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In this video we're going to synthesize a quinazolinone heterosilic compound using acetoanthanilic
acid and aniline.
Before we start do know that this reaction achieves far better yields if you take measures
to ensure that there is no water present in any of the reagents.
As an example we've dried our starting material in a mid-shift desiccator for a week using
calcium chloride.
Let's get started.
First of all measure out 30 mils of dry toluene.
Set up a 100 mil flask equipped with a large magnetic stir bar.
Note that stirring is extremely important in this reaction, especially at the beginning.
Add the toluene to the dry flask.
And then start stirring.
Now measure out 10 grams of dry acetoanthanilic acid.
We're using a crude batch we made from some fairly impure anthranilic acid and so it's
a gray color.
We wanted to test to see if we could use dry but fairly crude starting materials in this
reaction successfully.
With stirring, add this to the flask containing the toluene.
It won't dissolve much, but it will form a suspension.
If your solid clumps together at this point then it is not dry enough and your yields
will suffer badly.
Now measure out a slight molar excess amount of your chosen aniline.
We're using 5.5 grams of aniline here.
As before we're testing to see how quality affects the yield, so we're using an old bottle
of aniline which is a dark color with a brownish tint.
It is however dry.
Add the aniline to the stirred suspension in the flask.
Use a small amount of toluene to wash the beaker and add to the flask.
Here's our mixture.
Nothing is going to happen just yet.
Set the flask up with a condenser and using ice cold water circulating.
Set up a drying.
Set up a drying.
Place the tube on the top of the condenser so that the contents are protected from atmospheric
moisture.
Now measure out 20 mils of dry toluene.
Pour this into a small dry conical flask.
And now measure out 6 mils of phosphorus trichloride.
This will act as a dehydrating agent in the reaction and remove water as it is formed.
You can also use phosphorus oxychloride.
And possibly penta chloride as well.
Add this to the toluene in the flask in order to make a solution.
Cover the beaker in wrap so as to protect from moisture and to avoid fumes of HCL gas.
Now set up the flask containing our stirred suspension of starting materials in a cold
water bath.
Make sure that the mixture is still stirring well.
And now set up the flask.
And make sure your condenser water is ice cold in order to make sure we don't lose any
valuable phosphorus trichloride.
Now, temporarily detach the drying tube from the top of the condenser.
And using the pipette, add a very small amount of the phosphorus trichloride solution into
the flask.
You'll immediately see some white fumes and there will be a slight temperature increase
in the flask.
Wait for the flask to cool back down and then add another small portion.
Make sure you go nice and slow and don't allow the temperature in the flask to go too high.
You'll start to notice a yellowish deposit forming in the flask.
Keep the addition going slowly.
About halfway through you'll notice that further addition doesn't cause any further increase
in temperature.
At this point you can remove the water bath.
As you can see the precipitate is quite thick.
Make sure though that the mixture is still stirring.
And use an ice pack if you need to in order to keep the flask cool.
Complete addition took about 20 minutes.
At this point reconnect the drying tube and gently heat the flask.
Get the gentle reflux going in the flask.
And keep stirring.
And going as much as you can.
Be sure to use strong ventilation as a lot of HCl gas will be produced and will exit
the drying tube.
Keep the reflux going for the next hour and half.
And then switch off the heat and allow to cool.
Temporarily dismantle the apparatus and use a spatula to push any solids on the walls
of the flask down.
Wash the walls.
Now set up the apparatus again.
Only this time for simple distillation.
The aim now is to distill off about half the toluene and drive off any residual water
azeotropically.
We used some foil to insulate the still head and speed this up.
A small amount of HCl was evolved during distillation.
After we collected 30 mils we turned off the heat.
And then allowed the flask and contents to cool down to room temperature.
Now set up for vacuum filtration.
Transfer the contents of the flask into the filter.
And then use a little toluene to wash out the reaction flask and add to the filter.
Give the mixture a stir to make sure it's completely dissolved.
Make sure it's homogenous.
And then filter the solids until you have a semi-dry paste.
Now prepare around 30 mils of toluene to wash the solids.
Mix up well as before.
And then filter again.
This time keep the pump running and break up the paste occasionally to dry it as much
as possible.
Here's what we're left with.
The dry mixture of our product.
Some starting materials.
And possibly some inorganic salts.
Crush this up into a fine powder.
Since this mixture contains our product as a hydrochloride salt, we will first freebase
this into an insoluble form by adding an alkali.
Measure out 10 grams of sodium hydroxide.
Add 80 mils of cold water in order to create a solution.
And then add our crude product.
As you add the solid you'll notice clumps of sticky freebase product forming in the
mixture.
Stir the mixture very well for at least 20 minutes and break up the lumps to ensure complete
conversion.
Filter the sticky residue off, and wash well with a small amount of water.
We're left with an unpleasant looking lump of sticky freebase product.
Around 15 grams in total.
Now we'll purify further by converting this back to the hydrochloride salt.
Prepare your mixture.
Pour a small amount of hot acetone.
And on a hot plate, add acetone to the product until nothing more dissolves.
This will take between 10 and 15 mils.
You may still have a yellow precipitate at this point that won't dissolve.
If so then you will need to filter this and re-react with sodium hydroxide as this is
unreacted hydrochloride salt.
Now we've got a solution of our freebase in hot.
Prepare 6 mLs of concentrated hydrochloric acid.
And, allowing the acetone to cool slightly, carefully add the acid.
The mixture may get hot and even boiled, so be cautious.
You can chill this down and crystallize but it results in losses of product.
So we placed on a hot plate and reduced down.
The mixture goes a slightly darker color as it is heated and boils.
Solids start to form, and hydrogen chloride gas is given off by the mixture as it reduces down.
Eventually you end up with a fairly dry product as you can see here.
Caked in the bottom of the beaker.
Measure out 30 mLs of toluene and add this to the beaker.
Scrape all the solids off the sides and bottom of the beaker so you're left with a solid suspended in the toluene.
Set up for vacuum filtration and filter the solids.
Take care to dry them as much as you can on the pump to remove toluene.
Now prepare 25 mLs of cold acetone.
Place the solids into a beaker.
Add the acetone.
And stir to form a fine suspension of solids.
Now filter the cream colored solids.
You can see the dark color coming off in the filtrate.
Allow to dry and then wash with another 20 mLs of cold acetone.
Allow the powder to dry thoroughly on the pump until it is very fine and dry.
Then collect the crude product.
And here it is.
Here are the grams of the hydrochloride salt of our target oxazolide and heterocyclic compound.
This is a 56% yield on the starting benacetylanthanilic acid.
To purify further you can re-crystallize from hot acetone.
This produces a pure white and fine microcrystalline powder like this.
This reaction is a great example of how complex looking structures can be built up on a pump.
Enriching blocks with some clever cyclosations.