Process for preparing bedaquiline by continuous flow at low temperature and products prepared by this process

Abstract

The present invention provides a method for preparing bedaquiline by continuous flow at low temperature, and the prepared product. This preparation method includes the following steps S1 to S3. Step S1: Feed liquid A and feed liquid B are subjected to a first continuous flow reaction by continuous flow to obtain reaction liquid D. Step S2: Reaction liquid D and feed liquid C are subjected to a second continuous flow reaction by continuous flow, with the reaction residence time of the first continuous flow reaction being 30 to 600 seconds, and the reaction residence time of the second continuous flow reaction being 30 to 200 seconds. Step S3: Quenching. The preparation method of the present invention has a high yield, and pure bedaquiline with a purity of 99.8% or more can be obtained by simply working up the crude product obtained by preparing bedaquiline by the method of the present invention.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to Chinese Patent Application No. 202310959686.6 filed on August 1, 2023 (title: Method for preparing bedaquiline by continuous flow at low temperature and product prepared by this method), the entire contents of which are incorporated herein by reference. The present invention relates to a process for preparing bedaquiline by continuous flow at low temperature and to the products prepared by this process. [Background technology]

[0002] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mycobacterium tuberculosis) and is the single pathogen responsible for the highest number of deaths (approximately 1.6 million people per year). Bedaquiline was approved by the FDA in 2012 for the treatment of multidrug-resistant and rifampicin-resistant tuberculosis (MDR / RR-TB). In 2018, the WHO reclassified bedaquiline as a first-line treatment for long-term treatment of MDR / RR-TB. The stereoselective construction of the Csp3-Csp3 bond at the consecutive chiral centers in this drug molecule is extremely challenging, and its high price remains due to the lack of an efficient industrialized synthesis route. Therefore, improving the production process, reducing synthesis costs, and enabling low-income individuals to afford the drug are urgent issues.

[0003] The original patent for the synthesis of β-quinoline (patent number CN101180302B) discloses a one-step synthesis method in which 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-acetone to obtain a mixture of four enantiomers of β-quinoline. The reaction mixture is then concentrated, treated with ethanol, and further resolved using the chiral resolving agent (R)-binaphthol phosphate to obtain β-quinoline (BDQ), although the overall yield is very low (7-9%). Furthermore, due to the efficiency of asymmetric catalytic synthesis, methods for obtaining β-quinoline using asymmetric catalytic synthesis have attracted the attention of scientists. Shibasaki and Chandrasekhar reported the construction of the first chiral carbon by asymmetric catalytic synthesis, followed by the construction of the second chiral carbon by asymmetric synthesis. However, all of these routes have problems such as multiple reaction steps, low yields, and high manufacturing costs. In 2020, a South African research group used a C2-symmetric chiral amine ligand to improve the diastereoselectivity of BDQ to 9:1 (ACSOmega 2020, 5, 3607-3611). They then used chiral resolution to obtain the optically pure target compound, but the product yield did not improve. Recently, Jamison et al. used fluid chemistry (Chem.Eur.J. 2022, e202201311) to improve the yield of this reaction route and obtain a mixture of four isomers. However, this technical solution still does not achieve efficient synthesis of the target product. Recently, Professor Zhang Wanbin's team at Shanghai Jiao Tong University published a strategy for the asymmetric synthesis of bedaquiline (Sci.ChinaChem.2022, 65, 1968-1977). Based on this synthetic route, they developed two routes for the asymmetric synthesis of bedaquiline using their own Li / Li bimetallic cooperative activation strategy. The results of the kettle-type reaction were 81% yield, 1.4:1dr, 91%ee, and 22% yield, 16:1dr, >99%ee, respectively.The synthesis of bedaquiline through the above reaction still has the technical problem of low yield, and in the post-treatment process, column chromatography is required to obtain a product with a purity of more than 99%, and is limited to the traditional kettle reaction process, which requires a long reaction time, complicated operations, is prone to impurities, and has safety issues due to the use of active butyllithium reagent.

[0004] Therefore, the conventional bedaquiline synthesis technology still has technical defects such as low yield, long production cycle, high cost, complicated operation, and low safety, etc. Therefore, the development of a new bedaquiline synthesis technology has important research significance and application value. Summary of the Invention

[0005] To solve the technical deficiencies of the prior art in the preparation of bedaquiline, such as low yield, long production cycle, high cost, complicated operation, and poor safety, the present invention provides a method for preparing bedaquiline at low temperature using a continuous flow method, and the product prepared by this method. The method of the present invention has a high yield, and by preparing bedaquiline using the method of the present invention, the purity of pure bedaquiline can reach 99.8% or more with just a simple workup of the resulting mixture after the quenching reaction, and the operation is simple, safe, and the production cycle is short.

[0006] According to the present invention, there is provided a method for preparing bedaquiline by continuous flow at low temperature, comprising the following steps S1 to S3: Step S1: Feed liquid A and feed liquid B are subjected to a first continuous flow reaction by continuous flow to obtain reaction liquid D, and the reaction residence time of the first continuous flow reaction is 30 seconds to 600 seconds; the feed solution A is a mixed reaction solution of (1S,2R)-2-amino-1,2-diphenylethanol, N-methylpiperazine, butyllithium, lithium chloride, and tetrahydrofuran, the feed solution B is a mixed solution of 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran, Step S2: subjecting the reaction solution D and the feed solution C to a second continuous flow reaction through continuous flow, the feed solution C being a mixed solution of 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran, and the reaction residence time of the second continuous flow reaction being 30 seconds to 600 seconds; Step S3: Quenching; A method is provided.

[0007] As known to those skilled in the art, a device for carrying out a continuous flow reaction may usually be a continuous flow reactor. In the present invention, the first continuous flow reaction and / or the second continuous flow reaction may be carried out in a continuous flow reactor. The continuous flow reactor is preferably a reaction pipe.

[0008] In the present invention, the reaction residence time of the first continuous flow reaction is preferably 30 s to 90 s or 180 s to 600 s, for example, 300 s, 360 s, 240 s, 600 s, 180 s, or 120 s. The first continuous flow reaction includes an acid-base reaction and a coordination reaction between the feed liquid A and the feed liquid B.

[0009] In the present invention, the reaction residence time of the second continuous flow reaction is preferably 30 s-60 s or 120 s-360 s, for example, 180 s, 300 s, 120 s, 360 s, 144 s or 90 s.

[0010] In the present invention, the reaction temperature of the first continuous flow reaction may 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.

[0011] In the present invention, the reaction temperature of the second continuous flow reaction may 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.

[0012] In step S1, the flow rate of the feed liquid A is preferably 10 to 500 mL / min, more preferably 10 to 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.

[0013] In step S1, the flow rate of the feed liquid B is preferably 10 to 500 mL / min, more preferably 10 to 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.

[0014] In step S2, the flow rate of the feed liquid C is preferably 10 to 500 mL / min, more preferably 10 to 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.

[0015] In step S2, as known to those skilled in the art, the flow rate of the reaction solution D can be determined after the feed solution A and the feed solution B enter, for example, a microchannel in a continuous flow reactor. The flow rate of the reaction solution D may 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.

[0016] In step S1, the ratio of the molar amount of the (1S,2R)-2-amino-1,2-diphenylethanol to the volume of the tetrahydrofuran in the feed solution A is preferably 0.1 to 0.7 mol / L, for example, 0.298 mol / L, 0.26 mol / L, 0.51 mol / L, 0.1428 mol / L, or 0.28 mol / L.

[0017] In step S1, the ratio of the molar amount of the N-methylpiperazine to the volume of the tetrahydrofuran in the feed solution A is preferably 0.1 mol / L to 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.

[0018] In step S1, the ratio of the molar amount of the lithium chloride to the volume of the tetrahydrofuran in the feed solution A is preferably 0.1 mol / L to 0.8 mol / L, for example, 0.408 mol / L, 0.354 mol / L, 0.7 mol / L, 0.196 mol / L, or 0.338 mol / L.

[0019] In step S1, the ratio of the molar amount of n-butyllithium to the volume of tetrahydrofuran in the feed solution A is preferably 0.4 mol / L to 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.

[0020] In step S1, the volume ratio of the 6-bromo-3-benzyl-2-methoxyquinoline to the tetrahydrofuran in the feed solution B 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.

[0021] In step S1, the volume ratio of 3-dimethylamino-1-naphthyl-1-propanone to tetrahydrofuran in the feed solution 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.

[0022] 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.

[0023] In step S1, the molar ratio of the (1S,2R)-2-amino-1,2-diphenylethanol to 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.

[0024] 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.

[0025] In step S1, the molar ratio of the n-butyllithium to the 6-bromo-3-benzyl-2-methoxyquinoline is preferably 1.0 to 10.0, more preferably 3.0 to 10.0, for example, 3.68 or 4.41.

[0026] 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.

[0027] In step S1, the mixed reaction solution of (1S,2R)-2-amino-1,2-diphenylethanol, N-methylpiperazine, butyllithium, lithium chloride, and tetrahydrofuran can be obtained by a conventional method in the art. For example, (1S,2R)-2-amino-1,2-diphenylethanol, N-methylpiperazine, butyllithium, lithium chloride, and tetrahydrofuran may be mixed and reacted.

[0028] 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 to 30 min, for example, 20 min or 30 min.

[0029] As known to those skilled in the art, tetrahydrofuran is used as a solvent in the reaction.

[0030] In step S1, the temperature of the mixed reaction solution 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.

[0031] In step S1, the mixed solution of 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran can be obtained by a conventional method in the art, for example, by mixing 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran.

[0032] In step S2, the mixed solution of 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran can be obtained by a conventional method in the art, for example, by mixing 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran.

[0033] In the present invention, the quenching method comprises: Scheme 1, wherein the quenching is carried out in a quenching apparatus, which is not a continuous flow reactor, and the quenching solvent can be a conventional quenching solvent in the art, preferably an ammonium chloride solution; or a method 2 in which a quench reaction is continuously carried out between the feed liquid E and the reaction liquid obtained in step S2, the feed liquid E being a quench solvent, the quench solvent being preferably a protic solvent, and the protic solvent may be methanol or ethanol, the flow rate of the feed liquid E being 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 quench reaction being carried out in a continuous flow reactor, and the continuous flow reactor being preferably a reaction piping; Includes.

[0034] In the present invention, preferably, step S3 is followed by post-treatment, which includes extraction, recrystallization, and slurrying.

[0035] The recrystallization solvent and the slurrying solvent may be any conventional recrystallization solvent and slurrying solvent in the art, and are preferably one or more of toluene, ethyl acetate, n-hexane, ethanol, isopropyl alcohol, benzene, and isopropyl ether. The ethanol is preferably absolute ethanol.

[0036] Preferably, the recrystallization method comprises the steps of removing the extraction solvent to obtain a filtrate, preparing a saturated solution of the filtrate and a recrystallization solvent, and crystallizing.

[0037] The method for removing the extraction solvent is preferably to separate out solids from the organic phase after the extraction using a rotary evaporator, and then to obtain the filtrate by filtration.

[0038] The crystallization method is preferably to cool the saturated solution of the filtrate and the recrystallization solvent to precipitate crystals from the supersaturated solution, and then filter the filtrate to remove the recrystallization solvent from the filtrate. The method for removing the recrystallization solvent from the filtrate is more preferably to spin-dry the filtrate. After spin-drying the filtrate, pure bedaquiline is obtained by slurrying it.

[0039] As known to those skilled in the art, the slurrying step typically further includes filtration to obtain pure bedaquiline.

[0040] In the present invention, the filtration method is a common method in the art, for example, suction filtration.

[0041] The present invention further provides products prepared by the above-described low temperature continuous flow process for preparing bedaquiline.

[0042] In the present invention, the overall reaction scheme for preparing said bedaquiline is as follows: [ka]

[0043] The inventors have found through research that, although dissolving 6-bromo-3-benzyl-2-methoxyquinoline in feed solution A and then mixing it with feed solution B to react does not have a significant effect on the reaction mechanism, the large amount of material in the reaction phase increases the viscosity of the fluid, which can result in clogging the continuous flow line, destroying the device, and preventing the reaction from proceeding.

[0044] Based on the common knowledge of the art, each preferred embodiment of the present invention can be obtained by arbitrarily combining each of the above preferred conditions.

[0045] All reagents and raw materials used in the present invention are commercially available products.

[0046] The beneficial effects of the present invention are as follows: In the present invention, the entire reaction phase of feed liquid A is used as a catalyst, and bedaquiline is prepared by combining a low-cost, high-reaction-efficiency asymmetric synthesis route with continuous flow technology. This avoids problems such as difficult temperature control and time-consuming dropwise addition and stirring that occur in conventional kettle-type reactions, shortens the production cycle, reduces the risks posed by active lithium reagents, and achieves a high yield. Furthermore, by preparing bedaquiline using the preparation method of the present invention, the purity of pure bedaquiline can reach 99.8% or more with just a simple work-up of the resulting mixture after the quenching reaction, which reduces operating costs and is highly suitable for industrial production and has important application value.

[0047] Furthermore, compared to Route A in the asymmetric synthesis strategy for bedaquiline by Professor Zhang Wanbin's team at Shanghai Jiao Tong University (Sci. China Chem. 2022, 65, 1968-1977), the process of the present invention requires only about 3 hours to input 100 g of raw materials each time and achieve the same yield or purity, whereas the method in this literature requires a reaction time of 37 hours. [Brief explanation of the drawings]

[0048] [Figure 1] 1 is a flow chart of a method for preparing bedaquiline by continuous flow at low temperature according to Example 1. [Figure 2] 1 is a flow chart of a method for preparing bedaquiline by continuous flow at low temperature according to Example 2. [Figure 3] 1 is a flowchart of a method for preparing bedaquiline by continuous flow at low temperature according to Example 6. Key words: i: continuous flow experimental pump, ii: check valve, iii: pre-cooling tube, iv: reaction tube, v: micromixer, T1: reaction temperature of feed liquid A and feed liquid B, T2: reaction temperature of the reaction system and feed liquid C, T3: quench temperature of the reaction system, reaction time t1: residence time of feed liquid A and feed liquid B in the reactor at temperature T1, t2: residence time of reaction liquid D and feed liquid C in the reactor at temperature T2. [Figure 4]FIG. 1 is an HPLC profile of racemic bedaquiline in Example 1 of the present invention. [Figure 5] FIG. 1 is an HPLC profile of bedaquiline in the crude product of Example 1 of the present invention. [Figure 6] FIG. 1 is an HPLC profile of bedaquiline in the crude product of Example 2 of the present invention. [Figure 7] FIG. 1 is an HPLC profile of bedaquiline in the crude product of Example 3 of the present invention. [Figure 8] FIG. 1 is an HPLC profile of bedaquiline in the crude product of Example 4 of the present invention. [Figure 9] FIG. 1 is an HPLC profile of bedaquiline in the crude product of Example 5 of the present invention. [Figure 10] FIG. 1 is an HPLC profile of bedaquiline in the crude product of Example 6 of the present invention. [Figure 11] FIG. 1 is an HPLC profile of the product after recrystallization of the crude product of Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0049] The present invention will be described in detail below with reference to specific examples. The following examples are intended to help those skilled in the art to further understand the present invention, but are not intended to limit the present invention. Those skilled in the art may make some modifications and improvements without departing from the spirit of the present invention. These modifications and improvements are also within the scope of protection of the present invention.

[0050] In the following examples, as known to those skilled in the art, enantiomeric excess is a measure of the purity of a chiral substance and indicates the degree to which one enantiomer is more abundant than the other in a sample. Purity is measured by HPLC using a Chiralpak AD-H chiral chromatography column manufactured by Daicel Corporation, with chromatographically pure isopropyl alcohol and n-hexane. dr values ​​are measured by nuclear magnetic resonance spectroscopy (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 this compound to 6-bromo-3-benzyl-2-methoxyquinoline.

[0051] Example 1 The flow chart of the process for preparing bedaquiline by continuous flow at low temperature according to Example 1 is shown in FIG.

[0052] Step S1: A dry 5-L reactor was charged with 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. Then, 150 mL (375 mmol) of a 2.5 M (2.5 mol / L) n-butyllithium n-hexane solution was added at −20° C., and the mixture was reacted for 30 minutes to obtain feed solution A. 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-neck flask, and 750 mL of anhydrous tetrahydrofuran was added and mixed uniformly to prepare feed solution B. The raw material 2 (3-dimethylamino-1-naphthyl-1-propanone) (26.9 g, 102 mmol) was placed in a 5 L one-necked flask, and 750 mL of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed solution C. Here, 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.

[0053] Step S2: Feed solution A and feed solution B were pumped into the first micro reactor tube to carry out a first continuous flow reaction, yielding reaction solution D. The reaction temperature T1 was set to -20°C, and the reaction residence time t1 was set to 5 min.

[0054] Step S3: Reaction solution D and feed solution C were pumped into the second micro reactor to carry out a second continuous flow reaction, with the reaction temperature T2 set to -60°C and the reaction residence time t2 set to 3 min.

[0055] Step S4: Quenching: The reaction solution from step S3 was drained from the second microreaction tube and introduced into 2 L of saturated ammonium chloride solution for quenching, with the quenching temperature T3 being −60° C. The reaction solution after quenching was collected to obtain a mixture containing bedaquiline.

[0056] Step S5: Post-treatment: Extraction, recrystallization and slurrying

[0057] Extraction: The mixture was extracted with ethyl acetate (3 times * 1 L) in a 5 L reaction vessel, and the organic phase was collected to obtain the crude product.

[0058] Recrystallization: The extraction solvent was removed to obtain a filtrate, and a saturated solution of the filtrate and the recrystallization solvent was prepared and crystallized. The extraction solvent was removed by precipitating the organic phase after extraction using a rotary evaporator and filtering the filtrate. The crystallization method involved cooling the saturated solution of the filtrate and the recrystallization solvent, precipitating crystals from the supersaturated solution, filtering the filtrate, and then rotary drying the filtrate. The cooling temperature was -20°C to -15°C. Specifically, the organic phase after extraction was subjected to rotary evaporation using a rotary evaporator. When a solid precipitated, the evaporation was stopped and the mixture was left overnight to precipitate the first solid, which was then suction filtered to obtain the filtrate. The filter cake was washed with n-hexane. Most of the filter cake consisted of diastereomers and ligands. An equal amount of n-hexane to the organic solvent was added to the filtrate, which was then cooled. Crystals were precipitated from the supersaturated solution, which was then suction filtered until most of the filtrate was the desired product. The filtrate was then rotary dried to obtain the second solid.

[0059] Slurrying: The second solid was mixed with ethanol, slurried at room temperature for 12 hours, filtered under suction, the filter cake was washed with n-hexane, and dried under vacuum at room temperature to obtain pure bedaquiline.

[0060] Nuclear magnetic resonance analysis of the crude product showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 95%. The ee value of bedaquiline obtained by HPLC was 60%. The yield was calculated using the formula: yield = x * y / n, where triphenylmethane was used as the internal standard and the integral of the characteristic peak of the internal standard was set to 1, 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.

[0061] The obtained pure bedaquiline was a white solid, and the purity of bedaquiline in the pure product was ≧99.8% and the content of single impurities was <0.1% as detected by HPLC. The structural property data of bedaquiline are as follows: 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)

[0062] Example 2 The flow chart of the preparation method of bedaquiline according to Example 2 is shown in FIG.

[0063] Step S1: A dry 5-L reactor was charged with 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. Then, 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 minutes to obtain feed solution A. 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-neck flask, and 750 mL of anhydrous tetrahydrofuran was added thereto. The mixture was mixed uniformly to prepare feed solution B. 3-Dimethylamino-1-naphthyl-1-propanone (2) (26.9 g, 102 mmol) was placed in a 5 L one-neck flask, and 750 mL of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed solution C. The flow rate of feed solution A was 15 mL / min, the flow rate of feed solution B was 15 mL / min, and the flow rate of feed solution C was 15 mL / min.

[0064] Step S2: Feed solution A and feed solution B were pumped into the first micro reactor tube to carry out a first continuous flow reaction, yielding reaction solution D. The reaction temperature T1 was set to -20°C, and the reaction residence time t1 was set to 5 min.

[0065] Step S3: Reaction solution D and feed solution C were pumped into the second micro reactor to carry out a second continuous flow reaction. The reaction temperature T2 was set to -60°C, and the reaction residence time t2 was set to 3 min.

[0066] Step S4: Quenching: The reaction solution from step S3 was drained from the second microreaction tube and quenched by introducing it into 2 L of saturated ammonium chloride solution. The quenching temperature T3 was set to -60°C. The reaction solution after quenching was collected to obtain a mixture containing bedaquiline.

[0067] Step S5: Post-treatment: Extraction, recrystallization and slurrying The crude product was obtained by extraction as in Example 1. The pure product was obtained by similar recrystallization and slurry steps.

[0068] Nuclear magnetic resonance analysis revealed a dr of 1:1 and a yield of 91% for the crude bedaquiline (triphenylmethane was used as an internal standard). HPLC analysis revealed an ee of 84% for bedaquiline.

[0069] HPLC detection revealed that the purity of bedaquiline in the pure product was ≥ 99.8% and the single impurity content was < 0.1%. The structural property data of bedaquiline are as follows: 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)

[0070] Example 3 The flow chart of the preparation method of bedaquiline according to Example 3 is shown in FIG.

[0071] Step S1: A dry 5-L reactor was charged with 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. Then, 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 minutes to obtain feed solution A. 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-neck flask, and 750 mL of anhydrous tetrahydrofuran was added thereto. The mixture was mixed uniformly to prepare feed solution B. 3-Dimethylamino-1-naphthyl-1-propanone (raw material 2) (26.9 g, 102 mmol) was placed in a 5 L one-neck flask, and 750 mL of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed solution C. The flow rate of feed solution A was 20 mL / min, the flow rate of feed solution B was 15 mL / min, and the flow rate of feed solution C was 15 mL / min.

[0072] Step S2: Feed solution A and feed solution B were pumped into the first micro reactor tube to carry out a first continuous flow reaction, yielding reaction solution D. The reaction temperature T1 was set to -20°C, and the reaction residence time t1 was set to 5 min.

[0073] Step S3: Reaction solution D and feed solution C were pumped into the second micro reactor to carry out a second continuous flow reaction, with the reaction temperature T2 set to -60°C and the reaction residence time t2 set to 3 min.

[0074] Step S4: Quenching: The reaction solution from step S3 was drained from the second microreaction tube and quenched by introducing it into 2 L of saturated ammonium chloride solution, and the quenching temperature T3 was set to −60° C. The reaction solution after quenching was collected to obtain a mixture containing bedaquiline.

[0075] Step S5: Post-treatment: Extraction, recrystallization and slurrying The crude product was obtained by extraction as in Example 1. The pure product was obtained by similar recrystallization and slurry steps.

[0076] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 91% (triphenylmethane was used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 90%.

[0077] HPLC detection revealed that the purity of bedaquiline in the pure product was ≥ 99.8% and the single impurity content was < 0.1%. The structural property data of bedaquiline are as follows: 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)

[0078] Example 4 The flow chart of the preparation method of bedaquiline according to Example 4 is shown in FIG.

[0079] Step S1: A dry 5 L reactor was charged with 20.8 g (490 mmol, 2.9 equiv) of lithium chloride, 76.6 g (359 mmol, 2.1 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 47.8 mL (431 mmol, 2.5 equiv) of N-methylpiperazine, and 1.2 L of anhydrous tetrahydrofuran. 300 mL (750 mmol) of a 2.5 M n-butyllithium solution in n-hexane was added at −20° C., and the mixture was reacted for 30 minutes to obtain feed solution A. 55.8 g of raw material 1 (170 mmol) was placed in a 5 L single-neck flask, and 1.5 L of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed solution B. 60 g (227.5 mmol) of 3-dimethylamino-1-naphthyl-1-propanone was placed in a 5 L single-neck flask, and 1.5 L of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed liquid C. The flow rate of feed solution A was 15 mL / min, the flow rate of feed solution B was 15 mL / min, and the flow rate of feed solution C was 15 mL / min. Step S2: Feed solution A and feed solution B were pumped into the first micro reactor tube to carry out a first continuous flow reaction, yielding reaction solution D. The reaction temperature T1 was set to -20°C, and the reaction residence time t1 was set to 5 min. Step S3: Reaction solution D and feed solution C were pumped into the second micro reactor to carry out a second continuous flow reaction, with the reaction temperature T2 set to -60°C and the reaction residence time t2 set to 3 min. Step S4: Quenching: The reaction solution from step S3 was drained from the second microreaction tube and quenched by introducing it into 2 L of saturated ammonium chloride solution, and the quenching temperature was set to 0° C. The reaction solution after quenching was collected to obtain a mixture containing bedaquiline. Step S5: Post-treatment: Extraction, recrystallization and slurrying The crude product was obtained by the same extraction steps as in Example 1. The pure product was obtained by the same recrystallization and slurry steps.

[0080] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 93% (triphenylmethane used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 86%.

[0081] HPLC detection revealed that 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)

[0082] Example 5 The flow chart of the preparation method of bedaquiline according to Example 5 is shown in FIG.

[0083] Step S1: A dry 5-L reactor was charged with 34.6 g (816 mmol, 2.4 equiv) of lithium chloride, 127.5 g (598 mmol, 1.8 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 79.5 mL (717 mmol, 2.1 equiv) of N-methylpiperazine, and 2.3 L of anhydrous tetrahydrofuran. 500 mL (1250 mmol) of a 2.5 M n-butyllithium solution in n-hexane was added at −20° C., and the mixture was reacted for 30 minutes to obtain feed solution A. 111.6 g of raw material 1 (340 mmol) was placed in a 5 L single-neck flask, and 2.5 L of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed solution B. 104 g of 3-dimethylamino-1-naphthyl-1-propanone (408 mmol) was placed in a 5 L one-neck flask, and 2.5 L of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed liquid C. The flow rate of feed solution A was 15 mL / min, the flow rate of feed solution B was 15 mL / min, and the flow rate of feed solution C was 15 mL / min. Step S2: Feed solution A and feed solution B were pumped into the first micro reactor tube to carry out a first continuous flow reaction, yielding reaction solution D. The reaction temperature T1 was set to -20°C, and the reaction residence time t1 was set to 5 min. Step S3: Reaction solution D and feed solution C were pumped into the second micro reactor to carry out a second continuous flow reaction, with the reaction temperature T2 set to -60°C and the reaction residence time t2 set to 3 min. Step S4: Quenching: The reaction solution from step S3 was drained from the second microreaction tube and quenched by introducing it into 2 L of saturated ammonium chloride solution, and the quenching temperature was set to 0° C. The reaction solution after quenching was collected to obtain a mixture containing bedaquiline. Step S5: Post-treatment: Extraction, recrystallization and slurrying The crude product was obtained by extraction as in Example 1. The pure product was obtained by similar recrystallization and slurry steps.

[0084] Nuclear magnetic resonance analysis revealed a dr of 1.2:1 for the crude bedaquiline in a yield of 89% (triphenylmethane was used as an internal standard). HPLC analysis revealed an ee of 63% for bedaquiline.

[0085] As a result of HPLC detection, 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)

[0086] Example 6 The flow chart of the preparation method of bedaquiline according to Example 6 is shown in FIG.

[0087] Step S1: A dry 5-L reactor was charged with 34.6 g (816 mmol, 2.4 equiv) of lithium chloride, 127.5 g (598 mmol, 1.8 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 79.5 mL (717 mmol, 2.1 equiv) of N-methylpiperazine, and 2.3 L of anhydrous tetrahydrofuran. 500 mL (1250 mmol) of a 2.5 M n-butyllithium solution in n-hexane was added at −20° C., and the mixture was reacted for 30 minutes to obtain feed solution A. 111.6 g of raw material 1 (340 mmol) was placed in a 5 L single-neck flask, and 2.5 L of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed solution B. 104 g of 3-dimethylamino-1-naphthyl-1-propanone (408 mmol) was placed in a 5 L one-neck flask, and 2.5 L of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed liquid C. The flow rate of feed solution A was 15 mL / min, the flow rate of feed solution B was 15 mL / min, and the flow rate of feed solution C was 15 mL / min. Step S2: Feed solution A and feed solution B were pumped into the first micro reactor tube to carry out a first continuous flow reaction, yielding reaction solution D. The reaction temperature T1 was set to -20°C, and the reaction residence time t1 was set to 5 min. Step S3: Reaction solution D and feed solution C were pumped into the second micro reactor to carry out a second continuous flow reaction, with the reaction temperature T2 set to -60°C and the reaction residence time t2 set to 3 min. Step S4: Quench: 1 L of absolute ethanol was placed in a 5 L single-neck flask to serve as feed solution E. The reaction solution obtained in step S3 and feed solution E were placed in a third microreaction tube to carry out a continuous quench reaction. The flow rate of feed solution E was 10 mL / min, and the quenching temperature was 0°C. The reaction solution after quenching was collected to obtain a mixture containing bedaquiline. Step S5: Post-treatment: Extraction, recrystallization and slurrying The crude product was obtained by extraction as in Example 1. The pure product was obtained by similar recrystallization and slurry steps.

[0088] Nuclear magnetic resonance analysis revealed that the dr of bedaquiline in the crude product was 1.2:1, with a yield of 92% (triphenylmethane used as an internal standard). HPLC analysis revealed that the ee of bedaquiline was 68%.

[0089] As a result of HPLC detection, 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)

[0090] Example 7 Example 7 was the same as Example 1, except that the reaction temperature T1 of the first continuous flow reaction was -30°C and the reaction temperature T2 of the second continuous flow reaction was -70°C.

[0091] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 91% (triphenylmethane was used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 78%.

[0092] As a result of HPLC detection, 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)

[0093] Example 8 Example 8 was the same as Example 7, except that the reaction temperature T2 of the second continuous flow reaction was set to -80°C.

[0094] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 91% (triphenylmethane was used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 78%.

[0095] As a result of HPLC detection, 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)

[0096] Example 9 Example 9 was the same as Example 2, except that the reaction temperature T2 of the second continuous flow reaction was set to -70°C.

[0097] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 92% (triphenylmethane used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 88%.

[0098] As a result of HPLC detection, 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)

[0099] Example 10 Example 10 was the same as Example 2, except that the flow rates of feed liquid A, feed liquid B, and feed liquid C were 10 mL / min, t1 = 6 min, t2 = 5 min, and quench temperature was -60°C, respectively.

[0100] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 91% (triphenylmethane was used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 84%.

[0101] As a result of HPLC detection, 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)

[0102] Example 11 Example 11 was the same as Example 2, except that the quench temperatures in steps S1 and S4 were changed.

[0103] Step S1: A dried 5 L reactor was charged with 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. Then, 150 mL (375 mmol) of 2.5 M n-butyllithium in n-hexane was added at −20°C, and the mixture was reacted for 20 minutes to obtain feed solution A. 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-neck flask, and 750 mL of anhydrous tetrahydrofuran was added thereto. The mixture was mixed uniformly to prepare feed solution B. 3-Dimethylamino-1-naphthyl-1-propanone (2) (26.9 g, 102 mmol) was placed in a 5 L one-neck flask, and 750 mL of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed solution C. The flow rate of feed solution A was 15 mL / min, the flow rate of feed solution B was 15 mL / min, and the flow rate of feed solution C was 15 mL / min.

[0104] The quench temperature in step S4 was set to -60°C.

[0105] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 88% (triphenylmethane used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 80%.

[0106] As a result of HPLC detection, 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).

[0107] Example 12 Example 12 was the same as Example 2, except that the volume of tetrahydrofuran used and the reaction residence time in step S1, and the quench temperature in step S4 were changed.

[0108] Step S1: A dry 5-L reactor was charged with 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. Then, 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 minutes to obtain feed solution A. 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-neck flask, and 500 mL of anhydrous tetrahydrofuran was added thereto. The mixture was mixed uniformly to prepare feed solution B. 3-Dimethylamino-1-naphthyl-1-propanone (28.9 g, 127.5 mmol) was placed in a 5 L one-neck flask, and 500 mL of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed solution C. The flow rate of feed solution A was 15 mL / min, and the flow rate of feed solution B was 15 mL / min. The reaction residence time of the first continuous flow reaction in step S2 was set to t1 = 4 min. The reaction residence time of the second continuous flow reaction in step S3 was set to t2 = 2 min. The quench temperature in step S4 was set to -60°C. Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 86% (triphenylmethane as an internal standard). HPLC analysis showed that the ee of bedaquiline was 76%.

[0109] As a result of HPLC detection, 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)

[0110] In Example 12, compared with Example 2, the amount of anhydrous tetrahydrofuran in each reaction phase was smaller, which corresponds to changing the concentration of materials during the reaction process and shortening the residence time in the reactor, which resulted in some fluctuations in the reaction results and lower yields and ee values. However, after recrystallization of the product, a product with purity that met the requirements was finally obtained.

[0111] Example 13 Example 13 was the same as Example 2, except that the volume of tetrahydrofuran used in step S1 and the quenching temperature in step S4 were changed.

[0112] Step S1: A dry 5 L reactor was charged with 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 1.25 L of anhydrous tetrahydrofuran. Then, 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 minutes to obtain feed solution A. 27.9 g of raw material 1 (85 mmol) was placed in a 5 L single-neck flask, and 1.5 L of anhydrous tetrahydrofuran was added thereto. The mixture was mixed uniformly to prepare feed solution B. 3-Dimethylamino-1-naphthyl-1-propanone (2) (26.9 g, 102 mmol) was placed in a 5 L one-neck flask, and 1.5 L of anhydrous tetrahydrofuran was added thereto and mixed uniformly to prepare feed solution C. The flow rate of feed solution A was 15 mL / min, the flow rate of feed solution B was 15 mL / min, and the flow rate of feed solution C was 15 mL / min. The reaction residence time of the first continuous flow reaction in step S2 was set to t1 = 10 min. The reaction residence time of the second continuous flow reaction in step S3 was set to t2 = 6 min. The quench temperature in step S4 was set to -60°C.

[0113] Nuclear magnetic resonance analysis revealed a dr of 1:1 for the crude bedaquiline, with a yield of 94% (triphenylmethane as an internal standard). HPLC analysis revealed an ee of 89% for bedaquiline.

[0114] As a result of HPLC detection, 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)

[0115] In Example 13, compared with Example 2, the dosage of anhydrous tetrahydrofuran in each reaction phase was higher, which corresponds to changing the concentration of materials during the reaction process, and the residence time in the reactor was longer, and the achieved yield and ee value were both better.

[0116] Example 14 Example 14 was the same as Example 4, except that the flow rate of each feed solution and the reaction residence time were changed.

[0117] The flow rates of feed liquid A, B, and C were set to 12 mL / min, 12 mL / min, and 12 mL / min, respectively. 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.

[0118] Nuclear magnetic resonance analysis revealed that the dr of bedaquiline in the crude product was 1:1.2, with a yield of 87% (triphenylmethane as an internal standard). HPLC analysis revealed that the ee of bedaquiline was 76%.

[0119] As a result of HPLC detection, 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)

[0120] In Example 14, compared with Example 4, the flow rate in each reaction phase was lower, the residence time in the reactor was shorter, and the achieved yield and ee value were all lower, and the dr value was also lower. Although the results obtained by changing the flow rate conditions during the reaction process varied to some extent within the range of error, after recrystallization of the product, a product with purity that met the requirements was finally obtained.

[0121] Example 15 Example 15 was the same as Example 4, except that the flow rates of feed liquid A, feed liquid B, and feed liquid C were 20 mL / min, 20 mL / min, the reaction residence time of the first continuous flow reaction was t1 = 3 min, and the reaction residence time of the second continuous flow reaction was t2 = 2 min.

[0122] Nuclear magnetic resonance analysis revealed a dr of 1:1 for the crude bedaquiline, with a yield of 90% (triphenylmethane as an internal standard). HPLC analysis revealed an ee of 81% for bedaquiline.

[0123] As a result of HPLC detection, 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)

[0124] Example 16 Example 16 was the same as Example 4, except that the reaction temperature T1 of the first continuous flow reaction was -10°C and the reaction temperature T2 of the second continuous flow reaction was -50°C.

[0125] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 88% (triphenylmethane used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 74%.

[0126] As a result of HPLC detection, 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. 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,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))

[0127] In Example 16, T1 and T2 were both higher, and the achieved yield and ee value were both slightly lower than in Example 4. This is because the results obtained by changing the temperature conditions during the reaction process vary to some extent within the margin of error.

[0128] Example 17 Example 17 was the same as Example 4, except that the reaction temperature T1 of the first continuous flow reaction was set to -80°C.

[0129] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 88% (triphenylmethane used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 72%.

[0130] As a result of HPLC detection, 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)

[0131] Example 18 Example 18 was the same as Example 2, except that the residence time of the first continuous flow reaction was t1 = 30 s and the residence time of the second continuous flow reaction was t2 = 30 s.

[0132] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 89% (triphenylmethane used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 83%.

[0133] As a result of HPLC detection, 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)

[0134] Example 19 Example 19 was the same as Example 2, except that the temperature T2 of the second continuous flow reaction was set to -20°C.

[0135] Nuclear magnetic resonance analysis showed that the dr of bedaquiline in the crude product was 1:1, with a yield of 87% (triphenylmethane used as an internal standard). HPLC analysis showed that the ee of bedaquiline was 85%.

[0136] As a result of HPLC detection, 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).

[0137] Example 20 Example 20 was the same as Example 4, except that the reaction temperature T2 of the second continuous flow reaction was set to 0°C.

[0138] Nuclear magnetic resonance analysis revealed that the dr of bedaquiline in the crude product was 1:1.2, with a yield of 60% (triphenylmethane as an internal standard). HPLC analysis revealed that the ee of bedaquiline was 59%.

[0139] As a result of HPLC detection, 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).

[0140] Example 21 Example 21 was the same as Example 4, except that the flow rates of feed liquid A, feed liquid B, and feed liquid C were set to 30 mL / min, the residence times of the reaction liquids were shortened, and the reaction residence time for the first continuous flow reaction was set to t1 = 2 min, and the reaction residence time for the second continuous flow reaction was set to t2 = 1.5 min.

[0141] Nuclear magnetic resonance analysis revealed that the dr of bedaquiline in the crude product was 1:1.4, with a yield of 68% (triphenylmethane used as an internal standard). HPLC analysis revealed that the ee of bedaquiline was 60%.

[0142] As a result of HPLC detection, 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)

[0143] Effect Example 1 The enantiomeric excess (i.e., ee value) of the crude bedaquiline product obtained in Examples 1-21 was measured.

[0144] Chromatography conditions Column: Chiralpak AD-H chiral chromatography column manufactured by Daicel Corporation, Japan HPLC analysis equipment: Shimadzu LC-2010 Mobile phase: chromatographically pure isopropyl alcohol and n-hexane Flow rate: 0.5mL / min Hexane / i-PrOH=98 / 2 (wherein the volume ratio is the ratio of isopropyl alcohol to n-hexane) Detection wavelength: 220 nm

[0145] Figure 4 is the HPLC profile of the racemate of bedaquiline, which is required to determine the ee value of bedaquiline, where the peak area and retention time of this racemate are shown in Table 1 below.

[0146] Table 1: Peak area and retention time data for racemic bedaquiline [Table 1]

[0147] Figure 5: HPLC trace of bedaquiline in the crude product of Example 1, the peak areas and retention times of which are shown in Table 2 below.

[0148] Table 2: Peak area and retention time data for bedaquiline from Example 1 [Table 2]

[0149] The ee value of bedaquiline measured in Example 1 was 60%.

[0150] FIG. 6 is the HPLC trace of bedaquiline in the crude product of Example 2, and its peak area and retention time are shown in Table 3 below.

[0151] Table 3: Peak area and retention time data for bedaquiline from Example 2 [Table 3]

[0152] The ee value of bedaquiline measured in Example 2 was 84%.

[0153] FIG. 7 is the HPLC trace of bedaquiline in the crude product of Example 3, and its peak area and retention time are shown in Table 4 below.

[0154] Table 4: Peak area and retention time data for bedaquiline from Example 3 [Table 4]

[0155] The ee value of bedaquiline measured in Example 3 was 90%.

[0156] FIG. 8 is the HPLC trace of bedaquiline in the crude product of Example 4, and its peak area and retention time are shown in Table 5 below.

[0157] Table 5: Peak area and retention time data for bedaquiline from Example 4 [Table 5]

[0158] The ee value of bedaquiline measured in Example 4 was 86%.

[0159] FIG. 9 is the HPLC trace of bedaquiline in the crude product of Example 5, and its peak area and retention time are shown in Table 6 below.

[0160] Table 6: Peak area and retention time data for bedaquiline from Example 5 [Table 6]

[0161] The ee value of bedaquiline measured in Example 5 was 63%.

[0162] Figure 10: HPLC profile of bedaquiline in the crude product of Example 6, the peak areas and retention times of which are shown in Table 7 below.

[0163] Table 7: Peak area and retention time data for bedaquiline from Example 6 [Table 7]

[0164] The ee value of bedaquiline measured in Example 6 was 68%.

[0165] The ee values ​​of bedaquiline in Examples 7-21 were measured using the same method as above, and the measurement results are as shown above.

[0166] Effect Example 2 The purity of bedaquiline after workup of the mixtures of Examples 1-21 was determined.

[0167] Chromatography conditions Column: Chiralpak AD-H chiral chromatography column manufactured by Daicel Corporation, Japan HPLC analysis equipment: Shimadzu LC-2010 Mobile phase: chromatographically pure isopropyl alcohol and n-hexane Flow rate: 0.5mL / min Hexane / i-PrOH=98 / 2 Detection wavelength: 230 nm

[0168] Figure 11 shows the spectrum of the product after recrystallization in Example 1, and its peak areas and retention times are shown in Table 8 below. As shown in Table 8, bedaquiline is peak number 9, its purity is 99.864%, and the contents of impurities related to the synthesis of bedaquiline are all less than 0.1%.

[0169] Table 8: Peak area and retention time data for the product after recrystallization in Example 1 [Table 8]

[0170] Although only some examples of the present invention have been described above, the present invention is not limited to the specific embodiments described above, and all equivalent changes and modifications made based on the claims of the present invention are included in the scope of the present invention.

Claims

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

2. The first continuous flow reaction and / or the second continuous flow reaction are carried out in a continuous flow reactor, which is preferably a reaction pipe; and / or The reaction residence time of the first continuous flow reaction is 30 s-90 s or 180 s-600 s, for example, 300 s, 360 s, 240 s, 600 s, 180 s, or 120 s; and / or 2. The method of claim 1, wherein the reaction residence time of the second continuous flow reaction is 30 s-60 s or 120 s-360 s, for example, 180 s, 300 s, 120 s, 360 s, 144 s, or 90 s.

3. 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 2. The method of claim 1, wherein the quenching temperature is between -80°C and 0°C, preferably between -60°C and 0°C, for example 0°C or -60°C.

4. In step S1, the flow rate of the feed solution A 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 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 2. The method according to claim 1, wherein in step S2, the flow rate of the feed solution 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 30 mL / min.

5. The quenching method comprises: Scheme 1, wherein the quenching is carried out in a quencher, the quencher is not a continuous flow reactor, and the quenching solvent is preferably an ammonium chloride solution; or Scheme 2, in which a quench reaction is continuously carried out between a feed liquid E and the reaction liquid obtained in step S2, the feed liquid E is a quench solvent, the flow rate of the feed liquid E is preferably 10 to 500 mL / min, more preferably 10 to 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, the quench solvent is preferably a protic solvent, and the protic solvent is more preferably methanol or ethanol; 2. The method of claim 1, comprising:

6. In the feed solution A, the ratio of the molar amount of the (1S,2R)-2-amino-1,2-diphenylethanol to the volume of the tetrahydrofuran is 0.1 mol / L to 0.7 mol / L, for example, 0.298 mol / L, 0.26 mol / L, 0.51 mol / L, 0.1428 mol / L, or 0.28 mol / L; and / or In the feed solution A, the ratio of the molar amount of the N-methylpiperazine to the volume of the tetrahydrofuran is 0.1 mol / L to 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 solution A, the ratio of the molar amount of the lithium chloride to the volume of 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, or 0.338 mol / L; and / or In the feed solution A, the ratio of the molar amount of the n-butyllithium to the volume of the tetrahydrofuran is 0.4 mol / L to 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 solution B, the volume ratio of the 6-bromo-3-benzyl-2-methoxyquinoline to the tetrahydrofuran is 0.04 mol / L to 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 solution C, the volume ratio of 3-dimethylamino-1-naphthyl-1-propanone to the tetrahydrofuran is 0.04 mol / L to 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; and / or 2. The method according to claim 1, wherein the molar ratio of N-methylpiperazine to 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 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-butyllithium 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 2. The method according to claim 1, wherein the molar ratio of 3-dimethylamino-1-naphthyl-1-propanone to 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. After step S3, further include post-treatment, which includes extraction, recrystallization and slurrying; 2. The method of claim 1, wherein the recrystallization solvent and the slurrying solvent are preferably one or more of toluene, ethyl acetate, n-hexane, ethanol, isopropyl alcohol, benzene, and isopropyl ether.

9. The recrystallization method includes the steps of removing the extraction solvent to obtain a filtrate, preparing a saturated solution of the filtrate and a recrystallization solvent, and crystallizing to obtain diastereomers of bedaquiline; The method for removing the extraction solvent preferably comprises precipitating a solid from the organic phase after the extraction using a rotary evaporator, and then filtering the precipitate to obtain the filtrate; The crystallization method is preferably to cool the saturated solution of the filtrate and the recrystallization solvent, precipitate crystals from the supersaturated solution, and then filter the filtrate to remove 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.; and / or 9. The method according to claim 8, wherein the filtrate is rotary dried and then slurried to obtain pure bedaquiline.

10. A product prepared by the method of any one of claims 1 to 7.

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