Biscatalytic system of chiral metals containing chelating ligands and its application in asymmetric synthesis of bedaquiline

Abstract

The present invention discloses a bimetallic synergistic catalytic system containing a chelating ligand and its application in the asymmetric synthesis of bedaquiline. Specifically, in the bimetallic synergistic catalytic system, a chelating ligand formed by a non-chiral secondary amine and lithium chiral amino alcohol increases the equilibrium constant of the reaction, promoting the addition reaction of 6-bromo-3-benzyl-2-methoxyquinoline (I) and 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (II) to proceed in the forward direction, and this bimetallic synergistic catalytic system significantly improves the yield of the target product (1R,2S)-bedaquiline.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and relates to a bichiral metal cooperative catalytic system containing a chelating ligand and its application in the asymmetric synthesis of bedaquiline. Specifically, it relates to a chelating ligand formed by an achiral secondary amine and lithium chiral amino alcohol, and this chelating ligand promotes the high-yield asymmetric synthesis of bedaquiline in the bichiral metal system. Background Art

[0002] Tuberculosis (TB) is the disease that causes the most deaths worldwide by a single pathogen. Its lethality has exceeded that of AIDS globally, causing millions of deaths every year. More seriously, drug-resistant tuberculosis has emerged, threatening the health of all mankind. To improve the situation, scientists have invested a great deal of energy in research and development. Bedaquiline belongs to the class of diarylquinoline compounds and is the first new anti-tuberculosis drug in nearly fifty years. It was approved by the FDA for marketing in the United States in 2012 and is the first new drug approved for the treatment of multi-drug resistant tuberculosis. In 2016, it was approved by the China Food and Drug Administration and officially launched in the Chinese market. Bedaquiline has two consecutive chiral centers and four optical isomers, and only the (1R,2S) configuration is effective for medicinal use. One-step construction of consecutive chiral centers of trisubstituted and tetrasubstituted carbons remains a huge challenge in chemical synthesis. Since Johnson & Johnson developed the first industrial synthesis route in 2004, it has been used until now due to the commercial availability of raw materials and the simplicity of the synthesis route. However, this type of method has a low yield and high cost. Currently, a course of treatment with bedaquiline still costs more than 60,000 yuan, which is difficult for ordinary families to afford. Improving the synthesis method and reducing the production cost so that low-income people can afford the medicine is an urgent problem facing drug researchers at home and abroad.

[0003] The synthesis patent of the original research (1R,2S)-bedaquiline (patent authorization number: CN101180302B) discloses a one-step synthesis method. From 6-bromo-3-benzyl-2-methoxyquinoline (I) at low temperature (-72 to -78 °C), after deprotonating the benzyl position with lithium diisopropylamide (LDA), it is added to 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (II) to obtain a mixture of 4 optical isomers of bedaquiline. The reaction material is concentrated, treated with ethanol, and then resolved by the chiral resolving agent (R)-binaphthol phosphate to obtain (1R,2S)-bedaquiline (A), with a very low overall yield of only 7-9%. In addition, due to the high efficiency of asymmetric catalytic synthesis, the method of obtaining bedaquiline by asymmetric catalytic synthesis has also attracted extensive attention from scientists. Shibasaki (J. Am. Chem. Soc. 2010, 132, 7905-7907) and Chandrasekhar (Eur. J. Org. Chem. 2011, 2057-2061) respectively reported constructing the first carbon chirality by an asymmetric catalytic method and then constructing the second carbon chirality by asymmetric synthesis. This route has problems such as many reaction steps, low yield, and high manufacturing cost. In addition, a research group in South Africa in 2020 used a C2-symmetric chiral amine ligand to improve the diastereoselectivity of BDQ to 9:1 (ACS Omega 2020, 5, 3607-3611), and then used the method of chiral resolution to obtain the optically pure target compound, but the yield of the target product still has not been significantly improved. Recently, Jamison et al. used flow chemistry (Chem. Eur. J. 2022, e202201311) to improve the yield of bedaquiline in this industrial production route, but still did not achieve the asymmetric synthesis of the target product. Therefore, it is necessary to develop a more efficient asymmetric synthesis method to improve the yield of the target product (1R,2S)-bedaquiline. SUMMARY OF THE INVENTION

[0004] The purpose of the present invention is to address the deficiencies of the above-mentioned existing technologies, and provide a dual-chiral metal cooperative catalytic system containing a chelating ligand and its application in the asymmetric synthesis of bedaquiline; this system uses an achiral secondary amine to form lithium amide with n-butyllithium, and the lithium amide then forms a chelating ligand with lithium chiral amino alcohol, which improves the equilibrium constant of the addition reaction of 6-bromo-3-benzyl-2-methoxyquinoline I and 3-dimethylamino-1-naphthalen-1-yl-propan-1-one II, shifts the reaction to the positive direction, greatly improves the yield of the target product, and realizes the high-yield asymmetric synthesis of bedaquiline. At the same time, adding LDA as a base in this system can also achieve the same effect.

[0005] In the previous research of the present invention, the strategy of using a bimetallic synergistic system containing lithium amino alcohol and weak intermolecular forces solved the problem of low selectivity of the target product (99.5% ee and 16:1 dr), but the reaction yield was relatively low. Through density functional theory (DFT) calculations, the present invention found that during the addition reaction of 6-bromo-3-benzyl-2-methoxyquinoline I and 3-dimethylamino-1-naphthalen-1-one II, the product precursor exists in the form of an ion pair in the reaction system, and the target product can be obtained after quenching with a protic solvent. It was found that in the previously developed bimetallic synergistic catalytic bedaquiline system, adding an achiral secondary amine ligand can form lithium amide under the action of butyllithium, which can form a chelating ligand with chiral lithium amino alcohol ( Figure 1 ). Simplifying the model, after DFT simulation of the yield and comparing with the reaction system before addition, adding a bidentate or monodentate achiral ligand can obtain a more stable intermediate, increase the equilibrium constant of the reaction, and promote the addition reaction of 6-bromo-3-benzyl-2-methoxyquinoline I and 3-dimethylamino-1-naphthalen-1-one II to proceed in the forward direction ( Figure 8 ), maintaining the stereoselectivity of the original product and further increasing the reaction yield. Finally, the target product was obtained with high ee value and high yield (after recrystallization, ee > 99%).

[0006] The object of the present invention is achieved by the following technical solutions:

[0007] In the first aspect, the present invention provides a bimetallic synergistic catalytic system for synthesizing (1R,2S)-bedaquiline, wherein the bimetal is n-butyllithium and other lithium salts, and the bimetallic synergistic catalytic system contains a chelating ligand;

[0008] The chelating ligand is formed by lithium amide and chiral lithium amino alcohol, the lithium amide is generated from an achiral secondary amine and n-butyllithium, and the chiral lithium amino alcohol is in-situ generated from amino alcohol and n-butyllithium;

[0009] Or the chelating ligand is formed by lithium diisopropylamide, an achiral secondary amine and lithium amino alcohol, and the chiral lithium amino alcohol is in-situ generated from amino alcohol and n-butyllithium.

[0010] Using the bimetallic synergistic catalytic system containing a chelating ligand of the present invention for the asymmetric synthesis of bedaquiline greatly improves the yield of the target product (1R,2S)-bedaquiline on the basis of high stereoselectivity. This bimetal is different from the traditional two metals. Considering the reaction mechanism, the activation processes participated by two parts of lithium salts act synergistically to become the "bimetal".

[0011] As an embodiment, the general structural formula of the achiral secondary amine forming the chelating ligand is where R 1 and R2 a linear alkyl group selected from C1-3, or a cycloalkyl group of C3-8, where the cycloalkyl group can be all-carbon or substituted with heteroatoms such as N, O, S, etc., and the N atom can be substituted with methyl, ethyl, etc., R 1 , R 2 can be the same or different, R 1 , R 2 can form a ring of C3-8, where the cycloalkyl group can be all-carbon or substituted with heteroatoms such as N, O, S, etc., and the N atom can be substituted with methyl, ethyl, etc.

[0012] As an embodiment, the achiral secondary amine is selected from dimethylamine, diethylamine, pyrrolidine, N-methylpiperazine, morpholine, thiomorpholine, piperazine, cyclohexylamine, cyclobutylamine, cycloheptylamine, cyclooctylamine (the structural formula is as Figure 2 shown).

[0013] As an embodiment, the amino alcohol is (1S,2R)-2-amino-1,2-diphenylethanol.

[0014] As an embodiment, the other lithium salts are selected from one or more of lithium carbonate, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium acetate, lithium hydroxide, lithium sulfate, n-butyllithium, lithium diisopropylamide, lithium tetramethylpiperidide, lithium hexamethyldisilazide.

[0015] In a second aspect, the present invention also relates to the use of the dual-chiral metal synergistic catalytic system containing the achiral chelating ligand in the synthesis of (1R,2S)-bedaquiline. Under the temperature condition of -78°C to 0°C, in the dual-metal synergistic catalytic system containing the achiral chelating ligand, an organic solution of 6-bromo-3-benzyl-2-methoxyquinoline (I) is added dropwise for reaction, and then an organic solution of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one (II) is added continuously for reaction. The obtained product is separated and purified to obtain (1R,2S)-bedaquiline.

[0016] As an embodiment, the organic solvents used in the organic solution include one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, diisopropyl ether, ethylene glycol dimethyl ether.

[0017] As an embodiment, the reaction time of the organic solution of 6-bromo-3-benzyl-2-methoxyquinoline (I) added dropwise is 10 minutes to 12 hours. It can be 10 - 30 min, 30 - 50 min, 50 - 60 min, 1 - 1.5 h, 1.5 - 2 h, 2 - 2.5 h, 2.5 - 3 h, 3 - 3.5 h, 3.5 - 4 h, 4 - 4.5 h, 4.5 - 5 h, 5 - 5.5 h, 5.5 - 6 h, 6 - 7 h, 7 - 8 h, 8 - 9 h, 9 - 10 h, 10 - 11 h, 11 - 12 h, etc.

[0018] As an embodiment, the reaction time of the organic solution of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one (II) added is 10 minutes to 12 hours. It can be 10 - 30 min, 30 - 50 min, 50 - 60 min, 1 - 1.5 h, 1.5 - 2 h, 2 - 2.5 h, 2.5 - 3 h, 3 - 3.5 h, 3.5 - 4 h, 4 - 4.5 h, 4.5 - 5 h, 5 - 5.5 h, 5.5 - 6 h, 6 - 7 h, 7 - 8 h, 8 - 9 h, 9 - 10 h, 10 - 11 h, 11 - 12 h, etc.

[0019] As an embodiment, the method comprises the following steps:

[0020] S1-1. Other lithium salts, amino alcohols, achiral secondary amines and n-butyllithium react at -80 °C to 0 °C for 10 min to 2 h in the presence of a solvent; in some embodiments, they react at -30 °C to 0 °C for 30 min.

[0021] Or S1-2. Other lithium salts, amino alcohols, achiral secondary amines and n-butyllithium react at -80 °C to 0 °C for 10 min to 2 h in the presence of a solvent, and then lithium diisopropylamide is added and the reaction continues at -80 °C to 0 °C for 10 min to 2 h; in some embodiments, they react at -30 °C to 0 °C for 10 min, and then lithium diisopropylamide is added and the reaction continues at -30 °C to 0 °C for 30 min.

[0022] S2. 6-Bromo-3-benzyl-2-methoxyquinoline (I) is added dropwise to the system of step S1-1 or S1-2. After addition, the mixture is stirred and reacted for 10 min to 12 h, the temperature is lowered to -59 °C to -78 °C, and then 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one (II) is added and the reaction continues for 10 min to 12 h.

[0023] As an embodiment, the reaction time for forming the chelating ligand in step S-1 or S1-2 is 1 minute to 2 hours. It can be 1 - 10 min, 10 - 20 min, 20 - 30 min, 30 - 40 min, 40 - 50 min, 50 - 60 min, 1 - 1.5 h, 1.5 - 2 h, etc.

[0024] As an embodiment, in step S-1, n-butyllithium is added in the form of a n-hexane solution of n-butyllithium, and the solvent includes tetrahydrofuran.

[0025] As an embodiment, in step S-2, n-butyllithium is added in the form of a n-hexane solution of n-butyllithium, and lithium diisopropylamide is added in the form of a tetrahydrofuran / n-heptane / ethylbenzene solution of lithium diisopropylamide, and the solvent includes tetrahydrofuran.

[0026] As an embodiment, in step S1-1, the amounts of other lithium salts, amino alcohols, achiral secondary amines and n-butyllithium are 0.1 to 5 equivalents, 1 to 5 equivalents, 0.1 to 5 equivalents and 1 to 5 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (I), respectively. In some embodiments, the amounts of other lithium salts, amino alcohols, achiral secondary amines and n-butyllithium are 2 to 2.4 equivalents, 1.5 equivalents, 2.1 equivalents and 3.7 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (I), respectively.

[0027] As an embodiment, in step S1-2, in step S1-2, the amounts of other lithium salts, amino alcohols, achiral secondary amines, n-butyllithium and lithium diisopropylamide are 0.1 to 5 equivalents, 1 to 5 equivalents, 0.1 to 5 equivalents, 1 to 5 equivalents and 1 to 5 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (I), respectively. In some embodiments, the amounts of other lithium salts, amino alcohols, achiral secondary amines, n-butyllithium and lithium diisopropylamide are 2.4 equivalents, 1.8 equivalents, 1.8 equivalents, 1.8 equivalents and 1.8 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (I), respectively.

[0028] As an embodiment, in step S2, the equivalent ratio of 6-bromo-3-benzyl-2-methoxyquinoline to 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one is 1:1 to 10. In some embodiments, the equivalent ratio is 1:1.2.

[0029] As an embodiment, in step S1-1 or S1-2, the solvent is selected from one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diisopropyl ether, ethylene glycol dimethyl ether.

[0030] The present invention has the following beneficial effects:

[0031] In the currently reported work, the highest yield of (1R,2S)-bedaquiline monomer is 30%, while in the present invention, the yield of (1R,2S)-bedaquiline can be as high as 62%, and its enantioselectivity >99% after recrystallization. Brief Description of the Drawings

[0032] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments read in conjunction with the accompanying drawings:

[0033] Figure 1 Synthesis schematic diagram of the asymmetric synthesis of bedaquiline of the present invention; in the figure, R 1 and R 2 are arbitrary substituents of any secondary amine, and can be respectively selected from straight-chain alkyl groups of C1-3 or cycloalkyl groups of C3-8. The cycloalkyl group can be all-carbon or substituted with heteroatoms such as N, O, S, etc. The N atom can be substituted with methyl, ethyl, etc. R 1 , R 2 can be the same or different. R 1 , R 2 can form a ring of C3-8. The cycloalkyl group can be all-carbon or substituted with heteroatoms such as N, O, S, etc. The N atom can be substituted with methyl, ethyl, etc.; L is a non-chiral secondary amine ligand;

[0034] Figure 2 Structural formula of the preferred non-chiral diamine ligand;

[0035] Figure 3 1H NMR spectrum of the product (1R,2S)-bedaquiline;

[0036] Figure 4 1H NMR spectrum with a dr value of 1.8:1;

[0037] Figure 5 1H NMR spectrum with a dr value of 2.5:1;

[0038] Figure 6 Liquid chromatography spectrum with an ee value of 91%;

[0039] Figure 7 Liquid chromatography spectrum with an ee value of 99%;

[0040] Figure 8 Simplified model of DFT simulated yield;

[0041] Figure 9 DFT simulated chelating ligand structure model. Detailed Description of the Invention

[0042] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made. These all belong to the protection scope of the present invention.

[0043] The method for asymmetric synthesis of (1R,2S)-bedaquiline with high yield according to the present invention, the synthesis schematic diagram is as follows Figure 1 .

[0044] In the following examples, the reaction temperature is preferably low temperature, -78°C to 0°C, the total reaction time can be set to 12 minutes to 26 hours. First step: the formation time of the chiral metal catalytic system containing the chelating ligand is 1 to 120 minutes. Second step: adding the raw material 6-bromo-3-benzyl-2-methoxyquinoline (I), the reaction time is 10 minutes to 12 hours. Third step: adding the organic solution of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one (II), the reaction time is 10 minutes to 12 hours.

[0045] In the following examples, the enantiomeric excess percentage (i.e., ee value) is measured by HPLC (chiral column). The instrument used for HPLC analysis is LC-2010 of Shimadzu Corporation, and the specific operating conditions are: using the Chiralpak AD-H chiral chromatographic column produced by Daicel Corporation of Japan.

[0046] Example 1

[0047] Under nitrogen protection, in a dry 50 mL Schlenk tube, add lithium chloride 67.8 mg (1.6 mmol, 2.0 equiv), (1S,2R)-2-amino-1,2-diphenylethanol 246.4 mg (1.2 mmol, 1.5 equiv), pyrrolidine 141.0 μL (1.7 mmol, 2.1 equiv), anhydrous tetrahydrofuran 6 mL. Place the reaction flask in a cold trap (0°C), slowly add 1.8 mL (2.9 mmol) of 1.6 M n-butyllithium in hexane solution. Pyrrolidine and amino alcohol lithium form a stable chelating ligand ( Figure 9 ). After reacting for 30 minutes, slowly dropwise add a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in THF (8 mL) within 1 hour, and continue stirring for 1 h after addition. Then lower the temperature of the cold trap to -60°C, and within the subsequent 60 minutes, slowly add a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one and 6 mL of THF, and keep the temperature of the reaction system at -60°C during the dropping process. After addition, continue the reaction for 2 h. According to DFT calculation ( Figure 8 ), it shows that in the subsequent process, the previously formed chelating ligand will form a stable intermediate with the raw materials in the reaction system, promoting the forward reaction. After the reaction is completed, quench the reaction with saturated ammonium chloride solution at low temperature, transfer to room temperature, extract with ethyl acetate (3×5 mL), and obtain a clean product by column chromatography (yield 59%) ( Figure 3 ,1 1H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 83%. The product was recrystallized with a mixed solvent of isopropanol and isopropyl ether to obtain the target product with an ee value of >99%.

[0048] Example 2

[0049] Under nitrogen protection, 166.7 mg (1.9 mmol, 2.4 equiv) of lithium bromide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 141.0 μL (1.7 mmol, 2.1 equiv) of pyrrolidine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (0 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for thirty minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise over one hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -78 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added while maintaining the temperature of the reaction system at -78 °C. After addition, the reaction was continued for 2 h. The reaction process was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was transferred to room temperature. It was extracted with ethyl acetate (3 × 5 mL), and a clean product was obtained by column chromatography (yield 61%, 1HNMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 83%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0050] Example 3

[0051] Under nitrogen protection, 254.3 mg (1.9 mmol, 2.4 equiv) of lithium iodide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 141.0 μL (1.7 mmol, 2.1 equiv) of pyrrolidine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-20 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for thirty minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in THF (8 mL) was slowly added dropwise over one hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -60 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -60 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was transferred to room temperature. It was extracted with ethyl acetate (3 × 5 mL), and a clean product was obtained by column chromatography (yield 64%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.3:1, and the ee value of the product measured by HPLC was 88%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0052] Example 4

[0053] Under nitrogen protection, 67.8 mg (1.6 mmol, 2.0 equiv) of lithium chloride, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 147.8 μL (1.7 mmol, 2.1 equiv) of morpholine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (0 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for thirty minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise over one hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -60 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added while maintaining the temperature of the reaction system at -60 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and purified by column chromatography to obtain a clean product (yield: 90%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.8:1( Figure 4 ), and the ee value of the product measured by HPLC was 90%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1( Figure 7 ).

[0054] Example 5

[0055] Under nitrogen protection, 166.7 mg (1.9 mmol, 2.4 equiv) of lithium bromide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 147.8 μL (1.7 mmol, 2.1 equiv) of morpholine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-20 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for thirty minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise over one hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -60 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -59 °C to -62 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was transferred to room temperature. It was extracted with ethyl acetate (3 × 5 mL), and a clean product was obtained by column chromatography (yield 90%)( 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 2.5:1( Figure 5 ), and the ee value of the product measured by HPLC was 91%( Figure 6 ). The target product with >99% ee was obtained by the same recrystallization method as in Example 1( Figure 4 ).

[0056] Example 6

[0057] Under nitrogen protection, 254.3 mg (1.9 mmol, 2.4 equiv) of lithium iodide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 147.8 μL (1.7 mmol, 2.1 equiv) of morpholine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-20 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for thirty minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in THF (8 mL) was slowly added dropwise over one hour, and stirring was continued for 1 h after addition. Then the temperature of the cold trap was lowered to -78 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -78 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and the pure product was obtained by column chromatography (yield: 59%)( 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.6:1, and the ee value of the product measured by HPLC was 87%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0058] Example 7

[0059] Under nitrogen protection, 67.8 mg (1.6 mmol, 2.0 equiv) of lithium chloride, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 188.6 μL (1.7 mmol, 2.1 equiv) of N-methylpiperazine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-10 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for thirty minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise over one hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -60 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -60 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was transferred to room temperature. It was extracted with ethyl acetate (3 × 5 mL), and the pure product was obtained by column chromatography (yield: 73%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 91%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0060] Example 8

[0061] Under nitrogen protection, 166.7 mg (1.9 mmol, 2.4 equiv) of lithium bromide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 188.6 μL (1.7 mmol, 2.1 equiv) of N-methylpiperazine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-10 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for thirty minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise over one hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -78 °C, and within the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added while maintaining the temperature of the reaction system at -78 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and purified by column chromatography to obtain a clean product (yield: 68%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.3:1, and the ee value of the product measured by HPLC was 86%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0062] Example 9

[0063] Under nitrogen protection, 254.3 mg (1.9 mmol, 2.4 equiv) of lithium iodide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 188.6 μL (1.7 mmol, 2.1 equiv) of N-methylpiperazine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-10 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for 30 minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise over 1 hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -60 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -59 °C to -62 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was transferred to room temperature. It was extracted with ethyl acetate (3 × 5 mL), and a clean product was obtained by column chromatography (yield 69%) Figure 3 , 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 86%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0064] Example 10

[0065] Under nitrogen protection, 67.8 mg (1.6 mmol, 2.0 equiv) of lithium chloride, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 86.1 μL (1.7 mmol, 2.1 equiv) of dimethylamine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-10 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for 30 minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in THF (8 mL) was slowly added dropwise over 1 hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -60 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -59 °C to -62 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was transferred to room temperature. It was extracted with ethyl acetate (3 × 5 mL), and a clean product was obtained by column chromatography (yield: 57%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 81%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0066] Example 11

[0067] Under nitrogen protection, 166.7 mg (1.9 mmol, 2.4 equiv) of lithium bromide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 86.1 μL (1.7 mmol, 2.1 equiv) of dimethylamine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (0 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for thirty minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in THF (8 mL) was slowly added dropwise over one hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -70 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -70 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and purified by column chromatography to obtain a clean product (yield: 56%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 80%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0068] Example 12

[0069] Under nitrogen protection, 254.3 mg (1.9 mmol, 2.4 equiv) of lithium iodide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 86.1 μL (1.7 mmol, 2.1 equiv) of dimethylamine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (0 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for 30 minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in THF (8 mL) was slowly added dropwise over 1 hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -50 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -50 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was transferred to room temperature. The product was extracted with ethyl acetate (3 × 5 mL), and a clean product was obtained by column chromatography (yield: 59%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H).). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 83%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0070] Example 13

[0071] Under nitrogen protection, 67.8 mg (1.6 mmol, 2.0 equiv) of lithium chloride, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 175.9 μL (1.7 mmol, 2.1 equiv) of diethylamine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-30 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for 30 minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise over 1 hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -60 °C, and within the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added while maintaining the reaction system temperature at -59 °C to -62 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and purified by column chromatography to obtain a clean product (yield: 55%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H).). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 82%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0072] Example 14

[0073] Under nitrogen protection, 166.7 mg (1.9 mmol, 2.4 equiv) of lithium bromide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 175.9 μL (1.7 mmol, 2.1 equiv) of diethylamine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-10 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for 30 minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise over 1 hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -78 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -78 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and purified by column chromatography to obtain a clean product (yield 54%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H).). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 80%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0074] Example 15

[0075] Under nitrogen protection, 254.3 mg (1.9 mmol, 2.4 equiv) of lithium iodide, 246.4 mg (1.2 mmol, 1.5 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 175.9 μL (1.7 mmol, 2.1 equiv) of diethylamine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (0 °C), and 1.8 mL (2.9 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for 30 minutes, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in THF (8 mL) was slowly added dropwise over 1 hour. After addition, stirring was continued for 1 h. Then the temperature of the cold trap was lowered to -78 °C, and within the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added dropwise while maintaining the temperature of the reaction system at -78 °C. After addition, the reaction was continued for 2 h. The reaction process was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and purified by column chromatography to obtain a clean product (yield: 58%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H).). The dr value of the product measured by crude NMR was 1.4:1, and the ee value of the product measured by HPLC was 81%. The target product with >99% ee was obtained by the same recrystallization method as in Example 1.

[0076] Example 16

[0077] Under nitrogen protection, 81.4 mg (1.9 mmol, 2.4 equiv) of lithium chloride, 298.6 mg (1.4 mmol, 1.76 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 188.6 μL (1.7 mmol, 2.1 equiv) of N-methylpiperazine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-20 °C), and 0.88 mL (1.4 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for ten minutes, 0.77 mL (1.4 mmol) of 2.0 M LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was added dropwise. After reacting at -20 °C for half an hour, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise within one hour. After addition, stirring was continued for 2 h. Then the temperature of the cold trap was lowered to -60 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added while maintaining the temperature of the reaction system at -60 °C. After addition, the reaction was continued for 2 h. The reaction process was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and the pure product was obtained by column chromatography (yield: 58%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by crude NMR was 2:1, and the ee value of the product measured by HPLC was 94%.

[0078] Example 17

[0079] Under nitrogen protection, 81.4 mg (1.9 mmol, 2.4 equiv) of lithium chloride, 298.6 mg (1.4 mmol, 1.76 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol (L1), 141.0 μL (1.7 mmol, 2.1 equiv) of pyrrolidine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-30 °C), and 0.88 mL (1.4 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for ten minutes, 0.77 mL (1.4 mmol) of 2.0 M LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was added dropwise. After reacting for half an hour at -30 °C, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise over one hour. After addition, stirring was continued for 2 h. Then the temperature of the cold trap was lowered to -78 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added while maintaining the temperature of the reaction system at -78 °C. After addition, the reaction was continued for 2 h. The reaction process was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and purified by column chromatography to obtain a clean product (yield: 61%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the crude product measured by NMR was 1.9:1, and the ee value of the product measured by HPLC was 92%.

[0080] Example 18

[0081] Under nitrogen protection, 81.4 mg (1.9 mmol, 2.4 equiv) of lithium chloride, 298.6 mg (1.4 mmol, 1.76 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 147.8 μL (1.7 mmol, 2.1 equiv) of morpholine, and 6 mL of anhydrous tetrahydrofuran were added to a dry 50 mL Schlenk tube. The reaction flask was placed in a cold trap (-10 °C), and 0.88 mL (1.4 mmol) of a 1.6 M n-butyllithium hexane solution was slowly added. After reacting for ten minutes, 0.77 mL (1.4 mmol) of 2.0 M LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was added dropwise. After reacting at -10 °C for half an hour, a solution of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF was slowly added dropwise within one hour. After addition, stirring was continued for 2 h. Then the temperature of the cold trap was lowered to -78 °C, and within the subsequent 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one in 6 mL of THF was slowly added while maintaining the temperature of the reaction system at -78 °C. After addition, the reaction was continued for 2 h. The reaction procedure was the same as in Example 1. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution at low temperature, transferred to room temperature, extracted with ethyl acetate (3 × 5 mL), and purified by column chromatography to obtain a pure product (yield: 55%) 11H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 - 7.46 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.88 - 6.87 (m, 3H), 5.89 (s, 1H), 4.21 (s, 3H), 2.54 - 2.50 (m, 1H), 2.13 - 2.00 (m, 2H), 1.97 (s, 6H), 1.95 - 1.90 (m, 1H). The dr value of the product measured by 1H NMR of the crude product was 2:1, and the ee value of the product measured by HPLC was 91%.

[0082] The above description is only for some embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and all equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope of the present invention.

Claims

1. A bimetallic cooperative catalytic system for synthesizing (1 R ,2 S )-bedaquiline, characterized in that The bimetal is n-butyllithium and other lithium salts, and the bimetal synergistic catalytic system contains a chelating ligand; The chelating ligand is formed by lithium amide and chiral lithium amino alcohol. The lithium amide is generated from achiral secondary amine and n-butyllithium. The chiral lithium amino alcohol is in-situ generated from (1 S ,2 R )-2-amino-1,2-diphenylethanol and n-butyllithium; The achiral secondary amine is selected from dimethylamine, diethylamine, dipropylamine, dibutylamine, pyrrolidine, N -methylpiperazine, morpholine, thiomorpholine, piperazine, cyclohexylamine, cyclobutylamine, cycloheptylamine or cyclooctylamine; The other lithium salts are selected from one or more of lithium carbonate, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium acetate, lithium hydroxide, lithium sulfate, lithium diisopropylamide, lithium tetramethylpiperidine, and lithium hexamethyldisilazide.

2. A method for the asymmetric synthesis of (1 R ,2 S )-bedaquiline, characterized in that, Under the temperature condition of -78 °C to 0 °C, in the bimetallic synergistic catalytic system as described in claim 1, an organic solution of 6-bromo-3-benzyl-2-methoxyquinoline (I) is added dropwise, and then 3- N , N -dimethylamino-1-naphthalen-1-yl-propan-1-one (II) is added, and the obtained product is separated and purified to obtain (1 R ,2 S )-bedaquiline.

3. The method for the asymmetric synthesis of (1 R ,2 S )-bedaquiline according to claim 2, characterized in that The method comprises the following steps: S1. Other lithium salts, amino alcohol, achiral secondary amine and n-butyllithium react at -80°C to 0 °C for 10 min to 2 h in the presence of a solvent; S2. Add an organic solution of 6-bromo-3-benzyl-2-methoxyquinoline (I) dropwise to the system in step S1. After the addition, stir the reaction for 10 min to 12 h, and lower the temperature to -59 °C to -78 °C and continue to add N , N an organic solution of 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (II), and react for 10 min to 12 h.

4. The method for the asymmetric synthesis of (1 R ,2 S )-bedaquiline according to claim 3, characterized in that In step S1, the amounts of other lithium salts, amino alcohol, achiral secondary amine and n-butyllithium are 0.1 to 5 equivalents, 1 to 5 equivalents, 0.1 to 5 equivalents and 1 to 5 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (I), respectively.

5. The method for the asymmetric synthesis of (1 R ,2 S )-bedaquiline according to claim 3, characterized in that In step S2, the equivalent ratio of 6-bromo-3-benzyl-2-methoxyquinoline and 3- N , N -dimethylamino-1-naphthalen-1-yl-propan-1-one is 1:1 to 10.

6. The method for the asymmetric synthesis of (1 R ,2 S )-bedaquiline according to claim 3, characterized in that In step S1, the solvent is selected from one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diisopropyl ether, and ethylene glycol dimethyl ether; the organic solvent used in the organic solution in step S2 is tetrahydrofuran.

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