tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (418 mg) prepared by the method described in WO2004/074291 in THF (12 mL) was added 0.5 M 3,4-dichlorophenylmagnesium bromide-THF (4.7 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (455 mg). cooling the mixture was extracted with ethyl acetate The extract was washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (418 mg) prepared by the method described in WO2004/074291 in THF (12 mL) was added 0.5 M 3,4-dichlorophenylmagnesium bromide-THF (4.7 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (455 mg). cooling the mixture was extracted with ethyl acetate The extract was washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (1.30 g (6.04 mmol) 107.1 (prepared as described in WO2004074291) in DCM (20 mL) was treated with N-methyl-benzylamine (0.857 mL, 6.64 mmol) and stirred at rt for 30 min. Sodium triacetoxyborohydride (1.54 g, 7.25 mmol) was then added, and the reaction mixture was stirred at room temperature for 24 hr. Excess hydride was quenched by the addition of H2O and the mixture was extracted with EtOAc (2×). The combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo, absorbing onto 8 g SiO2. Purification by flash column chromatography (ISCO 40 g SiO2, 20% EtOAc/Hexanes then gradient to 80% EtOAc/hexanes) afforded tert-butyl 6-(benzyl(methyl)amino)-1,4-oxazepane-4-carboxylate (0.759 g) 107.2 as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.35-7.28 (m, 4H), 7.27-7.19 (m, 1H), 4.19-4.10 (m, 1H), 4.06-4.03 (m, 1H), 3.99-3.95 (m, 1H), 3.87 (m, 1H), 3.77-3.75 (m, 2H), 3.64-3.56 (m, 1H), 3.50 (ddd, J=3.0, 9.9, 12.5 Hz, 1H), 3.26-3.12 (m, 2H), 3.11-2.98 (m, 1H), 2.33-2.22 (m, 3H), 1.53-1.33 (m, 9H); LCMS (ESI) m/z: 321.20 [M+H]+. the reaction mixture was stirred at room temperature for 24 hr Excess hydride was quenched by the addition of H2O the mixture was extracted with EtOAc (2×) The combined organic layers were dried with MgSO4 filtered concentrated in vacuo absorbing onto 8 g SiO2 Purification by flash column chromatography (ISCO 40 g SiO2, 20% EtOAc/Hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate 38.2 (1.23 g, 5.74 mmol) in 1,4-dioxane (20 mL) and H2O (20 mL) was treated with sodium periodate (2.46 g, 11.49 mmol) and a solution of 2.5% OsO4 in t-BuOH (0.36 mL, 0.028 mmol). The reaction mixture was stirred at room temperature for 18 hrs. The resulting yellow-white suspension was diluted with H2O and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide a brown oil (1.30 g) that was used immediately without further purification. The crude tert-Butyl 6-oxo-1,4-oxazepane-4-carboxylate (4.4 g, 20.4 mmol) was dissolved in THF (100 mL) and treated with Et3N (11.4 mL, 81.8 mmol) and hydroxylamine hydrochloride (3.1 g, 45.0 mmol). The mixture was stirred at room temperature over the weekend. The mixture was concentrated in vacuo to dryness and the residue was suspended between EtOAc and water. The aqueous layer was extracted with EtOAc. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (4.8 g) of a semisolid product 38.3. LCMS m/z=253.1 [M+Na], 461.3 [2M] with two equal peaks observed (oxyme stereoisomers presumably). Used without further purification. was used immediately without further purification The mixture was concentrated in vacuo to dryness The aqueous layer was extracted with EtOAc The organics were washed with brine dried over MgSO4 filtered concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate 38.2 (1.23 g, 5.74 mmol) in 1,4-dioxane (20 mL) and H2O (20 mL) was treated with sodium periodate (2.46 g, 11.49 mmol) and a solution of 2.5% OsO4 in t-BuOH (0.36 mL, 0.028 mmol). The reaction mixture was stirred at room temperature for 18 hrs. The resulting yellow-white suspension was diluted with H2O and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide a brown oil (1.30 g) that was used immediately without further purification. The crude tert-Butyl 6-oxo-1,4-oxazepane-4-carboxylate (4.4 g, 20.4 mmol) was dissolved in THF (100 mL) and treated with Et3N (11.4 mL, 81.8 mmol) and hydroxylamine hydrochloride (3.1 g, 45.0 mmol). The mixture was stirred at room temperature over the weekend. The mixture was concentrated in vacuo to dryness and the residue was suspended between EtOAc and water. The aqueous layer was extracted with EtOAc. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (4.8 g) of a semisolid product 38.3. LCMS m/z=253.1 [M+Na], 461.3 [2M] with two equal peaks observed (oxyme steroisomers presumably). Used without further purification. was used immediately without further purification The mixture was concentrated in vacuo to dryness The aqueous layer was extracted with EtOAc The organics were washed with brine dried over MgSO4 filtered concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (418 mg) prepared by the method described in WO2004/074291 in THF (12 mL) was added 0.5 M 3,4-dichlorophenylmagnesium bromide-THF (4.7 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (455 mg). cooling the mixture was extracted with ethyl acetate The extract was washed successively with dil. hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (1.30 g (6.04 mmol) 107.1 (prepared as described in WO2004074291) in DCM (20 mL) was treated with N-methyl-benzylamine (0.857 mL, 6.64 mmol) and stirred at rt for 30 min. Sodium triacetoxyborohydride (1.54 g, 7.25 mmol) was then added, and the reaction mixture was stirred at room temperature for 24 hr. Excess hydride was quenched by the addition of H2O and the mixture was extracted with EtOAc (2×). The combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo, absorbing onto 8 g SiO2. Purification by flash column chromatography (ISCO 40 g SiO2, 20% EtOAc/Hexanes then gradient to 80% EtOAc/hexanes) afforded tert-butyl 6-(benzyl(methyl)amino)-1,4-oxazepane-4-carboxylate (0.759 g) 107.2 as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.35-7.28 (m, 4H), 7.27-7.19 (m, 1H), 4.19-4.10 (m, 1H), 4.06-4.03 (m, 1H), 3.99-3.95 (m, 1H), 3.87 (m, 1H), 3.77-3.75 (m, 2H), 3.64-3.56 (m, 1H), 3.50 (ddd, J=3.0, 9.9, 12.5 Hz, 1H), 3.26-3.12 (m, 2H), 3.11-2.98 (m, 1H), 2.33-2.22 (m, 3H), 1.53-1.33 (m, 9H); LCMS (ESI) m/z: 321.20 [M+H]+. the reaction mixture was stirred at room temperature for 24 hr Excess hydride was quenched by the addition of H2O the mixture was extracted with EtOAc (2×) The combined organic layers were dried with MgSO4 filtered concentrated in vacuo absorbing onto 8 g SiO2 Purification by flash column chromatography (ISCO 40 g SiO2, 20% EtOAc/Hexanes