Transcript LECTURE 10

LECTURE 10
Classification of heterocyclic
compounds on the basis of their
chemical structure. Derivatives of
5-nitrofuran as antimicrobial
agents
associate prof. Mosula L.M.
 The plan
 1. Concept about heterocyclic
compounds and their classification.
 2. Derivatives of 5-nitrofuran as
antimicrobial agents: Nitrofurazone,
Nitrofurantoin, Furazolidone.
Concept about heterocyclic compounds
and their types

 Heterocyclic compounds are compounds, which
contain cycles with atoms Carbon and other
elements – heteroatoms (more often Оxygen,
Nitrogen, Sulphur). Such compounds widespread in
the nature (vitamins, antibiotics, enzymes, alkaloid)
also can be easily synthesized. Heterocyclic
compounds can contain cycles from three to six and
more atoms and to contain odes of one to four
heteroatoms, but the greatest practical value have
five-and hexatomic heterocycles.
Trimonial heterocycles:
Ethylene imine (aziridine)
N
Ethylene oxide
O
H
Pentatomic heterocycles with one heteroatom:
5
4
.. 1
O
H
1 N ..
2
3
furan
2
5
3
4
pyrol
5
4
.. 1
S
2
3
thiophene
Pentatomic heterocycles with two heteroatoms:
5
H1
N
4
pyrazol
N2 5
3
4
H1
N
S1
2
N
imidazole
3
5
2
4
N3
5
4
1
SH
2
NH
3
O 1
5
2
4
N3
1,3-thiazole 1,3-thiazolidin 1,3-oxazole
Pentatomic heterocycles with three
and four heteroatoms:
O1
5
N 2
4
N 3
S 1
5
N
2
4
N
3
S1
5
N
4
5
2
N2
3
H1
N
N
4
N3
5
H1
N
N
4
1,2,3-oxadiazole
1,3,4-thiadiazole
1,2,4- thiadiazole
1,3,4-triazole
1,2,3,4-tetrazole
N2
N
3
Condensed derivatives with pentatomic
heterocycles:
7
6
7
O 1
2
5
3
4
6
H
N 1
7
6
2
N3
5
4
H1
N
5
N
2 N
3
4
NH
N
benzofuran
benzimidazole
indole
purine
 Feature of structure and chemical properties of
pentatomic heterocycles
 Furan is pentatomic heterocycle with one
heteroatom – atom Oxygen:
O 1

5
2
4
3
 Pentatomic heterocycles with one heteroatom
(furan, pyrol, thiophene) have properties of
aromatic compounds. -Position is most reactive.
For its compounds characteristic are reactions of
halogenation, alkylation, acylation, sulphonation,
nitration.
Drugs –derivatives of furan
In medical practice use derivatives of 5-nitrofuran
5
O 1
2
O2N
4
3
Syntetical derivatives of 5-nitrofurfurol, which has substituens
in position 2.
O2N
5
4
O
1
2 CH
NR
3
It is general formula of 5-nitroderivatives of furan series with
bactericidal action.
 Nitrofurazone
 (Nitrofural, Ph Eur monograph 1135)

Nitrofuralum

Furacilinum

H
O2N
O
C
N
O
N
H
C
NH2

 C6H6N4O4
198.1
59-87-0

 DEFINITION

 Nitrofural contains not less than 97.0 per cent and not
more than the equivalent of 103.0 per cent of 2-[(5-
nitrofuran-2-yl)methylene]diazanecarboxamide,
calculated with reference to the dried substance.
Synthesis
 Synthesis nitrofurazone (furacilinum) from furfurol (furilaldehyde):
 1. Furfurol nitration
O
O
O
O
HONO2 O N
2
C
H (CH3CO)2O
H
furfurol
O
C
CH3
O
CH
O
C
CH3
H2SO4
O2N
HOH
-2 CH3COOH
5-nitrofurfuroldiacetate
O
O
C
H
5-nitrofurfurol
O
O
O
O
(CH3CO)2O
C
O
O
H2O, H2SO4
-2CH3COOH
O
O
O
O2N
C
H
CH3
O
CH
H
C
C
CH3COONO2
HNO3 + C5H5N
CH3
O
O
O2N
C
CH3
O
CH
O
C
CH3
*Acetylnitrate –is anhydride СН3СООН and HNO3:
O
O
H3C
+ HO-NO2
C
OH
-H2O
H3C
C
O
NO2
2. Condensation 5-nitrofurfurol with semicarbazide
hydrochloride.
O2N
C
+ H2N-NH-C-NH2. HCl
O
=
O
O
O
O
O2N
CH
N
NH
C
NH2 + H2O + HCl
H
5-nitrofurfurol
semicarbazide hydrochloride
semicarbazone 5-nitrofurfurol (nitrofural)
CHARACTERS
A yellow or brownish-yellow, crystalline powder, very slightly
soluble in water, slightly soluble in alcohol.






IDENTIFICATION
First identification B.
Second identification A, C, D.
A. UV-spectroscopy.
B. Examine by infrared (IR) absorption spectrophotometry.
C. Examine by thin-layer chromatography.
D. Dissolve about 1 mg in 1 ml of dimethylformamide R and add 0.1 ml of
alcoholic potassium hydroxide solution R. A violet-red colour is
produced.
O-
O
O
N+
H
C
O
N
N
H
C
H3C
NH2
O
N
+
C
H
H3C
O-
O
N
O
+
O
H
C
N
N
C
H3C
NH2
*
H N+
O
C
H
H3C

Other reactions:
 1. With alkali solution.

OO
Some crystals of drug add in flask, dissolutions in mix of 5 ml
water R and 5 ml 10 % solution NaOH - orange-red colour are
formed:
+
N
O-
O
O
H
C
N
N
H
C
NH2
+
NaOH
-
Na O
O
+
N
O
H
C
N
N
C
NH2
salt of nitronic acid
(orange-red colour)
Other nitrofurans with alkali solutions yields too coloured
products.
+ H2O
O
O2N
O
H
C
N
N
H
C
H
NH2
+ 2NaOH + H2O
O2N
O
t
C
O
+ NH3
+ Na2CO3 + H2N
At heating of salt of nitronic acid (product) allocated ammonia NH3 (smell and wet
litmus paper becames blue colour in steam of boiling solution):
2. Melting point (230 С to 236 С).
3. Other colored reactions:
№ Reagents
Result
1.
95 % ethanol, 10 % solution CuSO4, 10 Dark-red solution and precipitate
% solution NaOH
2.
Perhydrol (30 % solution Н2О2), 30 % Light-yellow colour
solution NaOH
3.
95 % ethanol, 5 % solution sodium Red solution and precipitate
nitroprusside Na2[Fe(CN)5NO]
4.
Nesler reagent (solution K2[HgI4] in Red-brown colour
NH2
 TESTS

 pH (2.2.3)
 To 1.0 g add 100 ml of carbon dioxide-free water R. Shake
and filter. The pH of the filtrate is 5.0 to 7.0.
 Loss on drying (2.2.32)
 Not more than 0.5 per cent, determined on 1.000 g by drying
in an oven at 100-105 °C.

 Sulphated ash (2.4.14)
 Not more than 0.1 per cent, determined on 1.0 g.

ASSAY
 1. UV-spectrophotometry.
 2. Iodometry, back titration (In the alkaline medium) .

O
O2N
O
H
C
N
N
H
C
+
2I2
O
NH2
O2N
O
H
C
N
N
H
+
C
NH2
2HI
I2 + 2NaOH → NaI + NaIO + H2O;
NaIO + NaI + H2SO4 → I2I + Na2SO4I + H2O,
I2 + 2Na2S2O3 → 2NaI + Na2S4O6.
Еm = М. м./4
STORAGE
Еm (list
= М.of
м./4
Store protected from light
strong substance!).
Action and use
Antibacterial, topical antiprotozoan.
Ph Eur
;
Nitrofurantoin


General Notices
(Ph Eur monograph 0101)
 Furadoninum
 Furadantin
 Chemiofuran
O2N
3
2
5
O
1
2 CH
N
O
1
N
NH
4
5
4
3
.
H2O
O
C8H6N4O5
238.2
67-20-9
DEFINITION
Nitrofurantoin contains not less than 98.0 per cent and not more
than the equivalent of 102.0 per cent of 1-[[(5-nitrofuran-2yl)methylene]amino]imidazolidine-2,4-dione,
calculated
with reference to the dried substance.
Synthesis
Synthesis of Nitrofurantoin (Furadoninum) from 5nitrofurfurol:
NH2
O
O
O2N
5
+
C
H
5-nitrofurfurol
N
O
4
1
O
O
O
2
NaOH
NH
3
- H2O
O2N
CH
N
N
NH
O
1-aminohydantoin
Nitrofurantoin
CHARACTERS
A yellow, crystalline powder or yellow crystals, odourless or
almost odourless, very slightly soluble in water and in
alcohol, soluble in dimethylformamide.
IDENTIFICATION
A. UV-spectroscopy.
B. Reaction with alcoholic solution of alkali. Dissolve about 10
mg in 10 ml of dimethylformamide R. To 1 ml of the solution add 0.1 m
of 0.5 M alcoholic potassium hydroxide. A brown colour develops.

Other reaction:
 1. SP Х. Reaction with water solution of alkali.

Some crystals of drug add in flask, dissolutions in mix of 5 ml water
R and 5 ml 30 % solution NaOH - dark-red colour develops:
O
O2N
CH
N
4 NaOH
N
O
NH
O
_
O
NaO
+
N
O
O
CH
N
N
CH2C
+ Na2CO3 + NH3 +
H2O
ONa
TESTS
 Loss on drying (2.2.32)

Not more than 1.0 per cent, determined on 1.00 g by drying in an oven at 100 °C to
105 °C.



Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.

 ASSAY
 1. UV-spectrophotometry.
 2. Alkalimetry, non-aqueous titration
 Exact shot of drug dissolves in protophilic dissolvent (DMF,
pyridine, butylamine) and titrate with standard solution of
sodium methylate CH3ONa (or sodium methoxide, lithium
methoxide – International Pharmacopoeia) in the presents
DMF and dioxane (indicator – thymol dark blue).
 Еm = М. м.
STORAGE
Store protected from light, at a temperature below 25 °C (list
of strong substance!).
Ph Eur
Action and use
Antibacterial.
Preparations
Nitrofurantoin Oral Suspension
Nitrofurantoin Tablets
Ph Eur
Furazolidone
General Notices
Furazolidonum
Diafurone
Furoxon
5
O
4
1
O2N
2 CH
4
C8H7N3O5
225.2
5
N
3
O 1
N
3
2
O
67-45-8
DEFINITION
Furazolidone is 3-(5-nitrofurfurylideneamino)oxazolidin-2one. It contains not less than 97.0% and not more than 103.0%
Synthesis
Synthesis furazolidone from 5-nitrofurfurol by means of
reaction condensation with 3-aminooxazolidone-2:
O
O
O2N
C
O
+
H2N
N
O -H O
2
O2N
CH
N
N
O
H
O
O
CHARACTERISTICS
A yellow, crystalline powder.
Very slightly soluble in water and in ethanol (96%); practically
insoluble in ether .
IDENTIFICATION
A. The infrared absorption spectrum.
B. With alcoholic solution of alkali. Dissolve 1 mg
in 1 ml of dimethylformamide and add 0.05 ml of 1M
ethanolic potassium hydroxide. A deep blue colour is
produced.
Other reaction:
1. SP Х. With water solution of alkali.
Some crystals of drug add in flask, dissolutions in mix
of 20 ml water R and 5 ml 30 % solution NaOH and heating brown colour is produced. _
O
O
O2N
CH
N
O 3 NaOH
N
NaO
O
+
N
O
CH
N N CH2CH2OH + Na2CO3 + H2O
TESTS
Acidity or alkalinity
Shake 1 g for 15 minutes with 100 ml of carbon dioxide-free
water and filter. The pH of the filtrate is 4.5 to 7.0,
Nitrofurfural diacetate
Carry out in subdued light the method for thin-layer
chromatography. Any spot corresponding to nitrofurfural diacetate
in the chromatogram obtained with solution (1) is not more intense
than the spot in the chromatogram obtained with solution (2).
Loss on drying
When dried to constant weight at 105°, loses not more than
0.5% of its weight. Use 1 g.
Sulphated ash
Not more than 0.1%
STORAGE
Furazolidone should be protected from light (list of strong
substance!).
Action and use
Antibacterial; antifungal; antiprotozoal.
Thanks for
attention!