Reaction Steps
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852; 2.51 g, 6.86 mmol), (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (For the preparation of β-amino acid intermediates see Examples 2f-1 described below) (2 g, 6.86 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.74 g, 7.2 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (18 mL). N-Methylmorpholine (3 mL, 27.44 mmol) was added and the mixture was stirred at 25° C. for 2 h. Triethylamine (3.82 mL, 27.44 mmol) was added and the mixture stirred at 60° C. for 16 h. Upon cooling, the mixture was slowly added to a 1.0 M aqueous hydrochloric acid solution (200 mL) while stirring. The product precipitated immediately. Stirring was continued for 5 min. The solid was collected by vacuum filtration, rinsed with water (2×60 mL) and dried in vacuo for 16 h to afford the desired product, (1S,2R,3S,4R)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (1.94 g, 3.27 mmol, 48%), as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.20-1.23 (1H, m), 1.38-1.61 (5H, m), 2.50-2.53 (1H, m), 2.62 (1H, d, J=3.2 Hz), 2.98 (1H, d, J=9.3 Hz), 3.52 (1H, d, J=9.4 Hz), 4.40 (1H, d, J=15.7 Hz), 4.95 (1H, d, J=14.9 Hz), 7.12-7.16 (2H, m), 7.30-7.34 (3H, m), 7.97 (1H, dd, J1=8.6 Hz, J2=1.4 Hz), 8.07 (1H, d, J=1.7 Hz).
