Julius Sim, Entry #2, Week 2 at UPenn

This is Julius, and I've just finished my second week at UPenn, working in the chemistry department at the Ballatore Lab (working on organic synthetic chemistry targeted at Alzheimer's drugs).

To give this week an overview, I was able to begin to run parts of my own reaction , under the supervision of Anne-Sophie, with the goal of being able to independently synthesize possible compounds in the future. In addition, I was joined in the lab by another high schooler, a girl named Maya, who worked in the lab last year, who will be staying at the lab with me for around 3 weeks.

So, last/this week, I've started to work on my own reaction to produce:

5-Chloro-6-(2,4,6-trifluorophenyl)-N-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-7-amine (C₁₃H₆ClF₆H₅)

The name of the compound is rather complicated, so we often simply refer to it in the lab as the "pyrimidine", the family of compounds that this specific analogue belongs to. While I'm working to create this specific pyrimidine, Maya will be working to create a slightly different one, with the same basic structure but a different functional group attached to the NH.

So in planning the reaction, we needed to react (get ready) 5,7-dichloro-6-(2,4,6-trifluorophenyl) [1,2,4] triazolo [1,5-a] pyrimidine with 2,2,2-trifluoroethylamine. Since both of these reagents are solids we also needed a solvent, utilizing DiEA (N,N-diisopropylethylamine) to dissolve the pyrimidine reagent. Last, we added DMF (dimethylformamide) to the reaction mixture, allowing the reaction mixture to stir for >13 hours. This was all according to a procedure outlined in a 2007 article published in J. Med. Chem. by Zhang, et. al. To run this reaction though, we needed to first create the pyrimidine reagent in a reaction that by itself requires several steps and reagents.

The reaction to create the reagent pyrimidine (used in the final reaction) requires two important steps, a reaction synthesizing trifluorophenyl malonate, then a subsequent reaction synthesizing the reagent pyrimidine. While trifluorophenyl malonate is actually commercially available (meaning we can purchase it online), it is a very expensive chemical compound, meaning that synthesizing it ourselves in the lab would help the budget (commercial factors are consideration in science too!).

After synthesizing the trifluorophenyl malonate product AND purifying it, we utilized it to create the reagent pyrimidine. Then, utilizing the crude mixture of the pyrimidine (meaning we didn't purify it and there were still impurities present), we went through the reaction as outlined above.



While the steps taken in each reaction involved different reagents, the general steps were very similar: reaction set-up, reaction, "work up", column chromatography, TLC/NMR/LC-MS, purification, drying/Rota Vapor. While the first two steps are relatively self-explanatory, the next four are a bit more complicated (and constitute a large portion of work in the lab). "Work-up" refers to a very basic isolation of the desired product into a "crude mixture"from the rest of the "reaction mixture", a combination of reaction by-products and remaining starting material. The next two steps, TLC/NMR/LC-MS and purification, involve identifying the specific product within the "crude mixture" and utilizing knowledge of the compound's polarity to isolate it (>95% purity). The last step, drying/Rota Vapor, only applies if the desired product is a solid; since it will be solution after purification, this step simply involves evaporating the solvent and leaving the solid.

 "Allez La France" (Come on France!). Dates to the 2014 World Cup. My Post-doc Anne-Sophie is French. 

Example of reaction in progress; note the nitrogen balloon. Many of our reactions are air/moisture sensitive, meaning that the flasks must be completely filled with nitrogen before the reaction.