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3.4. (−)-(30S)-4-(30-Amino-20-oxopyrrolidin-10 -yl)-benzonitrile (R)-mandelic acid salt (S)-4
(R)-Mandelic acid (0.23 g, 1.5 mmol), water (0.39 g) and salicylaldehyde (0.06 g, 0.42 mmol) were
added to a slurry of rac-4 (3.0 g, 8.49 mmol) in IPA (12.0 mL). The slurry was heated to reflux, stirred
for 24 h and monitored by chiral HPLC. The slurry was cooled to 22°C and filtered. The solids were
washed with IPA (3.5 mL) and dried to afford 2.34 g of (S)-4 as a white powder (78% yield, 98.7%.
(S)-Configuration determined by chiral HPLC (see below for chiral method). [α]36525=−66.2 (c=1.01,
DMSO). Mp: 177°C. IR (cm−1) ν 2222, 1730. 1H NMR (400 MHz, d6-DMSO): δ 1.87 (1H, dq, J=12.2,
9.8 Hz), 2.41 (1H, dddd, J=12.2, 8.4, 6.7, 1.7 Hz), 3.76 (1H, td, J=10.6, 8.4 Hz), 3.83 (1H, td, J=9.4, 1.7
Hz), 4.81 (1H, s), 7.22 (1H, tt, J=7.2, 1.6 Hz), 7.28 (2H, complex t, J≈7.3 Hz), 7.38 (2H, complex d,
J≈7.5 Hz), 7.86 (2H, complex d, J≈9.1 Hz), 7.91 (2H, complex d, J≈9.1 Hz). 13C NMR (500 MHz, d6-
DMSO): δ 25.24, 44.44, 52.41, 72.97, 106.01, 118.80, 119.06, 126.40, 126.70, 127.63, 133.11, 142.09,
142.98, 173.26, 174.65. Anal. calcd for C19H19N3O4: C, 64.58; H, 5.42; N, 11.89. Found: C, 64.42; H,
5.44; N, 11.92.
3.5. (−)-(30S)-4-(30-Amino-20-oxopyrrolidin-10 -yl)-benzonitrile hydrochloride salt 1
To a slurry of (S)-4 (200.0 g, 0.57 mol) in ethyl acetate (1.2 L) was added conc. HCl (70.7 mL, 0.85
mol). The mixture was heated to 50°C and stirred for 1 h. The slurry was cooled to 24°C and filtered. The
solid was washed with ethyl acetate (1×200 mL) and dried in a vacuum oven at 60°C to afford 131.2 g
(97.5% yield) of 1 as a white powder, 98.0% (S)-enantiomer as determined by chiral HPLC (CrownPak
(−) column (15 cm×4.6 mm), 35°C, isocratic, mobile phase: 5% MeOH/95% 7% aq. HClO4, λ=280 nm).
Purity 99.9% by achiral HPLC [Synchropak SCD-100 column (25 cm×4.6 mm), gradient mobile phase:
A=0.05% trifluoroacetic acid in water and B=0.05% trifluoroacetic acid in acetonitrile; gradient table;
0–0.2 min 95%A/5%B, 30 min. 33%A/67%B, 30.5 min. 95%A/5%B]. [α]36525=−66.2 (c=1.05, H2O).
Mp: 272°C. IR (cm−1) ν 2226, 1708. 1H NMR (400 MHz, d6-DMSO): δ 2.15 (1H, ddt, J=12.0, 10.8, 9.7
Hz), 2.54 (1H, dddd, J=12.0, 8.8, 6.8, 1.0 Hz), 3.87 (1H, td, J=9.7, 6.8 Hz), 3.97 (1H, td, J=9.7, 1.0 Hz),
4.27 (1H, dd, J=10.8, 8.8 Hz), 7.91 (4H, s), 8.73 (3H, br s). 13C NMR (500 MHz, d6-DMSO): δ 23.17,
44.82, 51.13, 106.52, 118.67, 119.31, 133.22, 142.49, 169.97. Anal. calcd for C11H12ClN3O·0.25H2O:
C, 54.50; H, 4.95; Cl, 14.45; N, 17.34. Found: C, 54.67; H, 5.15; Cl, 14.51; N, 17.37.
Acknowledgements
The authors thanks Richard P. Frost, Jennifer M. Hayes, Daniel L. Sweeney, Patricia M. Finnegan and
the physical methodology department for their analytical support.
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