June 4, 2013
Make 7-azanorbornane on an industrial scale in four steps. Despite the title of N. B. Ambhaikar and co-inventors’ patent, “Process for preparing azabicyclic compounds”, it only describes a process for preparing 7-azanorbornane (5) and its HCl salt (6). The inventors state that compound 5 is an intermediate in the synthesis of pharmaceutical compounds, but they do not mention any.
The patent’s examples describe the preparation of 5 and its precursors on a kilogram scale. The first step is protecting the amino group in 1 by converting it to tert-butoxycarbonyl (BOC) derivative 2 with the anhydride (BOC)2O in the presence of Na2CO3. The product is isolated in 88.8% yield. The reaction can also be carried out with K2CO3, but the yield is not reported.
In the second step, 2 is treated with methanesulfonyl chloride (MsCl) in the presence of Et3N to form methanesulfonate 3 in 96.6% isolated yield. In step three, the BOC group is removed by adding CF3CO2H in two batches. The product is amine salt 4. The recovered salt contains excess CF3CO2H; and as a result, the yield appears to be >100%.
In the final stage, the CF3CO2H salt is treated with NaOH to cyclize it to the desired compound. Azanorbornane 5 is recovered by fractional distillation; treating the fractions with concd HCl gives hydrochloride salt 6. The salt is recovered as a solid, dried, and recrystallized from MeOH and MeOH–THF. Although the examples contain significant detail, the product’s final yield and purity are not reported.
The process is an efficient method for preparing 7-azanorbornane and its salt. It is clearly suitable for large-scale production. (Vertex Pharmaceuticals [Cambridge, MA]. US Patent 8,404,865, March 26, 2013; Keith Turner)