SYNTHESIS

Synthesis is a crucial process in the drug industry as it is responsible for the

development of new, effective, and safe drugs. Here are some reasons why
synthesis is important in the drug industry:
1. Discovery of new drugs: Synthesis plays a crucial role in the discovery of
new drugs by creating new compounds with potential therapeutic effects.
Synthesis enables chemists to modify and optimize the chemical structure of
existing compounds to improve their pharmacological activity and reduce
toxicity. Synthesis is also important for creating analogs of existing drugs,
which may have improved properties or novel mechanisms of action.
2. Drug optimization: Synthesis is used to optimize the properties of lead
compounds that are identified during drug discovery. Chemists can make
structural modifications to lead compounds to improve their pharmacological
activity, selectivity, and bioavailability. Synthesis can also help to reduce the
toxicity and improve the stability of lead compounds.
3. Scale-up and production: Once a lead compound has been identified and
optimized, synthesis is used to produce the drug in large quantities. Synthesis
allows for the efficient production of the drug, ensuring that it is available in
sufficient quantities for clinical trials and for eventual commercialization.
4. Quality control: Synthesis is essential for quality control in the drug
industry. The synthesized drug can be characterized and analyzed to ensure
that it meets the required standards of purity, identity, potency, and safety.
5. Intellectual property: Synthesis is a key component of patent protection
in the drug industry. The synthesis of novel compounds and methods for
synthesizing drugs can be patented, protecting the investment made by
pharmaceutical companies in developing new drugs.
Overall, synthesis is a critical process in the drug industry, enabling the
discovery, optimization, scale-up, and production of new drugs. It also plays a
crucial role in quality control, intellectual property, and ultimately, in
improving the health and well-being of people.

The synthesis of a drug involves several processes that are crucial to the
development of a new therapeutic agent. Here are some of the common steps
involved in the synthesis of drugs:
 1. Design and synthesis of lead compounds: This is the first step in the
synthesis of a drug. The design and synthesis of lead compounds involves the
identification and creation of a molecule with a desirable pharmacological
profile. The lead compound should have potent activity against the target, good
selectivity, and low toxicity.
2. Optimization of lead compounds: After identifying a lead compound, it is
subjected to further modifications to optimize its pharmacological properties.
This process is called lead optimization, and it involves synthesizing analogs of
the lead compound with various modifications to improve activity, selectivity,
and pharmacokinetic properties.
3. Scale-up and production: Once a lead compound is optimized, it is scaled
up to produce larger quantities of the drug. The synthesis of the drug involves
optimizing the reaction conditions, such as temperature, pressure, and
solvents, to produce the drug efficiently and with high purity.
4. Purification and isolation: The synthesized drug is then purified and
isolated using various techniques such as crystallization, distillation,
chromatography, and filtration. Purification is essential to remove impurities
and ensure that the drug is of the required purity and quality.
5. Characterization: The synthesized drug is characterized to ensure that it
has the correct chemical structure, purity, identity, and potency. This is done
using various analytical techniques such as NMR, mass spectrometry, HPLC, and
IR spectroscopy.
6. Preclinical and clinical testing: Once the drug is synthesized and
characterized, it undergoes preclinical and clinical testing to determine its
safety, efficacy, and pharmacokinetic properties. Preclinical testing involves
testing the drug in animals, while clinical testing involves testing the drug in
humans.
7. Regulatory approval: Finally, the drug undergoes regulatory approval by
the relevant authorities to ensure that it meets the required standards of safety
and efficacy. This involves submitting the drug for review by regulatory
agencies such as the FDA, EMA, or PMDA.
Overall, the synthesis of a drug involves a series of complex and interdependent
steps that are crucial to the development of a new therapeutic agent.
The purification of drugs is a critical step in the drug development process, as it
ensures that the drug is of the required purity and quality. Here are some
common methods used for purifying drugs:
1. Chromatography: Chromatography is a powerful technique used to
separate and purify complex mixtures of compounds. In the drug industry,
high-performance liquid chromatography (HPLC) and gas chromatography (GC)
are commonly used for drug purification. HPLC is particularly useful for
separating and purifying small molecules, while GC is useful for volatile
compounds.
2. Crystallization: Crystallization is a method of purifying solid compounds.
In this method, the drug is dissolved in a suitable solvent and then allowed to
cool, causing the drug to crystallize. The crystals are then collected by filtration
and washed to remove impurities.
3. Distillation: Distillation is a technique used to separate and purify
volatile compounds. In this method, the drug is heated, causing it to vaporize.
The vapor is then condensed and collected, leaving behind impurities and other
non-volatile compounds.
4. Filtration: Filtration is a simple and effective method of purifying drugs.
In this method, the drug is dissolved in a suitable solvent and then passed
through a filter. The filter removes impurities, leaving behind a purified drug.
5. Extraction: Extraction is a method of purifying drugs that are present in
complex mixtures. In this method, the drug is extracted from the mixture using
a suitable solvent. The solvent is then evaporated, leaving behind a purified
drug.
6. Electrophoresis: Electrophoresis is a technique used to purify proteins
and other large molecules. In this method, the drug is subjected to an electric
field, causing it to migrate through a gel. The gel separates the drug based on its
size and charge, allowing for purification.
Overall, the purification of drugs is a critical step in the drug development
process, as it ensures that the drug is of the required purity and quality. The
method used for purifying a drug depends on the nature of the drug and the
impurities present, and often involves a combination of different purification
techniques.
 Elucidating Organic Molecules

 You are expected to be able to identify organic functional groups, their properties, how to test
for their presence and how they are made

Functional groups

 The table below summarises the tests to identify the presence of certain functional groups and
the reactions to make them

Functional groups, their reactions & identifying tests table

Functional Group Test Production

Hydrogenation of alkenes using

H2, Pt/Ni catalyst and heat
Alkane
Cracking of crude oil using heat
and Al2O3 catalyst
Elimination of halogenoalkanes
by heating it with
NaOH(ethanol) Dehydration of
Alkene Decolourises bromine water
alcohols using hot Al2O3 catalyst

Cracking of crude oil using heat

and Al2O3 catalyst
Fee-radical substitution of
alkanes using UV and a halogen

Form silver halide precipitate with Electrophilic addition of

dilute nitric acid, silver nitrate and
hydrogen halides to alkenes
Halogenoalkane
dilute ammonia solution (AgCI =
Nucleophilic substitution of an
(primary, secondary and tertiary) white, AgBr = cream and AgI = alcohol, e.g. by reaction with
yellow) HX (g) or with KCl and
concentrated H2SO4 or
concentrated H3PO4 or with
PCl3 and heat or with PCl5 or
with SOCl2
Alcohol React with carboxylic acid and Electrophilic addition of alkenes
sulfuric acid to make esters using hot steam, concentrated
(primary, secondary and tertiary) which have fruity smells phosphoric(VI) acid as a catalyst

Primary alcohols get oxidised to Oxidation of alkenes using cold,

aldehydes (give positive test
 dilute KMnO4 to form a diol

Nucleophilic substitution of
halogenoalkanes using heat and
with Fehling's and Tollens' NaOH (aq)
solution and carboxylic acids
Reduction of aldehydes and
Secondary alcohols are oxidised ketones using NaBH4 and
to ketones (positive test with LiAlH4 (aldehydes are reduced
2,4-DNPH but not Fehling's and to primary alcohols and ketones
Tollens' solution) are reduced to secondary
alcohols)
Tertiary alcohols can not be
oxidised Reduction of carboxylic acid
using LiAlH4

Hydrolysis of esters using dilute

acid or dilute alkali
Silver mirror in Tollens' reagent Oxidation of primary alcohols by
and red precipitate in Fehling's
reagent and red slowly adding
Aldehyde solution
warm alcohol to acidified K2Cr2O7 or
Orange precipitate with 2,4- KMnO4 and distillation
DNPH
Oxidation of secondary alcohols by
reagent and red slowly adding
Ketone Orange precipitate with 2,4-DNPH
warm alcohol to acidified K2Cr2O7 or
KMnO4 and distillation

Oxidation of aldehydes and

ketone acidified K2Cr2O7 or
KMnO4 and refluxing
React with carbonates to form
Hydrolysis of nitriles with dilute
Carboxylic Acid CO2 gas which will turn limewater
acid or dilute alkali followed by
cloudy acidification

Hydrolysis of ester with dilute

acid or dilute alkali followed by
acidification
Condensation reaction of alcohols
Ester Have sweet, fruity smells and carboxylic acids with hot,
concentrated H2SO4 as catalyst

Amine Turns universal indicator blue / Nucleophilic substitution of

 halogenoalkanes when heated
purple
under pressure with NH3 (ethanol)

Nucleophilic substitution of
halogenoalkanes when heated
Nitrile
under pressure with KCN (ethanol)
and heat

Types of reactions

 You should also be aware of the different type of reactions that functional groups can undergo

Reactions of functional groups table

Type of reaction Definition Reagents Products

The addition of alkenes

Hydrogenation H2, Pt / Ni catalyst Alkanes
with hydrogen

The process in which

large, less useful
hydrocarbon molecules
Cracking are broken down into Al2O3 catalyst and heat Alkanes and alkenes
smaller, more useful
molecules in an oil
refinery

The reaction in which

halogen atoms substitute
for hydrogen atoms in
alkanes, The mechanism
involves steps in which
Free-radical substitution Halogen and UV light Halogenoalkane
reactive free radicals are
produced (initiation),
regenerated (propagation)
and consumed
(termination)

Electrophilic Addition The mechanism of the Electrophile (eg. Br2 , Halogenoalkane

reaction in which an NaOH, KCN, NH3 and HBr)
electrophile attacks the
 C=C bond and addition
across the double bond
occurs

The mechanism of the

reaction in which a
nucleophile attacks the Halogenoalkane, alcohol,
Nucleophilic Addition Nucleophile (e.g. HCN)
carbon atom in a carbonyl nitrile or amine
group and addition across
the C=O bond occurs

The replacement of an
atom by another atom or
group of atoms after Electrophile (eg. Br2,
Electrophilic Substitution
initial attack by an NaOH, KCN, NH3 and HBr
electron—deficient
species

The mechanism of the

organic reaction in which
a nucleophile attacks a
carbon atom carrying a
Nucleophilic Substitution potential positive charge. Nucleophile (eg. HCN)
This results in the
replacement of an atom
carrying a partial negative
charge by the nucleophile

The loss of electrons or

Oxidising agent such as Alcohol, aldehyde, ketone
Oxidation gain of oxygen of an atom,
acidified K2Cr2O7 or KMnO4 or carboxylic acid
ion or molecule

The gain of electrons or Alkene, aldehyde, primary

Reducing agent such as
Reduction loss of oxygen of an atom, and secondary alcohol,
NaBH4 or LiAlH4
ion or molecules carboxylic acid

The breakdown of a
Water or dilute acid or
Hydrolysis compound by water or by
alkali
dilute acids or alkali

Condensation A reaction in which two Two molecules that can Small molecule and a
organic molecules join react with each other larger molecule
 together an din the
process eliminate a small
molecule such as water or
hydrogen chloride

Oxidising & reducing agents

 Certain functional groups only react with specific oxidising and reducing agents which you
should be aware of

Oxidising & reducing agents table

Oxidising Agent

Oxidises Oxidation Product Colour Change

Aldehydes then
Primary alcohols Orange to green
carboxylic acids

Secondary alcohols Ketones Orange to green

Acidified potassium
dichromate (K2Cr2O7 / Tertiary alcohols X
H2SO4)

Aldehydes Carboxylic acids Orange to green

Ketones X

Aldehydes then
Primary alcohols Purple to colourless
carboxylic acids

Secondary alcohols Ketones Purple to colourless

Acidified potassium
permanganate (K2Mn2O4 / Tertiary alcohols X
H2SO4)

Aldehydes Carboxylic acids Purple to colourless

Ketones X
 Alkenes Diol Purple to colourless

Reducing Agent

Reduces Reduction Product

Carboxylic acids X

Aldehyde Primary alcohol

Sodium borohydride (NaBH4)
Ketone Secondary alcohol

Alkene X

Carboxylic acids Aldehyde then primary alcohol

Aldehyde Primary alcohol

Lithium aluminium hydride (LiAlH4)
Ketone Secondary alcohol

Alkene X

Carboxylic acids X

Aldehyde X
Hydrogen and Pt / Ni Catalyst (H2,
Pt / Ni catalyst)
Ketone X

Alkene Alkane

Tests

 The test also requires you to distinguish between the different tests that identify functional
groups in a compound

Tests identifying functional groups in a compound table

 Functional Group Tested Colour Change

Clear blue solution turns opaque

Fehling's Solution Aldehydes red/orange as a precipitate is
formed

Tollens' Reagent Aldehydes Silver mirror

Bromine water changes from

Bromine water Alkenes
orange/yellow

2,4—dinitrophenylhydrazine (2,4— Carbonyl compounds (aldehydes

Orange precipitate
DNPH) and ketones)

Yellow precipitate of
lodoform Methyl ketone (CH3CO—) group
triiodomethane

AgCl = white AgBr = cream & Agl =

Silver nitrate and ammonia Halogens
yellow

Worked example

Identify which tests give positive results with the following compounds and which oxidising and
reducing agents the compounds react with.

Answers:
Synthesis are required to get the desired product from the
starting [Link] can achieved that through the single
step reaction or multi step reactions.
Properties of functional groups
 In addition to the functional groups mentioned in the
AS course, with additional functional groups and
their properties including:
o Arenes

o Halogenoarenes
 o Carboxylic acids (and derivatives)
o Phenols
o Amides
o Amino acids
o Acyl chlorides

Reactions of functional groups

o The reactions by which these functional groups
can be produced
o The reactions that these functional groups
undergo
Multi-Step Synthetic Routes
 Many organic molecules are made in multi-step
synthetic routes

 These multi-step synthetic include reactions covered

in the A level course in addition to those in the AS
course
Analysis of Synthetic Routes
 Apply your knowledge on functional groups and their
reactions by critically analysing a given synthetic
route in terms of:
o The type of reaction

o The reagents used for each step

o Any possible by-products

Organic Synthetic Routes
DRUGS
How do we go about designing new molecules to fight diseases?

The new drug will need to stop particular bacteria or viruses working. The structural features may be
associated with the active site on a particular enzyme needed for an essential function of the pathogen
(the disease-causing organism).

Once these structural features have been identified, we can then predict the shape of a molecule that
would fit into, and then block, the active site.

The functional groups present are also very important to ensure the drug can bind into the active site
effectively.

The intermolecular bonds formed between the drug and its target molecule could involve hydrogen
bonding, ionic attraction, dipole–dipole forces, and instantaneous dipole–induced dipole forces.

Computers are now used to judge the fit between a potential drug molecule and a receptor site on its
target molecule. Such ‘molecular modelling’ h as greatly speeded up the process of designing new
medicines.

Scientists using X-ray crystallography (a method in which a sample is irradiated with X-rays and the
pattern is analysed by computer) worked out the shape of HIV protease in 1988. Knowing its structure
made the search for drugs to fight AIDS much quicker and cheaper than traditional trial-and-error
methods.

Researchers realised that if a molecule could be discovered that could block its active site, this might
be one step on the route to finding a cure for AIDS. Knowing the molecule that the enzyme worked on
(its substrate), researchers
were able to construct similar molecules on the computer screen to fit the active site.

molecular modelling has helped in the search for new and improved medicinal drugs. For Example

 the method used to determine the structure of HIV protease

 how anti-viral drugs work

 the time and costs involved.

The pharmaceutical industry is constantly searching for new drugs. Research chemists have
discovered
that most of these drugs contain at least one chiral centre, where two mirror-image isomers
are called enantiomers and they will be optically active. They differ only in their ability to rotate the
plane
of polarised light to the left or to the right, and in their potential biological activity (and hence their
effectiveness as medicines).

Using conventional organic reactions to make the desired product will yield a 50 : 50 mixture of the
two
enantiomers. We call this a racemic mixture. Although the physical and chemical properties of the
enantiomers will be identical, each differs in its biological (or pharmaceutical) activity, i.e. the effect
the
drug has on the body.

For example, naproxen is a drug used to treat the pain caused by arthritis. One of its enantiomers will
ease the pain but the other can cause liver damage.
Another example of the need to separate the enantiomers from a racemic mixture, one enantiomer of
a
drug used to treat tuberculosis (TB) is effective, whereas the other can cause blindness.

about 80% of new drugs patented are single enantiomers.

Using pure enantiomers will be beneficial as it:

 reduces the patient’s dosage by half as the pure enantiomer is more potent, i.e. has better
therapeutic
activity (thereby cutting the cost of production)

 minimises the risk of side-effects (thereby protecting patients from further problems and
protecting
drug companies from possible legal action for damages if serious side-effects do occur).

Preparing pure enantiomers for use as drugs

Optical resolution
By following a traditional synthetic route to make the compound, resulting in a racemic (50 : 50)
mixture. Then they separate the two enantiomers in a process called optical resolution.

This involves using a pure enantiomer of another optically active compound (called a chiral auxiliary)
that
will react with one of the isomers in the mixture. The new product formed will now have different
properties
and so can be separated by physical means. For example, their solubility in a given solvent will differ
so the
unwanted enantiomer and the new product can be separated by fractional crystallisation. The new
product
is then converted back to the desired enantiomer in a simple reaction (e.g. by adding dilute alkali).
The crystallisation is repeated many times to ensure purity. This method is difficult, time-consuming,
uses
extra reagents and involves the disposal of half the original racemic mixture.

Large volumes of organic solvents (often harmful to the environment) are used in the process.
However,
chemists are now using supercritical carbon dioxide as a solvent, which is much safer. At 31 °C and 73
atmospheres pressure, CO2 is a suitable non-polar solvent for many drug derivatives in the racemic
resolution process. The solubility of the derivatives can be changed simply by varying the density of
the
solvent. The solvent, which is non-toxic, is easily removed by reducing the pressure and then recycling
it to
use in the process again.

We can also use high-performance liquid chromatography (HPLC) to separate a racemic mixture, as
long as
the stationary medium (i.e. the solid that packs the column) is itself optically active.

Using optically active starting materials

This technique uses starting materials that are themselves optically active and in the same orientation
as
the desired product. These are often naturally occurring compounds such as carbohydrates or L-amino
acids. The biochemist will choose from this ‘chiral pool’. The synthetic route is designed to keep any
intermediates and the final product formed in the same enantiomeric form. As a result, there is no
need to
carry out the costly separation process needed when a racemic mixture is produced.

Chiral catalysts
Chemists are also developing new chiral catalysts that ensure only one specific enantiomer is formed
in a
reaction. The benefits of these catalysts are that only small quantities are needed and they can be
used
over and over again, although the catalyst itself can be expensive. A ruthenium (Ru) organometallic
catalyst is used in the production of naproxen, a drug to treat arthritis.
Often scientists need a combination of optical resolution and chiral synthesis in the production of a
pharmaceutically active, pure enantiomer.

The pharmaceutical industry can also use enzymes to promote stereoselectivity and produce single
enantiomer
products. The specific shape and the nature of the molecular interactions at the active site of
an enzyme (a biological catalyst) ensure that only one enantiomer will be formed, as in living things.
The
enzymes are often immobilised (fixed in place) on inert supports. This enables the reactants to be
passed
over them without the need to separate the product from the enzymes after the reaction.
However, it can be expensive isolating enzymes from living things. Using whole organisms, such as
bacteria, can reduce this cost. In recent times, synthetic enzymes designed for a particular synthesis
have
also been made. Therefore, a search for a suitable enzyme from the limited pool available from natural
sources is not always necessary.
Overall, using an enzyme process might take longer to develop than a conventional synthetic route,
but in
the long run the benefits generally outweigh the disadvantages. There are fewer steps needed in the
synthesis route, resulting in a ‘greener’ process.
The impact of chiral technology on the pharmaceutical
industry
Taxol
The anti-cancer drug Taxol was originally obtained from
the bark of the Pacific yew tree. Unfortunately, it occurs
in such small amounts that it was estimated that you
would have to cut down six 100 year-old trees to get
enough Taxol to treat just one patient.
Clearly that is impossible, and so a lot of work went into
finding a way of synthesising the drug in the lab. Because
Taxol is a seriously complicated molecule, that wasn't so
easy. However, eventually it was done.
Here is the structure of Taxol shown as a skeletal formula.
The Taxol molecule has a lot of chiral centres. These are
carbon atoms which have four different groups attached to
them. You can spot them very easily in this particular
diagram of the structure of Taxol, because these are the
ones which show the spatial arrangement of the atoms
using either dotted or solid wedges.
There will be a very large number of possible optical
isomers of Taxol, so why is only one of them likely to be
present in the yew tree?
In any biological system, molecules are synthesised and
broken down by reactions involving enzymes, but
enzymes work by a lock-and-key mechanism. A molecule
has to be exactly the right shape to fit the enzyme.
Different arrangements around a chiral centre will force
an entirely different shape on the molecule, and it may
well no longer fit the enzyme. So enzyme systems will
tend to produce a single optical isomer because that is the
only shape they can work with.

So why is the presence of chiral centres important to drug

design?
Each chiral centre will have two possible arrangements of
bonds around it. A different arrangement of bonds will
mean a differently shaped molecule. And differently
shaped molecules won't necessarily fit the active site of an
enzyme, or whatever else the drug needs to attach to.
A fairly simple example of a drug with a single chiral
centre is thalidomide - a drug which was prescribed for
morning sickness in pregnancy in the 1950s. The chiral
centre is circled in red below:

This will have two optical isomers. One was the right
shape and so did what it was supposed to, but the other
one behaved completely differently, causing major birth
defects. It is believed that the isomer responsible
interfered with DNA.
These days, a lot of effort goes into producing a single
isomer of a drug. Chemical reactions frequently produce
mixtures of optical isomers. Trying to produce just one
isomer is known as asymmetric synthesis.
Reasons for producing drugs consisting of a single active
isomer:
 It lowers the chances of undesirable side-effects due
to the other isomers.
 It is cheaper in the long-run, because it is a waste of
money and materials producing a drug half of which
(or more) is of no use.
  The patient can be given smaller doses if all the drug
is active.

Chirality is hardly a new concept in

chemistry, yet advances in chiral
technology have had a growing impact on
pharmaceutical research and development
Arguments over the past few years. Chiral technology
that now exerts a strong influence on rational
developing drug design. It aids the conception and
single discovery of new receptor-based or
isomers is enzyme-inhibiting small molecule drugs,
somehow especially where high selectivity of action
too is sought. Its acceptance is largely because
difficult or there is now an abundance of technology
too in place for the manufacture of single-
expensive enantiomer chiral drugs.
are no For those unfamiliar with chiral technology,
longer the term encompasses the range of
valid techniques for producing the single-handed
forms (enantiomers) of compounds that have
sufficient molecular complexity to be chiral -
that is, when molecules cannot be
superimposed on their mirror images. Since
the specificity of drugs increases as the
molecules become more complex, the drive
for more specific drugs will lead to a greater
proportion being chiral. If a drug is chiral,
then in biological terms the enantiomers
invariably differ in activity. One may
specifically interact with a cell receptor to
produce the desired outcome while the other
might have no useful application or might
have an unwanted effect through some other
interaction.
In the clear-cut example where one isomer of
a chiral compound is 'good' and the other
'bad', there is obvious benefit from
developing the drug as the single isomer to
enhance its safety and tolerability. In
addition, this can also speed the progress of
the drug through regulatory channels,
thereby saving R&D costs.