1. SYNTHON APPROACH Presented by Prof. Dr. A G Nikalje
Head Department of Pharmaceutical Chemistry,
Y.B. Chavan College Of Pharmacy
Dr. Rafiq Zakaria Campus Aurangabad

2. TERMINOLOGIES
Synthon: An idealized fragment (cation or anion) formed by disconnection.
Target Molecule: A molecule to be synthesized.
Analysis/ Retro synthetic analysis: It is a process of break down of target molecule into available starting materials by FGI and disconnection.
Disconnection: An operation which involve breaking of bond between two atom to form possible starting materials.
The symbol for FGI / disconnection is ( / )
Reagent: Compound used in the practice of synthon. 2

3. STEPS FOR DESIGNING A SYNTHESIS

4. Recognize the functional groups in the target molecule.
ANALYSIS
Recognize the functional groups in the target molecule.
Disconnect by known reliable methods using FGI if necessary to produce the right functional group.
Repeat as necessary to reach available starting materials. 4

5. Check that a rational order of events have been chosen.
SYNTHESIS
Write out the plan according to the analysis, adding reagents and conditions.
Check that a rational order of events have been chosen.
Check the points about chemo selectivity so unwanted or side reactions don’t occur. (if necessary use protecting groups)
Modify the plan according to unexpected failures or successes in the laboratory. 5

6. Aromatic electrophilic substitution

7. Reagents for aromatic electrophilic substitution
Synthon
Reagent
Reaction R+
RBr+ AlCl3; ROH+ H+
Friedel Craft’s alkylation
RCO+
RCOCl+ ALCl3
Friedel Craft’s acylation
NO2+
HNO3+ H2SO4
Nitration
Cl+
Cl2+ FeCl3
Chlorination
Br+
Br2+ Fe
Bromination
+SO2OH
H2SO4
Sulphonation
+ SO2Cl
ClSO3H
Chlorsulphonation
ArN2+
Diazocoupling

8. Aromatic side chains by functional group interconversion

9. Aromatic side chains by functional group interconversionX
Reagent
Reduction
-NO2
-NH2
H2, Pd, C, Sn, Con. HCl
-COR
-CH(OH)R
NaBH4
-CH2R
Zn/Hg, Con. HCl
Oxidation
-CH2Cl
-CHO
Hexamine
-COOH
KMnO4
-CH3
OCOR
R’CO3H
Substitution
-CCl3
Cl2, PCl5
-CF3
SbF5
-CN
HO- , H2O

10. Aromatic compounds made by nucleophilic displacement of diazonium salt
Reagent HO
H2O RO
ROH CN
Cu(1)CN Cl
Cu(1)Cl Br
Cu(1)Br I KI Ar
ArH H
H3PO2 or EtOH/H+

11. Direction and activation in aromatic electrophilic substitutuion
Group
Activation
O, P
(ortho, para director)
NR2,NH2, OR, OH, Alkenyl, Aryl, Alkyl,
COO-, H, Halide
Activating
(electron donating)
Electronically neutral M
(meta director)
CX3, (X=F, Cl etc), COOH, COR, CHO, SO3H, NO2
Deactivating
(electron withdrawing)

12. Synthons for 1,n-di X synthesis
2-Group relationship
Synthon
Reagent
1,1
1,2
1,3

13. 1) PARACETAMOL
STEP 1: ANALYSIS

14. STEP 2: SYNTHESIS
PARACETAMOL

15. 2) SACCHARINE
STEP 1: ANALYSIS

16. STEP 2: SYNTHESIS
SACCHARINE

17. 3) PROPANIL: IUPAC name
N-(3,4-dichlorophenyl)propanamide ; Herbicide
STEP 1: ANALYSIS

18. STEP 2: SYNTHESIS
PROPANIL

19. 4) TRIMETHOPRIM
STEP 1: ANALYSIS 19

20. STEP 2: SYNTHESIS 20

21. 5) FENTANYL: IUPAC Name N-(1-(2-Phenylethyl)-4-piperidinyl)-N-phenylpropanamide
STEP 1: ANALYSIS 21

22. STEP 2: SYNTHESIS 22

23. 6) NIFEDIPINE
STEP 1: ANALYSIS 23

24. STEP 2: SYNTHESIS 24

25. 7) ASPIRIN
STEP 1: ANALYSIS 25

26. STEP 2: SYNTHESIS
Oxidation
FC Alkylation 26

27. 8) SALBUTAMOL
STEP 1: ANALYSIS
C-C 27

28. STEP 2: SYNTHESIS
AlCl3
FC Acylation TM 28

29. 9) BENZOCAINE
STEP 1: ANALYSIS 29

30. STEP 2:SYNTHESIS 30

31. 10) PROPRANOLOL
STEP 1: ANALYSIS 31

32. STEP 2: SYNTHESIS

33. 11.Rosiglitazone Analysis:
C-O
C-N

34. Synthesis:
Chloropyridine
Rosiglitazone

35. Best of luck 35