Selective Protection and Functionalization of Morphine: Synthesis and Opioid Receptor Binding Properties of 3-Amino-3-desoxymorphine Derivatives,1

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Abstract
As part of an effort to identify novel opioid receptor interactive agents, we recently prepared a series of 8-(substituted)amino analogues of cyclazocine. We found the chiral 8-phenylamino (NHC6H5) cyclazocine derivative to have subnanomolar affinity for κ opioid receptors and a 2-fold lower affinity for μ opioid receptors. To determine if the benefits of (substituted)amino groups could be extended to the morphine core structure, we have made five novel 3-amino-3-desoxymorphine derivatives of general structure 5 where RR‘N = H2N, CH3NH, (CH3)2N, C6H5NH, and C6H5CH2NH. Relative to morphine, these derivatives had 38−273-fold, 11−41-fold, and 10−141-fold lower affinity for μ, δ, and κ opioid receptors, respectively. Target compounds were made via Pd-catalyzed amination of a morphine 3-trifluoromethylsulfonate substrate where the 6-OH group was protected with a tert-butyldiphenylsilyl group. To make 6-tert-butyldiphenylsilyloxymorphine selectively, a new high-yield method was developed whereby morphine was bis-silylated using normal conditions followed by selective removal of the 3-tert-butyldiphenylsilyl group with catalytic tetrabutylammonium fluoride.

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