tert-butyl 3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptane-6-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: To a solution of 3,3-Dimethyl-1-oxa-6-aza-spiro[3.3]heptane-6-carboxylic acid tert-butyl ester (60 mg, 0.27 mmol) in DCM (3 ml) at 0° C. was added trifluoroacetic acid and the reaction stirred at room temperature for 1 hr. The reaction was concentrated to give an oil which was used crude in the next step. The oily residue was dissolved in n-BuOH (3 ml) and diisopropylethylamine (171 mg, 1.35 mmol, 0.24 ml) and N-{4-[4-Chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-propionamide (93 mg, 0.24 mmol) was added. The mixture was heated to 100° C. and stirred for 18 hrs. The reaction was allowed to cool to room temperature and diluted with brine (20 ml) and ethyl acetate (20 ml). The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate to give the title compound as a pale orange solid 25 mg, 20%. 1H NMR (d6-DMSO, 400 MHz) 1.08 (3H, m), 1.20 (6H, s), 1.98 (3H, s), 2.34 (2H, q), 3.78 (2H, d), 4.14-4.15 (4H, m), 5.35 (1H, s), 5.61 (1H, brs), 7.47 (2H, d), 7.70 (2H, d), 9.24 (1H, s), 10.07 (1H, s), 11.43 (1H, s). ES+ 480. The reaction was concentrated to give an oil which The mixture was heated to 100° C. stirred for 18 hrs to cool to room temperature The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate

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

実験手順: To a solution of tert-butyl 3-hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)azetidine-1-carboxylate (0.20 g, 0.82 mmol) in THF (4 ml) was added in rapid succession, KOtBu (0.19 g, 1.72 mmol) and p-toluenesulfonylchloride (0.16 g, 0.82 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes to give the title compound as a colorless oil 0.13 g, 70%. 1H NMR (CDCl3, 400 Mhz) 1.25 (6H, s), 1.45 (9H, s), 3.89 (2H, d), 4.12 (2H, d), 4.20 (2H, s). extracted with ethyl acetate The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes

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

実験手順: To a solution of 3,3-Dimethyl-1-oxa-6-aza-spiro[3.3]heptane-6-carboxylic acid tert-butyl ester (60 mg, 0.27 mmol) in DCM (3 ml) at 0° C. was added trifluoroacetic acid and the reaction stirred at room temperature for 1 hr. The reaction was concentrated to give an oil which was used crude in the next step. The oily residue was dissolved in n-BuOH (3 ml) and diisopropylethylamine (171 mg, 1.35 mmol, 0.24 ml) and N-{4-[4-Chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-propionamide (93 mg, 0.24 mmol) was added. The mixture was heated to 100° C. and stirred for 18 hrs. The reaction was allowed to cool to room temperature and diluted with brine (20 ml) and ethyl acetate (20 ml). The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate to give the title compound as a pale orange solid 25 mg, 20%. 1H NMR (d6-DMSO, 400 MHz) 1.08 (3H, m), 1.20 (6H, s), 1.98 (3H, s), 2.34 (2H, q), 3.78 (2H, d), 4.14-4.15 (4H, m), 5.35 (1H, s), 5.61 (1H, brs), 7.47 (2H, d), 7.70 (2H, d), 9.24 (1H, s), 10.07 (1H, s), 11.43 (1H, s). ES+ 480. The reaction was concentrated to give an oil which The mixture was heated to 100° C. stirred for 18 hrs to cool to room temperature The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate

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

実験手順: To a solution of 3,3-Dimethyl-1-oxa-6-aza-spiro[3.3]heptane-6-carboxylic acid tert-butyl ester (60 mg, 0.27 mmol) in DCM (3 ml) at 0° C. was added trifluoroacetic acid and the reaction stirred at room temperature for 1 hr. The reaction was concentrated to give an oil which was used crude in the next step. The oily residue was dissolved in n-BuOH (3 ml) and diisopropylethylamine (171 mg, 1.35 mmol, 0.24 ml) and N-{4-[4-Chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-propionamide (93 mg, 0.24 mmol) was added. The mixture was heated to 100° C. and stirred for 18 hrs. The reaction was allowed to cool to room temperature and diluted with brine (20 ml) and ethyl acetate (20 ml). The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate to give the title compound as a pale orange solid 25 mg, 20%. 1H NMR (d6-DMSO, 400 MHz) 1.08 (3H, m), 1.20 (6H, s), 1.98 (3H, s), 2.34 (2H, q), 3.78 (2H, d), 4.14-4.15 (4H, m), 5.35 (1H, s), 5.61 (1H, brs), 7.47 (2H, d), 7.70 (2H, d), 9.24 (1H, s), 10.07 (1H, s), 11.43 (1H, s). ES+480. The reaction was concentrated to give an oil which The mixture was heated to 100° C. stirred for 18 hrs to cool to room temperature The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate

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

実験手順: To a solution of tert-butyl 3-hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)azetidine-1-carboxylate (0.20 g, 0.82 mmol) in THF (4 ml) was added in rapid succession, KOtBu (0.19 g, 1.72 mmol) and p-toluenesulfonylchloride (0.16 g, 0.82 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes to give the title compound as a colorless oil 0.13 g, 70%. 1H NMR (CDCl3, 400 Mhz) 1.25 (6H, s), 1.45 (9H, s), 3.89 (2H, d), 4.12 (2H, d), 4.20 (2H, s). extracted with ethyl acetate The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes

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

実験手順: To a solution of tert-butyl 3-hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)azetidine-1-carboxylate (0.20 g, 0.82 mmol) in THF (4 ml) was added in rapid succession, KOtBu (0.19 g, 1.72 mmol) and p-toluenesulfonylchloride (0.16 g, 0.82 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes to give the title compound as a colorless oil 0.13 g, 70%. 1H NMR (CDCl3, 400 Mhz) 1.25 (6H, s), 1.45 (9H, s), 3.89 (2H, d), 4.12 (2H, d), 4.20 (2H, s). extracted with ethyl acetate The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes

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

実験手順: To a solution of 3,3-Dimethyl-1-oxa-6-aza-spiro[3.3]heptane-6-carboxylic acid tert-butyl ester (60 mg, 0.27 mmol) in DCM (3 ml) at 0° C. was added trifluoroacetic acid and the reaction stirred at room temperature for 1 hr. The reaction was concentrated to give an oil which was used crude in the next step. The oily residue was dissolved in n-BuOH (3 ml) and diisopropylethylamine (171 mg, 1.35 mmol, 0.24 ml) and N-{4-[4-Chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-propionamide (93 mg, 0.24 mmol) was added. The mixture was heated to 100° C. and stirred for 18 hrs. The reaction was allowed to cool to room temperature and diluted with brine (20 ml) and ethyl acetate (20 ml). The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate to give the title compound as a pale orange solid 25 mg, 20%. 1H NMR (d6-DMSO, 400 MHz) 1.08 (3H, m), 1.20 (6H, s), 1.98 (3H, s), 2.34 (2H, q), 3.78 (2H, d), 4.14-4.15 (4H, m), 5.35 (1H, s), 5.61 (1H, brs), 7.47 (2H, d), 7.70 (2H, d), 9.24 (1H, s), 10.07 (1H, s), 11.43 (1H, s). ES+ 480. The reaction was concentrated to give an oil which The mixture was heated to 100° C. stirred for 18 hrs to cool to room temperature The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate

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

実験手順: To a solution of tert-butyl 3-hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)azetidine-1-carboxylate (0.20 g, 0.82 mmol) in THF (4 ml) was added in rapid succession, KOtBu (0.19 g, 1.72 mmol) and p-toluenesulfonylchloride (0.16 g, 0.82 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes to give the title compound as a colorless oil 0.13 g, 70%. 1H NMR (CDCl3, 400 Mhz) 1.25 (6H, s), 1.45 (9H, s), 3.89 (2H, d), 4.12 (2H, d), 4.20 (2H, s). extracted with ethyl acetate The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes

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

実験手順: To a solution of 3,3-Dimethyl-1-oxa-6-aza-spiro[3.3]heptane-6-carboxylic acid tert-butyl ester (60 mg, 0.27 mmol) in DCM (3 ml) at 0° C. was added trifluoroacetic acid and the reaction stirred at room temperature for 1 hr. The reaction was concentrated to give an oil which was used crude in the next step. The oily residue was dissolved in n-BuOH (3 ml) and diisopropylethylamine (171 mg, 1.35 mmol, 0.24 ml) and N-{4-[4-Chloro-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-phenyl}-propionamide (93 mg, 0.24 mmol) was added. The mixture was heated to 100° C. and stirred for 18 hrs. The reaction was allowed to cool to room temperature and diluted with brine (20 ml) and ethyl acetate (20 ml). The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate to give the title compound as a pale orange solid 25 mg, 20%. 1H NMR (d6-DMSO, 400 MHz) 1.08 (3H, m), 1.20 (6H, s), 1.98 (3H, s), 2.34 (2H, q), 3.78 (2H, d), 4.14-4.15 (4H, m), 5.35 (1H, s), 5.61 (1H, brs), 7.47 (2H, d), 7.70 (2H, d), 9.24 (1H, s), 10.07 (1H, s), 11.43 (1H, s). ES+480. The reaction was concentrated to give an oil which The mixture was heated to 100° C. stirred for 18 hrs to cool to room temperature The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 2.5% MeOH in ethyl acetate

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

実験手順: To a solution of tert-butyl 3-hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)azetidine-1-carboxylate (0.20 g, 0.82 mmol) in THF (4 ml) was added in rapid succession, KOtBu (0.19 g, 1.72 mmol) and p-toluenesulfonylchloride (0.16 g, 0.82 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes to give the title compound as a colorless oil 0.13 g, 70%. 1H NMR (CDCl3, 400 Mhz) 1.25 (6H, s), 1.45 (9H, s), 3.89 (2H, d), 4.12 (2H, d), 4.20 (2H, s). extracted with ethyl acetate The organic layer was dried (Na2SO4) concentrated to give an oil The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes