1-BENZYL-HEXAHYDRO-4H-AZEPIN-4-ONE

113. Intermediate 1-19: l-benzylazepan-4-one1-18 1-19[00418] To a mixture of benzyl bromide (5.0 g, 29 mmol, 1.0 eq) and 1-18 hydrochloride salt (4.4 g, 29 mmol, 1.0 eq, Aldrich) in acetone (10 mL) was added solid KAzepan-4-one HCI (32 g, 214 mmol), benzyl bromide (40 g, 235 mmol), K2003 (36 g, 257 mmol) and water (40 mL) were dissolved in THF (160 mL) and stirred at 50 00 for3 h. The reaction mixture was diluted with H20 (500 mL), extracted with EtOAc (3 x200 mL), and combined organics dried (Na2504) and the solvents were removed in vacuo. The crude residue was purified by column chromatography (Normal phase, Neutral silica gel, 60-120 mesh, 0 to 15percent EtOAc in hexane) to give 1-benzylazepan-4- one (18.0 g, 41.5percent) as a yellow liquid.LCMS (Method F): m/z 204 (M+H) (ES), at 0.91 mm6.01.37.04 6.01.46.04 6.01.46.04 l-Benzyl-azepan-4-one 6 mL benzyl bromide was added to 5 g azepane-4-one hydrochloride and 18.5 g potasium carbonate in 50 mL THF and 25 mL water. The mixture was stirred 5h at 50 °C, evporated, diluted with water and extracted with ethyl acetate. The organic layer was evaporated. The residue was purified by chromatographie on silica gel (petrolether/ ethyl acetate:8/2) to give 5 g of the desired product. RStep 3: Step 3:Step-1: N-methyl-N-nitrosourethane (1.39 ml, 10.8 mmol) was added dropwise to a solution of 1-benzyl-4-piperidone (2.0 g, 10.6 mmol) in methanol (4 ml) at -15°C over a period of 30 minutes while maintaining the temperature at -5°C or lower. During the addition, barium oxide (65 mg, 0.423 mmol) was added thereto in small portions. The resulting mixture was stirred overnight at -15°C and then filtered, and the filtrate was distilled under reduced pressure to remove the solvent and diethyl ether was added to the residue. The insoluble material was filtered off and a saturated aqueous sodium hydrogencarbonate solution was added to the filtrate, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1) to obtain 1-benzyl-4-azepanone (662 mg, 31percent).1H-NMR (CDCl3) δ; 1.84 (2H, m), 2.54 (2H, m), 2.60 (2H, m), 2.73 (4H, s), 3.65 (2H, s), 7.25 (5H, m).(a) A solution of 1-benzyl-4-azepanone (610 mg, 3.00 mmol) in diethyl ether (8 ml) was added to a suspension of lithium aluminum hydride (57 mg, 1.50 mmol) in diethyl ether (5 ml) at 0C and stirred for 1 hour. Water (0.057 ml), a 2N-aqueous sodium hydroxide solution (0.114 ml) and then water (0.171 ml) were added to the reaction mixture, and the resulting mixture was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 1/1, chloroform/methanol = 30/1) to obtain 1-benzyl-4-azepanol (516 mg, 84%).1H-NMR (CDCl3) delta; 1.52-1.81 (4H, m), 1.87 (1H, m), 1.96 (1H, m), 2.44 (1H, m), 2.53 (1H, m), 2.77 (1H, m), 2.87 (1H, m), 3.67 (2H, m), 4.08 (1H, m), 7.28 (5H, m).A solution of 1-benzyl-4-azepanone (610 mg, 3.00 mmol) in diethyl ether (8 ml) was added to a suspension of lithium aluminum hydride (57 mg, 1.50 mmol) in diethyl ether (5 ml) at 0C and stirred for 1 hour. Water (0.057 ml), a 2N-aqueous sodium hydroxide solution (0.114 ml) and water (0.171 ml) were added to the reaction mixture, and the resulting mixture was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluents: hexane/ethyl acetate = 1/1 and chloroform/methanol = 30/1) to obtain 1-benzyl-4-azepanol (516 mg, 84%).General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5% (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 C. For ChKRED20, 40% (v/v) 2-propanol and a reaction temperature of 40 C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5% (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 C. For ChKRED20, 40% (v/v) 2-propanol and a reaction temperature of 40 C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.

Molecular Weight:203.28
XLogP3:1.6
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:203.131014166
Monoisotopic Mass:203.131014166
Topological Polar Surface Area:20.3
Heavy Atom Count:15
Complexity:209
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes