Synthesis method of bedaquiline enantiomer impurity
By using S-binaphthol phosphate as a resolving agent and recrystallization method, the synthesis problem of bedaquiline enantiomer impurities was solved, high-purity separation was achieved, the operation process was simplified, the cost and environmental impact were reduced, and it was suitable for drug quality control.
Patent Information
- Application Number
- CN202510861058.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-25
- Publication Date
- 2025-09-02
AI Technical Summary
The prior art is difficult to effectively synthesize and control the enantiomeric impurities of bedaquiline, which affects the stability and efficacy of drugs. The existing methods have problems such as complex operation, high cost and great environmental pollution.
The classic chiral resolution method is used, using S-binaphthol phosphate as the splitting agent, combined with recrystallization method, and the enantiomeric impurities of bedaquiline were separated from the chiral mixture, and efficient separation is achieved by optimizing the reaction solvent and temperature control.
The separation of enantiomeric impurities of bedaquiline is achieved with high purity (more than 99%). It is easy to operate, low risk, low cost, and low environmental pollution. It is suitable for drug quality control.
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Figure CN120574170A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of drug synthesis, and more specifically to a method for synthesizing bedaquiline enantiomeric impurity (1S, 2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol. Background Art
[0002] Bedaquiline fumarate is a diarylquinoline antimycobacterial drug that acts by inhibiting adenosine triphosphate synthase (ATP synthase), an enzyme essential for mycobacterial replication. It is used in combination with other antituberculosis drugs to treat multidrug-resistant tuberculosis. It is a member of the quinoline family, a member of the naphthalene family, an organobromine compound, an aromatic ether, a tertiary alcohol, and a tertiary amine amino group, and a conjugate base of benzimidazole (2+). There is no cross-resistance with other drugs.
[0003] The structure of bedaquiline fumarate is shown below:
[0004]
[0005] This drug is a chiral drug with two epimeric impurities and one enantiomeric impurity; the corresponding structures are shown below:
[0006]
[0007] The presence of drug impurities in a drug not only renders it ineffective but can also affect its stability and efficacy, and even be harmful to human health. Therefore, when synthesizing such a drug, it is necessary not only to remove diastereomeric impurities but also to strictly control enantiomeric impurities according to the original research standards.
[0008] Therefore, drug impurity research is an essential link in drug research, production, storage and clinical application.
[0009] In summary, the targeted synthesis of this enantiomeric impurity facilitates the establishment of an analytical method for this impurity, which is of great significance for the quality control of Bedaquiline (fumarate) API. Summary of the Invention
[0010] In view of this, the main purpose of the present invention is to provide a method for synthesizing bedaquiline enantiomeric impurities. The present invention selects a suitable resolving agent and uses a classical chiral resolution method and recrystallization method to obtain the bedaquiline enantiomeric impurities; the resolving agent has not been reported in the literature, and the solvent and ratio used for recrystallization have not been reported.
[0011] To achieve the above object, the technical solution of the present invention is as follows:
[0012] A method for separating (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol shown in formula 4 from a chiral mixture, using S-binaphthol phosphate as a resolving agent.
[0013] Furthermore, the chiral mixture comprises four configurations shown in the following formulas 1 to 4, and the method specifically comprises:
[0014] (1) first separating the epimers represented by Formula 1 and Formula 2 to obtain a mixture comprising Formula 3 and Formula 4;
[0015] (2) using S-binaphthol phosphate (S-BNP) as a resolving agent, separating (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol as shown in formula 4 from the mixture;
[0016] Among them, the structures shown in Formula 1 to Formula 4 are as follows:
[0017]
[0018] Among them, Formula 1 is the SS configuration, Formula 2 is the RR configuration, Formula 3 is the RS configuration, and Formula 4 is the SR configuration.
[0019] Furthermore, step (1) is specifically as follows:
[0020] The raw materials are dissolved in a reaction solvent A, and after the temperature is raised to react, a crystallization solvent A is added to crystallize, and the mixture is centrifuged and washed to obtain a mixture comprising Formula 3 and Formula 4;
[0021] Wherein, the solvent A is at least one of tetrahydrofuran and toluene, preferably tetrahydrofuran; the crystallization solvent A is at least one of ethanol and methanol, preferably ethanol.
[0022] Furthermore, in step (1), the reaction temperature is 55°C to 65°C, preferably 60°C; and the crystallization temperature is -5°C to 5°C, preferably 2 to 3°C.
[0023] Furthermore, in step (1), the mass volume ratio of the racemic bedaquiline to the reaction solvent A and the crystallization solvent A is 1 g:1.5 ml~2.3 ml:3 ml~6 ml, and the preferred ratio is 1 g:1.7 ml:4 ml.
[0024] Furthermore, step (2) specifically includes:
[0025] S21: mixing the mixture obtained in step (1) with reaction solvent B and S-binaphthol phosphate, heating the mixture for reaction, cooling and stirring once, centrifuging once, heating and beating, cooling and stirring twice, and centrifuging twice to obtain the resolved salt shown in Formula 5 below;
[0026]
[0027] S22: mixing the obtained resolved salt with reaction solvent C and alkali metal carbonate solution, performing a primary temperature reaction, adding an extraction solvent, extracting and stratifying, washing the organic layer, and concentrating to obtain a concentrate; mixing the concentrate with a recrystallization solvent, performing a secondary temperature reaction, cooling and crystallizing, centrifuging, washing the filter cake, and drying to obtain the product shown in Formula 4;
[0028] Wherein, in step S21, the reaction solvent B is a mixed system of acetone and DMSO, or ethyl acetate, or a mixed system of ethyl acetate and DMSO, preferably a mixed system of acetone and DMSO;
[0029] In step S22, the reaction solvent C is toluene, the alkali metal carbonate solution is at least one of potassium carbonate and sodium carbonate; the extraction solvent is a mixed solvent consisting of water and ethanol; and the recrystallization solvent is composed of toluene and ethanol, or tetrahydrofuran and ethanol.
[0030] Furthermore, in step S21,
[0031] The temperature of the temperature-raising reaction and the temperature of the temperature-raising beating are both 55°C to 60°C, preferably 58°C;
[0032] The time for heating reaction is 1h~2h; the time for heating beating is 40-80min;
[0033] The temperature of the first cooling and stirring and the second cooling and stirring is 15°C to 20°C, preferably 18°C;
[0034] The time for the first cooling and stirring is 1.5h to 2.5h; the time for the second cooling and stirring is 1h to 2h.
[0035] Furthermore, in step S21, when the temperature is raised for beating, the reaction solvent B is used as the beating solvent.
[0036] Furthermore, in step S21, the reaction solvent B is a mixed system of acetone and DMSO;
[0037] When the mixture is mixed with the reaction solvent B and S-binaphthol phosphate, the mixing ratio of the mixture to acetone, DMSO, and S-binaphthol phosphate is 1g:18ml-22ml:0.5ml-0.8ml:0.6g-0.7g; the preferred ratio is 1g:20ml:0.64ml:0.63g;
[0038] When the temperature is increased and the pulp is beaten, the mixing ratio of the mixture to acetone and DMSO is 1 g: 5 ml to 10 ml: 0.5 ml to 0.8 ml.
[0039] Furthermore, in step S21, the reaction solvent B is ethyl acetate,
[0040] When the mixture is mixed with the reaction solvent B and S-binaphthol phosphate, the mixing ratio of the mixture to ethyl acetate and S-binaphthol phosphate is 1g:45ml-60ml:0.6g-0.7g; the preferred ratio is 1g:50ml:0.63g;
[0041] When the temperature is raised and the pulp is beaten, the mixing ratio of the mixture to ethyl acetate is 1g:75ml~100ml.
[0042] Furthermore, in step S22,
[0043] The primary heating reaction temperature is 78°C to 82°C, preferably 80°C, and the reaction time is 15 to 25 minutes;
[0044] The secondary temperature reaction temperature is 48°C to 52°C, preferably 50°C, and the time is 25 to 35 minutes;
[0045] The temperature during cooling and crystallization is 0°C to 5°C, preferably 3°C, and the time is 40 to 80 minutes.
[0046] Furthermore, in step S22, the mixing ratio of the splitting salt to the reaction solvent C, the alkali metal carbonate solution and the extraction solvent is 1g:8ml~12ml:6.5g~8.5g:7ml~11ml, wherein the volume ratio of water to ethanol in the extraction solvent is 10~15:1.
[0047] Furthermore, the recrystallization solvent is composed of tetrahydrofuran and ethanol, and the mixing ratio of the concentrate to tetrahydrofuran and ethanol is 1g:3.2ml~4ml:10ml~15ml; the preferred ratio is 1g:3.5ml:11.5ml.
[0048] In summary, the present invention involves the following reaction routes:
[0049]
[0050] Compared with the prior art, the present invention has the following advantages:
[0051] The present invention uses S-binaphthol phosphate as a resolving agent, and can effectively separate the impurity (1S, 2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol from a racemic mixture containing four configurations (SS / RR / SR / RS). After resolution and purification, the enantiomeric impurity (1S, 2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol is obtained with a chiral purity of more than 99% and a related substance purity of more than 99%. The method is convenient to operate, has an extremely low experimental risk factor, has little environmental pollution, and has a high purity of the obtained sample at a low cost. BRIEF DESCRIPTION OF THE DRAWINGS
[0052] Figure 1 This is the liquid phase spectrum of the racemate bedaquiline.
[0053] Figure 2 This is the liquid phase spectrum of bedaquiline enantiomers.
[0054] Figure 3 In the figure, A is the liquid phase blank spectrum of the purity of related substances of the final product; B is the liquid phase spectrum of the purity of related substances of the final product.
[0055] Figure 4 In the figure, A is the liquid phase blank spectrum of the enantiomeric purity of the final product; B is the liquid phase spectrum of the enantiomeric purity of the final product.
[0056] Figure 5 This is the high-resolution mass spectrum of the final product.
[0057] Figure 6 This is the H NMR spectrum of the final product.
[0058] Figure 7 This is the C NMR spectrum of the final product.
[0059] Figure 8 It is the single crystal configuration analysis map of the final product, among which the code SAMP7759 is the detection code of impurity H by the outsourced testing agency. DETAILED DESCRIPTION
[0060] The following description sets forth numerous specific details to facilitate a thorough understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art may make similar modifications without departing from the scope of the present invention. Therefore, the present invention is not limited to the specific implementations disclosed below.
[0061] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in this specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.
[0062] Unless otherwise specified, the materials and reagents used in the present invention can be obtained from commercial products in the art.
[0063] In the following examples, the racemate bedaquinoline raw material used has a liquid phase spectrum as shown in FIG. Figure 1 shown.
[0064] Example 1
[0065] (1) 50.0 g of the rotatory bedaquiline and 85.0 mL of tetrahydrofuran were added to a 100 mL reaction flask in sequence, and the temperature was raised to 60° C. and stirred for 30 min; the material was hot filtered into a 500 mL reaction flask, and the temperature was raised to 65° C. 200.0 mL of ethanol was added dropwise over 1.5 to 2.0 h, and the temperature was stirred for 30 min after the addition was completed; the material was cooled to 3° C., stirred for 1.0 h, centrifuged, and the filter cake was washed to obtain about 10.1 g of bedaquiline enantiomer, with a yield of 20.2%; the liquid phase analysis spectrum of bedaquiline enantiomer is shown as follows Figure 2 As shown, the purity of RS / SR is 79% and the purity of SS / RR is 18%.
[0066] (2) 5.0 g of bedaquiline enantiomer, 100.0 mL of acetone, 3.2 mL of dimethyl sulfoxide (DMSO), and 3.14 g of S-binaphthol phosphate were added to a 250 mL reaction flask in sequence, heated to 58°C and stirred for 1.5 h, then cooled to 18°C and stirred for 2.0 h; the material was centrifuged and returned to the flask, and slurried with a mixed solution of 37.5 mL of acetone and 3.2 mL of dimethyl sulfoxide at 58°C for 1 h; cooled to 18°C and stirred for 1.5 h, and centrifuged to obtain 2.82 g of the resolved salt (theoretical amount is 6.43 g), with a net yield of 43.9%. [Theoretical amount calculation basis: (Wherein, 555.5 is the molecular weight of the bedaquiline enantiomer, and 903.79 is the molecular weight of the resolved salt)]
[0067] (3) 2.82 g of the resolved salt, 28.2 mL of toluene, and 21.6 g of a 10% potassium carbonate aqueous solution were added to a 100 mL reaction flask in sequence, and the temperature was raised to 80°C and stirred for 20 min; a mixed solution of 19.5 mL of water and 1.5 mL of ethanol was added and allowed to stand for stratification. After the aqueous layer was separated, the organic layer was washed twice with 30.0 mL of water; the organic layer was dehydrated with 2.0 g of anhydrous sodium sulfate and filtered into a 100 mL reaction flask, and the material was concentrated to dryness at 60°C; 1.0 g of the concentrate was added to 3.5 mL of tetrahydrofuran and heated to dissolve. 11.5 mL of ethanol was added dropwise at 50° C. and the mixture was stirred for 0.5 h. The temperature was lowered to 3° C. and stirred for 1 hour. The material was centrifuged and the filter cake was washed. The mixture was dried under reduced pressure at 65° C. for 6 hours to obtain 0.879 g of (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol impurity in a yield of 87.9%.
[0068] In order to improve the stability of the final product prepared in this example, it was combined with fumaric acid, and the resulting compound was named impurity H;
[0069] Liquid phase analysis of impurity H showed the following results: Figure 3-4 ; The impurity H was analyzed by mass spectrometry, nuclear magnetic resonance, single crystal culture, etc., and the results are as follows Figure 5-8 It can be seen that the final product prepared in this example has an enantiomeric purity of 99.8%, a purity of related substances of 99.7%, and an SR configuration.
[0070] Explanation of Related Substance Purity: Liquid phase detection methods for related substances can only separate enantiomers and diastereomers. Enantiomers RS and SR configurations produce the same peak, while diastereomers SS and RR configurations produce the same peak. Liquid phase detection methods for enantiomers produce separate peaks for each of the RS and SR configurations. High related substance and enantiomeric purity indicates that the target product is a single-configuration compound.
[0071] The corresponding NMR analysis is as follows:
[0072]
[0073] exist 1 In the H NMR spectrum, 32 hydrogen proton signals can be observed, including one unsaturated hydrogen proton signal δ H 8.73 (1H, s); 15 benzene ring hydrogen proton signals δ H 8.65-8.64 (1H, m), δ H 8.20(1H,s),δ H 7.93-7.90 (2H, m), δ H 7.71-7.70 (4H, m), δ H7.54-7.52 (1H, m), δ H 7.36-7.33(1H,t,J=15.6,7.7Hz),δ H 7.21-7.20 (2H, m), δ H 6.89-6.86 (3H, m); 2 olefin proton signals δ H 6.51 (2H, s); 1 methine proton signal δ H 5.83 (1H, s); 1 methoxyl proton signal δ H 4.23 (3H, s); 2 methylene hydrogen proton signals δ H 2.86(1H,brs),δ H 2.42(1H,brs),δ H 2.01-2.01(1H,m),δ H 1.89 (1H, brs); 2 methyl hydrogen proton signals δ H 2.14(6H,s).
[0074] exist 13 C NMR spectrum can observe 30 carbon signals, including 6 overlapping carbon signals (δ C 167.3, 134.6, 129.6, 127.3, 124.8, 43.0), combined with two-dimensional nuclear magnetic resonance, it can be determined that: 2 carboxyl carbon signals (δ C 167.3,167.3); 5 unsaturated carbon signals (δ C 160.8,138.9,134.6,134.6,129.3); 22 benzene ring carbon signals (δ C 143.2,140.8,140.1,134.1,132.0,129.9,129.7,129.6,129.6,128.5,128.2,127.3,127.3,127.1,126.9,126.6,126.0,125.8,124.8,124.8,124.1,116.5); 1 seasonal carbon signal (δ C 79.6); 1 methoxy carbon signal (δ C 54.3); 2 methylene carbon signals (δ C 54.0,33.8); 1 methine carbon signal (δ C 49.7); 2 methyl carbon signals (δ C 43.0,43.0).
[0075] The obtained compound can be inferred to be consistent with the structure from the NMR spectrum and mass spectrum.
[0076] Example 2
[0077] (1) 50.0 g of the rotatory bedaquiline and 85.0 mL of tetrahydrofuran were added to a 100 mL reaction flask in sequence, and the temperature was raised to 60° C. and stirred for 30 min; the material was hot filtered into a 500 mL reaction flask, and the temperature was raised to 65° C. 200.0 mL of ethanol was added dropwise over 1.5 to 2.0 h, and the temperature was stirred for 30 min after the addition was completed; the material was cooled to 3° C., stirred for 1.0 h, centrifuged, and the filter cake was washed to obtain about 10.1 g of bedaquiline enantiomer (purity: 79% RS / SR, 18% SS / RR), with a yield of 20.2%.
[0078] (2) 5.0 g of bedaquiline enantiomer, 250.0 mL of ethyl acetate, and 3.14 g of S-binaphthol phosphate were added to a 500 mL reaction flask in sequence, the temperature was raised to 58°C and the mixture was stirred for 1.5 h, then cooled to 18°C and stirred for 2.0 h; the material was returned to the flask after centrifugation and slurried with 400.0 mL of ethyl acetate solution at 58°C for 1 hour; the temperature was lowered to 18°C and the mixture was stirred for 1.5 h, and centrifuged to obtain 2.0 g of the resolved salt with a yield of 31.1%.
[0079] (3) 2.0 g of the resolved salt, 20.0 mL of toluene, and 15.5 g of a 10% potassium carbonate aqueous solution were added to a 100 mL reaction flask in sequence, and the temperature was raised to 80°C and stirred for 20 min; a mixed solution of 19.5 mL of water and 1.5 mL of ethanol was added and allowed to stand for stratification, and after the aqueous layer was separated, the organic layer was washed twice with 30.0 mL of water; the organic layer was dehydrated with 2.0 g of anhydrous sodium sulfate and filtered into a 100 mL reaction flask, and the material was concentrated to dryness at 60°C; 1.0 g of the concentrate was added with 3.5 mL of tetrahydrofuran was heated to dissolve, 11.5 mL of ethanol was added dropwise at 50°C, and the mixture was kept warm with stirring for 0.5 h; the temperature was lowered to 3°C, and the mixture was kept warm with stirring for 1 h. The material was centrifuged and the filter cake was washed; and the mixture was dried under reduced pressure at 65°C for 6 h to obtain 0.87 g of (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol impurity with a yield of 87.0% (enantiomeric purity: 94.6%, purity of related substances: 99.2%).
[0080] Example 3
[0081] The difference between this embodiment and embodiment 1 is that in step (1), the reaction solvent tetrahydrofuran is replaced by toluene in equal amounts, and the rest remain unchanged.
[0082] In this example, 3.23 g of bedaquiline enantiomer was prepared with a yield of 6.46%.
[0083] Example 4
[0084] The difference between this embodiment and embodiment 1 is that in step (1), the crystallization solvent ethanol is replaced by methanol in equal amounts, and the rest remains unchanged.
[0085] In this example, 6.7 g of bedaquiline enantiomer was prepared with a yield of 13.4%.
[0086] Example 5
[0087] The difference between this embodiment and embodiment 1 is that in step (2), dimethyl sulfoxide is not added, and the rest remains unchanged.
[0088] In this example, the amount of acetone used in the preparation process was increased to 1.8 to 2 times the amount used in Example 1. Otherwise, the system would be too thick and the impurity removal effect would be insignificant. In this example, the amount of acetone used was double that in step (2) of Example 1, resulting in 1.36 g of the resolved salt, with a net yield of 21.1%.
[0089] Comparative Example 1
[0090] The difference between this embodiment and embodiment 1 is that in step (3), the method of adding 10% aqueous potassium carbonate solution and then heating to 80°C and keeping stirring for 20 minutes is replaced by adding 10% aqueous sodium carbonate solution and then heating to 80°C and keeping stirring for 1.0 hour.
[0091] In this example, the amount, yield and purity of the target product are basically the same as those in Example 1.
[0092] Comparative Example 2
[0093] The comparison of the ratio optimization of the reagent dosage is as follows. The difference between this embodiment and embodiment 2 (the molar ratio of bedaquinoline enantiomer to S-binaphthol phosphate is 1:1) is that in step (2), the amount of S-binaphthol phosphate added is 5 g. Although the increase in the amount of S-binaphthol phosphate leads to an increase in the concentration of the reactants, which theoretically accelerates the reaction rate, it is found in actual experiments that the addition of excessive S-binaphthol phosphate greatly increases the consistency of the system, making it difficult to pour the product and causing impurities to be wrapped.
[0094] Comparative Example 3
[0095] A method for extracting bedaquiline enantiomeric impurities using preparative separation techniques involves dissolving the raw material in tetrahydrofuran, first removing the diastereomers using a liquid phase method for the relevant substance, and collecting a mixed solution of the RS and SR enantiomers. A liquid phase enantiomeric detection method is then used to collect the SR configuration solution, and the solvent is evaporated to obtain the highly purified target product. While this method can also yield a highly purified target product, it requires a high preparation process, requires a large amount of solvent, and the target product is typically obtained in milligram quantities, resulting in a significantly higher cost than the present invention.
[0096] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0097] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.
Claims
1. A method for separating (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol of Formula 4 from a chiral mixture, characterized in that: S-binaphthol phosphate was used as the resolving agent.
2. The method according to claim 1, characterized in that The chiral mixture comprises four configurations shown in Formulas 1 to 4 below, and the method specifically comprises: (1) first separating the epimers represented by Formula 1 and Formula 2 to obtain a mixture comprising Formula 3 and Formula 4; (2) using S-binaphthol phosphate as a resolving agent, separating from the mixture (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol as shown in Formula 4; Among them, the structures shown in Formula 1 to Formula 4 are as follows:
3. The method according to claim 2, characterized in that Step (1) is specifically as follows: The raw materials are dissolved in a reaction solvent A, and after the temperature is raised to react, a crystallization solvent A is added to crystallize, and the mixture is centrifuged and washed to obtain a mixture comprising Formula 3 and Formula 4; Wherein, the solvent A is at least one of tetrahydrofuran and toluene, preferably tetrahydrofuran; the crystallization solvent A is at least one of ethanol and methanol, preferably ethanol.
4. The method according to claim 3, characterized in that In step (1), the reaction temperature is 55°C to 65°C, preferably 60°C; the crystallization temperature is -5°C to 5°C, preferably 2 to 3°C.
5. The method according to claim 3, characterized in that In step (1), the mass volume ratio of the racemic bedaquiline to the reaction solvent A and the crystallization solvent A is 1 g:1.5 ml~2.3 ml:3 ml~6 ml, and the preferred ratio is 1 g:1.7 ml:4 ml.
6. The method according to claim 2, characterized in that Step (2) specifically includes: S21: mixing the mixture obtained in step (1) with reaction solvent B and S-binaphthol phosphate, heating the mixture for reaction, cooling and stirring once, centrifuging once, heating and beating, cooling and stirring twice, and centrifuging twice to obtain the resolved salt shown in Formula 5 below; S22: mixing the obtained resolved salt with reaction solvent C and alkali metal carbonate solution, performing a primary temperature reaction, adding an extraction solvent, extracting and stratifying, washing the organic layer, and concentrating to obtain a concentrate; mixing the concentrate with a recrystallization solvent, performing a secondary temperature reaction, cooling and crystallizing, centrifuging, washing the filter cake, and drying to obtain the product shown in Formula 4; Wherein, in step S21, the reaction solvent B is a mixed system of acetone and DMSO, or ethyl acetate, or a mixed system of ethyl acetate and DMSO, preferably a mixed system of acetone and DMSO; In step S22, the reaction solvent C is toluene, the alkali metal carbonate solution is at least one of potassium carbonate and sodium carbonate; the extraction solvent is a mixed solvent consisting of water and ethanol; and the recrystallization solvent is composed of toluene and ethanol, or tetrahydrofuran and ethanol.
7. The method according to claim 6, characterized in that In step S21, The temperature of the temperature-raising reaction and the temperature of the temperature-raising beating are both 55°C to 60°C, preferably 58°C; The time for heating reaction is 1h~2h; the time for heating beating is 40-80min; The temperature of the first cooling and stirring and the second cooling and stirring is 15°C to 20°C, preferably 18°C; The time for the first cooling and stirring is 1.5h to 2.5h; the time for the second cooling and stirring is 1h to 2h.
8. The method according to claim 6, characterized in that In step S21, when the temperature is raised for beating, the reaction solvent B is used as the beating solvent.
9. The method according to claim 8, characterized in that In step S21, the reaction solvent B is a mixture of acetone and DMSO; When the mixture is mixed with the reaction solvent B and S-binaphthol phosphate, the mixing ratio of the mixture to acetone, DMSO, and S-binaphthol phosphate is 1g:18ml-22ml:0.5ml-0.8ml:0.6g-0.7g; the preferred ratio is 1g:20ml:0.64ml:0.63g; When the temperature is increased and the pulp is beaten, the mixing ratio of the mixture to acetone and DMSO is 1 g: 5 ml to 10 ml: 0.5 ml to 0.8 ml.
10. The method according to claim 8, characterized in that In step S21, the reaction solvent B is ethyl acetate, When the mixture is mixed with the reaction solvent B and S-binaphthol phosphate, the mixing ratio of the mixture to ethyl acetate and S-binaphthol phosphate is 1g:45ml-60ml:0.6g-0.7g; the preferred ratio is 1g:50ml:0.63g; When the temperature is raised and the pulp is beaten, the mixing ratio of the mixture to ethyl acetate is 1g:75ml~100ml.
11. The method according to claim 6, characterized in that In step S22, The primary heating reaction temperature is 78°C to 82°C, preferably 80°C, and the time is 15 to 25 minutes; The secondary temperature reaction temperature is 48°C to 52°C, preferably 50°C, and the time is 25 to 35 minutes; The temperature during crystallization is 0°C to 5°C, preferably 3°C, and the time is 40 to 80 minutes.
12. The method according to claim 6, characterized in that In step S22, the mixing ratio of the splitting salt to the reaction solvent C, the alkali metal carbonate solution and the extraction solvent is 1g:8ml-12ml:6.5g-8.5g:7ml-11ml, wherein the volume ratio of water to ethanol in the extraction solvent is 10-15:
1.
13. The method according to claim 6, characterized in that The recrystallization solvent is composed of tetrahydrofuran and ethanol. The mixing ratio of the concentrate to tetrahydrofuran and ethanol is 1g:3.2ml-4ml:10ml-15ml; the preferred ratio is 1g:3.5ml:11.5ml.