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

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 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.
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STEPS FOR DESIGNING A SYNTHESIS

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 ANALYSIS

1. Recognize the functional groups in the target molecule.

2. Disconnect by known reliable methods using FGI if

necessary to produce the right functional group.

3. Repeat as necessary to reach available starting materials.

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 SYNTHESIS

1. Write out the plan according to the analysis, adding

reagents and conditions.
2. Check that a rational order of events have been
chosen.
3. Check the points about chemo selectivity so
unwanted or side reactions don’t occur. (if necessary
use protecting groups)
4. Modify the plan according to unexpected failures or
successes in the laboratory.
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Aromatic electrophilic substitution

H + X
X
R R

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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+ ArN2+ Diazocoupling

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Aromatic side chains by functional group
interconversion

Y X
R R

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Aromatic side chains by functional group interconversion
Y X Reagent
Reduction
-NO2 -NH2 H2, Pd, C, Sn, Con. HCl
-COR -CH(OH)R NaBH4
-COR -CH2R Zn/Hg, Con. HCl
Oxidation
-CH2Cl -CHO Hexamine
-CH2R -COOH KMnO4
-CH3
-COR OCOR R’CO3H
Substitution
-CH3 -CCl3 Cl2, PCl5
-CCl3 -CF3 SbF5
-CN -COOH HO- , H2O
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Aromatic compounds made by nucleophilic
displacement of diazonium salt
_
z
HONO + ArZ
ArNH2 ArN2

Z 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+
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Direction and activation in aromatic
electrophilic substitutuion
Direction Group Activation
O, P NR2,NH2, OR, OH, Activating
(ortho, para Alkenyl, Aryl, Alkyl, (electron donating)
director)
COO-, H, Halide Electronically neutral
M CX3, (X=F, Cl etc), Deactivating
(meta director) COOH, COR, CHO, (electron
SO3H, NO2 withdrawing)
Synthons for 1,n-di X synthesis
2-Group Synthon Reagent
relationship
R1
R1
+
1,1 OH
O
R2 R2

1,2
+ OH O O
X
O
+ R R
R
R

1,3 O O

+
R R
 O
1) PARACETAMOL
HN CH3

OH
STEP 1: ANALYSIS
O
HN CH3 NH2 NO2
FGI FGI

C N

OH OH OH

C N FGI

OH
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STEP 2: SYNTHESIS

OH OH OH OH
NO2
HNO3 Sn-HCl
+
H2SO4 Zn-HCl
(1:2)
NO2 NH2
ortho para
CH3COCl

OH

NHCOCH3

PARACETAMOL

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2) SACCHARINE

STEP 1: ANALYSIS

O O O
OH S N OH
C N
NH
SO2 SO2 NH2 SO3H

FGI

CH3 C S CH3

SO3H

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STEP 2: SYNTHESIS

CH3 CH3 CH3

ClSO3H NH3

SO3H SO2NH2

KMnO4

O
O
OH
NH
SO2 SO2NH2

SACCHARINE

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

STEP 1: ANALYSIS

HN COCH2CH3 NH2

FGI + ClCOCH2CH3
Cl Cl
C N
Cl Cl

FGI

NO2
FGI

Cl C N
Cl
Cl Cl

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STEP 2: SYNTHESIS

NO2 NH2

HNO3 H2/ Pd / C

Cl H2SO4
Cl Cl
Cl Cl Cl

CH3CH2COCl

HN COCH2CH3

Cl
Cl
PROPANIL

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 4) TRIMETHOPRIM

STEP 1: ANALYSIS
NH2
N
N O O

MeO C N H NH2
MeO NH2
FGI +
MeO H2N NH

OMe MeO
OMe

O O

Br O O Enolate OC2H5 OC2H5

MeO alkylation
MeO
+ C2H5O OC2H5

MeO MeO
OMe OMe

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 STEP 2: SYNTHESIS
O O
O O
NaOH C2H5O OC2H5

C2H5O OC2H5 MeO

MeO
Diethyl malonate
OMe

NaCl
DMSO
O
O
HO
OC2H5
OC2H5
HCOOC2H5 MeO
MeO

MeO
MeO
OMe
OMe

NH
H2N NH2

NH2
NH2
N N
N N
NH2
POCl 3 MeO
MeO
NH3
MeO
MeO
OMe
OMe

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

STEP 1: ANALYSIS

N N H3C Cl HN N
H3C +
O O

HN NH
Cl
+

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STEP 2: SYNTHESIS

HN NH

N NH
H3C
H3C Cl
O
O

Cl

N N
H3C
O

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 6) NIFEDIPINE

STEP 1: ANALYSIS

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STEP 2: SYNTHESIS

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7) ASPIRIN

STEP 1: ANALYSIS

O O
OH OH
+ CH3COCl
O CH3 OH

CH3

OH
OH

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STEP 2: SYNTHESIS

O
CH3Cl CH3 KMnO4 OH

OH AlCl3 Oxidation
OH OH
FC Alkylation

CH3COCl

O
OH

O CH3

Aspirin

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8) SALBUTAMOL

STEP 1: ANALYSIS

C-C

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 STEP 2: SYNTHESIS

O O O
HO HO
Br2 HO
CH3COCl
HO Br
AlCl3 HO CH3 CHCl3 HO
FC Acylation O
O
CH3
H3C NH2
CH3

HO
OH O
HO CH3 LiAlH4 HO CH3
N CH3 N CH3
H H2, Pd/C HO H
CH3 CH3
TM O

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 9) BENZOCAINE

STEP 1: ANALYSIS
O O
H2N H2N + C2H5OH
OC2H5 OH

O
O2N
OH

C N
CH3 O2N CH3

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 STEP 2:SYNTHESIS

NO2

CH3 O2N CH3 + CH3

O KMnO4

O
O2N
OH

Pd/H2

O C2H5OH O
H2N H2N
OC2H5 OH

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10) PROPRANOLOL

STEP 1: ANALYSIS

C N
CH3
OH
H CH3
+ HN
OH
O N CH3
CH3 O +
CH2

C O

H2
Cl C
+
O
OH

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STEP 2: SYNTHESIS

H2 -HCl
Cl C
+
O OH

OH O +
CH2

CH3
NH2
CH3

OH
H CH3
O N
CH3

Propranolol

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11.Rosiglitazone
Analysis:

C-O

C-N
Synthesis:
H
N OH
+
Cl CH3 F N N
N OH
CH3
Chloropyridine O

H
O N O

N N O S
H3C
N N O
O
CH3
NH
S
Rosiglitazone
O
O
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