Reaction Steps
In a 500-mL three-neck round bottom flask was dissolved K2CO3 (37.3 g, 270 mmol, 3.8 eq.) in 120 mL water. (2S)-1-(benzyl{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-3-phenoxy-2-propanol hydrobromide (Example 86, 40 g, 180 mmol, 1.0 eq.) was then added. To the resulting suspension was then added 130 mL isopropanol, p-carbomethoxyphenyl boronic acid (20.5 g, 114 mmol, 1.6 eq.) and 10% Pd/C (3.77 g, 1.78 mmol, 0.025 eq.). The resulting suspension was heated at reflux for 4 hours, cooled to 40° C., and 159 mL ethylacetate was added. This suspension was heated to 50° C. and filtered and washed with 100 mL warm (55° C.) ethylacetate. The filtrate separated to two phases. The aqueous phase was separated, and the organic phase was transferred to a 1-L three-neck round bottom flask, to which was added 300 mL ethyl acetate, 10% Pd-C (7.2 g, 0.89 mmol, 0.05 eq.) and a solution of sodium formate (14.4 g, 211 mmol, 3.0 eq.) in 80 mL water. The resulting suspension was refluxed for 6 hours. Methanesulfonic acid (28 g, 146 mmol, 4.1 eq.) was added to the reaction at a temperature ≧50° C. The resulting suspension was filtered; the organic filtrate was separated and washed with 60 mL water. The organics were distilled to half of the original volume, cooled and methyl 4-[(2R)-2-({[(2S)-2-hydroxy-3-phenoxypropyl]amino}methyl)-3,4-dihydro-2H-Chromen-6-yl]benzoate methanesulfonate filtered and washed with ethylacetate. The dry white crystalline product (15.5 g, 80% yield) was used without further purification. NMR (DMSO-d6) δ1.77 (m, 1H), 2.10 (m 1H), 2.42 (s, 3H, HSO3CH3), 2.90 (m, 2H), 3.12 (dd, J=8, 1.8 Hz, 1H), 3.36 (m, 2H), 3.85) (s, 3H), 4.02 (m, 2H), 4.25 (m, 1H), 4.50 (tt, J=7, 1.5 Hz, 1H), 5.87 (bs, 1H, OH), 6.95 (m, 4H, ArH), 7.33 (t, J=7 Hz, 2H, ArH), 7.52 (m, 2H, ArH), 7.77 (d, J=8 Hz, 2H, ArH), 7.95 (d, J=8 Hz, 2H, ArH); MS (EI): m/z 448 (MH+).
