tert-butyl 2-oxopiperidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Compound 10f was synthesized by an adaptation of Procedure 7, substituting compound 7f for compound 6a, and substituting N-Boc-piperidone for N-carbethoxynortropinone. MS m/z=420.3 (M+1).

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

実験手順: Following Procedure 7, substituting compound 7a for compound 6a and substituting N-Boc-piperidone for N-carbethoxynortropinone, the title compound 2b was synthesized. MS m/z (MH+) 334.8.

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

実験手順: To a solution of thiazole (470 mg) in dry THF (10 mL) at −78° C. was added nBuLi (2.5 m in hexanes, 2.21 mL). After 30 minutes BOC-piperidone (1 g) was added and the reaction mixture was gradually warmed to room temperature. After stirring overnight, the reaction mixture was quenched with water, extracted with ethyl acetate, dried (MgSO4) and the solvent removed in vacuo to yield an oil which was purified using flash chromatography to yield 4-hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester. Cleavage of the BOC group with HCl yielded 4-thiazol-2-yl-piperidin-4-ol. the reaction mixture was quenched with water extracted with ethyl acetate dried (MgSO4) the solvent removed in vacuo to yield an oil which was purified

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

実験手順: To a solution of nBuLi (2.5 m in hexanes, 2.00 mL) at −50° C. was added 2-bromopyridine (780 mg) in dry ether (10 mL). After 10 minutes an ethereal solution of BOC-piperidone (1.16 g) was added and the reaction mixture was gradually warmed to room temperature. After 1 hour, the reaction mixture was quenched with ammonium chloride solution, extracted with ether, dried (MgSO4) and the solvent removed in vacuo to yield an oil which was purified using flash chromatography to yield 4′-Hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester. Cleavage of the BOC group with HCl yielded 2′,3′,5′,6′-tetrahydro-1′H-[2,4]bipyridinyl-4′-ol. the reaction mixture was quenched with ammonium chloride solution extracted with ether dried (MgSO4) the solvent removed in vacuo to yield an oil which was purified

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a −70° C. stirred solution of N-Boc-piperidone (500 mg, 2.5 mmol) in tetrahydrofuran (11 mL) was added lithium diisopropylamine (1.37 mL of a 2 M solution in tetrahydrofuran, 2.75 mmol). The reaction mixture was stirred for 2 h, warmed to 0° C., and N-phenyltriflamide (955 mg, 2.67 mmol) was added. The solution was allowed to warm to room temperature and was stirred for 12 h. The reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) afforded tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (240 mg): 1H NMR (300 MHz, CDCl3) δ 5.77 (s, 1H), 4.05 (m, 2H), 3.63 (m, 2H), 2.45 (m, 2H), 1.48 (s, 9H). to warm to room temperature was stirred for 12 h The reaction mixture was concentrated under reduced pressure Purification by flash column chromatography (3:1 hexanes/ethyl acetate)

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 2-bromo-1,4-difluorobenzene (5.15 g, 25.9 mmol) in dry THF (77 ml, 15 v) at −78° C. was added i-PrMgCl (2M, 19.5 ml, 38.8 mmol) drop wise and stirred for 1 h at room temperature then cooled again to −78° C. and added tert-butyl 2-oxopiperidine-1-carboxylate (dissolved in dry THF) (6.0 g, 31.0 mmol) drop wise and reaction mixture was stirred for 2 h at room temperature. After completion of reaction, quenched with sat.NH4Cl solution and diluted with ethyl acetate. Organic layer was separated and water layer was extracted with ethyl acetate. Combined organic layer were washed with water, brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude Int-17 (9.4 g) which was directly used for the next step. then cooled again to −78° C. reaction mixture was stirred for 2 h at room temperature After completion of reaction quenched NH4Cl solution and diluted with ethyl acetate Organic layer was separated water layer was extracted with ethyl acetate Combined organic layer were washed with water, brine dried over anhydrous Na2SO4 concentrated under reduced pressure to afford crude Int-17 (9.4 g) which

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

実験手順: A solution of piperidin-2-one (25 g, 252.2 mmol) in acetonitrile (250 ml) was cooled to 0° C. and added DMAP (6.1 g, 50.4 mmol) and triethyl amine (25.5 g, 252.2 mmol) and stirred for 10 min at same temperature then added (BOC)2O (66 g, 302.6 mmol) and continue stirring for 2 h at room temperature. After completion of starting material, solvent was removed and residue was re-dissolved in ethyl acetate and washed with water, brine and dried over Na2SO4 and concentration to afford crude product as brown liquid (31.8 g) which was used directly for the next step. 1H NMR (300 MHz, CDCl3) δ 3.66-3.62 (2H, m), 2.52-2.47 (2H, m), 1.83-1.79 (4H, m), 1.52 (9H, s) ppm. After completion of starting material, solvent was removed residue was re-dissolved in ethyl acetate washed with water, brine dried over Na2SO4 and concentration

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

実験手順: A solution of piperidin-2-one (25 g, 252.2 mmol) in acetonitrile (250 ml) was cooled to 0° C. and added DMAP (6.1 g, 50.4 mmol) and triethyl amine (25.5 g, 252.2 mmol) and stirred for 10 min at same temperature then added (BOC)2O (66 g, 302.6 mmol) and continue stirring for 2 h at room temperature. After completion of starting material, solvent was removed and residue was re-dissolved in ethyl acetate and washed with water, brine and dried over Na2SO4 and concentration to afford crude product as brown liquid (31.8 g) which was used directly for the next step. 1H NMR (300 MHz, CDCl3) δ 3.66-3.62 (2H, m), 2.52-2.47 (2H, m), 1.83-1.79 (4H, m), 1.52 (9H, s) ppm. After completion of starting material, solvent was removed residue was re-dissolved in ethyl acetate washed with water, brine dried over Na2SO4 and concentration

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

実験手順: A solution of N-BOC-piperidone (0.205 g, 1.03 mmol), t-butylsulphinamide (0.13 g, 1.07 mmol) and titanium tetraethoxide (0.42 ml, 2.0 mmol) in dry THF (5 ml) was refluxed under nitrogen for 5 h. The cooled solution was diluted with brine (10 ml) and ethyl acetate (10 ml). The suspension was shaken, the filtered through Celite, washing with ethyl acetate (10 ml). The two-phase filtrate was separated and the organic layer was dried (Na2SO4) filtered and concentrated to give the crude sulphinimine (0.293 g). The crude sulphinimine (0.293 g) was suspended in dry THF (2 ml) and stirred at room temperature under nitrogen. A solution of 3-chlorobenzyl magnesium bromide (ca. 4 mmol) (freshly prepared as a solution in diethyl ether from 3-chlorobenzylbromide and magnesium turnings) was added to give an orange solution. After 3 hours, the mixture was diluted with saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (20 ml). The extract was washed with water (20 ml), brine (10 ml), dried (Na2SO4), filtered and concentrated. Flash column chromatography, eluting with 50% ethyl acetate-hexanes, gave 4-(3-chlorobenzyl)-4-(2-methylpropane-2-sulphinylamino)-piperidine-1-carboxylic acid tert-butyl ester as a straw-coloured foam (0.139 g, 0.324 mmol, 31%). LC-MS (LCT) m/z 451, 453 [M+Na+], Rt 8.22 min. the filtered through Celite washing with ethyl acetate (10 ml) The two-phase filtrate was separated the organic layer was dried (Na2SO4) filtered concentrated to give the crude sulphinimine (0.293 g) stirred at room temperature under nitrogen was added to give an orange solution extracted with ethyl acetate (20 ml) The extract was washed with water (20 ml), brine (10 ml) dried (Na2SO4) filtered concentrated Flash column chromatography, eluting with 50% ethyl acetate-hexanes

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

実験手順: A solution of N-BOC-piperidone (0.205 g, 1.03 mmol), t-butylsulphinamide (0.13 g, 1.07 mmol) and titanium tetraethoxide (0.42 ml, 2.0 mmol) in dry THF (5 ml) was refluxed under nitrogen for 5 h. The cooled solution was diluted with brine (10 ml) and ethyl acetate (10 ml). The suspension was shaken, the filtered through Celite, washing with ethyl acetate (10 ml). The two-phase filtrate was separated and the organic layer was dried (Na2SO4) filtered and concentrated to give the crude sulphinimine (0.293 g). The crude sulphinimine (0.293 g) was suspended in dry THF (2 ml) and stirred at room temperature under nitrogen. A solution of 3-chlorobenzyl magnesium bromide (ca. 4 mmol) (freshly prepared as a solution in diethyl ether from 3-chlorobenzylbromide and magnesium turnings) was added to give an orange solution. After 3 hours, the mixture was diluted with saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (20 ml). The extract was washed with water (20 ml), brine (10 ml), dried (Na2SO4), filtered and concentrated. Flash column chromatography, eluting with 50% ethyl acetate-hexanes, gave 4-(3-chlorobenzyl)-4-(2-methylpropane-2-sulphinylamino)-piperidine-1-carboxylic acid tert-butyl ester as a straw-coloured foam (0.139 g, 0.324 mmol, 31%). LC-MS (LCT) m/z 451, 453 [M+Na+], Rt 8.22 min. the filtered through Celite washing with ethyl acetate (10 ml) The two-phase filtrate was separated the organic layer was dried (Na2SO4) filtered concentrated to give the crude sulphinimine (0.293 g) stirred at room temperature under nitrogen was added to give an orange solution extracted with ethyl acetate (20 ml) The extract was washed with water (20 ml), brine (10 ml) dried (Na2SO4) filtered concentrated Flash column chromatography, eluting with 50% ethyl acetate-hexanes

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

実験手順: Compound 10f was synthesized by an adaptation of Procedure 7, substituting compound 7f for compound 6a, and substituting N-Boc-piperidone for N-carbethoxynortropinone. MS m/z=420.3 (M+1).