azetidin-3-yloxy-tert-butyl-dimethylsilane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-azetidine (300 mg, 1.6 mmol) was combined with dichloromethane (16 mL) to give a brown solution. N,N-Diisopropylethylamine (455 mg, 615 μl, 3.52 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (355 mg, 1.44 mmol) in dichloromethane (10 mL) was added during 25 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 12 g, ethyl acetate/n-heptane 1/1) to give the title compound (320 mg, 67%) as white waxy solid; GC-MS (EI) 302.0 (M)+. to give a brown solution Afterwards the reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in n-heptane) This material was purified by a second chromatography (aminophase 12 g, ethyl acetate/n-heptane 1/1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-azetidine (300 mg, 1.6 mmol) was combined with dichloromethane (16 mL) to give a brown solution. N,N-Diisopropylethylamine (455 mg, 615 μl, 3.52 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (355 mg, 1.44 mmol) in dichloromethane (10 mL) was added during 25 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 12 g, ethyl acetate/n-heptane 1/1) to give the title compound (320 mg, 67%) as white waxy solid; GC-MS (EI) 302.0 (M)+. to give a brown solution Afterwards the reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in n-heptane) This material was purified by a second chromatography (aminophase 12 g, ethyl acetate/n-heptane 1/1)

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

Procedure: A solution of tert-butylchlorodimethylsilane (12.01 g, 79.69 mmol) in DCM (20 mL) was added dropwise to a stirred solution of azetidin-3-ol hydrochloride (CAS no. 18621-18-6) (8.73 g, 79.69 mmol) and anhydrous N-ethyl-N-isopropylpropan-2-amine (34.1 mL, 199.22 mmol) in DCM (20 mL) cooled to 10° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated, diluted with EtOAc (75 mL), and washed sequentially with saturated NaHCO3 (25 mL), water (20 mL), and saturated brine (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the product (11.1 g, 74%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.87 (9H, m), 2.80 (1H, s), 3.57-3.61 (2H, m), 3.67-3.71 (2H, m), 4.57-4.64 (1H, m). The reaction mixture was concentrated diluted with EtOAc (75 mL) washed sequentially with saturated NaHCO3 (25 mL), water (20 mL), and saturated brine (20 mL) The organic layer was dried (MgSO4) filtered evaporated

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Use 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (prepared essentially as described in Preparation 1)(979 mg, 2.3 mmol), 3-(tert-butyldimethyl-silanyloxy)-azetidine (880 mg, 4.7 mmol), palladium (II) acetate (51.6 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (211 mg, 0.23 mmol), BINAP (racemic, 215 mg, 0.345 mmol), cesium carbonate (1.1 g, 3.45 mmol), anhydrous toluene (50 mL) and degas and fill with nitrogen (3 times). Seal the system with septum and tighten it with copper wire when necessary. Heat the mixture at 95° C. for 8 h. Dilute with EtOAc, wash with saturated aqueous sodium bicarbonate solution, brine, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound (763 mg, 72%). degas Seal the system with septum Dilute with EtOAc wash with saturated aqueous sodium bicarbonate solution, brine dry (sodium sulfate) concentrate purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes)

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

Procedure: Add 20% palladium hydroxide on activated carbon (0.946 g) and ethanol (20 mL) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the mixture at RT for 15 min. Vent the hydrogen from the reaction vessel and purge the reaction vessel with nitrogen. Add 1-benzhydryl-3-(tert-butyl-dimethylsilanyloxy)-azetidine (3.89 g, 0.0110 mol) and ethanol (80 mL) to the pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the reaction at RT for 6 h. Turn off the agitation, vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Sample the reaction mixture for analysis. Once the reaction is shown to be complete, filter the reaction mixture to remove the catalyst, concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 2 M ammonia in methanol:DCM) to give the title compound (889 mg, 43%). Purge the reaction vessel with nitrogen seal the vessel purge the reaction vessel with nitrogen Purge the reaction vessel with nitrogen seal the vessel agitate the reaction at RT for 6 h purge the vessel with nitrogen filter the reaction mixture to remove the catalyst concentrate purify (silica gel chromatography, eluting with 5:95 to 10:90 2 M ammonia in methanol:DCM)

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

Procedure: Add 20% palladium hydroxide on activated carbon (0.946 g) and ethanol (20 mL) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the mixture at RT for 15 min. Vent the hydrogen from the reaction vessel and purge the reaction vessel with nitrogen. Add 1-benzhydryl-3-(tert-butyl-dimethylsilanyloxy)-azetidine (3.89 g, 0.0110 mol) and ethanol (80 mL) to the pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the reaction at RT for 6 h. Turn off the agitation, vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Sample the reaction mixture for analysis. Once the reaction is shown to be complete, filter the reaction mixture to remove the catalyst, concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 2 M ammonia in methanol:DCM) to give the title compound (889 mg, 43%). Purge the reaction vessel with nitrogen seal the vessel purge the reaction vessel with nitrogen Purge the reaction vessel with nitrogen seal the vessel agitate the reaction at RT for 6 h purge the vessel with nitrogen filter the reaction mixture to remove the catalyst concentrate purify (silica gel chromatography, eluting with 5:95 to 10:90 2 M ammonia in methanol:DCM)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ditrichloromethyl carbonate (2.38 g, 8.02 mmol, 1.50 equiv) in dichloromethane (20 mL) was added a solution of 3-[(tert-butyldimethylsilyl)oxy]azetidine (1 g, 5.34 mmol, 1.00 equiv) in dichloromethane (5 mL) dropwise with stirring at 0° C. over 30 min. Stirring was continued for 30 min whereupon a solution of triethylamine (810 mg, 8.00 mmol, 1.50 equiv) in dichloromethane (5 mL) was added dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined, washed with 2×40 mL of sodium chloride (sat.), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). Purification afforded 1.3 g (97%) of 3-[(tert-butyldimethylsilyl)oxy]azetidine-1-carbonyl chloride as a light yellow liquid. Stirring was added dropwise with stirring at 0° C. in 30 min The resulting solution was stirred overnight at room temperature The reaction was then quenched by the addition of 20 mL of sodium bicarbonate (sat.) The resulting solution was extracted with 3×20 mL of ethyl acetate washed with 2×40 mL of sodium chloride (sat.) dried over anhydrous sodium sulfate concentrated under vacuum Purification

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ditrichloromethyl carbonate (2.38 g, 8.02 mmol, 1.50 equiv) in dichloromethane (20 mL) was added a solution of 3-[(tert-butyldimethylsilyl)oxy]azetidine (1 g, 5.34 mmol, 1.00 equiv) in dichloromethane (5 mL) dropwise with stirring at 0° C. over 30 min. Stirring was continued for 30 min whereupon a solution of triethylamine (810 mg, 8.00 mmol, 1.50 equiv) in dichloromethane (5 mL) was added dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined, washed with 2×40 mL of sodium chloride (sat.), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). Purification afforded 1.3 g (97%) of 3-[(tert-butyldimethylsilyl)oxy]azetidine-1-carbonyl chloride as a light yellow liquid. Stirring was added dropwise with stirring at 0° C. in 30 min The resulting solution was stirred overnight at room temperature The reaction was then quenched by the addition of 20 mL of sodium bicarbonate (sat.) The resulting solution was extracted with 3×20 mL of ethyl acetate washed with 2×40 mL of sodium chloride (sat.) dried over anhydrous sodium sulfate concentrated under vacuum Purification

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

Procedure: Into a solution of benzyl 3-[(tert-butyldimethylsilyl)oxy]azetidine-1-carboxylate (4.2 g, 13.06 mmol, 1.00 equiv) in ethanol (15 mL) was added palladium carbon (1.3 g, 0.30 equiv) at 0° C. in water/ice bath. The resulting solution was stirred overnight at room temperature. The solids were filtered off. The resulting mixture was concentrated under vacuum to afford 2.2 g (90%) of 3-[(tert-butyldimethylsilyl)oxy]azetidine (50.4) as a light yellow liquid. The solids were filtered off The resulting mixture was concentrated under vacuum

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

Procedure: A solution of tert-butylchlorodimethylsilane (12.01 g, 79.69 mmol) in DCM (20 mL) was added dropwise to a stiffed solution of azetidin-3-ol hydrochloride (CAS no. 18621-18-6) (8.73 g, 79.69 mmol) and anhydrous N-ethyl-N-isopropylpropan-2-amine (34.1 mL, 199.22 mmol) in DCM (20 mL) cooled to 10° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated, diluted with EtOAc (75 mL), and washed sequentially with saturated NaHCO3 (25 mL), water (20 mL), and saturated brine (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the product (11.1 g, 74%). 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.87 (9H, m), 2.80 (1H, s), 3.57-3.61 (2H, m), 3.67-3.71 (2H, m), 4.57-4.64 (1H, m). The reaction mixture was concentrated diluted with EtOAc (75 mL) washed sequentially with saturated NaHCO3 (25 mL), water (20 mL), and saturated brine (20 mL) The organic layer was dried (MgSO4) filtered evaporated

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

Procedure: A mixture of 295 (200 mg, 0.696 mol), DCM (1 mL) and TFA (1 mL) was stirred for 1 h at room temperature, concentrated under reduced pressure; NaOH (1 M, 15 mL) was added to the residue and the suspension was extracted with DCM, the extract was dried (anhydrous Na2SO4) and concentrated, to afford title compound 296 (90.4 mg, 69% yield) as a syrup. MS (m/z): 188.1 (M+1). concentrated under reduced pressure NaOH (1 M, 15 mL) was added to the residue the suspension was extracted with DCM the extract was dried (anhydrous Na2SO4) concentrated