Reaction Steps
A solution of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (0.974 g, 2.57 mmol), 4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidineacetic acid (1.20 g, 2.57 mmol), and N,N-diisopropylethylamine (1.8 mL, 10.3 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 5 min. To this mixture, 1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenamine bis-hydrochloride 4 (0.80 g, 2.34 mmol) was added and stirring was continued for 18 h. The solution was heated to 100° C. for 1 h. The solution was cooled and poured into a saturated solution of aqueous sodium bicarbonate. A fine green precipitate was collected by filtration, and the solid was purified by reverse phase C18 HPLC eluted with a gradient of water/acetonitrile/trifluoroacetic acid 10/90/0.1 to 90/10/0.1. The cis product 19 was isolated as a colorless solid (0.386 g 22%): 1H NMR (DMSO-d6) δ 1.76 (m, 4 H), 2.72-3.02 (m, 4 H), 3.16 (d, 2 H), 3.29-3.46 (m, 3 H), 3.54-3.75 (m, 2 H) superimposed on 3.72 (s, 3 H), 3.92-4.07 (m, 3 H), 4.53-4.65 (m, 1 H), 6.63 (d, 1 H), 6.70-6.77 (m, 2 H), 7.04 (br s, 3 H), 7.59 (br s, 1 H), 7.99 (t, 1 H), 8.37 (d, 1 H), 8.74 (m, 2 H), 8.96 (d, 1 H), 10.5-10.71 (br s, 1 H), and 11.03 (s, 1 H); MS m/e 512 (MH+). A mixture of cis/trans isomers ˜8/2 0.490 g (28%) was also obtained as well as the purified trans isomer 20 as a colorless solid (0.136 g, 8%): 1 HNMR (DMSO-d6) δ 1.70 (m, 6 H), 2.63-3.81 (m, 9 H) superimposed on 3.72 (s, 3 H), 3.83-4.00 (m, 3 H), 4.47-4.60 m, 1 H), 6.67-6.82 (m, 3 H), 7.02 (br s, 3 H), 7.21 (d, 1 H), 7.70 (t, 1 H), 8.14 (d, 1 H), 8.50-8.73 (m, 3 H), 9.70-10.10 (brs, 1 H), and 11.0 (s, 1 H);); MS m/e 512 (MH+) (Scheme 33).
