4-Methylmorpholine → (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

Participants

Reaction Steps

The stereoisomer of 2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoic acid designated as 8A1-isomerA (crude product from above), (1S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-1-carboxylate (9) (1 eq), N-methylmorpholine (0.106 mL, 2.5 eq) and O-(7-azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (101 mgm, 1 eq) in a mixture of N,N-dimethylformamide (1.2 mL) and tetrahydrofuran (0.2 mL) was stirred at room temperature for 18 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 crude product, which was purified by silica gel column chromatography. Elution with a solvent gradient from hexane to 20% ethyl acetate/hexane gave pure (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.

Provenance & Evidence