Acetonitrile → 6-Methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

Participants

Reaction Conditions

Reaction Steps

Dissolve 2,3-bis-(2-methanesulfonyloxyethyl)-1-methoxybenzene (474.4 g, 1.346 mol) in acetonitrile (7 L) and split the mixture into two equal lots. In two separate runs, add concentrated ammonium hydroxide (3.5 L) and charge the solution into a pressure vessel (PARR apparatus). Heat the solution in a closed reactor to 100° C. over 20 min (internal pressure reaches about 100 psi), and maintain at 100° C. until the reaction is complete (about 1 h, HPLC monitored). Cool the reaction mixture to RT. Combine the two lots and concentrate. Dissolve the residue in MTBE (3.5 L) and water (3.5 L). Adjust the pH to 6.5 using 2 N NaOH or 1 N HCl as appropriate (typically the pH is about pH=5.1 and the adjustment requires about 50 mL 2 N NaOH). Discard the organic layer, adjust the aqueous layer to pH=13 using 50% NaOH (˜150 mL). Extract with MTBE (2×3.5 L), wash the combined organic layers with brine (3.5 L), dry (sodium sulfate) and concentrate to give the title compound as a crude yellow oil that solidifies upon standing (179.3 g). Use the material for the next step without further purification. Prepare an analytical sample by purification by two Kugelrohr distillations to give a clear oil that solidifies upon standing.

Provenance & Evidence