Triethylamine → 1-Benzoyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester

Participants

Reaction Steps

A stirred solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (5.1 g) in anhydrous tetrahydrofuran (140 ml), at 23° C. and under an atmosphere of argon, was treated with benzotriazol-lyloxytris(dimethylamino)phosphonium hexafluorophosphate (8.61 g). After stirring for 1 hour the mixture was treated with 1-benzoyl-4-(4-amino-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (5.48 g, Reference Example 8) then with triethylamine (9.1 ml), dimethylaminopyridine (0.2 g) and dimethylformamide (5 ml). The resulting mixture was stirred at 23° C. for 2 days then evaporated (40° C. and 2.7 kPa). The residue was treated with ethyl acetate (300 ml) and the resulting solution was washed twice with water (200 ml), twice with hydrochloric acid (200 ml, 1N), then twice with aqueous sodium bicarbonate solution (200 ml, 10%), then with brine (100 ml), then with water (100 ml), then dried over magnesium sulphate and then evaporated (40° C. and 2.7 kPa). The resulting white meringue was triturated with diethyl ether (50 ml) for 20 hours affording the title compound (9.6 g) as a white powder, m.p. 130° C. 1H-NMR [500 MHz, (CD3)2SO at 383° K.]: δ 1.15 (t, J=7 Hz, 3H); 2.30 (s, 3H); 3.33 (m, 1H); 3.50 to 3.70 (m, 2H); 3.62 (s, 2H); 3.77 (m, 1H); 3.85 to 4.00 (m, 2H); 3.91 (s, 3H); 4.10 (q, J=7 Hz, 2H); 6.89 (bd, J=8 Hz, 1H); 6.95 to 7.05 (m, 1H); 7.04 (d, J=2 Hz, 1H); 7.15 (t, J=8 Hz, 1H); 7.20 (d, J=7.5 Hz, 1H); 7.25 (d, J=8 Hz, 2H); 7.45 (m, 3H); 7.54 (m, 4H); 7.69 (d, J=8 Hz, 1H); 8.01 (d, J=8 Hz, 1H); 8.16 (s, 1H); 8.22 (s, 1H); 9.56 (s, 1H). MS [DCI (reactant gas, ammonia)]: 635[M+H]+.

Provenance & Evidence