LECTURE 11- 12

Derivatives of pyrrolidine,
pyrazolone and pyrazolidindione:
its properties, analysis, storage,
action and use. Derivatives of
imidazole, imidazoline, triazole

Associate prof. Mosula L.M.

 The plan
1. Derivatives of pirolidine as drugs: piracetam
(Nootropilum), polyvinylpyrrolidone .
2. Derivatives of pyrazolone-5 as drugs: phenazone
(antipyrine), dipyrone (metamizole sodium),
budirol (propiphenazonum).
3. Derivatives of pyrazolidine-3,5-dione as drugs:
phenylbutazone, tribuzonum, kebuzone.
4. Derivatives of imidazole as drugs : thiamazole
(mercazolil), metronidazole.
5. Derivatives of imidazoline as drugs: naphazoline
nitrate, hylometazoline hydrochloride (halazolin),
clonidine hydrochloride.
6. Derivatives of triazole as drugs: thiotriazolinum.
 A heterocycle or heterocyclic compound is an
organic compound in which the carbon ring includes at least one
atom in addition to carbon (S, O, N, etc.).

Derivatives of pirolidine as drugs

Pyrrole – not satureted pentatomic heterocycle with one
heteroatom of Nitrogene:

N
H

Pyrrolidine – satureted pentatomic heterocycle with

one heteroatom of Nitrogene:
N
H

As drugs most often are used derivatives of 2-oxopyrrolidine (2-

4 3
pyrrolidone) :
2
Like drugs: piracetam, O
5
N
polyvinylpyrrolidone and its combined preparations . H 1
  Piracetam
 General Notices

 (Ph Eur monograph 1733)

 Pyracetamum
O
Nootropilum N

CH 2 C NH 2

O
C6H10N2O2 142.2
DEFINITION
2-(2-Oxopyrrolidin-1-yl)acetamide.
Content
98.0 per cent to 102.0 per cent (dried substance).
CHARACTERS
Appearance. White or almost white, powder.
Solubility. Freely soluble in water, soluble in ethanol (96 per
cent).
 IDENTIFICATION
1. (PhBr). Infrared absorption spectrophotometry.

2. (not pharmacopoeial reaction). Reaction with

solution of alkaly at heating; ammonia gas are
formed, which identificated by waited red litmus paper –
paper becames blue.
TESTS
Inadmisible impurities not present in the test substance.

ASSAY
1. (BrPh). Liquid chromatography.
2. Modificated Keldal”s method. Test substance
hydrolyzed by alkaly; Nitrogen deformed in the
ammonia.
 STORAGE

Protected from light.

Action and use

Central nervous system stimulant.

Ph Eur
 Polyvinylpyrrolidone

O
N

CH CH 2 n

It is polymer of N-vinyl-2-oxopyrrolidine or N-vinyl-

pyrrolidone.

Synthesis from γ-butyrolactone

NH3
O -H2O O O
O N N

H CH CH 2 n
 Action and use

Detoxic agent, plasma substitute.

It is a part of such preparations:
1. Haemodesum.
2. Neohaemodesum
 Pyrazole (1,2-diazole) is pentatomic heterocycles
with two heteroatoms of Nitrogene in the positions 1, 2:
3 4

2N 5
1 N

Pyrazoline is a partially hydrogenated cycle of pyrazole:

4 3

2
NH
5
N 1
H
 Completely hydrogenated cycle (saturated compound) of
pyrazole names pyrazolidine: 4 3

2
NH
5
N 1
H

In the medical practice as antiseptic, anti-inflammatory

and febrifuges agents are used derivatives of
pirazolone-5 (pyrazyl ketone) (pyrazoline,
containing in the position 5 ketogroup С=О): phenazone,
metamizol sodium (analginum), propiphenazone.
4 3

2
5
NH
O N 1
H
To derivatives of pyrazolidine-3,5-dione concerns
drugs: phenylbutazone, tribuzonum, kebuzon.
4 3 O

2
5
NH
O N 1
H

Derivatives of pirazolone-5
(pyrazyl ketone)
For phenylbutazone, dipyrone (metamizole sodium),
propiphenazone is characteristic the general formula:
R CH3

N CH3
O N

C6H5
 Phenazone
General Notices
(Ph Eur monograph 0421)
Antipyrine CH3
Phenazonum
Antipyrinum N CH3
O N
Analgesin
Sedatin

C11H12N2O 188.2
DEFINITION
Phenazone contains not less than 99.0 per cent and not more than the
equivalent of 100.5 per cent of 1,5-dimethyl-2-phenyl-1,2-
dihydro-3H-pyrazol-3-one, calculated with reference to the dried
substance.
 Synthesis
Synthesis of Phenazone (antipyrine) from
phenylhydrazine and acetacetic ester*
* Acetacetic ester are synthesed by means of Klyaizen
reaction: condensation two molecules of ethylacetate
СН3СООС2Н5 at heating in the presents of sodium ethylate
С2Н5ОNa:
Acetacetic ester
O
H O O
H3C C O
C2H5ONa
O C2H5 + H C C _ C H OH H3C C CH2 C O C2H5
2 5
H O C2H5
 Synthesis of Phenazone consists of three stages.
1. Interaction Acetacetic ester with phenylhydrazine and
formation phenylhydrazone acetacetic ester, and then 1-
phenyl-3-methylpyrazolone-5:

CH2 C CH3 CH2 C CH3 H2C C CH3

O O
C O C N 100 0C O C N
C2H5 O NH2 -H2O C2H5 O N
HN -C2H5OH
HN
2. Methylation the received product by means of
methyliodide CH3I or methyl ester of benzene sulphonic
acid C6H5–SO2–O–CH3 with formation of intermediate
product – salts of quarternary base:
H2C C CH3 HC C CH3
+ H
O C N O C N
N N CH3
+
_
SO3
SO2OCH3

3. Formation of Phenazone at action of alkali NaOH on the

received salt quarternary base:
 HC C CH3 HC C CH3
+ H
O C N O C N CH3
N CH3 N
+ NaOH +
_
SO3
SO3Na

CHARACTERS

A white or almost white, crystalline powder or

colourless crystals, very soluble in water, in alcohol
and in methylene chloride.
 IDENTIFICATION
First identification A, B.
Second identification A, C, D.
A. Melting point (2.2.14): 109 °C to 113 °C.
B. Examine by infrared absorption spectrophotometry
(2.2.24), comparing with the spectrum obtained with phenazone CRS.
Examine the substances prepared as discs using potassium bromide R.
C. Reaction with sodium nitrite in the acid medium. To 1 ml
of solution S (see Tests) add 4 ml of water R and 0.25 ml of dilute
sulphuric acid R. Add 1 ml of sodium nitrite solution R. A green
colour develops.

H3C H3C N O
NaNO2
H3C N H2SO4 H3C N
N O N O
C6H5 C6H5
 TESTS
Inadmisible impurities not presents in the test substance
ASSAY
Iodometry, back titration.
Dissolve 0.150 g in 20 ml of water R. Add 2 g of sodium acetate
R and 25.0 ml of 0.05 M iodine. Allow to stand protected from light
for 30 min. Add 25 ml of methylene chloride R and shake until the
precipitate dissolves. Titrate with 0.1 M sodium thiosulphate, using
1 ml of starch solution R, added towards the end of the titration, as
indicator. Carry out a blank titration.
1 ml of 0.05 M iodine is equivalent to 0,009411 g of
C11H12N2O.
H3C H3C I
+ I2 + HI;
H3C N H3C N
N N
O O
C6H5 C6H5
 The formed precipitate of 4-iodoantipyrine (iodopyrine) can adsorb
a quantity of iodine I2 on the surface, therefore for precipitate dissolution
add methylene chloride (chloroform) (shake until the precipitate
dissolves).
Sodium acetate CH3COONa add for fixation formed iodide acid HI:
HI + CH3COONa  NаI + CH3COOH;
I2 + 2Na2S2O3  2NaI + Na2S4O6.
Еm = М. м./2

STORAGE
Store protected from light (list of strong means!).

Action and use

Anaesthetic, antipyretic, resolvent.
Release forms: a powder and tablets - 0,25 g.
 Dipyrone
General Notices
(Metamizole
Sodium, Ph Eur monograph 1346)
Metamizolum natricum
Analginum
Analgetin

C13H16N3NaO4S,H2O 351.4
DEFINITION
Metamizole sodium contains not less than 99.0 and not more than the
equivalent of 100.5 per cent of sodium [(1,5-dimethyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazol-4-yl)-N-
methylamino]methanesulphonate, calculated with reference to the
dried substance.
Synthesis
Synthesis from 4-aminoantipyrine
 Synthesis consists of 3 stages.
1. Interaction 4-aminoantipyrine with benzaldehyde
С6Н5СНО with formation benzylidenaminoantipyrine:
H2N CH3 C6H5CHO C6H5 HC N CH3
N CH3
N CH3
O N
O N
C6H5
C6H5

2. Methylation benzylidenaminoantipyrine by means of

dimethylsulphate (СН3)2SO4 with formation
4-methylaminoantipyrine:
H

C6H5 HC N CH3 (CH3)SO4 N CH3

H3C
N CH3 N CH3
O N O N

C6H5 C6H5
3. Interaction 4-methylaminoantipyrine with a mix of solutions
of formaldehyde НСНО and sodium hydrogensulphyde
NaHSO3 (differently НО–СН2–SO3Na):

O
H C + NaHSO3 HO-CH2-SO3Na
H
H
H3C
N CH3
N CH3
H3C + HO-CH2-SO3Na
N CH3 _HO NaO3SH2C
2
N CH3
O N
O N
C6H5
C6H5
 CHARACTERS
A white or almost white, crystalline powder, very soluble in water,
soluble in alcohol.

IDENTIFICATION
First identification A, D.
Second identification B, C, D.

A. Examine by infrared absorption

spectrophotometry (2.2.24), comparing with the spectrum obtained
with metamizole sodium CRS.

B. Oxidation of preparation by means of strong

hydrogen peroxide solution
Dissolve 50 mg in 1 ml of strong hydrogen peroxide solution R. A
blue colour is produced which fades rapidly and turns to intense red in
a few minutes.
 Mechanism of oxidation
Interaction of dipyrone with differents oxidaizers (chloramine,
chlorinated lime, solution of iron(ІІІ) chloride, hydrogen peroxide
and other) is bused on formation not stability colored
tetraoxiderivative of pirazolone-5, which change the colour after
same minutes, then dioxiderivative is formed:
H3C HO OH HO OH
H
N CH3 O
[O],HCl N C C CH3
NaO-O2S-H2C SO2 + H C + _ 2H O
N CH3 _ H H 3C
NaCl 2
O N O C N CH3
N
C6H5
C6H5
O O
H
N C C CH3
H3C
O C N CH3
N

C6H5
 C. Oxidation of preparation by means of potassium
iodate with the next revealing of oxidation products (see
mechanism of reaction B)
Identification of oxidation products (SO2 и HCHO):
5SO2 + 2KIO3  I2 + 4SO3 + K2SO4

SO3Na NaO3S SO3H HO3S

HO H O H OH HO CH2 OH
+ H2SO4(conc) [O]
H C H _ H O
2
HO OH HO OH

SO3Na NaO3S SO3H HO3S

SO3H HO3S

[O] HO CH O

_
H2O
HO OH

SO3H HO3S
 D. 0.5 ml of solution S (see Tests) gives reaction (a) of
sodium (2.3.1):
.Na+ + [Sb(OH)6]– → Na[Sb(OH)6] ↓
white precipitate
TESTS
The inadmisible impurities are not presents in the test
substance ASSAY
Iodometry, direct titration
Dissolve 0.200 g in 10 ml of 0.01 M hydrochloric acid previously
cooled in iced water and titrate immediately, dropwise, with 0.05 M
iodine. Before each addition of 0.05 M iodine dissolve the precipitate by
swirling. At the end of the titration add 2 ml of starch solution R and
titrate until the blue colour of the solution persists for at least 2 min. The
temperature of the solution during the titration must not exceed 10 °C.
1 ml of 0.05 M iodine is equivalent to 16.67 mg of
 H3C H3C
N CH3 +
IV N CH3 _ VI
NaO-O2S-H2C
N CH3 + J2 + 2H2O
H
H N CH3
.J + NaHSO4 + HJ + HCHO
O N O N

C6H5 C6H5

Еm (C13H16N3NaO4S, H2O) = М m./2

STORAGE
Store protected from light.

Action and use

Analgesic.
Ph Eur
 Propiphenazonum (latin name) (not pharmacopoeial drug)
Budirol H3C 4 3
CH CH3
Causytin H3C 2
N CH3
O 5 N 1

The chemical name: 1-phenyl-2,3-dimethyl-4-isopropyl-

pyrazolone-5
(4-isopropylantipyrine).
CHARACTERS
Appearance. White or slightly yellowish crystal powder without a
smell, bitter taste.
Solubility. Slightly soluble in water, freely soluble in alcohol,
methylenchloride, chloroform and ether.
 Chemical properties
Unlike antipyrine propiophenazonum shows the expressed
reducing properties, because it is derivative partially hydrogenated
pyrazoline and is presence alkyl radical at С4, interfering reactions,
characteristic for antipyrine.
Like analginum propiophenazonum is oxidised even slight
oxidizers.

Identification

1. IR-spectroscopy.

2. UV-spectroscopy.
 3. Reaction with solution of silver nitrate
At action on solution of substance of solution silver nitrate
AgNO3 there is a violet colour, and then precipitate of grayish-brown
colour (precipitate of metal silver).
H3C HO OH HO OH
H3C
CH CH3
CH C C CH3
H3C + 4AgNO3+ 4H2O 4Ag + 4HNO3 +
N CH3 H3C _ 2H O
O C N CH3 2
O N
N
C6H5
C6H5
O O
H3C
CH C C CH3
+ 4Ag + 4HNO3
H3C
O C N CH3
N
 4. Reaction with solution of iron (ІІІ) chloride
At action on water-alcoholic solution of substance several drops of
solution iron(ІІІ) chloride FeCl3 there is a red-brown colour, which is
passed after addition chloride acid HCl to the yellow colour.
H3C HO OH HO OH
H3C
CH CH3
CH C C CH3
H3C + 4FeCl3+ 4H2O 4FeCl2 + 4HCl +
N CH3 H3C _ 2H O
O C N CH3 2
O N
N
C6H5
C6H5
O O
H3C
CH C C CH3
+ 4FeCl2 + 4HCl
H3C
O C N CH3
N

C6H5
5. Reaction with generalalkaliodal reagents (on tertiary
atom of Nitrogen)
With generalalkaliodal reagents the preparation forms precipitates of
 Assay
Acidimetry, non-aqueous titration
Shot of substance dissolve in dioxane and titrate with standard
solution of perchloric acid HClO4 in the presence of ice
СН3СООН (indicator - crystal violet).
H3C H3C
CH CH3 O O CH CH3
_
H3C
N CH3
+ HClO4
CH3COOH
H3C
N
+
CH3 . ClO 4
O N O N
H
C6H5 C6H5
Storage
The list of strong substances. In densely corked container, in
the place protected from light.
Action and use
Anaesthetic, antipyretic, resolvent.
Is a part of the combined preparations.
 Derivatives of pyrazolidine-3,5-dione
Phenylbutazone
General Notices
Phenylbutazonum
O
Butadion H3C H2C H2C H2C
4 3

Butadionum 2
5 1 N
Pyrazolidin O N

C19H20N2O2 308.4
DEFINITION
4-Butyl-1,2-diphenylpyrazolidine-3,5-dione.
Content
99.0 per cent to 101.0 per cent (dried substance).
 Synthesis
Condensation of diethyl ester of butylmalonic acid with
hydrazono-benzene:
O
H ONa O
C4H9 C C C4H9 C4H9
OC2H5 H C2H5ONa H+
O C N C6H5 N C6H5
+ _ 2C H OH O N
OC2H5 N C6H5 2 5 O N
H N
C6H5 C6H5
C6H5

CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Practically insoluble in water, sparingly soluble in alcohol.
It dissolves in alkaline solutions.
 IDENTIFICATION
First identification A, C.
Second identification A, B, D.
A. Melting point (2.2.14): 104 °C to 107 °C.
B. Thin-layer chromatography (2.2.27).
C. Infrared absorption spectrophotometry.
D. Reaction of oxidation by sodium nitrite in the acetic medium
Chemism. Reaction is based on splitting (decomposition) of butadiene molecule and
oxidation of hydrazono-benzene С6Н5–NH–NH–C6H5 to painted azobenzene: С6Н5–N=N–
C6H5 (A brownish-red to violet-red precipitate is formed):
H
H O
O H H
C4H9
C4H9 C C OH +
N N
N C6H5
C
O N
O OH [O]
C6H5
_ CO
2

C4H9 CH2 COOH N N

[H+]

+ _
N N HSO3

H
 TESTS
The inadmisible impurities are not presents in the test substance
ASSAY
Alkalimetry, direct titration in the presence of acetone
(acid properties of phenylbutazone)
(indicator - bromothymol blue solution. Titrate until a blue colour is obtained).
Em = М. м.

H
O OH ONa
C4H9 C4H9 C4H9
NaOH

N C6H5 N C6H5 _ H2O N C6H5

O N O N O N

C6H5 C6H5 C6H5

 STORAGE
Protected from light.

Action and use

Anti-inflammatory; analgesic.
Ph Eur
 Tribuzonum*  Kebuzone*
 Ketophezon

CH3 H

CH3 C C CH2 CH2 4 3

O
2 H
CH3 O 5
1 N C6H5 4 3
O N CH3 C CH2 CH2 O
5 2
C6H5 O 1 N C6H5
O N

The chemical name: 4 (4,4- C6H5

dimethyl-3-oxopenthyl)- The chemical name:
1,2-diphenyl- 1,2- diphenyl -4 (3 '-
pyrazolidindione-3,5 oxobutyl)-
pyrazolidindione-3,5
 Tribuzonum show anti-inflammatory, analgetic and
febrifugal (antipyretic) action.
The release form: tablets for 0,25

Kebuzone also show anti-inflammatory and analgetic

action.
The release forms: drage (0,25 g), ampoules (5 ml of 20
% of intravenously solution for injection).
Thanks for attention!