7-Azabicyclo[2,2,1]heptane hydrochloride

In two separate batches :- To a stirred solution of PI (380 g; 1.51 mol) in THF (3 1) at 0°C was added solid pellets of lithium aluminium hydride (229.4 g; 6.04 mol) over a period of 2 hours under nitrogen. The resulting grey suspension was allowed to warm to room temperature and stirred for 4 days after which HPLC showed no remaining starting material. The reaction mixture was diluted with THF (11), cooled to 0°C and solid sodium sulfate decahydrate was added over a period of 2 hours with rapid agitation. When the effervescence had subsided, the resulting suspension was filtered and the filtrate acidified with gaseous HC1 affording a thick white precipitate which was collected by filtration, washed with THF (2 x 500 ml) and dried to a constant weight to afford Ml (batch 1: 86.8 g; 43percent) (batch 2: 97.3 g ; 49percent) as a white solid. The filter cakes obtained from the first filtration were suspended in 6N NaOH (400 ml) and filtered. The filtrate was extracted with diethyl ether (4 1). The organic layer was acidified with gaseous HC1 affording a thick white precipitate which was collected by filtration, washed with diethyl ether (2 x 500 ml) and dried to a constant weight in a vacuum oven at 40°C to afford M I. HCI (105. 9 g) as a white solid. Yield: 72percentIn two separate batches: To a stirred solution of 26 (380 g; 1. 51 mol) in THF (3 1) at 0°C was added solid pellets of lithium aluminium hydride (229.4 g ; 6.04 mol) over a period of 2 hours under a blanket of nitrogen. The resulting grey suspension was allowed to warm to room temperature and stirred for 4 days after which HPLC showed no remaining starting material. The reaction mixture was diluted with THF (1 1), cooled to 0°C and solid sodium sulfate decahydrate was added over a period of 2 hours with rapid agitation. When the effervescence had subr sided, the resulting suspension was filtered and the filtrate acidified with gaseous HC1 affording a thick white precipitate which was collected by filtration, washed with THF (2 x 500 ml) and dried to a constant weight to afford 108 (batch 1: 86.8 g; 43percent) (batch 2: 97.3 g; 49percent) as a white solid. The filter cakes obtained from the first filtration were suspended in 6N NaOH (400 ml) and filtered. The filtrate was extracted with diethyl ether (4 1). The organic layer was acidified with gaseous HC1 affording a thick white precipitate which was collected by filtration, washed with diethyl ether (2 x 500 ml) and dried to a constant weight in a vacuum oven at 40°C to afford 27. HC1 (105.9 g) as a white solid. Yield: 72percentIn two separate batches :- To a stirred solution of PI (380 g; 1.51 mol) in THF (3 1) at 0°C was added solid pellets of lithium aluminium hydride (229.4 g; 6.04 mol) over a period of 2 hours under nitrogen. The resulting grey suspension was allowed to warm to room temperature and stirred for 4 days after which HPLC showed no remaining starting material. The reaction mixture was diluted with THF (11), cooled to 0°C and solid sodium sulfate decahydrate was added over a period of 2 hours with rapid agitation. When the effervescence had subsided, the resulting suspension was filtered and the filtrate acidified with gaseous HC1 affording a thick white precipitate which was collected by filtration, washed with THF (2 x 500 ml) and dried to a constant weight to afford Ml (batch 1: 86.8 g; 43percent) (batch 2: 97.3 g ; 49percent) as a white solid. The filter cakes obtained from the first filtration were suspended in 6N NaOH (400 ml) and filtered. The filtrate was extracted with diethyl ether (4 1). The organic layer was acidified with gaseous HC1 affording a thick white precipitate which was collected by filtration, washed with diethyl ether (2 x 500 ml) and dried to a constant weight in a vacuum oven at 40°C to afford M I. HCI (105. 9 g) as a white solid. Yield: 72percentGeneral procedure: N-Benzoyl-7-azabicyclo[2.2.1]heptane (4a). Trans-4-aminocyclohexyl p-toluensulfonate hydrobromide(1 g, 7.5 mmol) was dissolved in ethanol (110 mL) and water (30 mL), and then NaOH 1 M (25 mL)was added. The mixture was stirred at room temperature for 20 h, and then quenched by adding HCl4 M in 1, 4-dioxane (5 mL). Stirring was continued for 20 min at r.t., and the mixture was evaporatedunder reduced pressure. NaOH 10% (10 mL) was added to the residue, and free amide was extractedwith ether (3 x 30 mL). This solution was evaporated, and the residue was redissolved in dry CH2Cl2(30 mL). DIPEA (2 mL, 9.3 mmol) was added to the resulting solution, and the mixture was stirredfor 10 min at 0 C. Then, benzoyl chloride (1.1 mL, 9.1 mmol) was slowly added. Stirring wascontinued for 30 min. The ice bath was removed, and the mixture was allowed to warm to r.t. Stirringwas continued for 4 h, and then the mixture was quenched by pouring it into water. The aqueousand organic layers were separated, and the aqueous phase was extracted with dichloromethane(3 50 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a yellow oil. The crude product was purified byopen column chromatography (CH2Cl2/ethyl acetate 9:1) to afford 4a as a white solid (52.0 mg, 35%).General procedure: N-Benzoyl-7-azabicyclo[2.2.1]heptane (4a). Trans-4-aminocyclohexyl p-toluensulfonate hydrobromide(1 g, 7.5 mmol) was dissolved in ethanol (110 mL) and water (30 mL), and then NaOH 1 M (25 mL)was added. The mixture was stirred at room temperature for 20 h, and then quenched by adding HCl4 M in 1, 4-dioxane (5 mL). Stirring was continued for 20 min at r.t., and the mixture was evaporatedunder reduced pressure. NaOH 10% (10 mL) was added to the residue, and free amide was extractedwith ether (3 x 30 mL). This solution was evaporated, and the residue was redissolved in dry CH2Cl2(30 mL). DIPEA (2 mL, 9.3 mmol) was added to the resulting solution, and the mixture was stirredfor 10 min at 0 C. Then, benzoyl chloride (1.1 mL, 9.1 mmol) was slowly added. Stirring wascontinued for 30 min. The ice bath was removed, and the mixture was allowed to warm to r.t. Stirringwas continued for 4 h, and then the mixture was quenched by pouring it into water. The aqueousand organic layers were separated, and the aqueous phase was extracted with dichloromethane(3 50 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a yellow oil. The crude product was purified byopen column chromatography (CH2Cl2/ethyl acetate 9:1) to afford 4a as a white solid (52.0 mg, 35%).General procedure: N-Benzoyl-7-azabicyclo[2.2.1]heptane (4a). Trans-4-aminocyclohexyl p-toluensulfonate hydrobromide(1 g, 7.5 mmol) was dissolved in ethanol (110 mL) and water (30 mL), and then NaOH 1 M (25 mL)was added. The mixture was stirred at room temperature for 20 h, and then quenched by adding HCl4 M in 1, 4-dioxane (5 mL). Stirring was continued for 20 min at r.t., and the mixture was evaporatedunder reduced pressure. NaOH 10% (10 mL) was added to the residue, and free amide was extractedwith ether (3 x 30 mL). This solution was evaporated, and the residue was redissolved in dry CH2Cl2(30 mL). DIPEA (2 mL, 9.3 mmol) was added to the resulting solution, and the mixture was stirredfor 10 min at 0 C. Then, benzoyl chloride (1.1 mL, 9.1 mmol) was slowly added. Stirring wascontinued for 30 min. The ice bath was removed, and the mixture was allowed to warm to r.t. Stirringwas continued for 4 h, and then the mixture was quenched by pouring it into water. The aqueousand organic layers were separated, and the aqueous phase was extracted with dichloromethane(3 50 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a yellow oil. The crude product was purified byopen column chromatography (CH2Cl2/ethyl acetate 9:1) to afford 4a as a white solid (52.0 mg, 35%).Trans-4-aminocyclohexyl p-toluensulfonate hydrobromide(1 g, 7.5 mmol) was dissolved in ethanol (110 mL) and water (30 mL), and then NaOH 1 M (25 mL)was added. The solution was stirred at room temperature for 20 h, and then quenched by addingconcentrated HCl 4 M (5 mL). Stirring was continued for 20 min at r.t., and then the solution wasevaporated under reduced pressure. NaOH 10% (10 mL) was added to the residue. Free amidewas extracted with ether (3 30 mL), then HCl in 1, 4-dioxane (1 mL) was added, and the mixturewas evaporated. The residue was redissolved in dry CH2Cl2 (30 mL). DIPEA (2 mL, 9.3 mmol) wasadded to the resulting solution, and the mixture was stirred for 10 min at 0 C. Then, p-tolyl benzoylchloride (1.6 mL, 9.1 mmol) was slowly added. Stirring was continued for 30 min. The ice bath wasremoved, and the mixture was allowed to warm to r.t., and further stirred for 4 h, then quenchedby pouring it into water. The aqueous and organic layers were separated, and the aqueous phasewas extracted with dichloromethane (3 30 mL). The combined organic phase was washed withbrine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a yellowoil. The crude product was purified twice by open column chromatography (n-hexane/ethyl acetate (1:1) and dichloromethane/ethyl acetate (9:1)) to afford 4d as a yellow solid. Recrystallization affordedtransparent crystals (238.6 mg, 11%). M.p.: 105-107 C. 1H-NMR (400 MHz, CDCl3), (ppm): 7.449 (d, J = 8 Hz, 2H), 7.188 (d, J = 8Hz, 2H), 4.720 (br. s, 1H), 4.148 (br. s, 1H), 2.377 (s, 3H), 1.899-1.810 (s, 4H), 1.508-1.466 (m, 4H). 13C-NMR (100 MHz, CDCl3), (ppm): 169.03, 140.72, 133.50, 128.96, 127.97, 77.36, 30.60, 28.87, 21.56. ESI-HRMS: Calculated for C14H17NNaO+ [M + Na]+: 238.1202. Found: 238.1217.Anal. Calcd. for C14H17NO2: C, 78.10; H, 7.96; N, 6.51. Found: C, 77.76; H, 7.90; N, 6.58.