Serdexmethylphenidate chloride

Azstarys(Serdexmethylphenidate chloride) is a drug composed of two active ingredients, Serdexmethylphenidate and Dexmethylphenidate. Azstarys was approved by the FDA in 2021 for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 years and older.

Serdexmethylphenidate is a prodrug form of dexamethylphenidate that works by breaking down in the gastrointestinal tract to release dexamethylphenidate. This breakdown generally occurs within a few hours of administration, thus, serdexmethylphenidate provides a prolonged effect compared to immediate-release dexamethylphenidate. Dexamethylphenidate works by binding to dopamine receptors and inhibiting dopamine reuptake, thereby increasing dopamine levels in synapses, which is beneficial for improving symptoms in patients with ADHD.

The synthesis of serdexmethylphenidate started with the hydrochloride salt of dexmethylphenidate 7.7. It is carried out in two steps:
Step 1: coupling benzyl cyanide (7.1) with 2-chloropyridine (7.2) to generate racemic nitrile (7.3), which is then hydrated with concentrated sulfuric acid to obtain the corresponding amide (7.4). Reduction of the pyridine ring under hydrogenation conditions using platinum dioxide as a catalyst gave a 4:1 mixture of erythro:threo isomers (rac-7.5:rac-7.6). Next, chiral salt separation using dibenzoyl-D-tartaric acid (d-DBTA) and subsequent destruction of the salt with sodium hydroxide solution gave the free base (7.6). Finally, the amide was converted to the ester using concentrated sulfuric acid in methanol, paving the way for treatment with ethereal hydrochloric acid to give the hydrochloride (7.7).

Step 2: The di-tert-butoxy-protected nicotinyl-L-serine group (7.10) was synthesized by coupling tert-butoxy-protected L-serine (7.8) with nicotinic acid (7.9) using propylphosphonic anhydride as a coupling reagent. The carboxylmethyl unit was introduced by treating dexmethylphenidate hydrochloride (7.7) with chloromethyl chloroformate (7.11) in the presence of a base. After the reaction mixture was concentrated, the intermediate (7.12) was treated with pyridine (7.10) in acetonitrile. Subsequently, acidification with hydrochloric acid in dioxane and crystallization from methyl isobutyl ketone/heptane finally gave Serdexmethylphenidate (7).