LECTURE № 15
Theme: Derivatives of benzodiazepine and
phenothiazine: properties, analysis, storage,
action and use. Derivative of acridine as
antiseptic.
Associate prof. Mosula L.M.
The plan
1. The condensed five-membered heterocycles:

- derivatives of indole as anti-inflammatory agent
(indometacin).
- derivative of benzimidazole as antispasmodic and
antihypertensive agent (Bendazoli hydrochloridum,
Dibazolum).
2. The condensed six-membered heterocycles:
- derivative of 8-hydroxyquinoline as antiseptic
(Chinosolum).
- derivative of acridine as antiseptic (ethacridine lactate
monohydrate).
4
5
3
Derivatives of indole as drugs
2
6
7
N1
H
Indole (benzopyrrole, benzoimidol) – is condensed
system, which consist of benzene and pyrrole (pentatomic
heterocycle with heteroatom of Nitrogen):
For indole are characteristic aromatic properties,
reactions electrophilic substitution on positions 2, 3 and 6,
most reactive is position 3 with max electronic density.
Because in the molecule of indole is “pyrrole“ atom of
Nitrogen group–NH has weak acid properties.
To derivatives of indole concern many natural and
synthetic drugs.
Indometacin
General Notices
(Ph Eur monograph 0092)
Indometacinum
4
C19H16ClNO4
357.8
 DEFINITION
 Indometacin contains
not less than 98.5 per
cent and not more than
the equivalent of 100.5
per cent of [1-(4chlorobenzoyl)-5methoxy-2-methylindol-3yl]acetic acid, calculated
with reference to the
dried substance.
H3CO
5
3
2
6
7
N1
CH3
C
O
Cl
CH2COOH
 CHARACTERS
 A white or yellow, crystalline powder, practically insoluble in
water, sparingly soluble in alcohol.




 IDENTIFICATION
First identification A, C.
Second identification A, B, D, E.


A. Melting point (2.2.14): 158 °C to 162 °C.
B. UV-spectroscopy.
C. IR-absorption spectrophotometry.

D and E – chemical methods.
The test substance is practically insoluble in water, therefore the
first can make mineralization (for example, melting with mix
K2CO3 and KNO3), after that can make all reactions for chlorideiones.
- Reaction with si1ver nitrate in the nitric-acid medium; white curdled
precipitate is formed:
Cl– + Ag+  AgCl 
AgCl + 2NH4OH = [Ag(NH3)2]Cl + 2H2O
- Reaction with oxidizer (for example, К2Cr2O7) in the sulphatic-acid
medium; toxic gas Cl2 is alocated:
6KCl + K2Cr2O7 + 7H2SO4 = 3Cl2 + Cr2(SO4)3 + 4K2SO4 + 7H2O
Cr2O72– + 14H+ + 6е  2Cr3+ + 7Н2О
2Cl– – 2е  Cl2
MnO2 + 4HCl = MnCl2 + Cl2 + 2H2O
MnO2 + 4H+ + 2е  Mn2+ + 2H2O
2Cl– – 2е  Cl2
 E. (BrPh). Reaction with dimethylaminobenzaldehyde solution

To 0.5 ml of the solution in alcohol prepared in identification test D, add 0.5 ml of
dimethylaminobenzaldehyde solution R2. A precipitate is formed that dissolves on
shaking. Heat on a water-bath. A bluish-green colour is produced. Continue to
heat for 5 min and cool in iced water for 2 min. A precipitate is formed and the
colour changes to light greyish-green. Add 3 ml of alcohol R. The solution is
clear and violet-pink in colour.
D. (BrPh). Reaction of alcoholic solution of test substance with solution of
hydroxylamine hydrochloride (hydroxamic reaction)
CH2COOH
H3CO
CH2COOH
H3CO
O
NH2OH . HCl
N
CH3
+
N
C
O
Cl
CH3
H
Cl
Fe
O
FeCl3
Cl
C
3
O
N
H
violet-pink colour
C
OH
N
H
 ASSAY



(BrPh). Alkalimetry, direct titration
Dissolve 0.300 g in 75 ml of acetone R, through which nitrogen R, free from carbon
dioxide, has been passed for 15 min. Maintain a constant stream of nitrogen through
the solution. Add 0.1 ml of phenolphthalein solution R. Titrate with 0.1 M sodium
hydroxide. Carry out a blank titration.
1 ml of 0.1 M sodium hydroxide is equivalent to 35.78 mg of C19H16ClNO4.
CH2COOH
H3CO
N
CH3
+ NaOH
N
C
CH3
C
O
Cl
CH2COONa
H3CO
O
Cl
Em = М. m.
+ H2O
 STORAGE

 Store protected from light.
 Action and use










Anti-inflammatory; analgesic.
Preparations
Indometacin Capsules
Indometacin Suppositories
Ph Eur
Derivative of benzimidazole
Bendazoli hydrochloridum
SP Х
Dibazolum
N
N
CH2
. HCl
H
2-benzylbenzimidazole hydrochloride or 2(phenylmethyl)-1H-benzimidazole hydrochloride
CHARACTERS
A white or grayish-white or yellowish-white crystalline powder,
hygroscopic, melting point 182–186 С;
slightly soluble in water, acetone and chloroform, freely soluble
in alcohol, practically insoluble in ether
Identification
1. SP Х. Reaction with solution of iodine in the
hydrochloric-acid medium (reaction for heterocyclic atoms
of Nitrogen)
Dissolve 0,02 g in 5 ml of water, add 3 drops of dilute
hydrochloric acid HCl, 2–3 drops of 0,05 М solution of iodine I2
and shakes; reddish-silvery precipitate (dibazol periodide) is
formed:
N
2
+ 3J2 + 2H
N
+
HCl
CH2
H
At temperature not more then 25 С.
N
2
N
H
CH2
. J2 . HJ
2. SP Х. Reaction for chloride-iones after precipitation
of dibasol-base by means of solution of ammonia
DibasolHCl + NH4OH  Dibasol + NH4Cl + H2O
base
AgNO3 + NH4Cl = AgCl↓ + NH4NO3
white
AgCl + 2NH4OH = [Ag(NH3)2]Cl + 2H2O
[Ag(NH3)2]Cl + 2HNO3 → AgCl↓ + 2NH4NO3
3. Reaction with solution of alkali
DibasolHCl + NаOH  Dibasol + NаCl + H2O
base
Tests
1. Specific impurity - о-phenylendiamine. Reagent iron(ІІІ) chloride FeCl3 in the hydrochloric-acid medium; any
pink colour not can be.
ASSAY
1. SP Х. Acidimetry, non-aqueous titration
Dissolve 0,15 g in 10 ml of anhydrous acetic acid, add 5 ml of
mercury acetate solution and titrate with 0,1 М perchloric acid (as
indicator – solution of crystalline violet). Ttitrate to occurrence
bluish-green colour of solution.
Carry out a blank titration.
Em = М. m.
N
2
N
.
CH2
+ 2HClO4 + Hg(CH3COO)2
CH3COOH
HCl
H
+
N
H
2
_
N
H
CH2
. ClO4
+ HgCl2 + 2CH3COOH
2. Alkalimetry in the presence of organic solvent (titration
of bonded HCl).
DibasolHCl + NаOH  Dibasol + NаCl + H2O
Em = М. м.
3. Argentometry, direct titration in the presence of acetone
and solution of sodium acetate (Morh method)
T – AgNO3;
Ind – solution of K2CrO4 (titrate to occurrence red-orange colour - Ag2CrO4).
Acetone add for dibasol-base fixation, solution of sodium acetate add for nitric acid
fixation.
DibasolHCl + 2AgNO3  Dibasol-Ag + AgCl + HNO3
2AgNO3 + K2CrO4 = Ag2CrO4 + 2KNO3
CH3COONa + HNO3  NaNO3 + CH3COOH
Em = М.m. /2
4. Thiocyanatometry, substitute titration
To alcoholic solution of test substanse add solution of
concentrated AgNO3 in the presence NH4OH; white precipitate of Agsalt of dibasol is formed. Filtrate and precipitate dilute with HNO3.
Equivalent quantity of AgNO3 titrate with standard solution of NH4SCN
(as indicator – iron ammonium sulphate FeNH4(SO4)2). Titrate to
occurrence pink colour.
N
N
AgNO3
NH4OH
CH2 C6H5
N
H
+ NH4NO3+ H2O
N
CH2
C6H5
Ag
N
N
HNO3
N
Ag
CH2
C6H5
AgNO3
N
CH2
C6H5
H
AgNO3 + NH4SCN = AgSCN↓ + NH4NO3
3NH SCN + FeNH (SO ) = Fe(SCN) + 2(NH ) SO
STORAGE
Store protected from light.
Action and use
Antispasmodic and antihypertensive agent
Derivatived of quinoline as drugs
Quinoline – is condensed dicyclic compound, which
consists of benzene and pyridine cycles (benzopyridine)
5
4
3
6
2
7
8
N
1
Quinoline was discovered in 1834 in coal. Quinoline is
bactericidal, antiseptic and antipyretic agent, but quinoline
is vetry toxic (nerve toxine!), therefore asdrug quinoline
not use. The introduction different substituents to quinoline
ring can lower its toxicity.
Derivatives of quinoline have different pharmacological
activity:
1. Antimalarial agents: derivatives of 4-aminoquinoline,
derivatives of 8-aminoquinoline.
2. Antiseptic and antibacterial agents: derivatives of 8hydroxyquinoline.
3. Anesthetic agent: derivative of 4-quinolincarboxylic
acid.
Derivatives of 8-hydroxyquinoline
The non-substituted derivatives of 8-hydroxyquinoline
(chinosolum), and substituted derivatives with haloid substituents on the
5 and 7 positions of quinoline cycle (Chiniofonum, Enteroseptol) and
substituted derivatives with nitro-group on 5 position of the ring
(Nitroxolinum) have antibacterial, antiparasitic and antimicotic activity.
Chemical properties
Derivatives of 8-hydroxyquinoline is ampholytes. But their acid
properties are strongest (influence of heteroatom of Nitrogen on mobility
atom of Hydrogen from phenolic hydroxyl (–ОН) unlike phenols.
Therefore 8-hydroxyquinoline is soluble in carbonates (this property is
used at identification).
The second property this derivatives – formation of chelate complexes
with cations of metals.
Chinosolum
N
OH
SP X
H2SO4
2
8-hydroxyquinoline sulphate
CHARACTERS
A yellow fine-crystalline powder, melting point
175–178 С;
freely in water, slightly soluble in alcohol,
practically insoluble in ether and chloroform
.
IDENTIFICATION
1. SP Х. Reaction with iron(ІІІ) chloride (for
phenolic hydroxyl)
+ FeCl3
3
+ 3HCl
N
OH
N
O
Fe
3
bluish-green colour
2. SP Х. Reaction with solution of sodium carbonate
To 1 ml of test solution add solution of Na2CO3;
precipitate is formed, soluble in excess of reagent.
+ Na2SO4 + H2O + CO2
H2SO4 + Na2CO3
N
OH
N
OH
2
2
+ Na2CO3
+ H2O + CO2
2
N
OH
N
ONa
3. SP Х. Reaction for sulphate-iones:
а) with solution of ВаCl2 in the medium of HCl:
SO42– + Ва2+  ВаSO4
white
ASSAY
1. SP Х. Alkalimetry in the presence of chloroform
Disolve 0,5 g in 50 ml of water, add 20 ml of
chloroform (for extraction and dilution of 8hydroxyquinoline) and titrate with 0,1 М NaOH (as indicator –
phenolphthalein). Titrate to occurrence pink colour.
H2SO4 + 2NaOH
2
+ Na2SO4 + 2H2O
N
OH
N
2
OH
Е = М. m./2
STORAGE
Store protected from light.
Action and use
Antiseptic
Derivatives of acridine
Acridine is the condensed heterocyclic system,
which consist of pyridine and two benzene cycles (or
quinoline and benzene):
8
9
1
7
2
6
5
N
10
3
4
In the medical practice as drugs are used such
derivatives of acridine: quinacrine (antimalarial agent),
aminoquinacrine (antimecotic agent), ethacridine lactate
monohydrate (antiseptic agent).
2. ГФ Х. Реакция с раствором барий хлорида
(наличие NaHCO3)
К 10 мл раствора препарата (1:100) прибавляют 5 мл раствора
барий хлорида BaCl2; выпадает желтый осадок, растворимый в 2
мл разбавленной хлоридной кислоты. В осадок выпадает белый
осадок ВаСО3, цвет которого (желтый) обусловлен наличием в нем
примеси 8-окси-7-йод-5-сульфохинолина.
Ва2+ + СО32–  ВаСО3
3. ГФ Х. Реакция с раствором феррум(ІІІ) хлорида
(на фенольный гидроксил)
К 10 мл того же раствора прибавляют 1 каплю раствора
феррум(ІІІ) хлорида FeCl3; появляется зеленое окрашивание.
SO3H
SO3H
+ FeCl3
3
N
I
OH
+ 3HCl
N
I
O
Fe
3
Ethacridine lactate monohydrate
General Notices
(Ph Eur monograph 1591 )
Rivanolum
Aethacridini lactas
C18H21N3O4,H2O
361.4
DEFINITION
7-Ethoxyacridine-3,9-diamine (2RS)-2hydroxypropanoate.
Content
99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance
Yellow crystalline powder.
Solubility
Sparingly soluble in water, very slightly soluble in alcohol,
practically insoluble in methylene chloride.
IDENTIFICATION
First identification A.
Second identification B, C, D.
A. Infrared absorption spectrophotometry (2.2.24).
B. Mix 0.1 ml of solution S (see Tests) and 100 ml of water R.
The solution is greenish-yellow and shows a strong green fluorescence
in ultraviolet light at 365 nm. Add 5 ml of 1 M hydrochloric acid. The
fluorescence remains.
C. To 0.5 ml of solution S add 1.0 ml of water R, 0.1 ml of a 10
g/l solution of cobalt chloride R and 0.1 ml of a 50 g/l solution of
potassium ferrocyanide R. The solution is green.
D. Alkalizing of test solution with the subsequent revealing
lactate-ions in the filtrate
To 50 ml of solution S add 10 ml of dilute sodium hydroxide solution R.
Filter. To 5 ml of the filtrate, add 1 ml of dilute sulphuric acid R. 5 ml of the solution
obtained gives the reaction of lactates (2.3.1) (add some drops of 0,05 M solution
KMnO4 and heat up; violet colouring of solution disappears).
Alkali precipitates from ethacridine lactate solution a yellow precipitate
of ethacridine-base:
Ethacridine  lactate + NaOH = Ethacridine  + Na-lactate +
Н2О
yellow
In filtrate lactate-ions reveales by means of solution KMnO4 in the sulphatic
O is observed :
acid medium - decolouration
of solution KMnO4
O
H
2 H3C
H
C
5 H3C
OH
2 H3C
ONa
OH
H
C
+ H2SO4
C
C
OH
OH
O
O
+ 2KMnO4 + H2SO4 =
C
OH
+ Na2SO4
C
5 H3C
+ 5CO2 + 2MnSO4 + K2SO4 + 8H2O
C
H
decolouration of solution
Other reaction:
1. Reaction diazotization (for primary aromatic amino group)
5 ml of solution acidify diluted HCl and add 1 ml of sodium
nitrite solution NaNO2; there is dark-red colouring (diazonium
salt).
NH2
NH2
OC2H5
NaNO2,HCl
H2N
OC2H5
N
+
N
N
Cl-
N
dark red colour of diazonium salt
2. Reaction with solution of iodine
2. Reaction with iodine solution
To 5 ml of the same solution add 3 drops of 0,05 M iodine
solution I2; the blue-green precipitate, soluble in 95 % alcohol, is
formed.
NH2
H
NH2
OC2H5
. H3C
H2N
N
H
H
C
OH
I
O
C
OC2H5
. H3C
+ 2I2
OH
H2N
N
I
blue-green precipitate
H
C
OH
O
C
+ 2HI
OH
ASSAY
(BrPh). Acidimetry, non-aqueous titration (see phthivazid)
Dissolve 0.270 g in 5.0 ml of anhydrous formic acid R. Add 60.0 ml of
acetic anhydride R and titrate with 0.1 M perchloric acid,
determining the end-point potentiometrically (2.2.20).
1 ml of 0.1 M perchloric acid is equivalent to 34.34 mg of
C18H21N3O4.
Other method:
Iodochlorometry, back titration
NH2
H
NH2
OC2H5
. H3C
H2N
N
H
H
C
OH
I
O
C
OC2H5
+ 2ICl
OH
+
H2N
N
I
ICl + KI = I2 + KCl
I2 + 2Na2S2O3 = 2NaI + Na2S4O6
Em (С15Н15N3OС3Н6O3) = М m./4
H3C
H
C
OH
+ 2HCl
O
C
OH
STORAGE

 Protected from light.

 Action and use

 Antiseptic.

 Ph Eur
Thanks for attention!