluoromethylamine derivative are different. In this example, the chiral α-trifluoromethylamine derivative is synthesized using pyrrolidinecarbonyl-protected α-amino-trifluoromethyl acetate and methyl 3-bromobenzoate as raw materials.

[0169] The specific synthesis steps are as follows:

[0170] To a reaction tube that was dried in an oven and equipped with a magnetic stir bar, zinc powder (0.6 mmol, 3.0 equiv), methyl 3-bromobenzoate (0.4 mmol, 2.0 equiv), magnesium chloride (0.40 mmol, 2.0 equiv), ligand L1 (0.02 mmol, 0.1 equiv), nickel(II) acetate tetrahydrate (0.02 mmol, 0.1 equiv), and pyrrolidinecarbonyl-protected α-amino-trifluoroacetate (0.2 mmol, 1.0 equiv) were added successively. The reaction tube was transferred to a nitrogen glove box, and a DMF:THF mixed solvent (1.5 mL, v1:v2 = 1:1) was injected. After sealing, it was removed from the glove box. The reaction mixture was vigorously stirred to evenly suspend the reducing agent, and the reaction was continued at 0 °C for 36 hours. After completion of the reaction, it was quenched with saturated sodium chloride solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and finally purified by flash column chromatography on silica gel to obtain the target product, i.e., a white solid compound 6, with a yield of 40% - 50% and an er value of 94:6.

[0171] The product compound 6 synthesized by the method of this example was characterized:

[0172] 1 H NMR (600 MHz, Chloroform-d) δ 9.73 (s, br, 1H), δ 8.16 (s, 1H), 8.07 (dd, J = 7.8, 1.4 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.94 (s, br, 1H), 6.78 (s, br, 1H), 6.69 (d, J = 9.5 Hz, 1H), 6.26 (s, br, 1H), 5.95 (dq, J H-H = 9.5 Hz, J H-F = 7.6 Hz, 1H), 3.93 (s, 3H); ( Figure 17 )

[0173] 13 C NMR (151 MHz, Chloroform-d) δ 166.5, 160.4, 133.5, 132.7, 130.9, 130.4, 129.1, 128.8, 124.5 (q, J = 281.7 Hz), 124.4, 123.0, 110.8, 110.2, 53.9 (q, J = 31.1 Hz), 52.4;

[0174] 19 F NMR (565 MHz, Chloroform-d) δ -73.39 (d, J = 7.6 Hz). ( Figure 18 )

[0175] HRMS(ESI)calcd for C 15 H 14 F3N2O3[M+H] + :327.0951; Found:327.0947.( Figure 19 )

[0176] HPLC(OD-H, hexane / isopropanol = 80 / 20(v / v%), flow 1.0 mL / min, UV detection at 254 nm) retention time = 5.20 min (major) and 5.79 min (minor). 94:6 er

[0177] [α] D 20 = +9 (c = 0.1, CHCl3, 94:6 e.r.).

[0178] The structural formula of the chiral α-trifluoromethylamine derivative (Compound 6) synthesized in this example is:

[0179]

[0180] Example 7

[0181] The synthesis method of this example is basically the same as that of the previous example, except that the raw materials used for synthesizing the chiral α-trifluoromethylamine derivative are different. In this example, the chiral α-trifluoromethylamine derivative is synthesized using pyrrolidinecarbonyl-protected α-amino-trifluoroacetate and 4-bromobenzoylbenzene as raw materials.

[0182] The specific synthesis steps are as follows:

[0183] To the reaction tube dried in an oven and equipped with a magnetic stir bar, zinc powder (0.6 mmol, 3.0 equiv), 4-bromobenzophenone (0.4 mmol, 2.0 equiv), magnesium chloride (0.40 mmol, 2.0 equiv), ligand L1 (0.02 mmol, 0.1 equiv), nickel(II) acetate tetrahydrate (0.02 mmol, 0.1 equiv), and pyrrolylcarbonyl-protected α-amino-trifluoroacetate (0.2 mmol, 1.0 equiv) were added in sequence. The reaction tube was transferred into a nitrogen glove box, and a DMF:THF mixed solvent (1.5 mL, v1:v2 = 1:1) was injected. After sealing, it was removed from the glove box. The reaction mixture was vigorously stirred to make the reducing agent uniformly suspended, and the reaction was continued at 0 °C for 36 hours. After the reaction was completed, it was quenched with saturated sodium chloride solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and finally purified by flash column chromatography on silica gel to obtain the target product, i.e., the white solid product compound 7, with a yield of 40% - 45% and an er value of 94:6.

[0184] The product compound 7 synthesized by the method of this example was characterized as follows:

[0185] 1 H NMR (600 MHz, Chloroform-d) δ 9.78 (s, br, 1H), 7.85 - 7.74 (m, 4H), 7.65 - 7.53 (m, 3H), 7.49 (t, J = 7.8 Hz, 2H), 6.95 (s, br, 1H), 6.78 (s, br, 1H), 6.71 (d, J = 9.4 Hz, 1H), 6.30 (s, br, 1H), 5.99 (dq, J H-H = 9.4 Hz, J H-F = 8.2 Hz, 1H); ( Figure 20 )

[0186] 13 C NMR (151 MHz, Chloroform-d) δ 196.0, 160.3, 138.4, 137.1, 137.1, 132.8, 130.5, 130.1, 128.4, 127.9, 124.4 (q, J = 281.7 Hz), 124.3, 122.9, 110.6, 110.3, 53.9 (q, J = 31.6 Hz); ( Figure 21 )

[0187] 19 F NMR (565 MHz, Chloroform-d) δ -72.9 (d, J = 8.2 Hz). ( Figure 22 )

[0188] HRMS(ESI)calcd for C 20 H 16 F3N2O2[M+H] + :373.1159;Found:373.1150.

[0189] HPLC(OD-H,hexane / isopropanol=80 / 20(v / v%),flow 1.0mL / min,UVdetection at254nm)retention time=8.64min(minor)and 9.96min(major).94:6er

[0190] [α] D 20 =-16(c=0.1,CHCl3,94:6e.r.).

[0191] The structural formula of the chiral α-trifluoromethylamine derivative (Compound 7) synthesized in this example is as follows:

[0192]

[0193] Example 8

[0194] The synthesis method of this example is basically the same as that of the previous example, except that the raw materials used for synthesizing the chiral α-trifluoromethylamine derivative are different. In this example, the chiral α-trifluoromethylamine derivative is synthesized using pyrrolidinecarbonyl-protected α-amino-trifluoromethyl acetate and 4-bromophenyl sulfone as raw materials.

[0195] The specific synthesis steps are as follows:

[0196] To a reaction tube that was dried in an oven and equipped with a magnetic stir bar, zinc powder (0.6 mmol, 3.0 equiv), 4-bromobenzenesulfone (0.4 mmol, 2.0 equiv), magnesium chloride (0.40 mmol, 2.0 equiv), ligand L1 (0.02 mmol, 0.1 equiv), nickel(II) acetate tetrahydrate (0.02 mmol, 0.1 equiv), and pyrrolidinecarbonyl-protected α-amino-trifluoroacetate (0.2 mmol, 1.0 equiv) were added successively. The reaction tube was transferred to a nitrogen glove box, and a DMF:THF mixed solvent (1.5 mL, v1:v2 = 1:1) was injected. After sealing, it was removed from the glove box. The reaction mixture was vigorously stirred to evenly suspend the reducing agent, and the reaction was continued at 0 °C for 36 hours. After the reaction was completed, it was quenched with saturated sodium chloride solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and finally purified by flash column chromatography on silica gel to obtain the target product, i.e., a white solid product, compound 8, with a yield of 80% - 85% and an er value of 97:3.

[0197] The product compound 8 synthesized by the method of this example was characterized as follows:

[0198] 1 H NMR (600 MHz, Methanol-d4) δ 8.01 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.06 (s, br, 1H), 6.97 (s, br, 1H), 6.20 (s, br, 1H), 6.10 (q, J H-F = 8.3 Hz, 1H), 3.13. (s, 3H); ( Figure 23 )

[0199] 13 C NMR (151 MHz, Methanol-d4) δ 161.5, 141.3, 139.5, 129.3, 127.4, 124.5 (q, J = 281.1 Hz), 124.2, 122.6, 112.1, 109.1, 53.6 (q, J = 31.7 Hz), 42.8; ( Figure 24 )

[0200] 19 F NMR (565 MHz, Methanol-d4) δ -74.10 (d, J = 8.3 Hz). ( Figure 25 )

[0201] HRMS (ESI) calcd for C 14 H 14 F3N2O3S [M+H] +: 347.0672; Found: 347.0666.

[0202] HPLC (OD-H, hexane / isopropanol = 80 / 20 (v / v%), flow 1.0 mL / min, UV detection at 254 nm) retention time = 15.59 min (minor) and 19.71 min (major). 97:3 e.r.

[0203] [α] D 20 = -42 (c = 0.1, CHCl3, 97:3 e.r.).

[0204] The structural formula of the chiral α-trifluoromethylamine derivative (Compound 8) synthesized in this example is:

[0205]

[0206] As can be seen from the above examples, when the synthesis method of the chiral α-trifluoromethylamine derivative of the present invention is used for the reaction, using α-amino-trifluoromethyl acetate and aryl bromide as substrates, under the action of a catalyst, a ligand, a reducing agent, and an additive, reacting at 0 °C for 36 hours can prepare the chiral α-trifluoromethylamine derivative. The present invention has the advantages of cheap catalyst metal, good functional group compatibility, simple operation, high yield and high stereoselectivity.

[0207] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various deformations or modifications within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for synthesizing a chiral α-trifluoromethylamine derivative, characterized in that, It includes the following steps: In the presence of a nickel catalyst, a ligand, a reducing agent, an additive and an organic solvent, react compound I with compound II to obtain compound III; The structural formulas of the said compound I, compound II and compound III are shown as follows: Wherein, R1 includes any one of pyrrolecarbonyl, benzoyl, thiophenecarbonyl (all are protecting groups); R includes any one of an ester group, H, an aldehyde group, a methoxy group, a halogen, a carbonyl group, a cyano group, a sulfone group, a trifluoromethyl group, a phosphate group, a sulfonamide; X is selected from Br or I.

2. The synthesis method according to claim 1, characterized in that, The said nickel catalyst includes nickel metal or a nickel compound, and the nickel compound includes at least one of nickel acetate, nickel bromide, nickel chloride; And / or, the said ligand includes a nitrogen-containing heterocyclic or its derivative, and the nitrogen-containing heterocyclic is selected from at least one of pyridine, quinine, carbazole; And / or, the said reducing agent is selected from at least one of zinc powder, manganese, triethylamine; And / or, the said additive includes at least one of magnesium chloride, magnesium bromide, zinc chloride; And / or, the said first organic solvent is selected from at least one of N,N-dimethylformamide, tetrahydrofuran, dichloromethane, acetonitrile.

3. The synthesis method according to claim 2, wherein The said ligand includes compound L1, and the structural formula of compound L1 is shown as follows:

4. The synthesis method according to claim 1, wherein The molar ratio of the said compound I, compound II, ligand, reducing agent, additive, nickel catalyst is 1:2.5 - 3:0.1 - 0.15:3.0 - 3.2:2 - 2.2:0.05 - 0.

15.

5. The synthesis method according to claim 1, characterized in that, The preparation method of the said compound I includes the following steps: A1. Heat and react compound IV with compound V in a second organic solvent, cool and then concentrate under reduced pressure, and purify to obtain compound VI; A2. React compound VI with pyridine in acetic anhydride, concentrate under reduced pressure to remove the unreacted acetic anhydride and pyridine, and obtain the product after purification; The structural formulas of the said compound IV, compound V and compound VI are shown as follows: Among them, Ar is selected from any one of them.

6. The synthesis method according to claim 5, characterized in that, In step A1, it includes at least one of the following technical features: One. The said second organic solvent includes 1,4-dioxane; Two. The molar ratio of the said compound IV to compound V is 1:1 - 2; Three. The said heating reaction is carried out under a nitrogen atmosphere, the temperature of the heating reaction is 110°C - 130°C, and the time is 1.5 - 2.5 h; Four. The said purification is carried out by recrystallization with dichloromethane or silica gel column chromatography.

7. The synthesis method according to claim 5, wherein In step A2, it includes at least one of the following technical features: One. The molar ratio of the said compound VI to pyridine is 8:1 - 12:1; Two. The said reaction is carried out under an argon atmosphere; the temperature of the reaction is 20 - 30°C, and the time is 10 - 14 h; Three. The temperature of the said concentration under reduced pressure is 60 - 80°C; Four. The said purification includes purification by silica gel chromatography column.

8. The synthesis method according to claim 1, characterized in that, The said synthesis method specifically includes the following steps: S1. Mix compound I, compound II, ligand, catalyst, reducing agent, additive in a first organic solvent, stir to make the reducing agent uniformly suspended, and continue the reaction; S2. After the reaction is completed, quench with saturated sodium chloride solution, take the aqueous phase and extract with ethyl acetate, combine the organic phases, dry and concentrate, and obtain the product after separation and purification.

9. The synthesis method according to claim 8, wherein In step S1, the temperature of the said reaction is -10 - 10°C, and the time is 24 - 48 h; And / or, in step S2, the drying is carried out using anhydrous magnesium sulfate; the separation and purification is carried out by silica gel column chromatography.

10. A chiral α-trifluoromethylamine derivative, characterized in that, Prepared by the synthesis method according to any one of claims 1-9.

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