GCE in Chemistry Pharma Industry A2 CS - nhehs.org.uk · chemistry in drug research (Unit 5 topic...

GCE

Chemistry

Edexcel Advanced Subsidiary GCE in Chemistry (8CH01)

Edexcel Advanced GCE in Chemistry (9CH01)

The Pharmaceutical Industry for A2 October 2007

Context study

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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

Context study (The Pharmaceutical Industry for A2) — Edexcel AS/A GCE in Chemistry (8CH01/9CH01) — Issue 1 — October 2007 © Edexcel Limited 2007

1

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.


2


3

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.

HOA

HO NO2 + HO

NO2

HO NH2

B

CHO N

H

C CH3

Oparacetamol

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.

chiral centre

O

ON

H

N

O

O

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.

H3C

OCH3CH3

N

O

S

N

N H

OCH3

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 suggested1 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.

CH3COCl C2H5COCl C6H5COCl (OH) C6H4COCl ………

CH3NH2 CH3CONHCH3 CH3CONHCH3 C6H5CONHCH3 (OH)C6H4CONHCH3

C2H5NH2 CH3CONHC2H5 C2H5CONHC2H5 C6H5CONHC2H5 (OH)C6H4CONHC2H5



…………..

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

Libraries


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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/ chemnow_combi.htm

www.chemsoc.org/networks/LearnNet/ paracetamol.htm

Chemistry Now — a series of short pamphlets for students available on line from the Royal Society of Chemistry.

http://media.wiley.com/product_data/ excerpt/82/04713702/0471370282.pdf

This is an excellent detailed introduction to the ideas involved in combinatorial chemistry by methods such as multiple parallel synthesis (MPS).

www.schoolscience.co.uk/content/4/biology/ glaxo

This gives information of creating medicines.

1569rl181007S:\LT\PD\SUPPORT\GCE IN CHEMISTRY PHARMA INDUSTRY A2 CS.DOC.1-15/0

http://www.chemsoc.org/networks/LearnNet/chemnow_combi.htm

http://www.chemsoc.org/networks/LearnNet/chemnow_combi.htm

http://www.chemsoc.org/networks/LearnNet/paracetamol.htm

http://www.chemsoc.org/networks/LearnNet/paracetamol.htm

http://media.wiley.com/product_data/excerpt/82/04713702/0471370282.pdf

http://media.wiley.com/product_data/excerpt/82/04713702/0471370282.pdf

http://www.schoolscience.co.uk/content/4/biology/�glaxo

http://www.schoolscience.co.uk/content/4/biology/�glaxo

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GCE in Chemistry Pharma Industry A2 CS - nhehs.org.uk · chemistry in drug research (Unit 5 topic...

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