Reaction Steps
1H NMR (300 MHz, CD3OD) δ 7.60 (d, 1H, J=2.3 Hz); 7.22–7.35 (m, 5H); 6.23 (d, 1H, J=2.4 Hz); 5.31 (s, 2H); 3.86 (dd, 1H, J1=4.7 Hz, J2'7.9 Hz); 3.78 (dd, 1H, J1=J2=6.7 Hz); 3.27–3.30 (m, 1H); 3.17 (dd, 1H, J1=8.1 Hz, J2=15.8 Hz); 1.82–1.91 (m, 1H); 1.68–1.74 (m, 2H); 0.98 (d, 3H, J=4.5 Hz); 0.96 (d, 3H, J=4.5 Hz). Anal. Calc'd. for C19H25N3O4.2/3H2O: % C, 61.44; % H, 7.15; % N, 11.31. Found: % C, 61.00; % H, 6.75; and % N, 11.17. (S,R)-2-[2-(1-benzyl-1H-pyrazol-3-yl)-1-carboxy-ethylamino]-4-methyl pentanoic acid: 1H NMR (300 MHz, CD3OD) δ 7.64 (d, 1H, J=2.4 Hz); 7.22–7.37 (m, 5H); 6.23 (d, 1H, J=2.3 Hz); 5.31 (s, 2H); 3.96–4.00 (m, 1H); 3.77–3.82 (m, 1H); 3.28–3.30 (m, 2H); 1.55–1.80 (m, 3H); 0.86 (d, 3H, J=6.6 Hz); 0.84 (d, 3H, J=6.4 Hz). 52-6a: (R=3,5-diCl-PhCH2) (S,S)-2-{1-carboxy-2-[1-(3,5-dichlorobenzyl)-1H-pyrazol-3-yl]-ethylamino}-4-methyl pentanoic acid. Crude pyrazole 3-carboxylic acid was treated with 3,5-dichlorobenzyl bromide in a manner analogous to the treatment of pyrazole 3-carboxylic acid with benzyl bromide. The same procedures were used to carry the material through to 2-[1-(3,5-dichlorobenzyl)-1H-pyrazol-3ylmethyl]-5-isopropyl-3,6-dimethyoxy-2,5-dihydropyrazine, which was isolated as a single isomer. Hydrolysis with HCl, preparation of the methyl ester, and alkylation of the amine proceeded as described above. 2-{2-[1-[1-(3,5-dichlorobenzyl)-1H-pyrazol-3-yl]-1-methoxycarbonyl-ethylamino}-4-methyl pentanoic acid benzyl ester was treated with NaOH as described above. Purification of the resulting diacid was accomplished by column chromatography (ISCO purification system, C-18 bondisil, H2O to MeOH over 30 min) to give a white powder. This material was dissolved in 1N NaOH solution (aqueous) and then treated with 1 N HCl (aqueous) until pH of 1 was obtained. The resulting precipitate was isolated by filtration to give a white solid (Compound LP). 1H NMR (300 MHz, CD3OD) δ 7.71 (d, 1H, J=2.0 Hz); 7.37 (s, 1H); 7.21 (s, 2H); 6.28 (d, 2H, J=2.4 Hz); 5.30 (s, 2H); 4.05 (dd, 1H, J1=4.9 Hz, J2=7.7 Hz); 3.93 (dd, 1H, J1=J2=6.9 Hz); 3.34 (dd, 1H, J1=4.5 Hz, J2=15.9 Hz); 3.21 (dd, 1H, J1=7.7 Hz, J2=15.9 Hz); 1.85–1.70 (m, 3H); 0.99 (d, 3H, J=2.8 Hz); 0.97 (d, 3H, J=2.4 Hz). Anal. Calc'd for C19H23Cl2N3O4.H2O: % C, 51.13; % H, 5.65; % Cl, 15.89; % N, 9.41. Found: % C, 51.41; % H, 5.24; % Cl, 16.24; and % N, 9.42.
