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

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

STEPS FOR DESIGNING A SYNTHESIS

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

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

Aromatic electrophilic substitution

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

Aromatic side chains by functional group interconversion

Aromatic side chains by functional group interconversion X 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

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+

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)

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

1) PARACETAMOL STEP 1: ANALYSIS

STEP 2: SYNTHESIS PARACETAMOL

2) SACCHARINE STEP 1: ANALYSIS

STEP 2: SYNTHESIS SACCHARINE

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

STEP 2: SYNTHESIS PROPANIL

4) TRIMETHOPRIM STEP 1: ANALYSIS 19

STEP 2: SYNTHESIS 20

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

STEP 2: SYNTHESIS 22

6) NIFEDIPINE STEP 1: ANALYSIS 23

STEP 2: SYNTHESIS 24

7) ASPIRIN STEP 1: ANALYSIS 25

STEP 2: SYNTHESIS Oxidation FC Alkylation 26

8) SALBUTAMOL STEP 1: ANALYSIS C-C 27

STEP 2: SYNTHESIS AlCl3 FC Acylation TM 28

9) BENZOCAINE STEP 1: ANALYSIS 29

STEP 2:SYNTHESIS 30

10) PROPRANOLOL STEP 1: ANALYSIS 31

STEP 2: SYNTHESIS

11.Rosiglitazone Analysis: C-O C-N

Synthesis: Chloropyridine Rosiglitazone

Best of luck 35