Diazabicyclooctanones as inhibitors of serine beta-lactamases
A kind of technology of diazabis and cyclooctanone, applied in the field of combination of other active agents
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[0910] general method
[0911] In DMSO-d6 solution (δ in ppm), 1H NMR spectra were presented at 300 or 400 MHz using chloroform as a reference standard (7.25 ppm). When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), bs (broadened singlet), dd (two doublets), dt (two triplets), q (quadrupts). When coupling constants are provided, they are in Hertz (Hz).
[0912] All reactions were carried out under an inert atmosphere of nitrogen or argon unless otherwise specified (eg, hydrogenation reactions).
[0913] abbreviation
[0914] ACN Acetonitrile
[0915] DAST diethylaminosulfur trifluoride
[0916] DCM dichloromethane
[0917] DIPEA N,N-Diisopropylethylamine
[0918] DMAP 4-dimethylaminopyridine
[0919] DMSO Dimethyl sulfoxide
[0920] h hours
[0921] HMBC Heteronuclear Multiple Bond Correlation
[0922] p.s.i pounds per square hour
[0923] SO3: pyr pyridine trioxide-sulfur complex
[0924] TE...
example 1
[0928] Sodium (2S,5R)-7-oxo-2-(trifluoromethyl)-1,6-diazabicyclo[3.2.1]octyl-6-yl sulfate;
[0929]
[0930] Except starting from (5S)-5-(trifluoromethyl)-2-pyrrolidone, the use and targeting of avibactam (Ball, M. et al., Organic Process Research and Development, 2016, 20, 1799) Essentially the same method was reported to prepare this material.
[0931] a. tert-butyl (5S)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate
[0932]
[0933](5S)-5-(trifluoromethyl)-2-pyrrolidone (commercially available) was treated with triethylamine (5.5 mL, 4.0 g, 39.2 mmol) and DMAP (0.4 g, 0.1 mmol) at 0 °C from Manchester Organics) (5 g, 32.7 mmol) in DCM (60 mL) followed by the dropwise addition of a solution of di-tert-butyl dicarbonate (8.6 g, 39.2 mmol) in DCM (20 mL) over 10 min. After 0.5 h, the mixture was partitioned into DCM and 10% aqueous citric acid, and the organic extract was washed with water, dried (Na 2 SO 4 ) and evaporated to give an oil (9.4 g) which was chrom...
example 2
[0956] Sodium (2S,5R)-7-oxo-2-(difluoromethyl)-1,6-diazabicyclo[3.2.1]octyl-6-yl sulfate;
[0957]
[0958] a. (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid ethyl ester
[0959]
[0960] (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethyl ester oxalate was treated with potassium bicarbonate (16.3 g, 163 mmol) in water (150 mL) at 0 °C (15.0 g, 40.7 mmol; purchased from Frapps Chemicals Co, Zhejiang, China, http: / / www.frappschem.com) suspension in THF (150 mL). After 1 hour, the mixture was extracted with ethyl acetate, and the combined extracts were washed with water followed by brine, dried (Na 2 SO 4 ) and evaporated to give (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylic acid ethyl ester as a brown oil (10.0 g, 88%).
[0961] Ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (5.0 g, 18 mmol) in DCM (100 mL) was treated with DIPEA (12.5 mL, 72 mmol) at 0 °C solution followed by the addition of triphosgene (2.6 g, 9 ...
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