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

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

References

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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.