- Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity
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gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.
- Sun, Alexander W.,Bulterys, Philip L.,Bartberger, Michael D.,Jorth, Peter A.,O'Boyle, Brendan M.,Virgil, Scott C.,Miller, Jeff F.,Stoltz, Brian M.
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supporting information
p. 2686 - 2689
(2019/08/07)
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- A convenient synthesis of the antibacterial agent linezolid
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Starting with 3,4-difluorobenzoic acid (8) and (S)-epichlorohydrin (13) a convergent synthesis of linezolid (1) was developed that is attractive for large scale preparation of the drug. The synthetic strategy involves a 1+3 cycloaddition reaction between the chiral epoxide 11 (prepared from 13) and isocyanate 3 (obtained from 8) that was generated in situ by a Curtius rearrangement. The resulting Schiff base precursor of linezolid (12) crystallized from the reaction mixture and was readily converted to linezolid by an acid-catalyzed hydrolysis followed by an acetylation.
- McCarthy, James R.
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supporting information
p. 6846 - 6847
(2015/11/27)
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- PROCESS FOR OBTAINING RIVAROXABAN AND INTERMEDIATE THEREOF
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This invention relates to a procedure for obtaining a thiophene-2-carboxamide compound, specifically rivaroxaban, which comprises the (i) fragmentation of the N═C bond of a compound of formula 23 where R1 is selected among hydrogen, halogen, and (C1-C6)alkyl; and (ii) acylation of the resulting intermediate with 5-chloro-tiofen-2-carbonyl chloride in a solvent medium, in the presence of a base. The invention also relates to the compounds of formula 23 and their use in the obtention of rivaroxaban.
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Paragraph 0050; 0051; 0052
(2014/05/20)
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- PROCESSES FOR PREPARING RIVAROXABAN
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Processes and intermediates for preparing rivaroxaban, and analogs and derivatives thereof, and pharmaceutically acceptable salts of each of the foregoing, are described herein.
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Page/Page column 18-19
(2013/10/22)
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- A PROCESS FOR THE PREPARATION OF RIVAROXABAN BASED ON THE USE OF (S)-EPICHLOROHYDRIN
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The invention relates to the stereoisomers of 4-{4-[(S/R)-5-[(((aryl)methylene)- amino)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-ones described by the chemical formulae (S)-(9) and (R)-(9). The optical isomer of compound (9) with the (S)- configuration is industrially applicable for the manufacture of the antithrombotic drug rivaroxaban (1). The new preparation process of rivaroxaban comprises a reaction of (S)-1- chloro-3-(((aryl)methylene)amino)propan-2-ols (S)-(14) with alkyl 4-(3-oxomorpholine-4- yl)phenylcarbamates (15) providing the key intermediate (S)-(9), which is further subjected to hydrolytic deprotection and subsequent acylation, producing rivaroxaban. The commercially available (S)-epichlorohydrin has been conveniently used as the chiral building block for the production of the key intermediate.
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Page/Page column 20; 21
(2013/08/28)
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- PROCESS FOR OBTAINING RIVAROXABAN AND INTERMEDIATE THEREOF
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This invention relates to a procedure for obtaining a thiophene-2-carboxamide compound, specifically rivaroxaban, which comprises the (i) fragmentation of the N=C bond of a compound of formula 23 where R1 is selected among hydrogen, halogen, and (C1-C6)alkyl; and (ii) acylation of the resulting intermediate with 5-chloro-tiofen-2-carbonyl chloride in a solvent medium, in the presence of a base. The invention also relates to the compounds of formula 23 and their use in the obtention of rivaroxaban.
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Page/Page column 14
(2012/12/13)
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- PROCESSES FOR PREPARING LINEZOLID
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Processes and intermediates for preparing linezolid, and pharmaceutically acceptable salts thereof, are described herein.
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