Ketone synthesis (via dihydrolyl compound):

 

To a solution of tert-butyl [(2R,3S)-5-methylene-2-(2,4,5- trifluoroρhenyl)tetrahydro-2H-pyran-3-yl] carbamate (203 mg, 0.59 mmol) in tert-butyl alcohol (6 mL), acetone (3 mL) and water (1.5 mL) was added osmium tetroxide (0.113 mL of 2.5% solution in tert-butyl alcohol, 0.009 mmol). The resultant mixture was stirred at room temperature for 10 minutes and then treated with N-methylmorpholine N-oxide (92 mg, 0.79 mmol) and stirred. After two days, the reaction mixture was treated with aqueous sodium bisulfite solution (5 mL, 2.0 N) followed after 10 min by ethyl acetate. The organic layer was washed successively with 2N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated to yield tert-butyl [(2iϊ,3)-5-hydroxy-5-(hydroxymethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3- yl] carbamate which was used in the next step without further purification.

 

Patent reference: WO2010056708 (Merck)

Ketone synthesis (via carboxylic acid group):

 

Oxalyl chloride (949 mg, 4.8 mmol) and DMF (1 drop) was added to a slurry of 6-{4- [(benzylsulfonyl)carbamoyl]piperidin-l-yl}-5-cyano-2-methylnicotinic acid (1.05 g, 2.37 mmol) in DCM (20 mL) and the reaction was stirred at r.t. until all acid was consumed. The solvent and excess reagents were evaporated and the residue was dissolved in THF (30 mL). Ferric acetylacetonate (37 mg, 0.105 mmol) was added and the mixture was cooled in an ice/water bath. n-Butylmagnesium bromide was added dropwise to the red solution and the mixture was stirred for 10 minutes. Methanol (2 mL) was added and the solvent was evaporated. The residue was taken up in DCM and the organic phase was washed with water (emulsion). The mixture was acidified with 2 M HCl (10 mL) and the phases were separated. The organic phase was passed through a phase separator and evaporated to give 1.4 g of a crude product.The crude product was purified by preparative HPLC (Kromasil C8, using an increasing gadient of MeCN in water/0.2 % HOAc). This gave N- (benzylsulfonyl)- 1 -(3 -cyano-6-methyl-5 -pentanoylpyridin-2-yl)piperidine-4-carboxamide as a white solid. Yield: 823 mg (72%).

 

Patent reference: WO2010005385 (Astrazeneca)

Ketone synthesis (via hydrolyl group):

 

To a solution of 1-(2-chloro-5-nitropyridin-4-yl)ethanol (1.0 equiv.) in dichloromethane (0.1 M) was added Dess-Martin periodinane (1.8 eq.) and the solution was stirred for 16 hours. The solution was poured into ethyl acetate (800 mL), was washed with 1 :1 10% Na2S2O3 / NaHCO3(sat) (4x), with NaCl(sat), dried over MgSO4, filtered and concentrated yielding l-(2-chloro-5-nitropyridin-4-yl)ethanone (96%) as a yellow solid. 

 

Patent reference: WO2010026121 (Novartis)

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