1,4-Dioxane hydrochloride → HCID 86723187, compound

Participants

Reaction Conditions

Reaction Steps

To a 2:3 mixture of tert-butyl (2R,4R)-2-{[benzyl(3-ethoxy-3-oxopropyl)amino]methyl}-4-(benzyloxy)pyrrolidine-1-carboxylate and tert-butyl (2S,4R)-2-{[benzyl(3-ethoxy-3-oxopropyl)amino]methyl}-4-(benzyloxy)pyrrolidine-1-carboxylate (25 g, 0.050 mol, Part B) in methanol (125 mL) was added a solution of 4.0 M HCl/dioxane (125 mL) while maintaining the internal temperature below 5° C. The reaction mixture was allowed to stir at 20-25° C. for 22 hours and was then concentrated. The residue was stirred with toluene (250 mL) and 1 M sodium carbonate solution (250 mL). The organic layer was separated, washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and filtered. The toluene filtrate was heated to reflux at 115° C. for four hours and was then concentrated. The isomers were separated by silica gel column chromatography eluted with ethyl acetate/hexane (60:40) to give (8R,9aR)-2-benzyl-8-(benzyloxy)octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one (6.2 g, 35%) as dark brown oil. HPLC (column: Agilent ZORBAX® RX-C8, 150 mm×4.6 mm, 5 μm; gradient: 10-80% acetonitrile in 0.1% phosphoric acid/water over 13 minutes with a hold at 80% for an additional five minutes; flow rate: 1.0 mL/minute; temperature: 30° C.). Retention time for the titled isomer was 7.147 minutes and for the (8R,9aS) isomer, 6.704 minutes. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.23 (m, 10 H), 4.62-4.47 (m, 2 H), 4.11-3.96 (m, 2 H), 3.83-3.75 (m, 1 H), 3.64-3.56 (m, 3 H), 3.02-2.74 (m, 3 H), 2.61-2.53 (m, 1 H), 2.47-2.36 (m, 3 H), 1.88-1.79 (m, 1 H).

Provenance & Evidence