Purification process for selectively enriching (1R, 2S)-bedaquiline from bedaquiline optical isomer mixture

Abstract

The invention provides a purification process for selectively enriching (1R, 2S)-bedaquiline from a bedaquiline optical isomer mixture, which comprises the following steps: providing the bedaquiline optical isomer mixture; adding a mixed solvent formed by an organic solvent into the Bedaquiline optical isomer mixture, pulping at a preset temperature, and enriching (1R, 2S)-Bedaquiline in the mixed solvent. The process is simple, convenient and efficient, effectively improves the purity and yield of the target product, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to a purification process for selectively enriching (1R, 2S)-bedaquiline from a bedaquiline optical isomer mixture. Background Art

[0002] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, which causes 1.5 million deaths worldwide each year. Bedaquiline is a new anti-tuberculosis drug developed by Johnson & Johnson, which belongs to the diarylquinoline class of compounds. Bedaquiline has two chiral centers and four stereoisomers, of which only the (1R, 2S) configuration of bedaquiline has pharmacological effects. Its specific structure is as follows:

[0003]

[0004] At present, the only way to obtain (1R, 2S) bedaquiline molecules in the industrial production process is through chiral reagent splitting. This method requires the addition of an equal amount or even an excess of chiral splitting agent, and requires the use of a large amount of alkali-free bedaquiline molecules, which increases the instability of the bedaquiline molecules, is cumbersome to operate, and is costly. In addition, there are also some reports on the asymmetric synthesis of bedaquiline molecules. Shibasaki's group used yttrium and copper catalysis to achieve the asymmetric synthesis of (1R, 2S)-bedaquiline for the first time (J.Am.Chem.Soc.2010,132,7905-7907), Chandrasekhar's group achieved the asymmetric construction of (1R, 2S)-bedaquiline molecules through Sharpless asymmetric epoxidation (Eur.J.Org.Chem.2011,11,2057-2061), and Zhang Wanbin's group developed a Li / Li bimetallic synergistic catalytic system to synthesize (1R, 2S)-bedaquiline with high yield and high enantioselectivity. However, these methods have many steps, high costs, and the product ee value (enantioselective excess) is difficult to meet the quality requirements of pharmaceutical finished products. Therefore, the development of a new bedaquiline purification method is of great significance for improving product quality and reducing production costs. Summary of the invention

[0005] In view of the defects in the prior art, the object of the present invention is to provide a purification process for selectively enriching (1R, 2S)-bedaquiline from a mixture of bedaquiline optical isomers.

[0006] According to one aspect of the present invention, a purification process for selectively enriching (1R, 2S)-bedaquiline from a mixture of bedaquiline optical isomers is provided, comprising:

[0007] Providing a mixture of bedaquiline optical isomers;

[0008] A mixed solvent formed by an organic solvent is added to the mixture of bedaquiline optical isomers, and slurrying is performed at a preset temperature to enrich (1R, 2S)-bedaquiline in the mixed solvent.

[0009] Optionally, the provided bedaquiline optical isomer mixture is a mixture of (1R, 2S)-bedaquiline and any one or more of (1S, 2R)-bedaquiline, (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline.

[0010] Optionally, a mixed solvent formed by adding an organic solvent to the mixture of bedaquiline optical isomers, wherein the organic solvent is at least one of an ether solvent, an ester solvent, a ketone solvent, an aromatic solvent and an alkane solvent.

[0011] Preferably, the ether solvents include diethyl ether, isopropyl ether, n-propyl ether, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane; the ester solvents include methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, and butyl propionate; the ketone solvents include acetone and methyl ethyl ketone; the aromatic solvents include toluene, xylene, and mesitylene; the alkane solvents include petroleum ether, n-hexane, cyclohexane, and n-heptane.

[0012] Optionally, a mixed solvent formed by adding an organic solvent to the mixture of bedaquiline optical isomers, wherein: considering the production cost issue, the mixed solvent includes two organic solvents. Compared with a mixed solvent formed by more than two organic solvents, the use of two solvents to form a mixed solvent is beneficial to reducing production costs, and is easy to control, with less impurity content and solvent residues, which is beneficial to drug production.

[0013] Optionally, the two organic solvents have different polarities. According to the difference in solubility of bedaquiline and its optical isomers in mixed solvents of different polarities, the two organic solvents are respectively a first solvent and a second solvent, wherein the polarity of the first solvent is greater than the polarity of the second solvent, and the volume ratio of the first solvent to the second solvent is set to 1 / 0.1 to 50, which is conducive to obtaining a higher yield and optical purity.

[0014] Adjusting the solvent volume can control the dissolution quality of bedaquiline and its optical isomer mixture, thereby having an important influence on the yield and ee value of enrichment of (1R, 2S)-bedaquiline. Optionally, a mixed solvent formed by adding an organic solvent to the bedaquiline optical isomer mixture, wherein: the volume mass ratio of the mixed solvent to the bedaquiline optical isomer mixture is 1 to 100 mL / 1 g, and the volume mass ratio is determined in combination with the temperature and according to the solubility of the target product and impurities. The volume mass ratio is conducive to enriching the target product and improving the yield and selectivity of the target product.

[0015] Adjusting the temperature can change the solubility of the solvent, thus having an important influence on the yield and ee value of enriching (1R, 2S)-bedaquiline. Optionally, the beating at a preset temperature includes: suspending the bedaquiline optical isomer mixture in the mixed solvent at a temperature of -60 to 160°C and stirring. The temperature is determined according to the solubility of the product and impurities in solvents of different polarity. The temperature can better enrich the target product, which is conducive to improving the yield and selectivity of the target product.

[0016] Preferably, the beating at a preset temperature comprises: suspending the bedaquiline optical isomer mixture in the mixed solvent at a temperature of 25 to 60° C. and stirring.

[0017] Controlling the stirring time can optimize the production cycle. Optionally, the stirring time is 30 minutes to 48 hours.

[0018] Preferably, the stirring time is 4 h to 12 h, which can improve the efficiency of enriching the target product and shorten the production cycle.

[0019] The above-mentioned preferred conditions of the present invention can be used alone or in any combination without conflict.

[0020] In the present invention, (1R, 2S)-bedaquiline is enriched in a mixed solvent by slurrying, filtered and washed, and concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography is performed to obtain a clean product.

[0021] The invention utilizes a mixed solvent to slurry a mixture of bedaquiline optical isomers, and efficiently and selectively enriches a (1R, 2S)-bedaquiline product in the solution, so that its ee value reaches 90.2% to 99.9%, and the yield reaches up to 89%.

[0022] Compared with the prior art, the present invention has at least one of the following beneficial effects:

[0023] The present invention utilizes a mixed solvent beating method to selectively enrich (1R, 2S)-bedaquiline products in a solution from a mixture of bedaquiline optical isomers, so that the enantiomeric excess value thereof meets the quality requirements of the finished product, and the yield of the target product is also improved. The process of the present invention is simple and efficient, can effectively improve the purity and yield of the target product, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0025] Figure 1 The liquid phase spectrum (88% ee) of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline in the mixture of bedaquiline optical isomers before beating in Example 6-9 of the present invention;

[0026] Figure 2 The liquid phase spectrum of the product (1R, 2S)-bedaquiline (99.3% ee) in Example 6 of the present invention;

[0027] Figure 3 This is the liquid phase spectrum of the product (1R, 2S)-bedaquiline (99.9% ee) in Example 9 of the present invention. DETAILED DESCRIPTION

[0028] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several variations and improvements may be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0029] Example 1

[0030] In a dry 500 mL flask, add 15.0 g of a mixture of (1R, 2S)-bedaquiline and 5.0 g of (1S, 2R)-bedaquiline enantiomers (ee = 50%), add 50 mL of a mixed solution of tetrahydrofuran and 200 mL of methyl tert-butyl ether to the flask, stir at 25 ° C for 4 hours, then filter, wash the filter cake with the same ratio of tetrahydrofuran and methyl tert-butyl ether solution (3×20 mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then column chromatography to obtain a clean product with a yield of 70%. The ee value of the product measured by HPLC is 99.1%.

[0031] Example 2

[0032] In a dry 500mL flask, add a mixture of 18.1g (1R, 2S)-bedaquiline and 1.9g (1S, 2R)-bedaquiline enantiomers (ee = 81%), add a mixed solution of 50mL tetrahydrofuran and 200mL petroleum ether to the flask, stir at 25°C for 4 hours, then filter, wash the filter cake with tetrahydrofuran and petroleum ether solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 75%. The ee value of the product measured by HPLC is 99.3%.

[0033] Example 3

[0034] In a dry 500mL flask, add a mixture of 18.3g (1R, 2S)-bedaquiline and 1.7g (1S, 2R)-bedaquiline enantiomers (ee = 83%), add a mixed solution of 50mL tetrahydrofuran and 200mL toluene to the flask, stir at 60°C for 4 hours, then filter while hot, wash the filter cake with tetrahydrofuran and toluene solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 81%. The ee value of the product measured by HPLC is 93.3%.

[0035] Example 4

[0036] In a dry 500mL flask, add a mixture of 17.8g (1R, 2S)-bedaquiline and 2.2g (1S, 2R)-bedaquiline enantiomers (ee = 78%), add a mixed solution of 50mL of isopropyl ether and 200mL of methyl tert-butyl ether to the flask, stir at 25°C for 4 hours, then filter, wash the filter cake with isopropyl ether and methyl tert-butyl ether solution in the same proportion (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 65%. The ee value of the product measured by HPLC is 98.7%.

[0037] Example 5

[0038] In a dry 500mL flask, add 15.0g of (1R, 2S)-bedaquiline and 5.0g of a mixture of (1S, 2R)-bedaquiline enantiomers (ee = 50%), add 50mL of a mixed solution of tetrahydrofuran and 200mL of methyl tert-butyl ether to the flask, stir at -10°C for 4 hours, then filter while cold, wash the filter cake with tetrahydrofuran and methyl tert-butyl ether solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 56%. The ee value of the product measured by HPLC is 99.3%.

[0039] Example 6

[0040] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 50 mL ethyl formate and 200 mL n-hexane was added to the flask, stirred at 25 ° C for 4 hours, and then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same ratio (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 73%, and the ee value of the product was measured by HPLC. The results are as follows: Figure 2 , AD-H, 0.5 mL / min, Hexane / i-PrOH=98 / 2, 220 nm, the ee of the purified product in this example is 99.3%.

[0041] Example 7

[0042] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 50 mL 1,4-dioxane and 200 mL toluene was added to the flask, stirred at 100 ° C for 4 hours, and then filtered while hot, the filter cake was washed with 1,4-dioxane and toluene solution in the same ratio (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 80%, and the ee value of the product measured by HPLC was 95.1%.

[0043] Example 8

[0044] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 50 mL ethyl acetate and 200 mL n-hexane was added to the flask, stirred at 25 ° C for 4 hours, then filtered, the filter cake was washed with ethyl acetate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 70%, and the ee value of the product measured by HPLC was 99.3%.

[0045] Example 9

[0046] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 25 ° C for 4 hours, and then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same ratio (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 35%, and the ee value of the product was measured by HPLC. The results are as follows: Figure 3 AD-H, 0.5 mL / min, Hexane / i-PrOH=98 / 2, 220 nm. The ee of the purified product in this example is 99.9%.

[0047] Figure 1 The liquid phase spectrum of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline in the mixture of bedaquiline optical isomers before beating is shown, AD-H, 0.5mL / min, Hexane / i-PrOH=98 / 2, 220nm, and the bedaquiline ee=88% in the mixture of bedaquiline enantiomers and diastereomers in Examples 6-9. The purification process in the examples of the present invention is stable. In Examples 6-9, the product ee value is about 88% at the end of each reaction.

[0048] Example 10

[0049] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL acetone and 200mL n-hexane to the flask, stir at 25°C for 4 hours, then filter, wash the filter cake with acetone and n-hexane solution in the same proportion (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 75%. The ee value of the product measured by HPLC is 98.1%.

[0050] Embodiment 11

[0051] In a dry 1000mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 100mL acetone and 400mL n-hexane to the flask, stir at 25°C for 4 hours, then filter, wash the filter cake with acetone and n-hexane solution in the same proportion (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 86%. The ee value of the product measured by HPLC is 95.0%.

[0052] Example 12

[0053] In a dry 500 mL flask, add 27.0 g of (1R, 2S)-bedaquiline and 3.0 g of a mixture of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 25 mL of acetone and 100 mL of n-hexane to the flask, stir at 25 ° C for 4 hours, then filter, wash the filter cake with acetone and n-hexane solution in the same proportion (3×20 mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then column chromatography to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification is 63%, and the ee value of the product measured by HPLC is 98.9%.

[0054] Example 13

[0055] In a dry 500 mL flask, add 27.0 g of (1R, 2S)-bedaquiline and 3.0 g of a mixture of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50 mL of ether and 200 mL of n-hexane to the flask, stir at 25 ° C for 4 hours, then filter, wash the filter cake with ether and n-hexane solution in the same proportion (3×20 mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then column chromatography to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification is 52%, and the ee value of the product measured by HPLC is 99.0%.

[0056] Embodiment 14

[0057] In a dry 250mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add 50mL of a mixed solution of butyl propionate and 200mL of mesitylene to the flask, stir at 160°C for 4 hours, then filter while hot, wash the filter cake with butyl propionate and mesitylene solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 89%. The ee value of the product measured by HPLC is 90.2%.

[0058] Embodiment 15

[0059] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of n-propyl ether and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with n-propyl ether and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 51%. The ee value of the product measured by HPLC is 98.2%.

[0060] Example 16

[0061] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of methyl formate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with the same ratio of methyl formate and n-hexane solution (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 64%. The ee value of the product measured by HPLC is 98.5%.

[0062] Embodiment 17

[0063] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of propyl formate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with the same ratio of propyl formate and n-hexane solution (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 63%. The ee value of the product measured by HPLC is 98.1%.

[0064] Embodiment 18

[0065] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of isopropyl formate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with isopropyl formate and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 60%. The ee value of the product measured by HPLC is 98.2%.

[0066] Embodiment 19

[0067] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of butyl formate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with butyl formate and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 63%. The ee value of the product measured by HPLC is 97.2%.

[0068] Embodiment 20

[0069] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of methyl acetate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with methyl acetate and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 71%. The ee value of the product measured by HPLC is 98.9%.

[0070] Embodiment 21

[0071] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of propyl acetate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with propyl acetate and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 68%. The ee value of the product measured by HPLC is 99.1%.

[0072] Embodiment 22

[0073] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of isopropyl acetate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with isopropyl acetate and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 69%. The ee value of the product measured by HPLC is 98.2%.

[0074] Embodiment 23

[0075] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of butyl acetate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with butyl acetate and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 67%. The ee value of the product measured by HPLC is 97.2%.

[0076] Embodiment 24

[0077] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of butyl acetate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with butyl acetate and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 67%. The ee value of the product measured by HPLC is 97.2%.

[0078] Embodiment 25

[0079] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of methyl propionate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with the same ratio of methyl propionate and n-hexane solution (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 63%. The ee value of the product measured by HPLC is 98.2%.

[0080] Embodiment 26

[0081] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of propyl propionate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with the same ratio of propyl propionate and n-hexane solution (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 59%. The ee value of the product measured by HPLC is 98.5%.

[0082] Embodiment 27

[0083] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of isopropyl propionate and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with isopropyl propionate and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 61%. The ee value of the product measured by HPLC is 98.7%.

[0084] Embodiment 28

[0085] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of methyl ethyl ketone and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with methyl ethyl ketone and n-hexane solution in the same ratio (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 67%. The ee value of the product measured by HPLC is 97.7%.

[0086] Embodiment 29

[0087] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of xylene and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with a solution of xylene and n-hexane in the same proportion (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 72%. The ee value of the product measured by HPLC is 95.1%.

[0088] Embodiment 30

[0089] In a dry 500mL flask, add 27.0g of a mixture of (1R, 2S)-bedaquiline and 3.0g of (1S, 2R)-bedaquiline enantiomers (ee = 80%), add a mixed solution of 50mL of mesitylene and 200mL of n-hexane to the flask, stir at 25°C for 4 hours, then filter while hot, wash the filter cake with the same ratio of mesitylene and n-hexane solution (3×20mL), concentrate under reduced pressure to remove all solvents in the mother liquor, and then obtain a clean product by column chromatography with a yield of 71%. The ee value of the product measured by HPLC is 95.4%.

[0090] Embodiment 31

[0091] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 25 ° C for 6 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 36%, and the ee value of the product measured by HPLC was 99.8%.

[0092] Embodiment 32

[0093] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 25 ° C for 8 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 36%, and the ee value of the product measured by HPLC was 99.7%.

[0094] Embodiment 33

[0095] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 25 ° C for 10 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 37%, and the ee value of the product measured by HPLC was 99.5%.

[0096] Embodiment 34

[0097] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 25 ° C for 12 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 37%, and the ee value of the product measured by HPLC was 99.5%.

[0098] Embodiment 35

[0099] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 25 ° C for 30 minutes, and then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 23%, and the ee value of the product measured by HPLC was 99.6%.

[0100] Embodiment 36

[0101] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 25 ° C for 1 hour, and then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same ratio (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 26%, and the ee value of the product measured by HPLC was 99.6%.

[0102] Embodiment 37

[0103] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 25 ° C for 2 hours, and then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 30%, and the ee value of the product measured by HPLC was 99.7%.

[0104] Embodiment 38

[0105] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at -60 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 14%, and the ee value of the product measured by HPLC was 99.9%.

[0106] Embodiment 39

[0107] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at -50 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 15%, and the ee value of the product measured by HPLC was 99.9%.

[0108] Embodiment 40

[0109] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at -40 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 17%, and the ee value of the product measured by HPLC was 99.9%.

[0110] Embodiment 41

[0111] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at -30 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 19%, and the ee value of the product measured by HPLC was 99.9%.

[0112] Embodiment 42

[0113] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at -20 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 21%, and the ee value of the product measured by HPLC was 99.9%.

[0114] Embodiment 43

[0115] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at -10 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 25%, and the ee value of the product measured by HPLC was 99.9%.

[0116] Embodiment 44

[0117] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 0°C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3 × 20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product, the yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 28%, and the ee value of the product measured by HPLC was 99.9%.

[0118] Embodiment 45

[0119] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 10 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 30%, and the ee value of the product measured by HPLC was 99.9%.

[0120] Embodiment 46

[0121] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 40 ° C for 4 hours, and then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 35%, and the ee value of the product measured by HPLC was 98.9%.

[0122] Embodiment 47

[0123] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 10 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 60 ° C for 4 hours, and then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 40%, and the ee value of the product measured by HPLC was 97.1%.

[0124] Embodiment 48

[0125] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 5 mL ethyl formate and 245 mL n-hexane was added to the flask, stirred at 25 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 31%, and the ee value of the product measured by HPLC was 99.8%.

[0126] Embodiment 49

[0127] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 25 mL ethyl formate and 225 mL n-hexane was added to the flask, stirred at 25 ° C for 4 hours, and then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 45%, and the ee value of the product measured by HPLC was 98.7%.

[0128] Embodiment 50

[0129] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 25 mL ethyl formate and 225 mL n-hexane was added to the flask, stirred at 25 ° C for 4 hours, and then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 55%, and the ee value of the product measured by HPLC was 99.4%.

[0130] Embodiment 51

[0131] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 125 mL ethyl formate and 125 mL n-hexane was added to the flask, stirred at 25 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 86%, and the ee value of the product measured by HPLC was 97.8%.

[0132] Embodiment 52

[0133] In a dry 1000 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 100 mL ethyl formate and 400 mL n-hexane was added to the flask, stirred at 25 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 88%, and the ee value of the product measured by HPLC was 95.8%.

[0134] Embodiment 53

[0135] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 60 mL ethyl formate and 240 mL n-hexane was added to the flask, stirred at 25 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-hexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 80%, and the ee value of the product measured by HPLC was 98.8%.

[0136] Embodiment 54

[0137] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 50 mL of ethyl formate and 200 mL of cyclohexane was added to the flask, stirred at 25 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and cyclohexane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 72%, and the ee value of the product measured by HPLC was 99.1%.

[0138] Embodiment 55

[0139] In a dry 500 mL flask, a mixture of 14.1 g (1R, 2S)-bedaquiline, 0.9 g (1S, 2R)-bedaquiline, 14.1 g (1S, 2S)-bedaquiline and 0.9 g (1R, 2R)-bedaquiline (ee = 88%, dr = 1:1) was added, and a mixed solution of 50 mL ethyl formate and 200 mL n-heptane was added to the flask, stirred at 25 ° C for 4 hours, then filtered, the filter cake was washed with ethyl formate and n-heptane solution in the same proportion (3×20 mL), concentrated under reduced pressure to remove all solvents in the mother liquor, and then column chromatography was performed to obtain a clean product. The yield of (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline contained in the mixture before purification was 65%, and the ee value of the product measured by HPLC was 99.2%.

[0140] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various modifications or variations within the scope of the claims, which does not affect the essence of the present invention. The above preferred features can be used in any combination without conflicting with each other.

Claims

1. A purification process for selectively enriching (1R, 2S)-bedaquiline from a mixture of bedaquiline optical isomers, characterized in that: include: Providing a mixture of bedaquiline optical isomers; A mixed solvent formed by an organic solvent is added to the mixture of bedaquiline optical isomers, and slurrying is performed at a preset temperature to enrich (1R, 2S)-bedaquiline in the mixed solvent.

2. The purification process according to claim 1, characterized in that The provided bedaquiline optical isomer mixture is a mixture of (1R, 2S)-bedaquiline and any one or more of (1S, 2R)-bedaquiline, (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline.

3. The purification process according to claim 1, characterized in that An organic solvent is added to the bedaquiline optical isomer mixture to form a mixed solvent, wherein the organic solvent is at least one of an ether solvent, an ester solvent, a ketone solvent, an aromatic solvent and an alkane solvent.

4. The purification process according to claim 1, characterized in that An organic solvent is added to the bedaquiline optical isomer mixture to form a mixed solvent, wherein the mixed solvent comprises two organic solvents.

5. The purification process according to claim 4, characterized in that: The two organic solvents are respectively a first solvent and a second solvent, wherein the polarity of the first solvent is greater than that of the second solvent, and the volume ratio of the first solvent to the second solvent is 1 / 0.1-50.

6. The purification process according to claim 1, characterized in that: A mixed solvent formed by adding an organic solvent to the bedaquiline optical isomer mixture is prepared, wherein the volume mass ratio of the mixed solvent to the bedaquiline optical isomer mixture is 1 to 100 mL / 1 g.

7. The purification process according to claim 1, characterized in that: The slurrying at a preset temperature comprises: suspending the bedaquiline optical isomer mixture in the mixed solvent at a temperature of -60 to 160° C., and stirring.

8. The purification process according to claim 1, characterized in that: The slurrying at a preset temperature comprises: suspending the bedaquiline optical isomer mixture in the mixed solvent at a temperature of 25 to 60° C., and stirring.

9. The purification process according to claim 7 or 8, characterized in that: The stirring time is 30min~48h.

10. The purification process according to claim 7 or 8, characterized in that: The stirring time is 4h to 12h.

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