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A solution of sodium metabisulfate (14.5 g, 0.075 mol) in distilled water (60 mL) was added over 2h to a stirred mixture of 1 (23.2 g, 123 mmol), potassium cyanide (9.9 g, 153 mmol), and water (60 mL). The mixture was stirred at 25° C. for 5 hours. The mixture was extracted with ethyl acetate (2×100 mL) and the organics dried (MgSO4), and concentrated to give an oil which slowly solidified on standing at RT. The waxy solid was triturated with hexanes-ether (9:1) and filtered to give 14.9 g of the corresponding cyanohydrin. This solid was dissolved in acetic acid (25 mL) and the solution was diluted with concentrated HCl (75 mL). The solution was refluxed for 3 hours and concentrated to a solid mass. Toluene (100 mL) was added to the solid mass and the mixture was evaporated. This process was repeated one additional time. The resulting solid was then diluted with MeOH (100 mL) and treated with concentrated sulfuric acid (3.4 g). The solution was refluxed for 12 hours and concentrated to an oily residue which was diluted with a saturated solution of sodium bicarbonate (100 mL) and then extracted with EtOAc (2×100 mL). The organics were dried (MgSO4), filtered, concentrated, and chromatographed on silica gel (60percent hexanes/40percent EtOAc) to give 2 (11.2 g) as an amber oil.
A solution of sodium metabisulfate (14.5 g, 0.075 mol) in distilled water (60 mL) was added over 2h to a stirred mixture of 1 (23.2 g, 123 mmol), potassium cyanide (9.9 g, 153 mmol), and water (60 mL). The mixture was stirred at 25 C. for 5 hours. The mixture was extracted with ethyl acetate (2×100 mL) and the organics dried (MgSO4), and concentrated to give an oil which slowly solidified on standing at RT. The waxy solid was triturated with hexanes-ether (9:1) and filtered to give 14.9 g of the corresponding cyanohydrin. This solid was dissolved in acetic acid (25 mL) and the solution was diluted with concentrated HCl (75 mL). The solution was refluxed for 3 hours and concentrated to a solid mass. Toluene (100 mL) was added to the solid mass and the mixture was evaporated. This process was repeated one additional time. The resulting solid was then diluted with MeOH (100 mL) and treated with concentrated sulfuric acid (3.4 g). The solution was refluxed for 12 hours and concentrated to an oily residue which was diluted with a saturated solution of sodium bicarbonate (100 mL) and then extracted with EtOAc (2×100 mL). The organics were dried (MgSO4), filtered, concentrated, and chromatographed on silica gel (60% hexanes/40% EtOAc) to give 2 (11.2 g) as an amber oil.
N-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-benzyl-4-hydroxypiperidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16h;
4.1 Step 1: Synthesis of N-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1- benzyl-4-hydroxypiperidine-4-carboxamide
A mixture of 1-benzyl-4-hydroxypiperidine-4-carboxylic acid (436 mg, 1.85 mmol), (6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine (0.323 g, 1.85 mmol), HATU (1.05 g, 2.78 mmol) and DIPEA (717 mg, 5.56 mmol) in DMF (20 mL) was stirred at ambient temperature for 16 h. The reaction mixture was then partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, and the combined layers were washed sequentially with water, brine, and then dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (gradient elution, 0 to 10% methanol-DCM to give N-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-benzyl-4- hydroxypiperidine-4-carboxamide (218 mg, yield 30%) as a yellow solid. MS (ES+) C22H25N5O2 requires: 391, found 392 [M+H]+.