Method for kinetic resolution of aza-aromatic hydrocarbon / chiral phosphoric acid EDA compound

Abstract

The invention relates to the technical field of antiviral drugs and kinetic resolution, in particular to a method for kinetic resolution of an aza-aromatic hydrocarbon / chiral phosphoric acid EDA compound. The method specifically comprises the following steps: under visible light irradiation and a protective atmosphere, carrying out illumination reaction on a racemic nitrogen-containing heterocyclic compound shown as a formula I ', a reducing agent and a chiral phosphoric acid catalyst in an organic solvent to obtain chiral aza-arenes I and II; the method disclosed by the invention does not consider the electrical property difference of the substrate, expands the selection range of the substrate, does not participate in a photosensitizer and a transition metal catalyst, and is mild in reaction condition, high in resolution efficiency, high in atom economy and high in enantioselectivity. .

Description

Technical Field

[0001] This invention relates to the field of antiviral drugs and kinetic resolution technology, specifically to a method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphate EDA complex. Background Technology

[0002] Electron donor-acceptor complexes (EDA complexes) are a special class of material systems formed by the weak interaction between electron donors and acceptors, and they hold broad application prospects in the field of visible light photocatalysis. Unlike traditional systems that require the addition of a photocatalyst, EDA complexes do not require an additional photocatalyst. Instead, they undergo changes in optical properties through the weak interaction between the electron donor and acceptor, thereby absorbing light energy and promoting the breaking of chemical bonds, thus accelerating the reaction process. This characteristic gives EDA complexes unique advantages in various chemical reactions. For example, chiral nitrogen-containing aromatic compounds have wide applications in pharmaceuticals, natural products, and materials. Therefore, utilizing this excellent property of EDA complexes to obtain a rich variety of chiral nitrogen-containing aromatic compounds through kinetic resolution has significant research and application value.

[0003] Currently, the kinetic resolution of EDA complexes mainly focuses on EDA interactions between substrates. These interactions involve two or more substrates with different electronegativity approaching each other, followed by electron transfer under light irradiation, generating free radicals and initiating the kinetic resolution reaction. For example, existing literature reports the formation of EDA complexes between dihydropyridine derivatives and maleimide analogs via EDA interactions, followed by the generation of free radicals under light irradiation, which then undergo addition or addition-elimination reactions with alkenes. Furthermore, researchers have successfully achieved asymmetric Stetter reactions of free radicals by utilizing primary amine-catalyzed EDA interactions between unsaturated aldehydes and keto acids, providing a new strategy for asymmetric synthesis.

[0004] Although EDA complexes have shown great potential in chemical reactions, current research and applications mainly focus on forming EDA complexes by utilizing the electrical differences between two or more substrates. This requires the participation of photosensitizers and transition metal catalysts to induce kinetic resolution reactions of racemic substrates. This application mode has high requirements for the structure and properties of the substrates, requires the utilization of electrical differences between substrates, and requires the participation of photosensitizers and transition metal catalysts. This limits the application of EDA complexes in a wider range of chemical reactions. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex.

[0006] Currently, existing research on methods for generating EDA complexes through direct interaction between substrates and catalysts, followed by photo-driven kinetic resolution, still fails to adequately reflect their practical feasibility and effectiveness.

[0007] This invention utilizes racemic nitrogen-containing heterocyclic compounds as substrates and chiral phosphoric acid as a catalyst. The resulting EDA complex is then photoexcited to induce a kinetic resolution reaction, yielding chiral nitrogen-containing aromatic compounds with specific chiral tertiary alcohol, amine, or fluorine structural units. This method does not consider the electronic differences of the substrates, thus broadening the substrate selection range. Furthermore, it avoids the involvement of photosensitizers and transition metal catalysts, exhibits mild reaction conditions, high resolution efficiency, high atom economy, and high enantioselectivity.

[0008] To achieve the above objectives, the technical solution of the present invention is as follows.

[0009] The first aspect of this invention provides a method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex, comprising the following steps: Under visible light irradiation and a protective atmosphere, the racemic nitrogen-containing heterocyclic compound of Formula I', a reducing agent, and a chiral phosphoric acid catalyst undergo a kinetic resolution reaction in an organic solvent to obtain the chiral nitrogen-containing aromatic compound of Formula I and the chiral nitrogen-containing aromatic compound of Formula II; the specific chemical reaction formulas are as follows: Among them, R 1 and R 2 Each of the following is independently selected from H, C1-C3 alkyl, benzyl, phenyl, substituted phenyl, heteroaryl, benzo[a]heteroaryl, substituted benzo[a]heteroaryl, cycloalkyl, and benzo[a]cycloalkyl; R 3 X is selected from any one of pyridyl, substituted pyridyl, quinolinyl, and substituted quinolinyl; X is selected from any one of hydroxyl, substituted secondary amino, and fluorine.

[0010] The method of this invention mainly uses racemic nitrogen-containing heterocyclic compounds as substrates and chiral phosphoric acid as a catalyst. It utilizes the EDA complex formed by the racemic nitrogen-containing heterocyclic compound and chiral phosphoric acid, which undergoes a kinetic resolution reaction upon photoexcitation to obtain two chiral nitrogen-containing aromatic compounds with high added value. The chiral nitrogen-containing aromatic compounds prepared by this invention, possessing specific chiral tertiary alcohol, amine, or fluorine structural units, can provide drug molecules with specific spatial configurations and electron distributions, thereby endowing them with special biological activities and physicochemical properties, improving the efficacy and selectivity of antiviral drugs. The method of this invention has broad substrate universality, mild reaction conditions, high resolution efficiency, high atom economy, high enantioselectivity, and no metal involvement.

[0011] Preferred, R 1 and R 2 In this context, the heteroaryl group is thiophene; the benzoheteroaryl group is one of benzoxazolyl, dibenzothiophene, and dibenzopyridyl; the cycloalkyl group is a six-membered cycloalkyl group; the benzocycloalkyl group is a seven-membered cycloalkyl group; the substituent in the substituted phenyl group is one of C1-C4 alkyl, methoxy, methylthio, butyl, and halogen; and the substituent in the substituted benzoheteroaryl group is a phenyl group.

[0012] Preferred, R 3 In X, the substituent in the substituted pyridyl group is methyl, and the substituent in the substituted quinolinyl group is methyl. Preferably, in X, the substituted secondary amino group is an ethyl acetate-substituted secondary amino group.

[0013] Preferably, the reducing agent has the general structural formula shown in Formula III: Among them, R 4 It is phenyl, substituted phenyl, pyrene, or a six-membered cycloalkyl group; R 4 In this case, the substituent in the substituted phenyl group is a C1-C4 alkyl group or a halogen. Preferably, R 4 In this context, the substituted phenyl group is 4-butylphenyl, 4-Brphenyl, 4-methylphenyl, or 2-Brphenyl.

[0014] Preferably, the chiral phosphoric acid catalyst has the general structural formula shown in Formula IV: Among them, R 5 Substituents of phenyl, pyrene, naphthyl, or the substituents shown in formula (v), (vi), (vii), or (viii): ;R 5 In the substituted phenyl group, the substituent is a C1-C4 alkyl, phenyl, trifluoromethyl, methoxy or halogen.

[0015] Preferred, R 5 In this context, the substituted phenyl group is 2,3,4,5,6-pentamethylphenyl, 2-butylphenyl, 2-biphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,4,6-trimethylphenyl, 2,6-dimethyl-4-methoxyphenyl, or 2-Cl-4-butylphenyl.

[0016] Preferably, the molar ratio of the racemic nitrogen-containing heterocyclic compound shown in Formula I', the reducing agent, and the chiral phosphoric acid catalyst is 1:0.5 to 1:0.01 to 0.2; the reaction temperature is 25℃ to 45℃; the reaction time is 1h to 10h; and the organic solvent is any one of toluene, dichloroethane, tetrahydrofuran, diethyl ether, acetonitrile, and ethyl acetate.

[0017] Preferably, the visible light is visible light with a wavelength of 360nm to 450nm. For example, a 3-watt blue lamp can be used for illumination.

[0018] Preferably, the molar concentrations of the racemic nitrogen-containing heterocyclic compound shown in Formula I' and the chiral phosphoric acid catalyst are both not less than 0.01 M; the kinetic resolution selectivity constant s is 20–89. The kinetic resolution selectivity constant s is calculated based on experimental results and indicates the resolution efficiency.

[0019] A second aspect of the present invention provides a chiral aza-aromatic compound, said chiral aza-aromatic compound being prepared by the kinetic resolution method of the aza-aromatic / chiral phosphate EDA complex described in the first aspect, and the chiral aza-aromatic compound represented by Formula I and the chiral aza-aromatic compound represented by Formula II.

[0020] A third aspect of this invention provides the use of a chiral aza-aromatic compound in the preparation of an antiviral drug, wherein the chiral aza-aromatic compound is the chiral aza-aromatic compound of Formula I and Formula II described in the second aspect. Preferably, the virus is a coronavirus HCoV-NL63 cell or an H3N2 subtype influenza virus cell.

[0021] The beneficial effects of this invention are: 1. This invention utilizes racemic nitrogen-containing heterocyclic compounds as substrates and chiral phosphoric acid as a catalyst. The resulting EDA complex is then photoexcited to induce a kinetic resolution reaction, yielding chiral nitrogen-containing aromatic compounds with specific chiral tertiary alcohol, amine, or fluorine structural units. The method of this invention does not consider the electronic differences of the substrates, and it involves no photosensitizers or transition metal catalysts. The reaction conditions are mild, resulting in high resolution efficiency, high atom economy, high enantioselectivity, and no metal involvement.

[0022] 2. The substrate types involved in this invention are not limited by electrical conditions, have a wide range of selection, are simple and readily available, and produce a variety of products. Furthermore, the azo aromatic compounds constructed in this invention have tertiary alcohol units and quaternary carbon chiral centers substituted with secondary amine groups and fluorine atoms. No photocatalyst is added during the reaction. Using chiral phosphoric acid as an organic small molecule catalyst, it has the advantages of high catalytic efficiency, no metal residue in the reaction system, and is stable, efficient, simple to operate, environmentally friendly, high yield, good selectivity, and green and environmentally friendly.

[0023] 3. The method of the present invention obtains two chiral nitrogen-containing aromatic compounds through a simple one-step reaction, and the constructed α-tetrasubstituted chiral nitrogen-containing aromatic compounds have antiviral application prospects and are of great value for promotion and application. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0025] Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0026] In the following embodiments, unless otherwise specified, the methods described are conventional methods; and unless otherwise specified, the reagents and materials described are commercially available.

[0027] This invention provides a method for the kinetic resolution of a nitrogen-containing heterocyclic compound / chiral phosphoric acid EDA complex, comprising the following steps: under visible light irradiation and nitrogen protection, a racemic nitrogen-containing heterocyclic compound of formula I', a reducing agent of formula III, and a chiral phosphoric acid catalyst of formula IV undergo a kinetic resolution reaction in an organic solvent to obtain a chiral nitrogen-containing heterocyclic compound of formula I and a chiral nitrogen-containing heterocyclic compound of formula II; the specific chemical reaction formulas are as follows: .

[0028] Among them, R 1 and R 2 Each of the following is independently selected from H, C1-C3 alkyl, benzyl, phenyl, substituted phenyl, heteroaryl, benzo[a]heteroaryl, substituted benzo[a]heteroaryl, cycloalkyl, and benzo[a]cycloalkyl; R 3 X is selected from any one of pyridyl, substituted pyridyl, quinolinyl, and substituted quinolinyl; X is selected from any one of hydroxyl, substituted secondary amino, and fluorine.

[0029] R 4 It is phenyl, substituted phenyl, pyrene, or a six-membered cycloalkyl group; R 4 In this context, the substituents in the substituted phenyl group are C1-C4 alkyl groups or halogens. For example, R 4 In this context, the substituted phenyl group is 4-butylphenyl, 4-Brphenyl, 4-methylphenyl, or 2-Brphenyl.

[0030] R 5 Substituents of phenyl, pyrene, naphthyl, or the substituents shown in formula (v), (vi), (vii), or (viii): ;R 5 In the substituted phenyl group, the substituent is a C1-C4 alkyl, phenyl, trifluoromethyl, methoxy, or halogen group. Specifically, R 5In this context, the substituted phenyl group is 2,3,4,5,6-pentamethylphenyl, 2-butylphenyl, 2-biphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,4,6-trimethylphenyl, 2,6-dimethyl-4-methoxyphenyl, or 2-Cl-4-butylphenyl.

[0031] Specifically, the racemic nitrogen-containing heterocyclic compound represented by Formula I' is any one of the following compounds: .

[0032] Specifically, the chiral compound represented by Formula I is selected from one of the following compounds: .

[0033] Specifically, the chiral compound represented by Formula II is selected from one of the following compounds: .

[0034] Specifically, the reducing agent shown in Formula III is selected from one of the following compounds: .

[0035] Specifically, the chiral phosphoric acid catalyst shown in Formula IV is selected from one of the following compounds: .

[0036] The technical solution of the present invention will be further described below through specific embodiments.

[0037] In the following embodiments, unless otherwise specified, the methods described are conventional methods; and unless otherwise specified, the reagents and materials described are commercially available.

[0038] In the following examples, racemic aza-aromatic hydrocarbons and chiral phosphoric acid catalysts can be found in relevant literature: Y. Gao, S. Zhang, JC Antilla. ACS Catal. 2020, 10 , 10914-10919; T. Shao, Y. Li, et al . iScience 2019, 16 , 410; prepared and obtained. Organic solvents were purchased from Anaiji and Bailingwei Reagent Company.

[0039] Example 1 A method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex includes the following steps: Place λ at a distance of 2.0 cm from the reaction flask. max Under irradiation by a 3W blue LED lamp (420 nm) and nitrogen protection, 0.1 mmol of compound 1a', 0.1 mmol of the reducing agent (Formula III), and 0.02 mmol of the chiral phosphoric acid catalyst (Formula IV) were reacted in 1.0 mL of organic solvent to undergo a kinetic resolution reaction, yielding a chiral aza-aromatic compound composed of compounds 1a and 2a. The specific chemical reaction formulas are as follows:

[0040] .

[0041] The preliminary criteria were screened using the methods described above, as shown in Table 1.

[0042] Table 1 Preliminary Condition Screening b Determined by high performance liquid chromatography on a chiral stationary phase. ee / % 1a indicates the enantiomeric excess percentage of compound 1a; ee / % 2a indicates the enantiomeric excess percentage of compound 2a; NA indicates no yield.

[0043] As can be seen from the results in Table 1, firstly, using compound 1a' as the template substrate, fixing the reaction solvent as 1,2-dichloroethane, and the temperature at 25°C, the reaction was successful. oC. After reacting for 10 hours, the types of chiral phosphoric acid catalysts were screened, such as those numbered 1 to 14. It was determined that the chiral phosphoric acid catalyst c-1 with branched aryl substituents of 2,3,4,5,6-pentamethylbenzene yielded the best reaction results. Among them, the enantiomeric excess percentage of compound 1a was 55% ee; and the enantiomeric excess percentage of compound 2a was 80% ee.

[0044] Subsequently, using chiral phosphoric acid catalyst c-1 as the catalyst, the reaction solvents were screened, such as those numbered 14 to 19, and toluene was finally determined to be the optimal reaction solvent.

[0045] Further screening was conducted on the type of reducing agent, reaction temperature, and reaction time. Ultimately, it was found that it was impossible to simultaneously obtain the remaining raw material 1a and product 2a with high enantioselectivity.

[0046] Example 2 A method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex includes the following steps: Place λ at a distance of 2.0 cm from the reaction flask. max Under irradiation by a 3W blue LED lamp (420nm) and nitrogen protection, 0.1 mol of racemic compound 1a' was reacted with the reducing agent shown in Formula III and the chiral phosphoric acid catalyst shown in Formula IV in 1.0 mL of toluene. The reaction temperature was [not specified in the original text]. The resulting aza-aromatic chiral EDA complex was obtained; the aza-aromatic chiral EDA complex was a mixture of the chiral compounds shown in Formula I and Formula II. Detailed condition screening was performed according to the above method, as shown in Table 2.

[0047] .

[0048] Table 2 Detailed Filtering Criteria Note: (±)-1a' was used as the template substrate, at a scale of 0.1 mmol. b The values ​​represent the yields of column chromatography separation. The left side represents the yield of compound 1a, and the right side represents the yield of compound 2a. c The results were determined by high performance liquid chromatography. The left side shows the enantiomeric excess percentage of compound 1a, and the right side shows the enantiomeric excess percentage of compound 2a. d The selectivity constant s is calculated using the following formula:

[0049] s =ln[(1- C (1-ee) s )] / ln[(1- C (1+ee) s )]; C (Conversion rate) = ees / (ee s +ee p ).

[0050] in, s Represents the selectivity constant; C Indicates the conversion rate of raw material 1a; ln[(1- C (1-ee) s )] represents the rate constant for catalytic conversion of S configuration; ln[(1- C (1+ee) s [)] represents the rate constant for catalytic conversion of the R configuration. ee s Indicates the enantiomeric excess percentage of compound 1a; ee p This indicates the percentage of enantiomer excess of compound 2a.

[0051] Table 2 shows that the catalyst equivalent was first screened, and it was found that a 20 mol% chiral phosphoric acid intake resulted in the highest resolution efficiency. The effect of lamp distance on the reaction was then investigated, revealing that the reaction was more rapid when the reaction flask was placed close to the LED beads (0 cm), with a resolution efficiency (s) of 64 after 2 hours. Finally, the ratio of substrate 1a to reducing agent Rd-1 was carefully screened, and a 1:0.7 ratio was determined to be the optimal conversion condition.

[0052] Example 3 A method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex includes the following steps: .

[0053] 0.2 mmol of the racemic compound 1a', 0.04 mmol of the chiral phosphoric acid catalyst c-1, and 0.14 mmol of the reducing agent Rd-1 were added to a 10 mL reaction flask, followed by 2.0 mL of toluene. After thorough stirring, the flask was sealed, and air was removed from the reaction flask using a double-row tube freezing-vacuum method. This degassing process was repeated three times. The reaction flask was then placed in a 25°C incubator and stirred in the dark for 10 minutes. Finally, a λ was placed 2.0 cm away from the reaction flask. max Using a 3W blue LED lamp with a wavelength of 420nm as the light source, the reaction was stopped when the reactant conversion approached 50% under the illumination of the 3W blue LED lamp and nitrogen protection. Two-thirds of the solution was evaporated using a rotary evaporator, and the mixture was directly separated by alkaline silica gel column chromatography using a mixture of n-hexane and ethyl acetate in a volume ratio of 60–10:1 as the eluent, yielding 20.9 mg of compound 1a and 24.2 mg of compound 2a.

[0054] Compound 1a is a white solid with a melting point of 122.2℃~123.5℃, a yield of 42%, and a purity of 92% ee. -114.0(c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.6Hz, 1H), 7.83 – 7.72 (m, 2H), 7.59 – 7.52 (m, 3H), 7.37 – 7.29 (m, 3H), 7.28– 7.21 (m, 1H), 6.72 (brs, 1H), 2.03 (s, 3H); 13 C10 NMR (101 MHz, CDCl3) δ 164.3, 146.4, 145.5, 137.3, 129.9, 128.8, 128.3, 127.4, 127.2, 127.1, 126.6, 126.2, 118.5, 75.0, 28.6. ee was determined by high-performance liquid chromatography (HPLC) using a Chiralpak IJ column (4.6 mm inner diameter × 250 mm). The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of 60 / 40. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 9.8 min, and the retention time of the major enantiomer was 14.8 min.

[0055] Compound 2a is a colorless oil; yield 52%; 91% ee; +10.5 ( c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.81 –7.68 (m, 2H), 7.57 – 7.48 (m, 1H), 7.37 (dt, J = 13.2, 7.6 Hz, 4H), 7.30 – 7.20(m, 2H), 4.55 (q, J = 7.2 Hz, 1H), 1.86 (d, J = 7.2 Hz, 3H); 13C10 NMR (101 MHz, CDCl3) δ 165.1, 147.6, 144.6, 136.2, 129.2, 129.2, 128.4, 127.8, 127.4, 126.8, 126.4, 125.8, 120.6, 48.0, 20.4. ee was determined by high-performance liquid chromatography (HPLC) using a Chiralpak IJ column (4.6 mm inner diameter × 250 mm). The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of 95 / 5. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 10.7 min, and the retention time of the major enantiomer was 11.9 min.

[0056] Example 4 A method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex includes the following steps: .

[0057] In this embodiment, compound 1a' in Example 1 is replaced with compound 1b', and the other steps are the same as in Example 1, to obtain chiral products compound 1b and compound 2b; wherein: Compound 1b is a white solid with a melting point of 150.4℃~151.8℃; 22.3 mg, yield 38%; 92% ee; -140.4 ( c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 18.8, 8.5 Hz, 1H),7.87 – 7.67 (m, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.10 –6.94 (m, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.70 (s, 1H), 5.89 (d, J = 6.9 Hz, 1H), 1.98 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 164.2, 147.6, 146.6, 145.4, 140.6,137.2, 129.8, 128.7, 127.4, 127.0, 126.5, 119.3, 118.3, 107.6, 107.3, 100.9,74.8, 28.7. The ee was determined by high performance liquid chromatography (HPLC) using a CHIRALPAK IJ column with an inner diameter of 4.6 mm and an inner diameter of 250 mm. The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of n-hexane to isopropanol of 80 / 20. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 11.9 min, and the retention time of the major enantiomer was 13.7 min.

[0058] Compound 2b is a colorless oil; 27.7 mg, 50% yield; 88% ee; +6.7 ( c 1.0, CHCl3); 1 HNMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.81 –7.64 (m, 2H), 7.55 – 7.45 (m, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.90 – 6.79 (m,2H), 6.75 (d, J = 7.9 Hz, 1H), 5.90 (s, 2H), 4.41 (q, J = 7.2 Hz, 1H), 1.76 (d, J =7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.2, 147.8, 147.7, 146.1, 138.7,136.3, 129.3, 129.2, 127.5, 126.9, 125.9, 120.7, 120.6, 108.4, 108.2, 100.9, 47.8, 20.6. The ee was determined by high performance liquid chromatography (HPLC) using a CHIRALPAK IJ column with an inner diameter of 4.6 mm and a diameter of 250 mm. The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of n-hexane to isopropanol of 95 / 5. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 7.9 min, and the retention time of the major enantiomer was 13.5 min.

[0059] Example 5 A method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex includes the following steps: .

[0060] In this embodiment, compound 1a' in Example 1 is replaced with compound 1c', and the other steps are the same as in Example 1, to obtain chiral products compound 1c and compound 2c, wherein: Compound 1c: white solid, melting point 115.0℃~117.2℃; 29.1 mg, yield 41%; 90% ee; -179.5 ( c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 1.6 Hz, 1H), 8.26 –8.14 (m, 2H), 8.05 (d, J = 8.6 Hz, 1H), 7.88 – 7.71 (m, 4H), 7.63 (dd, J = 8.4,1.8 Hz, 1H), 7.58 – 7.50 (m, 1H), 7.48 – 7.40 (m, 2H), 7.35 (d, J = 8.6 Hz,1H), 6.89 (brs, 1H), 2.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.2, 145.5,143.1, 139.7, 138.3, 137.3, 135.5, 135.4, 129.9, 128.7, 127.4, 127.1, 126.6,126.6, 125.4, 124.2, 122.7, 122.5, 121.6, 119.1, 118.4, 75.1, 28.9. The ee was determined by high performance liquid chromatography (HPLC) using a CHIRALPAK IJ column with an inner diameter of 4.6 mm and an inner diameter of 250 mm. The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of n-hexane to isopropanol of 70 / 30. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 13.2 min, and the retention time of the major enantiomer was 17.5 min.

[0061] Compound 2c is a colorless oil; 34.6 mg, yield 51%; 91% ee; +17.0 ( c 1.0, CHCl3); 1 HNMR (600 MHz, CDCl3) δ 8.19 – 8.10 (m, 3H), 8.01 (d, J = 8.5 Hz, 1H), 7.87 –7.82 (m, 1H), 7.79 – 7.68 (m, 3H), 7.54 – 7.48 (m, 1H), 7.48 – 7.40 (m, 3H),7.25 (d, J = 8.5 Hz, 1H), 4.70 (q, J = 7.1 Hz, 1H), 1.92 (d, J = 7.2 Hz, 3H); 13C NMR(151 MHz, CDCl3) δ 165.1, 147.6, 141.2, 139.8, 137.6, 136.4, 135.8, 135.4,129.4, 129.2, 127.5, 127.0, 126.89, 126.6, 126.0, 124.2, 122.8, 122.8, 121.6,120.7, 120.6, 48.0, 20.7. The ee was determined by high performance liquid chromatography (HPLC) using a CHIRALPAK IJ column with an inner diameter of 4.6 mm and a diameter of 250 mm. The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of 70 / 30. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 6.3 min, and the retention time of the major enantiomer was 7.8 min.

[0062] Example 6 A method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex includes the following steps: In this embodiment, compound 1a' in Example 1 is replaced with compound 1d', and the other steps are the same as in Example 1, to obtain chiral products compound 1d and compound 2d; wherein: Compound 1d is a white solid; melting point 107.2℃~108.9℃; 23.3mg, yield 42%; 97% ee; -211.2( c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.85 – 7.73 (m, 2H), 7.67 – 7.60 (m, 2H), 7.58 – 7.50 (m, 1H),7.41 (d, J = 8.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.26 – 7.21 (m, 1H), 6.74(brs, 1H), 2.55 – 2.28 (m, 2H), 1.70 – 1.48 (m, 1H), 1.20 – 1.05 (m, 1H),0.96 (t, J = 7.3 Hz, 3H);13 C10 NMR (101 MHz, CDCl3) δ 163.3, 146.1, 145.4, 137.2, 129.8, 128.7, 128.2, 127.4, 127.0, 126.9, 126.5, 126.2, 118.4, 77.2, 42.7, 16.9, 14.4. ee was determined by high-performance liquid chromatography (HPLC) using a Chiralpak IJ column (4.6 mm inner diameter × 250 mm). The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of 80 / 20. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 7.8 min, and the retention time of the major enantiomer was 8.9 min.

[0063] Compound 2d was a colorless oil; 27.2 mg, yield 52%; 86% ee; -19.0 ( c 1.0, CHCl3); 1 HNMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.70 –7.55 (m, 2H), 7.43 – 7.35 (m, 1H), 7.31 (d, J = 7.4 Hz, 2H), 7.24 – 7.14 (m,3H), 7.10 (t, J = 7.3 Hz, 1H), 4.21 (t, J = 7.8 Hz, 1H), 2.34 – 2.16 (m, 1H), 2.17 – 2.01 (m, 1H), 1.35 – 1.16 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C10 NMR (101MHz, CDCl3) δ 164.3, 147.7, 143.5, 136.2, 129.2, 128.4, 128.2, 127.4, 126.8, 126.4, 125.8, 120.9, 54.1, 36.9, 21.1, 14.1. ee was determined by high-performance liquid chromatography (HPLC) using a Chiralpak IJ column (4.6 mm inner diameter × 250 mm). The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of 80 / 20. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 4.1 min, and the retention time of the major enantiomer was 5.9 min.

[0064] Example 7 A method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex includes the following steps: .

[0065] In this embodiment, compound 1a' in Example 1 is replaced with compound 1e', and the other steps are the same as in Example 1, to obtain chiral products compound 1e and compound 2e; wherein: Compound 1e is a white solid with a melting point of 136.2℃~137.7℃; 32.5 mg, yield 46%; 92% ee; +72.3 ( c 1.0, CHCl3); 1 H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.77 – 7.72 (m, 1H), 7.56 (t, J = 7.4Hz, 1H), 7.43 (d, J = 7.4 Hz, 2H), 7.35 – 7.20 (m, 4H), 6.89 (s, 1H), 6.82 (s, 2H), 2.28 (s, 3H), 1.78 (s, 6H); 13C NMR (151 MHz, CDCl3) δ 165.1, 148.5,145.8, 139.5, 138.5, 136.5, 136.3, 131.5, 129.8, 128.9, 128.1, 127.4, 127.1,127.0, 126.8, 121.6, 81.8, 23.9, 20.5. The ee was determined by high performance liquid chromatography (HPLC) using a CHIRALPAK IJ column with an inner diameter of 4.6 mm and a diameter of 250 mm. The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of 70 / 30. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 12.7 min, and the retention time of the major enantiomer was 18.4 min.

[0066] Compound 2e is a white solid with a melting point of 160.4℃~161.3℃; 43.0 mg, yield 51%; 84% ee; +82.0 ( c 1.0, CHCl3); 1 H NMR (600 MHz, CDCl3) δ 8.14 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.80 – 7.73 (m, 1H), 7.62 – 7.57 (m,3H), 7.55 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.6 Hz, 1H), 7.07 (brs, 1H), 6.85 (s, 2H), 2.30 (s, 3H), 1.77 (s, 6H; 13 C NMR (151 MHz, CDCl3) δ 164.1, 152.8, 145.7,138.8, 138.4, 137.0, 136.9, 131.7, 130.2, 129.2, 128.9, 128.9, 127.6, 127.4,127.2, 127.1, 126.9, 125.2, 125.2, 123.3, 121.5, 121.4, 81.7, 24.0, 20.6; 19FNMR (565 MHz, CDCl3) δ -62.27. ee was determined by high-performance liquid chromatography (HPLC) using a CHIRALPAKIJ column (4.6 mm inner diameter × 250 mm). The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of 70 / 30. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 7.1 min, and the retention time of the major enantiomer was 8.0 min.

[0067] Example 8 A method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex includes the following steps: .

[0068] In this embodiment, compound 1a' in Example 1 is replaced with compound 1f', and the other steps are the same as in Example 1, to obtain chiral products compound 1f and compound 2a; wherein: Compound 1f is a white solid with a melting point of 109.2℃~110.9℃; yield: 28.7 mg, 43%; 99% ee; -48.8 ( c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.79 – 7.65 (m, 2H), 7.57 – 7.49 (m, 1H), 7.47 – 7.38(m, 2H), 7.36 – 7.17 (m, 4H), 4.15 (q, J = 7.1 Hz, 2H), 3.32 (s, 2H), 1.96 (s,3H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.6, 164.9, 146.8,145.6, 136.1, 129.7, 129.2, 128.3, 127.2, 126.9, 126.7, 126.3, 120.0, 63.9,60.7, 45.4, 25.6, 14.1. The ee was determined by high performance liquid chromatography (HPLC) using a CHIRALPAK IJ column with an inner diameter of 4.6 mm and a diameter of 250 mm. The solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of 70 / 30. The flow rate was 1.0 mL / min, the temperature was 25 °C, and the detection wavelength was 230 nm. The retention time of the minor enantiomer was 6.3 min, and the retention time of the major enantiomer was 7.8 min.

[0069] Example 9 A method for the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex includes the following steps: .

[0070] In this embodiment, compound 1a' in Example 1 is replaced with compound 1ze', and the other steps are the same as in Example 1, to obtain chiral products compound 1ze and compound 2a; wherein: Compound 1ze is a colorless oil; 20.1 mg, yield 40%; 90% ee; +76.6 ( c 1.0, CHCl3); s = 35; 1 H NMR (400 MHz, CDCl3) δ 8.14 (t, J = 8.0 Hz, 2H), 7.83 – 7.77 (m, 1H), 7.77 – 7.68 (m, 1H), 7.65 (dd, J = 8.6, 1.7 Hz, 1H), 7.59 – 7.50 (m, 3H), 7.33(t, J = 7.7 Hz, 2H), 7.29 – 7.22 (m, 1H), 2.27 (d, J H,F = 23.6 Hz, 3H); 19 F NMR (376MHz, CDCl3) δ -146.0; 13 C NMR (101 MHz, CDCl3) δ 162.3 (d, J C,F= 28.1 Hz), 147.1, 144.0 (d, J C,F = 23.5 Hz), 136.7, 129.7, 129.5, 128.2, 127.5, 127.5, 127.5,127.3, 126.6, 124.7 (d, J C,F = 8.9 Hz), 118.1 (d, J C,F = 7.9 Hz), 98.9 (d, J = 173.0 Hz). ee was determined by high performance liquid chromatography (HPLC) using a CHIRALPAK IJ column, 4.6 mm inner diameter × 250 mm; the solvent system used was a mixture of n-hexane and isopropanol, with a volume ratio of n-hexane to isopropanol of 95 / 5; the flow rate was 1.0 mL / min; the temperature was 25 °C; the detection wavelength was 230 nm; the retention time of the minor enantiomer was 9.4 min, and the retention time of the major enantiomer was 10.2 min.

[0071] Example 10 A method for kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex is performed according to the method of Example 1, except that compound 1a' in Example 1 is replaced, as detailed in Table 3.

[0072] Table 3 Scope of Application for Template Substrates Note: "-" indicates no data.

[0073] Application Example 1 The chiral nitrogen-containing aromatic compounds prepared in the above examples were used as test compounds for evaluation at the cellular level.

[0074] Experimental materials: Viruses: Human coronavirus HCoV-NL63, influenza A virus H3N2. Cells: Rhesus monkey kidney cell line LLC-MK2, canine kidney cell line MDCK. Culture conditions: DMEM high-glucose medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin. Fetal bovine serum is denoted as FBS; penicillin-streptomycin is denoted as Penicillin / Streptomycin.

[0075] Test method: 1. Antiviral inhibition rate assay: Human coronavirus HCoV-NL63 was detected using the rhesus monkey kidney cell line LLC-MK2; influenza A virus H3N2 was detected using the canine kidney cell line MDCK. Cell seeding density was 2×10⁻⁶. 5 / well, 24-well plate, incubated overnight, cell growth coverage >90%. Discard the original culture medium, add 250 μL of virus dilution and 250 μL of compound dilution to each well, virus titer 2.6 × 10⁻⁶. 9 The test compound was diluted with DMEM complete medium (DMEM + 10% FBS + 1% Penicillin / Streptomycin) to a final concentration of 25 μM. After incubation at 34°C for 6 hours, the supernatant was discarded, and the cells were washed once with PBS. 250 μL of DMEM complete medium and 250 μL of the compound dilution buffer were added to each well to achieve a final concentration of 25 μM. The cells were incubated at 34°C for 48 hours, the supernatant was discarded, and cells were collected. RNA was extracted using an automated nucleic acid extractor for RT-qPCR to determine viral replication. Three control groups were set up: positive control group (10 µM positive control drug); virus infection group (virus only); and blank cell group (no virus and no compound). The virus infection group was designated as Non-drug, and the blank cell group as Blank.

[0076] 2. EC 50 Assay: Cells were subjected to a concentration of 1.3 × 10⁻⁶. 5 Cells were seeded at a density of [number] cells / well in 24-well plates. After overnight incubation, cell coverage exceeded 90%. The original culture medium in the cell culture wells was discarded, and 250 μL of virus dilution buffer (virus titer 2.6 × 10⁻⁶) was added to each well. 9The test compounds were diluted with 250 μL of different concentrations (20 μM, 4 μM, 0.8 μM, 0.16 μM, and 0.032 μM) using DMEM complete medium to achieve final concentrations of 10 μM, 2 μM, 0.4 μM, 0.08 μM, and 0.016 μM. The mixture was incubated at 34 °C for 6 h. After incubation, the supernatant was discarded, and the mixture was washed once with PBS. Each well was then filled with 250 μL of DMEM complete medium and 250 μL of different concentrations (20 μM, 4 μM, 0.8 μM, 0.16 μM, and 0.032 μM) to achieve final concentrations of 10 μM, 2 μM, 0.4 μM, 0.08 μM, and 0.016 μM. Cells were cultured at 34℃ for 48 hours. After culture, the supernatant was discarded, cells were collected, and RNA was extracted using an automated nucleic acid extractor. RT-qPCR was performed to determine HCoV-NL63 replication. Three control groups were set up: positive drug group (10µM positive drug), virus infection group (virus only), and cell blank group (no virus and no test compound).

[0077] 3. CC 50 Assay: Cells were subjected to a concentration of 3 × 10⁻⁶ cells / mL. 4 Cells were seeded at a density of [number] cells / well in 96-well plates. After overnight incubation, cell coverage exceeded 90%. The original culture medium was aspirated from the wells, and 100 μL of different concentrations of compound dilution buffer (500 μM, 100 μM, 20 μM, 4 μM, 0.8 μM, and 0 μM) were added to each well, with three replicates for each concentration. The cells were incubated at 34°C for 48 h. After incubation, the supernatant was discarded, and 20 μL of thiazolyl blue solution (MTT) was added to each well. The cytotoxicity of the test compound was detected using the MTT assay. Cells were incubated at 34°C for 4 h. After incubation, the supernatant was discarded, and 100 μL of dimethyl sulfoxide was added to each well. The cells were shaken on a shaker at 220 rpm and 25°C for 15 min. The absorbance at OD595 and OD630 was measured using a microplate reader, and cell viability was calculated using the formula. Two control groups were set up: a zeroing group (culture medium only) and a control group (cells and culture medium only).

[0078] Bioactivity results: Table 4 Anti-HCoV-NL63 Virus Activity Note: EC 50 It is the half-maximal effect concentration; CC 50 It is the half-maximal toxicity concentration; the therapeutic index is EC50. 50 and CC 50The therapeutic index ratio is used to assess a drug's therapeutic potential. A higher therapeutic index value indicates a stronger antiviral efficacy.

[0079] Remdesivir, a positive control drug against HCoV-NL63 virus, significantly inhibited viral replication at a concentration of 10 µM, with an inhibition rate of 97.11%. Compounds 1g, 1m, 1r, 1lt, 1y, 1z, and 1lv also significantly inhibited HCoV-NL63 replication at a concentration of 25 µM, with inhibition rates of 90.32%, 89.69%, 85.17%, 91.56%, 97.81%, 96.39%, and 90.47%, respectively. Furthermore, the EC50 of 1g, 1m, 1r, 1lt, 1y, 1z, and 1lv, along with the positive control drug remdesivir, was determined. 50 The values ​​are: 1.35µM, 2.23µM, 2.36µM, 1.65µM, 0.24µM, 0.62µM, 0.96µM, and 0.26µM, respectively; CC 50 The values ​​were 243.9, 289.7, 387.4, 220.3, 458.3, 449.1, 326.5, and 150.3, respectively; the treatment indices (SI) were 180.67, 129.91, 164.15, 133.52, 1938.66, 724.35, 340.10, and 578.08, respectively.

[0080] Table 5 Anti-H3N2 virus activity The antiviral positive control drug oseltamivir phosphate at a concentration of 10 µM significantly inhibited influenza virus replication, with an inhibition rate of 93.49%. In the initial screening, compounds 1i, 1k, 1n, 1w, 1x, 1s, and 1zb at 25 µM inhibited the replication of the H3N2 subtype influenza virus, with inhibition rates of 23.69%, 15.56%, 10.38%, 21.67%, 13.24%, 51.23%, and 46.89%, respectively. Furthermore, the EC50 of 1i, 1k, 1n, 1w, 1x, 1s, 1zb, and the positive control drug oseltamivir phosphate was determined. 50 They are: 39.85µM, 48.62µM, 58.41µM, 42.47µM, 56.64µM, 24.94µM, 18.96µM, 0.12µM; CC 50 The values ​​were 136.3µM, 98.4µM, 70.6µM, 120.8µM, 76.4µM, 220.8µM, 320.2µM, and 639.3µM, respectively; the therapeutic index (SI) were 3.42, 2.02, 1.21, 2.84, 1.35, 8.85, 16.89, and 5327.50, respectively.

[0081] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements 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 the kinetic resolution of a nitrogen-containing aromatic hydrocarbon / chiral phosphoric acid EDA complex, characterized in that, Includes the following steps: Under visible light irradiation and a protective atmosphere, the racemic nitrogen-containing heterocyclic compound of Formula I', a reducing agent, and a chiral phosphoric acid catalyst undergo a kinetic resolution reaction in an organic solvent to obtain the chiral nitrogen-containing aromatic compound of Formula I and the chiral nitrogen-containing aromatic compound of Formula II; the specific chemical reaction formulas are as follows: ； Among them, R 1 and R 2 Each of the following is independently selected from H, C1 to C3: alkyl, benzyl, phenyl, substituted phenyl, heteroaryl, benzo[a]heteroaryl, substituted benzo[a]heteroaryl, cycloalkyl and benzo[a]cycloalkyl; R 3 Selected from any one of pyridyl, substituted pyridyl, quinolinyl, and substituted quinolinyl; X is selected from any one of hydroxyl, substituted secondary amino, and fluorine.

2. The method for kinetic resolution of the aza-aromatic / chiral phosphoric acid EDA complex according to claim 1, characterized in that, R 1 and R 2 In this context, the heteroaryl group is thiophene; the benzoheteroaryl group is one of benzoxazolyl, dibenzothiophene, and dibenzopyridyl; the cycloalkyl group is a six-membered cycloalkyl group; the benzocycloalkyl group is a seven-membered cycloalkyl group; the substituent in the substituted phenyl group is one of C1-C4 alkyl, methoxy, methylthio, butyl, and halogen; and the substituent in the substituted benzoheteroaryl group is a phenyl group.

3. The method for kinetic resolution of the aza-aromatic / chiral phosphoric acid EDA complex according to claim 1, characterized in that, R 3 In the substituted pyridyl group, the substituent is methyl, and in the substituted quinolinyl group, the substituent is methyl.

4. The method for kinetic resolution of the aza-aromatic / chiral phosphoric acid EDA complex according to claim 1, characterized in that, In X, the substituted secondary amino group is a secondary amino group substituted with ethyl acetate.

5. The method for kinetic resolution of the aza-aromatic / chiral phosphoric acid EDA complex according to claim 1, characterized in that, The reducing agent has the following general structural formula as shown in Formula III: ； Among them, R 4 It is phenyl, substituted phenyl, pyrene, or a six-membered cycloalkyl group.

6. The method for kinetic resolution of the aza-aromatic / chiral phosphoric acid EDA complex according to claim 5, characterized in that, R 4 In this context, the substituted phenyl group is 4-butylphenyl, 4-Brphenyl, 4-methylphenyl, or 2-Brphenyl.

7. The method for kinetic resolution of the aza-aromatic / chiral phosphoric acid EDA complex according to claim 1, characterized in that, The chiral phosphoric acid catalyst has the general structural formula shown in Formula IV: ； Among them, R 5 Substituents of phenyl, pyrene, naphthyl, or the substituents shown in formula (v), (vi), (vii), or (viii): ； R 5 In the substituted phenyl group, the substituent is a C1-C4 alkyl, phenyl, trifluoromethyl, methoxy or halogen.

8. The method for kinetic resolution of the aza-aromatic / chiral phosphoric acid EDA complex according to claim 7, characterized in that, R 5 In this context, the substituted phenyl group is 2,3,4,5,6-pentamethylphenyl, 2-butylphenyl, 2-biphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,4,6-trimethylphenyl, 2,6-dimethyl-4-methoxyphenyl, or 2-Cl-4-butylphenyl.

9. The method for kinetic resolution of the aza-aromatic / chiral phosphoric acid EDA complex according to claim 1, characterized in that, The molar ratio of the racemic nitrogen-containing heterocyclic compound, reducing agent, and chiral phosphoric acid catalyst shown in Formula I' is 1:0.5 to 1:0.01 to 0.2; The reaction temperature is 25℃~45℃; the reaction time is 1h~10h; The organic solvent is any one of toluene, dichloroethane, tetrahydrofuran, diethyl ether, acetonitrile, and ethyl acetate.

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