A bimetallic synergistic promoter system and its application in the asymmetric synthesis of (R,S)-TBAJ-876

Abstract

The present invention discloses a bimetallic synergistic promotion system and its application in the asymmetric synthesis of (R, S)-TBAJ-876. Specifically, a metal lithium, sodium or potassium salt forms an amino metal compound with a chiral or achiral amine, and the amino metal compound and another metal form a synergistic promotion system. Under the action of a suitable ligand, the addition reaction of 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline and 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-acetone is synergistically promoted under low temperature conditions. This bimetallic synergistic promotion system has achieved the asymmetric synthesis of the anti-tuberculosis candidate drug (R, S)-TBAJ-876 with high yield and high selectivity for the first time.

Description

Technical Field

[0001] The present invention belongs to the technical field of asymmetric synthesis and relates to a bimetallic synergistic promotion system and its application in the asymmetric synthesis of (R, S)-TBAJ-876. The present invention particularly relates to the establishment of a bimetallic synergistic promotion system and the use of the system in the asymmetric synthesis of an anti-tuberculosis candidate drug (R, S)-TBAJ-876. Background Art

[0002] Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis. It ranks second in the incidence and mortality of legally reportable Class A and B infectious diseases. It is estimated that up to one-third of the world's population has dormant Mycobacterium tuberculosis lurking in their bodies, which is at risk of developing the disease at any time. The World Health Organization report shows that 1.6 million people worldwide were infected with tuberculosis in 2020. In addition, the incidence of drug-resistant tuberculosis is also increasing globally. In 2019, nearly 500,000 tuberculosis patients were resistant to rifampicin (RR-TB), of which 78% had developed multidrug-resistant tuberculosis (MDR-TB). The three countries with the highest incidence rates in the world are India (27%), China (14%) and Russia (8%). In 2005, Andries and his colleagues developed the first drug for the treatment of drug-resistant tuberculosis, bedaquiline fumarate (BDQ), with the structural formula:

[0003] In 2012, the US FDA accelerated its approval for marketing. The drug kills Mycobacterium tuberculosis by inhibiting its ATP synthase, becoming the first anti-TB drug with a new mechanism of action in nearly 40 years. It is also the first anti-tuberculosis drug specifically used for MDR-TB.

[0004] While the discovery and launch of BDQ, an anti-TB drug with a novel mechanism of action, marks a milestone in TB treatment, it also has significant drawbacks. Clinical data indicate that BDQ treatment for MDR-TB is associated with increased mortality and QT interval prolongation. Its high lipophilicity (log P7.25) not only facilitates binding to adipose tissue, thereby increasing the incidence of phospholipidosis, but also extends its terminal half-life to 5 to 6 months (Bioorganic & Medicinal Chemistry 2020, 28, 115-213). BDQ inhibits cardiac potassium hERG channels, leading to QT interval prolongation (delaying ventricular repolarization). This is particularly true when BDQ is used in combination with drugs such as fluoroquinolones and clofazimine, which may significantly increase cardiovascular adverse reactions and mortality. Therefore, the World Health Organization recommends the standardized promotion and implementation of regulatory measures for BDQ. Furthermore, strengthening the development of new drugs is essential. Recently, a series of studies have been conducted on second-generation BDQ analogues developed by the Tuberculosis Alliance, which are modified based on the diarylquinolone skeleton of BDQ. Compared with BDQ, these compounds have lower lipophilicity and lower hERG channel inhibition (Bioorganic & Medicinal Chemistry 2020, 28, 115213; Molecules 2020, 25, 1423; Bioorganic & Medicinal Chemistry 2019, 27, 1292; Antimicrobial Agents and Chemotherapy 2019, 63, e01191). In particular, TBAJ-876 has shown better medicinal potential ( Figure 1 ), and is currently undergoing Phase I clinical trials. Due to the difficulty of synthesizing its structure, the compound inventory required for Phase I clinical trials is far from sufficient. Therefore, the development of an efficient asymmetric synthesis method for TBAJ-876 is urgently needed.

[0005] TBAJ-876 has two chiral centers and four optical isomers. Clinical studies have shown that only (1R,2S)-TBAJ-876 is pharmaceutically active. To date, no asymmetric synthesis method has been reported to construct the chiral center of TBAJ-876 in a single step. The only existing synthetic route is relatively primitive, using chiral resolution to obtain the target compound with an overall yield of only 9%. Therefore, the development of more efficient methods for the synthesis of (1R,2S)-TBAJ-876 is necessary. Summary of the Invention

[0006] The purpose of the present invention is to develop a more efficient method for synthesizing (1R,2S)-TBAJ-876, and provide a bimetallic synergistic promotion system and its application in the asymmetric synthesis of (R,S)-TBAJ-876.

[0007] The object of the present invention is achieved through the following technical solutions:

[0008] In the first aspect, the present invention relates to a bimetallic synergistic promotion system for the asymmetric synthesis of the anti-tuberculosis candidate drug TBAJ-876. The bimetallic synergistic promotion system uses metallic lithium, sodium or potassium as the central metal, acts synergistically with other metals, and selects suitable ligands to form an efficient bimetallic synergistic promotion system; the ligands include amine ligands and chiral ether ligands.

[0009] As one embodiment of the present invention, the sources of metallic lithium, sodium and potassium ions are various salts.

[0010] As one embodiment of the present invention, sources of metallic lithium, sodium, and potassium ions include lithium carbonate, sodium carbonate, potassium carbonate, lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, potassium iodide, lithium fluoride, sodium fluoride, potassium fluoride, lithium acetate, sodium acetate, potassium acetate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium sulfate, sodium sulfate, potassium sulfate, n-butyl lithium, n-butyl sodium, n-butyl potassium, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium tetramethylpiperidinium, sodium tetramethylpiperidinium, potassium tetramethylpiperidinium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide.

[0011] As one embodiment of the present invention, an amine ligand is used to control metallic lithium, sodium or potassium ions to form lithium, sodium or potassium complexes.

[0012] As one embodiment of the present invention, the amine ligand is selected from the group consisting of A chiral or achiral amine, wherein R 1 、R 2 =C 1-16 A straight chain, branched or aromatic alkyl group, or C 3-7 Cycloalkyl, or three or less C 3-7 a cycloalkyl ring or a spiro ring; or R 1 and R 2 You can also R 3 Substituted phenyl, R 3 =H、C 1-6 Alkyl, halogen, C 1-6 Alkoxy, substituted phenyl or OCOR 4 , the halogen is F, Cl, Br or I, R 4 C1-6 The substituents on the benzene ring may be monosubstituted or polysubstituted, and the polysubstituted groups may be the same or different; R 1 and R 2 Can be the same or different.

[0013] As one embodiment of the present invention, the other metals are selected from sodium sulfate, NaH, sodium chloride, magnesium sulfate, magnesium acetate, magnesium chloride, zinc chloride, Zn(OTf)2, CuSO4, CuCl2, Cu(OTf)2, Yb(OTf)3, Bi(OTf)3, La(OTf)3, CaCl2, CaSO4, CaH2, CaO, lithium carbonate, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium acetate, lithium hydroxide, lithium sulfate, n-butyllithium, lithium diisopropylamide, lithium tetramethylpiperidinium, lithium hexamethyldisilazide, potassium chloride, and potassium sulfate.

[0014] As an embodiment of the present invention, the amine ligand and the chiral ether ligand are combined to activate the other metal; the chiral ether ligand has the structural formula

[0015] X, X' are selected from N atoms and O atoms, and X, X' may be the same or different;

[0016] R 1 、R 2 =C 1-16 A straight chain, branched or aromatic alkyl group, or C 3-7 Cycloalkyl, or three or less C 3-7 a cycloalkyl ring or a spiro ring; or R 1 and R 2 You can also R 3 Substituted phenyl, R 3 =H、C 1-6 Alkyl, halogen, C 1-6 Alkoxy, substituted phenyl or OCOR 4 , the halogen is F, Cl, Br or I, R 4 C 1-6 The substituents on the benzene ring may be monosubstituted or polysubstituted, and the polysubstituted groups may be the same or different; R 1 and R 2 Can be the same or different;

[0017] R 5 and R 6 C 1-6 Alkyl;

[0018] * indicates chirality, and the configuration can be RR, SS, RS or SR.

[0019] In a second aspect, the present invention relates to the use of a bimetallic synergistic promotion system in the asymmetric synthesis of the anti-tuberculosis drug candidate TBAJ-876.

[0020] In a third aspect, the present invention relates to a method for asymmetric synthesis of the anti-tuberculosis candidate drug TBAJ-876 using a bimetallic synergistic promotion system, wherein metallic lithium, sodium or potassium salts form amino metal compounds with chiral or achiral amine ligands, and the amino metal compounds and other metals form a synergistic promotion system, which, under the action of chiral ether ligands, synergistically promotes the addition reaction of 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline and 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone to obtain a mixed product of four optical isomers.

[0021] As one embodiment of the present invention, the amount of metallic lithium, sodium or potassium salt used is 0.1 to 5 equivalents of 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline.

[0022] As one embodiment of the present invention, the amount of other metals used is 0.01 to 5.0 times the equivalent of the metal lithium, sodium or potassium salt.

[0023] As one embodiment of the present invention, the amount of the amine ligand and the chiral ether ligand used is 0.1 to 5 equivalents of 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline, respectively, and the molar ratio of the amine ligand to the ether ligand is 1.0:0.1 to 5.0.

[0024] As an embodiment of the present invention, the molar ratio of 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline to 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone is 1:1.0-10.0.

[0025] As an embodiment of the present invention, the temperature of the addition reaction is -78 to 0°C.

[0026] As an embodiment of the present invention, the addition reaction time is 1 to 72 hours.

[0027] In one embodiment of the present invention, the solvent in the addition reaction includes one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diisopropyl ether, ethylene glycol dimethyl ether, toluene, xylene, n-hexane, cyclohexane, and n-pentane. The reaction is carried out at a low temperature of 0°C to -78°C using a commonly used polar or non-polar solvent in the laboratory for 1-20 hours to form a synergistic promotion system.

[0028] As one embodiment of the present invention, a bimetallic synergistic promotion system is established, and an amine forms an amino metal salt under the action of an organic base. The organic base is selected from one of n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium tetramethylpiperidinium, lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide, and can also be a reactant of various amines and butyl lithium. The amount of the organic base used is 0.1 to 5 times the equivalent of the amine.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] In the absence of a chiral inducing agent, the ratio of the two pairs of diastereomers is 1:2. In the present invention, a bimetallic synergistic promotion system is used for the first asymmetric synthesis of the anti-tuberculosis candidate drug (R,S)-TBAJ-876, with its dr value increased to 1:1 and er as high as 88:12. The total yield of the target compound (R,S)-TBAJ-876 is as high as 34%. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings:

[0032] Figure 1 Schematic diagram comparing the medicinal potential of BDQ and TBAJ-876;

[0033] Figure 2 is the asymmetric synthesis reaction scheme of the present invention;

[0034] Figure 3 Schematic diagram of the structure of chiral amine ligands (L1) to (L25);

[0035] Figure 4 Schematic diagram of the structures of achiral amine ligands (L26) to (L45);

[0036] Figure 5 Schematic diagram of the structures of ether ligands (L46) to (L53);

[0037] Figure 6 is the H NMR spectrum of the product TBAJ-876;

[0038] Figure 7 This is the NMR spectrum with a dr value (dr[(R,S)+(S,R)]:[(R,R)+(S,S)]) of 1:1. DETAILED DESCRIPTION

[0039] 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 are not intended to limit the present invention in any form. It should be noted that, for those skilled in the art, several variations and improvements can be made without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0040] The method for asymmetric synthesis of (R, S)-TBAJ-876 by a bimetallic synergistically promoted system of the present invention has the following reaction scheme: Figure 2 As shown, it can also be expressed by the following reaction formula:

[0041]

[0042] In the above reaction formula, “M 1 " represents metallic lithium, sodium, and potassium ions. In the bimetallic synergistic promotion system of the present invention, it is preferred to select one from lithium carbonate, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium acetate, lithium hydroxide, lithium sulfate, etc., as well as n-butyl lithium, lithium diisopropylamide, lithium tetramethylpiperidinium, lithium hexamethyldisilazide, etc. as the source of metallic lithium ions, and select one from the corresponding sodium salts and potassium salts as the source of metallic sodium and potassium ions.

[0043] In the above reaction formula, "La" represents the amine ligand that activates the metal lithium ion in the bimetallic synergistic promotion system, and its structural formula is A chiral or achiral amine, wherein R 1 、R 2 =C 1-16 A straight chain, branched or aromatic alkyl group, or C 3-7 Cycloalkyl, or three or less C 3-7 a cycloalkyl ring or a spiro ring; or R 1 and R 2 You can also R 3 Substituted phenyl, R 3 =H、C 1-6 Alkyl, halogen, C 1-6 Alkoxy, substituted phenyl or OCOR 4 ; The halogen is F, Cl, Br or I; R 4 C 1-6 The substituents on the benzene ring may be monosubstituted or polysubstituted, and the polysubstituted groups may be the same or different; R 1 and R 2 Preferably, the chiral amine in the amine-ether system is selected from Figure 3 Any one of the ligands (L1) to (L25) shown, preferably, the non-chiral amine in the amine-ether system is selected from Figure 4Any one of the ligands (L26) to (L45) shown.

[0044] In the above reaction formula, “Lb” represents the chiral ether ligand in the bimetallic synergistic promotion system, and its structural formula is Where X is a N atom or an O atom, and can be a nitrogen atom or an oxygen atom at the same time, or a nitrogen atom and an oxygen atom respectively. 1 、R 2 =C 1-16 A straight chain, branched or aromatic alkyl group, or C 3-7 Cycloalkyl, or three or less C 3-7 a cycloalkyl ring or a spiro ring; or R 1 and R 2 You can also R 3 Substituted phenyl, R 3 =H、C 1-6 Alkyl, halogen, C 1-6 Alkoxy, substituted phenyl or OCOR 4 ; The halogen is F, Cl or Br; R 4 C 1-6 The substituents on the benzene ring may be monosubstituted or polysubstituted, and the polysubstituted groups may be the same or different; R 1 and R 2 Can be the same or different. 5 and R 6 C 1-6 * indicates chirality, which can be RR, SS, RS or SR. Figure 5 Any one of the ligands (L46) to (L53) shown participates in the reaction.

[0045] In the above reaction formula, “M 2 " represents another metal that acts synergistically with the metal lithium ion in the bimetallic synergistic promotion system of the present invention, and the other metal is sodium sulfate, NaH, sodium chloride, magnesium sulfate, magnesium acetate, magnesium chloride, zinc chloride, Zn(OTf)2, CuSO4, CuCl2, Cu(OTf)2, Yb(OTf)3, Bi(OTf)3, La(OTf)3, CaCl2, CaSO4, CaH2, CaO, lithium carbonate, lithium chloride, lithium bromide, lithium iodide, lithium fluoride, lithium acetate, lithium hydroxide, lithium sulfate, n-butyl lithium, lithium diisopropylamide, lithium tetramethylpiperidinium, lithium hexamethyldisilazide, potassium chloride, potassium sulfate, etc., and its amount is 0.01 to 1.0 times the equivalent of the central metal salt.

[0046] In the above reaction formula, "Solvent" represents a solvent. In the method of synthesizing TBAJ-876 by synergistic promotion of bimetallic compounds of the present invention, there is no particular limitation on the solvent, as long as the solvent can cause the reaction to occur and obtain the target product. However, from the perspective of reaction yield and enantioselectivity and diastereoselectivity of the reaction, 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, and toluene, xylene, p-xylene, o-xylene, m-xylene, n-hexane, cyclohexane, n-pentane, etc., or a mixed solvent. After screening, it was found that the best results were obtained by using anhydrous toluene as the reaction solvent.

[0047] The present invention does not particularly limit the reaction time and reaction temperature. Considering the reaction yield and the selectivity of the target product, the reaction temperature can be preferably set to a low temperature of -78°C to 0°C, the reaction time can be set to 1 to 96 hours, the preferred bimetallic synergistic promotion system generation time is 30 to 120 minutes, and the raw material reaction time is 1 to 24 hours.

[0048] In the following examples, the enantiomeric excess percentage (i.e., ee value) was measured by HPLC (chiral column). The instrument used for HPLC analysis was LC-2010 from Shimadzu Corporation, and the specific operating conditions were: using Chiralpak AD-H chiral chromatographic column produced by Daicel Corporation of Japan. In the examples of the present invention, the instrument used for NMR analysis was Bruker ADVANCE III HD 400 (400 MHz, 1 H; 100MHz, 13 C).

[0049] Example 1

[0050] Under nitrogen protection, 1.5 mL of redistilled toluene and L7 (R, R)-bis-(1-phenylethyl)amine (0.30 mmol, 1.5 equiv., 67.6 mg) and CuSO4 (0.30 mmol, 1.5 equiv., 47.9 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and 1.6 M n-butyllithium in n-hexane solution (0.30 mmol, 1.5 equiv., 0.19 mL) was added and maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours, and then 5 mL of saturated aqueous ammonium chloride was added to the reaction system. The mixture was extracted with ethyl acetate (5 mL × 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 80%. The crude product was measured by nuclear magnetic resonance (NMR) with a dr value of 1:1.8. The product was isolated on a thick preparative plate (NMR hydrogen spectrum as shown in FIG. Figure 6 The ee value of the product was 40% as determined by HPLC.

[0051] Example 2

[0052] Under nitrogen protection, 1.5 mL of redistilled toluene, L7(R,R)-bis-(1-phenylethyl)amine (0.30 mmol, 1.5 equiv., 67.6 mg), and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L48 (S,S)-1,2-dipropoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 89.5 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C, and 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-yl)-1-oxo-2-oxo-1-oxo-2-oxo-1-oxo-2-oxo-2-oxo-3-nitropropene) (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 60%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.5. The product was isolated by thick preparative plate, and the ee value of the product was 15% by HPLC.

[0053] Example 3

[0054] Under nitrogen protection, 1.5 mL of redistilled toluene and L7(R,R)-bis-(1-phenylethyl)amine (0.30 mmol, 1.5 equiv., 67.6 mg) and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube and kept at -20°C. Then, a 1.6 M n-butyllithium n-hexane solution (0.30 mmol, 1.5 equiv., 0.19 mL) was added and kept at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L49 (S, S)-1,2-dibenzyloxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 118.4 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -78 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-[4-(2-[2 ...

[0055] Example 4

[0056] Under nitrogen protection, 1.5 mL of redistilled toluene and L7 (R, R)-bis-(1-phenylethyl)amine (0.30 mmol, 1.5 equiv., 67.6 mg) and NaCl (0.30 mmol, 1.5 equiv., 17.5 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and then a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added and maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L50 (S,S)-1-methoxy-2-propoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 81.1 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -50 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-[4-(2-[2-( ...

[0057] Example 5

[0058] Under nitrogen protection, 1.5 mL of redistilled toluene, L7(R,R)-bis-(1-phenylethyl)amine (0.30 mmol, 1.5 equiv., 67.6 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L51 (R)-2,2′-dimethoxy-1,1′-binaphthyl (0.30 mmol, 1.5 equiv., 94.3 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -78°C, and 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-yl)-1-nitropropene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 88%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:2.2. The product was isolated by thick preparative plate, and the ee value of the product was 36% by HPLC.

[0059] Example 6

[0060] Under nitrogen protection, 1.5 mL of redistilled toluene and L1(R)-1-(4-methoxyphenyl)ethyl)-2-propylamine (0.30 mmol, 1.5 equiv., 58.0 mg) and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -10°C, and a 1.6 M n-butyllithium n-hexane solution (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -10°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -10°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S, S)-1,2-dimethoxy-1,2-diphenylethane (0.50 mmol, 2.5 equiv., 121.2 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-oxo-2-oxo-1-yl)-1-nitropropene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours, and then 5 mL of saturated aqueous ammonium chloride was added to the reaction system. The mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 53%. The crude product had a dr value of 1:1.7 by nuclear magnetic resonance. The product was isolated by thick preparative plate, and the ee value of the product was 14% by high-performance liquid chromatography.

[0061] Example 7

[0062] Under nitrogen protection, 1.5 mL of redistilled toluene, L4(R)-N-(1-phenylethyl)cyclohexylamine (0.30 mmol, 1.5 equiv., 61.0 mg), and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -30°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -30°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-oxo-2-oxo-1-yl)-1,2-dihydro ...

[0063] Example 8

[0064] Under nitrogen protection, 1.5 mL of redistilled toluene, L6(R)-N-(1-phenylethyl)-2-naphthylamine (0.20 mmol, 1.0 equiv., 49.5 mg), and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -30°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -30°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -30°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S, S)-1,2-dimethoxy-1,2-diphenylethane (0.20 mmol, 1.0 equiv., 48.5 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-oxo-1-yl)-1-nitropropene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 81%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.6. The product was isolated by thick preparative plate, and the ee value of the product was 35% by HPLC.

[0065] Example 9

[0066] Under nitrogen protection, 1.5 mL of redistilled toluene, L8(R,R)-bis-(1-phenylpropyl)amine (0.30 mmol, 1.5 equiv., 76.0 mg), and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -40°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -30°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -40°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-oxo-1-yl)-1-nitropropene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 89%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.4. The product was isolated by thick preparative plate, and the ee value of the product was 35% by HPLC.

[0067] Example 10

[0068] Under nitrogen protection, 1.5 mL of redistilled toluene, L9(R,R)-bis-1-(4-methoxyphenylethyl)amine (0.30 mmol, 1.5 equiv., 85.6 mg), and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -40°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -40°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -40°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-yl)-1-nitropropene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 97%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.5. The product was isolated by thick preparative plate, and the ee value of the product was 25% by HPLC.

[0069] Example 11

[0070] Under nitrogen protection, 1.5 mL of redistilled toluene and L11(R)-2-methyl-1-phenyl-((R)-1-phenylethyl)-1-propylamine (0.30 mmol, 1.5 equiv., 76.0 mg) and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-2-oxo-1-yl)-1-piperidin-1-yl)propene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 60%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:2.3. The product was isolated by thick preparative plate, and the ee value of the product was 18% by HPLC.

[0071] Example 12

[0072] Under nitrogen protection, 1.5 mL of redistilled toluene, L12(R,R)-bis-(1-naphthylethyl)amine (0.30 mmol, 1.5 equiv., 97.7 mg), and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-2-oxo-1-yl)-1-piperidin-2-yl)-1-nitropropene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 88%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.7. The product was isolated by thick preparative plate, and the ee value of the product was 43% by HPLC.

[0073] Example 13

[0074] Under nitrogen protection, 1.5 mL of redistilled toluene, L14(R)-1-((1R,3R,5R,7R)-2-adamantyl)-N-((1R)-1-phenylethyl)-1-ethanamine (0.30 mmol, 1.5 equiv., 85.1 mg), and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a -20°C cold bath, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinyl)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-oxo-2-oxo-1-yl)propene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 80%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.8. The product was isolated by thick preparative plate, and the ee value of the product was 40% by HPLC.

[0075] Example 14

[0076] Under nitrogen protection, 1.5 mL of redistilled toluene, L15 (R)-1-(4-methoxyphenyl)-N-((R)-1-phenylpropyl)-1-propylamine (0.30 mmol, 1.5 equiv., 85.0 mg), and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours, and then 5 mL of saturated aqueous ammonium chloride was added to the reaction system. The mixture was extracted with ethyl acetate (5 mL × 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 73%. The dr value of the crude product was 1:1 as measured by nuclear magnetic resonance (NMR) (H-spectroscopy). Figure 7 ), the product was separated from the thick preparative plate, and the ee value of the product was determined to be 35% by high performance liquid chromatography.

[0077] Example 15

[0078] Under nitrogen protection, 1.5 mL of redistilled toluene, L16(R,R)-N,N-bis(1R,3R,5R,7R)-(2-adamantyl)-1,2-diphenylethyldiamine (0.30 mmol, 1.5 equiv., 144.2 mg), and MgSO4 (0.30 mmol, 1.5 equiv., 36.1 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a -20°C cold bath, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinyl)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-yl)-1-oxo-2-oxo-1-oxo-2-oxo-3-nitropropene) (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 70%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.3. The product was isolated by thick preparative plate, and the ee value of the product was 35% by HPLC.

[0079] Example 16

[0080] Under nitrogen protection, 1.5 mL of redistilled toluene, L17(R)-N-(2-methylphenyl)-1-phenylethylamine (0.30 mmol, 1.5 equiv., 67.6 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-2-oxo-1-yl)-1-piperidin-1-yl)propene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 84%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.6. The product was isolated by thick preparative plate, and the ee value of the product was 39% by HPLC.

[0081] Example 17

[0082] Under nitrogen protection, 1.5 mL of redistilled toluene, L20(1R,3R,5R,7R)-N-((R)-1-phenylethyl)-2-adamantylamine (0.30 mmol, 1.5 equiv., 76.6 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a -20°C cold bath, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-[4-(2-[2-( ...

[0083] Example 18

[0084] Under nitrogen protection, 1.5 mL of redistilled toluene, L21(1R,3R,5R,7R)-N-((R)-2-naphthylethyl)-2-adamantylamine (0.30 mmol, 1.5 equiv., 91.6 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a -20°C cold bath, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinium)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-yl)-1-oxo-2-oxo-1-oxo-2-oxo-1-oxo-2-oxo-2-oxo-3-nitropropene) (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 59%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.4. The product was isolated by thick preparative plate, and the ee value of the product was 57% by HPLC.

[0085] Example 19

[0086] Under nitrogen protection, 1.5 mL of redistilled toluene, L23(1R)-N-((7-methoxy-2,3-dihydro-1H-1-indenyl)-1-phenylpropyl)amine (0.30 mmol, 1.5 equiv., 88.6 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added and maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridinyl)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-oxo-2-oxo-1-yl)propene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 80%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.8. The product was isolated by thick preparative plate, and the ee value of the product was 40% by HPLC.

[0087] Example 20

[0088] Under nitrogen protection, 1.5 mL of redistilled toluene and L24(R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (0.30 mmol, 1.5 equiv., 62.8 mg) and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A, 0.20 mmol, 1.0 equiv., 83.6 mg) and diether ligand L46 (S,S)-1,2-dimethoxy-1,2-diphenylethane (0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) were reacted for one hour, and the temperature of the reaction system was lowered to -60 ° C. 3-N,N-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone (RM A solution of 1,4-dihydroxy-2-(2-(2-hydroxy-3-oxo-1-oxo-2-oxo-1-yl)propene (B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL) was reacted for 3-5 hours. Then, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. TBAJ-876 and its diastereomers were quickly separated by column chromatography. The yield of the product was 80%. Nuclear magnetic resonance (NMR) measurement of the crude product showed a dr value of 1:1.8. The product was isolated by thick preparative plate, and the ee value of the product was 40% by HPLC.

[0089] Example 21

[0090] Under nitrogen protection, 1.5 mL of redistilled toluene, L28 (0.6 mmol, 3.0 equiv., 34.5 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of a ligand (A, 0.20 mmol, 1.0 equiv., 83.6 mg) and a diether ligand (L46, 0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 85%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:1.8. The product was isolated by thick preparative plate, and the ee value of the product was 35% by HPLC.

[0091] Example 22

[0092] Under nitrogen protection, 1.5 mL of redistilled toluene, L29 (0.3 mmol, 1.5 equiv., 38.7 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of a ligand (A, 0.20 mmol, 1.0 equiv., 83.6 mg) and a diether ligand (L46, 0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 68%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:1.7. The product was isolated by thick preparative chromatography, and the ee value of the product was 30% by HPLC.

[0093] Example 23

[0094] Under nitrogen protection, 1.5 mL of redistilled toluene, L30 (0.3 mmol, 1.5 equiv., 44.1 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and then a 1.6 M n-butyllithium n-hexane solution (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of a ligand (A, 0.20 mmol, 1.0 equiv., 83.6 mg) and a diether ligand (L46, 0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 72%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:2. The product was isolated by thick preparative chromatography, and the ee value of the product was 40% by HPLC.

[0095] Example 24

[0096] Under nitrogen protection, 1.5 mL of redistilled toluene, L31 (0.3 mmol, 1.5 equiv., 29.1 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium n-hexane solution (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of 1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 80%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:1.5. The product was isolated by thick preparative chromatography, and the ee value of the product was 9% by HPLC.

[0097] Example 25

[0098] Under nitrogen protection, 1.5 mL of redistilled toluene, L32 (0.3 mmol, 1.5 equiv., 38.8 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and then a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of a ligand (A, 0.20 mmol, 1.0 equiv., 83.6 mg) and a diether ligand (L46, 0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 66%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:1.7. The product was isolated by thick preparative chromatography, and the ee value of the product was 35% by HPLC.

[0099] Example 26

[0100] Under nitrogen protection, 1.5 mL of redistilled toluene, 2,2,6,6-tetramethylpiperidine (L38, 0.3 mmol, 1.5 equiv., 50.6 μL), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of a ligand (A, 0.20 mmol, 1.0 equiv., 83.6 mg) and a diether ligand (L46, 0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 86%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:1. The product was isolated by thick preparative chromatography, and the ee value of the product was 76% as determined by HPLC.

[0101] Example 27

[0102] Under nitrogen protection, 1.5 mL of redistilled toluene, L41 (0.3 mmol, 1.5 equiv., 46.6 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of a ligand (A, 0.20 mmol, 1.0 equiv., 83.6 mg) and a diether ligand (L46, 0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 85%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:1.4. The product was isolated by thick preparative chromatography, and the ee value of the product was 48% by HPLC.

[0103] Example 28

[0104] Under nitrogen protection, 1.5 mL of redistilled toluene, L45 (0.3 mmol, 1.5 equiv., 50.2 mg), and Na2SO4 (0.30 mmol, 1.5 equiv., 42.6 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and a 1.6 M n-butyllithium solution in n-hexane (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of a ligand (A, 0.20 mmol, 1.0 equiv., 83.6 mg) and a diether ligand (L46, 0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 86%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:1.3. The product was isolated by thick preparative chromatography, and the ee value of the product was 42% by HPLC.

[0105] Example 29

[0106] Under nitrogen protection, 1.5 mL of redistilled toluene, 141.6 mg (1.9 mmol, 2.4 equiv) of potassium chloride and L45 (0.3 mmol, 1.5 equiv., 50.2 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and then a 1.6 M n-butyllithium n-hexane solution (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was kept at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of a ligand (A, 0.20 mmol, 1.0 equiv., 83.6 mg) and a diether ligand (L46, 0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 87%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:1.5. The product was isolated by thick preparative chromatography, and the ee value of the product was 41% by HPLC.

[0107] Example 30

[0108] Under nitrogen protection, 1.5 mL of redistilled toluene, 70.1 mg (1.2 mmol, 1.5 equiv) of sodium chloride, and L45 (0.3 mmol, 1.5 equiv., 50.2 mg) were added to a dry 25 mL Shrek tube. The reaction was placed in a low-temperature bath at -20°C, and then a 1.6 M n-butyllithium n-hexane solution (0.30 mmol, 1.5 equiv., 0.19 mL) was added. The temperature was maintained at -20°C. After one hour of reaction, the in situ generated lithium ammonia base was added to 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline (RM) at -20°C. A solution of a ligand (A, 0.20 mmol, 1.0 equiv., 83.6 mg) and a diether ligand (L46, 0.30 mmol, 1.5 equiv., 73.0 mg) in toluene (2.0 mL) was reacted for one hour, followed by the addition of a solution of 3-N,N-dimethylamino-1-(2,6-dimethoxypyridinyl)-1-propanone (RM B, 0.24 mmol, 1.2 equiv., 72.0 mg) in toluene (1.5 mL). After three hours of reaction, 5 mL of saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and TBAJ-876 and its diastereomers were rapidly separated by column chromatography. The yield of the product was 90%. Nuclear magnetic resonance analysis of the crude product showed a dr value of 1:1.6. The product was isolated by thick preparative plate, and the ee value of the product was 39% by HPLC.

[0109] The above description only describes 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 within the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. A bimetallic synergistic promoter system for asymmetric synthesis of the anti-tuberculosis drug candidate TBAJ-876, characterized in that: The bimetallic synergistic promotion system uses lithium as the central metal, synergistically acts with other metals, and selects appropriate ligands to form a bimetallic synergistic promotion system; the ligands include amine ligands and chiral ether ligands; The source of metallic lithium ions is n-butyl lithium; The other metals are selected from sodium sulfate, sodium chloride, magnesium sulfate, magnesium acetate, magnesium chloride, zinc chloride, CuSO4, CuCl2, CaCl2, CaSO4, potassium chloride, and potassium sulfate; Amine ligands are used to control metallic lithium ions to form lithium complexes; the amine ligands are selected from the following structural formulas: ； The amine ligand and the chiral ether ligand are combined to activate the other metal; the chiral ether ligand is selected from the following structural formula: 。 2. Use of the bimetallic synergistic promotion system as claimed in claim 1 in the asymmetric synthesis of the anti-tuberculosis drug candidate (R, S)-TBAJ-876.

3. A method for asymmetric synthesis of the anti-tuberculosis drug candidate (R, S)-TBAJ-876 using the bimetallic synergistic promotion system as claimed in claim 1, characterized in that: The metal lithium salt forms an amino metal compound with a chiral or non-chiral amine ligand. The amino metal compound and other metals form a synergistic promotion system. Under the action of the chiral ether ligand, the synergistic promotion system promotes the 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline and 3- N , N -dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone addition reaction to obtain a mixed product of four optical isomers.

4. The method according to claim 3, characterized in that The amount of the metal lithium salt used is 0.1 to 5 equivalents of 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline; the amount of other metals used is 0.01 to 5.0 equivalents of the metal lithium salt; the amounts of the amine ligand and the chiral ether ligand used are respectively 0.1 to 5 equivalents of 6-bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline.

5. The method according to claim 3, characterized in that 6-Bromo-3-(2,3,6-trimethoxypyridine)-2-methoxyquinoline and 3- N , N The molar ratio of 1-dimethylamino-1-(2,6-dimethoxypyridine)-1-propanone is 1:1.0~10.

0.

6. The method according to claim 3, characterized in that The temperature of the addition reaction is -78 to 0°C, and the time is 1 to 72 hours; the solvent in the addition reaction includes one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diisopropyl ether, ethylene glycol dimethyl ether, toluene, xylene, n-hexane, cyclohexane, and n-pentane.

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