Cloperastine Hydrochloride → tert-butyl (2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate

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A solution of (2S,4R)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [Marusawa, H.; Setoi, H.; Sawada, A.; Kuroda, A.; Seki, J.; Motoyama, Y.; Tanaka, H. Bioorganic & Medicinal Chemistry (2002), 10(5), 1399-1415] (1.0 g, 4 mmol) in THF (5 ml) was added to an ice-cooled suspension of LAH (0.6 g, 15 mmol) in THF (5 ml) under Ar. The reaction was stirred for 1 h after which time it was quenched by cautious addition of water. The resulting precipitate was filtered, rinsed with EtOAc and the organics concentrated. The crude (2S,4R)-4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.7 g, 3 mmol) thus obtained was then dissolved in CH2Cl2 (15 ml), saturated NaHCO3 (15 ml) was added followed by acetic anhydride (0.3 ml, 3 mmol) and the mixture stirred for 2 h. The reaction mixture was then separated, the organic phase dried (Na2SO4) and concentrated affording crude (2S,4R)-4-acetylamino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.62 g, 79%). Treatment of this with a 4 N solution of hydrochloric acid in dioxane afforded the title product (0.5 g, quant) as a yellow powder. MS: 159.1 (MH+).

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