A method for organocatalytic preparation of alpha-deuterium-alpha-trifluoromethyl amine compounds

Abstract

The application discloses a method for preparing alpha-deuterated-alpha-trifluoromethyl amine compounds by organic catalysis. The chiral product can be prepared by a betaine inner salt catalyst based on a cinchona alkaloid skeleton or a tertiary amine catalyst based on a cinchona alkaloid skeleton. The racemic product can be prepared by a non-chiral tertiary amine catalyst, a phase transfer catalyst or a crown ether. Meanwhile, the deuterium substitution reaction process adopts organic catalysis, has no transition metal residue risk, simple and mild conditions, good functional group compatibility, and the product is easy to purify. The method is suitable for the synthesis of alpha-deuterated-alpha-trifluoromethyl amine compounds of different types of substitution including alkyl and aryl, has high deuterium substitution rate and good selectivity.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for the organic catalytic preparation of α-deuterated-α-trifluoromethylamine compounds. Background Technology

[0002] Deuterated compounds have a wide range of important applications in chemistry, materials science, and life sciences. Deuterated molecules can be used as standards or internal standards for mass spectrometry, to enhance material performance, to study reaction mechanisms in chemical or enzyme-catalyzed reactions, and to study the absorption, distribution, metabolism, and excretion (ADME) characteristics of candidate drug molecules. Deuterated compounds can also serve as tracers to aid in the study of metabolic pathways and biotransformation processes. In particular, due to the kinetic isotope effect, CD bonds have a higher bond energy than CH bonds. Changing a hydrogen atom at a specific position in a candidate drug molecule to deuterium can reduce its degradation or epimerization rate, thereby improving the metabolic stability of the candidate drug molecule, enhancing efficacy, and reducing toxicity. Therefore, modifying existing or potential drug molecules into deuterated versions, or directly developing entirely new deuterated drug molecules, is an important approach in drug development.

[0003] In recent years, the approval of several deuterated drugs has brought new approaches to the treatment of many diseases. For example, in 2017, the U.S. Food and Drug Administration approved deuterated benzonazine for the treatment of chorea associated with Huntington's disease and tardive dyskinesia in adults, with projected annual sales of $2 billion by 2025. This drug's deuteration optimizes its metabolic and pharmacokinetic characteristics, thereby altering its efficacy, safety, and tolerability. The subsequent market launches of other drugs, including deuterated enzalutamide, donafenib, deuterated remidevir hydrobromide, deuterated colecizinib, and deuterated ruxolitinib, further illustrate the important application of deuterated compounds in drug development.

[0004] (Chiral) amines are extremely important structural units in medicinal chemistry, and are essential components of drug molecules. N Substitution of the -α-H group with deuterium is expected to significantly improve the metabolic stability of drugs, increase their duration of action, and reduce toxicity. Therefore, developing synthetic methods for α-deuterated amine compounds, especially drug molecules, is crucial. Introducing fluorine substituents, particularly trifluoromethyl groups, into drug molecules can alter their physicochemical properties, lipid solubility, metabolic stability, and electronegativity, enhancing bioavailability and targeting efficacy. Many drugs containing trifluoromethyl groups have been approved for marketing, including the antitumor drug sorafenib, the antidepressant fluoxetine, various cyclooxygenase inhibitors, and the anticytomegalovirus drug letemovir. Many candidate drug molecules and bioactive molecules with trifluoromethylamine structures are also under development.

[0005] Currently, the synthesis of α-deuterated amines mainly relies on transition metal-catalyzed HD exchange of amines or reduction of imines with deuterating reagents. These methods often suffer from problems such as transition metal residue, expensive deuterium sources, harsh conditions, limited substrate types, poor selectivity, and difficulties in synthesizing chiral deuterated amines. In particular, the asymmetric synthesis of α-deuterated trifluoromethylamines has only been reported in very few cases, and is limited to the synthesis of α-deuterated trifluoromethylamines with specific structural types. Asian J. Org. Chem. 2021, 10(6): 1530-1535.; Patent document with publication number WO 2010117932A1). Therefore, developing a widely applicable, transition metal-free, green, and efficient method for the synthesis of (chiral) α-deuterated-α-trifluoromethylamine compounds is of great value. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a method for the organic catalytic preparation of α-deuterated-α-trifluoromethylamine compounds. The deuteration reaction utilizes organic catalysis, eliminating the risk of transition metal residues. The conditions are simple and mild, with good functional group compatibility, and the product is easy to purify. This method is suitable for the synthesis of α-deuterated-α-trifluoromethylamine compounds with different types of substitutions, including alkyl and aryl groups, which were previously difficult to achieve. It exhibits high deuteration rates and good selectivity.

[0007] A method for preparing α-deuterated-α-trifluoromethylamine compounds by organocatalysis includes the following steps: (1) Trifluoromethyl ketone (Ⅰ) and substituted benzylamine (Ⅱ) were subjected to reflux reaction under acetic acid catalysis to obtain trifluoromethylamine compound (Ⅲ); (2) Under the action of an organic catalyst, the trifluoromethylimine compound (Ⅲ) obtained in step (1), the deuterium source and the solvent are mixed and reacted, extracted and purified to obtain chiral or racemic α-deuterated-α-trifluoromethylamine compound (Ⅳ). The organic catalyst is a chiral organic catalyst or a achiral organic catalyst; the chiral organic catalyst is one of a betaine-type inner salt catalyst based on the cinchona alkaloid framework and a tertiary amine catalyst based on the cinchona alkaloid framework; the achiral organic catalyst is one of a achiral tertiary amine catalyst, a phase transfer catalyst and a crown ether. The specific reaction route is as follows: , Wherein, R is a C1~C8 alkyl, substituted alkyl, C1~C8 alkenyl, substituted alkenyl, aryl, substituted aryl, polycyclic aryl, heterocyclic aryl, substituted heterocyclic aryl, alkyl or aryl substituted by a drug molecule or bioactive molecule; Ar is an aryl or heteroaryl substituted by a strong electron-withdrawing substituent; and "*" indicates that the atom is a chiral atom.

[0008] This invention enables the preparation of chiral or racemic α-deuterated-α-trifluoromethylamine compounds using organic catalysts. Specifically, chiral R and S configuration products can be prepared using betaine-type inner salt catalysts based on the cinchona alkaloid skeleton or tertiary amine catalysts based on the cinchona alkaloid skeleton; racemic products can be prepared using non-chiral tertiary amine catalysts, phase transfer catalysts, or crown ethers. Furthermore, the deuteration reaction utilizes organic catalysis, eliminating the risk of transition metal residues, providing simple and mild conditions, good functional group compatibility, and easy product purification. This invention is suitable for the synthesis of previously difficult-to-achieve α-deuterated-α-trifluoromethylamine compounds, including those with different types of substitutions such as alkyl and aryl groups, exhibiting high deuteration rates and good selectivity.

[0009] Preferably, in step (1), the trifluoromethyl ketone (I) has any of the following structures: .

[0010] Preferably, in step (1), the substituted benzylamine (II) is one of 4-nitrobenzylamine, 2-nitrobenzylamine, 4-esterbenzylamine, 4-chlorobenzylamine, 4-bromobenzylamine, and 4-trifluoromethylbenzylamine.

[0011] More preferably, the substituted benzylamine (II) is 4-nitrobenzylamine.

[0012] Preferably, in step (1), the molar ratio of trifluoromethyl ketone, substituted benzylamine, and acetic acid is 1~3:1:1.5.

[0013] Preferably, in step (1), the heating and reflux reaction time is 6 to 18 hours, and the reaction process is monitored by nuclear magnetic resonance hydrogen spectrum. The heating and reflux can be stopped when the yield no longer increases.

[0014] Preferably, in step (2), the structure of the betaine-type internal salt catalyst based on the cinchona alkaloid framework is as follows: or , The structure of the tertiary amine catalyst based on the cinchona alkaloid framework is as follows: or , Among them, R 1 Selected from one of hydrogen, alkyl, substituted alkyl, allyl, benzyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 2 Selected from hydrogen, m-hydroxybenzoyl, or substituted m-hydroxybenzoyl; R 3 Selected from one of hydrogen, halogen, alkyl, and aryl; R 4 Selected from one of hydrogen, alkoxy, and siloxy groups; R 5 Selected from one of hydrogen, hydroxyl, alkoxy, and siloxy groups; Ar 1It is selected from one of aryl, substituted aryl, and heteroaryl.

[0015] More preferably, the R 1 Selected from one of hydrogen, C1-C8 alkyl, substituted alkyl, allyl, benzyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 2 Selected from hydrogen, m-hydroxybenzoyl, or substituted m-hydroxybenzoyl; R 3 Selected from hydrogen, halogen, C1-C6 alkyl, aryl; R 4 Selected from one of hydrogen, C1~C10 alkoxy, and siloxy groups; R 5 Selected from one of hydrogen, hydroxyl, C1-C8 alkoxy, and siloxy groups; Ar 1 It is selected from one of aryl, substituted aryl, and heteroaryl.

[0016] More preferably, the preparation method of the betaine-type inner salt catalyst based on the cinchona alkaloid framework includes the following steps: Compound V or Compound VI was dissolved in acetonitrile with benzyl bromide and reacted at room temperature for 8-24 h. After purification, a betaine-type internal salt catalyst based on the cinchona alkaloid framework was obtained. The specific reaction route is as follows: .

[0017] More preferably, the molar ratio of compound V or compound VI to benzyl bromide is 1:1 to 1.2, and the concentration of compound V or compound VI in acetonitrile is 0.02 to 0.2 M.

[0018] In this invention, the preparation method of compound VI is as follows: Nature 2015, 523(7561):445-450. The method in the literature; in compound V, when R... 2 When it is H, please refer to J. Am. Chem. Soc . 2016, 138(37):12297-12302. The method described in the literature is used to prepare it when R 2 for , where R 6 The radical can be H, C1-C4 alkyl, C1-C4 alkoxy, acetyl, ester, or halogen. The specific preparation route is shown below: .

[0019] More preferably, the organic catalyst is a betaine-type internal salt catalyst based on a cinchona alkaloid framework, and the structure of the betaine-type internal salt catalyst based on a cinchona alkaloid framework is any of the following structures: .

[0020] Preferably, in step (2), the non-chiral tertiary amine catalyst is one of triethylamine, triethylenediamine, trimethylamine, diisopropylethylamine, tributylamine, and dimethylaniline; the phase transfer catalyst is one of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium fluoride, and benzyltriethylammonium bromide; and the crown ether is one of 18-crown-6 and 15-crown-5.

[0021] More preferably, the non-chiral organic catalyst is triethylamine or tetrabutylammonium bromide.

[0022] Preferably, in step (2), the deuterium source is at least one of heavy water, deuterated methanol, deuterated ethanol, and deuterated isopropanol.

[0023] More preferably, the deuterium source is heavy water.

[0024] Preferably, in step (2), the solvent is at least one of toluene, benzene, xylene, trimethylbenzene, diethyl ether, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, cyclopentylmethyl ether, dibutyl ether, 1,4-dioxane, etc.

[0025] More preferably, when the organic catalyst is a chiral organic catalyst, the solvent is toluene or diethyl ether; when the organic catalyst is a non-chiral organic catalyst, the solvent is one of dichloromethane, chloroform, ethyl acetate, and tetrahydrofuran.

[0026] Preferably, in step (2), the reaction temperature is 0~50 ℃ and the time is 1~60 h.

[0027] More preferably, the reaction temperature is 20~30 ℃ and the time is 24~48 h.

[0028] Preferably, in step (2), the molar ratio of the trifluoromethylimine compound (Ⅲ), the organic catalyst, and the deuterium source is 1:0.001~3:5~500.

[0029] More preferably, in step (2), when the organic catalyst is a chiral organic catalyst, an alkali is also added to the mixed reaction, wherein the molar ratio of trifluoromethylimine compound, chiral organic catalyst, deuterium source and alkali is 1:0.002~0.01:100~200:0.15~0.3; When the organic catalyst is a non-chiral organic catalyst, the molar ratio of the trifluoromethylimine compound, the non-chiral organic catalyst, and the deuterium source is 1:0.1~1:100~200; When the organic catalyst is a non-chiral organic catalyst, a base is also added to the mixed reaction, wherein the molar ratio of trifluoromethylimine compound, non-chiral organic catalyst, deuterium source and base is 1:0.1~1:100~200:3.

[0030] More preferably, in step (2), the alkali is at least one of hydroxide, carbonate, bicarbonate, phosphate, phenolate, and hydride.

[0031] More preferably, the alkali is one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, and potassium hydride.

[0032] The present invention also provides α-deuterated-α-trifluoromethylamine compounds prepared by the above method.

[0033] A method for preparing an α-deuterated-α-trifluoromethylamine hydrochloride compound includes the following steps: dissolving the above-mentioned chiral or racemic α-deuterated-α-trifluoromethylamine compound in an organic solvent, adding acid and reacting at 0~70 °C for 1~24 h, removing the organic solvent by vortexing, extracting with dilute hydrochloric acid, collecting the aqueous phase and evaporating to dryness to obtain the chiral or racemic α-deuterated-α-trifluoromethylamine hydrochloride compound.

[0034] The specific reaction route is as follows: .

[0035] Preferably, the acid is one of dilute hydrochloric acid, hydrochloric acid-methanol solution, hydrochloric acid-ethanol solution, hydrochloric acid-1,4-dioxane solution, hydrochloric acid-tetrahydrofuran solution, trifluoroacetic acid, dilute sulfuric acid, and citric acid.

[0036] More preferably, the acid is 1-4 mol / L dilute hydrochloric acid.

[0037] Preferably, the organic solvent is tetrahydrofuran or 1,4-dioxane.

[0038] The present invention also provides the application of the above-mentioned α-deuterated-α-trifluoromethylamine hydrochloride compounds as reagents for introducing deuterated trifluoromethyl groups into drug molecules.

[0039] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention enables the preparation of chiral or racemic α-deuterated-α-trifluoromethylamine compounds using organic catalysts. Specifically, chiral R and S products can be prepared using betaine-type inner salt catalysts based on the cinchona alkaloid skeleton or tertiary amine catalysts based on the cinchona alkaloid skeleton, while racemic products can be prepared using non-chiral tertiary amine catalysts, phase transfer catalysts, or crown ethers. Furthermore, the deuteration reaction utilizes organic catalysis, eliminating the risk of transition metal residues, providing simple and mild conditions, good functional group compatibility, and easy product purification. This invention is suitable for the synthesis of previously difficult-to-achieve α-deuterated-α-trifluoromethylamine compounds, including those with different types of substitutions such as alkyl and aryl groups, exhibiting high deuteration rates and good selectivity. Detailed Implementation

[0040] The present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited to the following embodiments.

[0041] All raw materials used in this invention are commercially available or prepared in the laboratory. Preparation method of organic catalyst QD-1, see references. J. Am. Chem. Soc . 2016, 138(37):12297-12302..

[0042] The preparation method of the organic catalyst QD-2 includes the following steps: (1) To a 10 mL solution of 2-chloro-5-hydroxybenzoic acid A1 (0.52 g, 3 mmol) in dichloromethane, imidazole (0.86 g, 12.6 mmol, 4.2 equiv.) and TBSCl (1.59 g, 10.5 mmol, 3.5 equiv.) were added sequentially. The reaction was stirred at room temperature until complete (monitored by TLC), then water was added to quench the reaction and the mixture was extracted with dichloromethane. The organic phase was washed sequentially with saturated sodium bicarbonate solution / saturated brine and dried over anhydrous sodium sulfate before concentration. The concentrated sample was purified by rapid column chromatography (petroleum ether / ethyl acetate) to obtain compound B1.

[0043] (2) Oxaloyl chloride (76.8 uL, 0.9 mmol, 3 equiv.) was added dropwise to a stirred solution of B1 (120 mg, 0.3 mmol) in dichloromethane (3 mL) at 0 °C, and a catalytic amount was added. N,N Dimethylformamide was used to slowly raise the reaction temperature to room temperature and continue stirring for 10 hours. The crude acyl chloride C1 was then concentrated under reduced pressure and used directly in the next reaction without purification.

[0044] (3) Dissolve D1 (57.3 mg, 0.1 mmol) in dichloromethane (3 mL) and add DMAP (4.9 mg, 0.04 mmol, 0.2 equiv.) and triethylamine (83 μL, 0.6 mmol, 3.0 equiv.). While stirring in an ice-water bath at 0°C, add C1 solution in dichloromethane (1 mL) dropwise. Continue stirring at 0°C for 30 minutes, then slowly raise to room temperature and continue stirring for 5 hours. After the reaction is complete, quench with saturated sodium bicarbonate solution and extract with dichloromethane (5 mL × 5). Wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude E1, which can be used for the next reaction without purification.

[0045] (4) Add HF (48-51 wt% in water, 50 μL) to the acetonitrile solution (2 mL) of the crude E1 product and stir at room temperature for 1 hour (TLC monitoring). After the reaction is complete, carefully add the reaction solution to 10 mL of saturated sodium bicarbonate solution. Extract the aqueous phase with dichloromethane (10 mL × 5). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product obtained is purified by silica gel column chromatography (CH2Cl2 to CH2Cl2 / MeOH = 10 / 1) to obtain pure compound formula VII-1.

[0046] (5) Add benzyl bromide F1 (43.5 mg, 1.1 equiv.) to the acetonitrile solution (2 mL) of the above formula VII-1. After stirring the reaction at room temperature for 16 hours, concentrate the solution under reduced pressure and purify it by silica gel column chromatography (CH2Cl2 to CH2Cl2 / MeOH = 10 / 1) to obtain pure white solid catalyst QD-2 (27 mg, 24% yield based on D1). 1 H NMR (500 MHz, Chloroform- d ) δ 9.25 (brs, 1H), 8.90 (d, J = 4.2 Hz, 1H), 8.73 (s, 1H), 8.27(d, J = 9.2 Hz, 1H), 8.13 – 8.03 (m, 1H), 7.75 – 7.63 (m, 8H), 7.52 – 7.44(m, 6H), 7.43 – 7.31 (m, 7H), 7.29 – 7.22 (m, 3H), 7.06 – 7.02 (m, 1H), 6.34(d, J= 11.6 Hz, 1H), 5.56 – 5.44 (m, 1H), 5.11 – 5.04 (m, 2H), 4.96 – 4.80(m, 2H), 4.17 (d, J = 11.9 Hz, 1H), 3.28 (t, J = 11.6 Hz, 1H), 3.02 – 2.90(m, 2H), 2.37 – 2.25 (m, 3H), 2.24 – 2.19 (m, 1H), 1.94 (s, 1H), 1.83 – 1.73(m, 3H), 0.89 – 0.87 (m, 1H), 0.56 (d, J = 3.2 Hz, 9H). 13 C NMR (126 MHz, Chloroform- d ) δ 164.41, 163.35, 162.67, 161.57, 156.40, 153.56, 152.95,150.61, 149.08, 148.97, 146.62, 140.42, 139.69, 139.46, 135.16, 134.71,133.90, 132.45, 131.94, 131.85, 131.75, 130.08, 129.60, 128.80, 128.37,128.16, 127.68, 127.51, 125.28, 124.67, HRMS (ESI-TOF): m / z : calcd. for C 65 H 57 Cl2N4O5 + [M-Br - ] + 1043.3701; found 1043.3698. Preparation method of organic catalyst Q-1, see references. J. Am. Chem. Soc . 2016, 138(37):12297-12302..

[0047] Example 1: Preparation of compound 3a (1) 1,1,1-trifluoroacetone (3 equiv.) and acetic acid (1.5 equiv.) were added sequentially to a chloroform solution (0.2 M) of 4-nitrobenzylamine (5 mmol, 1 equiv.) at 0 °C. The reaction was heated to reflux at 75 °C with stirring. After the 4-nitrobenzylamine was completely converted, the temperature was lowered to 0 °C and saturated sodium bicarbonate solution was slowly added to neutralize the acid. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by column chromatography (petroleum ether / dichloromethane = 20 / 1~1 / 1) to obtain compound 1a (882 mg, yield: 72%).

[0048] (2) Chiral version A: 1a (0.05 mmol, 1.0 equiv.), toluene (0.5 mL), and heavy water (181 μL, 200 equiv.) were added to a 2 mL sample vial. Then, catalyst QD-2 (0.0001 mmol, 0.2 mol%) and potassium carbonate solution (33 wt% heavy water solution, 6.0 μL, 0.015 mmol, 30 mol%) were added to the reaction mixture and stirred rapidly at room temperature for 24 hours. After the reaction was complete, the mixture was diluted with ethyl acetate and extracted three times. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness. Purification was achieved using silica gel column chromatography (petroleum ether / diethyl ether = 20 / 1~4 / 1) with a magnesium sulfate desiccant at the top to obtain the deuterated isomerized product 2a (10.0 mg, separation yield: 81%, 95% deuteration, 93% ee). The deuteration rate was determined using… 1 H NMR was used for determination, and ee value was determined by analytical HPLC using a Daicel chiral column. The enantiomers were prepared using catalyst Q-1 (9.4 mg, separation yield: 76%, 95% deuteration, -94% ee).

[0049] Racemic version B (Condition A): 1a (0.05 mmol, 1.0 equiv.), dichloromethane (0.25 mL), and heavy water (181 μL, 200 equiv.) were added to a 2 mL sample vial. Then, triethylamine (0.005 mmol, 10 mol%) was added to the reaction mixture, and the mixture was rapidly stirred at room temperature for 24 hours. After the reaction was complete, the mixture was diluted with ethyl acetate and extracted three times. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness to obtain pure racemic deuterated isomerized product 2a (12.3 mg, yield: 99%, 98% deuteration).

[0050] Compound 2a: 1 H NMR (600 MHz, Chloroform- d) δ 8.42 (s, 1H), 8.28 (d, J =8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 3.96 – 3.90 (m, 0.02H, 98% D), 1.46(s, 3H). 19 F NMR (565 MHz, Chloroform- d ) δ -76.31 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 162.15, 149.55, 140.56, 129.35, 125.29 (q, J = 279.8 Hz),123.90, 66.80 – 65.80 (m), 15.56 (q, J = 2.1 Hz). HRMS (ESI-TOF): 2a m / z :calcd for C 10 H9DF3N2O2 + [M+H] + 248.0752; found 248.0755. HPLC analysis [DaicelChiralpak IA-U, Hexanes / i -propanol = 98 / 2, 0.5 mL / min, λ = 254 nm, 25 ℃, t(major) = 4.09 min, t(minor) = 4.76 min]. (3) Dissolve the racemic 2a from step (2) in tetrahydrofuran (0.5 mL), add 1N dilute hydrochloric acid (0.5 mL), and stir the reaction solution at room temperature for 4 hours. After removing the tetrahydrofuran, add 0.5 mL of 1N dilute hydrochloric acid. Wash the aqueous solution three times with 1 mL of diethyl ether. After drying the aqueous phase, α-deuterated-α-trifluoromethylethylamine hydrochloride 3a (6.6 mg, separation yield: 88%, 98% deuteration rate) can be obtained. 1 H NMR (500 MHz, Methanol- d 4) δ 4.25 ‒ 4.17 (m, 0.02H, 98% D), 1.50 (s, 3H); 19 F NMR (471 MHz, Methanol- d 4) δ -77.95 (s);13 C NMR (126MHz, Methanol- d 4) δ 125.56 (q, J = 279.7 Hz), 50.01 – 49.00 (m), 12.35 (q, J = 2.0 Hz). HRMS (ESI-TOF): 3a m / z : calcd for C3H6DF3N + [M+H] + 115.0588; found115.0585.

[0051] The above results demonstrate that the hydrolysis process does not change the deuteration rate. Our previous work has already shown that this hydrolysis process does not change the ee value, therefore we will not verify whether the ee value changes in the chiral version here. This example has sufficiently illustrated the steps for preparing α-deuterated-α-trifluoromethylamine hydrochloride; subsequent examples will not demonstrate the hydrolysis step.

[0052] Example 2: Preparation of compound 2b (Ar=4-NO2C6H4)

[0053] The method for compound 2b is the same as in Example 1, except that 1,1,1-trifluorobutanone is used instead of 1,1,1-trifluoroacetone and different amounts of catalyst are used. Specifically, chiral version A uses 0.4 mol% catalyst QD-2 to obtain chiral 2b (9.3 mg, separation yield: 71%, 96% deuteration, 93% ee), and uses 0.4 mol% catalyst Q-1 to obtain enantiomer 2b (8.1 mg, separation yield: 62%, 95% deuteration, -93% ee). Racemic version B uses Condition A with triethylamine as a catalyst to obtain racemic 2b (12.0 mg, yield: 92%, 98% deuteration). The characterization data for compound 2b are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.37 (s, 1H), 8.29 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz,2H), 3.62 – 3.55 (m, 0.02H, 98% D), 2.06 – 1.95 (m, 1H), 1.93 – 1.84 (m, 1H),0.90 (t, J = 7.5 Hz, 3H). 19F NMR (471 MHz, Chloroform- d δ -74.63 (s). 13 CNMR (126 MHz, Chloroform- d ) δ 162.76, 149.55, 140.43, 129.41, 125.13 (q, J =280.3 Hz), 123.91, 73.44 – 72.53 (m), 21.97 (q, J = 1.9 Hz), 9.94. HRMS (ESI-TOF): 2b m / z : calcd for C 11 H 11 DF3N2O2 + [M+H] + 262.0908; found 262.0908. HPLC analysis [Daicel Chiralpak AS-3, Hexanes / i -propanol = 90 / 10, 1.0 mL / min, λ =272 nm, 25 ℃, t(major) = 4.73 min, t(minor) = 6.64 min]. Example 3: Preparation of compound 2c (Ar=4-NO2C6H4)

[0054] The method for compound 2c is the same as in Example 1, except that 1,1,1-trifluorohexanone is used instead of 1,1,1-trifluoroacetone and different amounts of catalyst are used. Specifically, chiral version A was obtained using 0.4 mol% catalyst QD-2 to yield chiral 2c (11.8 mg, separation yield: 82%, 96% deuteration, 93% ee), and enantiomeric version A was obtained using 0.4 mol% catalyst Q-1 to yield enantiomeric 2c (10.5 mg, separation yield: 73%, 94% deuteration, -93% ee). Racemic version B was obtained using Condition A with triethylamine as a catalyst to yield racemic 2c (13.4 mg, yield: 93%, 96% deuteration). The characterization data for compound 2c are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.36 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 7.98 (d, J= 8.8 Hz, 2H), 3.71 – 3.62 (m, 0.04H, 96% D), 1.96 – 1.84 (m, 2H), 1.43 – 1.30 (m, 2H), 1.29 – 1.13 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 19 F NMR (565 MHz, Chloroform- d )δ -74.70 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 162.69, 149.55, 140.45,129.40, 125.14 (q, J = 280.7 Hz), 123.91, 72.01 – 71.01 (m), 28.29, 27.49,22.19, 13.80. HRMS (ESI-TOF): 2c m / z : calcd for C 13 H 15 DF3N2O2 + [M+H] + 290.1222; found 290.1234. HPLC analysis [Daicel Chiralpak OX-3, Hexanes / i -propanol =99 / 1, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 10.59 min, t(minor) = 8.91min]. Example 4: Preparation of compound 2d (Ar=4-NO2C6H4)

[0055] The method for compound 2d is the same as in Example 1, except that 1,1,1-trifluoro-3-phenylpropanone is used instead of 1,1,1-trifluoropropanone and different amounts of catalyst are used. Specifically, chiral version A was obtained using 0.4 mol% catalyst QD-2 to yield chiral 2d (10.0 mg, separation yield: 62%, 92% deuteration, 87% ee), and enantiomeric 2d was obtained using 0.4 mol% catalyst Q-1 (9.2 mg, separation yield: 57%, 95% deuteration, -93% ee). Racemic version B was obtained using Condition A with triethylamine as a catalyst, followed by column chromatography purification to yield racemic 2d (12.9 mg, yield: 78%, 96% deuteration). The characterization data for compound 2d are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.24 (d, J = 8.8 Hz, 2H), 7.79 (d, J =8.8 Hz, 2H), 7.66 (s, 1H), 7.25 – 7.19 (m, 3H), 7.09 – 7.05 (m, 2H), 3.87 –3.80 (m, 0.08H, 92% D), 3.31 (d, J = 13.6 Hz, 1H), 3.05 (d, J = 13.6 Hz, 1H). 19 F NMR (565 MHz, Chloroform- d ) δ -74.84 (s). 13 C NMR (126 MHz, Chloroform- d )δ 163.07, 149.49, 140.30, 135.73, 129.89, 129.18, 128.56, 127.08, 124.99 (q, J = 281.4 Hz), 123.85, 73.52 – 72.56 (m), 35.40 (d, J = 2.1 Hz). HRMS (ESI-TOF): 2d m / z : calcd for C 16 H 13 DF3N2O2 + [M+H] +324.1065; found 324.1060. HPLC analysis [Daicel Chiralpak OD-3, Hexanes / i -propanol = 95 / 5, 1.0 mL / min, λ =272 nm, 25 ℃, t(major) = 7.18 min, t(minor) = 8.57 min]. Example 5: Preparation of compound 2e (Ar=4-NO2C6H4)

[0056] The method for compound 2e is the same as in Example 1, except that 1,1,1-trifluoro-4-phenylbutanone is used instead of 1,1,1-trifluoroacetone and different amounts of catalyst are used. Specifically, chiral version A uses 0.4 mol% catalyst QD-2 to obtain chiral 2e (12.5 mg, separation yield: 74%, 94% deuteration, 88% ee), and uses 0.4 mol% catalyst Q-1 to obtain enantiomeric 2e (11.3 mg, separation yield: 67%, 95% deuteration, -93% ee). Racemic version B uses Condition A with triethylamine as a catalyst to obtain pure racemic 2e (16.0 mg, yield: 95%, 97% deuteration). The characterization data for compound 2e are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.31 (d, J = 8.7 Hz, 1H), 8.29 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.30 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.15 (d, J = 7.0 Hz, 2H), 3.73 – 3.67 (m, 0.03H, 97% D), 2.76 – 2.69 (m, 1H), 2.55 –2.48 (m, 1H), 2.35 – 2.14 (m, 2H). 19 F NMR (471 MHz, Chloroform- d δ -74.50(s). 13 C NMR (126 MHz, Chloroform- d) δ 163.56, 149.63, 140.33, 139.81, 129.45,128.65, 128.36, 126.43, 125.05 (q, J = 280.9 Hz), 123.94, 70.98 – 70.13 (m), 31.20, 29.68. HRMS (ESI-TOF): 2e m / z : calcd for C 17 H 15 DF3N2O2 + [M+H] + 338.1221; found 338.1226. HPLC analysis [Daicel Chiralpak OD-3, Hexanes / i -propanol =95 / 5, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 10.11 min, t(minor) = 12.83min]. Example 6: Preparation of compound 2f (Ar=4-NO2C6H4)

[0057] The method for compound 2f is the same as in Example 1, except that 1,1,1-trifluoro-6-hepten-2-one is used instead of 1,1,1-trifluoroacetone and different amounts of catalyst are used. Specifically, chiral version A uses 0.4 mol% catalyst QD-2 to obtain chiral 2f (10.2 mg, separation yield: 68%, 93% deuteration, 90% ee), and uses 0.4 mol% catalyst Q-1 to obtain enantiomeric 2f (9.8 mg, separation yield: 65%, 94% deuteration, -88% ee). Racemic version B uses Condition A with triethylamine as a catalyst to obtain pure racemic 2f (14.0 mg, yield: 96%, 95% deuteration). The characterization data for compound 2f are as follows: 1 H NMR (500MHz, Chloroform- d ) δ 8.37 (s, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.8Hz, 1H), 5.75 (ddt, J= 17.0, 10.3, 6.7 Hz, 1H), 5.05 – 4.95 (m, 2H), 3.73 –3.65 (m, 0.05H, 95% D), 2.13 – 2.06 (m, 2H), 1.98 – 1.85 (m, 2H), 1.43 – 1.24(m, 2H). 19 F NMR (471 MHz, Chloroform- d δ -74.86 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 162.85, 149.57, 140.38, 137.63, 129.43, 125.01 (q, J = 295.3Hz), 123.91, 115.36, 71.83 – 71.19 (m), 33.12, 28.10, 24.68. HRMS (ESI-TOF):2f m / z : calcd for C 14 H 15 DF3N2O2 + [M+H] + 302.1222; found 302.1220. HPLC analysis[Daicel Chiralpak OX-3, Hexanes / i -propanol = 99 / 1, 1.0 mL / min, λ = 272 nm, 25℃, t(major) = 11.34 min, t(minor) = 9.58 min]. Example 7: Preparation of 2g of compound (Ar=4-NO2C6H4)

[0058] The method for compound 2g was the same as in Example 1, except that 5-benzyloxy-1,1,1-trifluoro-2-pentanone was used instead of 1,1,1-trifluoroacetone, and different amounts of catalyst were used. Specifically, chiral version A was obtained using 0.4 mol% catalyst QD-2 to yield chiral 2g (14.1 mg, separation yield: 74%, 95% deuteration, 90% ee), and enantiomeric version B was obtained using 0.4 mol% catalyst Q-1 to yield enantiomeric 2g (18.1 mg, separation yield: 95%, 98% deuteration, -92% ee). Racemic version B was obtained using Condition A with triethylamine as a catalyst to yield pure racemic 2g (17.2 mg, yield: 90%, 94% deuteration). The characterization data for compound 2g are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.32 (s, 1H), 8.27 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 8.8 Hz, 2H), 7.40 – 7.28 (m, 5H), 4.55 – 4.43 (m, 2H), 3.79 –3.73 (m, 0.05H, 95% D), 3.58 – 3.43 (m, 2H), 2.06 (ddd, J = 13.9, 9.6, 6.9Hz, 1H), 2.01 – 1.95 (m, 1H), 1.65 – 1.52 (m, 2H). 19 F NMR (471 MHz, Chloroform- d δ -74.69 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 163.37, 149.56,140.41, 138.06, 129.44, 128.44, 127.76, 127.67, 125.13 (q, J = 280.5 Hz),123.89, 73.18, 73.02, 69.72, 26.02, 25.54. HRMS (ESI-TOF): 2g m / z : calcd forC 19 H 19 DF3N2O3 + [M+H] +382.1484; found 382.1486. ​​HPLC analysis [Daicel ChiralpakOD-3, Hexanes / i -propanol = 98 / 2, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) =15.51 min, t(minor) = 18.10 min]. Example 8: Preparation of compound 2h (Ar=4-NO2C6H4)

[0059] The method for compound 2h is the same as in Example 1, except that 6-(1,3-dioxolane-2-yl)-1,1,1-trifluorohexane-2-one is used instead of 1,1,1-trifluoroacetone, and different amounts of catalyst are used. Chiral version A yielded chiral 2h (13.2 mg, isolated yield: 73%, 94% deuteration, 92% ee) using 0.4 mol% catalyst Q-1, and enantiomeric 2h (11.2 mg, isolated yield: 62%, 94% deuteration, -93% ee) using 0.4 mol% catalyst Q-1. Racemic version B yielded pure racemic 2h (17.3 mg, yield: 96%, 91% deuteration) using Condition A with triethylamine as a catalyst. The characterization data for compound 2h are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.37 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 4.81 (t, J = 4.7 Hz, 1H), 3.96 – 3.91 (m, 2H), 3.86 – 3.79 (m, 2H), 3.65 – 3.70 (m, 0.06H, 94% D), 1.94 – 1.88 (m, 2H), 1.67 –1.62 (m, 2H), 1.52 – 1.40 (m, 2H), 1.35 – 1.23 (m, 2H). 19 F NMR (471 MHz, Chloroform- d δ -74.67 (s). 13 C NMR (126 MHz, Chloroform- d) δ 162.86, 149.57,140.41, 129.44, 125.08 (q, J = 281.4 Hz), 123.91, 104.20, 71.85 – 71.05 (m), 64.85, 33.46, 28.53, 25.21, 23.35. HRMS (ESI-TOF): 2h m / z : calcd forC 16 H 19 DF3N2O4 + [M+H] + 362.1433; found 362.1447. HPLC analysis [Daicel ChiralpakOD-3, Hexanes / i -propanol = 90 / 10, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) =9.12 min, t(minor) = 11.10 min]. Example 9: Preparation of compound 2i (Ar=4-NO2C6H4)

[0060] The method for compound 2i is the same as in Example 1, except that 1-cyclohexyl-2,2,2-trifluoroethane-1-one is used instead of 1,1,1-trifluoroacetone and different amounts of catalyst are used. Specifically, chiral version A uses 0.4 mol% catalyst QD-2 to obtain chiral 2i (10.3 mg, separation yield: 65%, 94% deuteration, 94% ee), and uses 0.4 mol% catalyst Q-1 to obtain enantiomeric 2i (9.8 mg, separation yield: 62%, 93% deuteration, -95% ee). Racemic version B uses 1 equivalent of triethylamine as a catalyst in Condition A to obtain pure racemic 2i (12.3 mg, yield: 78%, 96% deuteration). The characterization data for compound 2i are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.29 (dt, J = 8.8, 2.0 Hz, 2H), 8.28 (s,1H), 7.97 (dt, J = 8.9, 2.0 Hz, 2H), 3.50 – 3.43 (m, 0.04H, 96% D), 2.02 (tt, J= 11.9, 3.3 Hz, 1H), 1.83 (d, J = 12.8 Hz, 1H), 1.80 – 1.72 (m, 3H), 1.69 –1.63 (m, 1H), 1.34 – 1.23 (m, 2H), 1.16 – 1.04 (m, 3H). 19 F NMR (471 MHz, Chloroform- d ) δ -70.24 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 162.41, 149.50,140.46, 129.38, 125.22 (q, J = 281.8 Hz), 123.91, 76.60 – 75.83 (m), 38.07, 30.12, 28.35, 26.04, 25.91. HRMS (ESI-TOF): 2i m / z : calcd for C 15 H 17 DF3N2O2 + [M+H] + 316.1378; found 316.1382. HPLC analysis [Daicel Chiralpak AS-3, Hexanes / i -propanol = 95 / 5, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 4.32 min, t(minor) = 8.26 min]. Example 10: Preparation of compound 2j (Ar=4-NO2C6H4)

[0061] The method for compound 2j is the same as in Example 1, except that 1,1,1-trifluoro-4-methoxy-2-butanone is used instead of 1,1,1-trifluoroacetone. Specifically, chiral version A was obtained using catalyst QD-2 to yield chiral 2j (10.3 mg, separation yield: 71%, 89% deuteration, 76% ee), and enantiomeric version A was obtained using catalyst Q-1 to yield enantiomeric 2j (8.6 mg, separation yield: 59%, 87% deuteration, -85% ee). Racemic version B was obtained using Condition A with triethylamine as a catalyst to yield pure racemic 2j (14.0 mg, yield: 96%, 91% deuteration). The characterization data for compound 2j are as follows: 1 H NMR (500 MHz, Chloroform- d δ8.40 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 4.04 – 3.97(m, 0.09H, 91%D), 3.48 – 3.43 (m, 1H), 3.29 (s, 3H), 3.22 (td, J = 10.2, 4.0Hz, 1H), 2.27 (ddd, J = 14.3, 10.4, 5.2 Hz, 1H), 2.00 (dt, J = 14.1, 3.5 Hz, 1H). 19 F NMR (471 MHz, Chloroform- d δ -74.86 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 163.83, 149.60, 140.47, 129.39, 125.29 (q, J = 279.9 Hz),123.93, 68.85 – 67.29 (m), 67.01, 58.46, 28.49. HRMS (ESI-TOF): 2j m / z : calcdfor C 12 H 13 DF3N2O3 + [M+H] + 292.1014; found 292.1009. HPLC analysis [DaicelChiralpak OD-3, Hexanes / i -propanol = 97 / 3, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 7.55 min, t(minor) = 6.96 min]. Example 11: Preparation of compound 2k (Ar=4-NO2C6H4)

[0062] The method for compound 2k is the same as in Example 1, except that 5-chloro-1,1,1-trifluoro-2-pentanone is used instead of 1,1,1-trifluoroacetone, and different amounts of catalyst are used. Specifically, chiral version A yielded chiral 2k (12.5 mg, separation yield: 81%, 91% deuteration, 83% ee) using 0.4 mol% catalyst Q-1, and enantiomeric 2k (12.8 mg, separation yield: 83%, 93% deuteration, -84% ee) using 0.4 mol% catalyst Q-1. Racemic version B yielded pure racemic 2k (15.4 mg, yield: 99%, 94% deuteration) using triethylamine as a catalyst under Condition A. The characterization data for compound 2k are as follows: 1 H NMR (500MHz, Chloroform- d ) δ 8.41 (s, 1H), 8.30 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8Hz, 2H), 3.79 – 3.70 (m, 0.06H, 94% D), 3.56 (td, J = 6.5, 2.5 Hz, 2H), 2.13(ddd, J = 13.8, 10.3, 6.1 Hz, 1H), 2.05 (ddd, J = 14.1, 10.3, 5.3 Hz, 1H),1.84 –1.71 (m, 2H). 19 F NMR (471 MHz, Chloroform- d δ -74.50 (s). 13 C NMR (126MHz, Chloroform- d ) δ 163.46, 149.68, 140.17, 129.50, 124.86 (q, J= 281.0Hz), 123.95, 71.48 – 70.47 (m), 44.08, 28.41, 26.56. HRMS (ESI-TOF): 2k m / z :calcd for C 12 H 12 DClF3N2O2 + [M+H] + 310.0675; found 310.0670. HPLC analysis[Daicel Chiralpak OX-3, Hexanes / i -propanol = 99 / 1, 1.0 mL / min, λ = 272 nm, 25℃, t(major) = 19.04 min, t(minor) = 16.95 min]. Example 12: Preparation of compound 2l (Ar=4-NO2C6H4)

[0063] The method for compound 2l is the same as in Example 1, except that 4-(3-pyridyl)-1,1,1-trifluoro-2-butanone is used instead of 1,1,1-trifluoroacetone, and different amounts of catalyst are used. Specifically, chiral version A yielded chiral 2l (13.7 mg, separation yield: 81%, 92% deuteration, 89% ee) using 0.4 mol% catalyst Q-1, and enantiomeric 2l (10.5 mg, separation yield: 62%, 93% deuteration, -79% ee) using 0.4 mol% catalyst Q-1. Racemic version B yielded pure racemic 2l (16.6 mg, yield: 98%, 89% deuteration) using triethylamine as a catalyst under Condition A. The characterization data for compound 2l are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.46 (dd, J = 4.9, 1.6 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 8.30 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 7.50 (dt, J = 7.8, 2.0 Hz, 1H), 7.23 (dd, J= 7.8, 4.8 Hz, 2H), 3.75 –3.67 (m, 0.08H, 92% D), 2.70 (ddd, J = 14.8, 8.9, 6.3 Hz, 1H), 2.55 (dt, J =14.3, 8.3 Hz, 1H), 2.31 – 2.23 (m, 2H). 19 F NMR (565 MHz, Chloroform- d ) δ -74.42 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 163.88, 149.78, 149.71, 147.99,140.10, 135.75, 135.35, 129.52, 124.83 (q, J = 281.1 Hz), 123.97, 123.57,72.05 – 69.51 (m), 29.68, 28.52. HRMS (ESI-TOF): 2l m / z : calcd forC 16 H 14 DF3N3O2 + [M+H] + 339.1174; found 339.1174. HPLC analysis [Daicel ChiralpakOD-3, Hexanes / i -propanol = 90 / 10, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) =27.75 min, t(minor) = 25.17 min]. Example 13: Preparation of compound 2m (Ar=4-NO2C6H4)

[0064] The method for processing racemic compound 2m is the same as in Example 1, except that 1,1,1-trifluoro-4-methyl-2-pentanone is used instead of 1,1,1-trifluoroacetone and 1 equivalent of triethylamine catalyst; Condition A using 1 equivalent of triethylamine as a catalyst yielded pure racemic 2m (13.3 mg, yield: 92%, 98% deuteration). Characterization data for compound 2m are as follows: 1 H NMR (600MHz, Chloroform- d) δ 8.39 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8Hz, 2H), 3.82 – 3.76 (m, 0.02H, 98% D), 1.92 (dd, J = 13.9, 4.1 Hz, 1H), 1.64(dd, J = 13.8, 10.1 Hz, 1H), 1.54 – 1.45 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H). 19 F NMR (565 MHz, Chloroform- d δ -74.73 (s). 13 CNMR (126 MHz, Chloroform- d ) δ 162.67, 149.56, 140.39, 128.69, 125.23 (q, J =280.4 Hz), 123.90, 69.86 – 69.20 (m), 37.24, 23.58, 23.42, 20.81. HRMS (ESI-TOF): 2m m / z : calcd for C 13 H 15 DF3N2O2 + [M+H] + 290.1222; found 290.1207. Example 14: Preparation of compound 2n (Ar=4-NO2C6H4)

[0065] The method for compound 2n is the same as in Example 1, except that 2,2,2-trifluoro-1-phenylethyl-1-one is used instead of 1,1,1-trifluoroacetone and different catalysts or solvents are used; chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2n (10.5 mg, separation yield: 68%, 96% deuteration, 84% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2n (12.5 mg, separation yield: 81%, 95% deuteration, -82% ee).

[0066] Racemic version B uses triethylamine as a catalyst and ethyl acetate / tetrahydrofuran as a solvent under Condition B, as follows: Trifluoromethylimine (0.05 mmol, 1.0 equiv.), ethyl acetate / tetrahydrofuran (0.667 / 0.333 mL), and heavy water (181 μL, 200 equiv.) are added to a 2 mL sample vial. Then, the preferred catalyst, triethylamine (0.005 mmol, 10 mol%), is added to the reaction solution and the mixture is rapidly stirred at room temperature for 24 hours. After the reaction is complete, the mixture is diluted with ethyl acetate and extracted three times. The combined organic phases are dried over anhydrous sodium sulfate and evaporated to dryness. Purification is achieved using silica gel column chromatography (petroleum ether / diethyl ether = 20 / 1~4 / 1) with a magnesium sulfate desiccant at the top to obtain pure racemic deuterated isomerized product 2n (12.9 mg, separation yield: 83%, 92% deuteration).

[0067] The characterization data of compound 2n are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.47 (s, 1H), 8.30 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.59 – 7.52 (m, 2H), 7.46– 7.37 (m, 3H), 4.87 (q, J = 7.4 Hz, 0.08H, 92% D). 19 F NMR (471 MHz, Chloroform- d δ -73.83 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 163.54, 149.63,140.50, 134.13, 129.51, 129.25, 128.77, 124.34 (q, J = 280.9 Hz), 123.91,75.44 – 74.28 (m). HRMS (ESI-TOF): 2n m / z : calcd for C 15 H 11 DF3N2O2 + [M+H] +310.0908; found 310.0908. HPLC analysis [Daicel Chiralpak AD-3, Hexanes / i -propanol = 90 / 10, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 11.24 min, t(minor) = 17.40 min]. Example 15: Preparation of compound 2o (Ar=4-NO2C6H4)

[0068] The method for compound 2o is the same as in Example 14, except that 2,2,2-trifluoro-1-(3-methylphenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-phenylethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2o (9.0 mg, separation yield: 56%, 95% deuteration, 84% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2o (12.3 mg, separation yield: 76%, 94% deuteration, -79% ee). Racemic version B uses triethylamine as catalyst under Condition B to obtain pure racemic 2o (12.9 mg, separation yield: 80%, 96% deuteration). The characterization data for compound 2o are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.46 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 9.4 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 4.83 (q, J = 7.5 Hz, 0.04H, 96% D), 2.39 (s, 3H). 19 F NMR (471 MHz, Chloroform- d δ -73.73 (s). 13 CNMR (126 MHz, Chloroform- d) δ 163.42, 149.61, 140.55, 138.58, 134.03, 130.01,129.50, 129.32, 128.65, 125.79, 124.40 (q, J = 280.9 Hz), 123.90, 75.30 –74.30 (m), 21.42. HRMS (ESI-TOF): 2o m / z : calcd for C 16 H 13 DF3N2O2 + [M+H] + 324.1065; found 324.1061. HPLC analysis [Daicel Chiralpak OJ-3, Hexanes / i -propanol = 80 / 20, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 24.90 min, t(minor) = 15.44 min]. Example 16: Preparation of compound 2p (Ar=4-NO2C6H4)

[0069] The method for compound 2p is the same as in Example 14, except that 2,2,2-trifluoro-1-(4-methylphenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-phenylethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2p (11.8 mg, separation yield: 73%, 95% deuteration, 83% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2p (14.1 mg, separation yield: 87%, 96% deuteration, -82% ee). Racemic version B uses triethylamine as catalyst and ethyl acetate / tetrahydrofuran as solvent. Condition B yields pure racemic 2p (13.7 mg, separation yield: 85%, 95% deuteration). The characterization data for compound 2p are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.45 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.6 Hz, 2H), 7.42 (d, J= 7.8 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 4.84 (q, J = 7.5 Hz, 0.05H, 95% D), 2.37 (s, 3H). 19 F NMR (471 MHz, Chloroform- d δ -73.91 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 163.33, 149.60,140.58, 139.22, 131.17, 129.47, 128.58, 124.43 (q, J = 280.8 Hz), 123.88,21.18. HRMS (ESI-TOF): 2p m / z : calcd for C 16 H 13 DF3N2O2 + [M+H] + 324.1065; found324.1067. HPLC analysis [Daicel Chiralpak OJ-3, Hexanes / i -propanol = 80 / 20, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 25.14 min, t(minor) = 18.45 min]. Example 17: Preparation of compound 2q (Ar=4-NO2C6H4)

[0070] The method for compound 2q is the same as in Example 14, except that 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-phenylethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2q (12.7 mg, separation yield: 75%, 92% deuteration, 79% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2q (14.6 mg, separation yield: 86%, 96% deuteration, -81% ee). Racemic version B uses triethylamine as catalyst under Condition B to obtain pure racemic 2q (12.2 mg, separation yield: 72%, 96% deuteration). The characterization data for compound 2q are as follows:1 H NMR (500 MHz, Chloroform- d ) δ 8.45 (s, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 6.92 (s, 2H), 4.83 (q, J = 7.5 Hz, 0.04H, 96% D), 3.82 (s, 3H). 19 F NMR (471 MHz, Chloroform- d δ -74.10 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 163.26, 160.22, 149.59, 140.58, 129.87, 129.46, 126.15,124.44 (q, J = 280.8 Hz), 123.89, 114.17, 74.65 – 73.60 (m), 55.29. HRMS(ESI-TOF): 2q m / z : calcd for C 16 H 13 DF3N2O3 + [M+H] + 340.1014; found 340.1028.HPLC analysis [Daicel Chiralpak OJ-3, Hexanes / i -propanol = 70 / 30, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 28.58 min, t(minor) = 21.87 min]. Example 18: Preparation of compound 2r (Ar=4-NO2C6H4)

[0071] The method for compound 2r is the same as in Example 14, except that 2,2,2-trifluoro-1-(4-hydroxyphenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-phenylethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2r (14.1 mg, separation yield: 87%, 96% deuteration, 77% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2r (13.7 mg, separation yield: 84%, 95% deuteration, -79% ee). Racemic version B uses triethylamine as catalyst under Condition B to obtain pure racemic 2r (14.6 mg, separation yield: 90%, 93% deuteration). The characterization data for compound 2r are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.45 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.81 (q, J = 7.5 Hz, 0.07H, 93% D). 19 F NMR (471MHz, Chloroform- d δ -74.13 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 163.31,156.38, 149.60, 140.56, 130.10, 129.48, 126.30, 124.40 (q, J = 281.2 Hz),123.90, 115.65. HRMS (ESI-TOF): 2r m / z : calcd for C 15 H 10 D2F3N2O3 + [M+H] + 327.0920; found 327.0915. HPLC analysis [Daicel Chiralpak AS-3, Hexanes / i-propanol = 90 / 10, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 16.98 min, t(minor) = 12.37 min]. Example 19: Preparation of compound 2s (Ar=4-NO2C6H4)

[0072] The method for compound 2s is the same as in Example 14, except that 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-phenylethyl-1-one and different catalysts or solvents are used; wherein, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2s (11.0 mg, separation yield: 67%, 92% deuteration, 82% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2s (12.3 mg, separation yield: 75%, 91% deuteration, -77% ee).

[0073] Racemic version B uses tetrabutylammonium bromide as a catalyst and ethyl acetate as a solvent in Condition C, as follows: Tetrabutylammonium bromide (TBAB) (0.005 mmol, 10 mol%) and p-chlorophenol (0.15 mmol, 3.0 equiv.) dissolved in ethyl acetate (0.5 mL) were added to a 2 mL sample vial, followed by the addition of heavy water (181 μL, 200 equiv.). Potassium hydride (KH, 30 wt% dispersion in mineral oil, 20 mg, 0.15 mmol, 3.0 equiv.) was then added and stirred for 10 minutes. Trifluoromethylimine (0.05 mmol, 1.0 equiv.) was then added to the reaction solution and the mixture was rapidly stirred at room temperature for 24 hours. After the reaction, the solution was diluted with ethyl acetate and extracted three times. The combined organic phases were dried over anhydrous sodium sulfate and then evaporated to dryness. Purification was performed using silica gel column chromatography (petroleum ether / diethyl ether = 20 / 1~4 / 1) with a magnesium sulfate desiccant in the upper section to obtain pure racemic deuterated isomerized product 2S (13.9 mg, separation yield: 85%, 96% deuteration). Characterization data for compound 2S are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.49 (s, 1H), 8.31 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.39 (td, J= 7.7, 5.4 Hz,1H), 7.34 – 7.28 (m, 2H), 7.13 – 7.07 (m, 1H), 4.86 (q, J = 7.3 Hz, 0.04H, 96% D). 19 F NMR (471 MHz, Chloroform- d ) δ -73.83 (s), -111.85 (td, J = 9.5, 6.0 Hz). 13 C NMR (126 MHz, Chloroform- d ) δ 164.04, 162.76 (d, J = 246.9 Hz),149.74, 140.25, 136.24 (d, J = 7.5 Hz), 130.28 (d, J = 8.2 Hz), 129.59, 124.37 (d, J = 3.1 Hz), 124.02 (q, J = 281.1 Hz), 123.95, 116.30 (d, J = 21.0Hz), 115.83 (d, J = 22.9 Hz), 74.49 – 73.60 (m). HRMS (ESI-TOF): m / z : calcdfor C 15 H 10 DF4N2O2 + [M+H] + 328.0814; found 328.0821. HPLC analysis [DaicelChiralpak OJ-3, Hexanes / i -propanol = 80 / 20, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 23.37 min, t(minor) = 12.21 min]. Example 20: Preparation of compound 2t (Ar=4-NO2C6H4)

[0074] The method for compound 2t is the same as in Example 19, except that 2,2,2-trifluoro-1-(4-fluorophenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2t (12.1 mg, separation yield: 74%, 96% deuteration, 85% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2t (12.8 mg, separation yield: 78%, 94% deuteration, -81% ee). Racemic version B uses tetrabutylammonium bromide as catalyst in Condition C to obtain pure racemic 2t (15.1 mg, separation yield: 92%, 95% deuteration). The characterization data for compound 2t are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.47(s, 1H), 8.30 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.54 (dd, J =8.6, 5.4 Hz, 2H), 7.15 – 7.07 (m, 2H), 4.85 (q, J = 7.3 Hz, 0.05H, 95% D). 19 FNMR (471 MHz, Chloroform- d ) δ -74.13 (s), -112.05 (tt, J = 9.6, 5.2 Hz). 13 CNMR (126 MHz, Chloroform- d ) δ 163.74, 163.16 (d, J = 248.6 Hz), 149.70,140.33, 130.44 (d, J = 8.1 Hz), 129.54, 124.30, 124.15 (q, J = 280.9 Hz),123.94, 115.80 (d, J = 21.7 Hz), 74.50 – 73.53 (m). HRMS (ESI-TOF): m / z :calcd for C 15 H 10 DF4N2O2 + [M+H]+ 328.0814; found 328.0809. HPLC analysis [DaicelChiralpak OJ-3, Hexanes / i -propanol = 80 / 20, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 25.83 min, t(minor) = 14.46 min]. Example 21: Preparation of compound 2u (Ar=4-NO2C6H4)

[0075] The method for compound 2u is the same as in Example 19, except that 2,2,2-trifluoro-1-(3-chlorophenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2u (8.6 mg, separation yield: 50%, 90% deuteration, 75% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2u (11.5 mg, separation yield: 67%, 89% deuteration, -77% ee). Racemic version B uses tetrabutylammonium bromide as catalyst in Condition C to obtain pure racemic 2u (14.4 mg, separation yield: 84%, 97% deuteration). The characterization data for compound 2u are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.48(s, 1H), 8.31 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.57 (s, 1H), 7.44 (d, J = 7.1 Hz, 1H), 7.40 – 7.33 (m, 3H), 4.83 (q, J = 7.4 Hz, 0.03H, 97% D). 19 F NMR (471 MHz, Chloroform- d δ -73.80 (s). 13 C NMR (126 MHz, Chloroform- d) δ 164.10, 149.76, 140.21, 135.88, 134.70, 130.01, 129.62,129.49, 128.85, 126.88, 123.99 (q, J = 280.9 Hz), 123.96, 74.97 – 73.61 (m).HRMS (ESI-TOF): m / z : calcd for C 15 H 10 DF3ClN2O2 + [M+H] + 344.0518; found 344.0497.HPLC analysis [Daicel Chiralpak OJ-3, Hexanes / i -propanol = 80 / 20, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 17.90 min, t(minor) = 11.67 min]. Example 22: Preparation of compound 2v (Ar=4-NO2C6H4)

[0076] The method for compound 2v is the same as in Example 19, except that 2,2,2-trifluoro-1-(4-chlorophenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2v (9.6 mg, separation yield: 56%, 93% deuteration, 72% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2v (11.7 mg, separation yield: 68%, 90% deuteration, -76% ee). Racemic version B uses tetrabutylammonium bromide as catalyst in Condition C to obtain pure racemic 2v (15.1 mg, separation yield: 88%, 95% deuteration). The characterization data for compound 2v are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.48(s, 1H), 8.30 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 7.50 (d, J= 8.3Hz, 2H), 7.44 – 7.35 (m, 2H), 4.84 (q, J = 7.3 Hz, 0.05H, 95% D). 19 F NMR (471MHz, Chloroform- d δ -73.98 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 163.92,149.73, 140.27, 135.33, 132.54, 130.01, 129.56, 129.01, 124.05 (q, J = 281.1Hz), 123.95, 74.78 – 73.59 (m).HRMS (ESI-TOF): m / z : calcd for C 15 H 10 DF3ClN2O2 + [M+H] + 344.0518; found 344.0519.HPLC analysis [Daicel Chiralpak OD-3,Hexanes / i -propanol = 95 / 5, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 9.96min, t(minor) = 14.87 min]. Example 23: Preparation of compound 2w (Ar=4-NO2C6H4)

[0077] The method for preparing compound 2w is the same as in Example 19, except that 2,2,2-trifluoro-1-(3-bromophenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one, and different catalysts or solvents are used. Chiral version A, using catalyst QD-1 and diethyl ether as solvent, yielded chiral 2w (12.6 mg, separation yield: 65%, 91% deuteration, 83% ee), and enantiomeric 2w (13.2 mg, separation yield: 68%, 90% deuteration, -77% ee) using catalyst Q-1 and diethyl ether as solvent. Racemic version B, using tetrabutylammonium bromide as catalyst under Condition C, yielded pure racemic 2w (17.7 mg, separation yield: 91%, 98% deuteration). Characterization data for compound 2w are as follows: 1H NMR (600 MHz, Chloroform- d ) δ 8.48(s, 1H), 8.30 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.72 (s, 1H), 7.54 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.29 (t, J =7.9 Hz, 1H), 4.82 (q, J = 7.3 Hz, 0.02H, 98% D). 19 F NMR (565 MHz, Chloroform- d δ -73.78 (s). 13 C NMR (151 MHz, Chloroform- d ) δ 164.13, 149.76, 140.20,136.14, 132.43, 131.72, 130.28, 129.62, 127.35, 124.00 (q, J = 281.0 Hz),123.95, 122.77, 74.60 – 73.62 (m). HRMS (ESI-TOF): m / z : calcd forC 15 H 10 DF3BrN2O2 + [M+H] + 388.0013; found 387.9997. HPLC analysis [DaicelChiralpak OJ-3, Hexanes / i -propanol = 80 / 20, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 14.78 min, t(minor) = 12.53 min]. Example 24: Preparation of compound 2x (Ar=4-NO2C6H4)

[0078] The method for compound 2x is the same as in Example 19, except that 2,2,2-trifluoro-1-(4-bromophenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one, and different catalysts or solvents are used. Chiral version A, using catalyst QD-1 and diethyl ether as solvent, yielded chiral 2x (11.2 mg, separation yield: 58%, 91% deuteration, 75% ee), and enantiomeric 2x (13.7 mg, separation yield: 71%, 90% deuteration, -75% ee) using catalyst Q-1 and diethyl ether as solvent. Racemic version B, using tetrabutylammonium bromide as catalyst, under Condition C, yielded pure racemic 2x (16.8 mg, separation yield: 87%, 98% deuteration). Characterization data for compound 2x are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.47 (s, 1H), 8.30 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 4.83 (q, J = 7.3 Hz, 0.02H, 98% D). 19 F NMR (471 MHz, Chloroform- d δ -73.89 (s). 13 C NMR (126 MHz, Chloroform- d ) δ163.95, 149.74, 140.25, 133.06, 131.98, 130.31, 129.57, 123.97 (q, J = 281.1Hz), 123.96, 123.54, 74.46 – 73.75 (m). HRMS (ESI-TOF): m / z : calcd forC 15 H 10 DF3BrN2O2 + [M+H] + 388.0013; found 388.0017. HPLC analysis [DaicelChiralpak OJ-3, Hexanes / i-propanol = 80 / 20, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 14.95 min, t(minor) = 13.15 min]. Example 25: Preparation of compound 2y (Ar=4-NO2C6H4)

[0079] The method for compound 2y is the same as in Example 14, except that 2,2,2-trifluoro-1-(4-vinylphenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-phenylethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2y (13.1 mg, separation yield: 78%, 91% deuteration, 79% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2y (15.6 mg, separation yield: 93%, 95% deuteration, -77% ee). Racemic version B, with triethylamine as catalyst, under Condition B, yields pure racemic 2y (12.1 mg, separation yield: 72%, 93% deuteration). The characterization data for compound 2y are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.81 (s, 1H), 8.63 (d, J = 8.7 Hz, 2H), 8.35 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.79(d, J = 8.3 Hz, 2H), 7.06 (dd, J = 17.6, 10.9 Hz, 1H), 6.13 (d, J = 17.6 Hz, 1H), 5.64 (d, J = 10.9 Hz, 1H), 5.20 (q, J = 7.4 Hz, 0.07H, 93% D). 19 F NMR (471 MHz, Chloroform- d δ -73.80 (s). 13 C NMR (126 MHz, Chloroform- d) δ163.55, 149.62, 140.47, 138.57, 136.01, 133.43, 129.49, 128.89, 126.52,124.31 (q, J = 281.3 Hz), 123.90, 115.04, 74.84 – 73.89 (m).HRMS (ESI-TOF): m / z : calcd for C 17 H 13 DF3N2O2 + [M+H] + 336.1065; found 336.1066. HPLC analysis[Daicel Chiralpak OD-3, Hexanes / i -propanol = 80 / 20, 1.0 mL / min, λ = 254 nm, 25 ℃, t(major) = 5.80 min, t(minor) = 8.18 min]. Example 26: Preparation of compound 2z (Ar=4-NO2C6H4)

[0080] The method for compound 2z is the same as in Example 14, except that 2,2,2-trifluoro-1-(4-(trimethylsilyl)ethynylphenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-phenylethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A, using catalyst QD-1 and diethyl ether as solvent, yielded chiral 2z (13.0 mg, separation yield: 64%, 93% deuteration, 76% ee), and enantiomeric 2z (15.2 mg, separation yield: 75%, 93% deuteration, -76% ee) using catalyst Q-1 and diethyl ether as solvent. Racemic version B, using triethylamine as catalyst, under Condition B, yielded pure racemic 2z (14.4 mg, separation yield: 71%, 96% deuteration). The characterization data for compound 2z are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.46 (s,1H), 8.32 – 8.27 (m, 2H), 8.02 – 8.00 (m, 2H), 7.55 – 7.44 (m, 4H), 4.85 (q, J = 7.3 Hz, 0.04H, 96% D), 0.25 (s, 9H). 19F NMR (471 MHz, Chloroform- d δ -73.78 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 163.82, 149.68, 140.34, 134.13,132.24, 129.54, 128.57, 124.26, 124.12 (q, J = 281.5 Hz), 123.93, 104.13,95.58, 74.94 – 73.98 (m), -0.12. HRMS (ESI-TOF): m / z : calcd for C 20 H 19 DF3N2O2Si + [M+H] + 406.1303; found 406.1313. HPLC analysis [Daicel Chiralpak OD-3,Hexanes / i -propanol = 95 / 5, 1.0 mL / min, λ = 254 nm, 25 ℃, t(major) = 6.78min, t(minor) = 7.94 min]. Example 27: Preparation of compound 2aa (Ar=4-NO2C6H4)

[0081] The method for compound 2aa is the same as in Example 14, except that ethyl 4-(2,2,2-trifluorotrifluoroacetyl)benzoate is used instead of 2,2,2-trifluoro-1-phenylethyl-1-one and different catalysts or solvents are used. Specifically, chiral version A, using catalyst QD-1 and diethyl ether as solvent, yielded chiral 2aa (8.0 mg, separation yield: 42%, 88% deuteration, 62% ee), and enantiomeric 2A (10.3 mg, separation yield: 54%, 90% deuteration, -65% ee) using catalyst Q-1 and diethyl ether as solvent. Racemic version B, using triethylamine as catalyst under Condition B, yielded pure racemic 2aa (16.8 mg, separation yield: 88%, 95% deuteration). The characterization data for compound 2aa are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.49 (s, 1H), 8.30 (d, J= 8.7 Hz, 2H), 8.09 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.64(d, J = 8.3 Hz, 2H), 4.92 (q, J = 7.3 Hz, 0.10H, 90% D), 4.39 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 19 F NMR (471 MHz, Chloroform- d δ -73.65 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 165.96, 164.08, 149.74, 140.23, 138.62,131.39, 129.90, 129.58, 128.73, 124.01 (q, J = 281.6 Hz), 123.95, 74.95 –73.90 (m), 61.19, 14.29. HRMS (ESI-TOF): m / z : calcd for C 18 H 15 DF3N2O4 + [M+H] + 382.1119; found 382.1118. HPLC analysis [Daicel Chiralpak OD-3, Hexanes / i -propanol = 80 / 20, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 6.71 min, t(minor) = 8.54 min]. Example 28: Preparation of compound 2ab (Ar=4-NO2C6H4)

[0082] The method for compound 2ab is the same as in Example 19, except that 2,2,2-trifluoro-1-(4-trifluorotolyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2ab (9.8 mg, separation yield: 52%, 85% deuteration, 77% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2ab (12.1 mg, separation yield: 64%, 83% deuteration, -72% ee). Racemic version B uses tetrabutylammonium bromide as catalyst in Condition C to obtain pure racemic 2ab (17.2 mg, separation yield: 91%, 98% deuteration). The characterization data for compound 2ab are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ8.51 (s, 1H), 8.31 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 4.93 (q, J = 7.2 Hz, 0.02H, 98% D). 19 F NMR (471 MHz, Chloroform- d ) δ -62.84 (s), -73.76 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 164.31, 149.81, 140.13, 137.89, 131.50 (q, J = 32.7 Hz),129.62, 129.18, 125.72 (q, J = 3.8 Hz), 123.98, 123.93 (q, J = 281.3 Hz), 123.77 (q, J = 272.3 Hz), 74.75 – 73.90 (m). HRMS (ESI-TOF): m / z : calcd forC 16 H 10 DF6N2O2 + [M+H]+ 378.0782; found 378.0792. HPLC analysis [Daicel ChiralpakAD-3, Hexanes / i -propanol = 95 / 5, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) =9.12 min, t(minor) = 10.53 min]. Example 29: Preparation of compound 2ac (Ar=4-NO2C6H4)

[0083] The method for compound 2ac is the same as in Example 19, except that 2,2,2-trifluoro-1-(3,5-difluoro-1-phenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one, and different catalysts or solvents are used. Chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2ac (10.4 mg, separation yield: 60%, 81% deuteration, 76% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2ac (11.9 mg, separation yield: 69%, 80% deuteration, -70% ee). Racemic version B uses tetrabutylammonium bromide as catalyst in Condition C to obtain pure racemic 2ac (15.8 mg, separation yield: 92%, 98% deuteration). Characterization data for compound 2ac are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ8.50 (s, 1H), 8.32 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 2.0 Hz, 2H), 7.16 – 7.09(m, 2H), 6.85 (ddd, J = 8.8, 6.4, 2.4 Hz, 1H), 4.83 (q, J = 7.1 Hz, 0.02H, 98% D). 19 F NMR (471 MHz, Chloroform- d ) δ -73.80 (s), -108.42 (t, J = 7.9 Hz). 13 C NMR (126 MHz, Chloroform- d) δ 164.53, 162.95 (dd, J = 249.8, 12.6 Hz),149.86, 140.00, 137.33 (t, J = 9.5 Hz), 129.68, 124.00, 123.70 (q, J = 281.3Hz), 111.85 (dd, J = 20.4, 6.7 Hz), 104.82 (t, J = 25.2 Hz), 74.46 – 73.32(m). HRMS (ESI-TOF): m / z : calcd for C 15 H9DF5N2O2 + [M+H] + 346.0720; found346.0727. HPLC analysis [Daicel Chiralpak AS-3, Hexanes / i -propanol = 95 / 5, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 6.64 min, t(minor) = 7.95 min]. Example 30: Preparation of compound 2ad (Ar=4-NO2C6H4)

[0084] The method for compound 2ad is the same as in Example 19, except that 2,2,2-trifluoro-1-(3,5-dichloro-1-phenyl)-ethyl-1-one is used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2ad (11.7 mg, separation yield: 62%, 80% deuteration, 73% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2ad (13.4 mg, separation yield: 71%, 75% deuteration, -67% ee). Racemic version B uses tetrabutylammonium bromide as catalyst in Condition C to obtain pure racemic 2ad (15.5 mg, separation yield: 82%, 98% deuteration). The characterization data for compound 2ad are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.49 (s, 1H), 8.32 (d, J= 8.7 Hz, 2H), 8.03 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 1.9 Hz, 2H), 7.40 (t, J = 1.9 Hz, 1H), 4.80 (q, J = 7.1 Hz, 0.02H, 98% D). 19 F NMR (471 MHz, Chloroform- d δ -73.72 (s). 13 C NMR (126 MHz, Chloroform- d ) δ 164.65, 149.88, 139.95, 137.03, 135.38, 129.72, 129.53,127.21, 124.00, 123.69 (q, J = 281.4 Hz). HRMS (ESI-TOF): m / z : calcd forC 15 H9DF3Cl2N2O2 + [M+H] + 378.0129; found 378.0130. HPLC analysis [DaicelChiralpak OD-3, Hexanes / i -propanol = 95 / 5, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 10.91 min, t(minor) = 12.44 min]. Example 31: Preparation of compound 2ae

[0085] The method for compound 2ae is the same as in Example 19, except that 1-(3,5-dichloro-4-fluoro-1-phenyl)-2,2,2-trifluoroethyl-1-one is used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one, and different catalysts or solvents are used. Specifically, chiral version A uses catalyst QD-1 and diethyl ether as solvent to obtain chiral 2ae (12.8 mg, separation yield: 65%, 77% deuteration, 71% ee), and uses catalyst Q-1 and diethyl ether as solvent to obtain enantiomeric 2ae (14.2 mg, separation yield: 72%, 73% deuteration, -68% ee). Racemic version B uses tetrabutylammonium bromide as catalyst in Condition C to obtain pure racemic 2ae (18.2 mg, separation yield: 92%, 99% deuteration). The characterization data for compound 2ae are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 8.50 (s, 1H), 8.32 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 6.2 Hz, 2H), 4.78 (q, J = 7.0 Hz, 0.01H, 99% D). 19 F NMR (471 MHz, Chloroform- d ) δ -73.97 (s), -114.09 (t, J = 6.2 Hz). 13 C NMR (126MHz, Chloroform- d ) δ 164.79, 154.62 (d, J = 252.8 Hz), 149.92, 139.85, 131.12(d, J = 5.0 Hz), 129.74, 129.18, 124.02, 123.60 (q, J = 281.4 Hz), 122.86 (d, J = 17.9 Hz), 73.72 – 72.88 (m). HRMS (ESI-TOF): m / z : calcd for C 15 H8DF4Cl2N2O2 + [M+H] +396.0034; found 396.0012. HPLC analysis [Daicel Chiralpak OD-3,Hexanes / i -propanol = 95 / 5, 1.0 mL / min, λ = 272 nm, 25 ℃, t(major) = 10.72min, t(minor) = 12.62 min]. Example 32: Preparation of compound 2af (Ar=4-NO2C6H4)

[0086] The method for racemic compound 2af was the same as in Example 19, except that 1-(2-fluoro-1-phenyl)-2,2,2-trifluoroethyl-1-one was used instead of 2,2,2-trifluoro-1-(3-fluorophenyl)-ethyl-1-one to give pure racemic 2af (12.4 mg, isolated yield: 76%, 98% deuteration). Characterization data for compound 2af are as follows: 1 H NMR (600 MHz, Chloroform- d ) δ8.51 (s, 0.98H), 8.30 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.77 (t, J = 7.3 Hz, 1H), 7.38 (dddd, J = 8.3, 7.3, 5.4, 1.8 Hz, 1H), 7.23 (td, J =7.6, 1.2 Hz, 1H), 7.13 (ddd, J = 9.7, 8.3, 1.2 Hz, 1H), 5.36 (q, J = 7.2 Hz, 0.08H, 92% D). 19 F NMR (565 MHz, Chloroform- d ) δ -73.80 (d, J = 4.1 Hz), -118.47 (dt, J = 10.0, 5.1 Hz). HRMS (ESI-TOF): 2af m / z : calcd for C 15 H 10 DF4N2O2 +[M+H] + 328.0814; found 328.0803. Example 33: Preparation of 2ag of drug molecule-derived compound (Ar=4-NO2C6H4) The application of this method in the derivatization and late-stage modification of drug molecules was validated in the preparation of compound 2ag. Using the nonsteroidal anti-inflammatory drug Oxaprozin as a starting material, the preparation route of compound 2ag is as described above. The method for preparing compound 2ag from 1ag is the same as in Example 1, except that 4-(4,5-diphenyloxazol-2-yl)-1,1,1-trifluorobut-2-one is used instead of 1,1,1-trifluoroacetone, and different amounts of catalyst are used. Specifically, chiral version A was prepared using 0.4 mol% catalyst QD-2 to obtain chiral 2ag (9.6 mg, separation yield: 63%, 93% deuteration, -88% ee); racemic version B was prepared using Condition A with triethylamine as a catalyst and purified by column chromatography to obtain racemic 2ag (15.1 mg, separation yield: 94%, 95% deuteration). The characterization data of compound 2ag are as follows: 1 H NMR (600 MHz, Chloroform- d ) δ 8.43 (s, 1H), 8.20 (d, J = 8.7 Hz, 2H), 7.90 (d, J = 8.7 Hz, 2H), 7.56 – 7.49 (m, 4H), 7.37 – 7.31 (m, 6H), 4.01– 3.94 (m, 0.07H, 93% D), 2.95 (td, J = 15.7, 7.0 Hz, 1H), 2.88 (td, J =15.7, 7.3 Hz, 1H), 2.57 – 2.47 (m, 2H). 19 F NMR (565 MHz, Chloroform- d ) δ -74.54 (s). 13 C NMR (151 MHz, Chloroform- d ) δ 164.33, 161.42, 149.56, 145.48,140.14, 132.12, 129.44, 128.70, 128.66, 128.63, 128.54, 128.18, 127.65,126.38, 124.89 (q, J= 280.6 Hz), 123.81, 26.08, 24.12. HRMS (ESI-TOF): m / z :calcd for C 26 H 20 DF3N3O3 + [M+H] + 481.1592; found 481.1583. HPLC analysis [DaicelChiralpak OD-3, Hexanes / i -propanol = 95 / 5, 1.0 mL / min, λ = 254 nm, 25 ℃, t(major) = 12.58 min, t(minor) = 13.76 min]. The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing α-deuterated-α-trifluoromethylamine compounds by organocatalysis, characterized in that, Includes the following steps: (1) Trifluoromethyl ketone and substituted benzylamine reacted under acetic acid catalysis to obtain trifluoromethylimine compounds; (2) Under the action of an organic catalyst, the trifluoromethylimine compound obtained in step (1), the deuterium source and the solvent are mixed and reacted, extracted and purified to obtain chiral or racemic α-deuterated-α-trifluoromethylamine compounds. The organic catalyst is a chiral organic catalyst or a achiral organic catalyst; the chiral organic catalyst is one of a betaine-type inner salt catalyst based on the cinchona alkaloid framework or a tertiary amine catalyst based on the cinchona alkaloid framework; the achiral organic catalyst is one of a achiral tertiary amine catalyst, a phase transfer catalyst, and a crown ether.

2. The method for preparing α-deuterated-α-trifluoromethylamine compounds by organocatalysis according to claim 1, characterized in that, In step (1), the trifluoromethyl ketone has any of the following structures: ； The substituted benzylamine is one of 4-nitrobenzylamine, 2-nitrobenzylamine, 4-esterbenzylamine, 4-chlorobenzylamine, 4-bromobenzylamine, and 4-trifluoromethylbenzylamine.

3. The method for preparing α-deuterated-α-trifluoromethylamine compounds by organocatalysis according to claim 1, characterized in that, In step (1), the molar ratio of trifluoromethyl ketone, substituted benzylamine, and acetic acid is 1~3:1:1.

5.

4. The method for preparing α-deuterated-α-trifluoromethylamine compounds by organocatalysis according to claim 1, characterized in that, In step (2), the structure of the betaine-type internal salt catalyst based on the cinchona alkaloid framework is as follows: or , The structure of the tertiary amine catalyst based on the cinchona alkaloid framework is as follows: or , Among them, R 1 Selected from one of hydrogen, alkyl, substituted alkyl, allyl, benzyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 2 Selected from hydrogen, m-hydroxybenzoyl, or substituted m-hydroxybenzoyl; R 3 Selected from one of hydrogen, halogen, alkyl, and aryl; R 4 Selected from one of hydrogen, alkoxy, and siloxy groups; R 5 Selected from one of hydrogen, hydroxyl, alkoxy, and siloxy groups; Ar 1 It is selected from one of aryl, substituted aryl, and heteroaryl.

5. The method for preparing α-deuterated-α-trifluoromethylamine compounds by organocatalysis according to claim 4, characterized in that, The preparation method of the betaine-type internal salt catalyst based on the cinchona alkaloid framework includes the following steps: Compound V or Compound VI was dissolved in acetonitrile with benzyl bromide and reacted at room temperature for 8-24 h. After purification, a betaine-type internal salt catalyst based on the cinchona alkaloid framework was obtained. The specific reaction route is as follows: 。 6. The method for preparing α-deuterated-α-trifluoromethylamine compounds by organocatalysis according to claim 1, characterized in that, In step (2), the non-chiral tertiary amine catalyst is one of triethylamine, triethylenediamine, trimethylamine, diisopropylethylamine, tributylamine, and dimethylaniline; the phase transfer catalyst is one of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium fluoride, and benzyltriethylammonium bromide; and the crown ether is one of 18-crown-6 and 15-crown-5.

7. The method for preparing α-deuterated-α-trifluoromethylamine compounds by organocatalysis according to claim 1, characterized in that, In step (2), the deuterium source is at least one of heavy water, deuterated methanol, deuterated ethanol, and deuterated isopropanol, and the solvent is at least one of toluene, benzene, xylene, trimethylbenzene, diethyl ether, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, cyclopentylmethyl ether, dibutyl ether, and 1,4-dioxane.

8. The method for preparing α-deuterated-α-trifluoromethylamine compounds by organocatalysis according to claim 1, characterized in that, In step (2), the molar ratio of the trifluoromethylimine compound, the organic catalyst, and the deuterium source is 1:0.001~3:5~500.

9. An α-deuterated-α-trifluoromethylamine hydrochloride compound, the preparation method of which includes the following steps: The chiral or racemic α-deuterated-α-trifluoromethylamine compound obtained by any one of the methods described in claims 1 to 8 is dissolved in an organic solvent, acid is added and the reaction is carried out at 0 to 70 °C for 1 to 24 h. After removing the organic solvent, dilute hydrochloric acid is added and the mixture is extracted with an organic solvent. The aqueous phase is collected and evaporated to dryness to obtain the chiral or racemic α-deuterated-α-trifluoromethylamine hydrochloride compound.

10. The use of the α-deuterated-α-trifluoromethylamine hydrochloride compound according to claim 9 as a reagent for introducing a deuterated trifluoromethyl group into a drug molecule.

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