GCE

Chemistry

Context study

Edexcel Advanced Subsidiary GCE in Chemistry

(8CH01)

Edexcel Advanced GCE in Chemistry (9CH01)

The Pharmaceutical Industry for A2

October 2007
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Contents

Introduction 1
The pharmaceutical industry 3
The importance of organic synthesis for the production of useful
products 3
The importance of understanding the mechanism of the reactions
taking place in the synthesis of stereo-specific drugs 4
How the pharmaceutical industry has adopted combinatorial
chemistry in drug research 5

Resources 10
Introduction

This document is designed to help teachers to understand the contemporary context of the
pharmaceutical industry. It should give teachers information on this context and on how to
research it further if they wish. This document could also be given to students as introductory
material.

Context study (The Pharmaceutical Industry for A2) — Edexcel AS/A GCE in Chemistry (8CH01/9CH01) 1
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The pharmaceutical industry

The importance of organic synthesis for the production of

useful products

(Unit 5 topic 5.4.3a)

This could be illustrated by discussion of the synthesis of paracetamol, which could provide a
useful way of revising sections of organic chemistry and could provide material for stretching
and challenging more able students.
One synthesis is as follows.

NO2
A
HO HO NO2 + HO

C H
HO NH2 HO N
C CH3
paracetamol O

Figure 1 — The synthesis of paracetamol

The reagent for step A is dilute sulfuric acid with sodium nitrate. The yield is approximately
25 per cent of 4-nitrophenol and 36 per cent of 2-nitrophenol.
The reagent for step B is sodium borohydride and it involves a palladium catalyst and sodium
hydroxide with a yield of 74 per cent.
The reagent for step C is ethanoic anhydride followed by water at room temperature.

Further study

• Identify the type of reaction and classification of the mechanism in step A. The mechanism
could be written based on an initial attack by the electrophile NO+ followed by oxidation
by nitrous acid in the system.
• Find out why two products are formed in this case.
• Classify the type of reaction in step B.
• Explain why the benzene ring does not become saturated with this reagent.
• Identify the type of reaction and classification of the mechanism in step C.

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• Suggest an alternative reagent for the acylation and then suggest what the additional
product would be if it were used.
• Suggest how the two isomers produced in step A could be separated.
• Calculate the mass of phenol needed to make 100 g of paracetamol, taking into account
the percentage yields given and assuming the yield in step C is 100 per cent.
• This synthesis route involves several stages, each of which may reduce the final yield of
product. Alternative syntheses are used in industry. Use the internet to find other
synthetic routes to paracetamol and compare their atom economy.

Background

Paracetamol was first synthesised in 1893 but was thought to deactivate the haemoglobin in
the blood. Reinvestigated in 1940s and first marketed in 1953 as being an analgesic, in place
of aspirin, safe for children and those with ulcers. Chronic use can cause liver damage.

The importance of understanding the mechanism of the

reactions taking place in the synthesis of stereo-specific drugs

(Unit 5 topic 5.4.3dv)

Student’s understanding of Sn1 and Sn2 mechanisms can be covered to introduce this topic. A
substitution reaction going via an Sn2 mechanism will ‘turn itself inside out’ but the product
should still be a single isomer. One that goes via an Sn1 mechanism will have gone via a planar
intermediate and will result in a racemic mixture. Many drugs are stereo-specific and only one
racemate is active, which effectively reduces the yield by 50 per cent. Knowing the
mechanism this can be taken into account. This may not matter if the other racemate is
inactive but in a classic example this was not so.

H O O
N
O N

chiral centre

Figure 2 — Thalidomide

Thalidomide was marketed as a safe mild sedative in 1956. Several years later mothers, who
had taken thalidomide during pregnancy, were giving birth to congenitally deformed babies.
Thalidomide is teratogentic and seems to interfere with DNA replication. How had this
happened? The research had been based on samples of thalidomide that were the l-form,
which is not teratogenic. When a synthesis of thalidomide was developed for commercial
production the chemists did not know that at least one step involved planar intermediate and
that a racemic mixture was being produced. The d-form is teratogenic. All drugs are now
tested for their teratogenicity. Thalidomide is now being actively considered as an anti-AIDS
drug.

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In some cases the two racemates may both be active but one more active than the other. An
example of this is the anti-ulcer drug omeprazole, which was developed as a racemic mixture
but later research showed that one of the isomers was more active than the other. The drug is
now being marketed as a single enantiomorph. Separation of stereoisomers by chemical and
physical methods is difficult. Medicinal chemists are now developing catalysts that enable
stereo-specific compounds to be produced.

OCH3
H3C CH3 OCH3
N
O
N S N
H
omeprazole

Figure 3 — Omeprazole

In this case the chirality is about the sulfur which has a lone pair of electrons and so is non-
planar.

How the pharmaceutical industry has adopted combinatorial

chemistry in drug research

(Unit 5 topic 5.4.3e)

The creation of a new medicine involves many stages and many years of research and testing.
A new drug may take 12 years to produce and only two in 10 000 compounds reach the
marketplace. In has been suggested 1 that humanity’s need for drugs and chemistry–based
materials could probably be satisfied by a very small fraction of chemical space (all the
possible chemical compounds that could exist). The only problem is that researchers do not
know their way around chemical space, so they don’t know where to find the right molecules.
As there is no universal panacea that will cure all know diseases, it is clearly necessary to
start from somewhere. The process is generally as follows.
Stage 1: Select the target
It is difficult to design a drug without understanding the way a condition or disease develops
in the body. A drug company will use the results of work into diseases to decide whether a
chemical could inhibit the development of the disease. This may involve work, for example,
with genes and the way they encode the structure of proteins.

1
Based on ‘Combinatorial chemistry with biological help’ — Chemistry world (vol 2 No 5 RSC).

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 Stage 2: Where to look?
Medicinal chemists will start to look at the shape of the molecules involved in the reactions in
the body, and will consider potential molecules that could bond with these and inhibit their
reactions.
• This may be done using computer models to design potential drug molecules.
• Chemistry will randomly screen the existing bank of molecules for effectiveness.
• They may screen molecules that are already known to have biological activity in the area,
called lead molecules, and look at possible ways in which these molecules may be
modified to increase their effectiveness, produce fewer side-effects, be cheaper to make
etc.
The synthesis of new compounds involves combinatorial chemistry or multiple parallel
synthesis (MPS).
Stage 3: Synthesis
The synthesis is not random. Pharmaceutical companies have large numbers of compounds
(called libraries) available that act as the basic building blocks for synthesis. A new synthesis
will generally start from molecules that have similar structures to those known to be active.
These will provide possible starting molecules for development of a potentially active
molecule by modification of the attached groups or changes in shape. They also have available
other libraries of molecules which are know to react with the molecules to be modified.
The example below shows the sixteen compounds that can be made from four amines and four
acid chlorides.

Libraries

CH3COCl C2H5COCl C6H5COCl (OH) C6H4COCl ………

CH3NH2 CH3CONHCH3 CH3CONHCH3 C6H5CONHCH3 (OH)C6H4CONHCH3
C2H5NH2 CH3CONHC2H5 C2H5CONHC2H5 C6H5CONHC2H5 (OH)C6H4CONHC2H5
C3H7NH2 CH3CONHC3H7 C2H5CONHC3H7 C6H5CONHC3H7 (OH)C6H4CONHC3H7
C4H9NH2 CH3CONHC4H9 C2H5CONHC4H9 C6H5CONHC4H9 (OH)C6H4CONHC4H9
…………..

Table 1 — The compounds produced from four amines and four acid chlorides

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The process is totally automated and carried out in small tubes in large plastic arrays. The
array generally has about 100 reaction vessels, each of which is identified by a unique bar
code (see picture).

Figure 4 — This apparatus adds the identity bar code and weighs each tube. The layout of the
trays for MPS can be seen

Thus 16 compounds could be produced very quickly. Addition, condensation, substitution,

reduction and oxidation could all be carried out using the technique. Many of the reactions are
carried out in solution. The solvent is not generally water, in which many biological molecules
have limited solubility, but dimethyl sulphoxide (DMSO), (CH3)2SO. If catalysts are needed
these can be added, and are generally bonded to the surface of inert polymers.

Figure 5 — In the apparatus above the reagents are added and the reactions take place

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Stage 4: Purification
The solution containing only a few millimoles of material is then analysed using HPLC (high
performance liquid chromatography). The equipment is set up to separate the product into
several fractions, each containing a pure product if a mixture of products is produced together
with the eluent. At this stage a racemic mixture may have been produced.

Figure 6 — The products of the reactions from the MPS are separated by HPLC and colleted in
the tubes in the rack

Stage 5: Labelling and storage

Part of the product of the HPLC is analysed in a mass spectrometer where its molar mass is
identified. Mass spectrometry is used because the process is sensitive enough to analyse very
small amounts of material. At this stage the medicinal chemist has no idea of the structure of
the compound present, only the library chemicals involved in its synthesis and its molar mass.
The material, still in DMSO, is sent for storage. As DMSO has a melting point of 18.5°C the
mixture is stored as a solid in a cold room.

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 Figure 7 — The small mass spectrometer used to identify the products is on the left of the
picture

Stage 6: Testing and development.

The compounds are then tested for biological activity in the chosen area and only those that
are active are identified by nmr. Synthesis work, with these active compounds, is then devised
for use in further research.

Figure 8 — The nmr machine

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Resources

Combinatorial chemistry with biological help — Chemistry world (vol 2 No 5, RSC)

Inspirational chemistry — resources for modern curricula — Royal Society of Chemistry
Molecule to Medicine — Produced by GlaxoSmithKline education section, this gives an outline
of the developmental processes involved in drug discovery and formulation
Paracetamol — Royal Society of Chemistry
Useful material is available online at:
www.chemsoc.org/networks/LearnNet/ Chemistry Now — a series of short pamphlets
chemnow_combi.htm for students available on line from the Royal
Society of Chemistry.
www.chemsoc.org/networks/LearnNet/
paracetamol.htm
http://media.wiley.com/product_data/ This is an excellent detailed introduction to
excerpt/82/04713702/0471370282.pdf the ideas involved in combinatorial
chemistry by methods such as multiple
parallel synthesis (MPS).
www.schoolscience.co.uk/content/4/biology/ This gives information of creating medicines.
glaxo

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October 2007

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