Methylphenidate enantiomers

Fig. 2-10. The effect of flow rate on the resolution of methylphenidate enantiomers on vancomycin CSP (250 x 4.6 mm). The mobile phase was methanol 1.0 % triethyl-ammonium acetate (95/5 v/v) pH 4.1 at ambient temperature (23 °C).

The (+)-enantiomer, DOV 21,947, is approximately twice as potent at NET and SERT as DOV 216,303. The minimum effective dose in both mouse tail suspension and rat FST models is 5mg/kg [87,88]. The (—)-enantiomer, DOV 102,677, is less potent than DOV 216,303 across all three transporters [89]. It is active in the FST in rats with a minimum effective dose of 20mg/kg. DOV 102,677 is as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. It is reportedly under development for the treatment of alcohol abuse and alcoholism [68]. 

As of 2006, there are several branded medications approved for the treatment of ADHD however, there are only three chemicals that make up the primary active ingredients in these drugs the (5)-enantiomer of amphetamine (1), the 2(/ ),2 (7 )-enantiomer of methylphenidate (2), and the (/ )-enantiomer of atomoxetine (3). An older approved ADHD drug, pemoline (Cylert ), was withdrawn from the market in 2005 due to reported... 

All three ADHD-approved chemical entities have at least one chiral center, a feature that has led to a number of interesting syntheses of these compounds over the years. Amphetamine (1) and methylphenidate (2) were discovered before the modern era of asymmetric and enantioselective synthesis, and are sold as racemic, single-enantiomer, and enantio-enriched formulations. Atomoxetine (3), hrst presented in a 1977 Eli Lilly patent, was developed as a single-enantiomer drug (Molloy and Schmiegel, 1977). 

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... 

Figure 25-8 Baseline separation of enantiomers of the drug Ritalin by HPLC with a chiral stationary phase. One enantiomer is pharmacologically active for treating attention deficit disorder and narcolepsy. The other enantiomer has little activity but could contribute to undesired side effects. Pharmaceutical companies are moving toward providing enantiomerically pure drugs, which could be safer than mixtures of optical isomers. [From R. Bakhtiar, L Ramos, and F. L. S. Tse, "Quantification of Methylphenidate in Plasma Using Chiral Uquid-Chromatography/Tandem Mass Spectrometry Application to Taxicokinetic Studies," Anal. Chim. Acta 2002, 469.261.]...

Recently, Aboul-Enein and Ah [100] carried out certain studies on the chiral resolution of methylphenidate on derivatives of cellulose and amylose. They observed that %-% interactions are also the important binding forces for the chiral resolution of aromatic racemates. The best resolution of methylphenidate (MPH) on a Chiralcel OB column was achieved when phenol or benzoic acid, separately, was used as the mobile phase additive. Phenol (benzoic acid) forms the MPH-phenol (MPH-benzoic acid) pair in which the possibility of %-% interaction between one of these pairs and CSP is greater than the possibility of 7t—7t interactions between MPH and CSP. Therefore, the resolution of MPH enantiomers was improved when phenol or benzoic acid served as the mobile... 

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

The active d enantiomer of methylphenidate may be slightly more than twice as efficacious as racemic d,l-methylphenidate... 

An example from our own laboratory is the methylphenidate bioanalyti-cal chiral LC-MS/MS assay in support of toxicokinetics (TK) and PK studies (vide infra). Attention-deflcit hyperactivity disorder (ADHD) is a recognized medical problem characterized by symptoms of inattention, hyperactivity, and impulsivity. Methylphenidate (MPH Ritalin methyl-alpha-phenyl-2-piperid-inacetate hydrochloride) is prescribed for the treatment of ADHD. MPH has two chiral centers yielding enantiomers with distinct pharmacokinetic and pharmacodynamic properties in humans. It is known that the t/-threo [2R,2 R]-MPH (i.e., (-i-)-threo) exhibits greater pharmacological activity than the... 

Methylphenidate (trade name Ritalin) is prescribed for attention deficit hyperactivity disorder (ADHD). Ritalin is a mixture of R,R and S,S isomers, even though only the R,R isomer is active in treating ADHD. (The single R,R enantiomer, called dexmethylphenidate, is now sold under the trade name Focalin.) Draw the structure of the R,R and S,S isomers of methylphenidate. 

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. 

Note should also be made that in some cases recrystallization reduces the enantiomeric excess, which can lead to crystallization of the racemate (94). In these cases the mother liquors contain moderately to highly enriched material. It is therefore important to plan the strategy at which point the enantiomer is recrystallized to optical purity. This may be from an enzymic resolution, or in the event that an asymmetric synthesis has failed, to deliver enantiopure product. As discussed in Section 3, the liquors from the diastereomeric resolution with DTTA of 88%de can be cleaved to the free base, and crystallization of the hydrochloride salt gives >98% ee. This is because of the fact that methylphenidate hydrochloride has a eutectic point of 30% ee. Davieset al. (95) and Winkler et al. (96) have prepared single enantiomer methylphenidate (29), Their approaches use an enantioselective synthesis the enantiomeric excesses are 86% and 69%, respectively, thus requiring recrystallization... 

The phase diagrams below highlight two typical cases, the first where the eutectic point E is close to the racemate, and the second where the eutectic approaches the single enantiomer as shown in Fig. 18.24. In the first case, it would be preferable to crystallize the enriched enantiomer to optical purity, e.g., methylphenidate. However, in the second case, a very stable racemic compound exists, giving rise to a high eutectic point. Here crystallization of enriched enantiomer mixture will only be successful at high ee. For example, verapamil hydrochloride requires that the ee be greater than 98%for crystallization to yield... 

Methylphenidate Metabolism. The metabolism and pharmacokinetics of methylphenidate have been studied extensively. Methylphenidate (8)is administered as the racemic threo isomer, but the (-)-threo enantiomer is more rapidly metabolized. 

The [ C]-(2S,2 S)-(-)-t/treo-enantiomer did not bind, indicating that the (2/ ,2 R)-(+)-t/treo-enantiomer 1 is the active form. Thus, to segregate the desired pharmacological activities from side effects, there is a great interest for preparing enantiomerically pure (2R,2 R)-(+)-t/treo-methylphenidate hydrochloride (1) on a large scale. 

Methylphenidate is readily absorbed after oral administration and reaches peak concentrations in plasma in about 2 hours. The drug is a racemate its more potent (+) enantiomer has a half-Ufe of about 6 hours, and the less potent (-) enantiomer has a half-life of about 4 hours. Concentrations in the brain exceed those in plasma. The main urinary metabolite is a deesterifled product, ritalinic acid, which accounts for 80% of the dose. The use of methylphenidate is contraindicated in patients with glaucoma. 

Dexmethylphenidate (FocaUn) is the rf-threo enantiomer of racemic methylphenidate. It is FDA approved for the treatment of ADHD and is listed as a schedule II controlled substance in the United States. 

Structure-activity studies of l-piperazino-3-phenylindanes led to the development of the potent and long-lasting neuroleptic, tefludazine (7a). The cis-isomer of tefludazine has 1/1000 the activity of 71 in blocking methylphenidate-induced stereotypy in mice. One member of the tefludazine series, the bisfluoro derivative (7b) was resolved the antidopaminergic activities resided in the (+)-enantiomer. The (-)-enantiomer, however, proved to be an active uptake inhibitor of... 

A number of enantiomers (aminoglutethimide, chlorpheniramine, chlorthalidone, fluoxetine, ibuprofen, ketoprofen, methylphenidate, metoprolol, phensuximide, propranolol, suprofen and mephenytoin) were separated on a -cyclodextrin column using 40/60 to 20/80 acetonitrile/water (0.1% triethylammonium acetate pH 4.1 or 7.1) mobile phase (analyte dependent) [1550]. 

Methylphenidate hydrochloride (Ritalin and Concerta [Novartis, Basel, Switzerland]) (11, Scheme 2.1) is a mild nervous system stimulant that is primarily prescribed for treatment of attention deficit hyperactivity disorder in children. Although it is marketed in its racemic form, it has been reported that the (+) enantiomer is 5 to 38 times more active than its racemate.Although previous syntheses of (+)-methylphenidate involved classic resolution, researchers at Novartis reported an enantioselective synthesis of (+)-methylphenidate in 1997. As depicted in Scheme 2.1, the synthesis began with a diastereoselective... 

Methylphenidate (Ritalin) is a behavioural stimulant used for the treatment of narcolepsy and attention deficit hyperactivity disorder (ADHD). It is commonly classified as a non-amfetamine but its nucleus is still present in that structure. The erytliro-racemate, i.e. (2 R,2"S)- and (2 S,2"R)-methylphenidate, shows negligible stimulant activity and is not used. The racemic threo-mcemate is responsible for activity but the (2 R,2"R)-enantiomer (dexmethylphenidate) displayed a more powerful inhibition of catecholamine uptake. 

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