Kilogram Synthesis of (S)-3-Aminopyran from l-Glutamic Acid

Abstract

We describe the development of a concise route to prepare kilogram quantities of (S)-3-aminopyran, a key intermediate in the synthesis of a Jak1 inhibitor. The chiral amine was introduced via a chiral-pool approach and involves using inexpensive, commercially available l-glutamic acid as the key starting material. Global protection, followed by reduction afforded the N-Boc-amino diol. Intramolecular Mitsunobu cyclization and deprotection afforded the desired compound in 30% overall yield over four steps without the use of chromatography.

Key words

aminopyran - Mitsunobu - intramolecular - cyclization - glutamic acid - chiral pool - diols

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• 7 HPLC conditions for chiral purity analysis; column: Chiralpak IA 0.46 cm × 25 cm, 5 μm; mobile phase: n-heptane–EtOH = 80:20 (v/v); detector: UV, λ = 214 nm; flow rate: 1.0 mL/min; column temp = 30 °C. (S)-3-Aminopyran: t _R = 10.09 min; (R)-3-aminopyran: t _R = 13.22 min.