Reaction Steps
To a biphasic solution of 7-[[4-cyanophenyl]methoxy]-4-propanoic acid, 3,4-dihydro-1H-1,4-benzodiazepine-2-thione-5-one, ethyl ester (1 gram, 2.36 mmol), methylene chloride (10 mL), water (10 mL), methyl iodide (0.2 mL) and a catalytic amount of tetrabutyl ammonium hydrogen sulphate at room temperature with vigorous stirring was added 1.2 mL of a 2N solution of sodium hydroxide. After 16 hours (overnight) the layers were seperated, the aqueous layer was washed 2×60 mL methylene chloride, and the combined organics were dried over sodium sulfate, decanted, and concentrated in vacuo. The resulting residue, 7-[[4-cyanophenyl]methoxy]-4-propanoic acid, 3,4-dihydro-1,4-benzodiazepine-2-methylmercaptyl-5-one, ethyl ester (1H NMR (CDCl3, δTMS) 7.70 (2H, d, 3JHH =8 Hz, 3,5H:4-NCC6H4), 7.56 (2H, 3JHH =8 Hz, 2,6H:4-NCC6H4), 7.49 (1H, d, 4JHH =3 Hz, C6 ArH), 7.18 (1H, d, 3JHH =9 Hz, C9 ArH), 7.15 (1H, dd, 4JHH =3 Hz, 3JHH =9 Hz, C8 ArH), 5.18 (2H, s, OCH2Ar), 4.16 (2H, q, 3JHH =7 Hz, OCH2), 3.94 (2H, t, 3JHH =7 Hz, NCH2), 3.91 (2H, s, C(S)CH2), 2.78 (2H, t, 3JHH =7 Hz, CH2CO2), 2.52 (3H, s, SMe), 1.24 (3H, t, 3JHH =7 Hz, CH2CH3); MS (FAB) cald. for C23H23N3 O4S 437.1, found MH+ 438.1), was dissolved in dry toluene (15 mL) and allowed to react with 0.23 grams pyridinium hydrogen chloride and 0.64 mL propargyl amine. The reaction was heated to reflux. After 5 hours, the reaction was allowed to cool to room temperature and the reaction concentrated in vacuo. The crude material was purified by column chromatography (SiO2, using ethyl acetate as the eluting solvent, Rf =0.1) to yield 4H-imidazo[1,2-a][1,4]benzodiazepine-5(6H)-propanoic acid, 8-[[4-cyanophenyl]methoxy]-1-methyl-6-oxo, ethyl ester (0.23 grams, 22%). 1H NMR (CDCl3, δTMS) 7.71 (2H, d, 3JHH =8 Hz, 3,5H:4-NCC6H4), 7.56 (2H, 3JHH =8 Hz, 2,6H:4-NCC6H4), 7.53 (1H, d, 4JHH =3 Hz, C6 ArH), 7.24 (1H, d, 3JHH =9 Hz, C9 ArH), 7.18 (1H, dd, 4JHH =3 Hz, 3JHH =9 Hz, C8 ArH), 5.21 (2H, dd, OCH2Ar), 4.52 (1H, d, 2JHH =16 Hz, C5H), 4.30 (1H, d, 2JHH =16 Hz, C5H), 4.16 (2H, q, 3JHH =7 Hz, OCH2), 3.89 (2H, m, NCH2), 2.66 (2H, m, CH2CO2), 2.29 (3H, s, C1-Me), 1.22 (3H, t, 3JHH =7 Hz, CH2CH3).
