1-Oxo Mirtazapine (Mirtazapine Impurity C) synthesis

Yield:191546-96-0 13%

Reaction Conditions:

with potassium carbonate;potassium iodide in N,N-dimethyl-formamide for 3 h;Heating / reflux;

Steps:

13
3,4,10,14b-tetrahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c][2]benzazepin-1(2H)-one; A mixture of crude 10,11-hydro-5H-benzo[e]pyrido[2,3-b]azepine-10-N-(2-chloroethyl)-carboxamide (2.4 g, 7.46 mmol), K₂CO₃ (3.5 g, 25.4 mmol) and Kl (2.7 g, 16.3 mmol) in DMF (100 ml) was heated to reflux while stirring. After 3 hours the heating was stopped and the mixture was stirred overnight while cooling to room temperature. The mixture was evaporated under vacuum at 85° C. Water (50 ml) was added and the mixture was extracted with a mixture of dichloromethane/methanol (95:5, 100 ml). The organic extract was concentrated under vacuum. The obtained brown oil was dissolved in acetone (10 ml). Upon addition of t-butyl methyl ether (50 ml) a beige precipitate was formed which was filtered over a glass filter under suction. Drying under vacuum gave 0.28 g of the title compound (13% yield) as a white solid. The remaining filtrate was evaporated under vacuum and the residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol=9.1 (R_f=0.1) to give another crop of the title compound as a white solid.Mass analysis: M⁺¹=280.¹H-NMR (CDCl₃) δ (ppm) 3.19 3H, s, N-CH₃; 3:30-3.44 2H, m; 3.49 1H, d, J=16.2 Hz, CHH; 3.71 1H, m; 4.42 1H, m; 4.83 1H, d, J=16.2 Hz, CHH; 5.90 1H, s; 6.63 μl, dd, J=5.1 and 7.5 Hz, ArH; 7.09 1H, m, ArH; 7.23 3H, m, ArH; 7.33 1H, d, J=6.9 Hz, ArH; 8.0 1H, dd, J=0.9 and 5.1 Hz, ArH.

References:

N.V. Organon US2008/255349, 2008, A1 Location in patent:Page/Page column 9

FullText