HETEROCYCLIC CHEMISTRY IN PHARMACEUTICAL CHEMISTRY

HETEROCYCLIC
A heterocyclic compound is one that contains a
ring made up of more than one kind of atom.
O
N
H
S
N O
O

Naming heterocycles
Saturated heterocycles are regarded as derivatives of
the related carbocycles.
A prefix is used to denote the presence and identity
of the heteroatom.
Aza- Nitrogen
Oxa- Oxygen
Thia- Sulphur
Phospha- Phosphorous

Naming heterocycles is dependent on:
Z
(H2C)n
 Type of the heteroatom Z
Ring size
Nature of ring (Saturated or Unsaturated

Ring Size Suffix Saturated Unsaturated
3 -ir -irane -irine
4 -et -etane -
ete
5 -ol -olane -ole
6 -in -inane -ine
7 -ep -epane -epine
8 -oc -ocane -ocine
9 -on -onane -onine
10 -ec -ecane -ecine

O S HN
Oxirane Thiirane
Aziridine
(Oxacyclopropane) (Thiacyclopropane) (Azacyclopropane)
O S NH
Oxetane Thietane Azetidine
O N
H
S
Oxolane
Thiolane
Azolidine
O
HN S
Oxirine
Azirine Thirine
S
F
2-Fluorothiirane
N
CH3
N-methylaziridine
(N-methylazacyclopropane)

N
O S H
N
Pyridine Furan Thiophen Pyrrole
5 Membered Rings
These are widely known and well studied
heterocycles. They have ending of –ole. The most
important ones are Furan, Thiophen and pyrrole
O S H
N
Furan Thiophen Pyrrole

O
S
N
H
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
N
H
S
H3C
4-Methyl pyrrole
Br
O2N
2-bromo-4-nitrothiophen S
NO2
Br
4-bromo-2-nitrothiophen
N
H
H
Pyrrolinium Cation
1(H) Pyrrolinium
N N
H
H
H
3(H) Pyrrolinium
H
H
H
O
H
H
3(H) Furaninium cation

Pyrridones
N
H O
H
H
1,3-Dihydro-pyrrol-2-one
4-Pyrrolin-2-one
N
H
Pyrrolidine
N
H
1H-Pyrrole
complete
reduction
N
H
O
H
H
Pyrrolidones
4-pyrrolin-2-one
N
H O
3-Pyrrolin-2-one
N
H O
2-hydroxypyrrole
O
S
S
H
O
O
S
S
Furan
1(H) Thiophen
O
H
H
2-3(H)-furanone
O
H
H
2-5(H)-furanone
O
Thiol-4-ene-2-one
O
Thiol-3-ene-2-one
OH
2-hydroxy thiophen

O
O
O
Furan-2,3-dione
5 Membered ring that contain 2 heteroatoms
(AZOLES)
N
H
N
S
N
O
N
O
N
1,3-Imidazole
1,3-Thiazole 1,3-Oxazole
1,2-Oxazole
(Isoxazole)
Note: The more electronegative atom is considered as position (1)

Some more compounds
N
H
N
O
N
S
N
O
N
H
H
O
Imidazol-4-one
O
Oxazol-5-one
O
H
H
Thiazol-2-one
O
1,3-Oxazol-5-one
N
H
H
N
Imidazolidine
N
H
N
4,5-dihydroimidazole
O
H
N
Oxazolidine
O
N
Oxazoline
O
N
O
N
O
N
O
N
  

2
3
-Oxazoline
4
2
-Oxazoline
-Oxazoline
-Isoxazoline

Synthesis of five member rings (Pyrroles, Furans,
Thiophenes) are prepared from -dicarbonyl
ɣ
compounds
•Paal-Knorr Synthesis for Pyrroles

CH3CCH2CH2CCH3
O O
+ (CH3)2CHNH2
CH3COOH,Heat, 17 h
N
H3C
CH3
CH(CH3)2
N-(1-methylethyl)-2,5-dimethyl
pyrrole
R
R
OO
R1
NH2, or P2O5 or P2S5
H2O
-
X
R
R
X = NR1
, O, S
CH3CCH2CH2CCH3
O O
P2S5, heat 140 - 150
S
CH3
H3C
60%
2,5-Dimethylthiophene
CH3CCH2CH2CCH3
O O
P2O5, heat
O CH3
H3C
2,5-Dimethylfuran

REACTIONS OF 5 MEMBER RINGS
Non aromatic heterocyclic amines have basicity constants that
approximate those of their acyclic counterparts
(CH3CH2)2NH Kb = 9.6 X 10-4
N
H
kb = 1.3 X 10-3
Pyrrolidine
N
H
kb = 2.5 X 10-4

Pyrrole, Furan and Thiophen all undergo normal aromatic hydrocarbon
reactions such as nitration, hydrogenation, sulfonation and Friedel-Crafts
acylation.
They are much reactive than Benzene. Electrophilic reactions take place
at positions 2 and 5. Position 2 is the most likely.
N
H
S
+ C6H5COCl
SnCl4
S
COC6H5
+ CHCl3
KOH
N
H
CHO

SIX MEMBER RINGS
N
H
Piperidine
O
Tetrahydro-pyran
N
Pyridine
O
4H-Pyran
Pyridine do not undergo alkylation and acylation due to the dipole moments
6 -membered rings containing two heteroatoms
The most importants are those containing 2-nitrogen atoms
N
N
N
N
N
N
1,2 position 1,3-position 1,4-position
NOTE: irrespective of the substituent the -aza number should carry the least algebraic sum.
Pyradazine pyrimidize
Pyrazine

SYNTHESIS OF PYRIDINE
Pyridine is synthesized by using the reaction of 1,5-diketones with ammonia to give unstale dihydropyridines
which are easily oxidized to pyridines
O O
NH3
2H2O
- N
H
[O]
N
Unstable
Synthesis of 2-methoxy-4-methyl-5-nitro pyridine
OMe
Me
O2N
Start
N
Me
NaNH2
(Xylene) N
Me
NH2
N N
N
H
N
N
Me
O2N
OMe
NO2
NH2
Me Me
NH2
O2N
HNO3/H2SO4
O
0
NaNH2
dil HCl Me
O2N
O
Cl
Me
O2N POCl3
PCl5, Heat
MeONa
MeOH

Six membered ring containing one heteroatom with the
ring joined to a pure Benzene ring
N
N
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
a
b
c d
e
a
b
c
d e
f
Naphthalene Quinoline
Benzo[b] pyridine
Isoquinoline
Benzo[c]pyridine
N
H O
Carbostyril
2-1(H)-Quinolone
Benzob[b]2-1H- pyridone
NH
O
1-Isoquinolone
1-2(H)-isoquinolone
Benzo[c] pyridone
N
OH
2-Quinolinol
2-hydroxy quinoline
Benzo[b]2-hydroxy pyridine

O O
N
O O
O
2-Phenyl chromone
O
Coumarin
Benzo pyran-2-one
Benzo pyran
Benzo-4(h)-pyran
O
Chromone Quinolizinium Cation

N
H
Benzo[b] pyrrole
(Indole)
O
Benzo[b] furan
Benzofuran
S
Benzo[b]thiophen
Benzothiophen
N
H H
Indolinium cation
N
H
H
Pyrrolinium cation
N
H
Br
Br
2-bromo-5-methyl indole
NH
Benzo [c] pyrrole
Isoindole
5 membered rings attached to benzene

Applied Quinolines used as medicines
8- Aminoquinolines
World war one brought about the development of 8
aminoquinolines as antimalarials
Several workers such as Paul Ehrlich, Guttman, Schuleman etc
brought about the development synthetic antimalarials active
against plasmodium called pamaquine.
N
N
H
R
MeO CH3
CH(CH2)3NH2
Primaquine
CH(CH2)3N(C2H5)2
CH3
Pamaquine
-(CH2)3-CHNH2
CH3
Quinocide
(CH2)5NHCH(CH3)2
Pentaquine
R =

Synthesis of Primaquine
NH2
NO2
MeO
Skraup synthesis
Glycerol, H2SO4
N
NO2
MeO
N
Sn/HCl
MeO
NH2
CH3
CH(CH2)3NH2. HBr
Br,
MeO
HN
CH
(CH2)3NH2
H3C
Condensation
Primaquine

SAR (Structure Activity Relationships
A 6-methoxy substituent appears not essential for antimalarial activity
Introduction of a 6-methyl group gives gives the a complete loss of
antimalarial activity
Additional substitution on the quinoline nucleus tend to decrease both
activity and toxicity
Reduction of quinoline nucleus to 1,2,3,4-tetrahydro analogues gives the
compound to retain antimalarial activity but with lower potency and
toxicity
Primaquine is the most effective and best tolerated and mostly used in this
group. It causes haemolysis recognisable by a dark or dark-brown urine.
Pamaquine is effective against exoerythrocytic forms of plasmodium in
the liver and against gametocytes

4-Aminoquinolines
Success with 8-aminoquinolines brought about research
centred on the quinine structure
It was found that position 4 of the quinine nucleus produces
changes with good antimalarial properties.
4-amino-7-chloroquinolines produced highest activity
Examples include Chloroquine, Sontoquine, amodiaquine
which are superior to other drugs.

Synthesis of 4-Aminoquinolines
NO2
1) Chlorination
ii) Reduction Cl NH2
HCOOH
warm
Cl
N
H
CHO
RNH2
Cl N
H
NR
heat with
Dimethyl malonate
Cl N
H
C(COOC2H5)2
+ RNH2
Immediate cyclisation
N
OH
COOC2H5
Cl
i)Saponify
NaOH
ii) acidify
N
OH
COOH
Cl
Heat 235o
CO2
-
N
Cl
OH
N
Cl
Cl
SOCl2
4,7-Dichloroquinoline
The 4-chloro group is more reactive than the 7-chloro hence it will react more readily with an appropriate
amine to give the desired quinoline derivative
N
+ H2NR
Cl
Cl
N
NR
Cl
H

N
Cl
NHR
R1
COMPOUND R R1
Chloroquine
(Resochin, Meraquine)
CH3
CH(CH2)3N(C2H5)2
-H
Hydroxychloroquine
(Plaquenil)
CH3
CH(CH2)3N
CHCH3
C2H5
OH
-H
Sontoquine
CH3
C
H
(CH2)3N(C2H5)2
-CH3
Amodiaquine
(Camoquine)
OH
CH2N(C2H5)2
CH2N(C2H5)2
-H

HETEROCYCLIC CHEMISTRY IN PHARMACEUTICAL CHEMISTRY

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