D-threo-methylphenidate

In 2001, Celgene obtained FDA approval to re-launch the single enantiomer dexmethyl-phenidate d-threo 2, formerly Dexedrine ) for ADHD under the brand name Focalin , and subsequently sold the product to Novartis, d-threo Methylphenidate has a 2.2 h... 

Scheme 17.10. Synthesis of d-threo methylphenidate via asymmetric CH insertion.

Methylphenidate as a secondary amine gives rise to four optical isomers d-threo, 1-threo, d-erythro, and 1-erythro. There is stereoselectivity in receptor site binding and its relationship to response. The standard preparation is comprised of the threo recemate as it appears to be the CNS active form. Moreover, recent data suggests that the d-methylphenidate isomer is the active form. This has led to the development of a purified d, threo-methylphenidate compound, Focalin. Studies have shown Focalin to be at least as effective as the racemate at half the dosage. Focalin is available in 2.5, 5, and 10 mg to approximate 5, 10, and 20 mg of d,l methylphenidate. 

Fig. 14. In vivo PET images from Volkow et al. (2001a) of the distribution volume of [llC]d-threo-methylphenidate (label dopamine transporter sites) in a control and a methamphetamine abuser. The images represent the level of the striatum (left) and the cerebellum (right) in a normal control and a methamphetamine abuser evaluated twice, during short and protracted abstinence. Note the reduction of striatal dopamine transporter binding following early abstinence and the reversal to more normal levels in binding in the methamphetamine abuser with protracted abstinence.

Chemists at Chiroscience took an alternative approach to the D- /ireo-methylphenidate (29) single enantiomer (63). An efficient resolution using L-(-)-di-toluoyl-tartaric acid (DTTA) was developed. This left the required D-threo diastereoisomer in solution with a di-astereomeric excess of 88%3neld in 55% chemical yield. Conversion of this salt to the free base and subsequent crystallization of the hydrochloride salt gave >98% ee D-threo methylphenidate in high purity in an overall yield of 42%. The enhancement of the ee is caused by the eutectic point of methylphenidate hydrochloride, which is at 30% ee. A more detailed description of this phenomenon will be discussed later in this section. 

A very elegant synthetic approach was reported a year later by Davies et al., leveraging asymmetric C-H activation chemistry to accomplish a one-pot synthesis of d-threo methyiphenidate (Scheme 17.10) (Davies et al., 1999). A-Boc piperidine (33) was selectively alkylated by the carbene formed by decomposition of diazoester 34 in a reaction mediated by 25 mol% of chiral Rh (II) catalyst 35, giving the A-Boc protected (2R,2 R) isomer in a single step. TFA was added to accomplish removal of the Boc group after the C-H insertion reaction was complete, affording (R,R)-methylphenidate (2) with an ee of 86% in 52% overall yield. 

Hubbard, J.W., Srinivas, N.R., Quinn, D., and Midha, K.K. (1989) Enantioselective aspects of the disposition of dl-threo-methylphenidate after the administration of a sustained-release formulation to children with attention deficit disorder. / Pharm Set 78 944-947. 

D-threo-Methyl- phenidate Drug enantiomer Methylphenidate 2002... 

Methylphenidate (MPH, Ritalin ) is a central nervous system stimulant that is used for the treatment of attention deficit disorders, with and without hyperactivity, and narcolepsy. MPH has two chiral centres and is marketed as a racemic mixture. It is known that d-threo-MP is pharmacologically more active than l-threo-MPH. The drag is rapidly metabohzed in humans to the inactive ritalinic acid. High-throughput analysis with chiral selectivity is demanded for the bioanalysis of MPH and its major metabolite. 

Dexmethylphenidate (focalin) is the d-threo enantiomer of racemic methylphenidate. It is FDA approved for the treatment of attention-deficit/hyperactivity disorder and is a schedule Il-con-trolled substance in the U.S. 

Srinivas, N.R. Hubbard, J.W. Korchinski, E.D. Midha, K.K. Enantiose-lective pharmacokinetics of dl-threo-methylphenidate in humans. Pharm. Res. 1993, 10, 14-21. 

---