Method for preparing bedaquiline using low-temperature continuous flow, and product prepared

Abstract

A method for preparing bedaquiline using a low-temperature continuous flow, and a product prepared. The preparation method comprises the following steps: step S1, carrying out first continuous flow reaction on a feed liquid A and a feed liquid B by using a continuous flow to obtain a reaction liquid D; step S2, carrying out second continuous flow reaction on the reaction liquid D and a feed liquid C by using a continuous flow, wherein the reaction residence time of the first continuous flow reaction is 30-600 s, and the reaction residence time of the second continuous flow reaction is 30-200 s; and step S3, carrying out quenching. The preparation method achieves a good yield, and by using the method for preparation of bedaquiline, a crude product obtained requires only simple post-treatment to achieve a purity of pure bedaquiline of up to 99.8%.

Description

A method for preparing bedaquiline in a low-temperature continuous flow process and the obtained product

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application number 202310959686.6, filed with the Patent Office of China on August 1, 2023, entitled "A method for preparing bedaquiline by low-temperature continuous flow and the product obtained", the entire contents of which are incorporated by reference into this application. Technical Field

[0003] The invention relates to a method for preparing bedaquiline in a low-temperature continuous flow process and the prepared product. Background Art

[0004] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and is the disease with the highest death toll from a single pathogen (approximately 1.6 million people annually). Bedaquiline received FDA approval in 2012 for the treatment of multidrug-resistant and rifampicin-resistant tuberculosis (MDR / RR-TB). In 2018, the World Health Organization reclassified anti-TB drugs, and bedaquiline was listed as the first-line drug of choice for the long-term treatment of MDR / RR-TB. The stereoselective construction of the Csp3-Csp3 bond at the continuous chiral center in this drug molecule is a challenging problem, and an efficient industrial synthesis route has not yet been achieved, resulting in its high price. Therefore, improving the production process, reducing the synthesis cost, and making the drug affordable for low-income people are urgent issues that need to be addressed.

[0005] The original patent for the synthesis of bedaquiline (patent authorization number: CN101180302B) discloses a one-step synthesis method. 6-bromo-3-benzyl-2-methoxyquinoline is deprotonated at the benzylic position with lithium diisopropylamide (LDA) at low temperature, followed by addition of 3-dimethylamino-1-naphthyl-1-propanone to produce a mixture of four optical isomers of bedaquiline. The reaction mixture is concentrated, treated with ethanol, and then resolved with the chiral resolving agent (R)-binaphthol phosphate to obtain bedaquiline (BDQ). The overall yield is very low (7-9%). Furthermore, due to the high efficiency of asymmetric catalytic synthesis, methods for obtaining bedaquiline using asymmetric catalysis have also attracted widespread attention. Shibasaki and Chandrasekhar reported separately using asymmetric catalysis to construct the first carbon chirality and then asymmetric synthesis to construct the second carbon chirality. However, these routes suffer from numerous reaction steps, low yields, and high manufacturing costs. In addition, a research team in South Africa used a C2-symmetrical chiral amine ligand in 2020 to increase the diastereoselectivity of BDQ to 9: 1 (ACSOmega2020, 5, 3607-3611), and subsequently used a chiral split method to obtain an optically pure target compound, but did not increase the yield of the product. Recently, Jamison et al. used fluid chemistry (Chem. Eur. J. 2022, e202201311) to improve the yield of the reaction route and obtain four mixed isomers. This scheme still did not achieve efficient synthesis of the target product. Not long ago, the team of Professor Zhang Wanbin of Shanghai Jiaotong University disclosed a strategy for the asymmetric synthesis of bedaquinoline (Sci. China Chem. 2022, 65, 1968-1977). Based on this synthetic route, the team used the Li / Li bimetallic synergistic activation strategy developed by itself to develop two routes for the asymmetric synthesis of bedaquinoline. The results of the autoclave reactions were 81% yield, 1.4:1 dr, 91% ee, and 22% yield, 16:1 dr, >99% ee, respectively. The above-mentioned reactions for synthesizing bedaquiline still suffer from the technical problem of low yield, and column chromatography is required during post-processing to obtain a product with a purity greater than 99%. Furthermore, the conventional autoclave reaction process is limited by long reaction times, cumbersome operations, and the generation of impurities. Furthermore, the use of active butyl lithium reagents poses safety risks.

[0006] In summary, the existing technology for synthesizing bedaquiline still has technical defects such as low yield, long production cycle, high cost, complex operation and low safety. Therefore, the development of new synthesis technology for bedaquiline has important research significance and application value.

[0007] Summary of the Invention

[0008] To address the technical deficiencies of existing bedaquiline preparation techniques, such as low yield, long production cycle, complex operation, and low safety, the present invention provides a low-temperature continuous flow method for preparing bedaquiline and the resulting product. The method of the present invention provides a high yield, and the resulting mixture after quenching requires only simple post-treatment to achieve a purity of over 99.8% for pure bedaquiline. The method is simple to operate, highly safe, and has a short production cycle.

[0009] The present invention provides a method for preparing bedaquiline by low-temperature continuous flow, which comprises the following steps:

[0010] Step S1: Feed liquid A and feed liquid B are subjected to a first continuous flow reaction using a continuous flow method to obtain a reaction liquid D; the reaction residence time of the first continuous flow reaction is 30s to 600s;

[0011] The feed liquid A is a mixed reaction liquid of (1S, 2R)-2-amino-1,2-diphenylethanol, N-methylpiperazine, butyl lithium, lithium chloride and tetrahydrofuran, and the feed liquid B is a mixed liquid of 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran;

[0012] Step S2: The reaction solution D and the feed solution C are subjected to a second continuous flow reaction using a continuous flow method; the feed solution C is a mixture of 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran;

[0013] The reaction residence time of the second continuous flow reaction is 30s to 600s;

[0014] Step S3: Quenching.

[0015] Those skilled in the art will appreciate that the apparatus for performing a continuous flow reaction may generally be a continuous flow reactor. In the present invention, the first continuous flow reaction and / or the second continuous flow reaction may be performed in a continuous flow reactor. The continuous flow reactor is preferably a reaction pipe.

[0016] In the present invention, the reaction residence time of the first continuous flow reaction is preferably 30s-90s or 180s-600s; for example, 300s, 360s, 240s, 600s, 180s or 120s. The first continuous flow reaction includes an acid-base reaction and a coordination reaction between the feed liquid A and the feed liquid B.

[0017] In the present invention, the reaction residence time of the second continuous flow reaction is preferably 30s-60s or 120s-360s; for example, 180s, 300s, 120s, 360s, 144s or 90s.

[0018] In the present invention, the reaction temperature of the first continuous flow reaction can be -80°C to 0°C, preferably -80°C to -20°C, more preferably -10°C to -30°C; for example, -10°C, -20°C, or -30°C.

[0019] In the present invention, the reaction temperature of the second continuous flow reaction can be -80°C to 0°C, preferably -80°C to -20°C, more preferably -50°C to -80°C; for example, -50°C, -60°C, -70°C, or -80°C.

[0020] In step S1, the flow rate of the feed liquid A is preferably 10-500 mL / min, more preferably 10-200 mL / min, particularly 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min.

[0021] In step S1, the flow rate of the feed liquid B is preferably 10-500 mL / min, more preferably 10-200 mL / min, particularly 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min.

[0022] In step S2, the flow rate of the feed liquid C is preferably 10-500 mL / min, more preferably 10-200 mL / min, particularly 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min.

[0023] In step S2, those skilled in the art will appreciate that the flow rate of the reaction solution D can be determined after the feed solutions A and B enter a continuous flow reaction device, such as a microchannel. The flow rate of the reaction solution D can be 10-500 mL / min, preferably 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min, or 30 mL / min.

[0024] In step S1, in the feed liquid A, the ratio of the molar amount of the (1S,2R)-2-amino-1,2-diphenylethanol to the volume of the tetrahydrofuran is preferably 0.1-0.7 mol / L; for example, 0.298 mol / L, 0.26 mol / L, 0.51 mol / L, 0.1428 mol / L, and 0.28 mol / L.

[0025] In step S1, in the feed liquid A, the volume ratio of the molar amount of the N-methylpiperazine to the tetrahydrofuran is preferably 0.1 mol / L-0.7 mol / L; for example, 0.355 mol / L, 0.312 mol / L, 0.170 mol / L, 0.609 mol / L, 0.1704 mol / L, 0.359 mol / L or 0.284 mol / L.

[0026] In step S1, in the feed liquid A, the volume ratio of the molar amount of the lithium chloride to the tetrahydrofuran is preferably 0.1 mol / L-0.8 mol / L; for example, 0.408 mol / L, 0.354 mol / L, 0.7 mol / L, 0.196 mol / L, and 0.338 mol / L.

[0027] In step S1, in the feed solution A, the volume ratio of the molar amount of the n-butyl lithium to the tetrahydrofuran is preferably 0.4 mol / L-1.2 mol / L; for example, 0.56 mol / L, 0.59 mol / L, 0.66 mol / L, 0.68 mol / L, 0.625 mol / L, 0.543 mol / L, 1.07 mol / L, or 0.3 mol / L.

[0028] In step S1, in the feed liquid B, the volume ratio of the 6-bromo-3-benzyl-2-methoxyquinoline to the tetrahydrofuran is preferably 0.04-1.0 mol / L, for example, 0.113 mol / L, 0.136 mol / L, 0.17 mol / L, or 0.057 mol / L.

[0029] In step S1, the volume ratio of 3-dimethylamino-1-naphthyl-1-propanone to tetrahydrofuran in the feed liquid C is preferably 0.04-1.0 mol / L, for example, 0.115 mol / L, 0.141 mol / L, 0.152 mol / L, 0.630 mol / L, 0.136 mol / L, 0.163 mol / L, or 0.255 mol / L.

[0030] In step S1, the molar ratio of the N-methylpiperazine to the 6-bromo-3-benzyl-2-methoxyquinoline is preferably 0.5-5.0, more preferably 1.5-5.0; for example, 4.5, 2.5, 2.1, or 2.

[0031] In step S1, the molar ratio of the (1S,2R)-2-amino-1,2-diphenylethanol and the 6-bromo-3-benzyl-2-methoxyquinoline is preferably 0.8-5.0, more preferably 1.5-5.0; for example, 3.0, 2.1, 1.8, or 2.0.

[0032] In step S1, the molar ratio of the lithium chloride to the 6-bromo-3-benzyl-2-methoxyquinoline is preferably 0.8-5.0, more preferably 1.5-5.0; for example, 2.9 or 2.4.

[0033] In step S1, the molar ratio of the n-butyl lithium to the 6-bromo-3-benzyl-2-methoxyquinoline is preferably 1.0-10.0, more preferably 3.0-10.0; for example, 3.68 or 4.41.

[0034] In step S1, the molar ratio of the 3-dimethylamino-1-naphthyl-1-propanone to the 6-bromo-3-benzyl-2-methoxyquinoline is preferably 0.8-5.0, more preferably 1.5-5.0; for example, 1.1, 1.2, 1.3, 1.5, or 2.5.

[0035] In step S1, the mixed reaction liquid of (1S,2R)-2-amino-1,2-diphenylethanol, N-methylpiperazine, butyllithium, lithium chloride and tetrahydrofuran can be obtained according to conventional methods in the art, for example, (1S,2R)-2-amino-1,2-diphenylethanol, N-methylpiperazine, butyllithium, lithium chloride and tetrahydrofuran are mixed and reacted.

[0036] The reaction temperature is preferably -80°C to 0°C, more preferably -80°C to -20°C, particularly -30°C to -10°C, for example -20°C and -60°C. The reaction time is preferably 10 min to 2 h, more preferably 20-30 min, for example 20 min or 30 min.

[0037] Those skilled in the art know that tetrahydrofuran serves as a solvent in the above reaction.

[0038] In step S1, the temperature of the mixed reaction liquid is preferably -80°C to 0°C, more preferably -80°C to -20°C, particularly -30°C to -10°C; for example, -20°C and -60°C.

[0039] In step S1, the mixed solution of 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran can be obtained by conventional methods in the art, for example, by mixing 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran.

[0040] In step S2, the mixed solution of 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran can be obtained by conventional methods in the art, for example, by mixing 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran.

[0041] In the present invention, the quenching method may include two methods:

[0042] Method 1: the quenching is carried out in a quenching device, which is not a continuous flow reactor; the quenching solvent can be a conventional quenching solvent in the art, preferably an ammonium chloride solution.

[0043] Alternatively, in method 2, the feed liquid E and the reaction liquid obtained in step S2 are subjected to a continuous quenching reaction, wherein the feed liquid E is a quenching solvent, wherein the quenching solvent is preferably a protic solvent, and the protic solvent may be methanol or ethanol. The flow rate of the feed liquid E may be 10-500 mL / min, preferably 10-200 mL / min, more preferably 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min. The continuous quenching reaction may be carried out in a continuous flow reactor, which is preferably a reaction pipe.

[0044] In the present invention, preferably, after step S3, post-processing is further included, and the post-processing includes extraction, recrystallization and beating.

[0045] The recrystallization solvent and the beating solvent can be conventional recrystallization solvents and beating solvents in the art, preferably one or more of toluene, ethyl acetate, n-hexane, ethanol, isopropanol, benzene, and isopropyl ether. The ethanol is preferably anhydrous ethanol.

[0046] Preferably, the recrystallization method comprises the following steps: removing the extraction solvent to obtain a filtrate, preparing a saturated solution of the filtrate and a recrystallization solvent, and crystallizing.

[0047] The method for removing the extracted solvent is preferably to precipitate solid from the organic phase after the extraction on a rotary evaporator, and filter to obtain the filtrate.

[0048] The crystallization method preferably comprises cooling the saturated solution of the filtrate and the recrystallization solvent to precipitate crystals from the supersaturated solution, filtering to obtain a filtrate, and removing the recrystallization solvent from the filtrate. The method for removing the recrystallization solvent from the filtrate is more preferably to spin-dry the filtrate. The cooling temperature is preferably -20°C to 0°C, more preferably -20°C to -15°C. After the filtrate is spin-dried, pure bedaquiline is obtained by beating.

[0049] Those skilled in the art know that in order to obtain pure bedaquiline, filtration is generally required after slurrying.

[0050] In the present invention, the filtration method may be a conventional method in the art, such as suction filtration.

[0051] The present invention also provides a product prepared by the above-mentioned low-temperature continuous flow method for preparing bedaquiline.

[0052] In the present invention, the overall reaction formula for preparing bedaquinoline is:

[0053] The inventors discovered in their research experiments that dissolving 6-bromo-3-benzyl-2-methoxyquinoline in feed liquid A and then mixing it with feed liquid B would not significantly affect the reaction mechanism. However, due to the large amount of material in this reaction phase, the fluid viscosity may increase, eventually clogging the continuous flow pipeline, causing damage to the equipment and preventing the reaction from proceeding.

[0054] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0055] The reagents and raw materials used in the present invention are commercially available.

[0056] The positive progress effect of the present invention is:

[0057] The present invention adopts the entire reaction phase of feed liquid A as a catalyst, combines a low-cost and high-efficiency asymmetric synthesis route with a continuous flow technology to prepare bedaquiline, avoids the problems of difficult temperature control, long dropwise addition and stirring time in traditional kettle reactions, shortens the production cycle, reduces the risk factor of operating active lithium reagents, and has a good yield. At the same time, when bedaquiline is prepared by the preparation method of the present invention, the obtained mixture after quenching reaction only requires simple post-treatment to achieve a purity of pure bedaquiline of more than 99.8%, reduces operating costs, is very suitable for industrial production, and has important application value.

[0058] Moreover, compared with Route A in the strategy for the asymmetric synthesis of bedaquiline disclosed by Professor Zhang Wanbin's team at Shanghai Jiao Tong University (Sci. China Chem. 2022, 65, 1968-1977), the process of the present invention only takes about three hours, based on the fact that 100 g of raw material is added each time and the same yield or purity is achieved, while the reaction time of the scheme in the literature requires 37 hours. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] FIG1 is a schematic diagram of the process flow of the method for preparing bedaquiline at low temperature and in continuous flow according to Example 1.

[0060] FIG2 is a schematic diagram of the process flow of the method for preparing bedaquiline by low-temperature continuous flow in Example 2.

[0061] FIG3 is a schematic diagram of the process flow of the method for preparing bedaquiline by low-temperature continuous flow in Example 6.

[0062] Description of reference numerals:

[0063] i is a continuous flow experimental pump, ii is a check valve, iii is a pre-cooling tube, iv is a reaction tube, v is a micro-mixing device, T1 is the temperature at which feed liquid A and feed liquid B react, T2 is the temperature at which the reaction system reacts with feed liquid C, T3 is the quenching temperature of the reaction system, reaction time t1 is the retention time of feed liquid A and feed liquid B in the reactor at temperature T1, and t2 is the retention time of reaction liquid D and feed liquid C in the reactor at temperature T2.

[0064] FIG4 is an HPLC chart of the racemate of bedaquiline of Example 1 of the present invention.

[0065] FIG5 is an HPLC chart of bedaquiline in the crude product of Example 1 of the present invention.

[0066] FIG6 is an HPLC chart of bedaquiline in the crude product of Example 2 of the present invention.

[0067] FIG7 is an HPLC chart of bedaquiline in the crude product of Example 3 of the present invention.

[0068] FIG8 is an HPLC chart of bedaquiline in the crude product of Example 4 of the present invention.

[0069] FIG9 is an HPLC chart of bedaquiline in the crude product of Example 5 of the present invention.

[0070] FIG10 is an HPLC chart of bedaquiline in the crude product of Example 6 of the present invention.

[0071] FIG11 is an HPLC chart of the product after recrystallization of the crude product of Example 1 of the present invention. DETAILED DESCRIPTION

[0072] 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.

[0073] In the following examples, those skilled in the art will recognize that enantiomeric excess (EE) is a measure of purity used for chiral substances. It reflects the extent to which one enantiomer is present in a sample in excess of the other. Purity was measured using HPLC on a Chiralpak AD-H chiral column manufactured by Daicel Corporation, with chromatographically grade isopropanol and n-hexane as the mobile phase. dr values ​​were measured using a nuclear magnetic resonance spectrometer (400 MHz or 500 MHz) using CDCl₃ as the solvent. In the following examples, the equiv value for each compound represents the molar ratio of the compound to 6-bromo-3-benzyl-2-methoxyquinoline.

[0074] Example 1

[0075] The process flow diagram of the method for preparing bedaquiline by low-temperature continuous flow in Example 1 is shown in FIG1 .

[0076] Step S1: In a dry 5L reactor, 10.5 g (245 mmol, 2.9 equiv) of lithium chloride, 38.3 g (178.5 mmol, 2.1 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 23.9 mL (213 mmol, 2.5 equiv) of N-methylpiperazine, and 600 mL of anhydrous tetrahydrofuran were added. 150 mL (375 mmol) of a 2.5 M (2.5 mol / L) n-butyllithium solution in n-hexane was added at -20°C, and the mixture was reacted for 30 min as feed solution A;

[0077] 27.9 g of raw material 1 (in the following examples, raw material 1 refers to 6-bromo-3-benzyl-2-methoxyquinoline) (85 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed uniformly to obtain feed liquid B;

[0078] The raw material 2 (3-dimethylamino-1-naphthyl-1-propanone) (26.9 g, 102 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed well to prepare the feed solution C.

[0079] Among them, the flow rate of feed liquid A is 15mL / min, the flow rate of feed liquid B is 15mL / min, and the flow rate of feed liquid C is 15mL / min.

[0080] Step S2: pumping feed liquid A and feed liquid B into the first micro-reaction tube for a first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20°C, and the reaction residence time t1 = 5 min;

[0081] Step S3: pumping the reaction solution D and the feed solution C into the second micro-reaction tube for a second continuous flow reaction, with a reaction temperature T2 of -60°C and a reaction residence time t2 of 3 min;

[0082] Step S4: Quenching: The reaction solution of step S3 is discharged from the second micro-reaction tube and introduced into 2 L of saturated ammonium chloride solution for quenching, and the quenching temperature T3 is -60°C; the quenched reaction solution is collected to obtain a mixture containing bedaquiline.

[0083] Step S5: Post-processing: extraction, recrystallization and beating

[0084] Extraction: The mixture was extracted with ethyl acetate (3 times*1 L) in a 5 L reactor, and the organic phase was collected to obtain a crude product.

[0085] Recrystallization: removing the extraction solvent to obtain a filtrate, preparing a saturated solution of the filtrate and the recrystallization solvent, and crystallizing;

[0086] The method for removing the extracted solvent is to precipitate solids from the organic phase after extraction on a rotary evaporator, and filter to obtain the filtrate; the crystallization method is to cool the filtrate and the saturated solution of the recrystallization solvent to precipitate crystals from the supersaturated solution, filter, filter to obtain a filtrate, and spin-dry the filtrate; the cooling temperature is -20°C to -15°C.

[0087] Specifically, the organic phase after extraction is evaporated on a rotary evaporator until solids precipitate, then stopped and allowed to stand overnight to precipitate the first solid, which is then filtered to obtain the filtrate. The filter cake is rinsed with n-hexane, and the filter cake is mostly composed of diastereomers and ligands. The filtrate is added with an amount of n-hexane equal to that of the organic solvent, cooled to allow crystals to precipitate from the supersaturated solution, and filtered until the filtrate is mostly composed of the target product. The filtrate is then spin-dried to obtain the second solid.

[0088] Beating: Mix the second solid with ethanol, beat at room temperature for 12 hours, filter, wash the filter cake with n-hexane, and dry in vacuo at room temperature to obtain pure bedaquiline.

[0089] Nuclear magnetic resonance (NMR) analysis of the crude product revealed a dr value of 1:1 for bedaquiline, resulting in a yield of 95%. HPLC analysis also revealed an ee value of 60%. The yield was calculated using triphenylmethane as the internal standard using the following formula: The characteristic peak of the internal standard is integrated as 1. Yield = x*y / n, where x = the integral of the characteristic peak of the product, y = the number of moles of the internal standard, and n = the molar amount of starting material 1.

[0090] The obtained pure bedaquiline was a white solid. HPLC analysis showed that the purity of the bedaquiline in the pure product was ≥99.8%, with a single impurity content of <0.1%. The structural characterization data of bedaquiline are shown below: 1H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0091] Example 2

[0092] The process flow diagram of the method for preparing bedaquiline in Example 2 is shown in FIG2 .

[0093] Step S1: In a dry 5L reactor, 10.5 g (245 mmol, 2.9 equiv) of lithium chloride, 38.3 g (178.5 mmol, 2.1 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 23.9 mL (213 mmol, 2.5 equiv) of N-methylpiperazine, and 600 mL of anhydrous tetrahydrofuran were added. 150 mL (375 mmol) of a 2.5 M n-butyllithium solution in n-hexane was added at -20°C and the mixture was reacted for 30 min as feed solution A;

[0094] 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed well to obtain feed liquid B;

[0095] 3-Dimethylamino-1-naphthyl-1-propanone (2) (26.9 g, 102 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed well to prepare the feed solution C.

[0096] Among them, the flow rate of feed liquid A is 15mL / min, the flow rate of feed liquid B is 15mL / min, and the flow rate of feed liquid C is 15mL / min.

[0097] Step S2: pumping feed liquid A and feed liquid B into the first micro-reaction tube for a first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20°C, and the reaction residence time t1 = 5 min;

[0098] Step S3: pumping the reaction solution D and the feed solution C into the second micro-reaction tube for a second continuous flow reaction, with a reaction temperature T2 of -60°C and a reaction residence time t2 of 3 min;

[0099] Step S4: Quenching: The reaction solution of step S3 is discharged from the second micro-reaction tube and introduced into 2 L of saturated ammonium chloride solution for quenching, and the quenching temperature T3 is -60°C; the quenched reaction solution is collected to obtain a mixture containing bedaquiline;

[0100] Step S5: Post-processing: extraction, recrystallization and beating

[0101] The crude product was obtained by the same extraction as in Example 1, and the pure product was obtained by the same recrystallization and beating steps.

[0102] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 91% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 84%.

[0103] HPLC analysis of the pure bedaquiline product revealed a purity of ≥99.8% and a single impurity level of <0.1%. The structural characterization data for bedaquiline are shown below: 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0104] Example 3

[0105] The process flow diagram of the method for preparing bedaquiline in Example 3 is shown in FIG2 .

[0106] Step S1: In a dry 5L reactor, 10.5 g (245 mmol, 2.9 equiv) of lithium chloride, 38.3 g (178.5 mmol, 2.1 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 23.9 mL (213 mmol, 2.5 equiv) of N-methylpiperazine, and 600 mL of anhydrous tetrahydrofuran were added. 150 mL (375 mmol) of a 2.5 M n-butyllithium solution in n-hexane was added at -20°C and the mixture was reacted for 30 min as feed solution A;

[0107] 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed well to obtain feed liquid B;

[0108] 3-Dimethylamino-1-naphthyl-1-propanone (raw material 2) (26.9 g, 102 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed well to prepare feed liquid C;

[0109] The flow rate of feed liquid A is 20 mL / min, the flow rate of feed liquid B is 15 mL / min, and the flow rate of feed liquid C is 15 mL / min.

[0110] Step S2: pumping feed liquid A and feed liquid B into the first micro-reaction tube for a first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20°C, and the reaction residence time t1 = 5 min;

[0111] Step S3: pumping the reaction solution D and the feed solution C into the second micro-reaction tube for a second continuous flow reaction, with a reaction temperature T2 of -60°C and a reaction residence time t2 of 3 min;

[0112] Step S4: Quenching: The reaction solution of step S3 is discharged from the second micro-reaction tube and introduced into 2 L of saturated ammonium chloride solution for quenching, and the quenching temperature T3 is -60°C; the quenched reaction solution is collected to obtain a mixture containing bedaquiline;

[0113] Step S5: Post-processing: extraction, recrystallization and beating

[0114] The crude product was obtained by the same extraction as in Example 1, and the pure product was obtained by the same recrystallization and beating steps.

[0115] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 91% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 90%.

[0116] HPLC analysis of pure bedaquiline revealed a purity of ≥99.8% and a single impurity level of <0.1%. The structural characterization data for bedaquiline are shown below:1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0117] Example 4

[0118] The process flow diagram of the method for preparing bedaquiline in Example 4 is shown in FIG1 .

[0119] Step S1: In a dry 5L reactor, 20.8g (490mmol, 2.9equiv) of lithium chloride, 76.6g (359mmol, 2.1equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 47.8mL (431mmol, 2.5equiv) of N-methylpiperazine, and 1.2L of anhydrous tetrahydrofuran were added. 300mL (750mmol) of a 2.5M n-butyllithium solution in n-hexane was added at -20°C and the mixture was reacted for 30min as feed solution A;

[0120] 55.8 g of raw material 1 (170 mmol) was placed in a 5 L single-necked bottle, and 1.5 L of anhydrous tetrahydrofuran was added and mixed well to prepare feed liquid B;

[0121] 60 g (227.5 mmol) of 3-dimethylamino-1-naphthyl-1-propanone was placed in a 5 L single-necked bottle, and 1.5 L of anhydrous tetrahydrofuran was added and mixed well to prepare the feed solution C.

[0122] The flow rate of feed liquid A is 15 mL / min, the flow rate of feed liquid B is 15 mL / min, and the flow rate of feed liquid C is 15 mL / min.

[0123] Step S2: pumping feed liquid A and feed liquid B into the first micro-reaction tube for a first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20°C, and the reaction residence time t1 = 5 min;

[0124] Step S3: pumping the reaction solution D and the feed solution C into the second micro-reaction tube for a second continuous flow reaction, with a reaction temperature T2 of -60°C and a reaction residence time t2 of 3 min;

[0125] Step S4: Quenching: The reaction solution of step S3 is discharged from the second micro-reaction tube and introduced into 2 L of saturated ammonium chloride solution for quenching at 0° C.; the quenched reaction solution is collected to obtain a mixture containing bedaquiline;

[0126] Step S5: Post-processing: extraction, recrystallization and beating

[0127] The same extraction steps as in Example 1 were used to obtain a crude product, and the same recrystallization and beating steps were used to obtain a pure product.

[0128] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 93% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 86%.

[0129] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89 (s, 1H), 8.60 (d, J = 8.8Hz, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.90 (d, J = 7.2Hz, 1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.51-7.46(m,1H),7.30(t,J=

[0130] 8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1H),4.21(s,3 H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0131] Example 5

[0132] The process flow diagram of the method for preparing bedaquiline in Example 5 is shown in FIG1 .

[0133] Step S1: In a dry 5L reactor, 34.6g (816mmol, 2.4equiv) of lithium chloride, 127.5g (598mmol, 1.8equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 79.5mL (717mmol, 2.1equiv) of N-methylpiperazine, and 2.3L of anhydrous tetrahydrofuran were added. 500mL (1250mmol) of a 2.5M n-butyllithium solution in n-hexane was added at -20°C and the mixture was reacted for 30min as feed solution A;

[0134] 111.6 g of raw material 1 (340 mmol) was placed in a 5 L single-necked bottle, and 2.5 L of anhydrous tetrahydrofuran was added and mixed well to prepare feed liquid B;

[0135] 104 g of 3-dimethylamino-1-naphthyl-1-propanone (408 mmol) was placed in a 5 L single-necked bottle, and 2.5 L of anhydrous tetrahydrofuran was added and mixed well to prepare the feed solution C.

[0136] The flow rate of feed liquid A is 15 mL / min, the flow rate of feed liquid B is 15 mL / min, and the flow rate of feed liquid C is 15 mL / min.

[0137] Step S2: pumping feed liquid A and feed liquid B into the first micro-reaction tube for a first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20°C, and the reaction residence time t1 = 5 min;

[0138] Step S3: pumping the reaction solution D and the feed solution C into the second micro-reaction tube for a second continuous flow reaction, with a reaction temperature T2 of -60°C and a reaction residence time t2 of 3 min;

[0139] Step S4: Quenching: The reaction solution of step S3 is discharged from the second micro-reaction tube and introduced into 2 L of saturated ammonium chloride solution for quenching at 0° C.; the quenched reaction solution is collected to obtain a mixture containing bedaquiline;

[0140] Step S5: Post-processing: extraction, recrystallization and beating

[0141] The crude product was obtained by the same extraction as in Example 1, and the pure product was obtained by the same recrystallization and beating steps.

[0142] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1.2:1, and the yield was 89% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined by HPLC to be 63%.

[0143] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0144] Example 6

[0145] The process flow diagram of the method for preparing bedaquiline in Example 6 is shown in FIG3 .

[0146] Step S1: In a dry 5L reactor, 34.6g (816mmol, 2.4equiv) of lithium chloride, 127.5g (598mmol, 1.8equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 79.5mL (717mmol, 2.1equiv) of N-methylpiperazine, and 2.3L of anhydrous tetrahydrofuran were added. 500mL (1250mmol) of a 2.5M n-butyllithium solution in n-hexane was added at -20°C and the mixture was reacted for 30min as feed solution A;

[0147] 111.6 g of raw material 1 (340 mmol) was placed in a 5 L single-necked bottle, and 2.5 L of anhydrous tetrahydrofuran was added and mixed well to prepare feed liquid B;

[0148] 104 g of 3-dimethylamino-1-naphthyl-1-propanone (408 mmol) was placed in a 5 L single-necked bottle, and 2.5 L of anhydrous tetrahydrofuran was added and mixed well to obtain the feed solution C.

[0149] The flow rate of feed liquid A is 15 mL / min, the flow rate of feed liquid B is 15 mL / min, and the flow rate of feed liquid C is 15 mL / min.

[0150] Step S2: pumping feed liquid A and feed liquid B into the first micro-reaction tube for a first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20°C, and the reaction residence time t1 = 5 min;

[0151] Step S3: pumping the reaction solution D and the feed solution C into the second micro-reaction tube for a second continuous flow reaction, with a reaction temperature T2 of -60°C and a reaction residence time t2 of 3 min;

[0152] Step S4: Quenching: 1 L of anhydrous ethanol was placed in a 5 L single-necked bottle as feed liquid E; the reaction solution obtained in step S3 and feed liquid E were added to a third micro-reaction tube for continuous quenching reaction, wherein the flow rate of feed liquid E was 10 mL / min; the quenching temperature was 0° C.; the quenched reaction solution was collected to obtain a mixture containing bedaquiline;

[0153] Step S5: Post-processing: extraction, recrystallization and beating

[0154] The crude product was obtained by the same extraction as in Example 1, and the pure product was obtained by the same recrystallization and beating steps.

[0155] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1.2:1, and the yield was 92% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 68%.

[0156] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0157] Example 7

[0158] The only difference between Example 7 and Example 1 is that the reaction temperature T1 of the first continuous flow reaction is -30°C, and the reaction temperature T2 of the second continuous flow reaction is -70°C. The remaining steps are the same.

[0159] The dr value of bedaquiline in the crude product was measured by nuclear magnetic resonance to be 1:1, the yield was 91% (using triphenylmethane as an internal standard), and the ee value of bedaquiline was 78% by HPLC.

[0160] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0161] Example 8

[0162] The only difference between Example 8 and Example 7 is that the reaction temperature T2 of the second continuous flow reaction is -80°C, and the remaining steps are the same.

[0163] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 91% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 78%.

[0164] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90(d,J= 7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.51-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7. 12(m,2H),6.88-6.87(m,3H),5.89(s,1H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0165] Example 9

[0166] The only difference between Example 9 and Example 2 is that the reaction temperature T2 of the second continuous flow reaction is -70°C, and the remaining steps are the same.

[0167] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 92% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 88%.

[0168] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0169] Example 10

[0170] The only difference between Example 10 and Example 2 is that the flow rate of feed liquid A is 10 mL / min, the flow rate of feed liquid B is 10 mL / min, the flow rate of feed liquid C is 10 mL / min, the reaction residence time t1 of the first continuous flow reaction is 6 min, and the reaction residence time t2 of the first continuous flow reaction is 5 min; the quenching temperature is -60°C; and the remaining steps are the same.

[0171] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 91% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 84%.

[0172] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0173] Example 11

[0174] The only difference between Example 11 and Example 2 is that step S1 is different and the quenching temperature in step S4 is different; the remaining steps are the same.

[0175] Step S1: In a dry 5L reactor, 8.7 g (203 mmol, 2.4 equiv) of lithium chloride, 36.3 g (170 mmol, 2.0 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 23.9 mL (170.4 mmol, 2 equiv) of N-methylpiperazine, and 600 mL of anhydrous tetrahydrofuran were added. 150 mL (375 mmol) of a 2.5 M n-butyllithium solution in n-hexane was added at -20°C, and the mixture was reacted for 20 min as feed solution A;

[0176] 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed well to obtain feed liquid B;

[0177] 3-Dimethylamino-1-naphthyl-1-propanone (2) (26.9 g, 102 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed well to prepare the feed solution C.

[0178] The flow rate of feed liquid A was 15 mL / min, the flow rate of feed liquid B was 15 mL / min, and the flow rate of feed liquid C was 15 mL / min.

[0179] The quenching temperature in step S4 is -60°C.

[0180] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 88% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 80%.

[0181] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0182] Example 12

[0183] The only difference between Example 12 and Example 2 is that the amount and volume of tetrahydrofuran in step S1 are different, the reaction residence time is different, and the quenching temperature in step S4 is different. The other steps are the same.

[0184] Step S1: In a dry 5L reactor, 10.5 g (245 mmol, 2.9 equiv) of lithium chloride, 38.3 g (178.5 mmol, 2.1 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 23.9 mL (213 mmol, 2.5 equiv) of N-methylpiperazine, and 350 mL of anhydrous tetrahydrofuran were added. 150 mL (375 mmol) of a 2.5 M n-butyllithium solution in n-hexane was added at -20°C, and the mixture was reacted for 30 min as feed solution A;

[0185] 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-necked bottle, and 500 mL of anhydrous tetrahydrofuran was added and mixed well to obtain feed liquid B;

[0186] 3-Dimethylamino-1-naphthyl-1-propanone (28.9 g, 127.5 mmol) was placed in a 5 L single-necked bottle, and 500 mL of anhydrous tetrahydrofuran was added and mixed well to prepare the feed liquid C.

[0187] Among them, the flow rate of feed liquid A is 15 mL / min, and the flow rate of feed liquid B is 15 mL / min.

[0188] The reaction residence time t1 of the first continuous flow reaction in step S2 is 4 min.

[0189] The reaction residence time t2 of the second continuous flow reaction in step S3 is 2 min.

[0190] The quenching temperature in step S4 is -60°C;

[0191] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 86% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 76%.

[0192] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0193] From the comparison between Example 12 and Example 2, it can be seen that the amount of anhydrous tetrahydrofuran used in each reaction phase is smaller, which is equivalent to changing the concentration of the materials during the reaction process, and the retention time in the reactor is shorter, which will cause some fluctuations in the reaction results, and the achieved yield and ee value are lower. However, the product will eventually obtain a product with purity that meets the requirements after recrystallization.

[0194] Example 13

[0195] The only difference between Example 13 and Example 2 is that the amount and volume of tetrahydrofuran in step S1 are different, and the quenching temperature in step S4 is different. The other steps are the same.

[0196] Step S1: In a dry 5L reactor, 10.5g (245mmol, 2.9equiv) of lithium chloride, 38.3g (178.5mmol, 2.1equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 23.9mL (213mmol, 2.5equiv) of N-methylpiperazine, and 1.25L of anhydrous tetrahydrofuran were added. 150mL (375mmol) of a 2.5M n-butyllithium solution in n-hexane was added at -20°C, and the mixture was reacted for 30min as feed solution A;

[0197] 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-necked bottle, and 1.5 L of anhydrous tetrahydrofuran was added and mixed well to obtain feed liquid B;

[0198] 3-Dimethylamino-1-naphthyl-1-propanone (2) (26.9 g, 102 mmol) was placed in a 5 L single-necked bottle, and 1.5 L of anhydrous tetrahydrofuran was added and mixed well to prepare the feed solution C.

[0199] The flow rate of feed liquid A is 15 mL / min, the flow rate of feed liquid B is 15 mL / min, and the flow rate of feed liquid C is 15 mL / min.

[0200] The reaction residence time t1 of the first continuous flow reaction in step S2 is 10 min.

[0201] The reaction residence time t2 of the second continuous flow reaction in step S3 is 6 min.

[0202] The quenching temperature in step S4 is -60°C.

[0203] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 94% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 89%.

[0204] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0205] From the comparison between Example 13 and Example 2, it can be seen that the amount of anhydrous tetrahydrofuran used in each reaction phase is larger, which is equivalent to changing the concentration of the materials during the reaction process, and the reactor retention time is longer, and the yield and ee value achieved are both better.

[0206] Example 14

[0207] The only difference between Example 14 and Example 4 is that the flow rate of each feed liquid and the reaction residence time are different, and the other steps are the same.

[0208] The flow rate of feed liquid A is 12 mL / min, the flow rate of feed liquid B is 12 mL / min, and the flow rate of feed liquid C is 12 mL / min.

[0209] The reaction residence time of the first continuous flow reaction was t1 = 4 min, and the reaction residence time of the second continuous flow reaction was t2 = 2.4 min.

[0210] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1.2, and the yield was 87% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 76%.

[0211] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0212] From the comparison between Example 14 and Example 4, it can be seen that the flow rate in each reaction phase is lower, and the reactor retention time is shorter, the yield and ee value achieved are lower, and the dr value is lower. The results obtained by changing the flow rate conditions during the reaction are within the error range, and there will be some fluctuations. The product will eventually be a product with purity that meets the requirements after recrystallization.

[0213] Example 15

[0214] The only difference between Example 15 and Example 4 is that the flow rate of feed liquid A is 20 mL / min, the flow rate of feed liquid B is 20 mL / min, the flow rate of feed liquid C is 20 mL / min, the reaction residence time t1 of the first continuous flow reaction is 3 min, and the reaction residence time t2 of the first continuous flow reaction is 2 min; the remaining steps are the same.

[0215] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 90% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 81%.

[0216] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0217] Example 16

[0218] The only difference between Example 16 and Example 4 is that the reaction temperature T1 of the first continuous flow reaction is -10°C, and the reaction temperature T2 of the second continuous flow reaction is -50°C.

[0219] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 88% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined by HPLC to be 74%.

[0220] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, and the single impurity was <0.1%. (1HNMR) 400MHz,CDCl3):δ8.89)s,1H),8.60)d,J=8.8Hz,1H),7.96)d,J=2.0Hz,1H),7.90)d,J=7.2Hz,1H),7.87)d,J=8.4Hz,1H),7.71)d,J=8.8Hz,1H),7.66-7.59)m,3H),7.5 1-7.46)m,1H),7.30)t,J=8.0Hz,1H),7.16-7.12)m,2H),6.88-6.87)m,3H),5.89)s,1H ),4.21)s,3H),2.54-2.50)m,1H),2.13-2.00)m,2H),1.97)s,6H),1.95-1.90)m,1H).).

[0221] Comparison of Example 16 with Example 4 shows that T1 and T2 are both higher, and the yield and ee values ​​achieved are slightly lower. This is because the results obtained by changing the temperature conditions during the reaction are within the error range, and there will be some fluctuations.

[0222] Example 17

[0223] The only difference between Example 17 and Example 4 is that the reaction temperature T1 of the first continuous flow reaction is -80°C.

[0224] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 88% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined by HPLC to be 72%.

[0225] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89 (s, 1H), 8.60 (d, J = 8.8Hz, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.90 (d, J = 7.2Hz, 1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.51-7.46(m,1H),7.30(t,J= 8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1H),4.21(s,3 H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0226] Example 18

[0227] The only difference between Example 18 and Example 2 is that the retention time t1 of the first continuous flow reaction is 30 s, and the retention time t2 of the second continuous flow reaction is 30 s.

[0228] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 89% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 83%.

[0229] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0230] Example 19

[0231] The only difference between Example 19 and Example 2 is that the temperature T2 of the second continuous flow reaction is -20°C.

[0232] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1, and the yield was 87% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined by HPLC to be 85%.

[0233] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0234] Example 20

[0235] The only difference between Example 20 and Example 4 is that the reaction temperature T2 of the second continuous flow reaction is 0°C.

[0236] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1.2, and the yield was 60% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 59%.

[0237] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90(d,J=7.2Hz ,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.51-7.46(m,1H),7.30(t,J =8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1H),4.21(s,3 H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0238] Example 21

[0239] The only difference between Example 21 and Example 4 is that the flow rates of feed liquid A, feed liquid B and feed liquid C are all 30 mL / min, which shortens the retention time of the reaction liquid. The reaction residence time of the first continuous flow reaction is t1 = 2 min; the reaction residence time of the second continuous flow reaction is t2 = 1.5 min.

[0240] The dr value of bedaquiline in the crude product was determined by nuclear magnetic resonance to be 1:1.4, and the yield was 68% (using triphenylmethane as the internal standard). The ee value of bedaquiline was determined by HPLC to be 60%.

[0241] The purity of bedaquiline in the pure product was ≥99.8% and the single impurity was <0.1%. 1H NMR (400MHz, CDCl3): δ8.89(s,1H),8.60(d,J=8.8Hz,1H),7.96(d,J=2.0Hz,1H),7.90 (d,J=7.2Hz,1H),7.87(d,J=8.4Hz,1H),7.71(d,J=8.8Hz,1H),7.66-7.59(m,3H),7.5 1-7.46(m,1H),7.30(t,J=8.0Hz,1H),7.16-7.12(m,2H),6.88-6.87(m,3H),5.89(s,1 H),4.21(s,3H),2.54-2.50(m,1H),2.13-2.00(m,2H),1.97(s,6H),1.95-1.90(m,1H).

[0242] Effect Example 1

[0243] The enantiomeric excess percentage (ie, ee value) of the crude bedaquiline of Example 1-21 was determined.

[0244] Chromatographic conditions:

[0245] The chromatographic column was Chiralpak AD-H produced by Daicel Corporation of Japan. The HPLC analysis instrument was LC-2010 produced by Shimadzu Corporation.

[0246] Mobile phase: chromatographic grade isopropanol and n-hexane

[0247] Flow rate: 0.5 mL / min

[0248] Hexane / i-PrOH=98 / 2 (here represents the volume ratio of isopropyl alcohol to n-hexane)

[0249] The detection wavelength is 220 nm.

[0250] Figure 4 is an HPLC graph of the racemate of bedaquinoline, which is required for determining the ee value of bedaquinoline. The peak area and retention time of the racemate are shown in Table 1 below.

[0251] Table 1. Peak area and retention time data of racemic bedaquiline

[0252] FIG5 is an HPLC chart of bedaquiline in the crude product of Example 1, and its peak area and retention time are shown in Table 2 below.

[0253] Table 2. Peak area and retention time data of bedaquiline of Example 1

[0254] The ee value of bedaquiline measured in Example 1 was 60%.

[0255] FIG6 is an HPLC chart of bedaquiline in the crude product of Example 2, and its peak area and retention time are shown in Table 3 below.

[0256] Table 3. Peak area and retention time data of bedaquiline of Example 2

[0257] The ee value of bedaquiline measured in Example 2 was 84%.

[0258] FIG7 is an HPLC chart of bedaquiline in the crude product of Example 3, and its peak area and retention time are shown in Table 4 below.

[0259] Table 4. Peak area and retention time data of bedaquiline of Example 3

[0260] The ee value of bedaquiline measured in Example 3 was 90%.

[0261] FIG8 is an HPLC chart of bedaquiline in the crude product of Example 4, and its peak area and retention time are shown in Table 5 below.

[0262] Table 5. Peak area and retention time data of bedaquiline of Example 4

[0263] The ee value of bedaquiline measured in Example 4 was 86%.

[0264] FIG9 is an HPLC chart of bedaquiline in the crude product of Example 5, and its peak area and retention time are shown in Table 6 below.

[0265] Table 6. Peak area and retention time data of bedaquiline of Example 5

[0266] The ee value of bedaquiline measured in Example 5 was 63%.

[0267] FIG10 is an HPLC chart of bedaquiline in the crude product of Example 6, and its peak area and retention time are shown in Table 7 below.

[0268] Table 7. Peak area and retention time data of bedaquiline of Example 6

[0269] The ee value of bedaquiline measured in Example 6 was 68%.

[0270] The ee of bedaquiline of Example 7-21 was measured using the same method as above, and the measurement results were as described above.

[0271] Effect Example 2

[0272] The purity of bedaquiline after post-treatment of the mixture of Examples 1-21 was determined.

[0273] Chromatographic conditions:

[0274] The chromatographic column was Chiralpak AD-H produced by Daicel Corporation of Japan. The HPLC analysis instrument was LC-2010 produced by Shimadzu Corporation.

[0275] Mobile phase: chromatographic grade isopropanol and n-hexane

[0276] Flow rate: 0.5 mL / min

[0277] Hexane / i-PrOH=98 / 2.

[0278] The detection wavelength is 230 nm.

[0279] Figure 11 is a spectrum of the product after recrystallization of Example 1, and its peak area and retention time are shown in Table 8. According to Table 8, bedaquiline is peak number 9, its purity is 99.864%, and the content of impurities related to the synthesis of bedaquiline is less than 0.1%.

[0280] Table 8. Peak area and retention time data of the recrystallized product of Example 1

[0281] 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 method for preparing bedaquiline by low temperature continuous flow, characterized in that: It includes the following steps: Step S1: subjecting feed liquid A and feed liquid B to a first continuous flow reaction by continuous flow to obtain reaction liquid D; the reaction residence time of the first continuous flow reaction is 30s to 600s; The feed liquid A is a mixed reaction liquid of (1S, 2R)-2-amino-1,2-diphenylethanol, N-methylpiperazine, butyl lithium, lithium chloride and tetrahydrofuran, and the feed liquid B is a mixed liquid of 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran; Step S2: the reaction solution D and the feed solution C are subjected to a second continuous flow reaction by continuous flow; the feed solution C is a mixture of 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran; the reaction residence time of the second continuous flow reaction is 30s to 600s; Step S3: Quenching.

2. The method for preparing bedaquiline by low-temperature continuous flow according to claim 1, characterized in that: The first continuous flow reaction and / or the second continuous flow reaction is carried out in a continuous flow reactor, and the continuous flow reactor is preferably a reaction pipe; And / or, the reaction residence time of the first continuous flow reaction is 30s-90s or 180s-600s; for example, 300s, 360s, 240s, 600s, 180s or 120s; And / or, the reaction residence time of the second continuous flow reaction is 30s-60s or 120s-360s; for example, 180s, 300s, 120s, 360s, 144s or 90s.

3. The method for preparing bedaquiline by low temperature continuous flow according to claim 1, characterized in that: The reaction temperature of the first continuous flow reaction is -80°C to 0°C, preferably -80°C to -20°C, more preferably -30°C to -10°C; for example, -10°C, -20°C or -30°C; And / or, the reaction temperature of the second continuous flow reaction is -80°C to 0°C, preferably -80°C to -20°C, more preferably -50°C to -80°C; for example, -50°C, -60°C, -70°C or -80°C; And / or, the quenching temperature is -80°C to 0°C, preferably -60°C to 0°C, for example 0°C or -60°C.

4. The method for preparing bedaquiline by low temperature continuous flow according to claim 1, characterized in that: In step S1, the flow rate of the feed liquid A is 10 to 500 mL / min, preferably 10 to 200 mL / min, more preferably 10 to 40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min; And / or, in step S1, the flow rate of the feed liquid B is 10 to 500 mL / min, preferably 10 to 200 mL / min, more preferably 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min; And / or, in step S2, the flow rate of the feed liquid C is 10 to 500 mL / min, preferably 10 to 200 mL / min, more preferably 10 to 40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30mL / min.

5. The method for preparing bedaquiline by low temperature continuous flow according to claim 1, characterized in that: The quenching method includes two methods: Mode 1: The quenching is carried out in a quenching device, and the quenching device is not a continuous flow reactor; the quenching solvent is preferably an ammonium chloride solution; Or, method two, the feed liquid E and the reaction liquid obtained in step S2 are subjected to a continuous quenching reaction, the feed liquid E is a quenching solvent, wherein the flow rate of the feed liquid E is preferably 10 to 500 mL / min, more preferably 10 to 200 mL / min, especially 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min; wherein the quenching solvent is preferably a protic solvent, and the protic solvent is more preferably methanol or ethanol.

6. The method for preparing bedaquiline by low-temperature continuous flow according to claim 1, characterized in that: In the feed liquid A, the volume ratio of the molar amount of the (1S, 2R)-2-amino-1,2-diphenylethanol to the tetrahydrofuran is 0.1 mol / L-0.7 mol / L; for example, 0.298 mol / L, 0.26 mol / L, 0.51 mol / L, 0.1428 mol / L, 0.28 mol / L; And / or, in the feed liquid A, the volume ratio of the molar amount of the N-methylpiperazine to the tetrahydrofuran is 0.1 mol / L-0.7 mol / L; for example, 0.355 mol / L, 0.312 mol / L, 0.170 mol / L, 0.609 mol / L, 0.1704 mol / L, 0.359 mol / L or 0.284 mol / L; And / or, in the feed liquid A, the volume ratio of the molar amount of the lithium chloride to the tetrahydrofuran is 0.1 mol / L-0.8 mol / L; for example, 0.408 mol / L, 0.354 mol / L, 0.7 mol / L, 0.196 mol / L, 0.338 mol / L; And / or, in the feed liquid A, the volume ratio of the molar amount of the n-butyl lithium to the tetrahydrofuran is 0.4 mol / L-1.2 mol / L; for example, 0.56 mol / L, 0.59 mol / L, 0.66 mol / L, 0.68 mol / L, 0.625 mol / L, 0.543 mol / L, 1.07 mol / L, or 0.3 mol / L; And / or, in the feed liquid B, the volume ratio of the 6-bromo-3-benzyl-2-methoxyquinoline to the tetrahydrofuran is 0.04 mol / L-1.0 mol / L, for example, 0.113 mol / L, 0.136 mol / L, 0.17 mol / L or 0.057 mol / L; And / or, in the feed liquid C, the volume ratio of 3-dimethylamino-1-naphthyl-1-propanone to tetrahydrofuran is 0.04 mol / L-1.0 mol / L, for example, 0.115 mol / L, 0.141 mol / L, 0.152 mol / L, 0.630 mol / L, 0.136 mol / L, 0.163 mol / L, 0.255 mol / L; And / or, the molar ratio of the N-methylpiperazine to the 6-bromo-3-benzyl-2-methoxyquinoline is 0.5-5.0, preferably 1.5-5.0; for example, 2.5, 2.1, 2 or 4.

5.

7. The method for preparing bedaquiline by low-temperature continuous flow according to claim 1, characterized in that: The molar ratio of the (1S, 2R)-2-amino-1,2-diphenylethanol to the 6-bromo-3-benzyl-2-methoxyquinoline is 0.8-5.0, preferably 1.5-5.0; for example, 2.1, 1.8, 2.0 or 3.0; And / or, the molar ratio of the lithium chloride to the 6-bromo-3-benzyl-2-methoxyquinoline is 0.8-5.0, preferably 1.5-5.0; for example, 2.9 or 2.4; and / or, the molar ratio of the n-butyl lithium to the 6-bromo-3-benzyl-2-methoxyquinoline is 1.0-10.0, preferably 3.0-10.0; for example, 3.68 or 4.41; And / or, the molar ratio of the 3-dimethylamino-1-naphthyl-1-propanone to the 6-bromo-3-benzyl-2-methoxyquinoline is 0.8-5.0, preferably 1.5-5.0; for example, 1.1, 1.2, 1.3, 1.5 or 2.

5.

8. The method for preparing bedaquiline by low-temperature continuous flow according to claim 1, characterized in that: After step S3, post-processing is also included, and the post-processing includes extraction, recrystallization and pulping; Wherein, the solvent for recrystallization and the solvent for slurrying are preferably one or more of toluene, ethyl acetate, n-hexane, ethanol, isopropanol, benzene, and isopropyl ether.

9. The method for preparing bedaquiline by low-temperature continuous flow as claimed in claim 8, characterized in that: The recrystallization method comprises the following steps: removing the extraction solvent to obtain a filtrate, preparing a saturated solution of the filtrate and a recrystallization solvent, and crystallizing to obtain a diastereoisomer of bedaquiline; Wherein, the method for removing the extracted solvent is preferably to precipitate solid from the organic phase after the extraction on a rotary evaporator, and filter to obtain the filtrate; Wherein, the crystallization method is preferably to cool the saturated solution of the filtrate and the recrystallization solvent to precipitate crystals from the supersaturated solution, filter to obtain a filtrate, and remove the recrystallization solvent in the filtrate; the method of removing the recrystallization solvent in the filtrate is more preferably to spin-dry the filtrate; the cooling temperature is preferably -20°C to 0°C, more preferably -20°C to -15°C; And / or, after the filtrate is spin-dried, pure bedaquiline is obtained by pulping.

10. A product prepared by the method for preparing bedaquiline by low-temperature continuous flow as claimed in any one of claims 1 to 7.

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