Triethylamine → (2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide

Participants

Reaction Steps

(1R)-2-Amino-1-(3-pyridinyl)ethanol dihydrochloride (U.S. Pat. No. 6,051,586) (5.73 g, 27.1 mmol), 1-hydroxybenzotriazole (6.67 g, 49.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcabodiimide hydrochloride (9.46 g, 49.3 mmol), and triethylamine (13.8 mL, 9.98 g, 98.7 mmol) were added successively to a stirred solution of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method A, 7.50 g, 24.7 mmol) in dichloromethane (100 mL). The reaction was stirred for 18 hours and then diluted with dichloromethane (300 mL). The solution was washed with saturated aqueous sodium bicarbonate (300 mL) and then the aqueous layer was back-extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 5-10% methanol/ethyl acetate gave the product (7.80 g, 74%) as a white solid: 1H NMR (acetone-d6, δ): 8.55 (d, J=1.6 Hz, 1 H), 8.44 (dd, J=4.7, 1.6 Hz, 1 H), 7.71 (ddd, J=7.9, 1.8, 1.8 Hz, 1 H), 7.59 (s, 1 H), 7.35-7.42 (m, 2 H), 7.27 (dd, J=7.9, 4.7 Hz, 1 H), 6.63 (d, 9.6 Hz, 1 H), 4.98 (d, J=4.2 Hz, 1 H), 4.85-4.93 (m, 1 H), 4.53 (dd, J=8.8, 3.4 Hz, 1 H), 3.38-3.70 (m, 2 H), 2.61-2.91 (m, 4 H), 2.16-2.28 (m, 2 H), 1.85-1.99 (m, 1 H); mass spectroscopy gave m/z=425.1 [M+H]+.

Provenance & Evidence