synthesis of atenolol and its impurity

1. Synthesis of
atenolol and its
impurity
Name: manthan prabhu
Synthesis of
atenolol and its
impurity
11/2/2017
1

2. INTRODUCTION
◦ Atenolol is a selective β1 receptor antagonist, a drug
belonging to the group of beta blockers, a class of drug
primarily used in cardiovascular diseases.
◦ Introduced in 1976, Atenolol was developed as a
replacement for propranolol in the treatment of
hypertension.
◦ It works by slowing down the heart and reducing
its workload.
O
NH2
O
NH
OH
CH3
CH3
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3. HISTORY
Dr. James Black 1st trade name
O
OH
NH CH3
CH3
PROPRANALOL
NH CH3
CH3
OH
PRONETHALOL
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4. BETA BLOCKER
◦ Beta blocker, also written β-blocker, is a class of
medications that are particularly used to manage
cardiac arrhythmias, and to protect the heart from a
second heart attack (myocardial infarction ) after a
first heart attack (i.e. secondary prevention)
◦ They are also widely used to treat hypertension.
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5. •Beta blockers are competitive antagonists that block the
receptor site for the endogenous Catecholamine epinephrine
(adrenaline) and nor epinephrine (noradrenalin) on
adrenergic Beta receptor, of the sympathetic nervous
system, which mediates the fight or fight-response.
NH
CH3
OH
OH
OH
OH
OH
NH2
OH
ADRENALINE NORADRENALIN
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6. ◦ Three known types of beta receptor are β1, β2, β3 receptor.
◦ β1 –adrenergic receptor : are located mainly in the heart
and kidney.
◦ β2 – adrenergic receptor : are located mainly in the lungs,
gastrointestinal tract , liver, uterus, vascular smooth muscles,
and skeletal muscle.
◦ β3 -adrenergic receptor : are located in fat cells.
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7. MODE OF ACTION
 Atenelol is a beta – adrenergic blocking agent that blocks the
effects of adrenergic chemicals, for example, adrenaline or
epinephrine, released by nerves of sympathetic nervous system.
 One of the important function of beta- adrenergic nerves is to
stimulate the heart muscle to beat more rapidly. By blocking
the stimulation by these nerves, atenelol reduces the heart rate
and is useful in treating abnormally rapid heart rhythm.
 Atenelol also reduces the force of contraction of heart muscle
and lowers the blood pressure.
 Atenelol is useful in treating angina.
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8. 11/2/2017 8

9. MEDICINAL USES :
The use of beta blocker around time of cardiac surgery decrease
the risk of heart dysrhythmias(irregular heart beats).
These are given during the congestive heart failure.
Hypertension.
Long QT syndrome. (disorder of heart electrical activity)
Acute myocardial infarction.
Ventricle tachycardia. [Fast heart rhythm that starts in the lower
part of heart( ventricals)]
Supraventricular tachycardia.
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10. 11/2/2017 10
SIDE EFFECTS :
 Dizziness
 Tiredness
 Drowsiness
 Depression
 Nausea
 Shortness of breath

11. NH2
O
O
OH
NH CH3
CH3
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Atenolol Structure

12. PROPERTIES OF ATENOLOL
IUPAC NAME :-– 2-[4[2-hydroxy -3-(propan-2 ylamino) propoxy] phenyl]
acetamide.
CAS No.: 29122-68-7
 MOLECULAR FORMULA : C14H22N2O3
MOLECULAR WT : 266.336 g/mol
MELTING POINT : 146-148
o
C
SOLUBILITY :- Freely soluble in methanol , soluble in acetic acid, DMSO,
sparingly soluble in 96% ethanol.
COLOUR :- white crystalline powder
 USES :- Anti- adrenergic ( beta-receptor), anti hypertension.
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13. OH
CH2O
OH
OH
NaCN
NC
OH
H2O
Pt. cat.
NH2
O
OH
OCl
NC
O
O
NH2
O
O
O
piperidinepiperidine
CH3
NH2
CH3
CH3
O
O
OH
NH CH3
CH3
CH3
O
NH
OH
CH3
CH3
H2O
pt cat.
org process research development
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14. org process Res Dev 1998,2,(4):274
NH2
O
OH
O
Cl
Piperidine
NH2
O
O
O
NH2
CH3
CH3
O NH
OH
CH3
CH3
NH2
O
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15. J. chem. Pharm.Res.,2012,4(1):375-382
NH3 gas
sulphur
IPA
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2-(4-hydroxyphenyl
acetamide
OH
+ ClCH3
O
Phenol Acetyl Chloride
AlCI3 CH3
O
OH
p- hydroxy acetophenone
NH2
O
OH
OCl
+
epichlorohdrin
NH2
O
O
O
NaOH
CH3
NH2
CH3
+
NH2
O
O
OH
NH CH3
CH3
Atenolol

16. Chem pharm bulll1998,46,(3):505
Atenolol
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2-(4-hydroxyphenyl
acetamide
OH
NH2
COOH
NaCN,NaOH
DMF,130O
C
OH
CN
4- hydroxy- benzyl cyanide
H2O
OH
NH2
O
+
O
Cl
N
H
piperidine
O O
NH2
O
4-(2,3-epoxypropoxy)-
phenylacetamide
CH3 CH3
NH2
isopropylamine
NH2
O
O NH CH3
CH3
OH
DL-4-hydroxyphenyl
gylcine

17. Atenolol Retrosynthesis
O
Cl
+
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O
OH
NH CH3
CH3
NH2
O C-N Bond disx
NH2
O
O
O
+
CH3
NH2
CH3
O-C Bond disx
OH
NH2
O
C-N Bond disx
OH
Cl
O
OH
OH
O

18. SYNTHESIS OF ATENOLOL :
proposed work
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NH2
O
OH
OCl
+
epichlorohdrin
NH2
O
O
O
NaOH
CH3
NH2
CH3+
NH2
O
O
OH
NH CH3
CH3
Atenolol
2-[4-(2-oxiranylmethoxy)
phenyl]acetamide

19. IMPURITY
Impurity are chemical substances inside a confined amount of
liquid, gas, or solid, which differ from the chemical
composition of the material or compound. Impurities are
either naturally occuring or added during synthesis of a
chemical or commercial product.
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20. Atenolol impurities by Europian
pharmacopeia
NH2
O
O
OH
OH
NH2
O
O
O
NH2
O
O
OH
Cl
NH2
O
O
OH
O
NH2
O
Atenolol EP Impurity B
Atenolol Impurity C
Atenolol EP Impurity D
Atenolol EP Impurity E
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21. NH2
O
O
OH
N
CH3
CH3
OH
O
CH3
O
O
OH
NH CH3
CH3
OH
O
Atenolol EP Impurity G
Atenolol EP Impurity F
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22. Atenolol impurity-G
◦ Compound name: atenolol impurity –G(EP)
◦ Chemical Name:- 2-[4-(2rs)-2-hydroxy-3-[(1-
methylethyl)amino]propoxy]phenyl]acetic acid..
◦ Molecular formula: C14 H21 NO4
◦ Molecular weight: 267.32
◦ Appearance :- off white solid
OH
O
O
OH
NH CH3
CH3
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23. Retrosynthesis of impurity G
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OH
O
O
OH
NH CH3
CH3
C-N Bond disx
NH2
O
O
O
+
CH3
NH2
CH3
C-O Bond disx
NH2
O
OH
C-N Bond disx
CH3
Cl
O
CH3
OH
O

24. O
OH
NH CH3
CH3
NH2
O MeOH
NaOH, heat Na
+
O
-
O
O
OH
NH CH3
CH3
OH
O
O
OH
NH CH3
CH3
Proposed Synthesis:-
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25. NH2
O
O
OH
N
CH3
CH3
OH
O
CH3
O
Atenolol impurity- F
◦ COMPOUND NAME:- atenolol impurity -F(EP)
◦ CHEMICAL NAME:-2,2[(1- methylethy)iminobis(2-
hydroxypropan-3,1- diyloxy-4,1-phenylene)]
diacetamide
◦ MOLECULAR FORMULA:-C25H35NO6
◦ MOLECULAR WEIGHT:- 473.56
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26. Retrosynthesis :-
O N
NH2
O
OH OH
O
NH2
O
CH3
CH3
N-C bond disx
+
NH2 CH3
CH3
NH2
O
O
O
NH2
O
OH
+
O-C bond disx
O
Cl
2eq
1 eq
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27. Synthesis of impurity F
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NH2
O
OH
+
OCl
Epichlorohydrin
NaOH
Step I :-
Step II :-
NH2
O
O
O
2 eq + CH3
NH2
CH3
NH2
O
O
OH
N
CH3
CH3
OH
O
NH2
O
1 eq
4-hydroxyphenyl
acetamide
NH2
O
O
O
2-[4-(2-oxyraylmethoxy)phenyl]
acetamide

28. Experimental work
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29. OH
E tOH
KOH solid
Allyl bromide, reflux, 80%
O
CH2
Phenol Allyl phenyl ether
SOLVENT SYSTEM :- 100 % PET ether
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30. OH O
CH2DMSO/ DMF
Na2co3/ KOH
Allyl Bromide, RT
SOLVENT SYSTEM :- 10% ETHYL
ACETATE IN PET ether
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31. Phenol
OH
Cl O
+
NaOH
24 hrs, RT
O
O
SOLVENT SYSTEM :- 10% ETHYL
ACETATE IN PET ether
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32. Phenol
OH
Cl O
+
O
O
Epichlorohydrin
EtOH
piperidine , RT
SOLVENT SYSTEM :- 10% ETHYL
ACETATE IN PET ether
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33. Refrences
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