4-Methylmorpholine → (1S,3aR,6aS)-2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

Participants

Reaction Steps

The stereoisomer of (1S,3aR,6aS)-ethyl 2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylate, designated as 10A1-isomer-A (85 mg) was dissolved in ethanol (3 mL) and treated with 2N aqueous sodium hydroxide solution (0.665 mL) at 65° C. for 2 hours. The reaction mixture was then diluted with ethyl acetate and washed successively with 1N hydrochloric acid, water, brine and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave the crude acid, designated as 11A1-isomer A, an isomer of (1S,3aR,6aS)-2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid. The crude compound of formula 11A1-isomer A was mixed with N-methylmorpholine (0.078 mL, 5 eq), 1-hydroxybenzotriazole (38.6 mgm, 2 eq), 1-ethyl-3-(3′-dimethylaminopropyl)carbodimide (55 mgm, 2 eq), and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (12) (123 mgm, 4 eq) and dissolved in a mixture of tetrahydrofuran and dichloromethane, and stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate, washed successively with 1N hydrochloric acid, water, brine and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude product (13A1-isomer A), an isomer of (1S,3aR,6aS)-2-(2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide.

Provenance & Evidence