tert-butyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate

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

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

Procedure: To a 0° C. solution of tert-butyl 3-methyleneazetidine-1-carboxylate (3.50 g, 20.7 mmol) in 115 mL CHCl3 was added 77% mCPBA (13.9 g, 62.0 mmol) in 3 batches. Isopropyl alcohol (2 mL) was added. The reaction mixture was stirred for 10 minutes, then warmed to ambient temperature and stirred. After 19 hours, the milky reaction mixture was cooled to 0° C., 10 mL isopropyl alcohol was added (reaction mixture clarified), and another 1 equivalent of mCPBA was added. The reaction mixture was warmed to ambient temperature and stirred 2 hours, then another 1 equivalent mCPBA was added portionwise. After a total of 40 hours, the reaction mixture was cooled to 0° C., and 200 mL of 1:1 saturated Na2S2O3/saturated NaHCO3 was added slowly by pouring portionwise through ice (internal temperature was monitored; an initial 10° C. exotherm was observed). The mixture was stirred for 30 minutes, then extracted with CHCl3, and combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (5-50% ethyl acetate in hexanes gradient) to give the desired product (1.0 g, 26.1% yield) as a clear colorless oil. stirred After 19 hours the milky reaction mixture was cooled to 0° C. (reaction mixture clarified) The reaction mixture was warmed to ambient temperature stirred 2 hours After a total of 40 hours, the reaction mixture was cooled to 0° C. by pouring portionwise through ice (internal temperature 10° C. exotherm The mixture was stirred for 30 minutes extracted with CHCl3 were dried (Na2SO4) filtered concentrated The crude was purified on silica gel (5-50% ethyl acetate in hexanes gradient)

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

Procedure: 1,1-Dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (51 mg, 0.28 mmol) was taken into THF (1 mL) followed by addition of morpholine (123 μL, 1.4 mmol) and the mixture was stirred for one hour at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed once with water then brine and the organic layer dried over anhydrous sodium sulfate. Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents. The combined pure fractions were concentrated and the residue treated with neat TFA (1 mL) for 5 minutes then concentrated. The residue was taken into methanol (2 mL) and basified to pH >10 by addition of Biorad AG-1X hydroxide form resin. Filtration and concentration afforded 3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H), 3.49 (d, 2H), 2.66 (s, 2H), 2.57-2.55 (m, 4H). The solution was then concentrated the residue partitioned with ethyl acetate and water The organic layer was washed once with water brine and the organic layer dried over anhydrous sodium sulfate Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography The combined pure fractions were concentrated the residue treated with neat TFA (1 mL) for 5 minutes then concentrated basified to pH >10 by addition of Biorad AG-1X hydroxide form resin Filtration and concentration

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

Procedure: 1,1-Dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (51 mg, 0.28 mmol) was taken into THF (1 mL) followed by addition of morpholine (123 μL, 1.4 mmol) and the mixture was stirred for one hour at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed once with water then brine and the organic layer dried over anhydrous sodium sulfate. Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents. The combined pure fractions were concentrated and the residue treated with neat TFA (1 mL) for 5 minutes then concentrated. The residue was taken into methanol (2 mL) and basified to pH >10 by addition of Biorad AG-1X hydroxide form resin. Filtration and concentration afforded 3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H), 3.49 (d, 2H), 2.66 (s, 2H), 2.57-2.55 (m, 4H). The solution was then concentrated the residue partitioned with ethyl acetate and water The organic layer was washed once with water brine and the organic layer dried over anhydrous sodium sulfate Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography The combined pure fractions were concentrated the residue treated with neat TFA (1 mL) for 5 minutes then concentrated basified to pH >10 by addition of Biorad AG-1X hydroxide form resin Filtration and concentration

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

Procedure: To a solution of 1,1-dimethylethyl 3-methylideneazetidine-1-carboxylate (2.96 g, 17.5 mmol) in chloroform (180 mL) was added 3-chloroperoxybenzoic acid (77%, 13.9 g, 62.0 mmol), and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions. The organic portion was isolated, dried over sodium sulfate, filtered and concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes) to give 1,1-dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (1.65 g, 51%), GC-MS for C9H15NO3: 185. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions The organic portion was isolated dried over sodium sulfate filtered concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes)

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

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

Procedure: To a 0° C. solution of tert-butyl 3-methyleneazetidine-1-carboxylate (3.50 g, 20.7 mmol) in 115 ml, CHCl3 was added 77% mCPBA (13.9 g, 62.0 mmol) in 3 batches. Isopropyl alcohol (2 mL) was added. The reaction mixture was stirred for 10 minutes, then warmed to ambient temperature and stirred. After 19 hours, the milky reaction mixture was cooled to 0° C., 10 mL isopropyl alcohol was added (reaction mixture clarified), and another 1 equivalent of mCPBA was added. The reaction mixture was warmed to ambient temperature and stirred 2 hours, then another 1 equivalent mCPBA was added portionwise. After a total of 40 hours, the reaction mixture was cooled to 0° C., and 200 mL of 1:1 saturated Na2S2O3/saturated NaHCO3 was added slowly by pouring portionwise through ice (internal temperature was monitored; an initial 10° C. exotherm was observed). The mixture was stirred for 30 minutes, then extracted with CHCl3, and combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (5-50% ethyl acetate in hexanes gradient) to give the desired product (1.0 g, 26.1% yield) as a clear colorless oil. stirred After 19 hours the milky reaction mixture was cooled to 0° C. (reaction mixture clarified) The reaction mixture was warmed to ambient temperature stirred 2 hours After a total of 40 hours, the reaction mixture was cooled to 0° C. by pouring portionwise through ice (internal temperature 10° C. exotherm The mixture was stirred for 30 minutes extracted with CHCl3 were dried (Na2SO4) filtered concentrated The crude was purified on silica gel (5-50% ethyl acetate in hexanes gradient)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of oxa-5-azaspiro[2.3]hexane-5-carboxylic acid tert-butyl ester (69 mg; prepared according to WO 2007/044515) in DMF (1 mL) was added to a suspension of 7-methoxy-2(1H)-quinolinone (60 mg; commercial) and Cs2CO3 (223 mg, 2 eq.) in DMF (2 mL). The reaction mixture was stirred at 80° C. for 10 days. The solvent was removed under reduced pressure and the residue was partitioned between water and EA. The aq. layer was extracted with EA. The combined org. layers were dried over Na2SO4, filtered, evaporated and purified by CC (DCM-MeOH 19:1 to 9:1) to afford the title intermediate as a yellow oil (12 mg, 10% yield). The solvent was removed under reduced pressure the residue was partitioned between water and EA The aq. layer was extracted with EA layers were dried over Na2SO4 filtered evaporated purified by CC (DCM-MeOH 19:1 to 9:1)

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

Procedure: 1,1-Dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (51 mg, 0.28 mmol) was taken into THF (1 mL) followed by addition of morpholine (123 μL, 1.4 mmol) and the mixture was stirred for one hour at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed once with water then brine and the organic layer dried over anhydrous sodium sulfate. Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents. The combined pure fractions were concentrated and the residue treated with neat TFA (1 mL) for minutes then concentrated. The residue was taken into methanol (2 mL) and basified to pH>10 by addition of Biorad AG-1X hydroxide form resin. Filtration and concentration afforded 3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H), 3.49 (d, 2H), 2.66 (s, 2H), 2.57-2.55 (m, 4H). The solution was then concentrated the residue partitioned with ethyl acetate and water The organic layer was washed once with water brine and the organic layer dried over anhydrous sodium sulfate Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography The combined pure fractions were concentrated the residue treated with neat TFA (1 mL) for minutes then concentrated basified to pH>10 by addition of Biorad AG-1X hydroxide form resin Filtration and concentration

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

Procedure: To a solution of 1,1-dimethylethyl 3-methylideneazetidine-1-carboxylate (2.96 g, 17.5 mmol) in chloroform (180 mL) was added 3-chloroperoxybenzoic acid (77%, 13.9 g, 62.0 mmol), and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions. The organic portion was isolated, dried over sodium sulfate, filtered and concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes) to give 1,1-dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (1.65 g, 51%), GC-MS for C9H5NO3: 185. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions The organic portion was isolated dried over sodium sulfate filtered concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes)

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

Procedure: 1,1-Dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (51 mg, 0.28 mmol) was taken into THF (1 mL) followed by addition of morpholine (123 μL, 1.4 mmol) and the mixture was stirred for one hour at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed once with water then brine and the organic layer dried over anhydrous sodium sulfate. Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents. The combined pure fractions were concentrated and the residue treated with neat TFA (1 mL) for 5 minutes then concentrated. The residue was taken into methanol (2 mL) and basified to pH>10 by addition of Biorad AG-1× hydroxide form resin. Filtration and concentration afforded 3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H), 3.49 (d, 2H), 2.66 (s, 2H), 2.57-2.55 (m, 4H). The solution was then concentrated the residue partitioned with ethyl acetate and water The organic layer was washed once with water brine and the organic layer dried over anhydrous sodium sulfate Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography The combined pure fractions were concentrated the residue treated with neat TFA (1 mL) for 5 minutes then concentrated basified to pH>10 by addition of Biorad AG-1× hydroxide form resin Filtration and concentration

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

Procedure: To a solution of 1,1-dimethylethyl 3-methylideneazetidine-1-carboxylate (2.96 g, 17.5 mmol) in chloroform (180 mL) was added 3-chloroperoxybenzoic acid (77%, 13.9 g, 62.0 mmol), and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions. The organic portion was isolated, dried over sodium sulfate, filtered and concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes) to give 1,1-dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (1.65 g, 51%), GC-MS for C9H15NO3: 185. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions The organic portion was isolated dried over sodium sulfate filtered concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes)