A process for the low temperature continuous flow preparation of bedaquiline and the product produced

Abstract

The application discloses a method for preparing bedaquiline in a low-temperature continuous flow and a prepared product. The preparation method comprises the following steps: step S1: feeding liquid A and feeding liquid B to perform a first continuous flow reaction in a continuous flow to obtain reaction liquid D; step S2: feeding the reaction liquid D and feeding liquid C to perform a second continuous flow reaction in a continuous flow; the reaction residence time of the first continuous flow reaction is 30s-600s; the reaction residence time of the second continuous flow reaction is 30s-200s; and step S3: quenching. The preparation method has high yield, and through the method, the purity of the pure bedaquiline can be up to 99.8% or more after simple post-treatment of the crude product obtained by preparing bedaquiline.

Description

Technical Field

[0001] This invention relates to a method for preparing bedaquiline using a low-temperature continuous flow process and the resulting product. Background Technology

[0002] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and is the leading cause of death from a single bacterium (approximately 1.6 million deaths annually). 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 anti-tuberculosis drugs, listing bedaquiline as the first-line drug for long-term treatment of MDR / RR-TB. The stereoselective construction of the Csp3-Csp3 bonds in the continuous chiral centers of this drug molecule is a highly challenging problem, and an efficient industrial-scale synthesis route has not yet been achieved, resulting in its high price. Therefore, improving the production process and reducing synthesis costs to make the drug affordable for low-income groups is an urgent issue to be addressed.

[0003] The original patent for the synthesis of bedaquiline (patent authorization number: CN101180302B) discloses a one-step synthetic method. This method involves the deprotonation of 6-bromo-3-benzyl-2-methoxyquinoline at the benzylic position using lithium diisopropylamino(LDA) at low temperature, followed by addition with 3-dimethylamino-1-naphthyl-1-propanone to obtain a mixture of four optical isomers of bedaquiline. The reaction mixture is concentrated, treated with ethanol, and then resolved by a 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, the method of synthesizing bedaquiline using asymmetric catalysis has attracted widespread attention from scientists. Shibasaki and Chandrasekhar reported methods for constructing the first carbon chirality using asymmetric catalysis, followed by the construction of the second carbon chirality using asymmetric synthesis. However, all of these routes suffer from problems such as multiple reaction steps, low yield, and high manufacturing costs. Furthermore, a research group in South Africa improved the diastereoselectivity of BDQ to 9:1 in 2020 using C2-symmetric chiral amine ligands (ACSOmega 2020, 5, 3607-3611). Subsequent chiral resolution yielded the optically pure target compound, but this did not improve the product yield. Recently, Jamison et al. used fluid chemistry (Chem. Eur. J. 2022, e202201311) to improve the yield of this reaction route, obtaining four mixed isomers. However, this approach still did not achieve efficient synthesis of the target product. Not long ago, Professor Zhang Wanbin's team at Shanghai Jiao Tong University disclosed a strategy for the asymmetric synthesis of bedaquiline (Sci. ChinaChem. 2022, 65, 1968-1977). Based on this synthetic route, the team developed two routes for the asymmetric synthesis of bedaquiline using their self-developed Li / Li bimetallic synergistic activation strategy. The batch reaction yielded 81% yield, 1.4:1 dr, 91% ee and 22% yield, 16:1 dr, >99% ee, respectively. The above reaction for synthesizing bedaquiline still faces technical challenges due to its low yield. Furthermore, column chromatography is required in the post-processing to obtain a product with a purity greater than 99%. It is also limited by traditional batch reaction processes, which involve long reaction times, cumbersome operation, and the potential for impurity generation. Additionally, the use of active butyllithium reagents poses safety risks.

[0004] In summary, existing synthetic technologies for bedaquiline still suffer from technical drawbacks such as low yield, long production cycle, high cost, complex operation, and low safety. Therefore, developing new synthetic technologies for bedaquiline has significant research and application value. Summary of the Invention

[0005] To address the shortcomings of existing technologies in the preparation of bedaquiline, such as low yield, long production cycle, complex operation, and low safety, this invention provides a method for preparing bedaquiline using a low-temperature continuous flow process and the resulting product. The method of this invention offers excellent yield, and the mixture obtained after the quenching reaction requires only simple post-processing to achieve a purity of over 99.8% for bedaquiline. The method is simple to operate, highly safe, and has a short production cycle.

[0006] This invention provides a method for preparing bedaquiline using a low-temperature continuous flow process, comprising the following steps:

[0007] Step S1: Feed liquid A and feed liquid B are subjected to a first continuous flow reaction to obtain reaction liquid D; the residence time of the first continuous flow reaction is 30s to 600s.

[0008] 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.

[0009] Step S2: The reaction solution D and the feed solution C are subjected to a second continuous flow reaction; the feed solution C is a mixture of 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran;

[0010] The residence time of the second continuous flow reaction is 30s to 600s;

[0011] Step S3: Quenching.

[0012] Those skilled in the art will understand that the equipment for conducting continuous flow reactions is typically a continuous flow reactor. In this invention, the first and / or second continuous flow reactions can be carried out in a continuous flow reactor. The continuous flow reactor is preferably a reaction pipe.

[0013] In this invention, the 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 the acid-base reaction and coordination reaction between the feed liquid A and the feed liquid B.

[0014] In this invention, the residence time of the second continuous flow reaction is preferably 30s-60s or 120s-360s; for example, 180s, 300s, 120s, 360s, 144s or 90s.

[0015] In this invention, the reaction temperature of the first continuous flow reaction can be -80℃ to 0℃, preferably -80℃ to -20℃, and more preferably -10℃ to -30℃; for example, -10℃, -20℃, and -30℃.

[0016] In this invention, the reaction temperature of the second continuous flow reaction can be -80℃ to 0℃, preferably -80℃ to -20℃, and more preferably -50℃ to -80℃; for example, -50℃, -60℃, -70℃, and -80℃.

[0017] In step S1, the flow rate of the feed liquid A is preferably 10-500 mL / min, more preferably 10-200 mL / min, and particularly 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min.

[0018] In step S1, the flow rate of the feed liquid B is preferably 10-500 mL / min, more preferably 10-200 mL / min, and particularly 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min.

[0019] In step S2, the flow rate of the feed liquid C is preferably 10-500 mL / min, more preferably 10-200 mL / min, and particularly 10-40 mL / min; for example, 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min.

[0020] In step S2, as those skilled in the art will know, the flow rate of the reaction solution D can be determined after the feed solutions A and B enter the equipment employing a continuous flow reaction, 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.

[0021] In step S1, the ratio of the molar amount of (1S,2R)-2-amino-1,2-diphenylethanol to the volume of tetrahydrofuran in the feed liquid A 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, or 0.28 mol / L.

[0022] In step S1, the molar ratio of N-methylpiperazine to the volume ratio of tetrahydrofuran in the feed solution A 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.

[0023] In step S1, the molar ratio of lithium chloride to tetrahydrofuran in the feed solution A 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, or 0.338 mol / L.

[0024] In step S1, the molar ratio of n-butyllithium to the volume ratio of tetrahydrofuran in the feed solution A 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.

[0025] In step S1, the volume ratio of 6-bromo-3-benzyl-2-methoxyquinoline to 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.

[0026] 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.

[0027] In step S1, the molar ratio of N-methylpiperazine to 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, 2.

[0028] In step S1, the molar ratio of (1S,2R)-2-amino-1,2-diphenylethanol and 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, 2.0.

[0029] In step S1, the molar ratio of lithium chloride to 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.

[0030] In step S1, the molar ratio of the n-butyllithium and 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.

[0031] In step S1, the molar ratio of 3-dimethylamino-1-naphthyl-1-propanone and 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, 2.5.

[0032] 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 conventional methods in the art, such as mixing (1S,2R)-2-amino-1,2-diphenylethanol, N-methylpiperazine, butyllithium, lithium chloride and tetrahydrofuran and reacting them.

[0033] The reaction temperature is preferably -80℃ to 0℃, more preferably -80℃ to -20℃, and particularly -30℃ to -10℃; for example, -20℃ and -60℃. The reaction time is preferably 10 min to 2 h, more preferably 20-30 min, for example, 20 min and 30 min.

[0034] Those skilled in the art will know that tetrahydrofuran is used as a solvent in the above reaction.

[0035] In step S1, the temperature of the mixed reaction solution is preferably -80℃ to 0℃, more preferably -80℃ to -20℃, and particularly -30℃ to -10℃; for example, -20℃ and -60℃.

[0036] In step S1, the mixture of 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran can be obtained by conventional methods in the art, such as mixing 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran.

[0037] In step S2, the mixture of 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran can be obtained by conventional methods in the art, such as mixing 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran.

[0038] In this invention, the quenching method may include two approaches:

[0039] In 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.

[0040] Alternatively, in method two, the feed solution E and the reaction solution obtained in step S2 undergo a continuous quenching reaction. The feed solution E is the quenching solvent, preferably a protic solvent, such as methanol or ethanol. The flow rate of the feed solution E can be 10-500 mL / min, preferably 10-200 mL / min, and 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 can be carried out in a continuous flow reactor, preferably a reaction pipeline.

[0041] In this invention, preferably, after step S3, a post-processing step is included, which includes extraction, recrystallization and pulping.

[0042] The recrystallization solvent and the pulping solvent can be conventional recrystallization solvents and pulping 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.

[0043] Preferably, the recrystallization method includes the following steps: removing the solvent from the extraction to obtain a filtrate, preparing a saturated solution of the filtrate and the recrystallization solvent, and crystallizing.

[0044] The preferred method for removing the solvent from the extraction is to precipitate a solid from the extracted organic phase using a rotary evaporator and then filter it to obtain the filtrate.

[0045] The crystallization method preferably involves cooling the saturated solution of the filtrate and the recrystallization solvent to precipitate crystals from the supersaturated solution, filtering to obtain the filtrate, and removing the recrystallization solvent from the filtrate; more preferably, the filtrate is removed by rotary evaporation; the cooling temperature is preferably -20°C to 0°C, more preferably -20°C to -15°C. After rotary evaporation, the filtrate is pulped to obtain pure bedaquiline.

[0046] Those skilled in the art will know that, in order to obtain pure bedaquiline, the pulping process generally includes filtration.

[0047] In this invention, the filtering method can be a conventional method in the art, such as vacuum filtration.

[0048] The present invention also provides a product prepared by the method for preparing bedaquiline at low temperature and continuous flow as described above.

[0049] In this invention, the overall reaction formula for preparing bedaquiline is:

[0050]

[0051] The inventors discovered during their research and experiments that if 6-bromo-3-benzyl-2-methoxyquinoline is dissolved together with feed liquid A and then mixed with feed liquid B for reaction, it will not have a significant impact on 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 equipment damage, and preventing the reaction from proceeding.

[0052] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0053] The reagents and raw materials used in this invention are all commercially available.

[0054] The positive and progressive effects of this invention are as follows:

[0055] This invention utilizes the entire reaction phase of feed liquid A as a catalyst, combining a low-cost and highly efficient asymmetric synthesis route with continuous flow technology to prepare bedaquiline. This avoids the problems of difficult temperature control, long dropping and stirring times in traditional batch reactions, shortens the production cycle, reduces the dangerous operation coefficient of active lithium reagents, and achieves excellent yield. Furthermore, the preparation method of this invention allows for the preparation of bedaquiline with a purity of over 99.8% after the quenching reaction mixture, requiring only simple post-processing. This reduces operating costs and makes it very suitable for industrial production, possessing significant application value.

[0056] Furthermore, compared to Route A in the asymmetric synthesis strategy of bedaquiline disclosed by Professor Zhang Wanbin's team at Shanghai Jiao Tong University (Sci.ChinaChem.2022,65,1968-1977), the process of this invention requires only about three hours to achieve the same yield or purity with 100g of raw materials per batch, while the reaction time of the proposed solution requires 37 hours. Attached Figure Description

[0057] Figure 1 This is a schematic diagram of the process flow for the low-temperature continuous flow preparation of bedaquiline in Example 1.

[0058] Figure 2 This is a schematic diagram of the process flow for the low-temperature continuous flow preparation of bedaquiline in Example 2.

[0059] Figure 3 This is a schematic diagram of the process flow for the low-temperature continuous flow preparation of bedaquiline in Example 6.

[0060] Explanation of reference numerals in the attached figures:

[0061] i is a continuous flow experimental pump, ii is a check valve, iii is a precooling pipe, iv is a reaction pipe, v is a micro-mixing device, T1 is the reaction temperature of feed liquid A and feed liquid B, T2 is the reaction temperature of the reaction system and feed liquid C, T3 is the quenching temperature of the reaction system, 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.

[0062] Figure 4 This is an HPLC chromatogram of the racemic mixture of bedaquiline from Example 1 of the present invention.

[0063] Figure 5 This is an HPLC chromatogram of bedaquiline in the crude product of Example 1 of the present invention.

[0064] Figure 6 This is an HPLC chromatogram of bedaquiline in the crude product of Example 2 of the present invention.

[0065] Figure 7 This is an HPLC chromatogram of bedaquiline in the crude product of Example 3 of the present invention.

[0066] Figure 8 This is an HPLC chromatogram of bedaquiline in the crude product of Example 4 of the present invention.

[0067] Figure 9 This is an HPLC chromatogram of bedaquiline in the crude product of Example 5 of the present invention.

[0068] Figure 10 This is an HPLC chromatogram of bedaquiline in the crude product of Example 6 of the present invention.

[0069] Figure 11 This is an HPLC chromatogram of the product obtained by recrystallization of the crude product in Example 1 of the present invention. Detailed Implementation

[0070] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention. These all fall within the scope of protection of the present invention.

[0071] In the following examples, those skilled in the art will understand that enantiomeric excess percentage is a purity measurement used for chiral substances. It reflects the degree to which the content of one enantiomeric substance in a sample is higher than that of another. Purity was determined by HPLC using a Chiralpak AD-H chiral column manufactured by Dassell, with chromatographically pure isopropanol and n-hexane as the mobile phase. dr values ​​were determined using nuclear magnetic resonance spectroscopy (400 MHz or 500 MHz) with CDCl3 as the solvent. In the following examples, the equiv values ​​for each compound represent the molar ratio of that compound to 6-bromo-3-benzyl-2-methoxyquinoline.

[0072] Example 1

[0073] The process flow diagram of the low-temperature continuous flow preparation method of bedaquiline in Example 1 is shown below. Figure 1 As shown.

[0074] Step S1: In a dry 5L reactor, add 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 600mL of anhydrous tetrahydrofuran. Add 150mL (375mmol) of a 2.5M (2.5mol / L) n-butyllithium solution in n-hexane at -20℃ and react for 30min as feed solution A.

[0075] 27.9g of raw material 1 (in the following examples, raw material 1 refers to 6-bromo-3-benzyl-2-methoxyquinoline) (85mmol) was placed into a 5L single-necked bottle, and 750mL of anhydrous tetrahydrofuran was added and mixed evenly to form feed solution B.

[0076] 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. The mixture was stirred evenly and used as feed solution C.

[0077] The flow rates of feed solution A, feed solution B, and feed solution C are all 15 mL / min.

[0078] Step S2: Pump feed liquid A and feed liquid B into the first microreactor to carry out the first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20℃ and the reaction residence time t1 = 5min;

[0079] Step S3: Pump the reaction solution D and the feed solution C into the second microreactor for a second continuous flow reaction. The reaction temperature T2 is -60℃ and the reaction residence time t2 = 3 min.

[0080] Step S4: Quenching: The reaction solution from step S3 flows out from the second microreaction tube and is quenched in 2L of saturated ammonium chloride solution at a quenching temperature T3 of -60℃; the quenched reaction solution is collected to obtain a mixture containing bedaquiline.

[0081] Step S5: Post-processing: extraction, recrystallization and pulping

[0082] Extraction: The mixture was extracted with ethyl acetate (3 times * 1L) in a 5L reactor, and the organic phase was collected to obtain the crude product.

[0083] Recrystallization: Remove the extraction solvent to obtain the filtrate, prepare a saturated solution of the filtrate and the recrystallization solvent, and crystallize;

[0084] The method for removing the solvent from the extraction is to precipitate the solid from the extracted organic phase on a rotary evaporator and filter it to obtain the filtrate; the method for crystallization is to cool the saturated solution of the filtrate and the recrystallization solvent to allow crystals to precipitate from the supersaturated solution, filter, obtain the filtrate, and then evaporate the filtrate to dryness; the cooling temperature is -20℃ to -15℃.

[0085] Specifically, the extracted organic phase is evaporated on a rotary evaporator until solids begin to precipitate, then allowed to stand overnight to precipitate the first solid. The filtrate is obtained by filtration. The filter cake is washed with n-hexane, and the filter cake contains mostly diastereomers and ligands. An equal volume of n-hexane as the organic solvent is added to the filtrate, and the mixture is cooled to allow crystals to precipitate from the supersaturated solution. The mixture is then filtered until the filtrate contains mostly the target product. The filtrate is then evaporated to dryness to obtain the second solid.

[0086] Pulping: The second solid and ethanol were mixed and pulverized at room temperature for 12 hours. The mixture was then filtered, the filter cake was washed with n-hexane, and dried under vacuum at room temperature to obtain pure bedaquiline.

[0087] The crude product was subjected to NMR analysis, and the dr value of bedaquiline in the crude product was found to be 1:1, with a yield of 95%. HPLC analysis showed that the ee value of bedaquiline was 60%. The yield was calculated using triphenylmethane as an internal standard, with the formula: yield = x*y / n, where x = the integral number of the product characteristic peak, y = the number of moles of the internal standard, and n = the molar amount of starting material 1.

[0088] The obtained pure bedaquiline was a white solid. HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0089] Example 2

[0090] The process flow diagram of the method for preparing bedaquiline in Example 2 is shown below. Figure 2 As shown.

[0091] Step S1: In a dry 5L reactor, add 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, 600mL of anhydrous tetrahydrofuran, and 150mL (375mmol) of 2.5M n-butyllithium in n-hexane at -20℃. React for 30min as feed solution A.

[0092] 27.9 g of raw material 1 (85 mmol) was placed into a 5 L single-necked bottle, 750 mL of anhydrous tetrahydrofuran was added, and the mixture was stirred evenly to form feed solution B.

[0093] 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. The mixture was stirred evenly and used as feed solution C.

[0094] The flow rates of feed solution A, feed solution B, and feed solution C are all 15 mL / min.

[0095] Step S2: Pump feed liquid A and feed liquid B into the first microreactor to carry out the first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20℃ and the reaction residence time t1 = 5min;

[0096] Step S3: Pump the reaction solution D and the feed solution C into the second microreactor for a second continuous flow reaction. The reaction temperature T2 is -60℃ and the reaction residence time t2 = 3 min.

[0097] Step S4: Quenching: The reaction solution from step S3 flows out from the second microreaction tube and is quenched in 2L of saturated ammonium chloride solution at a quenching temperature T3 of -60℃; the quenched reaction solution is collected to obtain a mixture containing bedaquiline.

[0098] Step S5: Post-processing: extraction, recrystallization and pulping

[0099] The crude product was obtained by the same extraction as in Example 1, and the pure product was obtained by the same recrystallization and pulping steps.

[0100] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 91% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 84% by HPLC.

[0101] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <0.1%. The structural characterization data of 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).

[0102] Example 3

[0103] The process flow diagram of the method for preparing bedaquiline in Example 3 is shown below. Figure 2 As shown.

[0104] Step S1: In a dry 5L reactor, add 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, 600mL of anhydrous tetrahydrofuran, and 150mL (375mmol) of 2.5M n-butyllithium in n-hexane at -20℃. React for 30min as feed solution A.

[0105] 27.9 g of raw material 1 (85 mmol) was placed into a 5 L single-necked bottle, 750 mL of anhydrous tetrahydrofuran was added, and the mixture was stirred evenly to form feed solution B.

[0106] 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. The mixture was stirred evenly and used as feed solution C.

[0107] The flow rate of feed solution A is 20 mL / min, the flow rate of feed solution B is 15 mL / min, and the flow rate of feed solution C is 15 mL / min.

[0108] Step S2: Pump feed liquid A and feed liquid B into the first microreactor to carry out the first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20℃ and the reaction residence time t1 = 5min;

[0109] Step S3: Pump the reaction solution D and the feed solution C into the second microreactor for a second continuous flow reaction. The reaction temperature T2 is -60℃ and the reaction residence time t2 = 3 min.

[0110] Step S4: Quenching: The reaction solution from step S3 flows out from the second microreaction tube and is quenched in 2L of saturated ammonium chloride solution at a quenching temperature T3 of -60℃; the quenched reaction solution is collected to obtain a mixture containing bedaquiline.

[0111] Step S5: Post-processing: extraction, recrystallization and pulping

[0112] The crude product was obtained by the same extraction as in Example 1, and the pure product was obtained by the same recrystallization and pulping steps.

[0113] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 91% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 90% by HPLC.

[0114] HPLC analysis showed that the purity of bedaquiline was ≥99.8%, with single impurities <0.1%. The structural characterization data of 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).

[0115] Example 4

[0116] The process flow diagram of the method for preparing bedaquiline in Example 4 is shown below. Figure 1 As shown.

[0117] Step S1: In a dry 5L reactor, add 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. Add 300mL (750mmol) of 2.5M n-butyllithium in n-hexane at -20℃ and react for 30min as feed solution A.

[0118] 55.8g of raw material 1 (170mmol) was placed into a 5L single-necked bottle, and 1.5L of anhydrous tetrahydrofuran was added. The mixture was stirred evenly and used as feed solution B.

[0119] 60g (227.5mmol) of 3-dimethylamino-1-naphthyl-1-propanone was placed into a 5L single-necked flask, and 1.5L of anhydrous tetrahydrofuran was added. The mixture was stirred well and used as feed solution C.

[0120] The flow rates of feed solution A, feed solution B, and feed solution C are all 15 mL / min.

[0121] Step S2: Pump feed liquid A and feed liquid B into the first microreactor to carry out the first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20℃ and the reaction residence time t1 = 5min;

[0122] Step S3: Pump the reaction solution D and the feed solution C into the second microreactor for a second continuous flow reaction. The reaction temperature T2 is -60℃ and the reaction residence time t2 = 3 min.

[0123] Step S4: Quenching: The reaction solution from step S3 flows out from the second microreaction tube and is quenched in 2L of saturated ammonium chloride solution at 0℃; the quenched reaction solution is collected to obtain a mixture containing bedaquiline.

[0124] Step S5: Post-processing: extraction, recrystallization and pulping

[0125] The crude product was obtained by the same extraction steps as in Example 1, and the pure product was obtained by the same recrystallization and pulping steps.

[0126] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 93% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 86% by HPLC.

[0127] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0128] Example 5

[0129] The process flow diagram of the method for preparing bedaquiline in Example 5 is shown below. Figure 1 As shown.

[0130] Step S1: In a dry 5L reactor, add 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. Add 500mL (1250mmol) of 2.5M n-butyllithium in n-hexane at -20℃ and react for 30min as feed solution A.

[0131] 111.6g of raw material 1 (340mmol) was placed into a 5L single-necked bottle, and 2.5L of anhydrous tetrahydrofuran was added. The mixture was stirred evenly and used as feed solution B.

[0132] 104 g of 3-dimethylamino-1-naphthyl-1-propanone (408 mmol) was placed in a 5 L single-necked flask, and 2.5 L of anhydrous tetrahydrofuran was added. The mixture was thoroughly mixed and used as feed solution C.

[0133] The flow rates of feed solution A, feed solution B, and feed solution C are all 15 mL / min.

[0134] Step S2: Pump feed liquid A and feed liquid B into the first microreactor to carry out the first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20℃ and the reaction residence time t1 = 5min;

[0135] Step S3: Pump the reaction solution D and the feed solution C into the second microreactor for a second continuous flow reaction. The reaction temperature T2 is -60℃ and the reaction residence time t2 = 3 min.

[0136] Step S4: Quenching: The reaction solution from step S3 flows out from the second microreaction tube and is quenched in 2L of saturated ammonium chloride solution at 0℃; the quenched reaction solution is collected to obtain a mixture containing bedaquiline.

[0137] Step S5: Post-processing: extraction, recrystallization and pulping

[0138] The crude product was obtained by the same extraction as in Example 1, and the pure product was obtained by the same recrystallization and pulping steps.

[0139] The dr value of bedaquiline in the crude product was determined to be 1.2:1 by NMR, with a yield of 89% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 63% by HPLC.

[0140] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0141] Example 6

[0142] The process flow diagram of the method for preparing bedaquiline in Example 6 is shown below. Figure 3 As shown.

[0143] Step S1: In a dry 5L reactor, add 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. Add 500mL (1250mmol) of 2.5M n-butyllithium in n-hexane at -20℃ and react for 30min as feed solution A.

[0144] 111.6g of raw material 1 (340mmol) was placed into a 5L single-necked bottle, and 2.5L of anhydrous tetrahydrofuran was added. The mixture was stirred evenly and used as feed solution B.

[0145] 104 g of 3-dimethylamino-1-naphthyl-1-propanone (408 mmol) was placed in a 5 L single-necked flask, and 2.5 L of anhydrous tetrahydrofuran was added. The mixture was stirred until homogeneous and used as feed solution C.

[0146] The flow rates of feed solution A, feed solution B, and feed solution C are all 15 mL / min.

[0147] Step S2: Pump feed liquid A and feed liquid B into the first microreactor to carry out the first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20℃ and the reaction residence time t1 = 5min;

[0148] Step S3: Pump the reaction solution D and the feed solution C into the second microreactor for a second continuous flow reaction. The reaction temperature T2 is -60℃ and the reaction residence time t2 = 3 min.

[0149] Step S4: Quenching: 1L of anhydrous ethanol is placed into a 5L single-necked bottle as feed solution E; the reaction solution obtained in step S3 and feed solution E are added to the third microreactor for continuous quenching reaction, wherein the flow rate of feed solution E is 10mL / min; the quenching temperature is 0℃; the quenched reaction solution is collected to obtain a mixture containing bedaquiline.

[0150] Step S5: Post-processing: extraction, recrystallization and pulping

[0151] The crude product was obtained by the same extraction as in Example 1, and the pure product was obtained by the same recrystallization and pulping steps.

[0152] The dr value of bedaquiline in the crude product was determined by NMR to be 1.2:1, with a yield of 92% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined by HPLC to be 68%.

[0153] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0154] Example 7

[0155] 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. All other steps are the same.

[0156] The dr value of bedaquiline in the crude product was determined by NMR to be 1:1, with a yield of 91% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined by HPLC to be 78%.

[0157] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0158] Example 8

[0159] 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 other steps are the same.

[0160] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 91% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 78% by HPLC.

[0161] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0162] Example 9

[0163] 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 other steps are the same.

[0164] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 92% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 88% by HPLC.

[0165] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0166] Example 10

[0167] 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 residence time of the first continuous flow reaction is t1 = 6 min, the residence time of the first continuous flow reaction is t2 = 5 min, and the quenching temperature is -60℃; all other steps are the same.

[0168] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 91% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 84% by HPLC.

[0169] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0170] Example 11

[0171] The only difference between Example 11 and Example 2 is that step S1 and the quenching temperature in step S4 are different; the rest of the steps are the same.

[0172] Step S1: In a dry 5L reactor, add 8.7g (203mmol, 2.4equiv) of lithium chloride, 36.3g (170mmol, 2.0equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 23.9mL (170.4mmol, 2equiv) of N-methylpiperazine, 600mL of anhydrous tetrahydrofuran, and 150mL (375mmol) of 2.5M n-butyllithium in n-hexane at -20℃. React for 20min as feed solution A.

[0173] 27.9 g of raw material 1 (85 mmol) was placed into a 5 L single-necked bottle, 750 mL of anhydrous tetrahydrofuran was added, and the mixture was stirred evenly to form feed solution B.

[0174] 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. The mixture was stirred evenly and used as feed solution C.

[0175] The flow rate of feed solution A is 15 mL / min, the flow rate of feed solution B is 15 mL / min, and the flow rate of feed solution C is 15 mL / min.

[0176] The quenching temperature in step S4 is -60℃.

[0177] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 88% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 80% by HPLC.

[0178] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0179] Example 12

[0180] The only differences between Example 12 and Example 2 are the amount and volume of tetrahydrofuran used in step S1, the reaction residence time, and the quenching temperature in step S4; the other steps are the same.

[0181] Step S1: In a dry 5L reactor, add 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 350mL of anhydrous tetrahydrofuran. Add 150mL (375mmol) of 2.5M n-butyllithium in n-hexane at -20℃ and react for 30min as feed solution A.

[0182] 27.9 g of raw material 1 (85 mmol) was placed into a 5 L single-necked bottle, 500 mL of anhydrous tetrahydrofuran was added, and the mixture was stirred evenly to form feed solution B.

[0183] 28.9 g (127.5 mmol) of 3-dimethylamino-1-naphthyl-1-propanone was placed in a 5 L single-necked flask, and 500 mL of anhydrous tetrahydrofuran was added. The mixture was thoroughly mixed and used as feed solution C.

[0184] The flow rate of feed liquid A is 15 mL / min, and the flow rate of feed liquid B is 15 mL / min.

[0185] The residence time of the first continuous flow reaction in step S2 is t1 = 4 min.

[0186] The residence time of the second continuous flow reaction in step S3 is t2 = 2 min.

[0187] The quenching temperature in step S4 is -60℃;

[0188] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 86% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 76% by HPLC.

[0189] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0190] Comparing Example 12 and Example 2, the amount of anhydrous tetrahydrofuran used in each reaction phase is less, which is equivalent to changing the concentration of the material in the reaction process and the residence time in the reactor is shorter. This will cause some fluctuations in the reaction results, and the yield and ee value achieved are both lower. However, after recrystallization, the product will eventually be a product with the required purity.

[0191] Example 13

[0192] The only difference between Example 13 and Example 2 is that the amount and volume of tetrahydrofuran used in step S1 are different, and the quenching temperature in step S4 is different; the other steps are the same.

[0193] Step S1: In a dry 5L reactor, add 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. Add 150mL (375mmol) of 2.5M n-butyllithium in n-hexane at -20℃ and react for 30min as feed solution A.

[0194] 27.9g of raw material 1 (85mmol) was placed into a 5L single-necked bottle, and 1.5L of anhydrous tetrahydrofuran was added. The mixture was stirred evenly and used as feed solution B.

[0195] 3-Dimethylamino-1-naphthyl-1-propanone (2) (26.9 g, 102 mmol) was placed in a 5 L single-necked flask, and 1.5 L of anhydrous tetrahydrofuran was added and mixed well to form feed solution C.

[0196] The flow rates of feed solution A, feed solution B, and feed solution C are all 15 mL / min.

[0197] The residence time of the first continuous flow reaction in step S2 is t1 = 10 min.

[0198] The residence time of the second continuous flow reaction in step S3 is t2 = 6 min.

[0199] The quenching temperature in step S4 is -60℃.

[0200] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 94% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 89% by HPLC.

[0201] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0202] Comparing Examples 13 and 2, the amount of anhydrous tetrahydrofuran used in each reaction phase is greater, which is equivalent to changing the concentration of the materials in the reaction process and the reactor retention time is longer, resulting in better yield and ee value.

[0203] Example 14

[0204] The only difference between Example 14 and Example 4 is that the flow rates of the feed liquids are different and the reaction residence times are different; all other steps are the same.

[0205] The flow rates of feed solution A, feed solution B, and feed solution C are all 12 mL / min.

[0206] The residence time for the first continuous flow reaction is t1 = 4 min, and the residence time for the second continuous flow reaction is t2 = 2.4 min.

[0207] The dr value of bedaquiline in the crude product was determined to be 1:1.2 by NMR, with a yield of 87% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 76% by HPLC.

[0208] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0209] Comparing Examples 14 and 4, the lower flow rate and shorter reactor retention time in each reaction phase resulted in lower yields, lower ee values, and lower dr values. The results obtained by changing the flow rate conditions during the reaction were within the error range and some fluctuations occurred. After recrystallization, the final product obtained had the required purity.

[0210] Example 15

[0211] 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 residence time of the first continuous flow reaction is t1 = 3 min, and the residence time of the first continuous flow reaction is t2 = 2 min; the rest of the steps are the same.

[0212] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 90% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 81% by HPLC.

[0213] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0214] Example 16

[0215] 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.

[0216] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 88% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 74% by HPLC.

[0217] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <0.1%. (¹H NMR) 400MHz, CDCl₃: δ 8.89 s, ¹H), 8.60 d, J = 8.8 Hz, ¹H), 7.96 d, J = 2.0 Hz, ¹H), 7.90 d, J = 7.2 Hz, ¹H), 7.87 d, J = 8.4 Hz, ¹H), 7.71 d, J = 8.8 Hz, 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).).

[0218] Comparing Examples 16 and 4, both T1 and T2 are higher, while the achieved yield and ee value are slightly lower. This is because the results obtained by changing the temperature conditions during the reaction process are within the error range and will have some fluctuations.

[0219] Example 17

[0220] The only difference between Example 17 and Example 4 is that the reaction temperature T1 of the first continuous flow reaction is -80°C.

[0221] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 88% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 72% by HPLC.

[0222] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0223] Example 18

[0224] The only difference between Example 18 and Example 2 is that the retention time t1 = 30s for the first continuous flow reaction and the retention time t2 = 30s for the second continuous flow reaction.

[0225] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 89% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 83% by HPLC.

[0226] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0227] Example 19

[0228] The only difference between Example 19 and Example 2 is that the temperature T2 of the second continuous flow reaction is -20°C.

[0229] The dr value of bedaquiline in the crude product was determined to be 1:1 by NMR, with a yield of 87% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 85% by HPLC.

[0230] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0231] Example 20

[0232] The only difference between Example 20 and Example 4 is that the reaction temperature T2 of the second continuous flow reaction is 0°C.

[0233] The dr value of bedaquiline in the crude product was determined to be 1:1.2 by NMR, with a yield of 60% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 59% by HPLC.

[0234] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0235] Example 21

[0236] 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 residence time of the reaction liquid. The residence time of the first continuous flow reaction is t1 = 2 min; the residence time of the second continuous flow reaction is t2 = 1.5 min.

[0237] The dr value of bedaquiline in the crude product was determined to be 1:1.4 by NMR, with a yield of 68% (using triphenylmethane as an internal standard). The ee value of bedaquiline was determined to be 60% by HPLC.

[0238] HPLC analysis showed that the purity of bedaquiline in the pure product was ≥99.8%, with single impurities <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).

[0239] Example 1

[0240] The enantiomeric excess percentage (ee value) of bedaquiline in the crude products of Examples 1-21 was determined.

[0241] Chromatographic conditions:

[0242] The chromatographic column was a Chiralpak AD-H chiral column manufactured by Daicel Corporation of Japan. The HPLC instrument used was a Shimadzu LC-2010.

[0243] Mobile phase: chromatographically pure isopropanol and n-hexane

[0244] Flow rate: 0.5 mL / min

[0245] Hexane / i-PrOH = 98 / 2 (this represents the volume ratio of isopropanol to n-hexane)

[0246] The detection wavelength is 220nm.

[0247] Figure 4 The table below shows the HPLC chromatogram of the racemic mixture of bedaquiline, which is required for determining the ee value of bedaquiline. The peak area and retention time of the racemic mixture are shown in Table 1.

[0248] Table 1. Peak area and retention time data of the racemic mixture of bedaquiline

[0249]

[0250] Figure 5 The HPLC chromatogram of bedaquiline in the crude product of Example 1 is shown in Table 2 below, with peak area and retention time as shown.

[0251] Table 2. Peak area and retention time data of bedaquiline in Example 1

[0252]

[0253]

[0254] In Example 1, the ee value of bedaquiline was measured to be 60%.

[0255] Figure 6 The HPLC chromatogram of bedaquiline in the crude product of Example 2 is shown in Table 3 below, with peak area and retention time as shown.

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

[0257]

[0258] In Example 2, the ee value of bedaquiline was measured to be 84%.

[0259] Figure 7 The HPLC chromatogram of bedaquiline in the crude product of Example 3 is shown in Table 4 below, with peak area and retention time as shown.

[0260] Table 4. Peak area and retention time data of bedaquiline in Example 3

[0261]

[0262] In Example 3, the ee value of bedaquiline was measured to be 90%.

[0263] Figure 8 The HPLC chromatogram of bedaquiline in the crude product of Example 4 is shown in Table 5 below, with peak area and retention time as shown.

[0264] Table 5. Peak area and retention time data of bedaquiline in Example 4

[0265]

[0266] In Example 4, the ee value of bedaquiline was measured to be 86%.

[0267] Figure 9 The HPLC chromatogram of bedaquiline in the crude product of Example 5 is shown in Table 6 below, with peak area and retention time as shown.

[0268] Table 6. Peak area and retention time data of bedaquiline in Example 5

[0269]

[0270] In Example 5, the ee value of bedaquiline was measured to be 63%.

[0271] Figure 10The HPLC chromatogram of bedaquiline in the crude product of Example 6 is shown in Table 7 below, with peak area and retention time as shown.

[0272] Table 7. Peak area and retention time data of bedaquiline in Example 6

[0273]

[0274] In Example 6, the ee value of bedaquiline was measured to be 68%.

[0275] The ee of bedaquiline in Examples 7-21 was determined using the same method described above, and the results are as previously stated.

[0276] Example 2

[0277] The purity of bedaquiline after post-treatment of the mixtures of Examples 1-21 was determined.

[0278] Chromatographic conditions:

[0279] The chromatographic column was a Chiralpak AD-H chiral column manufactured by Daicel Corporation of Japan. The HPLC instrument used was a Shimadzu LC-2010.

[0280] Mobile phase: chromatographically pure isopropanol and n-hexane

[0281] Flow rate: 0.5 mL / min

[0282] Hexane / i-PrOH = 98 / 2.

[0283] The detection wavelength is 230nm.

[0284] Figure 11 The product spectrum after recrystallization in Example 1 is shown in Table 8 below, with peak areas and retention times. According to Table 8, bedaquiline is peak number 9, with a purity of 99.864%, and the content of all impurities related to the synthesis of bedaquiline is less than 0.1%.

[0285] Table 8. Peak area and retention time data of the recrystallized product of Example 1

[0286] Peak Retention time high area area% 1 16.363 157 3817 0.008 2 17.525 197 4499 0.010 3 18.713 99 2596 0.006 4 22.207 90 1630 0.004 5 23.024 182 5075 0.011 6 23.986 95 1837 0.004 7 30.641 361 16913 0.038 8 31.689 148 5239 0.012 9 39.409 538360 45029123 99.864 10 43.762 148 6070 0.013 11 44.552 95 1749 0.004 12 69.853 130 5927 0.013 13 70.503 151 6089 0.014 total 540214 45090563 100.000

[0287] The above description is only of some embodiments of the present invention. It should be understood that the present invention is not limited to the specific embodiments described above. All equivalent changes and modifications made in accordance with the scope of the patent application of the present invention should be included in the scope of the present invention.

Claims

1. A method for preparing bedaquiline using a low-temperature continuous flow process, characterized in that, It includes the following steps: Step S1: Feed liquid A and feed liquid B are subjected to a first continuous flow reaction to obtain reaction liquid D; the residence time of the first continuous flow reaction is 30s to 600s. 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. The reaction temperature of the first continuous flow reaction is -80℃ to 0℃; Step S2: The reaction solution D and the feed solution C are subjected to a second continuous flow reaction; the feed solution C is a mixture of 3-dimethylamino-1-naphthyl-1-propanone and tetrahydrofuran; the residence time of the second continuous flow reaction is 30s to 600s; The reaction temperature for the second continuous flow reaction is -80℃ to 0℃; Step S3: Quenching; The quenching temperature is -80℃ to 0℃.

2. The method for preparing bedaquiline at low temperature using a continuous flow as described in claim 1, characterized in that, The first and / or second continuous flow reactions are carried out in a continuous flow reactor, which is a reaction pipeline; And / or, the residence time of the first continuous flow reaction is 30s-90s or 180s-600s; And / or, the residence time of the second continuous flow reaction is 30s-60s or 120s-360s.

3. The method for preparing bedaquiline at low temperature using a continuous flow as described in claim 1, characterized in that, The residence time of the first continuous flow reaction is 300s, 360s, 240s, 600s, 180s, or 120s. And / or, the residence time of the second continuous flow reaction is 180s, 300s, 120s, 360s, 144s or 90s.

4. The method for preparing bedaquiline using a low-temperature continuous flow method as described in claim 1, characterized in that, The reaction temperature of the first continuous flow reaction is -80℃ to -20℃; And / or, the reaction temperature of the second continuous flow reaction is -80 ℃ to -20 ℃; And / or, the quenching temperature is -60℃ to 0℃.

5. The method for preparing bedaquiline at low temperature using a continuous flow method as described in claim 1, characterized in that, The reaction temperature of the first continuous flow reaction is -30℃ to -10℃; And / or, the reaction temperature of the second continuous flow reaction is -50℃ to -80℃; And / or, the quenching temperature is 0°C or -60°C.

6. The method for preparing bedaquiline using a low-temperature continuous flow as described in claim 1, characterized in that, The reaction temperature of the first continuous flow reaction is -10℃, -20℃, or -30℃; And / or, the reaction temperature of the second continuous flow reaction is -50°C, -60°C, -70°C or -80°C.

7. The method for preparing bedaquiline at low temperature using a continuous flow as described in claim 1, characterized in that, In step S1, the flow rate of the feed liquid A is 10-500 mL / min; And / or, in step S1, the flow rate of the feed liquid B is 10-500 mL / min; And / or, in step S2, the flow rate of the feed liquid C is 10-500 mL / min.

8. The method for preparing bedaquiline at low temperature using a continuous flow as described in claim 1, characterized in that, In step S1, the flow rate of the feed liquid A is 10-200 mL / min; And / or, in step S1, the flow rate of the feed liquid B is 10-200 mL / min; And / or, in step S2, the flow rate of the feed liquid C is 10-200 mL / min.

9. The method for preparing bedaquiline using a low-temperature continuous flow as described in claim 1, characterized in that, In step S1, the flow rate of the feed liquid A is 10-40 mL / min; And / or, in step S1, the flow rate of the feed liquid B is 10-40 mL / min; And / or, in step S2, the flow rate of the feed liquid C is 10-40 mL / min.

10. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 1, characterized in that, In step S1, the flow rate of the feed liquid A is 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 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 mL / min, 12 mL / min, 15 mL / min, 20 mL / min or 30 mL / min.

11. The method for preparing bedaquiline using a low-temperature continuous flow as described in claim 1, characterized in that, The quenching method includes two approaches: Method 1: The quenching is carried out in a quenching device, which is not a continuous flow reactor; Alternatively, in method two, the feed solution E and the reaction solution obtained in step S2 undergo a continuous quenching reaction, wherein the feed solution E is the quenching solvent.

12. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 11, characterized in that, In Method 1, the quenching solvent is an ammonium chloride solution.

13. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 11, characterized in that, In Method 2, the flow rate of the feed liquid E is 10-500 mL / min.

14. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 11, characterized in that, In Method 2, the flow rate of the feed liquid E is 10-200 mL / min.

15. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 11, characterized in that, In Method 2, the flow rate of the feed liquid E is 10-40 mL / min.

16. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 11, characterized in that, In Method 2, the flow rate of the feed liquid E is 10 mL / min, 12 mL / min, 15 mL / min, 20 mL / min, or 30 mL / min.

17. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 11, characterized in that, In Method 2, the quenching solvent is a protic solvent, and the protic solvent is methanol or ethanol.

18. The method for preparing bedaquiline using a low-temperature continuous flow as described in claim 1, characterized in that, In the feed liquid A, the molar ratio of (1S,2R)-2-amino-1,2-diphenylethanol to the volume ratio of tetrahydrofuran is 0.1 mol / L to 0.7 mol / L. And / or, in the feed solution A, the molar ratio of the N-methylpiperazine to the volume ratio of the tetrahydrofuran is 0.1 mol / L to 0.7 mol / L; And / or, in the feed solution A, the molar ratio of lithium chloride to the volume ratio of tetrahydrofuran is 0.1 mol / L to 0.8 mol / L; And / or, in the feed liquid A, the butyllithium is n-butyllithium, and the molar amount of n-butyllithium to the volume ratio of tetrahydrofuran is 0.4 mol / L-1.2 mol / L; And / or, in the feed solution B, the volume ratio of 6-bromo-3-benzyl-2-methoxyquinoline to tetrahydrofuran is 0.04 mol / L - 1.0 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; And / or, the molar ratio of the N-methylpiperazine to the 6-bromo-3-benzyl-2-methoxyquinoline is 0.5-5.

0.

19. The method for preparing bedaquiline using a low-temperature continuous flow as described in claim 1, characterized in that, In the feed solution A, the molar ratio of (1S,2R)-2-amino-1,2-diphenylethanol to the volume ratio of tetrahydrofuran is 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 molar ratio of the N-methylpiperazine to the volume of the tetrahydrofuran is 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 molar ratio of lithium chloride to the volume ratio of tetrahydrofuran is 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 butyllithium is n-butyllithium, and the molar amount of n-butyllithium to the volume ratio of tetrahydrofuran is 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 6-bromo-3-benzyl-2-methoxyquinoline to tetrahydrofuran is 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 tetrahydrofuran is 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, the molar ratio of the N-methylpiperazine to the 6-bromo-3-benzyl-2-methoxyquinoline is 1.5-5.

0.

20. The method for preparing bedaquiline using a low-temperature continuous flow as described in claim 1, characterized in that, The molar ratio of the N-methylpiperazine to the 6-bromo-3-benzyl-2-methoxyquinoline is 2.5, 2.1, 2, or 4.

5.

21. The method for preparing bedaquiline using a low-temperature continuous flow as described in claim 1, characterized in that, The molar ratio of (1S,2R)-2-amino-1,2-diphenylethanol to 6-bromo-3-benzyl-2-methoxyquinoline is 0.8-5.0; And / or, the molar ratio of the lithium chloride to the 6-bromo-3-benzyl-2-methoxyquinoline is 0.8-5.0; And / or, the butyllithium is n-butyllithium, and the molar ratio of the n-butyllithium to the 6-bromo-3-benzyl-2-methoxyquinoline is 1.0-10.0; 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.

22. The method for preparing bedaquiline at low temperature using a continuous flow as described in claim 1, characterized in that, The molar ratio of (1S,2R)-2-amino-1,2-diphenylethanol to 6-bromo-3-benzyl-2-methoxyquinoline is 1.5-5.0; And / or, the molar ratio of the lithium chloride to the 6-bromo-3-benzyl-2-methoxyquinoline is 1.5-5.0; And / or, the butyllithium is n-butyllithium, and the molar ratio of the n-butyllithium to the 6-bromo-3-benzyl-2-methoxyquinoline is 3.0-10.0; And / or, the molar ratio of the 3-dimethylamino-1-naphthyl-1-propanone to the 6-bromo-3-benzyl-2-methoxyquinoline is 1.5-5.

0.

23. The method for preparing bedaquiline using a low-temperature continuous flow as described in claim 1, characterized in that, The molar ratio of (1S,2R)-2-amino-1,2-diphenylethanol to 6-bromo-3-benzyl-2-methoxyquinoline is 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 2.9 or 2.4; And / or, the butyllithium is n-butyllithium, and the molar ratio of the n-butyllithium to the 6-bromo-3-benzyl-2-methoxyquinoline is 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 1.1, 1.2, 1.3, 1.5 or 2.

5.

24. The method for preparing bedaquiline using a low-temperature continuous flow as described in claim 1, characterized in that, Following step S3, post-processing is also included, which includes extraction, recrystallization, and pulping.

25. The method for preparing bedaquiline at low temperature using a continuous flow as described in claim 24, characterized in that, The solvent for recrystallization and the solvent for pulping are one or more of toluene, ethyl acetate, n-hexane, ethanol, isopropanol, benzene, and isopropyl ether.

26. The method for preparing bedaquiline at low temperature using a continuous flow as described in claim 24, characterized in that, The recrystallization method includes the following steps: removing the solvent from the extraction to obtain a filtrate, preparing a saturated solution of the filtrate and the recrystallization solvent, and crystallizing to obtain the diastereomer of bedaquiline.

27. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 26, characterized in that, The method for removing the solvent from the extraction is to precipitate the solid from the extracted organic phase on a rotary evaporator and then filter it to obtain the filtrate.

28. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 26, characterized in that, The crystallization method involves cooling the saturated solution of the filtrate and the recrystallization solvent to allow crystals to precipitate from the supersaturated solution, filtering to obtain the filtrate, and removing the recrystallization solvent from the filtrate.

29. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 28, characterized in that, The method for removing the recrystallization solvent from the filtrate is to evaporate the filtrate by rotary drying.

30. The method for preparing bedaquiline at low temperature using a continuous flow as described in claim 29, characterized in that, After the filtrate is evaporated to dryness, pure bedaquiline is obtained by pulping.

31. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 28, characterized in that, The cooling temperature is -20℃ to 0℃.

32. The method for preparing bedaquiline at low temperature in a continuous flow as described in claim 28, characterized in that, The cooling temperature is -20℃ to -15℃.

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