Method for synthesizing (1R, 2S)-bedaquiline

Abstract

The invention discloses a method for synthesizing (1R, 2S)-bedaquiline, belongs to the technical field of drug synthesis, and discloses a method for synthesizing (1R, 2S)-bedaquiline by using a chiral reagent (I) in a key reaction for synthesizing bedaquiline, the chiral reagent asymmetrically induces a reaction between 6-bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthyl-1-acetone (2) to obtain a product (3), and the (1R, 2S)-bedaquiline is synthesized by using the product (3). The enantioselectivity of the reaction is improved, and the purpose of improving the overall yield is finally achieved. Reaction formula as follows: # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and specifically provides a method for synthesizing (1R,2S)-bedaquiline. Background Art

[0002] Bedaquiline fumarate was developed by Johnson & Johnson Pharmaceutical Company and was approved by the US FDA for marketing in December 2012 (trade name Sirturo), and is a drug for the treatment of drug-resistant tuberculosis. The chemical name of bedaquiline fumarate is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol fumarate, and the chemical structural formula is shown as follows:

[0003]

[0004] Bedaquiline exerts its anti-tuberculosis effect by inhibiting the ATP synthase of Mycobacterium tuberculosis and preventing Mycobacterium tuberculosis from using ATP to generate energy. This drug has become the first anti-tuberculosis drug with a completely new mechanism of action in the past more than 50 years, and is also the first drug specifically used for the treatment of drug-resistant tuberculosis. The time for its 50% cure rate is 13 weeks, and the time for its 80% cure rate is 6 months. Compared with combination drug use (2-4 drugs), the cure rate of this drug has been greatly improved, and the treatment cycle has been greatly shortened.

[0005] The bedaquiline molecule contains two chiral centers. Therefore, under non-chiral induction conditions, the chemical synthesis of bedaquiline will produce four isomers, namely (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol (A), (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol (A'), (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol (B) and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol (B'). A and A' are enantiomers of each other, and B and B’ are enantiomers of each other. A (A') and B (B') are diastereomers of each other.

[0006] Among the four isomers, the (1R,2S) isomer (A) has the best inhibitory effect on Mycobacterium tuberculosis (IC 90 value is 0.03) and is the medicinal configuration.

[0007]

[0008] The compound patent of the original research company (US2005148581) discloses a synthesis method: First, using p-bromoaniline and phenylpropanoyl chloride as raw materials, through acylation, cyclization, and substitution reactions, 6-bromo-3-benzyl-2-methoxyquinoline is obtained. Under the action of lithium diisopropylamide, 6-bromo-3-benzyl-2-methoxyquinoline and 3-dimethylamino-1-naphthalen-1-yl-propan-1-one react at low temperature (-72 to -78 °C) to generate a mixture of 4 isomers of bedaquiline, and (1R,2S)-bedaquiline is obtained by chiral HPLC separation. The yield of the last step is only about 4%. Although the reaction yield of the improved method of the original research company has increased (about 10%), it is still relatively low, resulting in high costs for the bulk drug.

[0009] The main synthesis steps are as follows:

[0010]

[0011] Other patents (CN 105085395 A, CN 107857727 A, CN 105175329 A, etc.) also report the synthesis methods of bedaquiline, but these methods cannot achieve the selective synthesis of (1R,2S)-bedaquiline and the conversion rate of the reaction is relatively low, resulting in no obvious improvement in the synthesis yield of bedaquiline. Therefore, to significantly improve the yield of bedaquiline, it is necessary to increase the conversion rate and selectivity of the reaction.

[0012] Among them, the selectivity of the reaction can be expressed by the enantiomeric excess (ee) and the ratio of diastereomers (dr). The terms enantiomeric excess and ratio of diastereomers are well-known to professionals in stereochemistry. The enantiomeric excess can be calculated by the formula ee = ([A] - [A'] / [A] + [A']) * 100%, and the ratio of diastereomers is expressed by the formula dr = ([A] + [A'] / [B] + [B']) * 100%.

[0013] Currently, only a few literatures report the selective synthesis of bedaquiline. In 2010, Shibasaki et al. first synthesized bedaquiline by an asymmetric catalysis method (J. Am. Chem. Soc. 2010, 132, 7905 - 7907). Two chiral centers of bedaquiline were constructed through a stereoselective proton transfer reaction catalyzed by a bimetallic yttrium complex and a one-step asymmetric allylation reaction, and then the synthesis of bedaquiline was completed through 6 subsequent transformations.

[0014]

[0015] This route constructs two chiral centers by means of asymmetric catalysis, with good stereoselectivity. However, the reaction route is relatively long and the yield is low (a total of 12 steps), the reagents used are expensive, and in addition, the chiral ligand used in the catalysis also needs to be synthesized in 7 steps, which is not suitable for industrial production.

[0016] In 2011, Chandrasekhar reported another synthetic route (Eur. J. Org. Chem. 2011, 2057 - 2061). This route obtains an epoxide through a Sharpless epoxidation reaction, and then selectively opens the ring with a phenyl Grignard reagent to construct the first carbon chiral center. However, the effect of this route in constructing the second chiral center is not ideal. When using an allylzinc reagent to carry out an addition reaction with a carbonyl compound, the dr value is only 0.67:1, and there are more unwanted stereoisomers.

[0017]

[0018] Since the patent protection for the original research route is about to expire, some researchers have also reported an improved asymmetric synthesis method on the original research route. In 2020, Naicker reported a method for selectively synthesizing bedaquiline by introducing a chiral amine reagent in the last step of the original research route (ACS Omega 2020, 5, 3607 - 3611). The diastereoselectivity of this reaction can be increased to 9:1, but the conversion rate of the reaction is only 30%, and the products contain two configurations of (1R,2S) and (1S,2R), and the ratio is close to 1:1, resulting in a still low content of the product with the desired configuration.

[0019]

[0020] Although the above - mentioned asymmetric synthesis methods can achieve the selective generation of products with the desired configuration, these asymmetric synthesis methods all have certain deficiencies, especially the conversion rate has not been significantly improved. Therefore, it is necessary to develop a suitable chiral reagent, which can promote the reaction to generate products with the desired configuration with high selectivity and conversion rate, and preferably this chiral reagent is cheap or can be recycled and reused. Only a chiral reagent that can achieve the above functions is suitable for the industrial large - scale production of bedaquiline. Summary of the Invention

[0021] In view of this, the purpose of the present invention is to provide a method for synthesizing (1R,2S) - bedaquiline that can significantly improve the enantioselectivity and conversion rate of the reaction, aiming to solve the problems of low conversion rate and high production cost of (1R,2S) - bedaquiline in the prior art.

[0022] To achieve the above - mentioned purpose, the present invention provides the following technical solutions:

[0023] The present invention provides a method for synthesizing (1R,2S)-bedaquiline, comprising the following steps:

[0024] A chiral reagent and an organolithium amine are added to an organic solvent to prepare a mixture, and 6-bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) are added to the mixture for reaction to obtain a product (3). The reaction formula is as follows:

[0025]

[0026] Among them, the chiral reagent has the structure shown in the general formula (II):

[0027]

[0028] In the general formula (II), X1 and X2 are each independently oxygen and nitrogen; M1 and M2 are each independently H, lithium, potassium, sodium, magnesium, calcium, zinc, C 1-6 alkyl; A and B are each independently a 4- to 7-membered saturated, unsaturated carbocyclic or heterocyclic ring; n is an integer of 1, 2, 3, 4, and 5; R 1a , R 2a , R 1b and R 2b are each independently hydrogen, deuterium, halogen, C 1-6 alkyl, aryl, nitro, substituted silyl; C 1-6 alkoxy, C 1-6 amino, optionally substituted C 2-6 alkynyl, wherein, R 2a and R 2b can be a ring connected together; the halogen atom can be F, Cl, Br or I; the aryl is phenyl or phenyl substituted with one, two or three substituents selected from the following groups: C 1-6 alkyl, C 1-6 alkyl or halogen.

[0029] Furthermore, the chiral reagent is preferably one of the following structures:

[0030]

[0031] Furthermore, the preparation method of the mixed solution includes: at room temperature, under nitrogen protection, adding the chiral reagent to the organic solvent, cooling to -40 to -80 °C, and then adding an organic amine and n-butyllithium to prepare an organolithium amine salt, and the organolithium amine salt can also be purchased as a finished product.

[0032] Further, a solution of 6-bromo-3-benzyl-2-methoxyquinoline (1) is added dropwise to the mixture, wherein the solution of 6-bromo-3-benzyl-2-methoxyquinoline (1) is 6-bromo-3-benzyl-2-methoxyquinoline (1) dissolved in an appropriate amount of the organic solvent; then a solution of 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) is added, wherein the solution of 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) is 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) dissolved in an appropriate amount of the organic solvent.

[0033] Further, after the reaction is completed, for the chiral reagents numbered 4, 6, 7, and 9, the method of alkali dissolution, acid precipitation, and then recrystallization can be adopted for recovery, and for the chiral reagents numbered 5 and 8, the method of recrystallization can be adopted for recovery.

[0034] Further, the organic amine is one of piperidine, pyrrolidine, diisopropylamine, diethylamine, and morpholine.

[0035] Further, the solvent is one of tetrahydrofuran, ether, methyltetrahydrofuran, toluene, dioxane, dimethyldiethylether, diethyldiethylether, and methyl tert-butyl ether, preferably one of tetrahydrofuran, ether, methyltetrahydrofuran, and toluene.

[0036] Further, the amount of the organic amine used is 0.5 to 2.0 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (1).

[0037] Further, the amount of the chiral reagent used is 0.1 to 3.0 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (1).

[0038] Further, the organic amine is pyrrolidine.

[0039] Further, the solvent is tetrahydrofuran.

[0040] In the specific preparation method of bedaquiline in this scheme, taking pyrrolidine as the preferred organic amine and tetrahydrofuran as the preferred solvent as an example, the following steps are included:

[0041] (1) Dissolve the chiral reagent in tetrahydrofuran, cool down to -40 to -80 °C, and add pyrrolidine and n-butyllithium thereto to prepare lithium pyrrolide.

[0042] (2) Subsequently, a tetrahydrofuran solution of 6-bromo-3-benzyl-2-methoxyquinoline is added dropwise to obtain the corresponding benzyllithium; the chiral reagent and benzyllithium form a complex chiral complex in the reaction system, and this complex can not only stabilize benzyllithium but also form a chiral selection space.

[0043] (3) Finally, a tetrahydrofuran solution of 3-dimethylamino-1-naphthalen-1-yl-propan-1-one is added at -40 to -80 °C, and the product formed is mainly the product with the desired configuration.

[0044] (4) After the reaction is completed, the chiral reagent is recovered by recrystallization or recrystallization after alkali dissolution and acid precipitation.

[0045] (5) After the reaction is completed, the organic phase is concentrated under reduced pressure to dryness to obtain the crude product of bedaquiline. The crude product is subjected to resolution and purification to obtain bedaquiline with high optical purity and chemical purity, which can be used to prepare bedaquiline fumarate.

[0046] The beneficial effects of the present invention are as follows:

[0047] 1. After induction with the chiral reagent, the conversion rate and enantioselectivity of the reaction are significantly improved (the conversion rate of the reaction is as high as 80%, and the enantioselectivity can reach A / A' = 90 / 10).

[0048] 2. The chiral reagent can be recovered and reused after the reaction is completed, which undoubtedly significantly reduces the production cost of the reaction. This chiral inducer is suitable for large-scale industrial production.

[0049] Other advantages, objects, and features of the present invention will be described to some extent in the subsequent specification, and to some extent, will be obvious to those skilled in the art based on the study of the following text, or can be taught from the practice of the present invention. The objects and other advantages of the present invention can be realized and obtained through the following specification. Detailed Embodiments

[0050] The present invention will be further illustrated below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. After reading the present invention, various equivalent modifications made by those skilled in the art to the present invention fall within the scope defined by the appended claims of this application.

[0051] The following measurement methods are generally applicable to each embodiment of the present invention.

[0052] 1. Purity Analysis

[0053] The purity of the product is determined using a high-performance liquid chromatograph SHIMADZU DGU-20A3R. The chromatographic column model is Shim-pack GIS C18 (250x4.6 mm, 5 μm). Mobile phase A is 0.1% phosphoric acid aqueous solution, mobile phase B is 100% acetonitrile, flow rate: 1 mL / min, detection wavelength: 254 nm.

[0054] 2. Chiral Purity Analysis

[0055] The chiral purity of the product was determined using a high-performance liquid chromatograph SHIMADZU DGU-20A3R, with a chromatographic column model of CHIRALPAK ZWIX(+)(0.40 cm I.D.×15 cm L×3 um), a mobile phase of methanol: formic acid: diethylamine = 1000 mL: 1.9 mL: 2.6 mL, a flow rate of 0.1 mL / min, and a detection wavelength of 254 nm.

[0056] Example 1

[0057] Under nitrogen protection, 7.17 g (24.37 mmol, 1.0 equiv) of (S)-S-5,5’,6,6’,7,7’,8,8’-octahydrobinaphthol (chiral reagent), 1.73 g (24.37 mmol, 1.0 equiv) of pyrrolidine, and 140 mL of THF were added to a dry 250 mL three-necked flask and stirred until dissolved at room temperature. The reaction flask was placed in a cold trap and cooled to -60 to -70 °C, and 29.24 mL (73.11 mmol, 3.0 equiv) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -60 to -70 °C for 40 min. 8.0 g (24.37 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 20 mL of THF and slowly added dropwise to the above reaction solution over 30 min, and the internal temperature was maintained at -40 to -80 °C during the addition process. After the addition, stirring was continued for 1 h. 6.65 g (29.24 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 20 mL of THF and added dropwise to the above reaction solution over 1 h, and the internal temperature was maintained at -60 to -70 °C during the addition process. After the addition, the reaction was continued for 2 h.

[0058] After the reaction was completed, 100 mL of saturated ammonium chloride solution was added to quench the reaction. The organic layer was taken for detection, and 25% of the raw material remained, and the enantioselectivity was A / A' = 83 / 17. The aqueous layer was separated from the reaction solution, and the organic layer was washed twice with 100 mL of 5% lithium hydroxide aqueous solution, and the aqueous phase was combined to recover the catalyst. The washed organic phase was concentrated to dryness under reduced pressure. The concentrate was dispersed in 120 mL of acetone, and 7.02 g of (R)-(-)-2,2'-dihydroxy-1,1'-binaphthyl phosphate resolving agent was added to obtain 6.83 g of the product phosphate mainly in the desired single configuration, with a yield of 31% and an HPLC purity of 96%.

[0059] The split salt was dispersed in 190 mL of toluene, and an aqueous potassium carbonate solution (5.86 g of potassium carbonate dissolved in 190 mL of water) was added to release the free base of the product. The toluene layer was obtained by liquid separation, and the toluene layer was concentrated under reduced pressure to obtain the free base. The free base was dispersed in 85 mL of isopropanol, 1.3 g of fumaric acid was added, and 4.42 g of bedaquiline fumarate was obtained by crystallization, with a yield of 27%, an HPLC purity of 99.4%, and an optical purity of 99.8%.

[0060] Example 2

[0061] Under nitrogen protection, 6.93 g (24.37 mmol, 1.0 equiv) of (S)-(-)-1,1'-bi-2-naphthylamine, 1.73 g (24.37 mmol, 1.0 equiv) of pyrrolidine and 140 mL of THF were added to a dry 250 mL three-necked flask, and the mixture was stirred until clear at room temperature. The reaction flask was placed in a cold trap and cooled to -70 to -80 °C, and 29.24 mL (73.11 mmol, 3.0 equiv) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -70 to -80 °C for 40 min. 8.0 g (24.37 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 20 mL of THF and slowly added dropwise to the above reaction solution over 30 min, and the internal temperature was maintained at -72 to -78 °C during the addition process. After the addition, stirring was continued for 1 h. 6.65 g (29.24 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 20 mL of THF and added dropwise to the above reaction solution over 1 h, and the internal temperature was maintained at -70 to -80 °C during the addition process. After the addition, the reaction was continued for 2 h.

[0062] After the reaction was completed, 100 mL of saturated ammonium chloride solution was added to quench the reaction. The organic layer was taken for detection, and 22% of the raw materials remained, and the enantioselectivity was A / A' = 85 / 15. The aqueous layer was separated from the reaction solution, and the organic phase was concentrated to dryness under reduced pressure and recrystallized from 50 mL of ethanol to obtain an off-white solid. The solid was dispersed in 120 mL of acetone, and 7.02 g of (R)-(-)-2,2'-dihydroxy-1,1'-binaphthyl phosphate resolving agent was added to obtain 7.27 g of the phosphate salt of the product with the desired single configuration mainly, with a yield of 33%, an HPLC purity of 95.2%.

[0063] The split salt was dispersed in 190 mL of toluene, and an aqueous potassium carbonate solution (5.86 g of potassium carbonate dissolved in 190 mL of water) was added to release the free base of the product. The toluene layer was obtained by liquid separation, and the toluene layer was concentrated under reduced pressure to obtain the free base. The free base was dispersed in 85 mL of isopropanol, 1.3 g of fumaric acid was added, and 4.91 g of bedaquiline fumarate was obtained by crystallization, with a yield of 30%, an HPLC purity of 99.2%, and an optical purity of 99.5%.

[0064] Example 3

[0065] Under nitrogen protection, 6.98 g (24.37 mmol, 1.0 equiv) of (S)-1,1'-bi-2-naphthol, 1.73 g (24.37 mmol, 1.0 equiv) of pyrrolidine and 140 mL of THF were added to a dry 250 mL three-necked flask, and the mixture was stirred until clear at room temperature. The reaction flask was placed in a cold trap and cooled to -50 to -60 °C. Then, 29.24 mL (73.11 mmol, 3.0 equiv) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -50 to -60 °C for 40 min. 8.0 g (24.37 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 20 mL of THF and slowly added dropwise to the above reaction solution over 30 min. During the addition process, the internal temperature was maintained at -40 to -80 °C. After the addition, stirring was continued for 1 h. 6.65 g (29.24 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 20 mL of THF and added dropwise to the above reaction solution over 1 h. During the addition process, the internal temperature was maintained at -50 to -60 °C. After the addition, the reaction was continued for 2 h.

[0066] After the reaction was completed, 100 mL of saturated ammonium chloride solution was added to quench the reaction. The organic layer was taken for detection. 32% of the raw materials remained, and the enantioselectivity was A / A' = 76 / 24. The aqueous layer of the reaction solution was separated, and the organic layer was washed twice with 100 mL of 5% lithium hydroxide aqueous solution. The aqueous phases were combined and the catalyst was recovered. The washed organic phase was concentrated to dryness under reduced pressure. The concentrate was dispersed in 120 mL of acetone, and 7.02 g of (R)-(-)-2,2'-dihydroxy-1,1'-binaphthyl phosphate resolving agent was added to obtain 5.5 g of the product phosphate mainly in the desired single configuration, with a yield of 25% and an HPLC purity of 93%.

[0067] The resolved salt was dispersed in 190 mL of toluene, and an aqueous potassium carbonate solution (5.86 g of potassium carbonate dissolved in 190 mL of water) was added to release the free base of the product. The toluene layer was separated by liquid-liquid extraction, and the toluene layer was concentrated under reduced pressure to obtain the free base. The free base was dispersed in 85 mL of isopropanol, and 1.3 g of fumaric acid was added. 3.27 g of bedaquiline fumarate was obtained by crystallization, with a yield of 20%, an HPLC purity of 99.1%, and an optical purity of 99%.

[0068] Example 4

[0069] Under nitrogen protection, 6.95 g (24.37 mmol, 1.0 equiv) of (S)-2-amino-2'-hydroxy-1,1'-binaphthalene, 2.44 g (24.37 mmol, 1.0 equiv) of N-methylpiperazine and 140 mL of 2-MeTHF were added to a dry 250 mL three-necked flask, and the mixture was stirred until clear at room temperature. The reaction flask was placed in a cold trap and cooled to -60 to -70 °C. Then, 29.24 mL (73.11 mmol, 3.0 equiv) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -60 to -70 °C for 40 min. 8.0 g (24.37 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 20 mL of THF and slowly added dropwise to the above reaction solution over 30 min. During the addition, the internal temperature was maintained at -40 to -80 °C. After the addition, stirring was continued for 1 h. 6.65 g (29.24 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 20 mL of THF and added dropwise to the above reaction solution over 1 h. During the addition, the internal temperature was maintained at -60 to -70 °C. After the addition, the reaction was continued for 2 h.

[0070] After the reaction was completed, the reaction was quenched by adding 100 mL of saturated ammonium chloride solution. The organic layer was taken for detection. 20% of the raw materials remained, and the enantioselectivity was A / A' = 90 / 10. The aqueous layer was separated from the reaction solution, and the organic layer was washed twice with 100 mL of 5% lithium hydroxide aqueous solution. The aqueous phases were combined and the catalyst was recovered. The washed organic phase was concentrated to dryness under reduced pressure. The concentrate was dispersed in 120 mL of acetone, and 7.02 g of (R)-(-)-2,2'-dihydroxy-1,1'-binaphthyl phosphate resolving agent was added to obtain 8.37 g of the phosphate salt of the product with the desired single configuration as the main component, with a yield of about 38% and an HPLC purity of 96%.

[0071] The resolved salt was dispersed in 190 mL of toluene, and an aqueous potassium carbonate solution (5.86 g of potassium carbonate dissolved in 190 mL of water) was added to release the free base of the product. The toluene layer was separated by liquid separation, and the toluene layer was concentrated under reduced pressure to obtain the free base. The free base was dispersed in 85 mL of isopropanol, and 1.3 g of fumaric acid was added to crystallize 5.73 g of bedaquiline fumarate, with a yield of 35%, an HPLC purity of 99.7%, and an optical purity of 99.9%.

[0072] Example 5

[0073] Under nitrogen protection, 7.32 g (24.37 mmol, 1.0 equiv) of (S)-2'-methoxy-[1,1'-binaphthalene]-2-ol, 2.12 g (24.37 mmol, 1.0 equiv) of morpholine and 140 mL of Et2O were added to a dry 250 mL three-necked flask and stirred until clear at room temperature. The reaction flask was placed in a cold trap and cooled to -60 to -70 °C. Then, 29.24 mL (73.11 mmol, 3.0 equiv) of a 2.5 M n-butyllithium hexane solution was added thereto, and the reaction was carried out at -60 to -70 °C for 40 min. 8.0 g (24.37 mmol, 1.0 equiv) of 6-bromo-3-benzyl-2-methoxyquinoline was dissolved in 20 mL of THF and slowly added dropwise to the above reaction solution over 30 min. During the addition process, the internal temperature was maintained at -40 to -80 °C. After the addition, stirring was continued for 1 h. 6.65 g (29.24 mmol, 1.2 equiv) of 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one was dissolved in 20 mL of THF and added dropwise to the above reaction solution over 1 h. During the addition process, the internal temperature was maintained at -60 to -70 °C. After the addition, the reaction was continued for 2 h.

[0074] After the reaction was completed, 100 mL of saturated ammonium chloride solution was added to quench the reaction. The organic layer was taken for detection. 33% of the raw materials remained, and the enantioselectivity was A / A' = 80 / 20. The aqueous layer of the reaction solution was separated, and the organic layer was washed twice with 100 mL of 5% lithium hydroxide aqueous solution. The aqueous phases were combined and the catalyst was recovered. The washed organic phase was concentrated to dryness under reduced pressure. The concentrate was dispersed in 120 mL of acetone, and 7.02 g of (R)-(-)-2,2'-dihydroxy-1,1'-binaphthyl phosphate resolving agent was added to obtain 5.73 g of the product phosphate mainly in the desired single configuration, with a yield of 26% and an HPLC purity of 94.8%.

[0075] The resolved salt was dispersed in 190 mL of toluene, and an aqueous potassium carbonate solution (5.86 g of potassium carbonate dissolved in 190 mL of water) was added to release the free base of the product. The toluene layer was separated by liquid separation, and the toluene layer was concentrated under reduced pressure to obtain the free base. The free base was dispersed in 85 mL of isopropanol, and 1.3 g of fumaric acid was added to crystallize 3.44 g of bedaquiline fumarate, with a yield of 21%, an HPLC purity of 99.0%, and an optical purity of 98.8%.

[0076] Example 6

[0077] Recovery of chiral reagent

[0078] To the aqueous lithium hydroxide solution combined in Example 1, 2M hydrochloric acid solution was added to adjust the pH to about 3 - 4. A large amount of white solid precipitated. After filtration, the filter cake was washed once with water, drained, and vacuum dried at 60 - 70 °C for 12 h to obtain 6.67 g of off-white solid, with a recovery rate of 93% and a purity > 99%.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the purpose and scope of the present technical solution, and they should all be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing (1R,2S)-bedaquiline, characterized in that, It includes the following steps: A chiral reagent and organolithium amine are added to an organic solvent to prepare a mixture. 6-Bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) are added to the mixture for reaction to obtain product (3). The reaction formula is as follows: Among them, the chiral reagent has the structure shown in general formula (II): In the general formula (II), X1 and X2 are each independently oxygen and nitrogen; M1 and M2 are each independently H, lithium, potassium, sodium, magnesium, calcium, zinc, C 1-6 alkyl group; A and B are each independently a 4- to 7-membered saturated or unsaturated carbocyclic or heterocyclic ring; n is an integer of 1, 2, 3, 4, and 5; R 1a , R 2a , R 1b and R 2b each independently is hydrogen, deuterium, a halogen, C 1-6 alkyl, aryl, nitro, a substituted silyl; C 1-6 alkoxy, C 1-6 amino, a C 2-6 alkynyl optionally substituted by a group, wherein R 2a and R 2b may be a ring connected together; the halogen atom may be F, Cl, Br or I; the aryl is phenyl or phenyl substituted by one, two or three substituents selected from the following groups: C 1-6 alkyl, C 1-6 alkyl or halogen.

2. A method for synthesizing (1R,2S)-bedaquiline according to claim 1, characterized in that, The chiral reagent is preferably one of the following structures:

3. A method for synthesizing (1R,2S)-bedaquiline according to claim 1, characterized in that, The preparation method of the mixed solution includes: at room temperature, under nitrogen protection, the chiral reagent is added to the organic solvent, the temperature is lowered to -40 to -80 °C, and then an organic amine and n-butyllithium are added to prepare the organolithium amine salt.

4. A method for synthesizing (1R, 2S)-bedaquiline according to claim 1, characterized in that: A solution of 6-bromo-3-benzyl-2-methoxyquinoline (1) is added dropwise to the mixture, and then a solution of 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) is added.

5. A method for synthesizing (1R, 2S)-bedaquiline according to claim 2, characterized in that: After the reaction is completed, for the chiral reagents numbered 4, 6, 7, and 9, the method of alkali dissolution, acid precipitation, and then recrystallization can be adopted for recovery. For the chiral reagents numbered 5 and 8, the method of recrystallization can be adopted for recovery.

6. A method for synthesizing (1R,2S)-bedaquiline according to claim 1, characterized in that: The organic amine is one of N-methylpiperidine, pyrrolidine, diisopropylamine, diethylamine, dimethylamine, or morpholine.

7. A method for synthesizing (1R, 2S)-bedaquiline according to claim 1, characterized in that: The solvent is one of tetrahydrofuran, ether, methyltetrahydrofuran, toluene, dioxane, dimethyldiethylether, diethyldiethylether, or methyl tert-butyl ether.

8. A method for synthesizing (1R, 2S)-bedaquiline according to claim 1, characterized in that: The dosage of the chiral reagent is 0.1 to 3.0 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (1).

9. A method for synthesizing (1R,2S)-bedaquiline according to claim 6, characterized in that: The organic amine is pyrrolidine, morpholine, or N-methylpiperazine.

10. A method for synthesizing (1R,2S)-bedaquiline according to claim 7, characterized in that: The solvent is tetrahydrofuran or ether.

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