Lidocaine

Lab 4: Multi-Step Synthesis of Lidocaine

[Adapted from http://www.ux1.eiu.edu/~cfthb/classes/2845/lidocaine.pdf]

[Reilly, T. J.; J. Chem. Ed. 1999, 76 (11), 1557]

Introduction:

Pain relief is big business, with billions of tablets and millions of injections of pain relievers used annually. Local anesthetics are an important and well-studied class of drugs. Most anesthetics are synthetic drugs that have been developed to avoid the narcotic effects of natural products, such as cocaine.

In this experiment the local anesthetic lidocaine will be synthesized as the free tertiary amine. (The water soluble hydrochloride salt is generally used in medicine, but is more difficult to purify.) Lidocaine is sold under various trade names, the most common of which is Xylocaine. It is noted for its relatively high anesthetic activity when applied to the skin or injected into nerves, and it has a low toxicity and incidence of side effects. The two-step reaction sequence illustrated below starts with 2,6-dimethylaniline. The synthesis involves acylation of this aniline using chloroacetyl chloride, a highly reactive acid chloride, followed by an SN2 displacement using diethylamine.

Safety Notes:

Handle all chemicals with care - avoid inhaling vapors or contact with skin. Flush affected areas with water if any of these come in contact with your skin:

Step #1 2,6-dimethylaniline (carcinogenic) / glacial (100%) acetic acid

chloroacetyl chloride (lachrymator; keep under the hood) bp 108(C

Step #2 3 M HCl / 3 M NaOH / diethylamine (keep under the hood) bp 56(C

Reaction Scheme

[pic]

EXPERIMENTAL PROCEDURE

Step #1 - Preparation of a-Chloro-2,6-dimethylacetanilide

In a clean, dry 125-mL Erlenmeyer flask, mix 6.0 g 6.2 mL; 50 mmol) 2,6-dimethyl-aniline, 30 mL glacial acetic acid, and 5.6 g (4.0 mL; 50 mmol) chloroacetyl chloride in that order, under the fume hood. Mildly warm this mixture on a hot plate with swirling for 4...