Method for selectively synthesizing bedaquiline

Abstract

The invention discloses a method for selectively synthesizing Bedaquiline, belongs to the technical field of medicine synthesis, and relates to a method for selectively synthesizing Bedaquiline, in a key reaction for synthesizing Bedaquiline, (I) an alkaline metal lithium salt catalyst is used, and 6-bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthyl-1-acetone (2) are catalyzed by the catalyst to react to obtain a product (3). Therefore, the conversion rate and diastereoselectivity of the reaction are improved, and the purpose of improving the overall yield is finally achieved. Reaction formula as follows: # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and specifically provides a method for selectively synthesizing bedaquiline. Background Art

[0002] Bedaquiline fumarate was developed by Johnson & Johnson Pharmaceutical Company and was approved by the US FDA for marketing in December 2012 (trade name Sirturo), and is a drug for treating drug-resistant tuberculosis. The chemical name of bedaquiline fumarate is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol fumarate, and its chemical structural formula is shown as follows:

[0003]

[0004] Bedaquiline inhibits the ATP synthase of Mycobacterium tuberculosis, preventing Mycobacterium tuberculosis from using ATP to generate energy, thereby playing an antituberculosis role. This drug has become the first antituberculosis drug with a completely new mechanism of action in the past more than 50 years, and is also the first drug specifically used to treat drug-resistant tuberculosis. The time for its 50% cure rate is 13 weeks, and the time for its 80% cure rate is 6 months. Compared with combination drug use (2-4 drugs), the cure rate of this drug has been greatly improved, and the treatment cycle has been greatly shortened.

[0005] The bedaquiline molecule contains two chiral centers. Therefore, the chemical synthesis of bedaquiline under non-chiral induction conditions will produce four isomers, namely (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol (A), (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol (A'), (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol (B) and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol (B'). A and A' have an enantiomeric relationship with each other, and B and B’ have an enantiomeric relationship with each other. A (A') and B (B') have a diastereomeric relationship with each other.

[0006] Among the four isomers, the (1R,2S) isomer (A) has the best inhibitory effect on Mycobacterium tuberculosis (IC 90 value is 0.03) and is the medicinal configuration.

[0007]

[0008] The original research company (US2005148581, CN101180302B) disclosed a synthesis method: First, using p-bromoaniline and phenylpropionyl chloride as raw materials, 6-bromo-3-benzyl-2-methoxyquinoline was obtained through acylation, cyclization, and substitution reactions. Under the action of lithium diisopropylamide, 6-bromo-3-benzyl-2-methoxyquinoline and 3-dimethylamino-1-naphthalen-1-one reacted at low temperature (-72 to -78 °C) to form a mixture of four isomers of bedaquiline. After chiral reagent resolution, (1R,2S)-bedaquiline was obtained, and the yield of the last step was only about 7-9%, and the other three isomers were discarded, resulting in a large amount of material waste.

[0009] The main synthesis steps are as follows:

[0010]

[0011] The synthesis method reported in the original research patent generates four isomers without selectivity and has a low reaction conversion rate, resulting in a very low yield of bedaquiline. Therefore, if we want to significantly improve the yield of bedaquiline, we must increase the reaction conversion rate and selectivity.

[0012] Among them, the selectivity of the reaction can be expressed by the enantiomeric excess (ee) and the ratio of diastereomers (dr). The terms enantiomeric excess and the ratio of diastereomers are well-known to professionals in stereochemistry. The enantiomeric excess can be calculated by the formula ee = ([A] - [A'] / [A] + [A']) * 100%, and the ratio of diastereomers is expressed by the formula dr = ([A] + [A'] / [B] + [B']) * 100%. Summary of the Invention

[0013] In view of this, the purpose of the present invention is to provide a method for selectively synthesizing bedaquiline that can significantly improve the reaction conversion rate, aiming to solve the problems of low conversion rate and high production cost of bedaquiline in the prior art.

[0014] To achieve the above purpose, the present invention provides the following technical solutions:

[0015] The present invention provides a method for selectively synthesizing bedaquiline, including the following steps:

[0016] Add an alkaline metal lithium salt catalyst, an organic amine, and n-butyllithium to an organic solvent to prepare a mixture, and add 6-bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthalen-1-one (2) to the mixture for reaction to obtain the product (3). The reaction formula is as follows:

[0017]

[0018] The basic metal lithium salt catalyst is selected from one or more combinations of lithium methoxide, lithium ethoxide, lithium hydroxide, lithium sulfate, lithium carbonate, lithium phosphate, C 1-12 alkyl carboxylate lithium and C 1-12 alkoxy lithium, preferably one of lithium methoxide, lithium ethoxide, tert-butyl lithium, lithium hydroxide, lithium carbonate, and lithium phosphate.

[0019] Furthermore, the reaction temperature is -40 to -80 °C.

[0020] Furthermore, the preparation method of the mixed solution includes: adding the basic metal lithium salt catalyst to the organic solvent, and then adding the organic amine and n-butyllithium under nitrogen protection and at a low temperature of -40 to -80 °C to prepare an organic amine lithium salt.

[0021] Furthermore, a solution of 6-bromo-3-benzyl-2-methoxyquinoline (1) is added dropwise to the mixture, and then a solution of 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) is added.

[0022] Furthermore, the organic amine is one of piperidine, pyrrolidine, diisopropylamine, diethylamine, dimethylamine, and morpholine.

[0023] Furthermore, the solvent is one of tetrahydrofuran, diethyl ether, methyltetrahydrofuran, toluene, dioxane, dimethyldiethylether, diethyldiethylether, and methyl tert-butyl ether, preferably one of tetrahydrofuran, diethyl ether, methyltetrahydrofuran, and toluene.

[0024] Furthermore, the dosage of the organic amine is 0.5 to 2 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (1).

[0025] Furthermore, the dosage of the basic metal lithium salt catalyst is 1 to 3 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (1).

[0026] The preparation method of bedaquiline in this scheme includes the following steps:

[0027] (1) Adding a basic metal lithium salt catalyst to an organic solvent, and then adding an organic amine and n-butyllithium under nitrogen protection and at a low temperature of -40 to -80 °C to prepare an organic amine lithium salt;

[0028] (2) Adding dropwise a solution of 6-bromo-3-benzyl-2-methoxyquinoline to obtain the corresponding diarylmethyllithium complex;

[0029] (3) Subsequently, adding a solution of 3-dimethylamino-1-naphthalen-1-yl-propan-1-one to generate a mixture of 4 isomers (A and A'; B and B'), where the required isomers A and A' are the main products;

[0030] (4) After the reaction is completed, the organic phase is concentrated under reduced pressure to dryness, slurried with ethanol to obtain the crude bedaquiline, and the crude product is purified by a resolution method to obtain bedaquiline with high optical purity and chemical purity, which can be used to prepare bedaquiline fumarate.

[0031] The beneficial effects of the present invention are as follows:

[0032] 1. After using an alkaline metal lithium salt catalyst such as lithium hydroxide, the diastereoselectivity and conversion rate of the reaction are significantly improved (dr = 8:1, conversion rate is 86%); without adding lithium hydroxide, the dr of the reaction is 1.2:1 and the conversion rate is 50%. In contrast, there are fewer diastereoisomers in the reaction solution, and after simple washing, it can be directly subjected to resolution treatment, ultimately resulting in a higher overall yield of bedaquiline.

[0033] 2. The alkaline metal lithium salt catalyst such as lithium hydroxide is commercially available and inexpensive, and significantly improves the reaction effect, making it suitable for large-scale industrial production.

[0034] Other advantages, objectives, and features of the present invention will be described to some extent in the subsequent specification, and to some extent, will be obvious to those skilled in the art based on the examination and research of the following text, or can be taught from the practice of the present invention. The objectives and other advantages of the present invention can be achieved and obtained through the following specification. Specific Embodiments

[0035] The present invention will be further clarified below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. After reading the present invention, various equivalent modifications made by those skilled in the art to the present invention fall within the scope defined by the appended claims of this application.

[0036] The following measurement methods are generally applicable to each embodiment of the present invention.

[0037] 1. Purity Analysis

[0038] The purity of the product is determined using a high-performance liquid chromatograph SHIMADZU DGU-20A3R. The chromatographic column model is Shim-pack GIS C18 (250x4.6mm, 5um). Mobile phase A is 0.1% phosphoric acid aqueous solution, mobile phase B is 100% acetonitrile, flow rate: 1 mL / min, detection wavelength: 254 nm.

[0039] 2. Optical Purity Analysis

[0040] The optical purity of the product was determined using a high performance liquid chromatograph SHIMADZU DGU-20A3R. The chromatographic column model was CHIRALPAK ZWIX(+)(0.40 cm I.D.×15 cm L×3 μm). The mobile phase was methanol: formic acid: diethylamine = 1000 mL: 1.9 mL: 2.6 mL. The flow rate was 0.1 mL / min, and the detection wavelength was 254 nm.

[0041] Example 1

[0042] Under nitrogen protection, 7.99 g (69 mmol) of lithium phosphate, 3.66 g (42 mmol) of morpholine and 100 mL of THF were added to a dry 500 mL three-necked glass reaction flask. The reaction flask was placed in a cold trap and cooled to -70 to -80 °C. 15.6 mL (39 mmol) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -70 to -80 °C for 30 min. 9.85 g (30 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 60 mL of THF and slowly added dropwise to the above reaction solution over 30 min. The internal temperature was maintained at -70 to -80 °C during the addition process. After the addition, stirring was continued for 1 h. 8.7 g (36 mmol) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 60 mL of THF and added dropwise to the above reaction solution over 0.5 h. The internal temperature was maintained at -70 to -80 °C during the addition process. After the addition, the reaction was continued for 10 min. The HPLC detection result of the reaction material: the diastereoisomer ratio dr = 5 / 1, and the conversion rate was 75%.

[0043] After the reaction was completed, 50 mL of saturated ammonium chloride solution was added to quench the reaction. The aqueous layer was separated from the reaction solution, and the organic layer was washed once more with 50 mL of saturated ammonium chloride solution. The washed organic phase was concentrated under reduced pressure to dryness. 80 mL of ethanol was added to the concentrate, and the mixture was stirred evenly at room temperature, filtered, and the filter cake was washed twice with ethanol and then dried by suction to obtain a solid crude product.

[0044] The crude product was dispersed in 150 mL of acetone, and 9.23 g of a chiral resolving agent (R)-binaphthyl phosphate resolving agent was added to form a salt. The salt was dispersed in 200 mL of toluene, and an aqueous potassium carbonate solution (6.0 g of potassium carbonate dissolved in 200 mL of water) was added to release the free base of the product. The toluene layer was separated, and the toluene layer was concentrated under reduced pressure to obtain 3.96 g of (1R,2S)-bedaquiline free base solid with high optical purity and chemical purity. The overall yield was 24%, the HPLC purity was 99.5%, and the optical purity was 99.1%.

[0045] Example 2

[0046] Under nitrogen protection, 3.59 g (69 mmol) of lithium ethoxide, 3.58 g (42 mmol) of piperidine and 100 mL of methyltetrahydrofuran were added to a dry 500 mL three-necked glass reaction flask. The reaction flask was placed in a cold trap and cooled to -60 to -65 °C. Then, 15.6 mL (39 mmol) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -60 to -65 °C for 30 min. 9.85 g (30 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 60 mL of methyltetrahydrofuran and slowly added dropwise to the above reaction solution over 30 min. During the addition process, the internal temperature was maintained at -60 to -65 °C. After the addition, stirring was continued for 1 h. 8.7 g (36 mmol) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 60 mL of methyltetrahydrofuran and added dropwise to the above reaction solution over 0.5 h. During the addition process, the internal temperature was maintained at -60 to -65 °C. After the addition, the reaction was continued for 10 min. The HPLC detection result of the reaction material: the diastereoisomer ratio dr = 4.3 / 1, and the conversion rate was 78%.

[0047] After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution. The organic layer was washed and concentrated under reduced pressure to dryness to obtain a crude solid. The crude product was purified by the resolution method in Example 1 to obtain 3.90 g of (1R,2S)-bedaquiline free base solid with high optical purity and chemical purity, and the overall yield was 23%. The HPLC purity was 99.7%, and the optical purity was 99.2%.

[0048] Example 3

[0049] Under nitrogen protection, 1.65 g (69 mmol) of lithium hydroxide, 2.99 g (42 mmol) of pyrrolidine and 100 mL of THF were added to a dry 500 mL three-necked glass reaction flask. The reaction was cooled to -60 to -70 °C, and 15.6 mL (39 mmol) of a 2.5 M n-butyllithium hexane solution was added thereto. The reaction was carried out at -60 to -70 °C for 30 min. 9.85 g (30 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 60 mL of THF and slowly added dropwise to the above reaction solution over 30 min. During the addition process, the internal temperature was maintained at -60 to -70 °C. After the addition, stirring was continued for 1 h. 8.7 g (36 mmol) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 60 mL of THF and added dropwise to the above reaction solution over 0.5 h. During the addition process, the internal temperature was maintained at -60 to -70 °C. After the addition, the reaction was continued for 10 min. The HPLC detection result of the reaction material: the diastereoisomer ratio dr = 8 / 1, and the conversion rate was 86%.

[0050] After the reaction was completed, 50 mL of saturated ammonium chloride solution was added to quench the reaction. The aqueous layer was separated from the reaction mixture, and the organic layer was washed once more with 50 mL of saturated ammonium chloride solution. The washed organic phase was concentrated under reduced pressure to dryness. 80 mL of ethanol was added to the concentrate, and the mixture was stirred evenly at room temperature, filtered, and the filter cake was washed twice with ethanol and then dried by suction to obtain the crude solid product.

[0051] The crude product was purified by the resolution method in Example 1 to obtain 4.78 g of (1R,2S)-bedaquiline solid with high optical purity and chemical purity, and the overall yield was 29%. The HPLC purity was 99.4%, and the optical purity was 99.3%.

[0052] Example 4

[0053] Under nitrogen protection, 5.10 g (69 mmol) of lithium carbonate, 3.07 g (42 mmol) of diethylamine, 10 mL of toluene, and 90 mL of tetrahydrofuran were added to a dry 500 mL three-necked glass reaction flask. The reaction flask was placed in a cold trap and cooled to -60 to -65 °C. Then, 15.6 mL (39 mmol) of a 2.5 M n-butyllithium hexane solution was added thereto, and the mixture was kept at -60 to -65 °C for reaction for 30 min. 9.85 g (30 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 60 mL of toluene and slowly added dropwise to the above reaction solution over 30 min. During the addition process, the internal temperature was maintained at -40 to -50 °C. After the addition was complete, stirring was continued for 1 h. 8.7 g (36 mmol) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 60 mL of toluene and added dropwise to the above reaction solution over 0.5 h. During the addition process, the internal temperature was maintained at -60 to -65 °C. After the addition was complete, the reaction was continued for 10 min. The HPLC detection result of the reaction materials: the diastereoisomer ratio dr = 4 / 1, and the conversion rate was 66%.

[0054] After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution. The organic layer was washed and then concentrated under reduced pressure to dryness to obtain the crude solid product. The crude product was purified by the resolution method in Example 1 to obtain 3.34 g of (1R,2S)-bedaquiline solid with high optical purity and chemical purity, and the overall yield was 20%. The HPLC purity was 99.2%, and the optical purity was 99.6%.

[0055] Example 5

[0056] Under nitrogen protection, 2.62 g (69 mmol) of lithium methoxide anhydrous, 4.25 g (42 mmol) of diisopropylamine, 10 mL of anhydrous dioxane and 90 mL of tetrahydrofuran were added to a dry 500 mL three-necked glass reaction flask. The reaction flask was placed in a cold trap and cooled to -60 to -65 °C. Then, 15.6 mL (39 mmol) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -60 to -65 °C for 30 min. 9.85 g (30 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 60 mL of anhydrous tetrahydrofuran and slowly added dropwise to the above reaction solution over 30 min. During the addition process, the internal temperature was maintained at -60 to -65 °C. After the addition, stirring was continued for 1 h. 8.7 g (36 mmol) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 60 mL of anhydrous tetrahydrofuran and added dropwise to the above reaction solution over 0.5 h. During the addition process, the internal temperature was maintained at -60 to -65 °C. After the addition, the reaction was continued for 10 min. The HPLC detection result of the reaction materials: the diastereoisomer ratio dr = 5 / 1, and the conversion rate was 81%.

[0057] After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed and concentrated under reduced pressure to dryness to obtain a solid crude product. The crude product was purified by the resolution method in Example 1 to obtain 4.16 g of (1R,2S)-bedaquiline solid with high optical purity and chemical purity, and the overall yield was 25%.

[0058] Example 6

[0059] Under nitrogen protection, 2.31 g (35 mmol) of lithium acetate anhydrous, 2.60 g (35 mmol) of lithium carbonate anhydrous, 4.25 g (42 mmol) of diisopropylamine and 100 mL of anhydrous ether were added to a dry 500 mL three-necked glass reaction flask. The reaction flask was placed in a cold trap and cooled to -60 to -65 °C. Then, 15.6 mL (39 mmol) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -60 to -65 °C for 30 min. 9.85 g (30 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 60 mL of anhydrous ether and slowly added dropwise to the above reaction solution over 30 min. During the addition process, the internal temperature was maintained at -60 to -65 °C. After the addition, stirring was continued for 1 h. 8.7 g (36 mmol) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 60 mL of anhydrous ether and added dropwise to the above reaction solution over 0.5 h. During the addition process, the internal temperature was maintained at -60 to -65 °C. After the addition, the reaction was continued for 10 min. The HPLC detection result of the reaction materials: the diastereoisomer ratio dr = 5 / 1, and the conversion rate was 65%.

[0060] After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed and concentrated under reduced pressure to dryness to obtain a crude solid product. The crude product was purified by the resolution method in Example 1 to obtain 3.29 g of (1R,2S)-bedaquiline solid with high optical purity and chemical purity, and the overall yield was 20%. The HPLC purity was 99.6%, and the optical purity was 99.2%.

[0061] Example 7

[0062] Under nitrogen protection, 7.59 g (69 mmol) of lithium sulfate, 1.50 g (21 mmol) of pyrrolidine, 1.83 g (21 mmol) of morpholine, 20 mL of anhydrous ethylene glycol diethyl ether and 80 mL of anhydrous tetrahydrofuran were added to a dry 500 mL three-necked glass reaction flask. The reaction flask was placed in a cold trap and cooled to -60 to -65 °C. Then, 15.6 mL (39 mmol) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -60 to -65 °C for 30 min. 9.85 g (30 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 60 mL of anhydrous tetrahydrofuran and slowly added dropwise to the above reaction solution over 30 min. During the addition process, the internal temperature was maintained at -60 to -65 °C. After the addition was completed, the mixture was stirred for 1 h. 8.7 g (36 mmol) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 60 mL of anhydrous tetrahydrofuran and added dropwise to the above reaction solution over 0.5 h. During the addition process, the internal temperature was maintained at -60 to -65 °C. After the addition was completed, the reaction was continued for 10 min. The HPLC detection result of the reaction mixture showed that the diastereoisomer ratio dr = 7 / 1 and the conversion rate was 72%.

[0063] After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed and concentrated under reduced pressure to dryness to obtain a crude solid product. The crude product was purified by the resolution method in Example 1 to obtain 4.09 g of (1R,2S)-bedaquiline solid with high optical purity and chemical purity, and the overall yield was 25%. The HPLC purity was 99.6%, and the optical purity was 99.2%.

[0064] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the present technical solution, and they should all be covered by the scope of the claims of the present invention.

Claims

1. A method for selectively synthesizing bedaquiline, characterized in that, It includes the following steps: A mixture is prepared by adding an alkaline metal lithium salt catalyst, an organic amine, and n-butyllithium to an organic solvent. 6-Bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) are added to the mixture for reaction to obtain product (3). The reaction formula is as follows: The alkali metal lithium salt catalyst is selected from one or more combinations of lithium methoxide, lithium ethoxide, lithium hydroxide, lithium sulfate, lithium carbonate, lithium phosphate, C 1-12 alkyl lithium carboxylate and C 1-12 lithium alkoxide.

2. A method for selectively synthesizing bedaquiline according to claim 1, characterized in that: The reaction temperature is -40 to -80 °C.

3. A method for selectively synthesizing bedaquiline according to claim 1, characterized in that, The preparation method of the mixed solution includes: adding the alkaline metal lithium salt catalyst to the organic solvent, and then adding the organic amine and n-butyllithium under nitrogen protection and at a low temperature of -40 to -80 °C to prepare an organic amine lithium salt.

4. A method for selectively synthesizing bedaquiline according to claim 1, wherein: A solution of 6-bromo-3-benzyl-2-methoxyquinoline (1) is added dropwise to the mixture, and then a solution of 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) is added.

5. A method for selectively synthesizing bedaquiline according to claim 1, characterized in that: The organic amine is one or a combination of more than one of piperidine, pyrrolidine, diisopropylamine, diethylamine, and morpholine.

6. A method for selectively synthesizing bedaquiline according to claim 1, characterized in that: The solvent is one or a combination of more than one of tetrahydrofuran, ether, methyltetrahydrofuran, toluene, dioxane, dimethyldiethylether, diethyldiethylether, and methyl tert-butyl ether.

7. A method for selectively synthesizing bedaquiline according to claim 1, wherein: The dosage of the organic amine is 0.5 to 2 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (1).

8. A method for selectively synthesizing bedaquiline according to claim 1, wherein: The dosage of the alkaline metal lithium salt catalyst is 0.1 to 3 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (1).

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