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 (0.75 grams, 1.77 mmol), prepared as described in part (c) of Example 3, methylene chloride (20 mL), water (20 mL), 0.2 mL methyl iodide, and a catalytic amount of tetrabutyl ammonium hydrogen sulfate was added 1.2 mL 2N sodium hydroxide. After 16 hrs, overnight, of vigorous stirring the layers were seperated. The aqueous layer was washed 3×30 mL methylene chloride and the combined organics were dried over sodium sulfate, decanted, and concentrated in vacuo. the resulting residue was dissolved in toluene (15 mL) and allowed to react with 0.23 grams (2.0 mmol) pyridinium hydrogen chloride and 0.64 grams (8.6 mmol) acetic hydrazide and the reaction was heated to reflux. After 5 hours, the reaction was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, using 5:95 methanol:methylene chloride as the eluting solvent) to yield 0.5 grams (63%) of 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-5(6H)-propanoic acid, 8-[[4-cyanophenyl]methoxy]-1-methyl-6-oxo, ethyl ester. 1H NMR (CDCl3, δTMS) 7.59 (2H, d, 3JHH =8 Hz, 3,5H:4-NCC6H4), 7.46 (2H, 3JHH =8 Hz, 2,6H:4-NCC6H4), 7.45 (1H, d, 4JHH =3 Hz, C6 ArH), 7.17 (1H, d, 3JHH =9 Hz, C9 ArH), 7.12 (1H, dd, 4JHH =3 Hz, 3JHH =9 Hz, C8 ArH), 5.12 (2H, dd, OCH2Ar), 4.61 (1H, d, 2JHH =16 Hz, C5H), 4.25 (1H, d, 2JHH =16 Hz, C5H), 4.01 (2H, q, 3JHH =7 Hz, OCH2), 3.77 (2H, m, NCH2), 2.57 (2H, m, CH2CO2), 2.46 (3H, s, C1-Me), 1.13 (3H, t, 3JHH =7 Hz, CH2CH3); 13C NMR (CDCl3) 171.1, 165.9, 157.6, 152.4, 150.5, 141.0, 132.4, 131.2, 127.5, 124.1, 119.4, 118.3, 116.8, 111.9, 69.3, 60.6, 45.2, 43.3, 32.4, 14.0, 12.1.
