2. synthesis-of-paracetamol.pdf

Synthesis-of-paracetamol

1. To synthesis and characterization of
paracetamol
Dr. Pawan Kumar Gupta
Associate Professor
SVKM's Institute of Pharmacy, Dhule, Maharashtra
https://sites.google.com/view/pawanpharma79/about-me?authuser=1

2. Introduction
•Paracetamoloracetaminophenisaverywidelyusedanalgesicandantipyretic.Itisarelativelysafedrug
(toxicityhasbeenobservedwithveryhighdoses).
•Itistypicallyusedformildtomoderatepainrelief.
•Itismildanalgesicanddoesnothaveanti-inflammatoryactivity
•Itisoftensoldincombinationwithothermedicationssuchasinmanycoldmedications
•Itsuedforseverepainsuchascancerpainandpainaftersurgery.
•Oftentakenorallyorrectally,butalsoI.V.
•Effect:last2hrsand4hrs.
•Itissafeatrecommendeddose.
•Seriousskinrushesmayrarelyoccurandtoohighdosecanresultinliverfailure.
•Itappearstobesafeinpregnancyandbreastfeedingwomen.
•ItisonWHO’slistofessentialmedicines,themosteffectiveandsafemedicinesneededinahealth
system.
•ParacetamolisavailableasagenericmedicationwithtradenamesincludingTylenolandPanadol,among
others.

3. Introduction
•Paracetamolconsistsofabenzeneringcore,substitutedbyonehydroxylgroupand
thenitrogenatomofanamidegroupinthepara(1,4)pattern.Theamidegroupisacetamide(Ethan
amide).Itisanextensivelyconjugatedsystem,asthelonepaironthehydroxyloxygen,thebenzenepi
cloud,thenitrogenlonepair,thep-orbitalonthecarbonylcarbon,andthelonepaironthecarbonyl
oxygenareallconjugated.
•Thepresenceoftwoactivatinggroupsalsomakethebenzeneringhighlyreactive
towardelectrophilicaromaticsubstitution.
•Asthesubstituentsareortho,para-directingandparawithrespecttoeachother,allpositionsonthe
ringaremoreorlessequallyactivated.
•Theconjugationalsogreatlyreducesthebasicityoftheoxygen'sandthenitrogen,whilemakingthe
hydroxylacidicthroughdelocalizationofchargedevelopedonthephenoxideanion.

4. Principle
•Paracetamoliseasilypreparedbynitratingphenol
withsodiumnitrate,separatingthedesiredp-nitro
phenolfromtheortho-byproduct,andreducing
thenitrogroupwithsodiumborohydride.
•Theresultantp-aminophenolisthenacetylated
withaceticanhydride.
•Inthisreaction,phenolisstronglyactivating,thus
thereactionrequiresonlymildconditionsnitration.
•Thisreactionisexothermic.
Paracetamolismadebyreacting4-aminophenolwith
ethanoicanhydride(morecommonlycalledacetic
anhydride).Thisreactionformsanamidebondand
ethanoicacidasabyproduct.Whenthereactionis
completetheparacetamolisthenisolatedandpurified.
Thesynthesisofparacetamolcanbebrokendowninto3
parts:
Part 1 –mix the reactants together to form paracetamol.
Part 2 –isolate crude paracetamol from the ethanoic acid
and unreacted starting materials.
Part 3 –purify paracetamol by recrystallisation

5. Mechanism of Reaction
•Thelonepairofelectronson
theamineof4-aminophenol
attackstheC=Obondofacetic
anhydridecausingittobreak.
•Nitrogenhasapositivecharge
butregainselectronsbylosing
aproton.
•Thenegativechargeonthe
oxygencomesbackinto
reformtheC=Obond.This
causestheotherC-Obondto
break.
•Theresultisanamidebond
formationandacarboxylicacid
by-product.

6. •REQUIREMENTS
•Round bottom flask
•Measuring cylinder
•Beaker
•Pasteur pipette
•Buchnerfunnel
•Glass rod
•Filter paper
•Dropper
•Hot plate with magnetic stirrer

7. Chemicals required:
•P-aminophenol
•Acetic anhydride
•Purified water
•Conc. H
2SO
4
•MeOH

8. Procedure
•1. Add 3.07 grams of 4-aminophenol into the 50 ml flask and add 18 ml of water into it.
•2. add 3.5 ml of ethanoicanhydride (also known as acetic anhydride). Add 2-3 drop conc. H
2SO
4 in the mixture.
•3. This reaction is exothermic (heat is released after mixing the reactants, and flask become warm.
•4. Put the flask on hot plate (with magnetic stirrer) and heat the mixture for 1hr (120°C). The reaction mixture
should become colorless.
•5. Allow the flask to cool slightly before placing it on the bench top
•6. Now, crystal of the crude product is appeared in the flask. Place the flask on ice-bath for sometime (until
complete crystal is formed)
•7. Filter the solution using suction pump with the help of Buchner funnel.
•8. Washing the product with cold water during the filtration
•9. allow the crude product to dry under vacuum (still attached with suction pump)
•10. measure the weight of the crude product (3.01 gm)
•11. Purification: Recrystallization of the crude product with the 50% MeOH in water solution
•12. Add 25-30 ml of recrystallization solvent into crude product with continuous stirring on hot plate (128
degree C)
•13. Cool the mixture in ice bath and filter the recrystallized product again and again with the cold water using
suction pump with the help of Buchner funnel.
•14. Final product is dried under vacuum

9. Calculations
1 mol of the p-aminophenol is equivalent to 1 mol of the paracetamol
C
6H
7NO
p-aminophenol
Mw: 109.13 C
8H
9NO
2
Paracetamol
Mw 151.16

10. •Theoretical yield:
•109.13 gm p-aminophenol forms 151.16 gm paracetamol
•1 gm-------------------------------= 151.16 / 109.13
•X gm------------------------------= (151.16 / 109.13)*x
•Therefore, ___3.07g ___p-aminophenol will form …….? (X) g
paracetamol
•X =(151.16 ×__3.07__)/ 109.13 = gm
•Theoretical yield = 4.25 gm
•Practical yield = 3.01 gm

11. Calculations
(3.01/4.25)*100 = 70.82 % yield

12. •https://www.youtube.com/watch?v=xY33L8SqMo4
•Synthesis, TLC, characterization of the product:
•https://www.youtube.com/watch?v=T02vP2s15F8
•Mechanism of Action:
•https://www.youtube.com/watch?v=UkcpOZ7AGBQ
•https://www.youtube.com/watch?v=249FNCSR-Cw
•https://slideplayer.com/slide/15785699/
•https://slideplayer.com/slide/13714086/