Development of a Synthesis For a Long-Term Oxazolidinone Antibacterial

Choy, Allison L.; Colbry, Norman L.; Huber, Christian; Pamment, Michael; Duine, Justin Van

doi:10.1021/op8001195

Cited by 27 publications

(20 citation statements)

References 15 publications

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“…1 ĲS)-3-Ĳ3-Fluoro-4-Ĳ4-Ĳpyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-5-Ĳ(4-methylpiperazin-1-yl)methyl)oxazolidin-2-one (13). 1 (17). 1 (15).…”

Section: 25unclassified

“…1) have been identified. 13,16,17 In our previous study, FYL-66, ĲS)-N-Ĳ(3-Ĳ3-fluoro-4-Ĳ4-Ĳpyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxooxazolidin-5yl)-methyl)acetamide (Fig. 1), the second oxazolidinone antibacterial, was recently approved in the U.S. for the treatment of adult acute bacterial skin and skin structure infections (ABSSSI) with 2-8-fold higher in vitro inhibitory activities and improved safety profile compared to Linezolid.…”

Section: Introductionmentioning

confidence: 99%

“…15 Pfizer scientists have recently described oxazolidinones 5 and 6 bearing reverse amide or carbamate side chains at C-5, whose structures are shown in Fig. [15][16][17] To explore the structure-activity relationship at the C-5 side chain of FYL-66, a series of analogues were designed and synthesized by introduction of various substituents at the C-5 position of the oxazolidinone ring. 13,16,17 In our previous study, FYL-66, ĲS)-N-Ĳ(3-Ĳ3-fluoro-4-Ĳ4-Ĳpyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-2-oxooxazolidin-5yl)-methyl)acetamide (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and antibacterial activity evaluation of C-5 side chain modified analogues of FYL-66, a potential agent against methicillin-resistant Staphylococcus aureus

Yang

Wang

et al. 2015

Med. Chem. Commun.

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FYL-66 and its hydrochloride FYL-67 have been identified as new chemical entities (NCE) with pronounced in vitro and in vivo activities against MRSA and MSSA. Aiming to explore the structure-activity relationship at the C-5 side chain of FYL-66 and find novel potential antibacterial agents, a series of analogues were designed and synthesized by the introduction of various substituents at the C-5 position of the oxazolidinone ring. Their in vitro antibacterial activities were also evaluated by the microdilution method. Novel compounds 31, 33, 37, 39 and 40 demonstrated potent antibacterial activities with MIC values in the range of 2-4 μg mL −1 . Difluoro-substituted analogue 40 was found to possess a good balance between antibacterial efficacy, physicochemical properties and safety profile. In a murine systemic infection model, analogue 40 showed comparable protection rates with FYL-66. The absolute bioavailability of 40 was 89.6% with half-lives of 8.87 ± 3.25 h (p.o.) and 5.40 ± 1.40 h (i.v.), respectively. Meanwhile, our findings show the importance of the C-5 side chain of FYL-66 and imply compounds with small C-5 substituents mimicking the acetamide group display better activities. It is also quite intriguing that different antibacterial effects are presented by analogues of FYL-66, Linezolid and other oxazolidinones with the same fluoro-substitution patterns of the acetyl group at the C-5 position. Med. Chem. Commun. This journal is Scheme 1 General synthetic route to compounds 11-23. Reagents and conditions: (a) (S)-glycidol, EtOH, 50°C, 35.1%; (b) diethyl carbonate, tBuOK, DMF, 60°C, 85.6%; (c) TsCl, DMAP, Et 3 N, DCM, r.t., 55.8%; (d) DIPEA, ACN, 80°C, 20-70%. Scheme 2 Synthetic route to compounds 24-25. Reagents and conditions: (a) for 24: acetyl chloride, Et 3 N, DCM, 0°C, then r.t., 58%; for 25: benzoyl chloride, Et 3 N, DCM, 0°C, then r.t., 64%. Scheme 3 Synthetic route to compounds 26-28. Reagents and conditions: (a) for 26: CH 3 ONa, CH 3 OH, r.t., 50%; (b) for 27: imidazole, NaH, DMF, r.t., 40%; for 28: thiophenethiol, NaH, DMF, r.t., 37%.MedChemComm Concise Article Scheme 4 Synthetic route to compounds 31. Reagents and conditions: (a) NaN 3 , DMF, 72°C, 89%; (b) TMSA, Cu/CuSO 4 ·5H 2 O, tBuOH, 65°C, 54%; (c) TBAF, AcOH, THF, r.t., 80%. Scheme 5 Synthetic route to compounds 33-41. Reagents and conditions: (a) PPh 3 , THF, r.t., then H 2 O, 45°C, 56%; (b) for 33: propionyl chloride, Et 3 N, DCM, 0°C, then r.t., 88%; for 34: ethyl formate, reflux, 80°C, 87%; for 35: MsCl, Et 3 N, DCM, 0°C, then r.t., 34.11%; for 36: dimethylsulfamoyl chloride, Et 3 N, DCM, 0°C, then r.t., 86%; for 37: CDI, methanol, MeONa, DCM, r.t., 79%; for 38: ethyl isocyanate, diisopropylethylamine, DCM, 0°C, then r.t., 75%; for 39: methyl fluoroacetate, 2,2,2-trifluoroethanol, 75°C, 82%; for 40: ethyl difluoroacetate, methanol, Et 3 N, 0°C, then r.t., 69%; for 41: 2,2,2-trifluoroacetic anhydride, Et 3 N, DCM, 0°C, then r.t., 69%. Scheme 6 Synthetic route to compounds 43-45. Reagents and conditions: (a) TEMPO, NaOCl, NaClO 2 , s...

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“…1 ĲS)-3-Ĳ3-Fluoro-4-Ĳ4-Ĳpyridin-2-yl)-1H-pyrazol-1-yl)phenyl)-5-Ĳ(4-methylpiperazin-1-yl)methyl)oxazolidin-2-one (13). 1 (17). 1 (15).…”

Section: 25unclassified

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and antibacterial activity evaluation of C-5 side chain modified analogues of FYL-66, a potential agent against methicillin-resistant Staphylococcus aureus

Yang

Wang

et al. 2015

Med. Chem. Commun.

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“…[89] With 3 mol% of Pd source and 6 mol% of JohnPhos 85, the reaction proceeded smoothly to give 87% of 82 on a 5-kg scale (Scheme 28). [89] With 3 mol% of Pd source and 6 mol% of JohnPhos 85, the reaction proceeded smoothly to give 87% of 82 on a 5-kg scale (Scheme 28).…”

Section: Other Pd-catalyzed C à C Cross-coupling Reactionsmentioning

confidence: 99%

Recent Applications of Palladium‐Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries

2009

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Palladium-catalyzed coupling reactions have become a central tool for the synthesis of biologically active compounds both in academia and industry. Most of these transformations make use of easily available substrates and allow for a shorter and more selective preparation of substituted arenes and heteroarenes compared to non-catalytic pathways. Notably, molecular-defined palladium catalysts offer high chemoselectivity and broad functional group tolerance. Considering these advantages, it is not surprising that several palladium-catalyzed coupling reactions have been implemented in the last decade into the industrial manufacture of pharmaceuticals and fine chemicals. In this review different examples from 2001-2008 are highlighted, which have been performed at least on a kilogram scale in the chemical and pharmaceutical industries.

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“…[12] The application of this method to the kilogram-scale synthesis of two drug candidates, a serine palmitoyl transferase inhibitor ( 3 ) [13] and a long-term oxazolidinone antibacterial ( 4 ) [14] illustrate the practicality and atom- and step-economical advantages of this C–H functionalization protocol. An analogous process wherein chlorodifluoroacetanilides are transformed to difluorooxindoles would similarly enable the rapid construction of these compounds from readily available starting materials; chlorodifluoroacetanilides can be prepared in one step by acylation of the corresponding (hetero)arylamines with inexpensive chlorodifluoroacetic anhydride.…”

mentioning

confidence: 99%

Palladium‐Catalyzed Intramolecular CH Difluoroalkylation: Synthesis of Substituted 3,3‐Difluoro‐2‐oxindoles

Shi

Buchwald

2014

Angew Chem Int Ed

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The synthesis of 3,3-difluoro-2-oxindoles through a robust and efficient palladium-catalyzed C–H difluoroalkylation is described. This process generates a broad range of difluorooxindoles from readily prepared starting materials. The use of BrettPhos as the ligand was crucial for high efficiency. Preliminary mechanistic studies suggest that oxidative addition is the rate-determining step for this process.

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Development of a Synthesis For a Long-Term Oxazolidinone Antibacterial

Cited by 27 publications

References 15 publications

Synthesis and antibacterial activity evaluation of C-5 side chain modified analogues of FYL-66, a potential agent against methicillin-resistant Staphylococcus aureus

Synthesis and antibacterial activity evaluation of C-5 side chain modified analogues of FYL-66, a potential agent against methicillin-resistant Staphylococcus aureus

Recent Applications of Palladium‐Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries

Palladium‐Catalyzed Intramolecular CH Difluoroalkylation: Synthesis of Substituted 3,3‐Difluoro‐2‐oxindoles

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