Pyridine → 4-(3-Methyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane

A solution of 4-(α-bromoacetyl)-l-azabicyclo[2.2.1] heptane hydrobromide (EP-0366304, Description 19) (3.0 g, 10.0mmol) in dry dimethylsulphoxide (50 ml) was stirred overnight at room temperature. The reaction was concentrated in vacuo ensuring that the water bath temperature did not exceed 60° C. Co-distillation with successive portions of toluene was used to remove residual dimethylsulphoxide. The residue was placed in an oil bath at 120° C. for 5 min. A stream of nitrogen was passed through the reaction vessel during this period, and the dimethylsulphide which was generated was trapped in a solution of sodium hypochlorite. The resulting crude 2-oxo-2-(1-azabicyclo[2.2.1]hept-4-yl) ethanal hydrobromide was immediately treated with a solution of acetamidrazone hydrochloride (1.1 g, 10.0 mmol) in dry methanol (30 ml) containing pyridine (0.8 ml, 10.0 mmol). The mixture was stirred overnight at room temperature and then heated under reflux for 1 h. The reaction was concentrated in vacuo, and the residue was treated at ice temperature with a saturated solution of potassium carbonate (25 ml). After extraction with chloroform (3×25 ml) the combined organic layers were dried over sodium sulphate and concentrated in vacuo. The resulting crude product was purified on a neutral alumina column using 1% ethanol in chloroform as eluant to give the title compound (E3) as an oil (0.63 g, 33%) which was converted into the hydrochloride salt m.p. 222° C. (dec) (from methanol-ether) . Hydrochloride salt:

1. concentrationThe reaction was concentrated in vacuo
2. customdid not exceed 60° C
3. distillationCo-distillation with successive portions of toluene
4. customto remove residual dimethylsulphoxide
5. waitA stream of nitrogen was passed through the reaction vessel during this period
6. temperatureheated
7. temperatureunder reflux for 1 h
8. concentrationThe reaction was concentrated in vacuo
9. additionthe residue was treated at ice temperature with a saturated solution of potassium carbonate (25 ml)
10. extractionAfter extraction with chloroform (3×25 ml) the combined organic layers
11. dry with materialwere dried over sodium sulphate
12. concentrationconcentrated in vacuo
13. customThe resulting crude product was purified on a neutral alumina column

ORD-Eintrag

ord-2aa012c751494793b2521c51fbdd4a3a

Quelldatensatz

uspto-grants-1994_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US05324724