Diisopropylethylamine → HCID 25164123, compound

Participants

Reaction Conditions

Reaction Steps

The (S)-2-amino-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-azepin-3-yl)-propionamide (406 g, 1.423 mol) is combined with dichloromethane (3 L) and the solution cooled to 0-2° C. To this solution is added (S)-2-hydroxy-3-methyl-butyric acid (168.1 g, 1.423 mol), hydroxybenzotriazole hydrate (239.7 g, 1.565 mol) and diisopropylethylamine (310 mL, 1.779 mol) which provides a slight exotherm. The contents are cooled back to about 4° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (286.5 g, 1.494 mol) is added. The reaction contents are allowed to gradually warm to room temperature. High-performance liquid chromatography analysis at 4.5 hours (temperature at 14° C.) indicates about 5% unreacted starting amine present. After stirring an additional 1-1.5 hour, the reaction contents are quenched into water (1000 mL) and the layers are separated. The dichloromethane layer is further extracted with water (1000 mL), 0.1 N HCl (1000 mL), saturated sodium bicarbonate (1000 mL) and finally saturated aqueous sodium chloride. The dichloromethane layer is then dried over magnesium sulfate, filtered and concentrated via rotary evaporation to provide the crude diastereomeric mixture (505 g) of the coupled product as tan foam. The isomers are separated by chiral chromatography employing a Chiralpak® AD column eluting with 100% methanol. Upon removal of the elution solvent from the isomer fractions, approximately 210 g of the first eluting isomer is recovered as a tan foam and for the desired isomer 2, approximately 220 g (44%) is recovered, also as a tan powder. The second eluting isomer is the desired (S,S,S)-diastereomer. Approximately 140 g of the title compound is taken up in acetone (1000 mL) and water (95 mL). The solution is heated on the rotary evaporator until no suspended particles are observed. The solution is transferred to a flask, equipped with overhead stirring, and water (2750 mL) is gradually added over 15 minutes. The resulting slurry is allowed to cool to room temperature, then filtered and the cake is rinsed with 20% acetone/water solution (650 mL). After vacuum drying at 40° C. overnight, approximately 102 g of the title example is recovered.

Provenance & Evidence