82586-55-8

82586-54-7

82586-55-8

The general procedure for the synthesis of (S)-2-((S)-2-(((S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino)propanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride from quinapril benzyl ester maleate was as follows: 1.73 g (3.29 mmol) of quinapril benzyl ester obtained in Example 6 (IlIc, R = Bn) was dissolved in 40 ml of ethyl acetate and about 1 ml of dry HCl was added.The hydrogenation reaction was carried out at 15-20 °C and atmospheric pressure (using a hydrogen balloon) with the addition of 5% Pd/C catalyst (about 100 mg). The progress of the reaction was monitored by LC-MS and after complete consumption of the feedstock, the catalyst was removed by filtration and the filtrate was concentrated. Grinding with methyl tert-butyl ether (MTBE) afforded the target product (S)-2-((S)-2-(((S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl)amino)propanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride as a colorless powder in the yield of 1.40 g (90% yield) with a purity of >98% by LC-MS (MH+ 439).1H NMR (showing two rotary isomers) data were as follows: δ 1.18, 1.25 (2t, 3H, OCH2CH3), 1.52 (2d, 3H, CH3), 2.08-2.30 (m, 2H, PhCH2CH2), 2.62, 2.78 (2m, 2H, PhCH2), 3.10-3.35 (m, 2H , H-4), 3.80, 3.93 (2m, 1H, NCHC=O), 4.14, 4.21 (2m, 2H, OCH2), 4.45-4.90 (3m, 3H, Hi, H-i', H-3), 5.15 (m, 1H, NHCHCH3), 7.15-7.35 (m, 9H, ArH), 9.80 (wide m, 2H , NH2), 12.80 (wide m, 1H, COOH). Quinapril hydrochloride can be further purified by ethyl acetate/toluene mixed solvent crystallization as described by S. Klutchko et al. (J. Med. Chem. 1986, 29, 1953-1961).