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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5406_Библиотеки_им_академика_М_И_Перельмана.pdf
282 Pharmaceutical Chemistry
QUESTIONS
1. Explain the medicinal uses of the following:
(a) Curcumin
(b) Azadirachta
(c) Vitamin C
(d) Antacid (ranitidine)
2. Write short notes on the following:
(a) Curcumin
(b) Azadirachta
(c) Vitamin C
(d) Antacid (ranitidine)
3. What are the major curcuminoids of curcumin?
4. What are the chemical constituents of neem?
5. How is nibidin useful for the social life?
6. How are curcumin and neem beneficial?
7. How is antioxidant property of vitamin C useful for the society?
8. How can vitamin C be produced by biosynthetic pathway?
9. What will be the consequences of deficiency of vitamin C?
10. What are antacids?
11. How does ranitidine work as antacid?
12. Write a brief note on medicinal importance of various medicinally important plants.
13. Which compounds are responsible for biological activity in garlic?
14. What are the home remedies of ginger and garlic?
15. What are the benefits of Ocimum?
16. How is Ocimum different from garlic and ginger?
17. Write the medicinal importance of ajwain.
18. What are the medicinal differences in ajwain and garlic?
19. How is garlic different from ginger and ajwain?
20. What are the common medicinal effects of ginger, tulsi, neem and ajwain?
12
Experiments
EXPERIMENT NO. 12.1
Aim: Preparation of aspirin
Structure:
COOH
OMe
O
Aspirin
Synonyms: Acetylsalicylic acid; Acetophen; Acetosal; Acetylin; Acetyl–SAL; ASA;
Acylpyrin; Arthrisin; Asatard; Caprin; Duramax; Entrophen; Saletin; Solpyron; Xaxa.
Methods: Aspirin may be prepared by any one of the following three methods:
Method–I: Aspirin may also be prepared from salicylic acid, acetic anhydride and a few
drops of concentrated sulphuric acid.
Theory
COOH
Salicylic
acid
OH
O
Me
Me
O
O
+
Acetic anhydride
conc. H
3-4 drops
SO
24
COOH
Aspirin
OMe
O
+
COOH
CH
3
Aspirin can be synthesized using acid catalyzed reaction between salicylic acid and acetic
anhydride. Acetic anhydride leads to CH
ion from the phenolic hydroxy group in salicylic acid yielded in CH
COO– anion which gets associated with the H+
3
COOH.
3
Reagents:
Salicylic acid: 6 g;
Acetic anhydride: 8.5 mL; and
Conc. H
: 3–4 drops.
2SO4
284 Pharmaceutical Chemistry
Procedure:
(1) In a clean and dry conical flask (100 mL), salicylic acid (6 g) is added.
(2) Then 8.5 mL of acetic anhydride and 3–4 drops of conc. H
are carefully added
2SO4
to the flask and shaken vigorously.
(3) Heat the reaction mixture on a water bath (60°C) for about 15–20 minutes with
frequent stirring or vigorous shaking.
(4) Reaction mixture is then cooled down at room temperature followed by pouring
reaction mixture in 250 mL beaker containing 100 mL cold water with continuous
shaking.
(5) Solid will precipitate in aqueous solution, then filter it through a Buchner funnel
using suction pump, washing it generously with cold water. Dry between the filter
paper or in an oven >60°C. The yield of white solid crude aspirin is about 7.75 g
having mp. of 133–134
Precautions: Glass apparatus must be absolutely dry, conc. H2SO
°C.
4
cautiously into the reaction mixture; the reaction mixture should not be warmed more
than 60°C and for 20 minutes.
Recrystallization: Recrystallize the crude product from a mixture of acetic acid and water
(1:1). The yield of pure colourless aspirin (mp. 134°C) is 7.25 g.
Yield: The theoretical yield is usually calculated as:
138 g of salicylic acid on reacting with 102 g of acetic anhydride yields aspirin = 180 g
? 6 g of salicylic acid shall yield aspirin = (180/138) u 6 = 7.82 g
Hence, theoretical yield of aspirin = 7.82 g
Reported practical yield = 7.5 g
Therefore, percentage practical yield = (Practical yield/Theoretical yield) u 100
= (7.5/7.82) u 100 = 95.90%
Questions for Viva Voce
(1) Why is the amount of acetic anhydride used in Method II for the same quantity of
salicylic acid, i.e., 1.5 mL more than Method I ?
(2) What is the specific role played by a few drops of concentrated sulphuric acid?
Method–II: It is prepared from salicylic acid, acetic anhydride and glacial acetic acid.
Theory:
COOH
OH
cylic acid Acetic anhydride
Sali
Me
+
Me
O
O
Glacial acetic acid
O
CH
COOH
3
COOH
Aspirin
Me
O
O
+
COOH
CH
3
Experiments 285
Salicylic acid interacts with acetic anhydride in the presence of glacial acetic acid whereby
the cleavage in acetic anhydride takes place with the formation of aspirin and a mole of
acetic acid. The glacial acetic acid helps in the generation of excess acetate ion which carries
the reaction in the forward direction. Acetic acid obtained as a product of reaction is reused
in the reaction itself.
Reagents
Salicylic acid: 6 g;
Acetic anhydride: 10 mL; and
Glacial acetic acid: 10 mL.
Procedure:
(1) Prepare a mixture of 10 mL each of acetic anhydride and glacial acetic acid in a 100
mL clean and dry beaker.
(2) Salicylic acid (6 g) is added in another 100 mL round-bottom flask and then the
above prepared mixture is added to the round-bottom flask and fit the same with a
reflux condenser.
(3) Reaction mixture is then boiled on sand bath or electric heating mantle for 35–45
minutes.
(4) After completion of reaction, reaction mixture is poured directly into 100 mL cold
water in a 500 mL beaker in one lot with vigorous stirring with a clean glass rod,
yielding shining tiny crystals of aspirin.
(5) Crude aspirin is then filtered on a Buchner funnel and the residue washed with
sufficient cold water and dried by using filter paper and oven below 60°C. The yield
of crude aspirin is approximately 7.5 g with mp. 133.5–135
°C.
Recrystallizatoin: The same procedure as stated under Method-I may be adopted.
Theoretical yield/Practical yield: The same procedure as stated under Method-I may be
adapted.
Physical parameters: Aspirin is obtained as monoclinic tablets or needle-like crystals, mp.
135°C (rapid heating); the melt gets solidified at 118°C; UV
484); CHCl
: 277 nm (E
3
1%
68). It is usually odourless, but in moist air it gets hydrolyzed
1 cm
(0.1 NH2SO4): 229 nm (E
max
1 cm
1%
slowly into salicylic acid and acetic acid, and overall acquires the odour of acetic acid. It is
fairly stable in dry air, 1 g dissolves in 300 mL water at 25°C, in 100 mL of water at 37 °C,
in 5 mL ethanol, 17 mL chloroform and 10–15 mL solvent ether.
Uses:
(1) It is used for the relief of minor aches and mild to moderate pain.
(2) It is recommended for arthritis and arthritis related conditions.
(3) It is also indicated for myocardial infarction prophylaxis.
(4) It is employed to reduce the risk of transient ischemic attacks in men.
286 Pharmaceutical Chemistry
Questions for Viva Voce
(1) Why is it necessary to recrystallize aspirin before being used as a medicine?
(2) Why must aspirin be stored in dry air or air-tight containers?
(3) What is the role of acetic acid in the reaction between salicylic acid and acetic
anhydride?
Method–III: Aspirin may also be synthesized by the interaction of salicylic acid with acetyl
chloride (i.e., on acid chloride) in the presence of pyridine which being a weak base rapidly
forms salts with strong acids.
Theory: Aspirin can be synthesized using salicylic acid and acetyl chloride. The acetylated
product eliminates one mole of HCl which later reacts with pyridine in the reaction mixture
to form the corresponding salt, i.e., pyridine hydrochloride.
COOH
a)
Salicylic acid Acetyl chloride
OH
+
b)
N
Pyridine Pyridinium hydrochloride
O
Cl Me
+
HCl
COOH
N
H
OMe
Aspirin
.HCl
+
HC
O
l
Reagents:
Salicylic acid: 6 g;
Acetyle chloride: 5 mL; and
Pyridine: 5 mL.
Procedure:
(1) Salicylic acid (6 g) is transferred to a 150 mL conical flask followed by the addition
of 5 mL of pure redistilled pyridine.
(2) Then this mixture is placed in an ice-bath at approximately 5–7°C.
(3) Acetyl chloride (5 mL) is then added in the above reaction mixture at cold condition
by using dropping funnel with constant and vigorous stirring.
(4) After complete addition of acetyl chloride, the reaction mixture is allowed to heat
over a water-bath for another 5–10 minutes.
(5) The reaction mixture is cooled, semi-solid residue is obtained, then the mixture is
followed by the addition of water (50 mL) and a few chips of ice with continuous
stirring/swirling.
(6) The crude aspirin is filtered on a Buchner funnel, washed with cold water and dried
either between the folds of filter paper or dried in an oven maintained below 60°C.
The yield of crude aspirin is 7.6 g with mp. 133–135.5°C.
Experiments 287
Recrystallization: The same procedure as stated under Method-I may be adopted.
Yield:
138 g of salicylic acid when reacted with 78.5 g of acetyl chloride shall yield 180 g aspirin.
So, 6 g of salicylic acid shall yield aspirin = (180/138) u 6 = 7.82 g
Hence, theoretical yield of aspirin = 7.82 g
Reported practical yield = 7.6 g
Therefore, percentage practical yield = (Practical yield/Theoretical yield) u 100
= (7.6/7.82) u 100 = 97.18
Questions for Viva Voce
(1) Why is the quantity of acetyl chloride just one half than the quantity of acetic
anhydride used in Method–I and Method–II?
(2) Explain the role of ‘pyridine’ in acetylation.
(3) What precautions must be followed during the addition of acetyl chloride?
EXPERIMENT NO. 12.2
Aim: Preparation of paracetamol
Structure:
O
HN Me
OH
Paracetamol
Synonyms: Acetaminophen; N-Acetyl-p-aminophenol; N-(4-Hydroxyphenyl) acetamide;
Calpol; Tylenol; Panadol; Disprol; Parmol; Valdol; Pacemol; Naprinol.
Theory:
O
NH
2
+
OH
p-Aminophenol Acetic anhydride
Me
Me
O
O
O
conc. H
3-4 drops
2
SO
4
HN Me
OH
Paracetamol
+
CH
COOH
3
Many preparative methods have been described for the synthesis of paracetamol, but
acetylation of p-aminophenol with acetic anhydride method is widely used. However, a
288 Pharmaceutical Chemistry
number of other routes of synthesis have also been discovered and used commercially,
namely:
(a) Phenol is converted to p-nitrosophenol and then reduced and acetylated.
(b) Late sixties: a single-step synthesis from nitrobenzene to p-aminophenol was
patented.
(c) Late seventies: monochlorobenezene was used followed by the nitration, hydrolysis
and then acetylation.
(d) Mid-eighties: phenol was used to synthesize 4-hydroxyacetophenone which on
rearrangement yielded paracetamol.
(e) Paracetamol synthesis was performed using p-nitrophenol followed by the
reduction and then acetylation with yield of about 97%.
Reagents:
p-Aminophenol : 6 g
Acetic anhydride : 6.5 mL
Conc. H
: 4 drops
2SO4
Procedure:
(1) p-Aminophenol (6 g) is transferred to a 100 mL cleaned and dried conical flask
followed by the addition of acetic anhydride (6.5 mL) and conc. H
(3-4 drops)
2SO4
cautiously and mixed well.
(2) Then the reaction mixture is allowed to warm on a water bath at 60°C for about
20–25 minutes with constant stirring.
(3) After completion of reaction, mixture is cooled at room temperature and poured
directly into a beaker having 100 mL of cold water (with a few chips of crushed ice)
with vigorous stirring.
(4) Crude product is filtered on a Buchner funnel, washed with plenty of cold water,
and the product is dried either between the folds of filter paper and air-dried or
dried in an electric oven maintained below 60°C. The yield of crude paracetamol is
approximately 6.8 g with mp. 169–170.5
°C.
Recrystallization: Crude product was dissolved in aqueous ethanol at warm condition
(60°C) and 2 g of C-charcoal is used as a decolourizing agent for 10 minutes. Filter the
mixture and the filtrate is concentrated over a water bath. Pure and white solid precipitate
of paracetamol yield is 6.5 g with mp. 169–170.5°C.
Yield:
109 g of p-Aminophenol on acetylation with 102 g of acetic anhydride, yields paracetamol
= 151 g
So, 6 g of p-Aminophenol shall yield paracetamol = (151/109) u 6 = 8.31 g
Hence, theoretical yield of paracetamol = 8.31 g
Reported practical yield = 6.8 g
Experiments 289
Therefore, percentage practical yield = (Practical yield/Theoretical yield) u 100
= (6.8/8.31) × 100 = 81.82%
Physical parameters: Paracetamol is slightly bitter taste and has mp. 169–170.5°C. It shows
21
d
1.293; UV
1
(ethanol): 250 nm (H 13800). It is slightly soluble in cold water while
max
considerably more soluble in hot water, soluble in many organic solvents, except nonpolar
solvents.
Uses:
(1) It is an effective antipyretic and analgesic agent.
(2) It is also useful in pain, headache, discomfort, fever, sometimes for cold and other
viral infections (given in combination), sometimes for a wide spectrum of arthritic
and rheumatic conditions involving musculoskeletal pain, dysmenorrhoea (pain in
association with menstruation), myalgias (tenderness or pain in the muscles), and
neuralgias (severe sharp pain occurring along the course of a nerve).
Questions for Viva Voce
(1) Is it possible to prepare paracetamol from p-Nitrophenol?
(2) What is the latest mode of synthesis for paracetamol by Pd-La/C catalytic
hydrogenation and acylation of p-Nitrophenol?
(3) What physicochemical analytical technique would you use to check its purity?
EXPERIMENT NO. 12.3
Aim: Preparation of benzoyl glycine (hippuric acid)
Structure:
H
O
N COOH
Benzoyl glycine
Synonyms: Hippuric acid; Benzoylaminoacetic acid; Benzamido-acetic acid.
Theory:
O
Benzoy
chloride
Cl
H
+
N
COOH
H
l
Glycine
NaOH
(10% solution)
H
O N COOH
Benzoyl glycine
+
HC
l
290 Pharmaceutical Chemistry
Glycine (D-aminoacetic acid) interacts with one mole of benzoyl chloride, in the presence
of 10% (w/v) NaOH solution, to yield benzoyl glycine with the elimination of one mole of
HCl. The excess of 10% NaOH solution serves two purposes, namely: first, to remove the
unreacted benzoyl chloride, and secondly, the HCl eliminated reacts with NaOH to yield
NaCl. Interestingly, both sodium benzoate and sodium chloride are water-soluble, whereas
the desired product benzoyl glycine being insoluble may be separated easily.
Reagents:
Glycine : 5 g;
Sodium hydroxide solution 10% (w/v) : 50 mL;
Benzoyl chloride : 10.8 g (9.0 mL);
Carbon tetrachloride : 20 mL;
Conc. HCl : 5 mL.
Procedure:
(1) In a 250 mL conical flask, dissolve glycine (5 g) in 10% NaOH solution (50 mL).
(2) Then benzoyl chloride (10.8 g or 9 mL, or five times to glycine) is added in small
fractions to the above prepared reaction mixture.
(3) Stopper the 250 mL flask securely with a rubber cork and shake the contents
vigorously after each addition unless and until all the benzoyl chloride has virtually
reacted.
(4) Stir vigorously and add a few grams of crushed ice into the solution and acidify the
contents by adding conc. HCl dropwise with constant stirring until the mixture
reached pH 5.0 (red) and pH 3.0 (blue-violet).
(5) Crystalline precipitate of benzoyl glycine comes out, then the mixture is allowed to
filter on a Büchner funnel, washed with cold water to remove excess of benzoyl
chloride.
(6) The solid precipitate is then put into a beaker containing CCl
(20 mL) and covered
4
with a clean water glass, and allowed to boil gently over a water bath for 10 minutes
at >70°C (it will extract any benzoic acid which may be produced during the
reaction).
(7) Then the resulting mixture is allowed to cool slightly. Filter under gentle suction
followed by washing using 2-3 slots of 10-20 mL of CCl
yield of the crude benzoyl glycine is 9.2 g with mp. 185–186.5
and dried properly. The
4
°C.
Recrystallization: Crude product is recrystallized using 100 mL of boiling distilled water
with the addition of 1–2 g of activated charcoal as a decolourizing carbon for 10 minutes
at 50°C. Then the hot mixture is filtered using Buchner funnel and the filtrate is kept for
cooling at room temperature, then again filter it. The pure solid is dried and yields 8.8 g
with mp. 186.5-187°C.
Yield:
75.07 g of glycine on reaction with 135.5 g of benzoyl chloride yields benzoyl glycine =
179.18 g
Experiments 291
? 5 g of glycine yields benzoyl glycine = (179.18/75.07) u 5 = 11.9 g
Hence, theoretical yield of benzoyl glycine = 11.9 g
Reported practical yield = 8.8 g
Therefore, percentage practical yield = (Practical yield/Theoretical yield) u 100
= (8.8/11.9) u 100 = 73.9%.
Physical parameters: It is obtained as crystals having mp. 187–188°C. It is freely soluble in
hot ethanol, hot water, and also soluble in aqueous solution of sodium phosphate.
Uses: Conjugation with amino acids is an important route in the conjugation of drug and
xenobiotic carboxylic acids for elimination. These amino acid conjugates are usually less
toxic than their precursor acids and hence, are excreted readily into the urine and bile.
Questions for Viva Voce
(1) What are the two specific roles played by excess of 10% NaOH solution?
(2) How does a small quantity of benzoic acid form along with benzoyl glycine?
(3) Why is it necessary to acidify the reaction mixture in the presence of crushed ice
with conc. HCl?
EXPERIMENT NO. 12.4
Aim: Preparation of diclofenac sodium
Structure
COO Na
Cl
H
N
Cl
Diclofenac sodium
Synonyms: 2-[(2, 6-Dichlorophenyl) amino] benzeneacetic acid monosodium salt; sodium
[o-(2, 6-dichlorophenyl) amino] phenyl] acetate.
Theory:
Cl Cl
NO
Cl
N-Chloroacetyl -N-
phenyl -2,6-
dichloroaniline
AlCl
-HCl
Cl
3
1-(2,6-Dichlorophenyl) -
2-indolinone
Cl
N
O
NaOH
EtOH
COO Na
Diclofenac sodium
Cl
H
N
Cl