The Half Decent Pharmaceutical Chemistry Blog

This is Georg Wittig, the lord of phosphonium ylides.

Last week, we used the reaction named after him to yield a derivative of 9-Anthraldehyde: 9-Styrylanthracene.

Although I've never seen the original recipe, our professor, right at the beginning, told us the yield couldn't be more than 50%. Sadly, as it turned out, no one was able to get anything more than 32%!

447.6 mg of benzyltriphenylphosphonium bromide and 228.92 mg of 9-anthraldehyde were placed in a round-bottom flask. We chose DMF as solvent, bearing in mind that removing it wouldn't be easy.

The mixture was stirred with the help of a magnetic stirrer: now, theoretically, this should be done at full tilt, but you'll end up with a lot of droplets on the whole inner surface of your flask.

In a nutshell, this means loss of products, thus, the speed of the stirrer has to be carefully adjusted, balancing the need for mixing the reagents and the aim of a decent yield.

After a while, 0.5 mL of NaOH (50% w/w) were added dropwise: the rationale behind this step has to be found in the relative stability of one of intermediate products.



Towards the end of any Wittig reaction, in fact, a derivative of oxetane is formed: so, a base is needed to brake this adduct and allow the reaction to go on smoothly.

The addition of the base and, eventually, some more DMF should also help you remove those aforementioned drops from the surface of the flask.

While the reagents were stirred for 45 minutes, 8 mL of a 1:1 propanol-water solution was prepared: these solvents were then added to precipitate the products (with this ylide we yield both isomers, although more Z than E form).

This first product was filtered with a Hirsch funnel and, then, recrystallized from 1-propanol (using approximately 8 mL).

In order to assay the purity of our styrylanthracene, a TLC was carried out: the mobile phase we were told to prepare was a 5:1 hexane-ethyl acetate solution.
Interestingly, the presence of styrylanthracene could be quickly detected, due to its natural blue fluorescence.

Then, the melting point (130°C) was compared to the one described in literature (130-132°C) and we were asked take a look at the IR spectrum as well. Speaking of which, I had to concentrate the suspension (a single drop of nujol and ALL the remaining product) as never before, so that I could see anything, apart from nujol.



To sum up, we reached the conclusion that the product was rather pure but, unfortunately, the yield was a depressing 26.44% (82.8 mg).

Finally, I'm happy to announce that Laboratoire Organique is underway!

In this series I'm going to describe some of  the experiments I'll do in my last lab course (before the graduation thesis). This lab is all about organic chemistry: we synthesize some drugs and perform some extraction of natural products.

Please, do not expect me to show you anything complicated or new: I guess most of the stuff here will look very simple to serious organic people, but, nevertheless, I thought it'd have been  nice to say goodbye to organic chemistry, posting what industrial pharmacists have to know, at least.

Still, this will never be Organic Prep Daily. Maybe it's an introduction to it.

For the first "episode", I've chosen an old friend: Nifedipine.

So, last Friday we began the one-pot synthesis of this drug, putting the reagent in 10 mL of isopropanol and heating under reflux throughout the week-end.

The mechanism is pretty simple:  a common Hantzsch synthesis. This means you solely need to yield an enamine and a Knoevenagel adduct.
Interestingly, this is achieved with three reagents, only: methylamino crotonate (0.5844g), methylacetoacetate (0.54mL) and 2-nitrobenzaldehyde (0.7706g).

So, while I was preparing myself for my structural biology exam, the reaction occurred.

 

 

Some drops of the yellow oil found in the round-bottom flask were used for assaying whether the reaction actually had taken place or not, with a TLC.

Then, the isopropanol was evaporated and I placed the flask in a water bath and tried to crystallize nifedipine through trituration. As precipitating solvent we had chosen n-hexane (3mL), sticking to literature, I believe.

Unfortunately, instead of a powder, a disgusting gel-like substance appeared: this required, predictably, the addition of some ethyl acetate (and, once again, some hexane).

Then, I used a Hirsch funnel for the final suction filtration of the crystals.

A TLC (mobile phase: hexane-ethyl acetate 1.5:1) confirmed my colleague and I had worked well, since the product was almost completely pure.

The yield was a not-so-exciting 43% (0.7452g), but the melting point was 169°C (expected 171-175°C) and the IR spectrum matched perfectly the one obtained with a standard solution.
 

 

 

 

Oh, and we are not allowed to play with the NMR...that's stuff for serious organic chemists, I guess.