Ethanone, 1-(3-hydroxy-2-pyridinyl)- (9CI)

Reference Example 58 1-(3-hydroxypyridin-2-yl)ethanone To a solution of 3-hydroxypyridine-2-carbonitrile (3.00 g, 25.0 mmol) in THF (50 mL) was added a 3M solution of methylmagnesium bromide in THF (25 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with 6N hydrochloric acid, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.43 g, quantitative) as a powder. The compound was used for the next step without purification.3-methyl-N4[(1S)-3-methyl-1-({[(4S, 7R)-7-methyl-3-oxo-1-(2-pyridinylsulfonyl) hexahydro-1H-azepin-4-yl]amino}carbonyl)butyl]furo[3, 2-b]pyridine-2-carboxamide; Preparation of 3-methylfuro[3, 2-b]pyridine-2-carboxylic acid (6-1); Under nitrogen, charge the flask with 3 M methyl magnesium chloride in THF (600 mL, 1.80 mol, 5.0 equiv) and THF (500 mL). Heat the solution to 60-65° C. and add a solution of 3-hydroxypicolinic acid (1) (50 g, 0.36 mole), triethylamine (50 mL, 0.36 mole) in THF (250 mL) to the reaction mixture over approximately 3 h. Continue heating at reflux for 2 h. Cool the reaction to 5-10° C. and add methyl formate (44 mL) keeping the reaction temperature less than 20° C. At 10° C., add 10percent aqueous HCl to a pH 34. Transfer to separatory funnel and allow the layers to separate. Remove the top organic phase and extract the aqueous phase with THF (250 mL). Combine the organic phases combined and concentrate to 13-15 volumes and add water (170 mL). Continue with the vacuum distillation until all the THF has been removed. Cool the solution to 10° C., stir 0.5 h, filter and dry 1-(3-hydroxypyridin2-yl)ethanone (2) as the tan solid (38.1 g, 77percent yield).l-(3-Hydroxypyridin-2-yl)ethanone (50) A flame-dried 250 mL round bottom flask was charged with methylmagnesium iodide in ether (67.0 ml, 200 mmol). This solution was stirred in an ice-H3-methyl-N4[(1S)-3-methyl-1-({[(4S, 7R)-7-methyl-3-oxo-1-(2-pyridinylsulfonyl) hexahydro-1H-azepin-4-yl]amino}carbonyl)butyl]furo[3, 2-b]pyridine-2-carboxamide; Preparation of 3-methylfuro[3, 2-b]pyridine-2-carboxylic acid (6-1); Under nitrogen, charge the flask with 3 M methyl magnesium chloride in THF (600 mL, 1.80 mol, 5.0 equiv) and THF (500 mL). Heat the solution to 60-65° C. and add a solution of 3-hydroxypicolinic acid (1) (50 g, 0.36 mole), triethylamine (50 mL, 0.36 mole) in THF (250 mL) to the reaction mixture over approximately 3 h. Continue heating at reflux for 2 h. Cool the reaction to 5-10° C. and add methyl formate (44 mL) keeping the reaction temperature less than 20° C. At 10° C., add 10percent aqueous HCl to a pH 34. Transfer to separatory funnel and allow the layers to separate. Remove the top organic phase and extract the aqueous phase with THF (250 mL). Combine the organic phases combined and concentrate to 13-15 volumes and add water (170 mL). Continue with the vacuum distillation until all the THF has been removed. Cool the solution to 10° C., stir 0.5 h, filter and dry 1-(3-hydroxypyridin2-yl)ethanone (2) as the tan solid (38.1 g, 77percent yield).l-(3-Hydroxypyridin-2-yl)ethanone (50) A flame-dried 250 mL round bottom flask was charged with methylmagnesium iodide in ether (67.0 ml, 200 mmol). This solution was stirred in an ice-HA solution of l-(3-hydroxypyridin-2-yl) ethanone (160 mg; 1.17 mmol), N -tert- butoxy carbonyl-3 -azetidinon (205 mg, 1.2 mmol) and pyrrolidine (0.1 mb, 1.2 mmol) in toluene (4 niL) was stirred at reflux for 28 hours. Upon completion of the reaction (monitored by TLC), the mixture was concentrated under vacuum, and the obtained dark brown residue was partitioned between EtOAc (30 mL) and 1 N hydrochloric acid (10 mL). The layers were separated. The aqueous layer was extracted with EtOAc (2x 20 mL). The combined organic extracts were successively washed with water (2x 20 mL), saturated NaHCCb solution (20 mL) and brine (20 mL). The residue, obtained after evaporation of the solvent was purified by flash silica gel column chromatography using 30 % n-hexane in EtOAc as eluent, to yield 100 mg (29 %) of the title compound.

Molecular Weight:137.14
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:137.047678466
Monoisotopic Mass:137.047678466
Topological Polar Surface Area:50.2
Heavy Atom Count:10
Complexity:136
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes