benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-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: A solution of (+/−) benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in saturated ammonium hydroxide aqueous solution and ethanol (1:1, 0.05 M solution) in a sealed steel bomb was heated to 70° C. for 5 h. After all volatile materials were removed by N2 gas stream, ethyl acetate and water were added for work-up. The crude regioisomeric mixture, benzyl 3-amino-4-hydroxypiperidine-1-carboxylate and benzyl 4-amino-3-hydroxypiperidine-1-carboxylate was reacted with Boc2O (1.0 equiv.) and triethylamine (1.0 equiv.) in dichloromethane (0.1 M solution). After stirred for 2 h at room temperature, the reaction mixture was extracted with dichloromethane. The polar (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxy-piperidine-1-carboxylate and nonpolar (+/−)-benzyl 4-(tert-butoxycarbonylamino)-3-hydroxypiperidine-1-carboxylate were obtained by flash column chromatography (20% to 40% EtOAc in hexanes, 28%, 51% each). LCMS (m/z): 351.1 (MH+), Rt=0.81 min, LCMS (m/z): 351.1 (MH+), Rt=0.83 min. The enantiomerically pure (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate and (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate were resolved by chiral HPLC (For analysis Rt=6.8 min and 9.1 min respectively; n-heptane:ethanol=70:30 (v:v), Chiralpak AD-H prep 250×4.6 mm at 1 mL/min. For preparative separation, n-heptane:ethanol=80:20 (v:v), Chiralpak AS 50×500 mm at 90 mL/min). After all volatile materials were removed by N2 gas stream, ethyl acetate and water were added for work-up the reaction mixture was extracted with dichloromethane

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

実験手順: 3-Chlorobenzoperoxoic acid (51.1 g, 228 mmol) was added portion wise to a solution of 5,6-dihydropyridine-1(2H)-carboxylate (33.0 g, 152 mmol) in DCM (200 mL) at 0° C. After 10 minutes at 0° C., the reaction was warmed to room temperature and stirred at room temperature for 4 hours. The reaction mixture was diluted with ether (800 mL), washed with 1N NaOH solution (2×200 mL), saturated N2SO3 solution (2×100 mL), brine (100 mL), dried (sodium sulfate) and concentrated in vacuo to give benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (35.0 g, 99%) as an oil. washed with 1N NaOH solution (2×200 mL), saturated N2SO3 solution (2×100 mL), brine (100 mL) dried (sodium sulfate) concentrated in vacuo

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

実験手順: Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (21.0 g, 92.0 mmol) was added to a stirred solution of 2,3-dimethylphenol (23.0 g, 188 mmol) and aqueous sodium hydroxide (100 ml, 2N, 200 mmol) in acetonitrile (400 ml). The reaction mixture was heated at reflux for 14 h. On cooling to room temperature, the reaction mixture was concentrated in vacuo before dilution with water (500 ml). Extraction with dichloromethane (4×100 ml) was followed by washing of the combined organics with aqueous sodium hydroxide (100 ml, 3N, 300 mmol), water (100 ml) and brine (100 ml). The organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish a crude product. Purification was carried out by silica gel chromatography using a gradient eluent system of iso-hexanes and ethyl acetate (100% iso-hexanes to 80:20 iso-hexanes:ethyl acetate) to furnish trans-benzyl-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate as a pale yellow syrup (16.8 g, 50%). The reaction mixture was heated at reflux for 14 h the reaction mixture was concentrated in vacuo before dilution with water (500 ml) Extraction with dichloromethane (4×100 ml) The organics were dried over anhydrous magnesium sulfate filtered concentrated in vacuo to furnish a crude product Purification

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

実験手順: A stirred solution of benzyl 3,6-dihydropyridine-1(2H)-carboxylate (20.0 g, 92.0 mmol) in dichloromethane (280 ml) was cooled to 0° C. A solution of m-chloroperoxybenzoic acid (22.5 g, approx. 130 mmol) in dichloromethane (560 ml) was added drop-wise and the resulting colourless reaction mixture warmed to room temperature. After an additional 4 h at room temperature (reaction complete by tlc using 50:50 hexane:ethyl acetate as eluent.) the reaction mixture was washed with aqueous potassium carbonate solution (5 wt %, 3×200 ml) and brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate as a yellow oil (22.0 g; 100%). was washed with aqueous potassium carbonate solution (5 wt %, 3×200 ml) and brine (200 ml) The organic layer was dried over anhydrous magnesium sulfate filtered concentrated in vacuo

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

実験手順: A stirred solution of benzyl 3,6-dihydropyridine-1(2H)-carboxylate (20.0 g, 92.0 mmol) in dichloromethane (280 ml) was cooled to 0° C. A solution of m-chloroperoxybenzoic acid (22.5 g, approx. 130 mmol) in dichloromethane (560 ml) was added drop-wise and the resulting colourless reaction mixture warmed to room temperature. After an additional 4 h at room temperature (reaction complete by tlc using 50:50 hexane:ethyl acetate as eluent.) the reaction mixture was washed with aqueous potassium carbonate solution (5 wt %, 3×200 ml) and brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate as a yellow oil (22.0 g; 100%). was washed with aqueous potassium carbonate solution (5 wt %, 3×200 ml) and brine (200 ml) The organic layer was dried over anhydrous magnesium sulfate filtered concentrated in vacuo

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

実験手順: 3-Chlorobenzoperoxoic acid (51.1 g, 228 mmol) was added portion wise to a solution of 5,6-dihydropyridine-1(2H)-carboxylate (33.0 g, 152 mmol) in DCM (200 mL) at 0° C. After 10 minutes at 0° C., the reaction was warmed to room temperature and stirred at room temperature for 4 hours. The reaction mixture was diluted with ether (800 mL), washed with 1N NaOH solution (2×200 mL), saturated N2SO3 solution (2×100 mL), brine (100 mL), dried (sodium sulfate) and concentrated in vacuo to give benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (35.0 g, 99%) as an oil. washed with 1N NaOH solution (2×200 mL), saturated N2SO3 solution (2×100 mL), brine (100 mL) dried (sodium sulfate) concentrated in vacuo

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

実験手順: 3-Chlorobenzoperoxoic acid (51.1 g, 228 mmol) was added portion wise to a solution of 5,6-dihydropyridine-1(2H)-carboxylate (33.0 g, 152 mmol) in DCM (200 mL) at 0° C. After 10 minutes at 0° C., the reaction was warmed to room temperature and stirred at room temperature for 4 hours. The reaction mixture was diluted with ether (800 mL), washed with 1N NaOH solution (2×200 mL), saturated N2SO3 solution (2×100 mL), brine (100 mL), dried (sodium sulfate) and concentrated in vacuo to give benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (35.0 g, 99%) as an oil. washed with 1N NaOH solution (2×200 mL), saturated N2SO3 solution (2×100 mL), brine (100 mL) dried (sodium sulfate) concentrated in vacuo

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

実験手順: A solution of (+/−) benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in saturated ammonium hydroxide aqueous solution and ethanol (1:1, 0.05 M solution) in a sealed steel bomb was heated to 70° C. for 5 h. After all volatile materials were removed by N2 gas stream, ethyl acetate and water were added for work-up. The crude regioisomeric mixture, benzyl 3-amino-4-hydroxypiperidine-1-carboxylate and benzyl 4-amino-3-hydroxypiperidine-1-carboxylate was reacted with Boc2O (1.0 equiv.) and triethylamine (1.0 equiv.) in dichloromethane (0.1 M solution). After stirred for 2 h at room temperature, the reaction mixture was extracted with dichloromethane. The polar (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate and nonpolar (+/−)-benzyl 4-(tert-butoxycarbonylamino)-3-hydroxypiperidine-1-carboxylate were obtained by flash column chromatography (20% to 40% EtOAc in hexanes, 28%, 51% each). LCMS (m/z): 351.1 (MH+), Rt=0.81 min, LCMS (m/z): 351.1 (MH+), Rt=0.83 min. The enantiomerically pure (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate and (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate were resolved by chiral HPLC (For analysis Rt=6.8 min and 9.1 min respectively; n-heptane:ethanol=70:30 (v:v), Chiralpak AD-H prep 250×4.6 mm at 1 mL/min. For preparative separation, n-heptane:ethanol=80:20 (v:v), Chiralpak AS 50×500 mm. at 90 mL/min). After all volatile materials were removed by N2 gas stream, ethyl acetate and water were added for work-up the reaction mixture was extracted with dichloromethane

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

実験手順: In an analogous manner to that described in Example 71(a)-(b), from benzyl rac-3-aza-7-oxa-bicyclo[4.1.0]heptane-3-carboxylate by reaction with 4-bromophenol there was obtained (3RS,4RS)-1-[4-(4-bromo-phenoxy)-3-hydroxy-piperidin-1-yl]-2-phenyl-ethanone as a colourless solid [Rf : 0.40 (SiO2, methylene chloride:ethyl acetate=2:1)], alkylation of which with 2-bromomethylnaphthalene gave benzyl (3RS,4RS)-4-(4-bromo-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 454, 456 (M-benzyl)+.

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

実験手順: In an analogous manner to that described in Example 71(a)-(b), from benzyl rac-3-aza-7-oxa-bicyclo[4.1.0]heptane-3-carboxylate by reaction with 4-bromophenol there was obtained (3RS,4RS)-1-[4-(4-bromo-phenoxy)-3-hydroxy-piperidin-1-yl]-2-phenyl-ethanone as a colourless solid [Rf : 0.40 (SiO2, methylene chloride:ethyl acetate=2:1)], alkylation of which with 2-bromomethylnaphthalene gave benzyl (3RS,4RS)-4-(4-bromo-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 454, 456 (M-benzyl)+.

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

実験手順: A mixture of benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (prepared according to a published literature procedure: Fink, Brian, et al., WO 2005/066176, 700 mg, 3.00 mmol), morpholine (0.581 mL, 6.00 mmol), and lithium perchlorate (639 mg, 6.00 mmol) in acetonitrile (10 mL) was heated at 80° C. for 4 h. Solvent was evaporated and the crude intermediate was dissolved in dichloromethane (10 mL), imidazole (654 mg, 9.60 mmol) and tert-butyldimethylchlorosilane (1357 mg, 9.00 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with dichloromethane and washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (220 g gold column, eluting with 5-30% ethyl acetate/hexanes) to give (+/−)-(3R,4R)-benzyl 4-((tert-butyldimethylsilyl)oxy)-3-morpholinopiperidine-1-carboxylate (Isomer A, 0.39 g) as a colorless oil and (+/−)-(3R,4R)-benzyl 3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidine-1-carboxylate (Isomer B, 0.43 g) as a colorless oil. The structures were confirmed by NMR studies (1H-1D, 13C-1D, COSY, NOESY, dept-1H-13C-HSQC, 1H-13C-HMBC). prepared Solvent was evaporated the crude intermediate was dissolved in dichloromethane (10 mL) washed with water and brine dried over sodium sulfate filtered concentrated The crude product was purified by flash chromatography on silica gel using an automated ISCO system (220 g gold column, eluting with 5-30% ethyl acetate/hexanes)