Chiral catalysis method for synthesizing (1R, 2S)-bedaquiline

Abstract

The invention discloses a chiral catalysis method for synthesis of (1R, 2S)-bedaquiline, and belongs to the technical field of drug synthesis, in a key reaction for synthesis of bedaquiline, (I) a metal lithium salt and a chiral reagent are combined for use, and the catalyst catalyzes a reaction of 6-bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthyl-1-acetone (2) to obtain a product (3). Therefore, the conversion rate and diastereoselectivity of the reaction are 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 chiral catalytic 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 its 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 therapy (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, the chemical synthesis of bedaquiline under non-chiral induction conditions 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' have an enantiomeric relationship with each other, and B and B' have an enantiomeric relationship with each other. A (A') and B (B') have a diastereomeric relationship with 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 originator company (US2005148581) discloses a synthesis method: First, using p-bromoaniline and phenylpropionyl 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 form a mixture of 4 isomers of bedaquiline, and (1R,2S)-bedaquiline is obtained by chiral HPLC separation, and the yield of the last step is only about 4%. Although the reaction yield of the improved method of the originator company has increased (about 10%), it is still relatively low, resulting in high costs of the active pharmaceutical ingredient. The main synthesis steps are as follows:

[0009]

[0010] 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 increase 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.

[0011] 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 the 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%.

[0012] At present, 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 through 6 subsequent transformations, the synthesis of bedaquiline was completed.

[0013]

[0014] This route constructs two chiral centers by means of asymmetric catalysis, with good stereoselectivity, but the reaction route is 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.

[0015] 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 allyl zinc 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.

[0016]

[0017] Since the patent protection of the original research route is about to expire, some researchers have also reported an asymmetric synthesis method improved 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 product contains two configurations of (1R,2S) and (1S,2R), with a ratio close to 1:1, and the content of the product with the required configuration is still very low.

[0018]

[0019] Although the above - mentioned asymmetric synthesis methods can achieve the selective generation of products with the required 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 required 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

[0020] In view of this, the purpose of the present invention is to provide a chiral catalytic method for synthesizing (1R,2S) - bedaquiline by using a lithium salt, a chiral reagent, and an organolithium amine in combination, which can maintain a high conversion rate while simultaneously increasing the proportion of the target isomer generated with high selectivity, thereby increasing the final yield of bedaquiline.

[0021] To achieve the above - mentioned purpose, the present invention provides the following technical solutions:

[0022] The present invention provides a chiral catalytic method for synthesizing (1R,2S)-bedaquiline, comprising the following steps:

[0023] Add a metal lithium salt, a chiral reagent, and a mixture prepared from an organic amine and n-butyllithium into an organic solvent, add 6-bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) to the mixture for reaction to obtain a product (3), and the reaction formula is as follows:

[0024]

[0025] The metal lithium salt is selected from one or a combination of lithium chloride, lithium bromide, lithium hydroxide, lithium sulfate, lithium carbonate, lithium phosphate, lithium trifluoroacetate, C 1-12 alkyl carboxylate lithium and C 1-12 alkoxyl lithium.

[0026] Furthermore, the chiral reagent has a 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 alkoxyl, 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] Further, the preparation method of the mixed solution includes: at room temperature, under nitrogen protection, adding the organic amine, the metal lithium salt, and the chiral reagent to the organic solvent, cooling the temperature to -40 to -80 °C, and then adding the n-butyllithium. The organolithium amine is prepared by the reaction of the organic amine and n-butyllithium, or it can also be directly purchased as a finished product.

[0032] Further, at a temperature of -40 to -80 °C, 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; after the addition, the low temperature is maintained for a period of time, and 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 chiral reagents can be recovered by the method of alkali dissolution, acid precipitation, and then recrystallization, and for the chiral reagents numbered 5 and 8, they can be recovered by the method of slurrying with ethanol and then recrystallization of the mother liquor.

[0034] Further, the organic amine is one of diisopropylamine, dimethylamine, morpholine, pyrrolidine, N-methylpiperazine, and piperidine.

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

[0036] Further, the dosage of the chiral reagent is 0.1 to 3.0 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (1).

[0037] Further, the dosage of the metal lithium salt is 0.1 to 3.0 equivalents, and the preferred dosage is 1.5 to 2.5 equivalents.

[0038] Further, the dosage of the organic amine is 0.5 to 2 equivalents of 6-bromo-3-benzyl-2-methoxyquinoline (1).

[0039] In this scheme, the specific preparation method of bedaquiline includes the following steps:

[0040] (1) Under nitrogen protection, dissolve the organic amine, the metal lithium salt, and the chiral reagent in the organic solvent, cool the temperature to -40 to -80 °C, and add n-butyllithium thereto. Here, the organolithium amine is prepared by the reaction of the organic amine and n-butyllithium, or it can also be directly purchased as a finished product.

[0041] (2) At a temperature of -40 to -80 °C, a solution of 6-bromo-3-benzyl-2-methoxyquinoline (1) is then added dropwise. After the addition is complete, it is kept at a low temperature for a period of time, and then a solution of the said 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) is added.

[0042] (3) After the reaction is completed, it is quenched, and resolution and purification are carried out to obtain purified bedaquiline.

[0043] (4) After the reaction is completed, the chiral reagent is recovered by using the method of recrystallization or alkali dissolution and acid precipitation.

[0044] The beneficial effects of the present invention are as follows:

[0045] 1. By using a chiral synthesis method in which a metal lithium salt, a chiral reagent, and an organolithium amine are used in combination, the conversion rate, enantioselectivity, and diastereoselectivity of the reaction are all significantly improved. The final separation yield of the product can reach more than 40%, which is much higher than the yields reported in current literature or patents. Using the catalyst or auxiliary ligand alone cannot achieve such good catalytic effects.

[0046] 2. After the reaction is completed, according to the properties of different chiral catalysts, the chiral reagent can be recovered by using the method of recrystallization or alkali dissolution and acid precipitation. The recovery rate (recovery rate > 85%) and purity (HPLC purity > 98%) of the chiral reagent are both very high, and it can be directly used in the reaction after drying. The chiral catalyst can still obtain satisfactory catalytic effects after being reused many times, which undoubtedly significantly reduces the production cost of the reaction. This chiral inducer is suitable for large-scale industrial production.

[0047] Other advantages, objectives, 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 objectives and other advantages of the present invention can be realized and obtained through the following specification. Detailed Embodiments

[0048] The following will further clarify the present invention in combination 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 forms of modification of the present invention by those skilled in the art all fall within the scope defined by the appended claims of this application.

[0049] The following measurement methods are generally applicable to each embodiment of the present invention.

[0050] 1. Purity Analysis

[0051] The purity of the product was determined by a high performance liquid chromatograph SHIMADZU DGU-20A3R. The chromatographic column was Shim-pack GIS C18 (250x4.6mm, 5um). Mobile phase A was 0.1% phosphoric acid aqueous solution, and mobile phase B was 100% acetonitrile. Flow rate: 1 mL / min, detection wavelength: 254 nm.

[0052] 2. Chiral purity analysis

[0053] The chiral purity of the product was determined by a high performance liquid chromatograph SHIMADZU DGU-20A3R. The chromatographic column was CHIRALPAK ZWIX(+) (0.40 cm I.D.×15 cm L×3um). Mobile phase was methanol: formic acid: diethylamine = 1000 mL: 1.9 mL: 2.6 mL. Flow rate: 0.1 mL / min, detection wavelength: 254 nm.

[0054] Example 1

[0055] Under nitrogen protection, (S)-(-)-1,1'-bi-2-naphthylamine (6.93 g, 24.37 mmol, 1.0 equiv), LiBr (2.12 g, 24.37 mmol), pyrrolidine (1.73 g, 24.37 mmol, 1.0 equiv) 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~-70 °C. A 2.5 M n-butyllithium hexane solution (29.24 mL, 73.11 mmol, 3.0 equiv) was added thereto. After the addition was completed, the reaction was carried out at -60~-70 °C for 0.5 h. 6-Bromo-3-benzyl-2-methoxyquinoline (8.0 g, 24.37 mmol, 1.0 equiv) was dissolved in 20 mL of THF and slowly added dropwise to the above reaction solution over 0.5 h. The internal temperature was maintained at -60~-70 °C during the addition process. After the addition was completed, stirring was continued for 1 h. 3-N,N-dimethylamino-1-naphthalen-1-yl-propan-1-one (6.65 g, 29.24 mmol, 1.2 equiv) was dissolved in 20 mL of THF and added dropwise to the above reaction solution over 1 h. The internal temperature was maintained at -60~-70 °C during the addition process. After the addition was completed, the reaction was continued for 2 h.

[0056] 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. 6% of the raw material remained. The enantioselectivity was A / A' = 85 / 15, and the diastereoselectivity dr = 2 / 1. The aqueous layer was separated from the reaction solution. After the organic layer was concentrated to dryness, it was slurried with 100 mL of ethanol and filtered. The chiral inducer was recovered from the ethanol solution. The obtained filter cake was dispersed in 120 mL of acetone, and 7.02 g of (R)-(-)-2,2'-dihydroxy-1,1'-binaphthyl phosphate was added to obtain 11.23 g of the product phosphate mainly in the desired single configuration, with a yield of 51% and an HPLC purity of 96%.

[0057] The phosphate obtained from the resolution 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. 7.37 g of bedaquiline fumarate was obtained by crystallization, with a yield of 45%, an HPLC purity of 99.6%, and an optical purity of 99.9%.

[0058] Example 2

[0059] Under nitrogen protection, (S)-S-5,5',6,6',7,7',8,8'-octahydrobinaphthol (7.17 g, 24.37 mmol, 1.0 equiv), LiCl (1.03 g, 24.37 mmol), morpholine (1.73 g, 24.37 mmol, 1.0 equiv) and 140 mL of THF 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 -70 to -80 °C. A 2.5 M n-butyllithium hexane solution (29.24 mL, 73.11 mmol, 3.0 equiv) was added thereto, and the reaction was carried out at -70 to -80 °C for 40 min. 6-Bromo-3-benzyl-2-methoxyquinoline (8.0 g, 24.37 mmol, 1.0 equiv) was dissolved in 20 mL of THF and slowly added dropwise to the above reaction solution over 30 min. The internal temperature was maintained at -70 to -80 °C during the addition process. After the addition was complete, stirring was continued for 1 h. 3-N,N-Dimethylamino-1-naphthalen-1-yl-propan-1-one (6.65 g, 29.24 mmol, 1.2 equiv) was dissolved in 20 mL of THF and added dropwise to the above reaction solution over 1 h. The internal temperature was maintained at -70 to -80 °C during the addition process. After the addition was complete, the reaction was continued for 2 h.

[0060] 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. 5% of the raw material remained, the enantioselectivity was A / A' = 88 / 12, and the diastereoselectivity dr = 2.3 / 1. 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 chiral inducer was recovered. The washed organic phase was concentrated under reduced pressure to dryness. The concentrate was dispersed in 120 mL of acetone, and 7.02 g of (R)-(-)-2,2'-dihydroxy-1,1'-binaphthyl phosphate was added to obtain 11 g of the product phosphate mainly in the desired single configuration, with a yield of 53% and an HPLC purity of 97%.

[0061] The phosphate obtained by resolution 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. 7.37 g of bedaquiline fumarate was obtained by crystallization, with a yield of 48%, an HPLC purity of 99.8%, and an optical purity of 99.9%.

[0062] Example 3

[0063] Under nitrogen protection, (S)-1,1'-bi-2-naphthol (6.98 g, 24.37 mmol, 1.0 equiv), Li3PO4 (2.82 g, 24.37 mmol), N-methylpiperazine (1.73 g, 24.37 mmol, 1.0 equiv) and 140 mL of THF 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 -50 to -60 °C. A 2.5 M n-butyllithium hexane solution (29.24 mL, 73.11 mmol, 3.0 equiv) was added thereto, and the reaction was carried out at -50 to -60 °C for 40 min. 6-Bromo-3-benzyl-2-methoxyquinoline (8.0 g, 24.37 mmol, 1.0 equiv) was dissolved in 20 mL of THF and slowly added dropwise to the above reaction solution over 30 min. The internal temperature was maintained at -50 to -60 °C during the addition process. After the addition, stirring was continued for 1 h. 3-N,N-Dimethylamino-1-naphthalen-1-yl-propan-1-one (6.65 g, 29.24 mmol, 1.2 equiv) was dissolved in 20 mL of THF and added dropwise to the above reaction solution over 1 h. The internal temperature was maintained at -50 to -60 °C during the addition process. After the addition, the reaction was continued for 2 h.

[0064] 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. 21% of the raw material remained, the enantioselectivity was A / A' = 78 / 22, and the diastereoselectivity dr = 4 / 1. 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 to recover the catalyst. The washed organic phase was concentrated under reduced pressure to dryness. The concentrate was dispersed in 120 mL of acetone, with a yield of 42% and an HPLC purity of 93%.

[0065] The phosphate obtained by resolution 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. 6.06 g of bedaquiline fumarate was obtained by crystallization, with a yield of 37%, an HPLC purity of 99.0%, and an optical purity of 99.3%.

[0066] Example 4

[0067] Under nitrogen protection, 6.95 g (24.37 mmol, 1.0 equiv) of (S)-2-amino-2'-hydroxy-1,1'-binaphthalene, LiCl (1.04 g, 24.37 mmol), 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 stirred until clear at room temperature. The reaction flask was placed in a cold trap and cooled to -60 to -70 °C. 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. The internal temperature was maintained at -40 to -80 °C during the addition process. After the addition was complete, 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. The internal temperature was maintained at -40 to -80 °C during the addition process. After the addition was complete, the reaction was continued for 2 h.

[0068] 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. 5% of the raw material remained, the enantioselectivity was A / A' = 92 / 8, and the diastereoselectivity dr = 2.5 / 1. 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 to recover the catalyst. The washed organic phase was concentrated under reduced pressure to dryness. The concentrate was dispersed in 120 mL of acetone, and 7.02 g of (R)-(-)-2,2'-dihydroxy-1,1'-binaphthyl phosphate was added to obtain 12.1 g of the product phosphate mainly in the desired single configuration, with a yield of about 55% and an HPLC purity of 97%.

[0069] The phosphate obtained from the resolution 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. Crystallization gave 8.18 g of bedaquiline fumarate, with a yield of 50%, an HPLC purity of 99.8%, and an optical purity of 99.9%.

[0070] Example 5

[0071] Under nitrogen protection, 7.32 g (24.37 mmol, 1.0 equiv) of (S)-2'-methoxy-[1,1'-binaphthyl]-2-ol, CH3COOLi (1.61 g, 24.37 mmol), 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. 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. The internal temperature was maintained at -40 to -80 °C during the addition process. After the addition was complete, 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. The internal temperature was maintained at -40 to -80 °C during the addition process. After the addition was complete, the reaction was continued for 2 h.

[0072] 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. 12% of the raw material remained. The enantioselectivity was A / A' = 80 / 20, and the diastereoselectivity dr = 2 / 1. 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 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 was added to obtain 8.59 g of the product phosphate mainly in the desired single configuration, with a yield of 39% and an HPLC purity of 95%.

[0073] The resolved phosphate 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. 5.73 g of bedaquiline fumarate was obtained by crystallization, with a yield of 35%, an HPLC purity of 99.1%, and an optical purity of 98.9%.

[0074] Example 6

[0075] Recovery of chiral reagent:

[0076] Toluene in an equal volume was added to the ethanol recovery solution after the post-treatment of Example 1. After stirring for 1 hour, a large amount of white solid of (S)-(-)-1,1'-bi-2-naphthylamine precipitated out. It was filtered, and the filter cake was washed once with water, dried by suction, and vacuum-dried at 30 - 40 °C for 16 h to obtain 5.95 g of off-white chiral reagent, with a recovery rate of 86%.

[0077] Example 7

[0078] Recovery of chiral reagent:

[0079] 2 M hydrochloric acid solution was added to the lithium hydroxide aqueous solution of Example 2 to adjust the pH to about 3 - 4. A large amount of white solid of (S)-S-5,5',6,6',7,7',8,8'-octahydrobinaphthol precipitated out. It was filtered, and the filter cake was washed once with water, dried by suction, and vacuum-dried at 60 - 70 °C for 16 h to obtain 6.7 g of off-white chiral reagent, with a recovery rate of 93%.

[0080] Finally, it should be noted that the above examples 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 chiral catalytic method for synthesizing (1R, 2S)-bedaquiline, characterized in that, It includes the following steps: A metal lithium salt, a chiral reagent, and an 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 a product (3). The reaction formula is as follows: The metal lithium salt is selected from one or a combination of lithium chloride, lithium bromide, lithium hydroxide, lithium sulfate, lithium carbonate, lithium phosphate, lithium trifluoroacetate, C 1-12 alkyl lithium carboxylate and C 1-12 lithium alkoxide.

2. A chiral catalytic method for synthesizing (1R, 2S)-bedaquiline according to claim 1, characterized in that, 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 represents hydrogen, deuterium, a halogen, C 1-6 alkyl, aryl, nitro, a substituted silyl group; C 1-6 alkoxy, C 1-6 amino, a C 2-6 alkynyl group optionally substituted by a group, wherein R 2a and R 2b may be joined together to form a ring; the halogen atom may be F, Cl, Br or I; the aryl group 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.

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

4. A chiral catalytic 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, adding the organolithium amine, the metal lithium salt, and the chiral reagent to the organic solvent, cooling to -40 to -80 °C, and then adding n-butyllithium.

5. A chiral catalytic method for synthesizing (1R, 2S)-bedaquiline according to claim 1, characterized in that: At a temperature of -40 to -80 °C, a solution of 6-bromo-3-benzyl-2-methoxyquinoline (1) is added dropwise to the mixture. After addition, it is kept at a low temperature for a period of time, and then a solution of 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (2) is added.

6. A chiral catalytic method for synthesizing (1R,2S)-bedaquiline according to claim 3, characterized in that: After the reaction is completed, for the chiral reagents numbered 4, 6, 7, and 9, the chiral reagent can be recovered by the method of alkali dissolution and acid precipitation. For the chiral reagents numbered 5 and 8, they can be recovered by recrystallization.

7. A chiral catalytic method for synthesizing (1R, 2S)-bedaquiline according to claim 1, characterized in that: The organolithium amine is one of diisopropylamine, dimethylamine, morpholine, pyrrolidine, N-methylpiperazine, and piperidine.

8. A chiral catalytic 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, and methyl tert-butyl ether.

9. A chiral catalytic 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).

10. A chiral catalytic method for synthesizing (1R,2S)-bedaquiline according to claim 1, characterized in that: The dosage of the metal lithium salt is 0.1 to 3.0 equivalents.

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