Ritalin Synthesis

Ritalin is a medicine that contains methylphenidate, a chemical that interacts with the central nervous system; specifically nerves responsible for impulse control and hyperactivity. It's common for Ritalin to be administered to patients with ADD, ADHD, and narcolepsy.

Methylphenidate's structure is fairly simple, actually. It's got two cyclic structures and an ester group. To synthesize this molecule, we'll need to obtain a benzene ring, a heterocyclic group containing nitrogen, and a malonic ester. Let's get started:

Step 1: Treat a malonic ester with sodium ethoxide (so as not to disrupt the ester group) and mix in some bromopiperidine (shown as the reagent in Step 1). The reaction will proceed in an SN1-type fashion, and I reckon we might get a mixture of products because sodium ethoxide can attack bromopiperidine... I think it's unlikely though because C=N is softly electrophilic, and enolates are softer than ethoxides, so soft goes with soft and the ethoxide would rather act as a base.

Step 2: Next, use H30+ and heat to decarboxylate. We're now left with an amino acid.

Step 3: Use two equivalents of triethylamine and TMSCl to create an enol equivalent of the amino acid. I used to equivalents because the acidic oxygen in the amino acid might compete for the trimethylsilyl group.

Step 4: Prepare a benzene ring electrophile stabilized by N2 through nitration, reduction, and subsequent treatment of benzene with NaNO2 and HCl.

Step 5: Mix the enol equivalent of the amino acid with the benzene electrophile to facilitate an attack.

The reason I used an enol equivalent instead of an enolate equivalent is because I'm worried that an enolate equivalent might attack from the harder oxygen end since the benzene electrophile is most likely hard, too. Using an enol equivalent using TMSCl would protect the oxygen, making attack from the carbon more likely. I'm not 100% sure whether the benzene electrophile is considered hard or soft.

Step 6: Work-up to hydrolyze any TMS-protected acidic oxygens from Step 3.

Step 8: Add methanol to the product and keep removing water to drive the esterification forward.

Ta-Da. Done. We've successfully prepared the main component of Ritalin, methylphenidate.