kilomentor | 27 August, 2009 17:23
Kilomentor has suggested in other blog entries, that process chemists think ahead of time about possible impurities that could contaminate their products arising from impurities in starting material when these impurities are unlikely to be removed by the downstream reactions or process step separations.
An example of such technology has appeared in a US patent application, US2005/0250961A1, authored by Muddasani Pulla Reddy, The application has since lapsed. The invention teaches methods for performing the Friedel-Craft reaction between glutaric anhydride and fluorobenzene catalyzed by aluminum chloride, so that even when standard commercial fluorobenzene containing 300-700 ppm of benzene is used as starting material, the isolated product will contain less than 0.05% of the unfluorinated, 4-benzoylbutyric acid as impurity in 4-(4-fluorobenzoyl)butyric acid. This 4-(4-fluorobenzoyl)butyric acid is an important intermediate for some syntheses of the medicine ezetimibe.
The full disclosure does not explain how or why the procedures taught decrease the amount of the defluorinated impurity. The document in fact does not provide a comparative example of 4-(4-fluorobenzoyl)butyric acid made according to the prior art literature that shows clearly by contrast the improvement taught. All that is said is that benzene is about 5 times more reactive than fluorobenzene to Friedel-Craft acylation. The teaching does not describe how the benzene reacts, what product the benzene forms or what stage in the process the impurity(ies) is(are) removed.
The requirement of a halogenated solvent such as methylene chloride or dichloroethane suggests to Kilomentor that the halogenated alkane solvent may react selectively with the benzene producing products that are more easily removed in one or more of the isolation steps. It appears that in each of the patent documents specific examples one-half the fluorobenzene is mixed with aluminum chloride and halogenated solvent before adding glutaric anhydride. In this mixing period before glutaric acid is introduced, the benzene impurity could have reacted with chloroalkane solvent catalyzed by the aluminum chloride.