The document discusses retrosynthetic analysis or disconnection approach in organic synthesis of drugs. It defines retrosynthesis as working backward from a target molecule to devise a suitable synthetic route. This is done through either disconnection, which involves imagined cleavage of a bond to form synthons or functional group interconversion. Basic rules for disconnection are that it forms stable fragment ions, with C-heteroatom bonds preferably cleaved and new functional groups introduced to produce stable fragments. Examples of several drug molecules and their potential retrosynthesis based on identified synthons are provided, including diphenhydramine, promethazine, triprolidine, nitroglycerine, isosorbide dinitrate, acetazol

1. Synthon or Disconnection or Retrosynthesis Approach in
Organic Synthesis of Drugs
Prepared By:
Aditi Kaushik
Assistant Professor
School of Pharmacy
MMUS, Ambala

2. Definition:
The process of working backward from target
molecule (TM) in order to devise the suitable
synthetic route.
Two approaches are:
● Disconnection
● Functional group interconversion

3. Disconnection
● A paper operation involving an imagined cleavage of the
bond.
● As a result of disconnection the positive and negative
components are formed known as SYNTHONS.
● Disconnection is shown by a wavy line like

4. Functional Group Interconversion (FGI)
The process of writing one functional group for another
to help in synthetic planning is known as FGI.
This can be done by
● Addition
● Subtraction
● Elimination
● Oxidation/Reduction
● Free radical reaction

5. SYNTHONS
● These are idealized fragments
● Synthons are shown by + or - signs like of
cations and anions (but not real one)
● May or may not be the intermediates of any
reaction

6. Basic Rules
Disconnection of the bonds should be that it form stable fragment ions.
For example:

7. 1. Always C-heteroatom (O,N,S) bond is broken and
electron pair is being transferred to the hetero atom
(as the hetero atom is more electronegative than
carbon).

8. 2. FGI method is used (i.e. introduction of the new
functional group) for producing the stable fragments.

9. 1) Diphenhydramine
Category: Antihistamine (H-1 receptor antagonists)
IUPAC name: 2-(diphenylmethoxy)-N,N-dimethylethanamine

11. Synthesis of Diphenhydramine from identified Synthons

12. Promethazine
Category: Antihistamine (H-1 receptor antagonists)
N,N-dimethyl-1-phenothiazin-10-ylpropan-2-amine

14. Synthesis of Promethazine from identified Synthons

15. Triprolidine
Category: Antihistamine
IUPAC name: 2-[(E)-1-(4-methylphenyl)-3-pyrrolidin-1-ylprop-1-enyl]pyridine

16. Nitroglycerine
Category: Antihistamine (H-1 receptor antagonists)
IUPAC name: 1,2,3-Trinitroxypropane

18. Synthesis of Nitroglycerine from identified Synthons

19. Isosorbide Dinitrate
Category:
IUPAC name: 1,4:3,6-dianhydro-2,5-di-O-nitro-D-glucitol

21. Synthesis of Isosorbide Dinitrate from identified Synthons

22. Acetazolamide
Category: Diuretics
IUPAC name: 5-acetamido-1,3,4-thiadiazol-2-sulfonamide

24. Synthesis of Acetazolamide from identified Synthons

25. Furosemide
Category: Diuretic
IUPAC NAME: 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid

27. Synthesis of Furosemide from identified Synthons

28. Disopyramide
Category: Anti-arrhythmic drug
IUPAC name: α-(2-diisopropylaminoethyl)-α-phenyl-2-pyridineacetamide

30. Synthesis of Disopyramide from identified Synthons

31. Warfarin
Category: Anti-Coagulant
IUPAC name: 3-(α-acetonylbenzyl)-4-hydroxycoumarin

33. Synthesis of Warfarin from identified Synthons

34. THANK YOU