Scalable Synthesis of High-Purity (R, R)-Dexmethylphenidate Free Base

Abstract

A practical method for the preparation of high-purity (R, R)-dexmethylphenidate free base was developed. The method involves a substitution reaction of 2-chloropyridine and phenylacetonitrile via hydrolysis followed by hydrogenation, configuration inversion, chiral resolution, methyl esterification, and salification to give high-purity dexmethylphenidate hydrochloride. The hydrochloride salt was then neutralized by powder sodium hydroxide overnight to give dexmethylphenidate free base with over 99% purity. This method can be used for the industrial production of the dexmethylphenidate patch API, which could also be further applied for the preparation of other types of amino acid ester free bases.Keywords: dexmethylphenidate, amino acid ester, free base, high purity IntroductionThe dexmethylphenidate hydrochloride slow-release capsule was developed by Novartis Inc. (Har et al., 2000), and it was approved by the US Food and Drug Administration (FDA) in May 2005 for the treatment of attention deficit hyperactivity disorder (ADHD) (Volkmar et al., 2003), which is the most commonly diagnosed behavioral disorder in children. In July of 2010, the FDA approved the methylphenidate patch developed by Shire Plc inc, Inc. It was the first non-oral drug for the treatment of ADHD and provided a more convenient treatment choice for children. The APIs used in the capsule or patch treatments have two major differences, dexmethylphenidate chloride is a chiral, optically pure molecule, where as methylphenidate is the racemic isomer. Furthermore, the hydrochloride salt of dexmethylphenidate is used in the capsule, but it is too hydrophilic to be used in the patch because of the hydrophobic property of skin, for which only the free base could be effective. The main functional groups on both dexmethylphenidate and methylphenidate are amino acid esters (Figure 1). Amino acid esters are not very stable and can be easily hydrolyzed when neutralizing the hydrochloride salt to free base, while there is no publication to report the synthesis method of high purity free base of this kind of compound. Thus, the development of high-purity dexmethylphenidate free base could be deemed as the key step for enabling the entire API development process to meet the safety and quality requirements currently accepted by the International Conference on Harmonization (ICH). As an effective therapeutic molecule, the synthesis of dexmethylphenidate has long attracted the attention (Prashad et al., 2001) of chemists around the world, and different synthetic methods have been invented and reported in the past decades. Of these, scientists from Novartis first invented a synthetic route in which the asymmetric aldol reaction was introduced as the key step; they later further improved upon this route. Following Novartis, additional scientists reported different methods (Gutman et al., 2007& Davies et al., 1999, such as the use of Evans amide as the key intermediate for the synthetic route by Matsumura (Matsumua et al., 1999& Matsumura et al., 2000 and...