654653-93-7

Usage

Uses

Used in Pharmaceutical Industry:
(αR,βS)-rel-Bedaquiline is used as an antitubercular agent for the treatment of tuberculosis. It is particularly effective against both drug-susceptible and multidrug-resistant strains of Mycobacterium tuberculosis due to its ability to inhibit mycobacterial ATP synthase, a crucial enzyme for bacterial survival and replication.
Used in Clinical Development:
(αR,βS)-rel-Bedaquiline is used as a promising candidate in clinical development for the treatment of tuberculosis. Its unique mechanism of action and high activity against various strains of Mycobacterium tuberculosis make it a valuable addition to the current arsenal of antitubercular drugs, potentially offering new treatment options for patients suffering from drug-resistant forms of the disease.

InChI:InChI=1/C32H31BrN2O2/c1-35(2)19-18-32(36,28-15-9-13-22-10-7-8-14-26(22)28)30(23-11-5-4-6-12-23)27-21-24-20-25(33)16-17-29(24)34-31(27)37-3/h4-17,20-21,30,36H,18-19H2,1-3H3/t30-,32-/m1/s1

Upstream product

• 10320-49-7 3-(dimethylamino)-1-(1-naphthalenyl)-1-propanone 
• 654653-93-7 rac-(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol 
• 916329-20-9 6-bromo-α-[2-(dimethylamino)ethyl]-2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol*(11bR)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin 4-oxide 
• 1229443-16-6 (3S,4R)-4-(6-bromo-2-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutyl-4-methylbenzenesulfonate 
• 124-40-3 dimethyl amine 
• 1298044-25-3 (2R)-2-(6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-2-phenylethanone 
• 1298044-27-5 (1R)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(naphthalen-1-yl)-1-phenylpent-4-en-2-ol 
• 1298044-29-7 C₃₀H₂₄BrNO₃ 
• 1298044-31-1 (4R)-4-(6-bromo-2-methoxyquinolin-3-yl)-3-(naphthalen-1-yl)-4-phenylbutane-1,3-diol 
• 1298044-33-3 (4R)-4-(6-bromo-2-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutyl methanesulfonate 
• 1298044-13-9 ethyl (E)-3-(6-bromo-2-chloroquinolin-3-yl)acrylate 
• 1298044-15-1 (E)-3-(6-bromo-2-chloroquinolin-3-yl)prop-2-en-1-ol 
• 1298044-17-3 (E)-3-(6-bromo-2-methoxyquinolin-3-yl)prop-2-en-1-ol 
• 1298044-10-6 [(2S,3S)-3-(6-bromo-2-methoxyquinolin-3-yl)oxiran-2-yl]methanol 

Downstream Products

• 1032265-50-1 C₃₉H₃₅BrN₂O₃ 

Relevant academic research and scientific papers

PROCESS FOR PREPARING (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol AND PHARMACEUTICALLY ACCEPTABLE SALT

The present invention relates to a process for the preparation of bedaquiline ((1R, 2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol) or a pharmaceutically acceptable salt thereof, the process comprising: isolating (1R, 2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol. The method can achieve large-scale preparation, so that the preparation method is an economical preparation method and has high yield.

Preparation method of bedaquiline and intermediate thereof

The invention discloses a preparation method of a bedaquiline racemate and a key intermediate compound used in the preparation method. According to the method for preparing the bedaquiline racemate, the ultra-low temperature reaction in the prior art is changed, and the ultra-low temperature reaction which is difficult to realize in the prior art is carried out at the conventional temperature, sothat large-scale industrialization becomes possible. Besides, the method provided by the invention greatly improves the conversion rate of the reaction substrate, improves the reaction yield, makes the product more easily crystallized and purified, and reduces the production cost at the same time.

Preparation method of bedaquiline

The invention provides a method for preparing bedaquiline shown as a formula IV (See the specification). The method comprises the step of reacting a compound II with a compound III. According to the method disclosed by the invention, the ultralow-temperat

Method for preparing bisarylquinoline antibiotics by optical resolution (by machine translation)

The present invention provides a method, for preparing bisarylquinoline antibiotics using optical resolution comprising separating optically pure, bromine - (αS,βR) - 6 - from)-(dimethylamino] - 2 - ethyl 6 - methoxy -S :phenyl - 3 3-quinolinolaquindox) in the three-dimensional isomer mixture of-phenyl - 3 3-quinolinolathanol in a high yield)% yield of the optically pure isomer mixture of the optically active agents] - 2 -yl-phenyl-3-quinolinolaquinola. (dimethylamino-methoxy-S :phenyl-3-quindox. (by machine translation)

Preparation method of bedaquiline racemate and intermediates thereof

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a bedaquiline racemate and intermediates thereof. According to the method disclosed by the invention, convenient, efficient and economical synthesis and industrial production of the bedaquiline and the intermediates thereof are realized. Specifically, the method provided by the invention has the following advantages that: the ultralow-temperature reaction required for preparing bedaquiline from a compound I and a compound II is thoroughly changed, and the original ultralow-temperature reaction which is difficult to realize industrially is changed into the reaction at a conventional temperature, so that large-scale industrial production becomes possible; according to the method disclosed by the invention, the conversion rate of the reaction substrate is greatly improved, the reaction yield is improved, the product is easier to crystallize and purify (recrystallizationof the intermediates can be realized by using a conventional solvent ethyl acetate or methanol), and meanwhile, the production cost is reduced.

Crystal structures of salts of bedaquiline

Bedaquiline [systematic name: 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol, C32H31BrN2O2] is one of two important new drugs for the treatment of drug-resistant tuberculosis (TB). It is marketed in the US as its fumarate salt {systematic name: [4-(6-bromo-2-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutyl]dimethylazanium 3-carboxyprop-2-enoate, C32H32BrN2O2 +·C4H3O4 -}, and about a dozen other salts of bedaquiline have been described in patent literature, but none have so far been structurally described. In a first communication, we present the crystal structure of bedaquilinium fumarate and of two new benzoate salts, as well as that of a degradation product of the reaction of bedaquilinium fumarate with sodium ethoxide, 3-benzyl-6-bromo-2-methoxyquinoline, C17H14BrNO. The fumarate and benzoate salts both feature cations monoprotonated at the dimethylamino group. The much less basic quinoline N atom remains unprotonated. Both salts feature a 1:1 cation-to-anion ratio, with the fumarate being present as monoanionic hydrofumarate. The conformations of the cations are compared to that of free base bedaquiline and with each other. The flexible backbone of the bedaquiline structure leads to a landscape of conformations with little commonalities between the bedaquiline entities in the various structures. The conformations are distinctively different for the two independent molecules of the free base, the two independent molecules of the hydrofumarate salt, and the one unique cation of the benzoate salt. Packing of the salts is dominated by hydrogen bonding. Hydrogen-bonding motifs, as well as the larger hydrogen-bonded entities within the salts, are quite similar for the salts, despite the vastly differing conformations of the cations, and both the hydrofumarate and the benzoate structure feature chains of hydrogen-bonded anions that are surrounded by and hydrogen bonded to the larger bedaquilinium cations, leading to infinite broad ribbons of anions, cations, and (for the benzoate salt) water molecules. The benzoate salt was isolated in two forms: as a 1.17-hydrate (C32H32BrN2O2 +·C7H5O2 -·1.166H2O), obtained from acetone or propanol solution, with one fully occupied water molecule tightly integrated into the hydrogen-bonding network of anions and cations, and one partially occupied water molecule [refined occupancy 16.6(7)%], only loosely hydrogen bonded to the quinoline N atom. The second form is an acetonitrile solvate (C32H32BrN2O2 +·C7H5O2 -·0.742CH3CN·H2O), in which the partially occupied water molecule is replaced by a 74.2(7)%-occupied acetonitrile molecule. The partial occupancy induces disorder for the benzoate phenyl ring. The acetonitrile solvate is unstable in atmosphere and converts into a form not distinguishable by powder XRD from the 1.17-hydrate.

PROCESS FOR THE PREPARATION OF BEDAQUILINE FUMARATE

The present disclosure relates to an improved process for the preparation of bedaquiline fumarate, comprising a step of preparing bedaquiline by reaction of 3-benzyl-6-bromo-2-methoxyquinoline 5 with 3-(dimethylamino)-l-(naphthalen-l-yl)propan-l-one 4 in the presence of lithium pyrrolidide.

Chiral inducer for synthesizing (1R,2S)-Bedaquiline

The invention relates to a chiral inducer for synthesizing (1R,2S)-Bedaquiline. Di(isopropyl)lithium ammonium takes off benzyl-bit protons from 6-bromo-3-benzyl-2-methoxy quinoline at a low temperature in the presence of the chiral inducer, i.e., lithium N-benzyl-L-prolinol and then is subjected to addition with 3-dimethylamino-1-naphthyl-1-acetone. Chiral o-amino lithium alkoxide remarkably increases the proportion of a target enantiomer, i.e., (1R,2S)-Bedaquiline and can be used for further preparing a drug, i.e., (1R,2S)-Bedaquiline fumarate.

For preparing beda quinoline intermediate and its preparation method and application

The invention discloses an intermediate for preparing bedaquiline and a preparation method therefor. The intermediate disclosed by the invention has the advantages that the intermediate avoids hydrogenation and enolization of an alpha-site in the intermediate, reduces occurrence of side reactions, and increases the conversion rate of raw materials and the total yield of reaction, and is suitable for large-scale industrial production. The intermediate for preparing bedaquiline is characterized by being a compound with a structural formula (9) or an optical isomer thereof: FORMULA is shown in the description.

Beda quinoline preparation method

The invention discloses a preparation method for bedaquiline. The preparation method comprises the following steps: enabling a compound (9) to be reacted with a reducing agent in a solvent; and then collecting racemate of bedaquiline from a reaction product. The preparation method has the advantages that the compound (9) is a novel compound which has not been reported in literature; the racemate of bedaquiline is prepared from a compound (8) and the compound (9); the obtained product is greatly increased in yield (greater than 47%) which is remarkably greater than the yield (26%) in the original patent; and the obtained racemate of bedaquiline is high in purity, stable and controllable in quality, and beneficial for subsequent resolution reaction, and has relatively great positive effects and relatively high practical application value. The reaction formula is shown as follows: a FORMULA as shown in the description.