4- Ethoxybenzoic acid

The term EBA cement is not quite exact, but is convenient to use and has been generally accepted. Originally this cement was a variant of the ZOE cement - its most important variant - and was based on a liquid which was a mixture of 2-ethoxybenzoic acid (EBA) and eugenol. More recently, eugenol has been replaced by other compounds of similar structure. All these cements contain EBA as a major constituent. 

Figure 9.6 The structure of 2-ethoxybenzoic acid, showing the two hydrogen-bonded configurations (Bagby Greener, 1985).

Molten 2-ethoxybenzoic acid (7) was added to a mixture of chlorosulfonic acid and thionyl chloride while keeping the reaction temperature below 25 °C. In this straightforward electrophilic aromatic substitution the ethoxy group directs the electrophile towards the ortho and para position whereas the carboxylic acid directs meta giving an overall selectivity for the attack at C-5. It was necessary to add thionyl chloride to transform the intermediate sulfonic acid into... 

Chlorosulfonation of 2-ethoxybenzoic acid was found to be very regioselective a mole of thionyl chloride needs to be added to ensure the intermediate sulfonic acid is converted to the sulfonyl chloride (see Scheme 16.3). The sulfonyl chloride was converted to sulfonamide 9 by reaction with A-methylpiperazine. Initially triethylamine was used as a base, and compound 9 could only be isolated as its hydrochloride-triethylamine double salt, which was very insoluble and difficult to use in subsequent steps. A key breakthrough was obtained when it was discovered that sulfonamide 9 also could be isolated as its highly crystalline zwitterion. 

The process was quickly redesigned to make use of this new finding. After completion of the chlorosulfonation, the reaction was quenched to give the sulfonyl chloride, which was collected by filtration. The water-wet sulfonyl chloride was resuspended in water and converted to the sulfonamide by reaction with A -methylpiperazine in water. At the end of the reaction, the pH was adjusted to the isoelectric point by the addition of aqueous sodium hydroxide and compound 9 collected by filtration. Hence, the only solvent used to convert 2-ethoxybenzoic acid to the sulfonamide 9 is water. 

Despite the very high yield with the fluoro series, the approach was particularly interesting for the chloro series via compound 13 as 2-chlorobenzoic acid is cheaper than 2-ethoxybenzoic acid. The synthesis of compound 13 is shown in Scheme 16.6."... 

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