ChemicalBook CAS DataBase List Bedaquiline fumarate

Bedaquiline fumarate synthesis

5synthesis methods

Product Name: Bedaquiline fumarate
CAS Number:845533-86-0
Molecular formula:C36H35BrN2O6
Molecular Weight:671.59

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.

843663-66-1 Synthesis

843663-66-1
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110-17-8 Synthesis

110-17-8
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845533-86-0
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Yield:845533-86-0 82%

Reaction Conditions:

in isopropyl alcohol at 20 - 70; for 18 h;Heating / reflux;

Steps:

A

A. Synthesis of the fumarate salt of αS, βR)-6-bromo-α-[2-fdimethylamino)ethyll- 2-methoxy-α- 1-naphthalenyl- β-phenyl-3-q uinolineethanol; 1Og (0.018 mol) of (αS, βR)-6-bromo-α-[2-(dimethylamino)ethyl]-2-methoxy-α-l- naphthalenyl-β-phenyl-3-quinolineethanol and 2.13 g (0.018 mol) of fumaric acid were suspended in 185 ml isopropanol. Dicalite (0.25g) and charcoal (0.25g) were added to the suspension. The mixture was refluxed for an hour, the reaction mixture was cooled to 70⁰C and filtered in the heat. The filter cake was washed with 10ml isopropanol.The mother liquor was slowly cooled to 50⁰C and stirred for 1 hour at this temperature.The reaction mixture was further cooled to room temperature and stirred for 16 hours. The crystals were filtered off and washed with 20 ml isopropanol. The wet cake was dried at 50⁰C during 16 hours.Yield: 1O g of (alpha S, beta R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy- alpha-l-naphthalenyl-beta-phenyl-3-quinolineethanol (2E)-2-butenedioate (1 :1) (white solid) (82%).

References:

WO2008/68231,2008,A1 Location in patent:Page/Page column 16

645-45-4 Synthesis