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Synthesis 2007(2): 219-224  
DOI: 10.1055/s-2006-958939
PAPER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of N 6 -[endo -2′-(endo-5′-Hydroxy)norbornyl]-8-(N-methylisopropylamino)-9-methyladenine (WRC-0571): A Potent and Selective Adenosine A1 Receptor Antagonist

Chunyang Jin*, Jason P. Burgess, Kenneth S. Rehder, George A. Brine
Organic and Medicinal Chemistry, Science and Engineering Group, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, USA
Fax: +1(919)5416499; e-Mail: cjin@rti.org;
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Publication History

Received 7 September 2006
Publication Date:
14 December 2006 (online)

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Abstract

A new versatile synthesis of N 6-[endo-2′-(endo-5′-hydroxy)norbornyl]-8-(N-methylisopropylamino)-9-methyladenine (WRC-0571), a highly potent and selective antagonist for adenosine A1 receptor, is presented. The overall yield is 14%. The key step involved the stereoselective reduction of endo-2-(diphenylmethyl­amino)norbornan-5-one to generate the endo-5-hydroxy substituent using the Luche reagent (NaBH4-CeCl3) at -40 °C.

Key words

WRC-0571 - Luche reduction - palladium-catalyzed amination

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7

The endo stereochemistry at C-2 of 9 was confirmed by NMR studies of compound 11.

8

Reduction of 10 to 11 using LiAlH4 or 9-BBN did not improve the stereoselectivity significantly. In the case of LiAlH4, some side reactions occurred to give a mixture of crude products as detected by 1H NMR spectroscopy.

16

The coupling reaction was also tried with a similar outcome using (N-methylisopropylamino)tributyltin, generated from N-methylisopropylamine(5) and (N,N-dimethylamino)tri-butyltin, and Pd[(2-furyl)3P]4 in toluene at 80 °C.