Hydrochloric Acid → HCID 131725819, compound

Temperature

-15 °C

A modification of a known procedure was followed (Kim et al., J. Org. Chem. 1985 50, 560–565). To a RT stirred solution of acid 6 (11.3 g, 34.6 mmol) in THF (100 mL) was added NMM (3.50 g, 34.6 mmol) and the reaction mixture was cooled to −15° C. (NaCl/ice/water bath). To the cooled reaction mixture was added a solution of benzyl chloroformate (6.17 g, 36.1 mmol) in THF (5 mL). After stirring at −15° C. for 2 min, the reaction mixture was warmed to 0° C. (ice/water bath) and stirred for 15 min. To the reaction mixture was added DMAP (1.05 g, 8.65 mmol) and reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was then treated with EtOAc (100 mL), water (100 mL), and carefully acidified with an aqueous solution of HCl (1 M). The organic layer was separated and washed with an aqueous solution of HCl (0.1 M, 2×50 mL). The combined aqueous layers were then extracted with EtOAc (2×100 mL). The combined organic layers were washed with an aqueous solution of NaHCO3 (5% w/v, 4×50 mL), brine (100 mL), and dried over magnesium sulfate. Removal of the solvent in vacuo gave the desired product 8 as a white amorphous solid (14.2 g, 33.9 mmol, 98% yield): mp 72–73.5° C.; Rf=0.58 (3:7 EtOAc/hexane); 1H NMR (300 MHz, D6-DMSO) δ 9.39 (t, 1 H, J=5.1 Hz), 7.32–7.37 (m, 5 H), 5.04–5.16 (m, 2 H, rotamers), 3.94–4.06 (m, 1 H), 3.12–3.18 (m, 2 H), 1.45–1.70 (m, 4 H), 1.36 (s, 9 H) ppm; 13C NMR (75 MHz, D6-DMSO) δ 172.4, 156.2 (q, J=35 Hz), 155.6, 136.0, 128.4, 128.0, 127.7, 116.0 (q, J=286 Hz), 78.3, 65.8, 53.4, 28.2, 27.8, 25.0 ppm (CH2—NHCOCF3 peaks obscured by residual D6-DMSO); IR (thin film) 3333, 1709 cm−1; HRMS calculated (M+2H−Boc, C14H18F3N2O3) 319.1270. found 319.1215.

1. customTo the cooled reaction mixture
2. stirringstirred for 15 min
3. additionTo the reaction mixture was added
4. temperatureto warm to RT
5. stirringstirred for 2 h
6. customThe organic layer was separated
7. washwashed with an aqueous solution of HCl (0.1 M, 2×50 mL)
8. extractionThe combined aqueous layers were then extracted with EtOAc (2×100 mL)
9. washThe combined organic layers were washed with an aqueous solution of NaHCO3 (5% w/v, 4×50 mL), brine (100 mL)
10. dry with materialdried over magnesium sulfate
11. customRemoval of the solvent in vacuo

ORD record

ord-2a472cc269ff4530ab2a675fc7f23163

Source dataset

uspto-grants-2006_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07067698B2