tert-butyl N-(4-oxocyclohexyl)carbamate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of tert-butyl 4-oxocyclohexylcarbamate (1.0 g, 4.7 mmol), 2-methylpropane-2-sulfinamide (0.63 g, 5.17 mmol) and Ti(OEt)4 (2.1 g, 9.2 mmol) in 10 mL of THF was stirred at 50-60° C. overnight. The mixture was cooled to room temperature and the residue purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 4-(tert-butylsulfinylimino)cyclohexylcarbamate (1.0 g, 67%) as an clear oil. MS: (M+H)+=317.3; 1H NMR (300 MHz, CDCl3): δ 4.88-4.86 (m, 1H), 3.83 (brs, 1H), 3.39-3.38 (m, 1H), 2.62-2.15 (m, 5H), 1.68-1.53 (m, 2H), 1.43 (s, 9H), 1.24 (s, 9H). The mixture was cooled to room temperature the residue purified by column chromatography (silica gel, 200-300 mesh eluting with a mixture of petroleum ether and ethyl acetate (4:1

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of tert-butyl 4-oxocyclohexylcarbamate (1.0 g, 4.7 mmol), 2-methylpropane-2-sulfinamide (0.63 g, 5.17 mmol) and Ti(OEt)4 (2.1 g, 9.2 mmol) in 10 mL of THF was stirred at 50-60° C. overnight. The mixture was cooled to room temperature and the residue purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 4-(tert-butylsulfinylimino)cyclohexylcarbamate (1.0 g, 67%) as an clear oil. MS: (M+H)+=317.3; 1H NMR (300 MHz, CDCl3): δ 4.88-4.86 (m, 1H), 3.83 (brs, 1H), 3.39-3.38 (m, 1H), 2.62-2.15 (m, 5H), 1.68-1.53 (m, 2H), 1.43 (s, 9H), 1.24 (s, 9H). The mixture was cooled to room temperature the residue purified by column chromatography (silica gel, 200-300 mesh eluting with a mixture of petroleum ether and ethyl acetate (4:1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of tert-butyl trans-4-hydroxycyclohexylcarbamate (2.0 g, 9.3 mmol) in 100 mL of dichloromethane was added PCC (3.0 g, 14 mmol) and celite (5.0 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a celite pad and the residue concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1, v/v) to give tert-butyl 4-oxocyclohexylcarbamate (1.6 g, 80%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 4.52 (brs, 1H), 3.94 (brs, 1H), 2.45-2.40 (m, 4H), 2.20-2.27 (m, 2H), 1.74-1.63 (m, 2H), 1.46 (s, 9H). The reaction mixture was filtered through a celite pad the residue concentrated under reduced pressure The crude compound was purified by column chromatography (silica gel, 200-300 mesh eluting with a mixture of ethyl acetate and petroleum ether (1:1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of tert-butyl trans-4-hydroxycyclohexylcarbamate (2.0 g, 9.3 mmol) in 100 mL of dichloromethane was added PCC (3.0 g, 14 mmol) and celite (5.0 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a celite pad and the residue concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1, v/v) to give tert-butyl 4-oxocyclohexylcarbamate (1.6 g, 80%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 4.52 (brs, 1H), 3.94 (brs, 1H), 2.45-2.40 (m, 4H), 2.20-2.27 (m, 2H), 1.74-1.63 (m, 2H), 1.46 (s, 9H). The reaction mixture was filtered through a celite pad the residue concentrated under reduced pressure The crude compound was purified by column chromatography (silica gel, 200-300 mesh eluting with a mixture of ethyl acetate and petroleum ether (1:1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (500 mg, 2.505 mmol) and 4-N-Boc-aminocyclohexanone (2.0 g, 9.38 mmol) in methanol (20 mL) was added zinc chloride (1.0 g, 7.34 mmol). The reaction was stirred for 2 h at room temperature, then sodium cyanoborohydride (700 mg, 11.14 mmol) was added portionwise over 2 h. The reaction was then heated to 40° C. and stirred for 24 h. LCMS showed that the reaction was mostly complete (11% starting amine remained with two product peaks 40% and 49% corresponding to the trans and cis products). The reaction was evaporated to dryness, taken up in EtOAc, washed with aq. NH4Cl, 1 N Na2CO3, brine, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Analogix, SF25-80 g, 10 to 30% EtOAc in hexanes). The cis-diastereomer was contaminated with 27% of the methyl 3-amino-5-chloro-2-methylbenzoate starting material. Trituration and filtration from a small volume of 10% EtOAc in hexanes gave the pure cis-diastereomer methyl 3-(((cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate (305 mg, 0.730 mmol, 29.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=6.85 (d, J=2.3 Hz, 1 H), 6.74 (d, J=2.0 Hz, 1 H), 6.62 (d, J=7.1Hz, 1 H), 4.66 (d, J=6.8 Hz, 1 H), 3.81 (s, 3 H), 3.47 (br. s., 2 H), 2.19 (s, 3 H), 1.75-1.51 (m, 8 H), 1.39 (s, 9 H). MS(ES) [M+H]+ 397.2. The reaction was then heated to 40° C. stirred for 24 h The reaction was evaporated to dryness washed with aq. NH4Cl, 1 N Na2CO3, brine dried (Na2SO4) filtered concentrated under vacuum The residue was purified by silica gel chromatography (Analogix Trituration and filtration from a small volume of 10% EtOAc in hexanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of morpholine (4.08 ml) and tert-butyl 4-oxocyclohexylcarbamate (10 g) stirred for 24 hours at room temperature in titanium(IV) isopropoxide (27.5 ml), methanol (10 ml) was added followed by careful addition of sodium borohydride (3.55 g). The reaction mixture was quenched with water, extracted with ether (2×100 mL), dried over magnesium sulfate, filtered and concentrated. The crude product was purified by FC (silica gel 200 g, 30%-100% acetone/hexanes) providing two products, the title compound and trans 4-morpholinocyclohexylcarbamate. The reaction mixture was quenched with water extracted with ether (2×100 mL) dried over magnesium sulfate filtered concentrated The crude product was purified by FC (silica gel 200 g, 30%-100% acetone/hexanes) providing two products

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of EXAMPLE 336B (1 g) and tert-butyl 4-oxocyclohexylcarbamate (0.877 g) stirred for 24 hours at room temperature in titanium (IV) isopropoxide (2.410 mL), methanol (2 mL) was added followed by careful addition of sodium borohydride (0.311 g). The reaction mixture was quenched with water, extracted with ether, dried and concentrated. The crude product was purified by flash chromotography (silica 80 g, 50%-100% acetone/hexanes) providing the product. The reaction mixture was quenched with water extracted with ether dried concentrated The crude product was purified by flash chromotography (silica 80 g, 50%-100% acetone/hexanes) providing the product