Lab.

(1): Preparation of Acetaminophen

Generic Name: Acetaminophen, Paracetamol

Trade Names: Panda, Panadol, Revanin.
Chemical names: 4-Hydroxyacetanilide, N-(4-Hydroxyphenyl) acetamide.
Use: Analgesic – antipyretic
m.p.169-171⁰C
Principle:
Acetaminophen can be prepared by acetylation of p-aminophenol with acetic anhydride
under warm condition.

Objectives:
 Synthesis and recrystallization (purification)
 Determination of the melting point
 TLC separation

Procedures:
1. To 3.75 ml of distilled water add 1.4 g of p-aminophenol, and 2 ml acetic acid
anhydride.
2. Shake well and warm on a hot plate until the solid is dissolved.
3. Allow to stand at room temperature for 15 minutes then cool in ice for 5 minutes.
4. Filter at the pump and wash the precipitate with a little cold water.
5. Crystallize the crude product from hot water (35-38ml) and dry in air.
6. Measure the melting point and do TLC.
7. calculate % yield

Recrystallization
 Dissolve the solid in suitable amount of boiled water on a hot plate.

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  Boil the solution in a water bath and filter it while “it is still hot” through a small piece of
cotton fitted in a funnel on a 250 ml conical flask.
 Cool in an ice filled ice bath and separate the crystals of acetanilide by filtration under suction
using a pre-weighed filter paper.
 Wash the crystals with 5 ml of cold water and drain well.
 Place the filter paper on a white paper, write your name, section, product name and physical
state.
 Air dry the crystals on a filter paper and determine their weight and melting point.

Note:
If the m.p. is unsatisfactory, dissolve the product in dilute alkaline (e.g. NaOH) to
neutralization point. (Explain this purification step).

NaOH H+

Na+ O-

Soluble

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Medicinal Chemistry Lab 2020/20201

Lab. (1): Preparation of Acetaminophen

Acetaminophen
 Generic Name: Acetaminophen (USP), Paracetamol (BP)
 Trade Names: Panda®, Panadol®, Revanin®.
 Uses: Analgesic and antipyretic
 Physicochemical properties:
- White or almost white crystalline powder.
- Slightly soluble in water, freely soluble in alcohol
- m.p. 169-171 °C
 Chemical names: 4-Hydroxyacetanilide
N-(4-Hydroxyphenyl) acetamide.

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Amide Formation:
I. Amine + Carboxylic acid

 Slow reaction
 Needs heat
 Acid will protonate the amine.

Coupling agents

EDCI
DDC 1-Ethyl-3-(3-
N,N'-Dicyclohexylcarbodiimide dimethylaminopropyl)
carbodiimide

 Good leaving group

 Fast reaction
 No heat
 Protein synthesis

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Amide Formation:
II. Amine + Acid Chloride

 Fast reaction
 Cl as a leaving group?
 Acid scavenger ?

Amide Formation:
III. Amine + Acetic anhydride

 Needs heat
 Slower than acid chloride and faster than carboxylic acid?
 Acetic anhydride is irritant

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Crystallization & recrystallization

 A purification technique for solids.
 It is a process of precipitating crystals from a solution due to change in

the solubility of the solute in the solvent.

 For the best crystallization, the compound should be very soluble in

the hot solvent and minimally soluble (or insoluble) in the cold
solvent.
 At the same time, the impurities should be highly soluble in the

solvent at both high and low solvent temperatures.

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Solvent for crystallization:

 Chemically inert
 Non toxic

 Cheap, avaliable

 It should be capable of easy removal from the purified crystals (low b.p).

Melting point
 The melting point of a substance is the temperature at which it changes state
from solid to liquid.
 The melting point of a substance is the temperature range over which the first

crystal of a solid just starts to melt and the last crystal completes its melting.
 it is characteristic of the particular compound.
o
 A melting point range is very narrow for pure solids (usually just 1 – 2 C )

 The presence of even a small amount of impurity will lower a compound’s

melting point by a few degrees and broaden the melting point temperature
range.