1-Hydroxybenzotriazole → Tert-butyl(2S,5R)-2-{4-[(3-cyclopropyl-1-oxo-2-oxa-8-azaspiro[4.5]dec-8-yl)carbonyl]-benzyl}-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate

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Reaction Steps

To a solution of 0.16 g (0.39 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 2 ml anhydrous DMF at ambient temperature was added 0.14 g (0.58 mmol) 3-cyclopropyl-2-oxa-8-azaspiro[4.5]decan-1-one from the above, followed by 0.12 g (0.58 mmol) EDCl, 0.08 g (0.58 mmol) HOBt, and 0.34 ml (1.94 mmol) N,N-diisopropylethylamine. The solution was stirred for 2 h at ambient temperature. The solution was poured into water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were extracted with brine (20 ml). It was dried over magnesium sulfate and concentrated. The residue was purified using a Biotage Horizon® system (50-100% ethyl acetate/hexanes mixture) to give 0.135 g of the title compounds as a mixture of diastereomers in a 50:50 ratio. The two diastereomers were separated by chiral HPLC employing a Daicel CHIRALPAK® OD® column (eluent: 40% IPA in Heptane). The first eluting diastereomer was designated as Isomer 1 and is colorless solid (0.030 g, 16%). LC/MS 589.3 (M+1). The second eluting diastereomer was designated as Isomer 2 and is a colorless solid (0.025 g, 13%). LC/MS 589.3 (M+1).

Provenance & Evidence