tert-butyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate

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

実験手順: Sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added to a solution of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) in dry THF (2 mL). The mixture was stirred for 10 min and then a solution of 8-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.111 g, 0.3101 mmol) in dry THF (3 mL) was added. The mixture was stirred overnight at room temperature. A second batch of sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added and the mixture was stirred overnight. Further batches of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) and sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) were added and the mixture was stirred for 3 nights. It was poured into methanol to quench the reaction, and then the solvent was evaporated. The residue was dissolved in EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (1×10 mL), filtered through a hydrophobic frit and evaporated to give tert-butyl-5-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]oxy-2-azabicyclo[2.2.1]heptane-2-carboxylate as a brown solid (269 mg) which was used in the next step without further purification. LCMS RT=4.23 min. M+1=535. The mixture was stirred overnight at room temperature the mixture was stirred overnight the mixture was stirred for 3 nights to quench the reaction the solvent was evaporated The residue was dissolved in EtOAc (10 mL) The layers were separated the aqueous was extracted with EtOAc (2×10 mL) The combined organic layers were washed with brine (1×10 mL) filtered through a hydrophobic frit evaporated

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Tert-butyl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.5 g, 7.0 mmol) and tetrabutylammonium bromide (0.35 g, 0.70 mmol) were stirred in sodium hydroxide (10 M) (30 mL, 1600 mmol)/toluene (30 mL) and heated to 60° C. 2-(2-Bromoethoxy)tetrahydropyran (4.4 g, 21 mmol) was added in 4 portions over 2 hours and heating continued overnight. Further 2-(2-bromoethoxy)tetrahydropyran (1 eq) was added and the reaction heated for a further 3 hours. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated in vacuo to afford a yellow oil. The reaction mixture was purified by flash chromatography, eluting with DCM then 90/10 DCM/MeOH to afford tert-butyl-5-(2-tetrahydropyran-2-yloxyethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.08 g). heating the reaction heated for a further 3 hours washed with water dried over Na2SO4 concentrated in vacuo to afford a yellow oil The reaction mixture was purified by flash chromatography eluting with DCM

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

実験手順: Sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added to a solution of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) in dry THF (2 mL). The mixture was stirred for 10 min and then a solution of 8-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.111 g, 0.3101 mmol) in dry THF (3 mL) was added. The mixture was stirred overnight at room temperature. A second batch of sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added and the mixture was stirred overnight. Further batches of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) and sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) were added and the mixture was stirred for 3 nights. It was poured into methanol to quench the reaction, and then the solvent was evaporated. The residue was dissolved in EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (1×10 mL), filtered through a hydrophobic frit and evaporated to give tert-butyl-5-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]oxy-2-azabicyclo[2.2.1]heptane-2-carboxylate as a brown solid (269 mg) which was used in the next step without further purification. LCMS RT=4.23 min. M+1=535. The mixture was stirred overnight at room temperature the mixture was stirred overnight the mixture was stirred for 3 nights to quench the reaction the solvent was evaporated The residue was dissolved in EtOAc (10 mL) The layers were separated the aqueous was extracted with EtOAc (2×10 mL) The combined organic layers were washed with brine (1×10 mL) filtered through a hydrophobic frit evaporated

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Tert-butyl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.5 g, 7.0 mmol) and tetrabutylammonium bromide (0.35 g, 0.70 mmol) were stirred in sodium hydroxide (10 M) (30 mL, 1600 mmol)/toluene (30 mL) and heated to 60° C. 2-(2-Bromoethoxy)tetrahydropyran (4.4 g, 21 mmol) was added in 4 portions over 2 hours and heating continued overnight. Further 2-(2-bromoethoxy)tetrahydropyran (1 eq) was added and the reaction heated for a further 3 hours. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated in vacuo to afford a yellow oil. The reaction mixture was purified by flash chromatography, eluting with DCM then 90/10 DCM/MeOH to afford tert-butyl-5-(2-tetrahydropyran-2-yloxyethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.08 g). heating the reaction heated for a further 3 hours washed with water dried over Na2SO4 concentrated in vacuo to afford a yellow oil The reaction mixture was purified by flash chromatography eluting with DCM