Dimethylformamide → LY-2452473

Participants

Reaction Conditions

Reaction Steps

Equip a 2 L reaction flask with a cooling bath, air stirrer, temperature probe, and addition funnel Charge the flask with (S)-2-amino-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile hydrochloride (62.8 g, 0.218 moles), DMF (188 mL), and triethylamine (33.4 mL, 0.240 mol). Cool the resulting solution to 0° C. using an ice/acetone bath. While maintaining the temp at <10° C., add isopropyl chloroformate (218 mL, 0.218 mol, 1 M in toluene) drop-wise via an addition funnel. When the addition is complete, remove the cooling bath was removed and allow the mixture to warm to ambient temperature. After 1 hour, analyze by HPLC to indicate the reaction is complete, and pour the mixture into a solution of deionized water (1256 mL) and EtOAc (1884 mL). Separate the layers, filter the organic layer, and re-wash with a 1:1 water:brine solution, then dry over Na2SO4. Concentrate in vacuo at 55° C. to about 15 volumes, and allow the resulting to cool to ambient temperature, affording a white precipitate. Add heptane (628 mL) and stir for 20 min. Concentrate the mixture back to about 15 volumes. Filter the solids, wash with heptane, and dry to give the titled compound as a fluffy white solid (68.9 g, 84.5%). 1H NMR (500 MHz, DMSO-d6), δ 8.49 (dd, 1H), 7.86 (d, 1H, J=1.5), 7.71-7.75 (m, 1H), 7.60 (d, 1H, J=9.0), 7.57 (d, 1H, J=9.0), 7.36 (dd, 1H), 7.28-7.26 (m, 1H), 7.14 (d, 1H, J=7.5), 5.44 (s, 2H), 4.79-4.72 (m, 1H), 4.71-4.66 (m, 1H), 3.22-3.20 (m, 1H), 3.16-3.12 (m, 1H), 2.73-2.66 (m, 2H), 1.16 (dd, 6H).

Provenance & Evidence