Methylphenidat, Methoxetamine, Methadone & Methylendioxybenzylmethylketone Synthesis

Methylphenidate Synthesis Simplified

Introduction

Methylphenidate, known as Ritalin and Concerta, can be synthesized through a relatively straightforward method. This synthesis doesn't require elaborate glassware, specialized equipment, or extreme conditions like high pressure or very low/high temperatures. The primary challenge lies in sourcing rare precursors such as 1-Phenyl-2-(piperidin-1-yl)ethanone-1,2-dione, which can often be obtained from specialty stores.

Isomer Complexity

Methylphenidate has four possible isomers due to its two chiral centers. The pharmacologically desired effects are primarily exhibited by d-threo-methylphenidate. The erythro diastereomers have different properties, including pressor effects not shared by the threo diastereomers. Originally, the drug was sold as a 4:1 mixture of erythro:threo diastereomers but was later reformulated to contain only the threo diastereomers. The term "TMP" refers to threo-methylphenidate without any erythro diastereomers. It's also commonly known as dexmethylphenidate or d-threo-methylphenidate.

Required Equipment and Glassware

• Three-necked round bottom flask
• Magnetic stirrer
• Retort stand and clamp
• Laboratory scale
• Buchner flask and funnel (or small Schott filter)
• Rotary evaporator
• Vacuum source
• Beakers
• Glass rod
• Ice water bath
• HCl dry gas apparatus
• Reflux condenser
• TLC kit (optional)
• Separatory funnel
• Conventional funnel
• Filter paper
• Flash chromatography kit
• Laboratory-grade thermometer
• Drip funnel
• Erlenmeyer flasks

Required Reagents

• 1-Phenyl-2-(piperidin-1-yl)ethane-1,2-dione
• p-Toluenesulfonhydrazide
• Anhydrous hydrochloric acid gas (HCl)
• Diethyl ether (Et2O)
• Ethanol (EtOH)
• Toluene
• Potassium tert-butoxide
• Tert butanol
• Distilled water (H2O)
• Sodium chloride (NaCl)
• Ethyl acetate (EtOAc)
• Magnesium sulfate (MgSO4)
• Methanol (MeOH)

Key Information on Methylphenidate Hydrochloride

• Boiling Point: 327.6 °C at 760 mm Hg
• Melting Point: 224-226 °C
• Molecular Weight: 269.767 g/mol
• Density: 1.1±0.1 g/mL (20 °C)
• CAS Number: 298-59-9

Synthesis Steps

Step 1: Tosylhydrazone Formation

1.     Combine 1-phenyl-2-(piperidin-1-yl)ethane-1,2-dione and p-toluenesulfonhydrazide in dimethoxyethane.
2.     Add anhydrous HCl gas and gently reflux the mixture.
3.     Cool to room temperature, inducing precipitation.
4.     Filter and wash the precipitate with cold ether.
5.     Air dry to obtain pure tosylhydrazone.

Step 2: Diazo Formation

1.     Dissolve tosylhydrazone in toluene.
2.     Add a 1 M solution of potassium tert-butoxide in tertbutanol.
3.     Reflux the mixture and monitor by color change.
4.     Wash the solution and purify by flash column chromatography.

Step 3: Amine Salt Formation

1.     Bubble anhydrous HCl gas through a solution of B-lactam in MeOH.
2.     Stir until the starting material disappears.
3.     Evaporate the solvent and triturate with ether.
4.     Collect the offwhite solid by filtration.
5.     Recrystallize to obtain white crystals of the amine salt.

This simplified process enables the synthesis of methylphenidate without the need for complex equipment or conditions.