Bedaquiline fumarate impurity and preparation method thereof

Abstract

The invention discloses a bedaquiline fumarate impurity and a preparation method thereof. The invention specifically discloses a compound as shown in a formula II or a salt thereof, and a preparation method of the compound as shown in the formula II. The compound shown in the formula II prepared by the preparation method disclosed by the invention is high in yield and purity, and the obtained compound shown in the formula II can be used as a reference substance for qualitative and quantitative analysis of the compound shown in the formula II in bedaquiline fumarate production, so that the quality standard of bedaquiline fumarate can be further improved.

Description

Technical Field

[0001] The invention relates to the field of synthesis of impurity reference substances, and in particular to a bedaquiline fumarate impurity and a preparation method thereof. Background Art

[0002] Bedaquiline fumarate, also known as (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol fumarate, is a white or off-white powder in its pure form. It is readily soluble in methanol and virtually insoluble in water. Bedaquiline fumarate tablets, marketed under the brand name Sirturo, are a novel anti-tuberculosis drug whose greatest strength lies in their unique therapeutic mechanism. They inhibit the ATP synthase of Mycobacterium tuberculosis, blocking its energy supply and preventing the bacteria from surviving and reproducing. Compared to traditional anti-tuberculosis drugs, bedaquiline fumarate tablets exhibit higher bactericidal activity and lower drug resistance. They can be used not only to treat multidrug-resistant tuberculosis but also for intensive treatment of sensitive tuberculosis, significantly improving treatment efficacy and cure rates.

[0003]

[0004] The structural formula of bedaquiline fumarate

[0005] The stereoselective construction of the Csp3-Csp3 bond at the continuity center in the bedaquiline fumarate molecule is a very challenging problem, which also makes it difficult to efficiently synthesize the drug. At present, the synthesis method of bedaquiline fumarate is still being optimized and iterated. WO2025025468A1 discloses an efficient synthesis method of bedaquiline fumarate, but new impurities are generated in the process route of this method. The confirmation of impurities in drugs and the study of impurity content levels are very important for the quality control of drugs. Only by confirming and synthesizing a certain amount of impurity reference substances can the production process and quality standards of bedaquiline fumarate be better improved, thereby improving the quality of drugs and reducing potential adverse reactions and toxic side effects. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the defects of the prior art in that the types and structures of substances that affect the quality of bedaquiline fumarate produced in a new process route for bedaquiline fumarate are uncertain, and qualitative and quantitative analysis of related substances cannot be performed due to the lack of reference substances. To this end, the present invention provides a bedaquiline fumarate impurity and a synthesis method thereof. The method is simple and convenient, and the yield and purity of the prepared compound of formula II are high. The obtained compound of formula II can be used as a reference substance for qualitative and quantitative analysis of the compound of formula II in the production of bedaquiline fumarate, thereby further improving the quality standard of bedaquiline fumarate.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] The present invention provides a compound of formula II or a salt thereof:

[0009] .

[0010] The present invention also provides a method for preparing the compound of formula II, which comprises the following steps:

[0011]

[0012] In an ether solvent, in the presence of an organometallic compound, the compound of formula I and benzaldehyde undergo a nucleophilic addition reaction to prepare the compound of formula II.

[0013] In one embodiment of the present invention, the ether solvent is R 1 -OR 2 or cyclic ether solvents;

[0014] Among them, R 1 and R 2 Independently C 1-6 alkyl.

[0015] In one embodiment of the present invention, R 1 and R 2 Independently C 1-4 Alkyl groups, such as methyl, ethyl or tert-butyl.

[0016] In a certain embodiment of the present invention, the R 1 -OR 2 For diethyl ether or methyl tert-butyl ether.

[0017] In one embodiment of the present invention, the cyclic ether solvent is a 4-8 membered cyclic ether solvent, preferably a 5-6 membered cyclic ether solvent.

[0018] In one embodiment of the present invention, the cyclic ether solvent contains 1-4 oxygen atoms;

[0019] Preferably, the cyclic ether solvent contains 1 or 2 oxygen atoms.

[0020] In one embodiment of the present invention, the cyclic ether solvent is a 5-6 membered cyclic ether solvent containing 1 or 2 oxygen atoms, such as tetrahydrofuran or 1,4-dioxane.

[0021] In a certain embodiment of the present invention, in the nucleophilic addition reaction, the volume ratio of the amount of the compound of formula I used to the ether solvent used is 0.1~1 mol / L, preferably 0.1~0.5 mol / L, for example 0.126 mol / L (in the present invention, when the organometallic compound is introduced into the reaction system in the form of an organic solvent solution of the organometallic compound, and the organic solvent solution is an ether solvent solution, this part of the "ether solvent" is not included in the volume calculation of the "ether solvent" in this technical solution).

[0022] In one embodiment of the present invention, the organometallic compound is a strongly basic organometallic compound; the strongly basic organometallic compound has the ability to complete the following transformations:

[0023] .

[0024] In one embodiment of the present invention, the strong alkaline organometallic compound is R 3 -X;

[0025] wherein X is an alkali metal, such as lithium, sodium or potassium;

[0026] R 3 C 1-10 Alkyl, -N(R 3a R 3b )or ;

[0027] R 3a and R 3b Independently C 1-6 Alkyl, preferably branched C 3-6 Alkyl groups, such as isopropyl;

[0028] Each R 3c Independently C 1-6 Alkyl, preferably C 1-3 Alkyl groups, such as methyl;

[0029] Each R 3d Independently C 1-6 Alkyl, preferably C 1-3 Alkyl groups, such as methyl.

[0030] In one embodiment of the present invention, R 3 C 1-10 Alkyl, more preferably C 3-10 Alkyl, for example n-butyl.

[0031] In one embodiment of the present invention, R 3 For n-butyl, or .

[0032] In one embodiment of the present application, R 3 -X is n-butyllithium, diisopropylaminolithium, potassium bis(trimethylsilyl)amide or lithium bis(trimethylsilyl)amide.

[0033] In one embodiment of the present application, R 3 -X is n-butyllithium or diisopropylaminolithium.

[0034] In one embodiment of the present application, the ratio of the amount of substance of the organometallic compound to the amount of substance of the compound of formula I used in the nucleophilic addition reaction is 1.0 to 2.0, preferably 1.2 to 1.6, for example 1.3 or 1.5.

[0035] In one embodiment of the present application, the organometallic compound is introduced into the reaction system in the form of an organic solvent solution of the organometallic compound;

[0036] The organic solvent in the organic solvent solution of the organometallic compound is preferably an ether solvent or a C 1-10 alkane solvent.

[0037] The ether solvent is as defined in any of the preceding embodiments.

[0038] The C 1-10 alkane solvent is preferably a C 3-6 alkane solvent, for example n-hexane.

[0039] In one embodiment of the present application, the organic solvent solution of the organometallic compound is a tetrahydrofuran solution of diisopropylaminolithium or a n-hexane solution of butyllithium.

[0040] The tetrahydrofuran solution of diisopropylaminolithium is preferably a tetrahydrofuran solution of diisopropylaminolithium at 1.0 to 3.0 mol / L, for example a tetrahydrofuran solution of diisopropylaminolithium at 2.0 mol / L.

[0041] The n-hexane solution of butyllithium is preferably a n-hexane solution of butyllithium at 2.0 to 3.0 mol / L, for example a n-hexane solution of butyllithium at 2.5 mol / L.

[0042] In one embodiment of the present application, when the organometallic compound is introduced into the reaction system in the form of an organic solvent solution of the organometallic compound, the addition is carried out dropwise.

[0043] In one embodiment of the present application, when the organometallic compound is introduced into the reaction system in the form of an organic solvent solution of the organometallic compound, the temperature of the reaction system is 0 °C or lower, preferably -100 °C to 0 °C, more preferably -78 °C to -50 °C or -30 °C to -20 °C, for example -78 °C or -25 °C.

[0044] In one embodiment of the present application, the ratio of the amount of substance of benzaldehyde to the amount of substance of the compound of formula I used in the nucleophilic addition reaction is 1.0 to 2.0, preferably 1.0 to 1.5, for example 1.2 or 1.3.

[0045] In one embodiment of the present application, the progress of the nucleophilic addition reaction is monitored by using a method commonly used in the art (for example HPLC or TLC), and the reaction is generally terminated when one of the raw materials in the reaction solution disappears or no longer reacts. The reaction time of the nucleophilic addition reaction is preferably 5 to 20 h, for example 10 h.

[0046] In one embodiment of the present application, the temperature of the nucleophilic addition reaction is 10°C to 40°C, preferably 20°C to 35°C, for example 25°C.

[0047] In one embodiment of the present application, the nucleophilic addition reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen or argon.

[0048] In one embodiment of the present application, the nucleophilic addition reaction is carried out at normal pressure.

[0049] In one embodiment of the present application, the materials used in the nucleophilic addition reaction only involve the materials mentioned in the technical solutions in the specification, and do not involve other materials.

[0050] In one embodiment of the present application, the materials used in the nucleophilic addition reaction consist of an ether solvent, an organometallic compound, a compound of formula I and benzaldehyde; or consist of an ether solvent, an organic solvent solution of an organometallic compound, a compound of formula I and benzaldehyde;

[0051] Preferably, the materials used in the nucleophilic addition reaction consist of tetrahydrofuran, a tetrahydrofuran solution of lithium diisopropylamide, a compound of formula I and benzaldehyde;

[0052] Or, the materials used in the nucleophilic addition reaction consist of tetrahydrofuran, a n-hexane solution of butyllithium, a compound of formula I and benzaldehyde.

[0053] In one embodiment of the present application, the method for preparing the compound of formula II further comprises one or more of the following post-treatment steps:

[0054] Quenching, extraction, drying, concentration and column chromatography purification;

[0055] The quenching is preferably quenched using a weakly acidic solution; the weakly acidic solution is preferably an aqueous ammonium chloride solution, for example a saturated aqueous ammonium chloride solution;

[0056] The extraction is preferably extracted using an ester solvent; the ester solvent is preferably ethyl acetate;

[0057] The drying is preferably carried out using anhydrous sodium sulfate;

[0058] The column chromatography purification preferably uses petroleum ether and ethyl acetate as mobile phases for column chromatography purification.

[0059] In one embodiment of the present invention, the preparation method of the compound of formula II comprises the following steps:

[0060] (1) mixing the ether solvent, the organometallic compound and the compound of formula I;

[0061] (2) adding benzaldehyde to produce a nucleophilic addition reaction to prepare the compound of formula II;

[0062] Preferably, the preparation method of the compound of formula II comprises the following steps:

[0063] (1) adding the organometallic compound to the ether solvent solution of the compound of formula I at low temperature under the protection of inert gas, and reacting until one of the raw materials disappears or no longer reacts;

[0064] Preferably, the reaction time is 5-30 min;

[0065] Preferably, the low temperature is below 0°C, preferably -100°C to 0°C;

[0066] More preferably, when the organometallic compound is butyllithium, the low temperature is -78°C to -50°C;

[0067] More preferably, when the organometallic compound is lithium diisopropylamide, the low temperature is -30 to -20°C, for example -25°C;

[0068] (2) Benzaldehyde is added to produce a nucleophilic addition reaction to prepare the compound of formula II.

[0069] In one embodiment of the present invention, the method for preparing the compound of formula II comprises any of the following steps:

[0070] Step (1): Add the compound of formula I to the reaction flask, evacuate, replace nitrogen, add an ether solvent, cool at -78~0°C, add the organic solvent solution of the organometallic compound dropwise, stir for 5~30 minutes, add benzaldehyde, and heat to room temperature for reaction for 8~16 hours, quench the reaction solution, extract with ethyl acetate, dry the organic phase, concentrate to obtain a crude product, and purify by silica gel column chromatography to obtain the compound of formula II; the organic solvent solution of the organometallic compound is preferably a n-hexane solution of butyl lithium;

[0071] Step (2): Add the compound of formula I to the reaction flask, evacuate, replace nitrogen, add an ether solvent, cool at -30~-20°C, add the organic solvent solution of the organometallic compound dropwise, stir for 10~20 minutes, then add benzaldehyde, and heat to room temperature for reaction for 8~12 hours, quench the reaction solution, extract with ethyl acetate, dry the organic phase, concentrate to obtain a crude product, and purify by silica gel column chromatography to obtain the compound of formula II; the organic solvent solution of the organometallic compound is preferably a tetrahydrofuran solution of lithium diisopropylamide;

[0072] Preferably, the method for preparing the compound of formula II is carried out through step (1) or step (2) (i.e., does not include other steps).

[0073] In one embodiment of the present invention, the silica gel column chromatography purification method is a conventional technique in the art.

[0074] In one embodiment of the present invention, the preparation method of the compound of formula II comprises the following steps:

[0075] Step (A): In an ether solvent, an organometallic compound and a compound of formula I undergo a hydrogen extraction reaction to prepare a compound of formula Ia;

[0076] ;

[0077] The temperature of the hydrogenation reaction is below 0°C, preferably -100°C to 0°C, more preferably -78°C to -50°C or -30°C to -20°C, for example -78°C or -25°C;

[0078] Step (B): In an ether solvent, the compound of formula Ia and benzaldehyde undergo a nucleophilic addition reaction to prepare the compound of formula II;

[0079]

[0080] Wherein, the definitions and usage amounts of the ether solvent, the organometallic compound, the compound of formula I and benzaldehyde are as described in any of the previous schemes;

[0081] The conditions and operation of the nucleophilic addition reaction are as described in any of the previous schemes;

[0082] Preferably, the method for preparing the compound of formula II is carried out through step (A) and step (B) (ie, does not include other steps).

[0083] The present invention also provides a use of a compound of formula II or a salt thereof as a standard, reference substance or test item in the impurity research, quality control or detection method of bedaquiline or a pharmaceutically acceptable salt thereof;

[0084] ;

[0085] The pharmaceutically acceptable salt of bedaquiline is preferably bedaquiline fumarate;

[0086] The detection method is preferably high performance liquid chromatography.

[0087] The present invention provides a method for detecting a compound of formula II or a salt thereof in bedaquiline or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula II or a salt thereof is used as a standard or reference substance and is detected by high performance liquid chromatography;

[0088] .

[0089] Unless otherwise specified, the terms used in this invention may be defined as follows:

[0090] In the present invention, the metal in the "organometallic compound" mainly exists in the form of atoms and is combined with other parts of the molecule through covalent or coordinate bonds; however, it does not exclude that in certain circumstances, the metal in the "organometallic compound" acts as a cation and combines with the corresponding anion through ionic bonds to form an organometallic compound.

[0091] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0092] The reagents and raw materials used in the present invention are commercially available.

[0093] The present invention has the positive and progressive effect of identifying and synthesizing an impurity (compound of Formula II) in bedaquiline fumarate. The synthesis method for the compound of Formula II provided by the present invention is simple and convenient, and the resulting compound of Formula II has high yield and purity. The compound of Formula II prepared by the preparation method of the present invention can be applied to the quantitative and qualitative analysis of bedaquiline fumarate production, further improving the quality standards of bedaquiline fumarate. The compound of Formula II prepared by the present invention needs to be controlled during the synthesis process of bedaquiline fumarate, and the synthesis of this impurity facilitates the development of more precise analytical methods (such as high-performance liquid chromatography) and a more stable production process, thereby improving the quality of the drug. DETAILED DESCRIPTION

[0094] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0095] The building-up reaction process of the present invention is as follows:

[0096]

[0097] Preparation of the structural compound shown in Formula II

[0098] Example 1

[0099] The compound of formula I (3.00 g, 12.6 mmol, 1.0 eq) was added to the reaction flask, and the mixture was evacuated and replaced with nitrogen. Tetrahydrofuran (100 mL) was added and cooled to -25°C. A solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 9.5 mL, 1.5 eq) was added dropwise. After stirring for 15 min, benzaldehyde (1.74 g, 16.4 mmol, 1.3 eq) was added and the temperature was raised to room temperature for 10 h. After completion of the reaction, saturated ammonium chloride solution (35 mL) was added, and ethyl acetate (30 mL*2) was added for extraction. The organic phase after extraction was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as the mobile phase in a volume ratio of 10:1 to 6:1. After concentration, the compound of formula II was obtained as a white solid (4.1 g, 95%) with an HPLC purity of 96.4%.

[0100] LC-MS (ESI) m / z 344.03 [M + H]+;

[0101] The H NMR spectrum of the compound represented by formula II: 1 H NMR (400 MHz, CDCl3) δ 7.87 (s,1H), 7.85 (d, J = 2.4 Hz, 1H), 7.71–7.68 (m, 1H), 7.67–7.64 (m, 1H), 7.41–7.39 (m, 2H), 7.37–7.33 (m, 2H), 7.32–7.28 (m, 1H), 4.05 (s, 3H), 2.90 (s,1H);

[0102] The carbon NMR spectrum of the compound represented by formula II: 13 C NMR (100 MHz, CDCl3) δ 158.8,143.4, 140.6, 133.2, 131.5, 128.7, 127.7, 127.5, 127.4, 126.9, 125.8, 125.4,116.4, 70.6, 52.7.

[0103] Example 2

[0104] The compound of Formula I (3.00 g, 12.6 mmol, 1.0 eq) was added to the reaction flask, and the mixture was evacuated and replaced with nitrogen. Tetrahydrofuran (100 mL) was added and the mixture was cooled to -78°C. A 2.5 M solution of butyllithium in n-hexane (6.6 mL, 16.4 mmol, 1.3 eq) was added dropwise. After stirring for 15 min, benzaldehyde (1.60 g, 15.12 mmol, 1.2 eq) was added and the temperature was raised to room temperature for 10 h. After completion of the reaction, saturated ammonium chloride solution (30 mL) was added, and ethyl acetate (30 mL*2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography with petroleum ether and ethyl acetate as the mobile phase in a volume ratio of 10:1 to 6:1. The compound of Formula II was obtained as a white solid (3.9 g, 92%) with an HPLC purity of 96.7%.

[0105] The H NMR spectrum of the compound represented by formula II: 1 H NMR (400 MHz, CDCl3) δ 7.87 (s,1H), 7.85 (d, J = 2.4 Hz, 1H), 7.71–7.68 (m, 1H), 7.67–7.64 (m, 1H), 7.41–7.39 (m, 2H), 7.37–7.33 (m, 2H), 7.32–7.28 (m, 1H), 4.05 (s, 3H), 2.90 (s,1H);

[0106] The carbon NMR spectrum of the compound represented by formula II: 13 C NMR (100 MHz, CDCl3) δ 158.8,143.4, 140.6, 133.2, 131.5, 128.7, 127.7, 127.5, 127.4, 126.9, 125.8, 125.4,116.4, 70.6, 52.7.

[0107] Example 3 Low-temperature continuous flow method for preparing bedaquiline

[0108] The following content is quoted from Example 1 in WO2025025468A1:

[0109] Step S1: In a dry 5L reactor, add 10.5 g (245 mmol, 2.9 equiv) of lithium chloride, 38.3 g (178.5 mmol, 2.1 equiv) of (1S,2R)-2-amino-1,2-diphenylethanol, 23.9 mL (213 mmol, 2.5 equiv) of N-methylpiperazine, and 600 mL of anhydrous tetrahydrofuran. Add 150 mL (375 mmol) of a 2.5 M (2.5 mol / L) n-butyl chrysene solution in n-hexane at -20°C and react for 30 min as feed solution A.

[0110] 27.9 g of raw material 1 (in the following examples, raw material 1 refers to 6-bromo-3-benzyl-2-methoxyquinoline) (85 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed uniformly to obtain feed liquid B:

[0111] The raw material 2 (3-dimethylamino-1-naphthyl-1-propanone) (26.9 g, 102 mmol) was placed in a 5 L single-necked bottle, and 750 mL of anhydrous tetrahydrofuran was added and mixed well to prepare the feed solution C.

[0112] Among them, the flow rate of feed liquid A is 15 mL / min, the flow rate of feed liquid B is 15 mL / min, and the flow rate of feed liquid C is 15 mL / min;

[0113] Step S2: pumping feed liquid A and feed liquid B into the first micro-reaction tube for a first continuous flow reaction to obtain reaction liquid D; the reaction temperature T1 is -20°C, and the reaction residence time t1 is 5 min;

[0114] Step S3: pumping the reaction solution D and the feed solution C into the second micro-reaction tube for a second continuous flow reaction, with a reaction temperature T2 of -60°C and a reaction residence time t2 of 3 min;

[0115] Step S4: quenching; the reaction solution of step S3 is discharged from the second micro-reaction tube and passed into 2 L of saturated ammonium chloride solution for quenching, and the quenching temperature T3 is -60 ° C; the quenched reaction solution is collected to obtain a mixture containing bedaquiline;

[0116] Step S5: post-processing: extraction, recrystallization and beating;

[0117] Extraction: The mixture was extracted with ethyl acetate (3 times * 1 L) in a 5 L reactor. The organic phase was collected and concentrated under reduced pressure to obtain crude bedaquiline.

[0118] Testing revealed that the crude bedaquiline product contained 1.2% of the compound of Formula II. This is significantly higher than the impurity limits for APIs stipulated in the ICH Tripartite Harmonized Guidelines (i.e., significantly higher than the reporting, identification, and qualification limits). Therefore, the compound of Formula II has a substantial impact on the pharmaceutical activity, toxic side effects, or adverse reactions of bedaquiline fumarate, and also has a substantial impact on the quality control of bedaquiline fumarate. Confirming the structure of the compound of Formula II and optimizing its preparation method will allow for the high-yield and high-purity preparation of the compound of Formula II. This will facilitate its use as a reference substance for qualitative and quantitative analysis of the compound of Formula II in bedaquiline fumarate production, further improving the quality standards of bedaquiline fumarate.

[0119] The technical solutions provided by the embodiments of the present invention are introduced in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the embodiments of the present invention. The description of the above embodiments is only applicable to help understand the principles of the embodiments of the present invention. At the same time, for those skilled in the art, according to the embodiments of the present invention, there may be changes in the specific implementation methods and application scopes. In summary, this specification should not be understood as limiting the present invention.

Claims

1. A compound of formula II or a salt thereof: 。 2. A method for preparing a compound of formula II, comprising the following steps: In an ether solvent, in the presence of an organometallic compound, the compound of formula I and benzaldehyde undergo a nucleophilic addition reaction to prepare the compound of formula II.

3. The preparation method according to claim 2, wherein It meets one or more of the following conditions: (1) The ether solvent is R 1 -OR 2 or cyclic ether solvents; Among them, R 1 and R 2 Independently C 1-6 alkyl; Preferably, R 1 and R 2 Independently C 1-4 an alkyl group, such as methyl, ethyl or tert-butyl; (2) The cyclic ether solvent is a 4-8 membered cyclic ether solvent, preferably a 5-6 membered cyclic ether solvent; (3) The cyclic ether solvent contains 1 to 4 oxygen atoms; Preferably, the cyclic ether solvent contains 1 or 2 oxygen atoms; (4) In the nucleophilic addition reaction, the volume ratio of the amount of the compound of formula I used to the volume of the ether solvent used is 0.1 to 1 mol / L, preferably 0.1 to 0.5 mol / L, for example 0.126 mol / L; (5) The organometallic compound is a strongly basic organometallic compound; the strongly basic organometallic compound has the ability to complete the following transformations; ； (6) In the nucleophilic addition reaction, the ratio of the amount of the organometallic compound used to the amount of the compound of formula I used is 1.0 to 2.0, preferably 1.2 to 1.6, for example 1.3 or 1.5; (7) The organometallic compound is introduced into the reaction system in the form of an organic solvent solution of the organometallic compound; the organic solvent in the organic solvent solution of the organometallic compound is preferably an ether solvent or C 1-10 Alkane solvent; the C 1-10 The alkane solvent is preferably C 3-6 Alkane solvents, such as n-hexane; (8) In the nucleophilic addition reaction, the ratio of the amount of benzaldehyde used to the amount of the compound of formula I used is 1.0 to 2.0, preferably 1.0 to 1.5, for example 1.2 or 1.3; (9) The temperature of the nucleophilic addition reaction is 10°C-40°C, preferably 20°C-35°C, for example 25°C; (10) The nucleophilic addition reaction is carried out under the protection of an inert gas; the inert gas is preferably nitrogen or argon; (11) The materials used in the nucleophilic addition reaction are composed of an ether solvent, an organometallic compound, a compound of formula I, and benzaldehyde; or, are composed of an ether solvent, an organic solvent solution of an organometallic compound, a compound of formula I, and benzaldehyde; (12) The method for preparing the compound of formula II further comprises one or more of the following post-treatment steps: Quenching, extraction, drying, concentration and column chromatography purification.

4. The preparation method according to claim 3, wherein It meets one or more of the following conditions: (1) R 1 -OR 2 is ethyl ether or methyl tert-butyl ether; (2) The cyclic ether solvent is a 5-6-membered cyclic ether solvent containing 1 or 2 oxygen atoms, such as tetrahydrofuran or 1,4-dioxane; (3) The strong alkaline organometallic compound is R 3 -X; wherein X is an alkali metal, such as lithium, sodium or potassium; R 3 C 1-10 Alkyl, -N(R 3a R 3b )or ; R 3 Preferably C 1-10 Alkyl, more preferably C 3-10 Alkyl groups, such as n-butyl; R 3a and R 3b Independently C 1-6 Alkyl, preferably branched C 3-6 Alkyl groups, such as isopropyl; Each R 3c Independently C 1-6 Alkyl, preferably C 1-3 Alkyl groups, such as methyl; Each R 3d Independently C 1-6 Alkyl, preferably C 1-3 Alkyl groups, such as methyl; Preferably, R 3 -X is n-butyllithium, lithium diisopropylamide, potassium bis(trimethylsilyl)amide or lithium bis(trimethylsilyl)amide; More preferably, R 3 -X is n-butyllithium or lithium diisopropylamide; (4) The organic solvent solution of the organometallic compound is a tetrahydrofuran solution of lithium diisopropylamide or a n-hexane solution of butyl lithium; The tetrahydrofuran solution of lithium diisopropylamide is preferably a 1.0-3.0 mol / L tetrahydrofuran solution of lithium diisopropylamide, for example a 2.0 mol / L tetrahydrofuran solution of lithium diisopropylamide; The n-hexane solution of butyl lithium is preferably a 2.0-3.0 mol / L n-hexane solution of butyl lithium, for example a 2.5 mol / L n-hexane solution of butyl lithium; (5) When the organometallic compound is introduced into the reaction system in the form of an organic solvent solution of the organometallic compound, the addition method is dropwise addition; (6) The materials used in the nucleophilic addition reaction are composed of tetrahydrofuran, a tetrahydrofuran solution of lithium diisopropylamide, a compound of formula I, and benzaldehyde; Alternatively, the materials used in the nucleophilic addition reaction are composed of tetrahydrofuran, a n-hexane solution of butyl lithium, a compound of formula I, and benzaldehyde; (7) The quenching is performed using a weak acidic solution; the weak acidic solution is preferably an aqueous ammonium chloride solution, such as a saturated aqueous ammonium chloride solution; (8) The extraction is performed using an ester solvent; the ester solvent is preferably ethyl acetate; (9) The drying is performed using anhydrous sodium sulfate; (10) The column chromatography purification is performed using petroleum ether and ethyl acetate as mobile phases; (11) When the organometallic compound is introduced into the reaction system in the form of an organic solvent solution of the organometallic compound, the temperature of the reaction system is below 0°C, preferably -100°C to 0°C, more preferably -78°C to -50°C or -30 to -20°C, for example -78°C or -25°C.

5. The preparation method according to claim 2, wherein The preparation method of the compound of formula II comprises the following steps: (1) mixing the ether solvent, the organometallic compound and the compound of formula I; (2) adding benzaldehyde to produce a nucleophilic addition reaction to prepare the compound of formula II; Preferably, the preparation method of the compound of formula II comprises the following steps: (1) adding the organometallic compound to the ether solvent solution of the compound of formula I at low temperature under the protection of inert gas, and reacting until one of the raw materials disappears or no longer reacts; Preferably, the reaction time is 5-30 min; Preferably, the low temperature is below 0°C, preferably -100°C to 0°C; More preferably, when the organometallic compound is butyllithium, the low temperature is -78°C to -50°C; More preferably, when the organometallic compound is lithium diisopropylamide, the low temperature is -30 to -20°C, for example -25°C; (2) Benzaldehyde is added to produce a nucleophilic addition reaction to prepare the compound of formula II.

6. The preparation method according to claim 2, wherein The preparation method of the compound of formula II comprises any of the following steps: Step (1): Add the compound of formula I to the reaction flask, evacuate, replace nitrogen, add an ether solvent, cool at -78~0°C, add the organic solvent solution of the organometallic compound dropwise, stir for 5~30 minutes, add benzaldehyde, and heat to room temperature for reaction for 8~16 hours, quench the reaction solution, extract with ethyl acetate, dry the organic phase, concentrate to obtain a crude product, and purify by silica gel column chromatography to obtain the compound of formula II; the organic solvent solution of the organometallic compound is preferably a n-hexane solution of butyl lithium; Step (2): Add the compound of formula I to the reaction flask, evacuate, replace nitrogen, add an ether solvent, cool at -30~-20°C, add the organic solvent solution of the organometallic compound dropwise, stir for 10~20 minutes, then add benzaldehyde, and heat to room temperature for reaction for 8~12 hours, quench the reaction solution, extract with ethyl acetate, dry the organic phase, concentrate to obtain a crude product, and purify by silica gel column chromatography to obtain the compound of formula II; the organic solvent solution of the organometallic compound is preferably a tetrahydrofuran solution of lithium diisopropylamide; Preferably, the preparation method of the compound of formula II is carried out through step (1) or step (2).

7. The preparation method according to claim 2, wherein The preparation method of the compound of formula II comprises the following steps: Step (A): In an ether solvent, an organometallic compound and a compound of formula I undergo a hydrogen extraction reaction to prepare a compound of formula Ia; ； Step (B): In an ether solvent, the compound of formula Ia and benzaldehyde undergo a nucleophilic addition reaction to prepare the compound of formula II; Preferably, the preparation method of the compound of formula II is carried out through step (A) and step (B).

8. The preparation method according to claim 7, wherein It meets one or more of the following conditions: (1) The temperature of the hydrogenation reaction is below 0°C, preferably -100°C to 0°C, more preferably -78°C to -50°C or -30°C to -20°C, for example -78°C or -25°C; (2) The definitions and usage amounts of the ether solvent, the organometallic compound, the compound of formula I and benzaldehyde are as described in any one of claims 2 to 6; The conditions and operation of the nucleophilic addition reaction are as described in any one of claims 2 to 6.

9. Use of a compound of formula II or a salt thereof as a standard, reference substance or test item in the study of impurities, quality control or detection of bedaquiline or a pharmaceutically acceptable salt thereof; ； The pharmaceutically acceptable salt of bedaquiline is preferably bedaquiline fumarate; The detection method is preferably high performance liquid chromatography.

10. A method for detecting a compound of formula II or a salt thereof in bedaquiline or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula II or its salt is used as a standard or reference substance and detected by high performance liquid chromatography; 。

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