SYNTHETIC METHODS IN

MEDICINAL CHEMISTRY
PCH 311

O.C POYI
2024
 Objective
• you should be able to design a multistep
synthesis to prepare a given product from
a given starting material, using any of the
reactions introduced
 DEFINITION
• The term synthesis means in Greek “put
together”.
• Synthetic organic chemistry is the “art” of
building-up complex molecular structures
of organic compounds putting together
smaller, easily accessible (commercially
available) compounds.
 DEFINITION
• Synthetic methods in organic chemistry
refer to the various chemical reactions and
techniques used to intentionally construct
complex organic molecules from simpler
starting materials, often utilizing a series of
steps to achieve the desired structure
• MEDICINAL CHEMISTRY; Medicinal
chemistry involves the creation and
refinement of molecules for the purpose of
creating or improving drugs.
• It is grounded in synthetic organic
chemistry, a discipline in which scientists
combine small molecules to create new
ones.
• The two central issues faced by
the medicinal chemist are
 “what to make” and

 “how to make it.”

common methods including:
 substitution reactions,
 elimination reactions,
 addition reactions,
 oxidation-reduction reactions,
 cross-coupling reactions,
 metathesis,
 C-H functionalization, and photocatalysis;
• the process of designing a synthetic route
is often done using a strategy called
retrosynthesis.
Key points about synthetic methods in
organic chemistry:
Goal:
• To create new organic compounds with
specific desired properties by carefully
manipulating functional groups and
molecular structures.
Building blocks:
• Organic synthesis typically starts with
readily available small molecules as
building blocks, gradually constructing
more complex molecules through a series
of reactions.
 Reaction types
• Nucleophilic substitution: Replacing an
atom or group with a nucleophile.
• Electrophilic addition: Adding atoms to a
double or triple bond with an electrophile.
• Elimination reactions: Removing atoms
from a molecule to create a double or
triple bond.
• Grignard reactions: Using organometallic
reagents to form new carbon-carbon
bonds.
• Diels-Alder reaction: A cycloaddition
reaction used to form cyclic compounds.
• Wittig reaction: Forming a carbon-carbon
double bond using a phosphorous ylide.
 Retrosynthesis
• A strategy where chemists work
backwards from the target molecule to
identify potential starting materials and
reaction sequences.
 Important
considerations
• Selectivity: Ensuring the desired product
is formed preferentially over other possible
byproducts.
• Yield: Maximizing the amount of desired
product obtained from the reaction.
• Stereochemistry: Controlling the spatial
arrangement of atoms in the final
molecule.
• The efforts of synthetic organic chemists
therefore are devoted not only to the total
synthesis of complex organic compounds
(target oriented synthesis), but also to the
development of new synthetic methods
(method oriented synthesis).
 Target Oriented Synthesis
• The goal of target oriented synthesis is the
obtainment of a more or less complex
organic molecule.
• It can be a natural bioactive compound, or a
compound derived from rational design as
potentially bioactive, or a compound of
commercial relevance, or even a compound
of theoretical interest.
• Drugs, flavors, nutraceuticals, new
materials are examples of the most
common and interesting targets.
 Method Oriented Synthesis
• The methods oriented synthesis is
devoted to the development of new
reagents, new catalysts, new reaction and
work-up procedures, in general to any
innovation that can improve a synthetic
procedure.
• Particular attention is devoted to the
yields, the stereochemical outcome, the
atomic economy of the reactions (in terms
of atoms of the reagents that are not
inserted in the products, and therefore
lost), and more generally to the
environmental impact of the process
 KOLBE SYNTHESIS
• Kolbe’s reaction, also known as Kolbe
Schmitt Reaction, is a type of addition
reaction named after Hermann Kolbe and
Rudolf Schmitt.
• When phenol is treated with sodium
hydroxide, phenoxide ion is generated.
• The phenoxide ion generated is more
reactive than phenol towards electrophilic
aromatic substitution reaction.
• Hence, it undergoes an electrophilic
substitution reaction with carbon dioxide,
which is a weak electrophile.
• Ortho-hydroxybenzoic acid (salicylic acid)
is formed as the primary product.
• This reaction is popularly known as
Kolbe’s reaction.
 EXAMPLE OF KOLBE
REACTION

The mechanism of Kolbe’s

reaction proceeds through the
nucleophilic addition of phenoxide to carbon
dioxide, yielding the salicylate.
• The salicylate formed further reacts with
the acid to form salicylic acid.
• It is a carboxylation reaction where
sodium phenoxide is heated with carbon
dioxide under a pressure of 100
atmospheres and a temperature of 125
degrees Celsius, and the resulting product
is treated with sulfuric acid to yield salicylic
acid (an aromatic hydroxy acid).
 Applications of
Kolbe’s Reaction
• When potassium Hydroxide is used in
Kolbe’s reaction, 4-Hydroxybenzoic acid
can be accessed.
• This is an important precursor for
parabens (parahydroxybenzoate or ester
of para-hydroxy benzoic acid, used as a
biocide in cosmetic products).
• Kolbe’s reaction can also be used for the
industrial synthesis of 3-hydroxy-2-
naphthoic acid, which is a common
precursor to azo dyes and pigments.
• Salicylic acid can be used to make aspirin
by reacting it with acetic anhydride. Aspirin
is commonly used as a painkiller.
 Reimer-Tiemann
Synthesis
• Reimer-Tiemann reaction is a chemical
reaction used for producing phenolic
aldehydes under the action of chloroform
and caustic alkaline on phenol in
industries.
• Reimer-Tiemann reaction is an aromatic
substitution reaction with great industrial
importance.
The reaction proceeds in the following steps:
• Formation of dichlorocarbene
• Nucleophilic reaction: The phenoxide
reacts with the electrophilic carbene
• Hydrolysis: The aldehyde is formed
• Reaction: When phenol, i.e. C6H5OH, is
treated with CHCl3 (chloroform) in the
presence of NaOH (sodium hydroxide), an
aldehyde group (-CHO) is introduced at
the ortho position of the benzene ring
leading to the formation of o-
hydroxybenzaldehyde.
• The reaction can be divided into normal
and abnormal transformations, depending
on the products.
• The normal reaction yields one or more
aldehydes, while the abnormal reaction
yields cyclohexadienones and ring-
expansion products.
•A common example of the Reimer Tiemann
reaction is the conversion of phenol to
salicylaldehyde (2-hydroxy benzaldehyde),
as shown below.
• Since hydroxides are not readily soluble in
chloroform, a biphasic solvent system is
employed to carry out the reaction.
• This biphasic solvent system can consist of
an aqueous hydroxide solution with an
organic phase that contains chloroform.
• These two reagents that are separated are
brought together for the reaction to occur.
• Techniques to bring these two reagents
together include – rapid mixing, phase-
transfer catalysts or the use of an
emulsifying agent.
• The reaction is quite effective when other
hydroxy-aromatic compounds are used,
for example, naphthols.

• Heterocyclic organic compounds that are

quite rich in electrons, such as pyrroles
and indoles, also can undergo the Reimer
Tiemann reaction.
• The reaction needs heat to initiate the
process. However, once the reaction has
begun, it can prove to be highly
exothermic and further increase the
reaction rate.
• This is the reason why the Reimer
Tiemann reaction is prone to thermal
runaways
The mechanism of the Reimer Tiemann reaction
can be explained in the below-given steps:
• The chloroform is deprotonated by the strongly
basic aqueous hydroxide solution, giving the
chloroform carbanion.
• This chloroform carbanion readily undergoes
alpha elimination, giving dichlorocarbene as the
product. As mentioned earlier, dichlorocarbene
is the main reactive species.
• The aqueous hydroxide also deprotonates the
phenol reactant, yielding a negatively charged
phenoxide.
• This negative charge is now delocalized into the
benzene ring, causing it to be far more
nucleophilic.
• This results in a nucleophilic attack on the
dichlorocarbene, forming an intermediate
dichloromethyl-substituted phenol.
• This intermediate is subjected to basic
hydrolysis to finally achieve the formation
of the desired ortho-hydroxybenzaldehyde.
HANTZSCH CONDENSATION
REACTION
• The Hantzsch condensation reaction is a
multicomponent organic transformation
that involves the condensation of an
aldehyde, a β-ketoester, and ammonia to
produce dihydropyridine derivatives.
• One-Pot Synthesis of Nifedipine
The corresponding synthesis of Nifedipine can be developed
in a 'one-pot' reaction (Hantzsch condensation). However, it
yields several products and therefore is not optimal.
• Two Steps Retrosynthesis Scheme of
Nifedipine
The retrosynthesis of Nifedipine presented here
involves two steps, but is more preferable
because it does not have the drawback of
impurities.
• Two Steps Synthesis of Nifedipine
In the first step, the benzylidine ester 4 is produced
(intermediate Knoevenagel product). A Hantsch reaction
follows with the ethyl 3-aminocrotonate 5, which leads to
the desired product.
 Carbon- Carbon Bond
Formation
• Carbon–carbon bond-forming reactions
are organic reactions in which a new
carbon–carbon bond is formed.
• They are important in the production of
many human-made chemicals such as
pharmaceuticals and plastics.
• A carbon–carbon bond is a covalent
bond between two carbon atoms.
• The most common form is the single bond
- sp3- hybridized orbitals,
• Double bond - sp2- hybridized orbitals,
• Triple bond - sp- hybridized orbitals,
 CHAINS AND BRANCHING
• Carbon is one of the few elements that
can form long chains of its own atoms, a
property called catenation.
• This coupled with the strength of the
carbon–carbon bond gives rise to an
enormous number of molecular forms,
many of which are important structural
elements of life
• Branching is also common in C−C
skeletons.
• Carbon atoms in a molecule are categorized
by the number of carbon neighbors they
have:
• A Primary carbon has one carbon neighbor.
• A Secondary Carbon has two carbon
neighbors.
• A Tertiary Carbon has three carbon
neighbors.
• A Quaternary carbon has four carbon
neighbors.
 Synthesis
Some examples of reactions which form
carbon–carbon bonds are the
• aldol reaction,
• Diels–Alder reaction,
• Grignard reaction,
• cross-coupling reactions,
• Michael reaction and
• Wittig reaction.
• The reverse reaction, where a carbon-
carbon bond is broken, is known
as carbon-carbon bond activation.