Synthesis of (R)-, (S)-, and (RS)-hydroxymethylmexiletine, one of the major metabolites of mexiletine

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

“…The hypotesis is supported by our previous experience that two of the main monohydroxylated mexiletine metabolites, the so-called p-hydroxymexiletine (PHM, Fig. 1) and hydroxymethylmexiletine (HMM), are less active than mexiletine in reducing I Na in both tonic and phasic block [7][8][9]. Herein, we report the synthesis and complete characterization of two new dihydroxylated analogs of mexiletine (1 and 2), which present themselves as valuable pharmacological tools for the study of sodium channel blocking activity.…”

“…On the other hand, deprotection with gaseous HBr afforded a mixture of 2 N HBr and a by-product resulting from an intramolecular condensation between the amino group and the hydroxyl group on the methyl in 2-position of the aromatic moiety (3,9-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ol hydrobromide). It was assessed by spectroscopic analyses, as already observed in the synthesis of HMM [9]. Subsequently, a satisfactory extraction of 2 from the hydrazinolysis deprotection of 16 was obtained using a buffer solution at pH 9 to 11 and with product finally obtained as the acetate salt 2 N CH 3 COOH.…”

“…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]. Compound 7 was refluxed for 19 h in a mixture of dioxane and water to give the corresponding diol 8 [14].…”

“…Then, in order to obtain the bromoderivative 15, compound 14 was reacted with N-bromosuccinimide and benzoyl peroxide [9,13]. Unfortunately, the yield of this reaction was very low (2%) because of the formation of a dibrominated derivative as a side-compound, with a R f value very close to the one of compound 15.…”

Recent contributions to the Diversity-Oriented Synthesis (DOS) mediated by iminium ions through multicomponent Mannich-type reactions

“…[28][29][30] In the past years, a series of selective serotonine (5-HT)-reuptake inhibitor (SSRI) antidepressants (e.g. Fluoxetine and Paroxetine) and selective norepinephrine (NE)-reuptake inhibitor antidepressants (e.g.…”