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Synthesis 2009(7): 1153-1162  
DOI: 10.1055/s-0028-1087989
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Practical Syntheses of Enantiomerically Pure Key Intermediates of Opioid Receptor-like 1 (ORL1) Antagonists

Takashi Yoshizumi*a,b, Akio Ohnob, Tomohiro Tsujitab, Hirobumi Takahashib, Osamu Okamotob, Ichiro Hayakawaa, Hideo Kigoshi*a
a Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennodai, Tsukuba 305-8571, Japan
Fax: +81(29)8534313; e-Mail: kigoshi@chem.tsukuba.ac.jp;
b Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba 300-2611, Japan
Fax: +81(29)8772029; e-Mail: takashi_yoshizumi@merck.com;
Further Information

Publication History

Received 4 November 2008
Publication Date:
06 March 2009 (online)

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Abstract

Practical syntheses of enantiomerically pure key intermediates of opioid receptor-like 1 (ORL1) antagonists are described. Our synthetic methodology features the preparation of multigram quantities of seven-membered key intermediate (-)-3 and six-membered one (-)-4 without the use of toxic tin reagents. In the case of (-)-3, the key step involved diastereoselective reduction using a sterically hindered reducing reagent. Our methodology allows for facile scale-up to afford the products in multigram quantities [in the case of (-)-4, >100-g quantities). These convenient approaches facilitate structure-activity relationship studies including in vivo cardiovascular adverse effects.

Key words

ORL1 antagonist - multigram-scale preparation - asymmetric synthesis - cycloalkano[1,2-b]pyridines - stereoselective reduction

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¹H NMR and RP-HPLC analyses of the reaction mixture indicated that the diastereoselectivity was >99:1.

13

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This levorotatory optical rotation for the (R)-isomer {[α]D ²6 -6.3 (c 1.00, CHCl3)} was not in agreement with the reported data for the (S)-isomer {[α]D -24.4 (c 2.67, CHCl3)}.¹6 However, the levorotatory optical rotation of the corresponding ester, methyl (2R)-2-[(benzyloxy)meth­-yl]pent-4-enoate {[α]D ²4 -5.9 (c 4.0, CHCl3)}, which we prepared from (R)-21, was reasonable, compared to the dextrorotatory optical rotation of the (S)-isomer {[α]D +3.2 (c 4.0, CHCl3)}.¹6