845533-86-0

Basic information

• Product Name: Bedaquiline (fuMarate)
• Synonyms: Bedaquiline (fuMarate);R 403323;(1R,2S)-1-(6-broMo-2-Methoxyquinolin-3-yl)-4-(diMethylaMino)-2-naphthalen-1-yl-1-phenylbutan-2-ol,(E)-but-2-enedioic acid;(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol fumarate;(1R,2S)-1-(6-Bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-2-butanol (2E)-2-butenedioate (1:1);Bedaquiline Fumarate salt
• CAS NO: 845533-86-0
• Molecular Formula: C₄H₄O₄*C₃₂H₃₁BrN₂O₂
• Molecular Weight: 653.56162
• Mol File: 845533-86-0.mol
• Article Data: 5

Chemical Properties

• Appearance: /
• Storage Temp.: Inert atmosphere,Room Temperature
• CAS DataBase Reference: Bedaquiline (fuMarate)(CAS DataBase Reference)
• NIST Chemistry Reference: Bedaquiline (fuMarate)(845533-86-0)
• EPA Substance Registry System: Bedaquiline (fuMarate)(845533-86-0)

Safety Data

• Hazardous Substances Data: 845533-86-0(Hazardous Substances Data)

Usage

Definition

ChEBI: A fumarate salt prepared from equimolar amounts of bedaquiline and fumaric acid. It is used in combination therapy for the treatment of pulmonary multi-drug resistant tuberculosis by inhibition of ATP synthase, an enzyme essential for the replication of th mycobacteria.

Clinical Use

Bedaquiline fumarate is a diarylquinone drug developed by Janssen Pharmaceutical which is marketed under the trade name Sirturo ®. The drug, which was approved in 2012 for the treatment of multidrug-resistant tuberculosis (MDR-TB), was developed in partnership with Johnson & Johnson and represents the first new tuberculosis therapy approved in over four decades. Bedaquiline is the first member of a new class of diarylquinone compounds whose mechanism of action inhibits Mycobaterium tuberculosis ATP synthase which deprives bacterium of energy.

Synthesis

Of the relatively few synthetic approaches to bedaquiline (or its fumarate salt) that have been reported, the most likely process-scale route is that described by Porstmann and co-workers from Janssen Pharmaceutical, and this route is outlined in the scheme. The synthesis was initiated by first freebasing commercially available dimethylaminoketone 31 with sodium hydroxide to provide naphthylone 32 in nearly quantitative yield. Subjection of commercially available quinoline 33 to LDA removed the benzyllic proton within this system and subsequent trap with naphthylone 32 gave rise to a mixture of diastereomers whereby the major diastereomer obtained from this reaction corresponded to the bedaquiline geometry. The minor diastereomer was resolved through multiple recrystallizations and seeding techniques. This racemate of the major diastereomer subsequently underwent a chiral resolution upon treatment with BINAP derivative 34 in refluxing DMSO and then upon cooling and subjection to aqueous base in warm toluene furnished bedaquiline 35 bearing the requisite (R,S)- configuration of the two vicinal chiral centers corresponding to that of the drug. The overall yield of the conversion of 33 to enantiopure 35 was 39%. Aminoquinolinol 35 was then prepared as the corresponding fumarate salt upon treatment with fumaric acid in the presence of isopropanol, and this salt formation delivered bedaquiline fumarate (VI) in 82% yield.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin and erythromycin - avoid concomitant use if for more than 14 days; avoid with moxifloxacin; concentration possibly reduced by rifampicin - avoid; possibly increased risk of ventricular arrhythmias with clofazimine. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - avoid. Antivirals: AUC increased by ritonavir, use with caution, avoid in combination with lopinavir.

Metabolism

Bedaquiline is metabolised mainly by the hepatic CYP3A4 isoenzyme to the N-monodesmethyl metabolite (M2), which is 4-6 times less active than the parent compound. Bedaquiline is excreted mainly in the faeces.

Upstream product

• 843663-66-1 bedaquiline 
• 110-17-8 (2E)-but-2-enedioic acid 
• 654655-80-8 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol 
• 501-52-0 3-Phenylpropionic acid 
• 316146-27-7 N-(4-bromophenyl)-3-phenylpropanamide 
• 654655-68-2 3-benzyl-6-bromo-2-chloro-quinoline 
• 645-45-4 hydrocinnamic acid chloride 

Downstream Products

• 843663-66-1 bedaquiline 

Relevant articles and documents

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.

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.

FUMARATE SALT OF (ALPHA S, BETA R)-6-BROMO-ALPHA-[2-(DIMETHYLAMINO)ETHYL]-2-METHOXY-ALPHA-1-NAPHTHALENYL-BETA-PHENYL-3-QUINOLINEETHANOL

The present invention relates to the fumarate salt of (alpha S, beta R)-6-bromo-alpha- [2-(dimethylamino)ethyl] -2-methoxy-alpha- 1 -naphthalenyl-beta-phenyl-3 - quinolineethanol, pharmaceutical compositions comprising as active ingredient said salt and to processes for their preparation.