反应详情

The title compound is obtained by a method analogous to the one described for example 1.23 except tert-butyl 3-(N-methyl-6-((3-methyl-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoate used in the synthesis was resolved by chiral chromatography; Column: Chiralpak AD-H. Dimensions: 10 mm×250 cm. Mobile Phase: 65/35 CO2/methanol. Flow Rate: 10 mL/min. Modifier: none. Retention time: 4.23 min (peak 1), 6.81 min. (peak 2; >99% ee). Peak 2 (1.15 g, 2.02 mmol) was then deprotected under the TFA/DCM previously reported. Concentration of the reaction mixture under reduced pressure provide a crude orange gum. Water (150 mL) added to the gum and NaOH 1M aq. added slowly until reaching pH 11 to obtain a clear solution of the crude. Acidification to pH4 with 1N HCl followed by filtration of the solid formed (washed with plenty of water) provide 3-(N-methyl-6-((3-methyl-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoic acid (915 mg, 88.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.91 (d, 3H) 0.95 (d, J=6.46 Hz, 3H) 1.49-1.59 (m, 1H) 1.61-1.71 (m, 1H) 1.71-1.82 (m, 1H) 2.52-2.55 (m, 2H) 2.92 (s, 3H) 3.53 (t, J=7.24 Hz, 2H) 5.09 (br. s., 1H) 6.56 (d, J=1.17 Hz, 1H) 7.44 (d, J=9.39 Hz, 1H) 7.50 (d, J=8.22 Hz, 2H) 7.54-7.65 (m, 1H) 7.67 (d, J=8.02 Hz, 2H) 7.75-7.82 (m, 2H) 7.83-7.89 (m, 2H) 8.00 (d, J=2.15 Hz, 1H) 12.27 (br. s., 1H); MS (M+1): 514.4.

1. customRetention time: 4.23 min (peak 1), 6.81 min. (peak 2; >99% ee)
2. customConcentration of the reaction mixture under reduced pressure provide a crude orange gum
3. additionaq. added slowly
4. customto obtain a clear solution of the crude
5. filtrationAcidification to pH4 with 1N HCl followed by filtration of the solid
6. customformed
7. wash(washed with plenty of water)