Stereospecific synthesis of mexiletine and related compounds: Mitsunobu versus Williamson reaction

Stereospecific synthesis of “para‐hydroxymexiletine” and sodium channel blocking activity evaluation

“…19 However, it will be possible to give the ultimate word in this regard only when all the major Mex metabolites, in the corresponding homochiral forms, have been tested in our and other relevant pharmacological assays (e.g., Purkinje and cardiac muscle fibers). On the other hand, variously 4-substituted (e.g., 4-methyl or 4-halogen) Mex analogs 22 should result more resistant to metabolical, aromatic hydroxylation and might present a longer duration of action. Provided that they are active in vitro and endowed with higher in vivo half-lives, they might represent the starting point for long-acting therapeutical agents, useful for the treatment of chronic diseases such as myotonic disorders.…”

“…26 The phthalimido alcohols (R)-and (S)-3 were submitted to condensation with 2,6-dimethylphenol (4), under Mitsunobu conditions, 27 as previously reported. 22 The introduction of the phenolic function in the 4-position of the aryloxy ring was easily performed adopting the three-step method proposed by Adejare and Sciberras 28 for the synthesis of 4-fluoro-1-naphtol. Briefly, the phthalimidoalkyl aryl ethers (R)-and (S)-5 underwent a FriedelCrafts acylation to give the corresponding methyl ketones (R)-and (S)-6 which, in turn, were subjected to a BaeyerVilliger oxidation giving the corresponding 4-acetoxy derivatives (R)-and (S)-7.…”

“…Compounds (R)-and (S)-3, (R)-and (S)-5, and ( -)-(R)-and (+)-(S)-Mex were prepared as previously described. 22 ( -)-(R)-and (+)-(S)-O-p-chlorophenylmandelic acids, used as chiral solvating agents (CSA), were prepared in our laboratories. 23,24 Instrumentation Yields refer to purified products and were not optimized.…”

Hydroxylated Analogs of Mexiletine as Tools for Structural‐Requirements Investigation of the Sodium Channel Blocking Activity

“…The structures of the compounds were confirmed by routine spectrometric and spectroscopic analyses. Compounds 5, 6, and 12-14 were prepared as described previously [7,9,10,17]. Only spectra for compounds not previously described are given.…”

“…2-[2-(2,6-Dimethylphenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione 6 was prepared as previously described [7,9,10], by protecting 2-amino-1-propanol 3 with phthalic anhydride 4 [11], and then by reacting the phthalimido alcohol 5 with 2,6-dimethylphenol, under Mitsunobu conditions [12]. Then, compound 6 was reacted with N-bromosuccinimide and benzoyl peroxide for 72 h to give the dibromoderivative 7 in 43% yield by modifying a procedure reported in the literature [9,13].…”