A bidentate metal cooperative catalytic system and its application in asymmetric synthesis of bedaquiline

Abstract

The application discloses a kind of bichiral metal synergistic catalytic system and its application in asymmetric synthesis bedaquiline;Specifically: metal lithium, sodium or potassium salt and another metal salt form bichiral metal synergistic catalytic system under the action of suitable ligand and additive, promote 6-bromo-3-benzyl-2-methoxyquinoline (I) and 3-dimethylamino-1-naphthyl-1-propanone (II) addition reaction and regulate its selectivity, first with high yield and high selectivity to obtain target product (1R,2S)-bedaquiline.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric synthesis technology, and relates to a biphasic metal synergistic catalytic system and its application in the asymmetric synthesis of bedaquiline; specifically, it relates to the establishment of a biphasic metal synergistic catalytic system and the use of the system, specifically in the asymmetric synthesis of the anti-tuberculosis drug (1R,2S)-bedaquiline. Background Technology

[0002] Tuberculosis (TB) is the leading cause of death worldwide from a single pathogen. my country sees nearly 900,000 new cases annually, accounting for 9% of global new cases. The prevalence of drug-resistant TB is particularly severe, exceeding the global average. Bedaquiline, a diarylquinoline compound, is the first novel anti-tuberculosis drug in nearly fifty years. Approved by the FDA in the US in 2012, it was the first new drug approved for treating multidrug-resistant TB. In 2016, it was officially launched in the Chinese market after approval by the my country Food and Drug Administration. Bedaquiline has four optical isomers, only the (1R, 2S) configuration is effective for pharmaceutical use. Currently, obtaining a single configuration of bedaquiline in industrial production requires chiral resolution. This method faces problems such as poor selectivity of the C-C bonds during addition product formation, the target product being a minor separation product, and low synthetic efficiency, resulting in low yield and high cost. Improving synthesis methods and reducing production costs so that low-income groups can afford medicines is an urgent problem facing drug researchers both at home and abroad.

[0003] The original (1R,2S)-bedaquiline synthesis patent (patent authorization number: CN101180302B) discloses a one-step synthesis method. Figure 1The reaction proceeds from 6-bromo-3-benzyl-2-methoxyquinoline (I) at low temperatures (-72 to -78 °C) via the debenzylic proton removal from lithium diisopropylamino(LDA), followed by addition with 3-dimethylamino-1-naphthyl-1-propanone (II) to generate a mixture of four optical isomers of bedaquiline. The reactants are concentrated, treated with ethanol, and then resolved by the chiral resolving agent (R)-binaphthol phosphate to obtain (1R,2S)-bedaquiline (A). The overall yield is very low, only 7–9%. Furthermore, the highly efficient synthesis via asymmetric catalysis has attracted the attention of scientists. Shibasaki (J. Am. Chem. Soc. 2010, 132, 7905-7907) and Chandrasekhar (Eur. J. Org. Chem. 2011, 2057-2061) reported methods for constructing the first chiral carbon using asymmetric catalysis, followed by asymmetric synthesis of the second chiral carbon. This route suffers from numerous reaction steps, low yield, and high manufacturing costs. A patent (patent authorization number: CN10686652A) increased the proportion of the (1R,2S)-bedaquinoline optical isomer in the reaction product using a chiral inducer, achieving an ee value of 90% and a dr value of 4:1, but the results were still unsatisfactory. Furthermore, a research group in South Africa improved the diastereoselectivity of BDQ to 9:1 in 2020 using C2-symmetric chiral amine ligands (ACS Omega 2020, 5, 3607-3611). Subsequent chiral resolution yielded optically pure target compounds, but the enantioselectivity of the target product remained unresolved. Therefore, it is necessary to develop more efficient asymmetric synthetic methods to obtain the target product (1R,2S)-betdaquiline. Summary of the Invention

[0004] The purpose of this invention is to address the shortcomings of the prior art by providing a biphasic metal synergistic catalytic system and its application in the asymmetric synthesis of bedaquiline; specifically, it relates to a biphasic metal synergistic catalytic system and its application in the asymmetric synthesis of the anti-tuberculosis drug (1R,2S)-bedaquiline.

[0005] The objective of this invention is achieved through the following technical solution:

[0006] In a first aspect, the present invention relates to a bidirectional metal-co-catalyzed system for the synthesis of (1R,2S)-betaquinoline, wherein lithium, sodium, or potassium salts synergistically act with other metal salts, and suitable ligands and additives are selected to form the bidirectional metal-co-catalyzed system. In this bidirectional metal-co-catalyzed system, suitable ligands are used to control the metal ions. This system can efficiently promote the synthesis of (1R,2S)-betaquinoline.

[0007] As one embodiment, the source of the lithium, sodium, or potassium salt is one or a combination of several of the following: n-butyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium, tetramethylpiperidinelithium, bis(trimethylsilylaminolithium), bis(trimethylsilylaminosodium), and bis(trimethylsilylaminopotassium).

[0008] As one embodiment, the other metal salts are metal halides, and the metal is Mg, Zn, Cu, Al, Ni, Co, Fe, Na, K, Ti, Ca, or Li. Specifically, it includes one or more of MgCl2, ZnCl2, CuCl2, AlCl3, NiCl2, CoCl2, FeCl3, NaCl, KCl, TiCl4, CaCl2, LiCl, LiBr, LiI, and LiF.

[0009] As one implementation scheme, the ligand structure is as follows: Where X and X' are selected from N and O atoms respectively (i.e., X and X' can be nitrogen atoms or oxygen atoms at the same time, or nitrogen atoms and oxygen atoms respectively); R 1 R 2 R 3 R 4 R 5 R 6 Selected from H and C respectively 1-16 Straight-chain or branched alkyl, aryl, or C 3-7 cycloalkyl groups, wherein the aryl group is R. 7 Substituted phenyl, R 7 For H, C 1-6 Alkyl, halogen, C 1-6 Alkoxy or OCOR 8 (The halogen is F, Cl, Br, or I), R 8 C 1-6 alkyl, R 7 Substitution can be mono- or poly-substituted, and poly-substituted substances can be the same or different; and R 1 R 2 R 3 R 4 R 5 R 6 Similar, different, or mutually reinforcing.

[0010] As one implementation, R in the ligand structure 1 and R 2 Same, different, or cyclic; R 3 and R 4 Same, different, or cyclic; R 3 and R 1 Non-cyclic or cyclic; R 5 and R 6Same, different, or cyclic; R 5 and R 2 Non-cyclic or cyclic; * indicates chirality, with configurations of RR, SS, RS, or SR.

[0011] As one implementation, the additive has the following structure: Organic bases, of which R 9 R 10 and R 11 H and C respectively 1-16 Straight-chain or branched alkyl, aryl, or C 3-7 cycloalkyl, aryl is R 12 Substituted phenyl, R 12 For H, C 1-6 Alkyl, halogen, C 1-6 Alkoxy or OCOR 13 (The halogen is F, Cl, Br, or I); R 13 C 1-6 Alkyl group; R 12 The substitution can be mono- or poly-substituted, and the polysubstituents can be the same or different; and R 9 R 10 and R 11 Similar, different, or mutually reinforcing.

[0012] As one embodiment, the organic base is selected from DBU, DBN, TMEDA, HMPA, DMAP, DABCO, TMP, DIPA, pyridine, pyrrolidine, adamantane, Sparteine, and tBuNHSi(CH)3.

[0013] Secondly, the present invention also relates to the use of the biphasic metal co-catalytic system described above in the synthesis of (1R,2S)-bedaquinoline. Under temperature conditions of -78°C to 0°C, in an organic solution of a biphasic metal co-catalytic system formed by the mixed reaction of lithium, sodium or potassium salts, other metal salts, ligands and additives, an organic solution of 6-bromo-3-benzyl-2-methoxyquinoline (I) is slowly added dropwise, followed by the addition of an organic solution of 3-N,N-dimethylamino-1-naphthyl-1-propanone (II), and the resulting product is separated and purified to obtain (1R,2S)-bedaquinoline.

[0014] As one implementation, the mixing reaction time is from 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.

[0015] As one implementation scheme, the reaction time for adding the organic solution of 6-bromo-3-benzyl-2-methoxyquinoline (I) is 10 minutes to 12 hours. Possible reaction times include 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, and 11-12 h.

[0016] As one implementation scheme, the reaction time for adding the organic solution of 3-N,N-dimethylamino-1-naphthyl-1-propanone (II) is 10 minutes to 12 hours. Possible reaction times include 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, and 11-12 h.

[0017] As one implementation, the amount of lithium, sodium, or potassium salt used is 1 to 5 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (I). The amounts can be 1-1.5 equivalents, 1.5-2 equivalents, 2-2.5 equivalents, 2.5-3 equivalents, 3-3.5 equivalents, 3.5-4 equivalents, 4-4.5 equivalents, or 4.5-5 equivalents.

[0018] As one embodiment, the amount of the other metal salt is 0.01 to 2.0 times the equivalent of 3-dimethylamino-1-naphthyl-1-propanone(II). It can be 0.01-0.1 equivalent, 0.1-0.5 equivalent, 0.5-1 equivalent, 1-1.5 equivalent, or 1.5-2 equivalent.

[0019] As one implementation scheme, the molar ratio of metal salt to chiral ligand is 1.0:0.1 to 5.0. It can be 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.2, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:5.

[0020] As one implementation, the amount of additive used is 0.1 to 20 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (I). It can be 0.1-0.5 equivalents, 0.5-1 equivalents, 1-1.5 equivalents, 1.5-2 equivalents, 2-5 equivalents, 5-10 equivalents, 10-15 equivalents, or 15-20 equivalents.

[0021] As one embodiment, the organic solvent used in the organic solution is selected from one or a mixture of several of the following: diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diisopropyl ether, ethylene glycol dimethyl ether, toluene, xylene, ethylbenzene, n-hexane, cyclohexane, n-heptane, and n-pentane.

[0022] The present invention has the following beneficial effects:

[0023] In the currently reported work, the highest ratio of the two diastereomers (A+A') / (B+B') is 9:1, and the best ee value of the target product (1R,2S)-bedaquiline is 90%. However, in this invention, while maintaining the enantioselectivity of the target product (1R,2S)-bedaquiline as high as 99%, the ratio of the two diastereomers (A+A') / (B+B') can be as high as 10:1. Attached Figure Description

[0024] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0025] Figure 1 This is a schematic diagram of the one-step synthesis of bedaquiline disclosed in CN101180302B;

[0026] Figure 2 This is a schematic diagram illustrating the asymmetric synthesis of bedaquiline according to the present invention;

[0027] Figure 3 The 1H NMR spectrum of the product (1R,2S)-bedaquinoline;

[0028] Figure 4 The 1H NMR spectrum is shown with a dr ratio of 4:1.

[0029] Figure 5 The 1H NMR spectrum is for a dr ratio of 7:1.

[0030] Figure 6 The 1H NMR spectrum is for a dr ratio of 10:1.

[0031] Figure 7 The 1H NMR spectrum is for a dr ratio of 20:1.

[0032] Figure 8 The liquid phase spectrum is for an ee value of 99%. Detailed Implementation

[0033] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention. These all fall within the scope of protection of the present invention.

[0034] The method of the present invention for the asymmetric synthesis of (1R,2S)-bedaquinoline using a biphasic metal co-catalytic system Figure 2 The reaction can be represented by the following equation:

[0035]

[0036] In the above reaction formula, "Ligand" represents the ligand for activating metal M1 and M2 ions. Its structural formula is as follows: Preferably, the chiral ligand can be selected from any one of the following formulas L1 to L12; in particular, after detailed screening, the optimal result can be obtained when L1 is selected for the reaction.

[0037]

[0038] In the above reaction formula, "M1" represents lithium, sodium, or potassium. In the bipolar metal-co-catalyzed preparation method of bedaquinoline of the present invention, the source is one or more combinations of n-butyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium, tetramethylpiperidinelithium, bis(trimethylsilylaminolithium), bis(trimethylsilylaminosodium), and bis(trimethylsilylaminopotassium). The amount used is 1 to 5 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (I).

[0039] In the above reaction formula, "M2" represents another metal that acts synergistically with M1 in the biphasic metal synergistic catalytic system of the present invention. Its source is MgCl2, ZnCl2, CuCl2, AlCl3, NiCl2, CoCl2, FeCl3, NaCl, KCl, TiCl4, CaCl2, LiCl, LiBr, LiI, LiF, etc. Its amount is 0.01 to 2.0 equivalents of 3-dimethylamino-1-naphthyl-1-propanone(II).

[0040] In the above reaction formula, "Additive" refers to the additive in the bipolar metal co-catalytic system. In the preparation method of bedaquinoline by bipolar metal co-catalysis of the present invention, the additive is preferably one of DBU (1,8-diazabicycloundec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), DIPA (N,N-diisopropylamine), DABCO (triethylenediamine), TMP (2,2,6,6-tetramethylpiperidine), HMPA (hexamethylphosphoric triamine), TMEDA (N,N,N',N'-tetramethylethylenediamine), and DMAP (4-dimethylaminopyridine). The amount of additive used is 0.1 to 20 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (I).

[0041] In the above reaction formula, "Solvent" indicates that the solvent forms an organic solution in the system. In the biphasic metal-co-catalyzed preparation method of bedaquiline of the present invention, there is no particular limitation on the solvent; the solvent only needs to enable the reaction to occur and yield the target product. However, from the viewpoint of reaction yield and enantiomeric selectivity, the solvent is preferably selected from ether solvents such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diisopropyl ether, ethylene glycol dimethyl ether, as well as toluene, xylene, n-hexane, cyclohexane, n-pentane, etc., one or a mixture of several such solvents. Among these, tetrahydrofuran was selected as the reaction solvent after screening to obtain the best results.

[0042] In the following embodiments, the reaction temperature is preferably low, ranging from -78°C to 0°C, and the total reaction time can be set from 12 minutes to 26 hours. The first step involves the formation of a bipolar metal catalytic system, with a reaction time of 1 to 120 minutes. The second step involves the addition of the starting material 6-bromo-3-benzyl-2-methoxyquinoline (I), with a reaction time of 10 minutes to 12 hours. The third step involves the addition of an organic solution of 3-N,N-dimethylamino-1-naphthyl-1-propanone (II), with a reaction time of 10 minutes to 12 hours.

[0043] In the following examples, the enantiomeric excess percentage (i.e., ee value) was determined by HPLC (chiral column). The instrument used for HPLC analysis was a Shimadzu LC-2010, and the specific operating conditions were: a Chiralpak AD-H chiral column manufactured by Daicel Corporation of Japan.

[0044] Example 1

[0045] Under nitrogen protection, in a dry 50 mL Shrek tube, 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 (L1), 120 μL (0.8 mmol, 1.0 equiv) of DBU, and 6 mL of anhydrous tetrahydrofuran were added. The reaction flask was placed in a cold trap (-40 °C), and 0.88 mL (1.4 mmol) of a 1.6 M n-butyllithium solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -40 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 60 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -59 °C to -62 °C. After the addition was complete, the reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 26%). The crude product had a dr value of 10:1 as determined by NMR and an ee value of 99% as determined by HPLC (liquid chromatogram as shown). Figure 8 (As shown).

[0046] Example 2

[0047] Under nitrogen protection, in a dry 50 mL Shrek tube, 138.9 mg (1.6 mmol, 2.0 equiv) of lithium bromide, 298.6 mg (1.4 mmol, 1.76 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol (L1), 598 μL (4.0 mmol, 5.0 equiv) of DBU, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -20 °C for 1 hour. Then, 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 two hours, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -78 °C. Over the next 120 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -78 °C throughout the addition. The reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature. The mixture was then cooled to room temperature, extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 22%). The crude product's dr value, determined by NMR, was 8:1, and its ee value, determined by HPLC, was 99% (NMR spectrum as shown). Figure 3 (As shown).

[0048] Example 3

[0049] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 139 μL (0.8 mmol, 1.0 equiv) of HMPA, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -20 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 90 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -59 °C to -62 °C. After the addition was complete, the reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature. The mixture was then cooled to room temperature, extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 22%). The crude product's dr value, determined by NMR, was 10:1, and the ee value, determined by HPLC, was 99% (NMR spectrum as shown). Figure 6 (As shown).

[0050] Example 4

[0051] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 139 μL (0.8 mmol, 1.0 equiv) of HMPA, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for one minute, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -20 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 90 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature between -59 °C and -62 °C. After the addition was complete, the reaction was continued for 3 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature. The mixture was then cooled to room temperature, extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 18%). The crude product had a dr value of 8:1 as determined by NMR and an ee value of 98% as determined by HPLC.

[0052] Example 5

[0053] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 139 μL (0.8 mmol, 1.0 equiv) of HMPA, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for one minute, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -20 °C for half an hour. Then, 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, followed by stirring for 10 minutes. The cold trap temperature was then lowered to -60 °C. Over the next 90 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -59 °C to -62 °C. After the addition was complete, the reaction was continued for 12 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 22%). The crude product had a dr value of 6:1 as determined by NMR and an ee value of 98% as determined by HPLC.

[0054] Example 6

[0055] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 139 μL (0.8 mmol, 1.0 equiv) of HMPA, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for five minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -20 °C for half an hour. Then, 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, followed by stirring for 12 hours. The cold trap temperature was then lowered to -60 °C. Over the next 90 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -59 °C to -62 °C. After the addition was complete, the reaction continued for 12 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature. The mixture was then cooled to room temperature, extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 29%). The crude product's dr value, determined by NMR, was 7:1, and the product's ee value, determined by HPLC, was 99% (NMR spectrum as shown). Figure 5 (As shown).

[0056] Example 7

[0057] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 139 μL (0.8 mmol, 1.0 equiv) of HMPA, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for five minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -20 °C for half an hour. Then, 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, followed by stirring for 10 minutes. The cold trap temperature was then lowered to -60 °C. Over the next 90 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -59 °C to -62 °C. After the addition was complete, the reaction was continued for 12 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 19%). The crude product showed a dr ratio of 7:1 according to NMR and an ee value of 97% according to HPLC.

[0058] Example 8

[0059] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 696 μL (4.0 mmol, 5.0 equiv) of HMPA, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -30 °C for 1 hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -50 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -50 °C throughout the addition. The reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature. The mixture was then cooled to room temperature, extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 18%). The crude product had a dr value of 20:1 as determined by NMR and an ee value of 99% as determined by HPLC (NMR spectrum as shown in Figure 1). Figure 7 (As shown).

[0060] Example 9

[0061] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 120 μL (0.8 mmol, 1.0 equiv) of DBU, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -30 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -60 °C throughout the addition. The reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature. The mixture was then cooled to room temperature, extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 25%). The crude product had a dr value of 13:1 as determined by NMR and an ee value of 99% as determined by HPLC.

[0062] Example 10

[0063] Under nitrogen protection, in a dry 50 mL Shrek tube, 152 mg (1.6 mmol, 2.0 equiv) of magnesium chloride, 298.6 mg (1.4 mmol, 1.76 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol (L1), 120 μL (0.8 mmol, 1.0 equiv) of TMEDA, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -30 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 60 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -80 °C. After the addition was complete, the reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 x 5 mL), and column chromatography yielded a clean product (yield 34%). The crude product had a dr value of 2:1 as determined by NMR and an ee value of 95% as determined by HPLC.

[0064] Example 11

[0065] Under nitrogen protection, in a dry 50 mL Shrek tube, 81.4 mg (1.9 mmol, 2.4 equiv) of lithium chloride, 492.7 mg (2.4 mmol, 3.0 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol (L1), 240 μL (1.6 mmol, 2.0 equiv) of TMEDA, and 6 mL of anhydrous tetrahydrofuran were added. The reaction flask was placed in a cold trap (-50 °C), and 0.88 mL (1.4 mmol) of a 1.6 M n-butyllithium solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -50 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -50 °C. After the addition was complete, the reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature. The mixture was then cooled to room temperature, extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 29%). The crude product had a dr value of 3:1 as determined by NMR and an ee value of 97% as determined by HPLC.

[0066] Example 12

[0067] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 600 μL (4.0 mmol, 5.0 equiv) of TMEDA, and 6 mL of anhydrous tetrahydrofuran were added. The reaction flask was placed in a cold trap (0 °C), and 0.88 mL (1.4 mmol) of a 1.6 M n-butyllithium solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -20 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 60 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -78 °C. After the addition was complete, the reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 28%). The crude product's dr value, determined by NMR, was 4:1, and its ee value, determined by HPLC, was 98% (NMR spectrum as shown). Figure 4 (As shown).

[0068] Example 13

[0069] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 0.88 mL (8.0 mmol, 10.0 equiv) of DABCO, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -10 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 60 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -78 °C. After the addition was complete, the reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 25%). The crude product had a dr value of 2:1 as determined by NMR and an ee value of 92% as determined by HPLC.

[0070] Example 14

[0071] Under nitrogen protection, in a dry 50 mL Shrek tube, add 59.1 mg (0.8 mmol, 1.0 equiv) of sodium chloride, 298.6 mg (1.4 mmol, 1.76 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol (L1), 176 μL (1.6 mmol, 2.0 equiv) of DABCO, and 6 mL of anhydrous tetrahydrofuran. Place the reaction flask in a cold trap (-20 °C), and slowly add 0.88 mL (1.4 mmol) of a 1.6 M n-butyllithium solution in n-hexane. After reacting for ten minutes, add dropwise 2.0 M... 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -20 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 60 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -50 °C. After the addition was complete, the reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 22%). The crude product had a dr value of 2:1 as determined by NMR and an ee value of 95% as determined by HPLC.

[0072] Example 15

[0073] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 40 μL (4.0 mmol, 5.0 equiv) of DABCO, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -30 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -78 °C. After the addition was complete, the reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 25%). The crude product had a dr ratio of 4:1 as determined by NMR and an ee value of 92% as determined by HPLC.

[0074] Example 16

[0075] Under nitrogen protection, in a dry 50 mL Shrek tube, 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), 98 mg (0.8 mmol, 1.0 equiv) of DMAP, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -20 °C for half an hour. Then, 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, followed by stirring for another 2 hours. The cold trap temperature was then lowered to -60 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -80 °C. After the addition was complete, the reaction was continued for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature. The mixture was then cooled to room temperature, extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (35% yield). The crude product had a dr ratio of 3:1 as determined by NMR and an ee value of 94% as determined by HPLC.

[0076] Example 17

[0077] Under nitrogen protection, in a dry 50 mL Shrek tube, 81.4 mg (1.9 mmol, 2.4 equiv) of lithium chloride, 232.4 mg (1.6 mmol, 2.0 equiv) of (3S,4R)-4-amino-2,5-dimethylhexanol (L2), 98 mg (0.8 mmol, 1.0 equiv) of DMAP, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -10 °C for half an hour. Then, 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, followed by stirring for another hour. The cold trap temperature was then lowered to -20 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -80 °C. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 37%). The crude product had a dr ratio of 4:1 as determined by NMR and an ee ratio of 91% as determined by HPLC.

[0078] Example 18

[0079] Under nitrogen protection, in a dry 50 mL Shrek tube, 81.4 mg (1.9 mmol, 2.4 equiv) of lithium chloride, 450.8 mg (2.0 mmol, 2.5 equiv) of (1S,2R)-2-amino-1,2-dicyclohexylethanol (L3), 14 μL (0.08 mmol, 0.1 equiv) of HMPA, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -10 °C for half an hour. Then, 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, followed by stirring for another hour. The cold trap temperature was then lowered to -20 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -80 °C. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 37%). The crude product had a dr value of 4:1 as determined by NMR and an ee value of 53% as determined by HPLC.

[0080] Example 19

[0081] Under nitrogen protection, in a dry 50 mL Shrek tube, 81.4 mg (1.9 mmol, 2.4 equiv) of lithium chloride, 82.1 mg (0.4 mmol, 0.5 equiv) of (1S,2R)-2-amino-1-cyclopentyl-2-phenylethanol (L4), 2.4 mL (16.0 mmol, 20.0 equiv) of TMEDA, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -10 °C for half an hour. Then, 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, followed by stirring for another hour. The cold trap temperature was then lowered to -20 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -80 °C. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 37%). The crude product had a dr value of 1:1 as determined by NMR and an ee value of 56% as determined by HPLC.

[0082] Example 20

[0083] Under nitrogen protection, in a dry 50 mL Shrek tube, 81.4 mg (1.9 mmol, 2.4 equiv) of lithium chloride, 231.9 mg (1.2 mmol, 1.5 equiv) of (1R,2S)-1-amino-3,3-dimethyl-1-phenylbutanol (L5), 98 mg (0.8 mmol, 1.0 equiv) of DMAP, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -10 °C for half an hour. Then, 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, followed by stirring for another hour. The cold trap temperature was then lowered to -20 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -80 °C. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 37%). The crude product had a dr value of 1:1 as determined by NMR and an ee value of 27% as determined by HPLC.

[0084] Example 21

[0085] Under nitrogen protection, in a dry 50 mL Shrek tube, 81.4 mg (1.9 mmol, 2.4 equiv) of lithium chloride, 149.3 mg (0.64 mmol, 0.8 equiv) of (1S,2R)-1-cyclopentyl-2-dimethylamino-2-phenylethanol (L6), 98 mg (0.8 mmol, 1.0 equiv) of DMAP, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -10 °C for half an hour. Then, 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, followed by stirring for another hour. The cold trap temperature was then lowered to -20 °C. Over the next 60 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -80 °C. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 34%). The crude product had a dr value of 1.6:1 as determined by NMR and an ee value of 49% as determined by HPLC.

[0086] Example 22

[0087] Under nitrogen protection, in a dry 50 mL Shrek tube, 180.9 mg (1.9 mmol, 2.4 equiv) of magnesium chloride, 574.8 mg (2.8 mmol, 3.5 equiv) of (1S,2R)-2-amino-1,2-di-p-fluorophenylethanol (L7), 98 mg (0.8 mmol, 1.0 equiv) of DMAP, and 6 mL of anhydrous tetrahydrofuran were added. 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 solution in n-hexane was slowly added. After reacting for ten minutes, 2.0 M N-butyllithium solution was added dropwise. 0.77 mL (1.4 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -10 °C for half an hour. Then, 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, followed by stirring for another hour. The cold trap temperature was then lowered to -20 °C. Over the next 60 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -80 °C. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (35% yield). The crude product had a dr value of 1.5:1 as determined by NMR and an ee value of 45% as determined by HPLC.

[0088] Example 23

[0089] Under nitrogen protection, in a dry 50 mL Shrek tube, add 1.3 mg (0.0096 mmol, 0.012 equiv) of zinc chloride, 0.6 mg (1.76 mmol, 2.2 equiv) of (1S,2R)-2-amino-1,2-di-m-methylphenylethanol (L8) 470.6 mg (1.76 mmol, 2.2 equiv), 98 mg (0.8 mmol, 1.0 equiv) of DMAP, and 6 mL of anhydrous tetrahydrofuran. Place the reaction flask in a cold trap (-10 °C), and slowly add 0.88 mL (1.4 mmol) of a 1.6 M n-butyllithium solution in n-hexane. After reacting for ten minutes, add dropwise 2.0 M... 0.5 mL (1.0 mmol) of LDA (tetrahydrofuran / n-heptane / ethylbenzene solution) was reacted at -10 °C for half an hour. Then, 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, followed by stirring for another hour. The temperature of the cold trap was then lowered to -20 °C. Over the next 60 minutes, 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of THF was slowly added, maintaining the reaction temperature at -80 °C. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. It was then extracted with ethyl acetate (3 × 5 mL) and column chromatography yielded a clean product (yield 33%). The crude product had a dr value of 2:1 as determined by NMR and an ee value of 78% as determined by HPLC.

[0090] Example 24

[0091] Under nitrogen protection, in a dry 50 mL Shrek tube, add 141.6 mg (1.9 mmol, 2.4 equiv) of potassium chloride, 674.4 mg (2.6 mmol, 3.2 equiv) of (1S,2R)-2-amino-1,2-di-o-methoxyphenylethanol (L9), and DMAP. Add 6 mL of 98 mg (0.8 mmol, 1.0 equiv) anhydrous tetrahydrofuran. Place the reaction flask in a cold trap (-10 °C) and slowly add 0.5 mL (0.8 mmol) of 1.6 M n-butyllithium in n-hexane. After reacting for ten minutes, add 0.4 mL (0.8 mmol) of 2.0 M bis(trimethylsilylamino)potassium (tetrahydrofuran solution) dropwise. After reacting for half an hour at -10 °C, slowly add 8 mL of 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in THF. The addition should be completed within one hour, and stirring should continue for 1 hour after the addition is complete. The cold trap temperature was then lowered to -20°C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone and 6 mL of THF was slowly added, maintaining the reaction temperature at -80°C during the addition. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. Extraction was performed with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 37%). The crude product showed a dr value of 1:1 according to NMR and an ee value of 57% according to HPLC.

[0092] Example 25

[0093] Under nitrogen protection, in a dry 50 mL Shrek tube, add 70.1 mg sodium chloride (1.2 mmol, 1.5 equiv), 685.6 mg (3.2 mmol, 4.0 equiv) of (1S,2S)-1,2-diphenylethane-1,2-diol (L10), 98 mg DMAP (0.8 mmol, 1.0 equiv), and 6 mL of anhydrous tetrahydrofuran. Place the reaction flask in a cold trap (-10 °C) and slowly add 1.6 mg of sodium chloride. 0.88 mL (1.4 mmol) of a tetrahydrofuran solution of M-tert-butyllithium was added dropwise after 10 minutes of reaction. Then, 0.8 mL (1.6 mmol) of 2.0 M bis(trimethylsilylamino) sodium (tetrahydrofuran solution) was added dropwise. After reacting at -10 °C for 30 minutes, 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 the addition was complete, stirring was continued for 1 hour. Then, the temperature of the cold trap was lowered to -20 °C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone in 6 mL of toluene was slowly added. The temperature of the reaction system was maintained at -80 °C during the addition. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with a saturated ammonium chloride solution at low temperature, and then extracted with ethyl acetate (3 × 5 mL) at room temperature. Column chromatography yielded a clean product (yield 39%). The crude product had a dr value of 1.8:1 as determined by NMR and an ee value of 61% as determined by HPLC.

[0094] Example 26

[0095] Under nitrogen protection, in a dry 50 mL Shrek tube, add 17.8 mg of calcium chloride (0.16 mmol, 0.2 equiv), 639.2 mg of (1S,2S)-2-methoxy-1,2-diphenyl-1-ethanol (L11) (2.8 mmol, 3.5 equiv), and DMAP. 98 mg (0.8 mmol, 1.0 equiv) of anhydrous tetrahydrofuran was added to a reaction flask in a cold trap (-10 °C). 0.88 mL (1.4 mmol) of 1.6 M sec-butyllithium in tetrahydrofuran was slowly added. After reacting for ten minutes, 1.3 mL (2.6 mmol) of 2.0 M bis(trimethylsilylamino)lithium (tetrahydrofuran solution) was added dropwise. After reacting for half an hour at -10 °C, 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 the addition was complete, stirring was continued for 1 hour. The cold trap temperature was then lowered to -20°C. Over the next 60 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone and 6 mL of ethylene glycol diethyl ether was slowly added, maintaining the reaction system temperature at -80°C during the addition. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. It was then extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 26%). The crude product had a dr value of 1:1 as determined by NMR and an ee value of 32% as determined by HPLC.

[0096] Example 27

[0097] Under nitrogen protection, in a dry 50 mL Shrek tube, 31.1 mg (0.24 mmol, 0.3 equiv) of anhydrous nickel chloride, 872.3 mg (3.6 mmol, 4.5 equiv) of (1S,2S)-1,2-dimethoxy-1,2-diphenylethane (L12), 440 μL (4.0 mmol, 5.0 equiv) of DABCO, and 6 mL of anhydrous tetrahydrofuran were added. The reaction flask was placed in a cold trap (-10 °C), and 0.4 mL (0.8 mmol) of 2.0 M LTMP (tetrahydrofuran solution) was slowly added. After reacting at -10 °C for half an hour, 262.6 mg (0.8 mmol, 1.0 equiv) of 3-benzyl-6-bromo-2-methoxyquinoline in 8 mL of THF solution was slowly added dropwise over one hour. After the addition was complete, stirring was continued for 1 hour. The cold trap temperature was then lowered to -20°C. Over the next 120 minutes, a solution of 212.8 mg (0.96 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthyl-1-propanone and 6 mL of 1,4-dioxane was slowly added, maintaining the reaction system temperature at -80°C during the addition. After the addition was complete, the reaction was continued for 4 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at low temperature, and the mixture was cooled to room temperature. It was then extracted with ethyl acetate (3 × 5 mL), and column chromatography yielded a clean product (yield 27%). The crude product had a dr value of 1:1 as determined by NMR and an ee value of 32% as determined by HPLC.

[0098] The above description is only of some embodiments of the present invention. It should be understood that the present invention is not limited to the specific embodiments described above. All equivalent changes and modifications made in accordance with the scope of the patent application of the present invention should be included in the scope of the present invention.

Claims

1. A chiral metal cooperative catalytic system for the synthesis of (1 R ,2 S )-bedaquiline, characterized in that, The lithium salt and other metal salt synergistically act, and a ligand and an additive are selected to form the double-chiral metal synergistic catalytic system; the source of the lithium salt is n-butyllithium and diisopropylaminolithium; the other metal salt is a metal halide, and the metal is Mg, Zn, Cu, Al, Ni, Co, Fe, Na, K, Ti, Ca or Li; the ligand is shown in formula L1 or L2: .

2. The bichiral metal co-catalyst system according to claim 1, characterized in that, The metal halide includes one or more of MgCl2, ZnCl2, CuCl2, AlCl3, NiCl2, CoCl2, FeCl3, NaCl, KCl, TiCl4, CaCl2, LiCl, LiBr, LiI, LiF.

3. The bichiral metal co-catalyst system according to claim 1, wherein The additive has the following structural formula: Organic bases, of which R 9 R 10 and R 11 H and C respectively 1-16 Straight-chain or branched alkyl, aryl, or C 3-7 cycloalkyl, aryl is R 12 Substituted phenyl, R 12 For H, C 1-6 Alkyl, halogen, C 1-6 Alkoxy or OCOR 13 ;R 13 C 1-6 Alkyl group; R 12 The substitution can be mono- or poly-substituted, and the polysubstituents can be the same or different; and R 9 R 10 and R 11 Similar, different, or mutually reinforcing.

4. The bichiral metal co-catalyst system according to claim 3, characterized in that, The organic base is selected from DBU, DBN, TMEDA, HMPA, DMAP, DABCO, TMP, DIPA, pyridine, pyrrolidine, adamantylamine, Spartaine or t BuNHSi(CH)3.

5. Use of the homochiral metal synergistic catalytic system according to any one of claims 1-4 in the synthesis of (1R,2R)-bedaquiline, characterized in that, R ,2 S )-bedaquiline, characterized in that, In the organic solution of the double chiral metal synergistic catalytic system formed by mixing the lithium salt, other metal salt, ligand and additive at the temperature of-78℃ to 0℃, slowly drop 6-bromo-3-benzyl-2-methoxyquinoline organic solution into the reaction, then continue to add 3- N , N -dimethylamino-1-naphthyl-1-propanone organic solution into the reaction, and the obtained product is separated and purified to obtain (1 R ,2 S )-bedaquiline.

6. Use according to claim 5, characterized in that, The amount of lithium salt is 1-5 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline; the amount of the other metal salt is 0.01-2.0 equivalents of dimethylamino-1-naphthyl-1-propanone; and the amount of additive is 0.1-20 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline. N , N -2.0 equivalents of dimethylamino-1-naphthyl-1-propanone; and the amount of additive is 0.1-20 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline.

7. Use according to claim 5, characterized in that, The organic solvent used in the organic solution is selected from a mixture of one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diisopropyl ether, ethylene glycol dimethyl ether, and toluene, xylene, ethylbenzene, n-hexane, cyclohexane, n-heptane, n-pentane.

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