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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5406_Библиотеки_им_академика_М_И_Перельмана.pdf
292 Pharmaceutical Chemistry
In the first step involved, the interaction between N-chloroacetyl-N-phenyl-2,6-
dichloroaniline and anhydrous AlCl
whereupon the indolin ring closure occurs to yield
3
1-(2,6-dichlorophenyl)-2-indolinone with the elimination of a mole of HCl. The second
step illustrates the formation of the corresponding sodium salt of diclofenac by treatment
of 1-(2,6-dichlorophenyl)-2-indolinone with NaOH in the presence of ethanol when the
indolinone ring ruptures (shown with dotted line) to obtain the desired product diclofenac
sodium.
Reagents:
N-Chloroacetyl-N-phenyl-2,6-dichloroaniline : 16 g;
Anhydrous Aluminium Chloride : 16 g;
Chloroform : 200 mL;
1-(2,6-Dichlorophenyl)-2-indolinone : 18.6 g;
Ethanol : 66 mL;
NaOH (2N) solution : 66 mL.
Procedure:
(1) In a 150 mL round-bottom flask, N-chloroacetyl-N-phenyl-2 (16 g), 6-dichloroaniline
(16 g) and anhydrous AlCl
hours at 160
°C.
(16 g) are mixed vigorously and heated gently for 2
3
(2) The resulting mixture thus obtained is allowed to cool and poured into a 500 mL
beaker containing 200 g of crushed ice with constant stirring. The coil which gets
separated is dissolved in 200 mL chloroform. The chloroform layer is subsequently
washed with 40 mL of deionised water; and dried over anhydrous Na
2SO4
and
concentrated under vacuum. The residue thus obtained is distilled and allowed to
cool thus yielding solid intermediate, 1-(2,6-dichlorophenyl)-2-indolinone (II) with
mp. 126–127
°C.
(3) Then ethanol (66 mL) and 2N NaOH (66 mL) solution is taken in 250 mL round-
bottom flask followed by the addition of 1-(2,6-dichlorophenyl)-2-indolinone (II)
(18.6 g) and refluxed for 4 hours. The resulting solution is then allowed to cool at
0–5°C for at least 4 hours. It results in solid crude crystals followed by the filtration
over a Buchner funnel. Then the crude product is washed with a little amount of
cold water, dried in the oven and yields 23.2 g having mp. 281–283°C.
Precautions:
(1) AlCl
must be heated gently up to 150°C for 2 hours, cooled to ambient temperature
3
and poured onto crushed ice with stirring to obtain the second intermediate.
(2) The second intermediate must be treated with dilute NaOH solution and refluxed
cautiously for 4 hours before allowing it to be chilled at 0–5°C for another similar
span.
Recrystallization: The crude product obtained above (23.2 g) is dissolved in minimum
amount of water, a few grams of activated decolourizing carbon may be obtained, filtered
and cooled to obtain 22.5 g of recrystallized product with mp. 283–285°C.
Experiments 293
Yield:
The theoretical yield has been calculated from 242.5 g of 1-(2,6-Dichlorophenyl)-2indolinone (II) on reacting with NaOH that yields diclofenac sodium = 318.13 g.
18.6 g of compound (II) shall yield diclofenac sodium = (318.13/242.5) u 18.60 = 24.40 g
Hence, theoretical yield of diclofenac sodium = 24.40 g
Reported practical yield = 23.2 g
Therefore, percentage practical yield = (Practical yield/Theoretical
yield) u 100 = (23.2/24.4)
u 100 = 95.08%.
Physical parameters: The crystals obtained from water have mp. 283–285°C. It exhibits
(methanol) 283 nm (H1.05 u 105); phosphate buffer (pH 7.2) 276 nm (H1.01 u 105). It
UV
max
has solubility at 25°C (mg. mL
–1
); deionized water (pH 5.2) > 9; methanol > 24; acetone 6;
acetonitrile < 1; cyclohexane < 1; HCl (pH 1.1) < 1; phosphate buffer (pH 7.2) 6. It has
dissociation constant pKa 4; and partition coefficient (n-octanol/aqueous buffer): 13.4.
Uses: It is a non-steroidal anti-inflammatory drug (NSAID) and used mainly as its sodium
and potassium salt for the relief of pain and inflammation in various conditions, such as:
musculoskeletal and joint disorders, viz., rheumatoid, arthritis, gout, osteoarthritis; and
ankylosing spondolytis; peri-articular disorders, for instance: bursitis (inflammation of a
bursa, especially. Those located between bony prominences and muscle or tendon, as the
shoulder and knee), and tendenitis (an inflammation of a tendon); soft-tissue disorders,
such as: sprains and strains; and other painful conditions, namely: renal colic, acute gout,
dysmenorrhoea, and following certain surgical procedures.
Questions for Viva Voce
(1) How would you accomplish the synthesis of diclofenac sodium in a laboratory?
(2) Why is the ‘potassium-salt’ of diclofenac dose usually recommended to patients
having hypertension?
EXPERIMENT NO. 12.5
Aim: Preparation of metronidazole
Structure:
OH
N
O2N
Metronidazole
Synonyms: 2-Methyl-5-nitroimidazole-1-ethanol; 1-(2-Hydroxyethyl)-2-methyl-5nitroimidazole; 1-(E-Ethylol)-2-methyl-5-nitro-3-azapyrrole.
Me
N
294 Pharmaceutical Chemistry
Theory:
H
ON
N
2
N
2-Methyl-5-
nitroimidazole
Me
+
Cl
Ethylene
chlorohydrin
OH
128-130°C
18 h
-HCl
O2N
Metronidazole
OH
N
Me
N
The reaction between 2-methyl-5-nitroimidazole and ethylene chlorohydrin at 128–130°C
for 18 hours results into the formation of metronidazole.
Reagents:
2-Methyl-5-nitroimidazole : 25.4 g
Ethylene chlorohydrins : 160 g
Sodium Hydroxide : 20 mL
Chloroform : 200 mL
Ethyl acetate : 90 mL
Procedure:
(1) In a 250 mL round-bottom flask, 2-methyl-5-nitroimidazole (25.4 g, 0.256 mol)
heated with ethylene chlorohydrins (160 g; 2 mol) must be at 128–130°C for 18
hours.
(2) The excess of chlorohydrin (~133 g) is taken off by distillation under reduced
pressure (30 mmHg).
(3) The resulting residue is then treated with distilled water (60 mL) and filtered. The
filtrate is then made alkaline by adding of NaOH solution (d = 1.33; 20 mL).
(4) The alkaline solution is then extracted thrice with chloroform (200 mL). The
collective chloroform is evaporated under vacuuo to yield ~15.5 g of a semisolid.
(5) Semisolid is taken in ethyl acetate (90 mL) and a small amount of activated charcoal
and stirred for 10 minutes followed by filtration and drying. The pure creamy white
crystalline powder of metronidazole yields 4.8 g with mp. 158–160
°C.
Yield:
The theoretical yield is calculated from 99 g 2-methyl-5-nitroimidazole on being reacted
with 80.51 g ethylene chlorohydrin yields metronidazole = 171.16 g.
Thus, 25.4 g 2-methyl-5-nitroimidazole shall yield metronidazole = (171.16/99) u 25.4
= 43.91 g
Hence, theoretical yield of metronidazole = 43.91 g
Reported practical yield = 4.8 g
Therefore, percentage practical yield = (Practical yield/Theoretical yield) u 100
= (4.8/43.91) u 100 = 10.93%
Experiments 295
Physical parameters: Cream colour crystals of metronidazole having mp. 158–160 °C. It is
soluble in polar solvents and diluted acids while sparingly soluble in dimethyl formamide.
The pH of a saturated aqueous solution stands at 5.8.
Uses:
(1) Metronidazole is used in the treatment of trichomoniasis, dracunculus (guinea
worm) while with idoquinol it is used to treat symptomatic amebiasis.
(2) It is an alternative drug used to treat giardiasis, balantidiasis, blastocystitis, and
infections caused by Entameba polecki and anaerobic bacteria.
(3) It is also used against gastrointestinal strains of Bacteroides fragilis; and vaginal
infections caused by Gardnerella vaginalis.
(4) It has been used successfully in the treatment of antibiotic-associated psedomembra-
nous colitis.
(5) It is also useful in Crohn’s disease (the term commonly used for a number of chronic
inflammatory diseases of the gastrointestinal tract (GIT)).
Questions for Viva Voce
(1) Why is the reaction mixture made alkaline after the removal of unreacted ethylene
chlorohydrin? Explain.
(2) How would you account for the ‘metronidazole’ as one of the most potent
antiprotozoal agents?
EXPERIMENT NO. 12.6
Aim: Preparation of chloramine-T
Structure:
Cl
N
S
Na
O
O
Chloramine -T
Synonyms: Chlorazene, Chloraseptine, Gansil, Tochlorine and Tolamine.
Theory: Method-I: Synthesis of chloramine-T using toluene-p-sulphonamide.
HN
2
Me
S
O
O
NaOCl
10% NaOH
Me
Cl
NaNS
O
Chloramine-T
Me
+
HO
2
O
296 Pharmaceutical Chemistry
The reaction between toluene-p-sulphonamide with freshly prepared sodium hypochlorite
solution (2 M) in the presence of 10% NaOH solution led to the formation of chloramine-T.
Reagents:
Toluene-p-sulphonamide : 3 gm;
Freshly prepared 2 M sodium hypochlorite solution : 18 mL;
10% NaOH : 16 mL.
Procedure: To a mixture of 2M sodium hypochlorite solution (18 mL) and 10% NaOH
solution (16 mL) in a 100 mL conical flask, followed by the addition of toluene-p-
sulphonamide (2 gm). Cork the flask and shake vigorously for 5–10 minutes until toluenep-sulphonamide shall undergo complete dissolution; and at the same time a white
crystalline chloramine-T would appear almost distinctly. Then heat the contents of the
flask until a clear solution is obtained followed by gradual cooling at room temperature
leading to fine needles of chloramine-T (while on ‘sudden-chilling’ in the form of distinct
characteristic leaflets). Filter the crude product using suction pump, and dry over CaCl
2
in
a desiccator.
Yield:
171 gm of toluene-p-sulphonamide on treatment with sodium hypochlorite gives
chloramine-T = 227.5 gm
? 2 g of Toluene-p-sulphonamide yields chloramine-T = (227.5 X 2) / 171 = 2.66 gm
Hence, theoretical yield of chloramine-T = 2.66 gm
Reported practical yield = 2.1 gm
Therefore, percentage practical yield = (Practical yield u 100)/
Theoretical yield
= (2.1 u 100)/2.66 = 79.0 %
Theory: Method-II: Synthesis of chloramine-T using dichloramine-T.
Me
2
Cl
N
S
Cl
OO
Dichloramine-T Chloramine-T
NaOH
Cl
NaNS
O
O
Me
+ NaOCl +
HO
2
Dichloramine-T when heated with sufficient amount of 10% NaOH solution led to the
formation chloramine-T.
Reagents:
Dichloramine-T : 2 gm
10% NaOH solution : 14 mL
Procedure: A solution of 10% NaOH (14 mL) in a 100 mL beaker is heated over an asbestoswire gauze gently until the solution is almost boiling, followed by the addition of
Experiments 297
dichloramine-T (2 gm) pinchwise with constant stirring. After addition, the mixture was
cooled in ice-cold water, and the desired product chloramine-T shall separate out as
crystals readily.
Crystalline product was filtered using suction pump and dried using CaCl
or H2SO4
2
under desiccator. The crude product was recrystallized using a small quantity of hot water.
Yield:
240.11 gm of dichloramine-T on treatment with NaOH solution yields chloramine-T =
227.5 gm
? 2 g of dichloramine-T shall yield chloramine-T = (227.5 u 2)/240 = 1.89 gm
Hence, theoretical yield of chloramine-T = 1.89 gm
Reported practical yield = 1.8 gm
Therefore, percentage practical yield = (Practical yield u 100)/
Theoretical yield
= (1.8 u 100)/1.89 = 95.23%
Melting point: Release of chlorine at 128–132
o
C while solid melts at 166–170oC.
Uses:
(1) It is used as an antiseptic and disinfectant.
(2) It is invariably applied to mucous membranes as a 0.1% aqueous solution.
EXPERIMENT NO. 12.7
Aim: Preparation of dichloramine-T
Structure:
Me
Me
-
CH
CH
HOCl
COOH
3
COONa
3
-H O
2
Cl
N
S
Cl
OO
Dichloramine-T
Me
Cl
N
Cl
S
OO
Dichloramine-T
Synonyms: N,N-dichloro-p-toluene sulphonamide; N,N-dichloro-4-methylbenzene
sulphonamide
Theory:
HNOS
22
sulphonamide
Toluene- -p
Me
NaOCl
-H O
2
Na
Cl
N
S
O
O
298 Pharmaceutical Chemistry
Toluene-p-sulphonamide on dissolving in an excess amount of sodium hypochlorite
solution led to the formation of toluene-p-sulphon-chloro-sodioamide, which being watersoluble does not ordinarily crystallise unless and until very concentrated solutions are
employed. Later, to this mixture acetic acid (weak acid) is added, and it readily interacts
with the hypochlorus acid yielding the dichloramine-T (or toluene-p-sulphon-dichloro
amide) as a water insoluble solid which separates out rapidly.
Reagents:
Sodium hypochlorite solution (2 M) : 32 mL
Toluene-p-sulphonamide : 2 gm
Glacial acetic acid/water (1 : 1) : 20 mL
Procedure:
(1) In a 250 mL beaker, freshly prepared sodium hypochlorite solution (2 M, 32 mL) is
diluted with water (32 mL).
(2) Then 2 g of toluene-p-sulphonamide (powder form) is added to the above prepared
solution with constant stirring until a clear solution appears.
(3) The resulting mixture is cooled in ice-water, and then glacial acetic acid/water
solution (20 mL, 1:1) is added at small intervals, with constant stirring until complete
precipitation takes place.
(4) Dichloramine-T separates at first as a fine emulsion which readily forms brittle
colourless crystals.
(5) Crystals are filtered using suction pump and washed well with water, and dried
preferably in desiccators or between the folds of filter paper.
(6) The crude product may be recrystallized from minimum amount of petroleum
ether.
Preparation of Sodium Hypochlorite Solution (2 M) (100 mL): In a 250 mL beaker dissolve
10 gm of NaOH in 20 mL water and cool the solution, followed by the addition of 50 gm
of crushed ice. Now counterpoise the beaker on a rough set of scales, and pass in chlorine
from a cylinder until an increase in weight of 72 gm is achieved. Make up the volume of
the solution to 100 mL and shake thoroughly. The solution should be kept in a cool, dark
place, but even then it slowly decomposes.
Yield:
171 gm of toluene-p-sulphonamide on reaction with NaOCl and acetic acid yields
Dichloramine-T = 240 gm
? 2 g of dichloramine-T shall yield chloramine-T = (240 u 2) / 171 = 2.8 gm
Hence, theoretical yield of chloramine-T = 2.8 gm
Reported practical yield = 2.1 gm
Therefore, percentage practical yield = (Practical yield u 100)/
Theoretical yield
= (2.1 u 100) / 2.8 = 75.0%
Experiments 299
Melting point: Dichloramine-T having melting point 82–84°C
Uses:
(1) It is well known as an antibacterial and antigermicidal agent.
(2) It is also used as an antiseptic and disinfectant.
EXPERIMENT NO. 12.8
Aim: Preparation of clotrimazole
Structure:
N
N
Cl
Clotrimazole
Synonyms: 1-[(2-chlorophenyl)diphenyl methyl]-1H-imidazole; 1(o-chlorotrityl)
imidazole; 1(o- chloro-D,D-diphenylbenzyl)imidazole
Theory:
N
Cl
Cl
o-Chlorophenyl-
diphenylmethyl chloride
+
Imidazole
H
N
Et N,
MeCN
3
N
-HCl
N
Cl
Clotrimazole
+
Et N.
Cl
3
To a mixture of o-chlorophenyldiphenylmethyl chloride in acetonitrile, add imidazole
followed by Et
N. HCl then liberates and combines with Et3N leading to the corresponding
3
salt.
Reagents:
o-chlorophenyldiphenylmethyl chloride : 5 gm
Imidazole : 1 gm
Acetonitrile : 17 mL
N : 1.5 mL
Et
3
Benzene : 33 mL
Acetone : 33 mL
300 Pharmaceutical Chemistry
Procedure: In a dry and clean 250 mL beaker containing acetonitrile (17 mL), add
o-chlorophenyl-diphenylmethyl chloride (5 gm) and imidazole (1 gm) and shake with
constant stirring until solution is clear. Then HCl is liberated and at that time, add Et
and continue stirring for additional 10-30 minutes. The liberated HCl reacts with Et
N and
3
3
N
forms corresponding salt in solid form. At room temperature, this salt can be filtered using
funnel. Then the reaction mixture collected was allowed to heat at 50°C for a duration of 3
hours to complete the reaction. After completion, the mixture is allowed to cool at room
temperature followed by the addition of benzene (33 mL), stirred gradually for another
10-15 minutes. Now the salt is washed off with water. The benzene solution is dried over
anhy. Na
and filtered followed by evaporation of benzene using evaporator. The
2SO4
concentrated solution upon cooling yields 5.3 gm of crude clotrimazole that separates. The
crude product is dissolved in minimum quantity of acetone that led to pure crystals of
clotrimazole having melting point of 146-150°C.
Yield:
313 gm of o-chlorophenyldiphenylmethyl chloride on reacting with imidazole yields
clotrimazole = 345 gm
? 5 g of o-chlorophenyldiphenylmethyl chloride shall yield clotrimazole = (345 u 5)/ 313
= 5.51 gm
Hence, theoretical yield of clotrimazole = 5.51 gm
Reported practical yield = 5.3 gm
Therefore, percentage practical yield = (Practical yield u 100)/Theoretical yield
= (5.3 u 100)/5.51 = 96.18 %
Melting point: After crystallization, melting point is 146–150°C.
Uses:
(1) It acts as a strong antifungal agent specially in the case of skin, mouth, nails, vagina,
bronchi, hands and feet fungal infections, etc.
EXPERIMENT NO. 12.9
Aim: Preparation of sorbic acid
Structure:
O
OHMe
Sorbic acid
Synonyms: 2,4-hexadienoic acid; 2-propenylacrylic acid
Theory:
Experiments 301
O
Me
Crotonaldehyde Malonic acid
OH
+
HC
2
COOH
COOH
Pyridine
-H O
2
Sorbic acid
O
OHMe
In the presence of pyridine, crotonaldehyde reacts with malonic acid leading to sorbic acid.
Pyridine acts as a base as well as catalyst in making the reaction proceed in the forward
direction only. This reaction is the best example of Knoevenagel condensation or so-called
Doebner condensation.
Reagent:
Malonic acid : 3.2 gm
Pyridine : 3 mL
Crotonaldehyde : 2.3 mL (2 gm)
Conc. sulphuric acid : 0.5-1 mL
Procedure:
(1) In a 100 mL round-bottom flask fitted with reflux condenser, add malonic acid
(2 gm), pyridine (freshly distilled, 2 mL) and crotonaldehyde (2 gm) with constant
shaking.
(2) Reaction mixture is then allowed to reflux at gentle heating using heating mantle
for 45–50 minutes. After that reaction, mixture is allowed to cool using ice-cold
water to bring down the temperature between 5 and 6°C.
(3) Then in another test tube, conc. H
(0.5 mL) is added to water (2 mL) very slowly
2SO4
and carefully and the diluted acid in ice-bath is chilled to about 5-6°C.
(4) Add the diluted acid in test tube to the previously prepared reaction mixture in
small fractions with constant shaking so as to neutralize the base and liberate the
desired sorbic acid.
(5) Sorbic acid readily separates as crystals from the resulting solution.
(6) Crude product is recrystallized using minimum amount of distilled water
(~5-10 mL) leading to colourless crystals.
Yield:
70 gm of crotonaldehyde on reacting with malonic acid yields sorbic acid = 112 gm
? 2 g of crotonaldehyde shall yield sorbic acid = (112 u 2) / 70 = 3.2 gm
Hence, theoretical yield of clotrimazole = 3.2 gm
Reported practical yield = 3.0 gm
Therefore, percentage practical yield = (Practical yield u 100)/Theoretical yield
= (3.0 u 100)/3.2 = 93.75%