Synthesis of Lidocaine

2011 Sharmaine S. Cady East Stroudsburg University

Skills to build:

Preparing reagents for synthesis Doing an SN2 reaction synthesis Using extraction to isolate the reaction product Using recrystallization to purify the product

Introduction Local anesthetics are among the most widely used drugs in the practice of medicine and dentistry. Their ability to provide a loss of sensation in a specific body part without loss of consciousness or impairment of central control of vital functions revolutionized surgical procedures in medicine and dentistry. Albert Niemann isolated cocaine and discovered its anesthetic properties in 1859-1860. The abuse potential and frequent fatalities led to the development of procaine (Novocaine), the first injectable local anesthetic, by Alfred Einhorn in 1905. Lidociane (Xylocaine) was developed by Niles Lofgren in 1943 and later marketed in 1948 and serves as the current standard by which all other local anesthetics are compared. Synthetic local anesthetics are classified into two groups: esters and amides. Both of these groups have the following three main parts: a. an aromatic group lipophilic portion b. a terminal secondary or tertiary amino group hydrophilic portion c. intermediate chain spatial link between the aromatic and amino groups The intermediate chain serves as the basis of the anesthetic classification (Figure 1). Procaine and lidocaine are ester and amide anesthetics, respectively. Local anesthetics work by decreasing the permeability of the nerve membrane to Na+ ions. A nerve fires when there is a rapid influx of sodium ions into the interior of the nerve cell. Local anesthetics block this depolarization of the nerve membrane, thereby, stopping the propagation of pain impulses along the nerve fibers.

Synthesis of Lidocaine
aromatic nucleus amino group

linkage

O C Ar O ester R1 N R3 R2

H N Ar C R1 N R3 R2

O amide

Figure 1. Classification of local anesthetics In solution, local anesthetics exist in both a neutral or base form and a charged or ion form. Only the base form can diffuse across the nerve membrane, while only the cation form produces anesthesia by binding to receptor sites inside the nerve cell. The pH of the environment and the pKa for a particular anesthetic determine the relative proportions of each form that is present. When pH = pKa, equal amounts of the ionized and free base form exist. According to LeChteliers principle, when the pH < pKa, more cations than free base are present as the following equilbrium shifts to the left:

BH+ + H2O ionized form

B + H3O+ free base

As a rule, local anesthetics with pKas closest to physiological pH (7.4) are most effective at producing profound anesthesia. The closer an anesthetics pKa is to physiological pH, the higher the percentage of free base that is available to cross the nerve membrane and provide anesthesia. The Henderson-Hasselbalch equation can be used to predict the ratio of free base to ion form:
[B] [BH ]

pH pK a log

Local anesthetics typically have pKas between 7.7 and 9.3. Lidocaine has a pKa of 7.8, while procaines pKa is 9.1. At pH 7.4, lidocaine exists 29% in its free base form and 71% in its ionized form.

Synthesis of Lidocaine
In this experiment, lidocaine will be synthesized in the free base form. While the soluble hydrochloride salt is more widely used in medicine, it is more difficult to purify. Starting with 2, 6-dimethylaniline, the synthesis is done in two steps: Step 1: amine + acid chloride amide (nucleophilic acylation substitution, NAS)

O Cl C

chloroacetyl chloride Cl NAS H3C CH3 O _ Cl + CH2Cl H2N CH3 O NaO2CCH3 H3C HN CH2Cl CH3

: NH2 H3C

2,6-dimethylaniline

water-soluble

solid amide

Step 2: alkyl halide + 2 amine 3 amine (SN2)

CH3 O Cl HN H3C CH2 CH3 HN : NH H3C O CH2 N CH3 CH3 CH2 + NH2
+

Cl

N-(2,6-dimethylphenyl)chloroacetamide

lidocaine

diethylamine hydrochloride

Reaction summary:

CH3 O : NH2 H3C CH3 ClCH2COCl chloroacetyl chloride 2,6-dimethylaniline H3C HN CH2Cl CH3 HNEt2 H3C HN O CH2 N CH3 CH3 CH2

diethylamine chloro-2,6-dimethylacetanilide lidocaine

Synthesis of Lidocaine
The product is then extracted with HCl and NaOH, filtered, and recrystallized from warm hexane. The melting point of the purified product is used to determine identity and purity.

Experimental Methods and Materials

Safety considerations Wear suitable protective clothing, gloves, and eye/face protection!

You should read the online MSDS for: Acetic Acid Chloroacetyl Chloride Diethylamine 2,6-Dimethylaniline Ethanol, Denatured Hexane Hydrochloric Acid Sodium Hydroxide Toluene

Synthesis of Lidocaine

Preparation of N-(2,6-dimethylphenyl)chloroacetamide In a clean, dry 125-mL Erlenmeyer flask, dispense 15.0 mL glacial acetic acid followed by 3.00 mL (2.95 g) 2,6-dimethylaniline from the pump dispensers. Add 2.00 mL (2.85 g) chloroacetyl chloride and 25.0 mL of half-saturated aqueous sodium acetate. The amide should precipitate at this point. Stir the product with 60 mL of cold distilled water and use vacuum filtration to collect the product. Press dry in the Buchner funnel and use immediately in the next step.

Preparation of lidocaine Transfer the amide to a 100-mL round-bottom flask containing 7.50 mL (5.29 g) diethylamine and 25 mL toluene. Place a stir bar inside the flask. Attach a condenser and reflux for 45 minutes. Cool the reaction mixture to room temperature and transfer to a clean, dry separatory funnel. Wash four times with 50-mL portions of water to remove diethylamine hydrochloride and excess diethylamine. Remove the aqueous layer and discard. Wash the organic layer with 20 mL 3 M HCl and remove the aqueous layer and save. Wash the organic layer once with 20 mL distilled water. Remove the aqueous layer and combine with the previous extract. Transfer the combined extracts to a 150-mL beaker and cool to 10 C in an ice bath. Add 3 M NaOH in 5 mL increments until the cold solution is strongly basic. Keep the temperature below 20 C at all times. Extraction steps:

CH3 O HN H3C CH2 N CH3 CH3 CH2 HCl H3C HN O

CH3 CH2 CH3 NH CH2 _ CH3 NaOH Cl

+

CH3 O HN H3C CH2 N CH3 CH3 CH2

lidocaine in toluene

lidocaine hydrochloride

oily layer of lidocaine

Note that the extraction procedure uses acidic and basic properties to provide a watersoluble and then water-insoluble form of lidocaine. Cool the solution in an ice bath to crystallize the product. Weigh the top of the Buchner funnel with a piece of filter paper. Collect the product by vacuum filtration. Wash with a small portion of cold, distilled water. Continue to pull a vacuum for 5 minutes and then complete drying in the hood until next week.

Synthesis of Lidocaine

Recrystallization Weigh the crude crystals. Place the crude product in a 25-mL beaker and add 1 mL of hexane per gram of crude product. Warm the beaker gently on a hot plate until the solid is dissolved. Cool in an ice bath to crystallize. Collect the crystals by vacuum filtration. Weigh them. Determine the limiting reagent, theoretical yield, and the percent yield of product. Perform a melting point determination on the dry crystals. Using the standard lidocaine provided, perform TLC on your product as a comparison.

References Department of Chemistry & Biochemistry, University of Maryland. Multi-step Synthesis of Lidocaine. http://www.chem.umd.edu/organiclabs/Chem243/Expt08.htm (accessed May 2006) Fortunato, P. M. Local Anesthetics. http://www.bethesda.med.navy.mil/careers/ postgraduate_dental_school/comprehensive_dentistry/Pearls/Pearlsd6.HTM (accessed May 2006) Reilly, T. J. J. Chem. Educ. 1999, 76, 1557.