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

Synthesis

The compound (CAS: 188624-92-2, 380 g, 1.51 mol) was dissolved in tetrahydrofuran (THF, 3 L) under nitrogen protection and cooled to 0°C. Lithium aluminum hydride (229.4 g, 6.04 mol) solid pellets were added in batches over a period of 2 hours. The reaction mixture was gradually warmed to room temperature with continuous stirring for 4 days until HPLC analysis showed complete consumption of the feedstock. Upon completion of the reaction, the reaction mixture was diluted with THF (11 L) and re-cooled to 0°C. Under rapid stirring, sodium sulfate decahydrate solid was added slowly over a period of 2 h until gas release ceased. The insoluble material was removed by filtration and the filtrate was acidified with gaseous hydrogen chloride to produce a white precipitate. The precipitate was collected by filtration, washed with THF (2 x 500 mL) and dried to constant weight to give 7-azabicyclo[2,2,1]heptane hydrochloride (M1, batch 1: 86.8 g, 43%; batch 2: 97.3 g, 49%). The filter cake from the first filtration was resuspended in 6 N sodium hydroxide solution (400 mL) and filtered. The filtrate was extracted with ether (4 L) and the organic layer was acidified with gaseous hydrogen chloride, again producing a white precipitate. The precipitate was collected by filtration, washed with ether (2 x 500 mL) and dried in a vacuum oven at 40 °C to constant weight to give finally 7-azabicyclo[2,2,1]heptane hydrochloride (M I.HCl, 105.9 g, 72%).

References

[1] Patent: WO2005/79805, 2005, A1. Location in patent: Page/Page column 61
[2] Tetrahedron, 2009, vol. 65, # 29-30, p. 5805 - 5816
[3] Patent: WO2005/80402, 2005, A1. Location in patent: Page/Page column 65
[4] Organic Letters, 2001, vol. 3, # 9, p. 1371 - 1373