Hydrochloric Acid → [(S)-7-Cyano-4-((2R,3S)-3-hydroxy-1-methyl-pyrrolidin-2-ylmethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester

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Reaction Steps

A solution of (2R,3S)-2-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3.10 g, 6.42 mmol) in ethanol (20 mL) is treated with 4 N hydrogen chloride in 1,4-dioxane (20 mL) and stirred at room temperature for 3 h. The resulted solution is concentrated in vacuo and suspended in ethyl acetate (200 mL) and treated with 2 N aqueous sodium hydroxide (70 mL). The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The resulting residue is dissolved in chloroform (100 mL) and treated with formaldehyde (1.45 mL, 19.27 mmol) and sodium triacetoxyborohydride (4.25 g, 19.27 mmol). The resulting suspension is stirred overnight at room temperature. The suspension is treated with saturated sodium bicarbonate solution (40 mL) and stirred for 30 min. The resulting suspension is diluted with dichloromethane (100 mL) and washed with water (3×100 mL) and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by medium pressure liquid chromatography, eluting with methanol:chloroform (5:95). Fractions containing pure product are combined and concentrated to afford 1.6 g (63%) of the title compound. LC-ES/MS m/z 397.2 [M+H]+, TR=1.78 min.

Provenance & Evidence