Oxazolidinone-quinolone hybrids as antibacterial compounds
Technology of a compound, oxazolidine, applied in the field of novel chimeric antibiotics
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[0429] All temperatures are expressed in °C. All analytical and preparative HPLC studies on non-chiral phases were performed using RP-C18 based columns. Analytical HPLC studies were performed on two different instruments with cycle times of ~2.5 minutes and ~3.5 minutes, respectively. Unless otherwise stated, values indicating MS correspond to the main peak ((M+H) + with + / -0.5 unit variation). In the NMR spectra, the coupling constant Jene is given in Hz and qui nt. refers to the quintet.
example 1
[0430] Example 1: (13S,16S)-1-cyclopropyl-7-fluoro-16-[2-fluoro-4-((5R)-2-oxo-5-[1,2,3]triazole- 1-ylmethyl-oxazolidine-3-yl)-phenoxymethyl]-16-hydroxy-4-oxo-1,4,13,15,16,17-hexahydro-12H-11- Oxa-1,14-diaza-cyclopenta[a]phenanthrene-3-carboxylic acid:
[0431] Note: Two synthetic methods described hereafter, namely Method A and Method B, have been used to prepare the compound of Example 1.
[0432] Method A:
[0433] 1. A.i. (5R)-3-(4-benzyloxy-3-fluoro-phenyl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one:
[0434] (5R)-5-Azidomethyl-3-(4-benzyloxy-3-fluoro-phenyl)-oxazolidin-2-one (1 g, 2.92 mmol; prepared according to WO 2004 / 096221 ) and 2,5-norbornadiene (1 ml, 9.93 mmol) in 10 ml of dioxane were refluxed for 24 hours. Dioxane was evaporated under reduced pressure and the residue was stirred in EA. The crystals were collected by filtration and dried in vacuo to afford 0.906 g (84%) of a pink solid.
[0435] 1 H NMR (DMSO d6 ; δppm): 3.85-3.88 (d d, 1H, J=8 and J=6...
example 2
[0513] Example 2: (13S,16S)-16-{4-[(5S)-5-(acetamido-methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy Methyl}-1-cyclopropyl-7-fluoro-16-hydroxy-4-oxo-1,4,13,15,16,17-hexahydro-12H-11-oxa-1,14- Diazol-cyclopenta[a]phenanthrene-3-carboxylic acid:
[0514] 2.i. (13S, 16S)-16-{4-[(5S)-5-(acetamido-methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-benzene Oxymethyl}-1-cyclopropyl-7-fluoro-16-hydroxy-4-oxo-1,4,13,15,16,17-hexahydro-12H-11-oxa-1,14 -Ethyl diazol-cyclopenta[a]phenanthrene-3-carboxylate:
[0515] Using the procedure of step 1.A.viii of Example 1 and from intermediate 1.A.vii (99 mg) and N-[(5S)-3-(3-fluoro-4-hydroxyphenyl)-2-oxo -Oxazolidine-5-ylmethyl]acetamide (54 mg; described in WO 2004 / 096221 ) starting from SiO 2 The title compound was obtained in 49% yield after chromatography (eluent DCM / MeOH 9 / 1) and crystallization from EA / hexane.
[0516] 1 H NMR (DMSO d6 ; δppm): 0.9-1.10 (4H, m); 1.25 (3H, t, J = 7.5); 1.83 (3H, s); 1.85 (1H, m); 2.42 (1H, m); 3.45 (2H, m )...
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