Purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline

Abstract

The invention provides a purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline, which comprises the following steps: providing an organic solvent; the method comprises the following steps: adding a Bedaquiline isomer mixture into an organic solvent, the Bedaquiline isomer mixture comprising (1S, 2R)-Bedaquiline, (1R, 2S)-Bedaquiline, (1R, 2R)-Bedaquiline and (1S, 2S)-Bedaquiline, pulping the Bedaquiline isomer mixture at a preset temperature, and enriching (1R, 2R)-Bedaquiline and (1S, 2S)-Bedaquiline in a mother solution; (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline contained in the mother liquor are filtered out, (1S, 2R)-bedaquiline and (1R, 2S)-bedaquiline contained in a filter cake are recovered, and a target product is obtained. The process is simple, convenient and efficient, effectively improves the dr value of the product, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline. Background Art

[0002] Tuberculosis (TB), as a global infectious disease caused by Mycobacterium tuberculosis, causes 1.5 million deaths worldwide each year. Among them, the emergence of multidrug-resistant (MDR) tuberculosis seriously threatens human health. In 2005, Andries and his collaborators developed the multidrug-resistant tuberculosis drug TMC 207, which was later approved by the FDA in 2012 as the first anti-tuberculosis specific drug in the past 40 years, namely bedaquiline fumarate, with the trade name Sirturo. Bedaquiline fumarate is the fumarate salt of bedaquiline, among which the bedaquiline molecule has anti-tuberculosis effect and 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] For a long time, the asymmetric synthesis of bedaquiline has been one of the key areas of concern in the pharmaceutical and health industry. However, as a bedaquiline molecule with two adjacent large steric chiral centers, its diastereoselectivity control has been difficult to solve. In 2006, Johnson & Johnson used bedaquiline diastereomers as seeds, and then used crystallization to selectively precipitate most of the bedaquiline diastereomers, and then achieved the purpose of purifying bedaquiline by column chromatography and crystallization (authorization announcement number: CN101180302B). Subsequently, Shibasaki's research group realized the asymmetric synthesis of (1R, 2S)-bedaquiline for the first time (J.Am.Chem.Soc.2010,132,7905-7907), but the diastereoselectivity of the reaction was poor. In 2011, Chandrasekhar's group achieved the asymmetric construction of (1R,2S)-bedaquiline molecules through Sharpless asymmetric epoxidation (Eur.J.Org.Chem.2011,11,2057-2061), but when constructing two adjacent chiral centers, the diastereoselectivity was poorly controlled, and the products of non-target configurations accounted for the majority. Recently, Zhang Wanbin's group developed a Li / Li bimetallic synergistic catalytic system to synthesize (1R,2S)-bedaquiline with high enantioselectivity and diastereoselectivity, but in order to improve the diastereoselectivity of the reaction, hexamethylphosphoric triamide was added to the reaction, which is difficult to apply to industrial production.

[0005] In summary, the methods reported so far generally have the problem of poor diastereoselectivity of the reaction, and the purification process of the product is relatively complicated and difficult to industrialize. Therefore, the development of a new bedaquiline purification method is of great significance for reducing production costs, improving product quality and promoting its industrial production. Summary of the invention

[0006] In view of the defects in the prior art, the object of the present invention is to provide a purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline.

[0007] According to one aspect of the present invention, a purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline is provided, comprising:

[0008] providing an organic solvent;

[0009] Adding a bedaquiline isomer mixture to the organic solvent, wherein the bedaquiline isomer mixture includes (1S, 2R)-bedaquiline, (1R, 2S)-bedaquiline, (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline, and beating the bedaquiline isomer mixture at a preset temperature to enrich (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline in the mother liquor;

[0010] The (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline contained in the mother liquor are removed by filtration, and the (1S, 2R)-bedaquiline and (1R, 2S)-bedaquiline contained in the filter cake are recovered to obtain the target product.

[0011] Furthermore, a bedaquiline isomer mixture is added to the organic solvent, wherein the bedaquiline isomer mixture includes (1S, 2R)-bedaquiline, (1R, 2S)-bedaquiline, (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline, and the dr value of bedaquiline synthesized by the currently reported bedaquiline synthesis method is not higher than 20:1. Therefore, the ratio of the total mass of (1S, 2R)-bedaquiline and (1R, 2S)-bedaquiline in the bedaquiline isomer mixture to the total mass of (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline is designed to be 1 / 0.05 to 20.

[0012] Optionally, a bedaquiline isomer mixture is added to the organic solvent, wherein the volume mass ratio of the organic solvent to the bedaquiline isomer mixture is determined according to the solubility of the target product and impurities, preferably, is 1 to 100 mL / g. This volume mass ratio is conducive to enriching the target product and improving the yield and selectivity of the target product.

[0013] Optionally, an organic solvent is provided, wherein: the selected organic solvent is determined based on the temperature and the solubility of the target product and impurities in the solvent. Preferably, the organic solvent is one or a combination of ester solvents, alcohol solvents and aromatic solvents, which is beneficial to improving the yield and selectivity of the target product. Other types of solvents cannot achieve this effect due to excessively high or low solubility.

[0014] Preferably, the ester solvent includes any one or more of methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate and propyl propionate.

[0015] Preferably, the alcohol solvent includes any one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol and n-pentanol.

[0016] Preferably, the aromatic solvent includes any one or more of toluene, xylene and mesitylene.

[0017] Preferably, the organic solvent provided comprises one or two solvents. Compared with a mixed solvent formed by two or more organic solvents, using two solvents to form a mixed solvent or using a single solvent is beneficial to reducing production costs, and is easy to control, with less impurity content and solvent residue, which is beneficial to drug production.

[0018] The two organic solvents have different solubilities for the target product. Specifically, the organic solvent is a first solvent and a second solvent. The solubility of (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline in the first solvent is greater than that in the second solvent. According to the difference in solubility of bedaquiline and its diastereoisomers in mixed solvents of different polarities, it is more preferred to set the volume ratio of the first solvent to the second solvent to 1 / 0.1 to 100, which is conducive to obtaining higher yield and diastereoselectivity.

[0019] The slurrying temperature is determined according to the solubility of the target product and impurities in different solvents. Optionally, the bedaquiline isomer mixture is slurried at a preset temperature, including: suspending the bedaquiline isomer mixture in an organic solvent at a temperature of -50 to 150°C and stirring. This temperature can better enrich the target product, which is beneficial to improving the yield and selectivity of the target product.

[0020] Optionally, the stirring time is 30 minutes to 48 hours. Controlling the stirring time can optimize the production cycle and improve the efficiency of enriching the target product.

[0021] The above-mentioned preferred conditions of the present invention can be used alone or in any combination without conflict.

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

[0023] The invention uses an organic solvent to slurry a bedaquiline isomer mixture, selectively dissolves (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline from the bedaquiline isomer mixture in a solution, removes the bedaquiline diastereomer by filtering, recovers (1S, 2R)-bedaquiline and (1R, 2S)-bedaquiline contained in the filter cake, and obtains the target product, which can make the dr (diastereomeric ratio) value of the product greater than 20:1. The invention can effectively improve the diastereomeric ratio of bedaquiline, has a simple and efficient process, 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 Schematic diagram of the purification process in the embodiment of the present invention;

[0026] Figure 2 is the hydrogen nuclear magnetic resonance spectrum of the mixture of bedaquiline and its diastereoisomers before purification in Examples 1-14 and 21-40 of the present invention, dr=1:1;

[0027] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the product of Example 1 of the present invention, dr = 3:1;

[0028] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the product of Example 9 of the present invention, dr>20:1. DETAILED DESCRIPTION

[0029] 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.

[0030] Figure 1 The process flow diagram of the purification process is shown in the figure.

[0031] Example 1

[0032] In a dry 500mL flask, add 25g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 50mL ethyl acetate and 200mL methanol to the flask, stir at 25°C for 30 minutes, then filter, wash the filter cake with ethyl acetate and methanol solution in the same ratio (3×20mL), and vacuum dry to obtain the bedaquiline product (yield 35%), as shown Figure 2 As shown, the DR value before purification was 1:1. Figure 3 The dr value of the product measured by the H NMR spectrum shown is 3:1.

[0033] Example 2

[0034] In a dry 500mL flask, 25g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1) were added to the flask. A mixed solution of 50mL of ethyl acetate and 200mL of ethanol was added, and the mixture was stirred at 25°C for 30 minutes, then filtered, and the filter cake was washed with ethyl acetate and ethanol solution in the same ratio (3×20mL), and vacuum dried to obtain the bedaquiline product (yield 37%), as shown in FIG. Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 6:1.

[0035] Example 3

[0036] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-bedaquiline (dr = 1:1) were added to a mixed solution of 25 mL of ethyl acetate and 225 mL of ethanol. The mixture was stirred at 25 ° C for 2 hours, then filtered, and the filter cake was washed with ethyl acetate and ethanol solution in the same ratio (3×20 mL). The bedaquiline product (yield 39%) was obtained by vacuum drying. Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 9:1.

[0037] Example 4

[0038] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-bedaquiline (dr = 1:1) were added to 250 mL of ethanol, stirred at 25 ° C for 2 hours, then filtered, the filter cake was washed with ethanol solution (3 × 20 mL), and vacuum dried to obtain the bedaquiline product (yield 38%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 12:1.

[0039] Example 5

[0040] In a dry 500mL flask, 25g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1) were added to the flask, 350mL of ethanol was added, stirred at 25°C for 2 hours, then filtered, the filter cake was washed with ethanol (3×20mL), and vacuum dried to obtain the bedaquiline product (yield 33%). The dr value of the product was 15:1 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0041] Example 6

[0042] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-configured bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configured bedaquiline (dr = 1:1) were added to the flask, 350 mL of ethanol was added, stirred at -50 ° C for 2 hours, then filtered, the filter cake was washed with ethanol precooled to -50 ° C (3 × 20 mL), and vacuum dried to obtain the bedaquiline product (yield 72%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 2:1.

[0043] Example 7

[0044] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-bedaquiline (dr = 1:1) were added to the flask. 250 mL of toluene was added, stirred at 110 ° C for 2 hours, and then filtered. The filter cake was washed with toluene (3×20 mL) and vacuum dried to obtain the bedaquiline product (yield 30%), as shown in Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 10:1.

[0045] Example 8

[0046] In a dry 500 mL flask, add 50 g of bedaquiline and its diastereoisomer mixture (dr = 1:1), add 250 mL of mesitylene to the flask, stir at 150 ° C for 2 hours, then filter, wash the filter cake with mesitylene (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 31%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 10:1.

[0047] Example 9

[0048] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-bedaquiline (dr = 1:1) were added to the flask. 250 mL of isopropanol was added, and the mixture was stirred at 25 ° C for 6 hours, then filtered, and the filter cake was washed with isopropanol (3×20 mL), and vacuum dried to obtain the bedaquiline product (yield 30%), as shown in FIG. Figure 2 As shown, the DR value before purification was 1:1. Figure 4 The dr value of the product measured by the H NMR spectrum shown is greater than 20:1.

[0049] Example 10

[0050] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-bedaquiline (dr = 1:1) were added to the flask, 50 mL of isopropanol was added, stirred at 25 ° C for 6 hours, then filtered, the filter cake was washed with isopropanol (3×10 mL), and vacuum dried to obtain the bedaquiline product (yield 40%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 18:1.

[0051] Embodiment 11

[0052] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-bedaquiline (dr = 1:1) were added to 250 mL of n-butanol, stirred at 110 ° C for 6 hours, then filtered, the filter cake was washed with n-butanol (3×20 mL), and vacuum dried to obtain the bedaquiline product (yield 35%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was greater than 20:1.

[0053] Example 12

[0054] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-bedaquiline (dr = 1:1) were added to the flask. 250 mL of n-pentanol was added, and the mixture was stirred at 110 ° C for 6 hours, then filtered, and the filter cake was washed with n-pentanol (3×20 mL) and vacuum dried to obtain the bedaquiline product (yield 35%), as shown in FIG. Figure 2As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was greater than 20:1.

[0055] Embodiment 13

[0056] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1) were added to the flask, 300 mL of n-pentanol was added, stirred at 110 ° C for 6 hours, then filtered, the filter cake was washed with n-pentanol (3×20 mL), and vacuum dried to obtain the bedaquiline product (yield 33%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was greater than 20:1.

[0057] Embodiment 14

[0058] In a dry 500 mL flask, 25 g of (1R, 2S)- and (1S, 2R)-bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-bedaquiline (dr = 1:1) were added to the flask. 250 mL of propyl propionate was added, stirred at 120 ° C for 6 hours, then filtered, the filter cake was washed with propyl propionate (3×20 mL), and vacuum dried to obtain the bedaquiline product (yield 28%), as shown in Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was greater than 20:1.

[0059] Embodiment 15

[0060] In a dry 500mL flask, 16.7g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 33.3g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:2) were added with 250mL of methanol, stirred at 25°C for 6 hours, then filtered, the filter cake was washed with methanol (3×20mL), and vacuum dried to obtain the bedaquiline product (yield 15%). The dr value of the product was 4:1 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0061] Example 16

[0062] In a dry 500mL flask, 16.7g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 33.3g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:2) were added with 250mL of methanol, stirred at 25°C for 24 hours, then filtered, the filter cake was washed with methanol (3×20mL), and vacuum dried to obtain the bedaquiline product (yield 15%). The dr value of the product was 3:1 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0063] Embodiment 17

[0064] In a dry 500mL flask, 16.7g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 33.3g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:2) were added to the flask with 200mL of ethanol, stirred at 25°C for 24 hours, then filtered, the filter cake was washed with ethanol (3×20mL), and vacuum dried to obtain the bedaquiline product (yield 20%). The dr value of the product was 11:1 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0065] Embodiment 18

[0066] In a dry 500mL flask, 16.7g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 33.3g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:2) were added to the flask with 200mL of ethanol, stirred at 25°C for 48 hours, then filtered, the filter cake was washed with ethanol (3×20mL), and vacuum dried to obtain the bedaquiline product (yield 19%). The dr value of the product was 11:1 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0067] Embodiment 19

[0068] In a dry 500mL flask, 10g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 40g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:4) were added to 300mL of methanol, stirred at 25°C for 48 hours, then filtered, the filter cake was washed with methanol (3×20mL), and vacuum dried to obtain the bedaquiline product (yield 40%). The dr value of the product was 1:1 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0069] Embodiment 20

[0070] In a dry 500mL flask, 10g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 40g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:4) were added to 300mL of n-butanol, stirred at 110°C for 48 hours, then filtered, the filter cake was washed with n-butanol (3×20mL), and vacuum dried to obtain the bedaquiline product (yield 15%). The dr value of the product was greater than 20:1 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0071] Embodiment 21

[0072] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 50 mL of ethyl acetate and 200 mL of ethanol to the flask, stir at 25 ° C for 1 hour, then filter, wash the filter cake with ethyl acetate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 37%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 6:1.

[0073] Embodiment 22

[0074] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 50 mL of ethyl acetate and 200 mL of ethanol to the flask, stir at 25 ° C for 4 hours, then filter, wash the filter cake with ethyl acetate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 35%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 6:1.

[0075] Embodiment 23

[0076] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 50 mL of ethyl acetate and 200 mL of ethanol to the flask, stir at 25 ° C for 6 hours, then filter, wash the filter cake with ethyl acetate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 36%), as shown Figure 2As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 6:1.

[0077] Embodiment 24

[0078] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 75 mL of ethyl acetate and 175 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with ethyl acetate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 30%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 4:1.

[0079] Embodiment 25

[0080] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 100 mL of ethyl acetate and 125 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with ethyl acetate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 26%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 3:1.

[0081] Embodiment 26

[0082] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 247.5 mL of ethyl acetate and 2.5 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with ethyl acetate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 10%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 1:1.

[0083] Embodiment 27

[0084] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of methyl formate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with the same ratio of methyl formate and ethanol solution (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 40%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 8:1.

[0085] Embodiment 28

[0086] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of ethyl formate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with ethyl formate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 37%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 6:1.

[0087] Embodiment 29

[0088] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of propyl formate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with the same ratio of propyl formate and ethanol solution (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 35%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product was 7:1 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0089] Embodiment 30

[0090] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of isopropyl formate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with the same ratio of isopropyl formate and ethanol solution (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 42%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 3:1.

[0091] Embodiment 31

[0092] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of butyl formate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with the same ratio of butyl formate and ethanol solution (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 44%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 4:1.

[0093] Embodiment 32

[0094] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of methyl acetate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with methyl acetate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 37%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 5:1.

[0095] Embodiment 33

[0096] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of propyl acetate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with the same ratio of propyl acetate and ethanol solution (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 40%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 5:1.

[0097] Embodiment 34

[0098] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of isopropyl acetate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with isopropyl acetate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 44%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 3:1.

[0099] Embodiment 35

[0100] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of butyl acetate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with butyl acetate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 43%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 4:1.

[0101] Embodiment 36

[0102] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of methyl propionate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with the same ratio of methyl propionate and ethanol solution (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 38%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 5:1.

[0103] Embodiment 37

[0104] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of ethyl propionate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with ethyl propionate and ethanol solution in the same ratio (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 35%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 5:1.

[0105] Embodiment 38

[0106] In a dry 500 mL flask, add 25 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:1), add a mixed solution of 25 mL of propyl propionate and 225 mL of ethanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with the same ratio of propyl propionate and ethanol solution (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 37%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 3:1.

[0107] Embodiment 39

[0108] In a dry 500 mL flask, add 25 g of a mixture of (1R, 2S)- and (1S, 2R)-configured bedaquiline and 25 g of a mixture of (1R, 2R)- and (1S, 2S)-configured bedaquiline (dr = 1:1), add 250 mL of n-propanol to the flask, stir at 25 ° C for 2 hours, then filter, wash the filter cake with n-propanol solution (3×20 mL), and vacuum dry to obtain the bedaquiline product (yield 31%), as shown Figure 2As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was greater than 20:1.

[0109] Embodiment 40

[0110] In a dry 500 mL flask, add 25 g of a mixture of (1R, 2S)- and (1S, 2R)-configured bedaquiline and 25 g of (1R, 2R)- and (1S, 2S)-configured bedaquiline (dr = 1:1), add 250 mL of xylene to the flask, stir at 140 ° C for 2 hours, then filter, wash the filter cake with xylene preheated to 140 ° C (3 × 20 mL), and vacuum dry to obtain the bedaquiline product (yield 31%), as shown Figure 2 As shown, the dr value before purification was 1:1, and the dr value of the product measured by nuclear magnetic resonance hydrogen spectrum was 10:1.

[0111] Embodiment 41

[0112] In a dry 500 mL flask, 47.6 g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 2.4 g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:0.05) were added, 150 mL of ethanol was added to the flask, stirred at 25 ° C for 2 hours, then filtered, the filter cake was washed with ethanol (3×20 mL), and vacuum dried to obtain the bedaquiline product (yield 80%). The dr value of the product was greater than 20:1 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0113] Embodiment 42

[0114] In a dry 500mL flask, add 5g of (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 45g of a mixture of (1R, 2R)- and (1S, 2S)-configuration bedaquiline (dr = 1:9), add 200mL of ethanol to the flask, stir at 25°C for 2 hours, then filter, wash the filter cake with ethanol (3×20mL), and vacuum dry to obtain the bedaquiline product (yield 19%). The dr value of the product is 1:2 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0115] Embodiment 43

[0116] In a dry 500mL flask, add 2.4g (1R, 2S)- and (1S, 2R)-configuration bedaquiline and 47.6g (1R, 2R)- and (1S, 2S)-configuration bedaquiline mixture (dr = 1:20), add 200mL ethanol to the bottle, stir at 25°C for 2 hours, then filter, wash the filter cake with ethanol (3×20mL), and vacuum dry to obtain the bedaquiline product (yield 22%). The dr value of the product is 1:6 as measured by hydrogen nuclear magnetic resonance spectroscopy.

[0117] 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 removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline, characterized in that: include: providing an organic solvent; Adding a bedaquiline isomer mixture to the organic solvent, wherein the bedaquiline isomer mixture includes (1S, 2R)-bedaquiline, (1R, 2S)-bedaquiline, (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline, and beating the bedaquiline isomer mixture at a preset temperature to enrich (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline in the mother liquor; The (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline contained in the mother liquor are removed by filtration, and the (1S, 2R)-bedaquiline and (1R, 2S)-bedaquiline contained in the filter cake are recovered to obtain the target product.

2. The purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline according to claim 1, characterized in that: A bedaquiline isomer mixture is added to the organic solvent, wherein the ratio of the total mass of (1S, 2R)-bedaquiline and (1R, 2S)-bedaquiline in the bedaquiline isomer mixture to the total mass of (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline is 1 / 0.05-20.

3. The purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline according to claim 1, characterized in that: Add the bedaquiline isomer mixture to the organic solvent, wherein the volume mass ratio of the organic solvent to the bedaquiline isomer mixture is 1 to 100 mL / g.

4. The purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline according to claim 1, characterized in that: The organic solvent is provided, wherein: the organic solvent is one or a combination of ester solvents, alcohol solvents and aromatic solvents.

5. The purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline according to claim 4, characterized in that: The ester solvent includes any one or more of methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate and propyl propionate.

6. The purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline according to claim 4, characterized in that: The alcohol solvent includes any one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol and n-pentanol.

7. The purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline according to claim 4, characterized in that: The aromatic solvent includes any one or more of toluene, xylene and mesitylene.

8. The purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline according to claim 4, characterized in that: The organic solvent is provided, and the organic solvent includes one or two solvents. When two solvents are used to form the organic solvent, the organic solvent is a first solvent and a second solvent. The solubility of (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline in the first solvent is greater than that in the second solvent. The volume ratio of the first solvent to the second solvent is 1 / 0.1 to 100.

9. The purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline according to claim 1, characterized in that: The bedaquiline isomer mixture is slurried at a preset temperature, comprising: suspending the bedaquiline isomer mixture in an organic solvent at a temperature of -50 to 150° C., and stirring.

10. The purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline according to claim 9, characterized in that: The stirring time is 30min~48h.

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