Hello,
I'm trying to figure out how this Nitrogen ring is closing in the synthesis of Deferasirox. Essentially, the reaction procedure is that salicylic acid reacts wtih salicyalmide to produce 2-(2-hydroxyphenyl)-4H-1,3-benzoxazin-4-one & two equivalents of H2O are lost in the reaction. To make Deferasirox, the product 2-(2-hydroxyphenyl)-4H-1,3-benzoxazin-4-one reacts with 4-hydrazino benzoic acid to make the final product Deferasirox.
Deferasirox (exjade) is actually an effective iron-chelator used in the treatment of blood diseases such as Thalasemmia in which as a consequence of the necessary blood transfusions for the patient, iron builds up in the patient to toxic levels, and must be removed with an iron-chelator such as Deferasirox. Deferasirox is actually terribly expensive for like a one month's dose at nearly 10 thousand dollars. Of course, the price depends on how much the patient needs depending upon the severity of the disease conditions.
So I found a synthesis of Deferasirox in a published paper, and of course it doesn't show the electron-flow mechanism. I was thinking if the amide nitrogen of salicylamide attacks the carbonyl of salicylic acid in acidic conditions then the two molecules could conjoin with a C=N bond. But that doesn't close the ring with the ether oxygen atom so maybe the phenyl group of salicylic acid is involved in doing that to get the intermediate
Does anybody have an idea how this synthesis mechanism might work?
I'd like to know mostly how the intermediate 2-(2-hydroxyphenyl)-4H-1,3-benzoxazin-4-one is produced.
Thanks!
Here is the source for the synthesis: http://www.tandfonline.com/doi/full/10.1080/00397911.2011.580068?scroll=top&needAccess=true
MLA citation: Rao, Vascuri Janardhana, et al. "Synthesis and Characterization of Related Substances of Deferasirox, an Iron (Fe3+) Chelating Agent." Synthetic Communications 42.21 (2012): 3200-3210.
I'll skip proton transfer steps to save time, but I believe this to be a reasonable mechanism. Allow the hydroxyl group of the salicylamide to attack the salicylic acid like in a standard Fischer-type esterification. One molecule of water is lost. Then, the amide nitrogen can attack the newly formed ester to form a tetrahedral intermediate. Another molecule of water is kicked out to form the product. This is the typical mechanism for imine formation. Forming an imine from an amide and an ester may seem weird, but there is a large driving force (forming new aromatic ring system).
I figured it out! It's shiff-base formation which turns the carbonyl group on salicylic acid onto an alcohol and then it can react with the phenyl group on salicylamide to make the end product with the heterocyclic ring. Once I rotated the molecules a little from the way they were presented and guessed with H's and O's needed to leave as waters I figured it out. Thanks for the advice. So can you think of any other cases in which new ring formation drives other interesting reactions, Alexander?
Thanks for the help!
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