The Production of Paracetamol

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The Production of Paracetamol

There are a variety of steps which are needed in order to produce paracetamol. The picture to the right shows the general steps which are needed to produce paracetamol.

The first step is mixing the phenol with nitric acid. This is called nitration. Eventually a black precipitate will form, which is 4-amino phenol.

Reaction 1 – Nitration of Phenol

C6H5OH + HNO3 C6H4OHNO2 + H2O

Filter the precipitate using a Buchner funnel, while washing with small amounts of cold, distilled water.

Reaction 2 – Reduction of nitro compounds to amine compounds

C6H4OHNO2 C6H4OHNH2 (with the presence of Tin and HCl as a catalyst)

Reaction 3 – Making Paracetamol

The 4-aminophenol is then reacted with ethanoic (acetic) anhydride.

+

Next, recrystallization needs to occur, which includes reacting with activated charcoal (to make the product white).

In recrystallization, the crude product is heated, and then the minimum amount of solvent (in this case, water) is added to dissolve the precipitate and filtration occurs. Next, crash cooling needs to occur, by letting the how mixture sit in an ice bath. When this happens, crash cooling occurs and the crystals separate out. This will allow the separation of the pure crystals to occur. Use suction filtration again to separate out any liquid present. Repeat recrystallization with activated charcoal to decolourise the mixture – this is how a pure product is formed.

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Analytical Instruments

Different analytical instruments can be used to identify whether or not paracetamol is actually present, or how pure the product is.

Below is an Mass Spectra analysis of the compound paracetamol, and the mass spectra of its reactants.

As the picture shows, the mass spectrum of all three vary. Even though some may have similar fragments (such as CH3

+ or CH3CO+ fragments being present on two of the molecules), the rest of the spectrum is very different in comparison. Therefore Mass Spectroscopy can be used in order to identify what compounds are present.

Similarly, in the Infrared Spectrum for all three compounds (which helps detect functional groups present) vary. This can be seen especially in the fingerprint region which is unique to each compound. Especially recognizable is the presence of an broad peak around 3500-

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3200. This is indicative of an OH group present, which can be seen on 4-aminophenol. This is again another way to test purity – absence of this peak indicates there is no 4-aminophenol, which suggests it has all reacted.

There are different types of analytical instruments that can be used to analyse compounds, whether they are present or what the purity of the compound is. In GCMS (Gas Chromatography Mass Spectra), a sample is vaporised in a column and the retention time in a long column is measured. The seperation is between the mobile phase, which is a inert gas, and the stationary phase, which is a waxy alkane. After seperation occurs, the sample can then be easily passed into the Mass Spectrum, which undergoes ionisation, deflection and detection. In this way, different samples can be analysed to see what it’s constituents are made up of as well as fragments of the sample. Only a sample which can be vaporised can be used in GC.

In Infrared, the sample is bombarded with Infrared Radiation. This analytical instrument is used to see the functional groups present in the compound at any one time. As mentioned above, the IR can be used to detect purity of sample (by absence of any specific wavelength [such as the OH group]).

HPLC stands for High Pressure Liquid Chromatography. The mobile phase is an eluent, where the liquid is put in. The stationary phase is made up of beads of silica. The mobile phase and the substance is pumped at high pressure into the column. The high pressure allows for seperation at a much quicker rate. The usual column length is from 10-30 cm.

Combinatorial Chemistry

Combinatorial Chemistry is a process that is used to find and identify compounds that can be used in medicine.

Stage 1: Hit Finding

Millions of compounds are tested to see if any of them can bind to the target protein. (The protein that wants to be changed). This process is automated with robots.

In this, a Boc molecule is attached at the NH2 side of the amino acids. This means only the Carboxylic Acid can be used in the reaction with an linker molecule attached to a polystyrene resin bead. Many amino acids are joined together, with the linker molecule being removed by Hydrofluroric acid.

Stage 2: Hit to Lead

Hits are analysed medicinal chemists looking to see if they have structural features in common. A simple, core chemical structure is found which is easily modified to improve it’s characteristics – a lead.

Stage 3: Lead Optimisation

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Chemists gradually refine the structure to improve the characteristics. This leads toBetter activity in tests, novelty, better pharmaceutical properties and less side effects.