A highly enantioselective synthetic method towards the α_2c-adrenoceptor antagonist ORM-10921

Abstract

The preparation of ORM-10921, a selective α2C-adrenoceptor antagonist with promising anti-psychotic properties, was successfully achieved using asymmetric α-alkylation of α,β-unsaturated imide and Bischler–Napieralski cyclization/asymmetric reduction as the key steps.

Synthesis, biological evaluation, and molecular modeling of ORM‐10921 and its analogs as α2C‐adrenoceptor antagonists

“…ORM‐10921 and one of its diastereoisomers could be obtained through a 10‐step reaction sequence as described in our previous work [ 19 ] (Scheme 1). Alcohol 1 was stepwise converted into acid 4 through oxidization, Wittig olefination and hydrolysis.…”

“…were prepared according to our previous method. [19] The InChI codes of the investigated compounds, together with some biological activity data, are provided as Supporting Information.…”

“…Then the crude imines were reduced by DIBAL-H in CH 2 Cl 2 at −78°C in a highly diastereo-selective manner (dr > 97/3, by NMR analysis of reaction mixture), which resulted in the corresponding products (16) with the desired configuration based on the same reaction mechanism. [19] Subsequently, debenzylation of 16 under the reductive condition led to alcohol (17). Upon chlorination with SOCl 2 and intramolecular N-alkylation, the corresponding ORM-10921 analogs (18) were smoothly produced.…”

“…[10][11][12] Therefore, we have recently established a highly enantioselective synthetic method for ORM-10921. [19] To our surprise, although there are attempts to reveal the interactions between α 2C -AR and its ligands, [26][27][28] the binding mode of ORM-10921 remains elusive. As a continuation of our previous work, herein we describe the synthesis and biological evaluation of the four stereoisomers of ORM-10921 and a set of its other analogs, and attempt to disclose the interactions between ORM-10921 and α 2C -AR.…”

“…So far, a number of structurally diverse α 2C -AR antagonists (Figure 1) have been developed. [9][10][11][12][18][19][20][21][22][23][24][25] For instance, JP-1302 is reported to be a potent α 2C -AR antagonist. [9] To our dismay, although JP-1302 is a tool drug frequently used in pharmacology studies, [9,17] it could not optimally enter the CNS.…”