Transcript 08 Arylaliphatic, aminobenzoic, aminosalicylic acids derivat

 LECTURE № 8
 Theme: Arylaliphatic and oaminobenzoic acids derivatives as
drugs. Acetanilide and esters of paminobenzoic acid derivatives as local
anesthetic. Procainamide
hydrochloride. Salts and derivatives of
p-aminosalicylic acid, which are used
in phthisiology
 Associate prof. Mosula L.M.


Derivatives arylaliphatic acids as drugs
To this group of druds concerns ibuprofen – 2-phenylpropionic acid
derivative.
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Ibuprofenum
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General Notices
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(Ph Eur monograph 0721)
Ibuprofen
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C13H18O2
M.m. = 206.3
DEFINITION
(2RS)-2-[4-(2-Methylpropyl)phenyl]propanoic acid.
Content
98.5 per cent to 101.0 per cent (dried substance).
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CHARACTERS
Appearance
White, crystalline powder or colourless crystals.
Solubility
Practically insoluble in water, freely soluble in acetone, in methanol and in
methylene chloride. It dissolves in dilute solutions of alkali hydroxides and
carbonates.
IDENTIFICATION
First identification A, C.
Second identification A, B, D.
A. Melting point (2.2.14): 75 °C to 78 °C.
B. UV-spectroscopy.
C. Infrared absorption spectrophotometry (2.2.24).
D. Thin-layer chromatography (2.2.27).
 TESTS
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 Solution S
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 Dissolve 2.0 g in methanol R and dilute to 20 ml with the same
solvent.
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 Appearance of solution
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 Solution S is clear (2.2.1) and colourless (2.2.2, Method II).
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 Angle of optical rotation (2.2.7)
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 - 0.05° to + 0.05°.
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 Dissolve 0.50 g in methanol R and dilute to 20.0 ml with the same
solvent.
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 ASSAY
 Alkalimetry of methanol solution, direct
titration
 Dissolve 0.450 g in 50 ml of methanol R. Add 0.4 ml of
phenolphthalein solution R1. Titrate with 0.1 M sodium
hydroxide until a red colour is obtained. Carry out a
blank titration.
H3C
CH
H3C
H3C
O
H2
C
H
C
CH3
CH
+ NaOH
C
OH
O
H3C
H2
C
H
C
C
CH3
 Еm (C13H18O2) = М m.
 1 ml of 0.1 M sodium hydroxide is equivalent to 20.63
mg of C13H18O2.
+ H2O
ONa
 Storage
 The list of strong substances. In the air-tight container, in the place
protected from light.
 Action and use
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 Anti-inflammatory; analgesic.
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 Preparations
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 Ibuprofen Cream
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 Ibuprofen Gel
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 Ibuprofen Oral Suspension
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 Ibuprofen Tablets
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 Ph Eur
 Derivatives of oaminobenzoic (anthranilic)
acid
 In medical practice are applied
substitution derivative Nphenylanthranilic acid:
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O
C
OH
anthranilic (o-aminobenzoic) acid
NH2
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O
C
N-phenylanthranilic acid
 In this group of drugs is presents
mefenamic acid and its sodium salt.
OH
N
H
 Mefenamic Acid
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Acidum mefenaminicum
Acidum mephenamicum
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(Ph Eur monograph 1240)
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O
2
1
3
OH
4
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C
6
5
6'
5'
1'
4'
N
H
2'
H3C
3'
CH3
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C15H15NO2 М m. = 241 g/mol
The chemical name: N - (2 ', 3 '-dimethylphenyl)-anthranilic acid.
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DEFINITION
Mefenamic acid contains not less than 99.0 per cent and not more than
the equivalent of 100.5 per cent of 2-[(2,3dimethylphenyl)amino]benzoic acid, calculated with reference to the
dried substance.
 CHARACTERS

 A white or almost white, microcrystalline powder, practically
insoluble in water, slightly soluble in alcohol and in
methylene chloride. It dissolves in dilute solutions of alkali
hydroxides.
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 It shows polymorphism.
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 IDENTIFICATION
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 First identification B.
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 Second identification A, C, D.
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A. UV-spectroscopy.
 B. Examine by infrared absorption
spectrophotometry (2.2.24),
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C. Dissolve about 25 mg in 15 ml of methylene
chloride R and examine in ultraviolet light at 365 nm;
the solution exhibits a strong greenish-yellow
fluorescence. Carefully add 0.5 ml of a saturated
solution of trichloroacetic acid R dropwise and examine
in ultraviolet light at 365 nm. The solution does not
exhibit fluorescence.
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D. Dissolve about 5 mg in 2 ml of sulphuric acid R
and add 0.05 ml of potassium dichromate solution
R1. An intense blue colour is produced, turning
rapidly to brownish-green.
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Other reaction:
Reaction with nitrites-ions NO2 - in the medium of concentrated sulphatic acid
H2SO4 (for presence of rest diphenylamine); organic dye of bright-dark blue
colour is formed:
R
R1
H
N
R1
R
R1
H2SO4(k)
R1
R1
R1
R
+ NO2
H
N
H
N
H2SO4
[O]
Derivative diphenylbenzidine
R
R1
R1
R1
R1
R
+
N
N
_
HSO4
H
sulphoimmonium salt of derivative diphenylbenzidine (dye of dark blue colour)
_
TESTS
Related substances
Examine by thin-layer chromatography (2.2.27), using a TLC silica gel GF254plate R.
2,3-Dimethylaniline, copper.
Loss on drying (2.2.32)
Not more than 0.5 per cent, determined on 1.000 g by drying at 100 °C to 105 °C.
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.
IMPURITIES
A. 2,3-dimethylaniline,
B. N-(2,3-dimethyphenyl)-2-[(2,3-dimethylphenyl)amino]benzamide.
ASSAY
 ASSAY
 1. Alkalimetry, non-aqueous titration.
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Ph Eur . Dissolve with the aid of ultrasound 0.200 g in 100 ml of warm
ethanol R, previously neutralised to phenol red solution R. Add 0.1 ml of
phenol red solution R and titrate with 0.1 M sodium hydroxide.
1 ml of 0.1 M sodium hydroxide is equivalent to 24.13 mg of
C15H15NO2.
SPU. Test substance (shows subacid properties) dissolve in dimethyl
formamide (alkaline solvent) and titrate with solution of sodium hydroxide
NaOH in the mix of methanol СН3ОН and benzene С6Н6 in the
presence of the indicator thymol dark blue before dark blue colouring.
O
O
C
C
ONa
OH
+ H2O
+ NaOH
N
H
N
H
H3C
CH3
Еm (C15H15NO2) = М m.
H3C
CH3
 Storage. The list of strong substances. In
dense corked container, in the dry place
protected from light.
 Action and use
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 Analgesic; anti-inflammatory.
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 Preparations
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 Mefenamic Acid Capsules
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 Mefenamic Acid Tablets
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 Ph Eur
 Esters of p-aminobenzoic acid
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General Notices
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(Ph Eur monograph 0011)
Benzocaine
O
H2N
C
O
C2H5
 Anaesthesinum
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Aethylis аminobenzoas*
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Benzocaine
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Еthyl аminobenzoate
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C9H11NO2
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М m. = 165,19
g/mol
 The chemical name: ethyl ester of p-aminobenzoic acid; ethyl-paminobenzoate.
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DEFINITION
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Benzocaine contains not less than 99.0 per cent and not more than
the equivalent of 101.0 per cent of ethyl 4-aminobenzoate,
calculated with reference to the dried substance.
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The first time it is synthesised in 1830, and in medicine as drug apply since 1902.
Obtaining
Initial raw materials is toluene С6H5СH3 , which nitrations by means of mix nitric
HNO3 and sulphatic H2SO4 acids, then to oxidize methyl group –СН3 to carboxylic
–СООН by means of chromic mix (solution K2Cr2O7 in H2SO4), to esterify by
ethanol С2Н5ОН and reduce nitrogroup–NO2 to an amino group–NH2 by means of
iron at presence of acetic acid СН3СООН:
H
HONO2 + H2SO4
NO2
NO2
K2Cr2O7+H2SO4
C2H5OH
-H2O
H2SO4
O
CH3
Toluene
t0
CH3
C
p-nitrotoluene
OH
p-nitrobenzoic
acid
NO2
NH2
Fe;CH3COOH
O
O
C
C
O
C2H5
O
C2H5
benzocaine
The received product clear recrystallization from the diluted alcohol with the activated coal
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CHARACTERS
A white, crystalline powder or colourless crystals, very slightly
soluble in water, freely soluble in alcohol.
IDENTIFICATION
First identification A, B.
Second identification A, C, D.
A. Melting point (2.2.14): 89 °C to 92 °C.
B. Examine by infrared absorption spectrophotometry (2.2.24),
comparing with the spectrum obtained with benzocaine CRS.
C. To about 50 mg in a test-tube add 0.2 ml of a 500 g/l solution of
chromium trioxide R. Cover the mouth of the tube with a piece of filter
paper moistened with a freshly prepared mixture of equal volumes of
a 50 g/l solution of sodium nitroprusside R and a 200 g/l solution of
piperazine hydrate R. Boil gently for at least 30 s. A blue colour
develops on the filter paper.
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D. Dissolve about 50 mg in alcohol R and dilute to 100 ml with the
same solvent. 2 ml of the solution gives the reaction of primary
aromatic amines (2.3.1).
 1. Reaction for primary aromatic amino group (SPU) (diazotization
with the next azocoupling).
 Some crystals of test substance dissolve in 2 ml of water R, acidify of
HCl R, add 0,2 ml of sodium nitrite solution R NaNO2 and through 1–2
mines add 1 ml of alkaline solution-naphthol; there is an intensive
orange or red colouring and, as a rule, the precipitate of the same
colour is formed.
+
N
NH2
N
N
HO
N
NaO
NaNO2
Cl-
HCl
COOC2H5
NaOH
COOC2H5
salt diazonium
COOC2H5
azo dye of red colour
2. Lignin test (of aromatic amino group, spend reaction to a newsprint!).
On a newsprint slice to put some crystals of substance and to moisten
with solution HCl; there is a yellow stain, which becomes in due course
orange.
The newsprint contains lignin, in which there are aromatic aldehydes.
At interaction with aromatic amines are formed azomethine dye (Schiff
base) with orange colour:
O
R
NH2 +
C
H
R1
R
H
N C
orange
R1 + H2O
 Other reactions (SPU):
 1. Alkaline hydrolysis with the next revealing of ethanol
С2H5OH with the help iodoform test (of ester group).
 Drug heat up with solution of sodium hydroxide NaOH and add
solution of iodine І2 before not disappearing yellow colouring; there
is iodoform smell СНІ3.
NH2
NH2
NaOH, t
COOC2H5
+
COONa
C2H5OH + 4I2 + 6NaOH → CHI3 ↓ + 5NaI + HCOONa + 5H2O
iodoform smell
C2H5OH
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2. Hydroxamic reaction (for ester group).
At alkaline hydrolysis of esters at presence hydroxylamine NH2OH are
formed hydroxamic acids, which with salts of heavy metals (it is the most
often Iron (ІІІ)) form the salts painted in red colour – hydroxamates:
O
O
R
NaOH
C
R
NH2OH
+
C
HN
O
O
3 R
C
OH
+ H2O
ONa
R1
O
+
H
FeCl3
HN
R1
ONa
R
Fe
C
HN
O
+ 3 NaCl
3
4. Oxidation of drug by means of chloramine at presence of chloride acid HCl
leads to formation of reaction product, which at churning (shake up) with ether
paints ether layer in orange colour.
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TESTS
Appearance of solution
Acidity or alkalinity
Loss on drying (2.2.32)
Sulphated ash (2.4.14)
g.
 ASSAY
 Nitritometry, direct titration
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Dissolve 0.400 g in a mixture of 25 ml of hydrochloric acid R and 50 ml of water R, add
3 g of potassium bromide R. Cool in ice-water and titrate by slowly adding 0.1 M
sodium nitrite with constant stirring.
Determine the end-point electrometrically or by the use of the prescribed indicator:
internal indicators: tropeolin 00 – before yellow colouring, a mix tropeolin 00 and
methylen dark blue – transition of red-violet colouring to blue, neutral red – before
dark blue colouring or
external indicators: potassium iodide test paper – before dark blue colouring.
In parallel spend control experience.
Carry out the determination of primary aromatic amino-nitrogen (2.5.8):
1) Diazotization of free aromatic amino group:
+
N
NH2
+ NaNO2 + 2HCl
COOC2H5
N
Cl- + NaCl + 2H2O
KBr
COOC2H5
 2) The excess drop of titrant NaNO2 reacts with КI of potassium
iodide test paper in the medium of HCl with formation of iodine I2
and consequently potassium iodide test paper becomes blue.
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T
 2NaNO2 + 2KI + 4HCl  I2 + 2NO + 2KCl + 2NaCl + 2H2O
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excess drop
 Еm (C9H11NO2) = М. м.
 1 ml of 0.1 M sodium nitrite is equivalent to 16.52 mg of
C9H11NO2.
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 STORAGE
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 Store protected from light.
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 Action and use
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 Local anaesthetic.
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 Ph Eur
 PROCAINAMIDE HYDROCHLORIDE
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(Ph Eur monograph 0567)
O
H2N
C
H
N
H2
C
H2
C
C2H5
N
.
HCl
C2H5
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Procainamidi hydrochloridum
Novocainamidum (N)
Procainamidum
Amidoprocain
C13H21N3O,HCl or C13H22ClN3O
М m. = 271,78 g/mol
The chemical name:4-amino-N-[2-(diethylamino)ethyl]benzamide
hydrochloride or β-diethylaminoethylamide of p-aminobenzoic acid
hydrochloride (SPU).
DEFINITION
Procainamide hydrochloride contains not less than 98.0 per cent and not
more than the equivalent of 101.0 per cent of 4-amino-N-[2(diethylamino)ethyl]benzamide hydrochloride, calculated with
reference to the dried substance.
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Obtaining (like obtaining of novocaine and benzocaine)
Initial raw materials is toluene C6H5CH3 which nitration, oxidize to p-nitrobenzoic
acid; acid chloride to condense with diethylaminoethylamine with the next reduction
of nitrogroup and acidifying by means of chloride acid:
NO2
NO2
NO2
H
H2N
K2Cr2O7
SOCl2
H2SO4
H2SO4
-SO2; -HCl
O
O
C
C
CH3
Cl
OH
NO2
NO2
+HCl
O
O
C2H5
C
HN
H2
C
H2
C
C2H5
C
N
C2H5
HN
H2
C
C2H5
N
C2H5
HONO2
CH3
H2
C
H2
C
H2
C
N
.
C2H5
HCl
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CHARACTERS
A white or very slightly yellow, crystalline powder, hygroscopic, very
soluble in water, freely soluble in alcohol, slightly soluble in acetone.
IDENTIFICATION
First identification
C, D.
Second identification
A, B, D, E.
A. Melting point (2.2.14): 166 °C to 170 °C.
B. UV-spectroscopy of an alkaline solution. Dissolve 10.0 mg in 0.1
M sodium hydroxide and dilute to 100.0 ml with the same solvent. Dilute
10.0 ml of the solution to 100.0 ml with 0.1 M sodium hydroxide.
Examined between 220 nm and 350 nm (2.2.25), the solution shows an
absorption maximum at 273 nm. The specific absorbance at the
maximum is 580 to 610.
C. Examine by infrared absorption spectrophotometry (2.2.24),
comparing with the spectrum obtained with procainamide hydrochloride
CRS.
 D. Dilute 1 ml of solution S to 5 ml with water R. The
solution gives reaction (a) of chlorides (2.3.1):
 AgNO3 + Procainamide HCl = AgCl↓ + Procainamide
HNO3
 *For salts of the organic bases test of solubility of formed
precipitate AgCl spend after filtration and washings of
precipitate by water. AgCl + 2NH4OH = [Ag(NH3)2]Cl +
2H2O
 At addition of HNO3 white precipitate AgCl again is
formed:
 [Ag (NH3) 2] Cl + 2HNO3 → AgCl ↓ + 2NH4NO3
 E. Dilute 1 ml of solution S (see Tests) to 2 ml with
water R. 1 ml of this solution gives the reaction of
primary aromatic amines (2.3.1).
 Reaction of solution S on primary aromatic
amines (SPU) (diazotization with the next
azocoupling).
 Some crystals of test substance dissolve in 2 ml
of water R, acidify of HCl R, add 0,2 ml of sodium
nitrite solution R NaNO2 and through 1–2 mines
add 1 ml of an alkaline solution-naphthol, there
is an intensive orange or red colouring and, as
a rule, the precipitate of the same colour is
formed.
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+
N
NH2
N
Cl
HCl
salt diazonium
HO
NaO
NaNO2
COOR
N N
NaOH
COOR
azo dye of red colour
R=NH-CH2-CH2-N(C2H5)2
COOR
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Other reactions:
Hydroxamic reaction of ester group, see benzocaine, reaction 3).
2. Reaction with ammonium vanadate.
To test solution add solution of ammonium vanadate NH4VO3,
sulphatic acid concentrated H2SO4 and heat up; dark red colouring
(difference from novocaine) is formed.
3. Lignin test (of aromatic amino group, see benzocaine, reaction 5).
O
R
HCl
C
NH2
+
R1
-H2O
R
N
H
C
H
4. Reaction with bromic water (of aromatic ring). To test
solution add bromic water Br2; the precipitate of
dibromoderivative is formed:
Br
R
NH2
+ Br2
R
NH2
Br
+ 2 HBr
R1
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TESTS
Solution S
Dissolve 2.5 g in carbon dioxide-free water R and dilute to 25 ml with
the same solvent.
Appearance of solution
Solution S is clear (2.2.1) and not more intensely coloured than
reference solution B6 (2.2.2, Method II).
pH (2.2.3)
The pH of solution S is 5.6 to 6.3.
Related substances
Examine by thin-layer chromatography (2.2.27), using silica gel
GF254 R as the coating substance.
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Heavy metals (2.4.8)
1.0 g complies with limit test C for heavy metals (20 ppm).
Prepare the standard using 2 ml of lead standard solution (10
ppm Pb) R.
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 °C to 105 °C.
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.
 ASSAY
 Nitritometry, direct titration
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Dissolve 0.2500 g in 50 ml of dilute hydrochloric acid R, add water R,
add 3 g of potassium bromide R. Cool in ice-water and titrate by slowly
adding 0.1 M sodium nitrite with constant stirring with indicator (SPU:
mix tropeolin 00 (4 drops) and methylen dark blue (2 drops)– transition
of red-violet colouring to blue) until blue colour.

 Carry out the determination of primary aromatic amino-nitrogen (2.5.8):
 1) Diazotization of free aromatic amino group:
+
N
NH2
+ NaNO2 + 2HCl
COOR
N
Cl- + NaCl + 2H2O
KBr
COOR
R = CH2CH2N(C2H
R=NH-CH2CH2
N(C2H5)2
5)2
 2) The excess drop of titrant NaNO2 reacts with КI of potassium
iodide test paper in the medium of HCl with formation of iodine I2 and
consequently potassium iodide test paper becomes blue.
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T
 2NaNO2 + 2KI + 4HCl  I2 + 2NO + 2KCl + 2NaCl + 2H2O
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excess drop
 Еm (C13H22ClN3O) = М. м.
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1 ml of 0.1 M sodium nitrite is equivalent to 27.18 mg of C13H22ClN3O.
STORAGE
Store in an airtight container , protected from light.
Action and use
Anti-arrhythmic.
Preparations
Procainamide Injection
Procainamide Tablets
Ph Eur
 Derivatives of acetanilide
 To derivatives of acetanilide С6Н5–NH–CO–CH3,
containing diethyl aminogen group
–N (C2H5) 2,
which causes local anesthetic effect, drugs – lidocaine
and trimecaine hydrochloride concern.
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Lidocaine
(in Ukraine)
Lidocainum
Xycainum
Xylocainum
С14Н22N2OHCl
М m. = 270,79 g/mol
The chemical name: 2-diethylamino-2,6dimethylacetanilide hydrochloride
 NOTE: The name Lignocaine was formerly used in the
United Kingdom.

 Preparation Lidocaine Ointment
 C14H22N2O
M.m. = 234.3 g/mol
 DEFINITION
 Lidocaine contains not less than 99.0 per cent and not
more than the equivalent of 101.0 per cent of 2(diethylamino)-N-(2,6-dimethylphenyl)acetamide,
calculated with reference to the anhydrous substance.
 CHARACTERS
 A white or almost white, crystalline powder, practically
insoluble in water, very soluble in alcohol and in
methylene chloride.
 (Ph Eur monograph 0227)
Lidocaine hydrochloride
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NOTE: The name Lignocaine Hydrochloride was formerly used in the
United Kingdom.
C14H22N2O,HCl,H2O
M.m. = 288.8 g/mol
DEFINITION
Lidocaine hydrochloride contains not less than 99.0 per cent and not
more than the equivalent of 101.0 per cent of 2-(diethylamino)-N(2,6-dimethylphenyl)acetamide hydrochloride, calculated with
reference to the anhydrous substance.
CHARACTERS
A white, crystalline powder, very soluble in water, freely soluble in
alcohol.
 Thanks for attention!