(1S,2R)-(-)-1-Amino-2-indanol → (3S)-3-(4-Hydroxyphenyl)-4-hexynoic acid

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Reaction Steps

A 5 L RB flask was charged with compound 1.3 (66.4 g, 325 mmol) and 2-propanol (1 L) and then heated to 70° C. (1S,2R)-1-amino-2-indanol (46.1 g, 309 mmol) was dissolved in 2-propanol (1 L) with gentle warming. The solution of amine was added to the dissolved carboxlic acid and the resulting solution was allowed to cool to room temperature. After 16 h, the crystals were collected and dried. The salt was re-suspended in 2 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 h. A small sample of the salt was decomposed with aqueous acid and the free carboxylic acid was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 90:10 hexanes:2-propanol) and was found to have 75% ee. The salt was re-suspended in 1.5 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16 h. This material was found to have 96% ee by chiral HPLC. This material was suspended in ethyl acetate (300 mL) and water (100 mL). Saturated aqueous KHSO4 (100 mL) was added with vigorous mixing. After two clear layers were obtained, the layers were separated and the aqueous layer extracted with ethyl acetate (100 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow oil which crystallized on drying in vacuo. Compound 1.4 was obtained as an off-white solid (23.5 g, 35%).

Provenance & Evidence