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Note | Regular issue | Vol 65, No. 2, 2005, pp.403-410
Published online, 24th December, 2004
DOI: 10.3987/COM-04-10279
Practical Syntheses of the Adhesion Molecule Inhibitor ER-49890 and Its Stereoisomer

Toshihiko Kaneko,* Fumihiro Ozaki, Richard S. J. Clark, Yuki Komatsu, and Kazuo Okano

*Tsukuba Research Laboratories, Eisai Co., ltd., 1-3 Tokodai 5-chome, Tsukuba-shi, Ibaraki 300-2635, Japan

Abstract

Practical synthetic routes to anti-[3-(10H-pyrazino[2,3-b][1,4]- benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetic acid (ER-49890, 1) and its syn-isomer are reported. The anti-(3-azabicyclo[3.3.1]non-9-yl)acetic acid side chain (anti-12) was synthesized stereoselectively using Pd/C hydrogenation in the presence of HCl. The syn-isomer (syn-12) was concisely obtained by crystallization as its oxalic acid salt from a 1:1 mixture of anti- and syn-isomers. The 10H-pyrazino[2,3-b][1,4]benzothiazine core (7) was prepared from commercially available 4-chloro-3-nitrobenzyl alcohol (13) in four steps and good yield.