843663-66-1Relevant academic research and scientific papers
Crystal structures of salts of bedaquiline
Bogandowich-Knipp, Susan,Byrn, Stephen R.,Clase, Kari L.,Okezue, Mercy,Purcell, Dale K.,Smith, Daniel,Smith, Pamela,Zeller, Matthias
, p. 1010 - 1023 (2020/11/13)
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
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, (2020/08/22)
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.
Method for preparing bisarylquinoline antibiotics by optical resolution (by machine translation)
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Paragraph 0084-0085, (2020/02/27)
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)
Beda quinoline preparation method
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Paragraph 0102; 0103; 0104; 0105, (2017/10/13)
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.
For preparing beda quinoline intermediate and its preparation method and application
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Paragraph 0094-0097, (2018/11/04)
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.
A method of high-efficiency production of beda quinoline
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Paragraph 0067-0069, (2017/09/26)
The invention relates to a method for high efficiency production of Bedaquiline. The method comprises that through optical resolution of 1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol, Bedaquiline and other isomers are obtained, the other isomers undergo a reaction under the action of an alkali to produce key intermediate compounds A and B, and the key intermediate compounds A and B are separated and undergo a reaction to produce Bedaquiline. The method realizes high efficiency production of Bedaquiline, prevents large waste of materials, saves a cost and is suitable for large scale industrial production.
Chiral inducer for synthesizing (1R,2S)-Bedaquiline
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Paragraph 0021; 0022; 0023, (2017/07/19)
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.
A highly efficient way to recycle inactive stereoisomers of Bedaquiline into two previous intermediates via base-catalyzed Csp3Csp3 bond cleavage
Kong, De-Long,Huang, Ye,Ren, Lai-Yang,Feng, Wen-Hua
, p. 790 - 792 (2015/08/03)
Abstract Bedaquiline is a new medicine for pulmonary multi-drug resistant tuberculosis (MDR-TB), which is a pure enantiomer with two chiral centers. The current industrial preparation process requires the separation of active Bedaquiline from a mixture of four isomers. Obviously, direct dispose of the other three undesired stereoisomers will cause significant waste and increase the unnecessary cost of production. Here, we developed an efficient, facile and scalable process for recycling the inactive stereoisomers of Bedaquiline. All these inactive stereoisomers could be recycled by their conversion to two important intermediates in the Bedaquiline synthesis via a base-catalyzed Csp3Csp3 bond cleavage of a benzyl alcohol intermediate. And the precise conditions and mechanism of the base-catalyzed cleavage reaction were discussed.
Practical syntheses of (2S)-R207910 and (2R)-R207910
Chandrasekhar, Srivari,Babu, G. S. Kiran,Mohapatra, Debendra K.
, p. 2057 - 2061 (2011/05/09)
Concise and practical syntheses of (2S)-R207910 (3a) and (2R)-R207910 (3b) have been achieved in high overall yield of 12 % in 10 steps for each isomer starting from a known intermediate following Sharpless asymmetric epoxidation, regioselective epoxide opening, modified allylzinc bromide addition as key reactions. Copyright
Catalytic asymmetric synthesis of R207910
Saga, Yutaka,Motoki, Rie,Makino, Sae,Shimizu, Yohei,Kanai, Motomu,Shibasaki, Masakatsu
supporting information; experimental part, p. 7905 - 7907 (2010/08/05)
The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate α-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)3 and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu4NCl, α-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienolate generation via deprotonation at the γ-position of 4, followed by regio- and enantioselective protonation at the α-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu4NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic allylation of ketone 3 was promoted by CuF·3PPh3·2EtOH (10 mol %) in the presence of KOtBu (15 mol %), ZnCl2 (1 equiv), and Bu4PBF4 (1 equiv), giving the desired diastereomer 2 in quantitative yield with a 14: 1 ratio without any epimerization at the α-stereocenter. It is noteworthy that conventional organometallic addition reactions did not produce the desired products due to the high steric demand and a fairly acidic α-proton in substrate ketone 3. This first catalytic asymmetric synthesis of R207910 includes 12 longest linear steps from commercially available compounds with an overall yield of 5%.
