Improving the Synthesis of Lidocaine: Using Arrays

Abstract:

Having improved the synthesis of α-chloro-2,6-dimethylacetanilide by using lab

arrays comparing different solvents (Taliaferro 2011), further refinement was

achieved by determining the optimum concentration with lab arrays. In this way, the

preparation of the precursor toward Lidocaine was improved from 50-66% yields to

excess of 90% yields (90-96%).

Published techniques for transforming α-chloro-2,6-dimethylacetanilide into

Lidocaine allowed for comparison of different solvents, temperatures, and reaction

concentrations. A traditional technique using refluxing toluene1 is less attractive due

to low yields (53-65%) and requires multiple extractions, while an alternative

procedure using excess diethylamine as the solvent requires at least 60 minutes2

(80-90% yields). The goal was to eliminate the use of toluene, a known carcinogen,

and minimize the reaction time.

Preparation of Lidocaine from α-chloro-2,6-dimethylacetanilide, traditionally carried

out in refluxing toluene for 90 minutes, results an average 50% yield. This reaction

was problematic for many reasons, including: health & disposal concerns of toluene,

time, & efficiency. In order to optimize the synthesis of Lidocaine, it was important to

study the use of solvent (or no solvent), the reaction temperature and heating

method, and various workup procedures.

References:

1. Experimental Organic Chemistry: A Miniscale and Microscale Approach, 4th ed., Gilbert, J.C.; Martin, S.F., Thomson Brooks/Cole, 2006, “Synthesis of Lidocaine”, p. 733 – 745.

2. http://pages.towson.edu/jdiscord/WWW/332_Lab_Info/332LabsIRPMR/Expt4aLidocaineA.pdf

Variables: Modifications

• Temperatures: 110oC; 100oC; 70oC; 68oC; 60oC; 55oC;

• Above 70oC increased decomposition

• Below 60oC only starting material recovered

• Solvent: Toluene, CPME, THF, iPrOH, Et2NH

• CPME ineffective due to insolubility of the acetanilide.

• Heating method: Hot water bath vs Microwave heating

• 70oC hot water bath: After 5 minutes

(1.92:1.00) acetanilide:lidocaine ratio)

• 68oC Microwave: After 5 minutes

(0.49:1.00) acetanilide:lidocaine ratio

This may indicate a change in mechanism between the two heating methods.

Funding Provided By:� SFASU Department of Chemistry� Robert A. Welch Foundation (Grant Number: AN-0008)

Hank Odneal, Stephanie Aills, & Arlen Jeffery

Department of Chemistry & Biochemistry

Stephen F. Austin State University

Discussion:

Optimizing a reaction is important in industry as the efficiency of a reaction can directly

impact the cost of production. Not only must one consider the percent yield of

production, but the reaction times, cost of the chemicals involved, the waste produced,

and the hazards involved in all of the above. Industry spends a large portion of the

research and development budget testing the efficiency of their operations in order to

maximize profit and minimize hazards to limit potential liability costs.

Toluene, when used as the solvent, helps dissolve the acetanilide due to its aromaticity,

but also prevents its complete removal by extraction. NMR spectra of the product always

indicated trace amounts of toluene with the Lidocaine. The initial goal of removing toluene

as a solvent lead to investigating of CPME (cyclopentyl methyl ether) as a substitute due

to its similar boiling point (106oC). CPME failed to be a good alternative as the

acetanilide did not dissolve well enough to promote the reaction under reflux.

Studies of solvent solubility for the acetanilide lead to ionic liquids as a viable solvent

replacement to dissolve the intermediate hydrochloride salts. The ionic liquid was

thought to be ideal for solubility and temperature reasons, but isolation of lidocaine from

the ionic liquid proved to be problematic. NMR indicated lidocaine with the ionic liquid

after five extractions. Strong base extractions with an ionic liquid are not feasible due to

possible Hofmann elimination of the solvent. It is possible that a continuous extraction

cycle could minimize the lidocaine in the ionic liquid, but it would not improve the

efficiency of the reaction.

Our studies and Literature2 indicated that temperatures above 70oC increased

decomposition rates. This lead to temperature studies required to promote the reaction.

Using THF as the solvent (3mL) and and diethylamine (3 equiv.), temperatures of 55oC,

60oC, and 68oC was studied using microwave heating for 40 minutes. Only starting

acetanilide was recovered at 55oC, indicating the energy of activation was not reached.

Trace Lidocaine was observed at 60oC, but Lidocaine was the primary product at 68oC.

Using only the acetanilide and diethylamine with microwave heating at 68oC for 30

minutes, Lidocaine was produced in 95-99% yields. This prompted a study to determine

the rates of reaction at 68oC. Two five-minute reactions were performed to test the

difference between heating the reaction in a water bath or a microwave. The water bath

was heated to 70oC and the microwave was set to 68oC. The comparison of these two

reactions show a significant increased rate of reaction in the microwave. This is

illustrated in Figure 1 where the reactant/product ratio is 1.92 in conventional heating

were it is 0.49 in microwave heating. Because of the extreme difference in rates between

these two reactions at similar temperatures, the implication of different mechanisms

becomes a possibility that could also be explored.

Conclusion:

The two-step synthesis of Lidocaine was increased from 30% (55% x 55%) to a 90% yield

(92% x 98%) by simple modification of the traditional synthetic procedures. In addition,

the reaction time was reduced from 90 minutes to 10 minutes in the microwave without

compromising the purity of the products (Figure 2). Future work exploring the kinetic

enhancement of microwave heating can be explored. Through these studies, it could be

determined if the order or the rate constant of the rate law is altered.

All Reactions 0.100g α-chloro-2,6-dimethylacetanilide

Et2NH Temp. (oC) Time (min) % Yield

3 eq. in toluene 110 90 55 ± 5

3 eq. in IL * 100 60 20

3 eq. in THF 68 MW 60 60 ± 5

15 eq. (solvent) 70 60 90 ± 4

15 eq. (solvent) 68 MW 30 98 ± 3

15 eq. (solvent) 70 5 27.3

15 eq. (solvent) 68 MW 5 58.7

* IL = 1-butyl-3-methylimidazolium hexafluorophosphate

Table 1: Reaction Array

Figure 1: NMR comparison: 5 min Reactions(Top) water bath 70oC (Bottom) MW 68oC

Figure 2: NMR of Pure compounds