A high speed parallel synthesis of 1,2-diaryl-1-ethanones :

Useful intermediates for the synthesis of COXIBS

Venugopal Rao Veeramaneni

Discovery Chemistry (Synthesis)

Ref: Venugopal rao Veeramaneni,

Veeramaneni Manojit Pal and Koteswar Rao Yeleswarapu;
Tetrahedron, 59 (2003) 3283 - 3290
 Highlights of the presentation

¾ Introduction of 1,2-diaryl-1-ethanones.
¾ Significance of parallel synthesis.
¾ Why we need COXIBS.
¾ Utilization of 1,2-diaryl ethanones in COXIBS.
COXIBS
¾ Known methods to prepare 1,2-diaryl ethanones.
¾ Our new method to synthesis 1,2-diaryl ethanones.
¾ Advantages / Conclusion

2
 Application of 1,2-diaryl-1-ethanones.

ƒ Versatile intermediates for the synthesis of alkaloids (Pavine,

Isopavine & Protoberberine).
ƒ Intermediates for the synthesis of Bioactive molecules.
i. Cox-2 inhibitors
ii. tamoxifen analogues
iii. p38 Map kinase inhibitors
iv. IL biosynthesis inhibitors
v. Catechol-O-methyl stransferase inhibitors
vi. Human neutrophil elastase inhibitors
vii. Platelet aggregation inhibitors.
viii. Active molecules in the treatment of Parkinson’s disease.
3
 Significance of parallel synthesis
• Parallel synthesis strategy has been shown to provide an
attractive lead development tool for the refinement of biological
activity.

• This strategy has been utilized successfully to generate a

library of heterocycles.

• This approach has been utilized for the synthesis of a number of

novel compounds having potential biological activity as well as
synthetic analogues of existing bioactive molecules.

4
Why we need COXIBS

5
 Why we need COXIBS

COXIBS are Non Steroidal Anti-inflammatory Drugs

Inflammation: Defensive reaction of the body tissues to

disease or damage, including redness, swelling, and heat.

* It may be acute or chronic, and may be accompanied by

the formation of pus.
* This is an essential part of the healing process.
* Inflammation is triggered by Infection agents, antigen –
antibody interactions and thermal / physical injury.

6
 How inflammation takes place
™Inflammation reactions to chemical, mechanical and
thermal stimuli is significantly enhanced in the presence
of Prostaglandins (PGs) and Leucotrienes (LTs).

™ PGs and LTs are enzymatically synthesized from

Arachidonic Acid by three different pathways.
» Lipoxygenase pathway
» Cyclooxygenase pathway
» Monooxygenase pathway

7
 DISCOVERY OF MECHANISM OF ACTION
& History of NSAIDS and COX –2 Inhibitors

áFirst anti-inflammatory drug was from Herbal,

introduced by Reverend Edward Stone in 1763 .
á First drug synthesized & introduced in 1860 by Kolbe
and Lautemann (Salicylic acid).
á Acetylsalicylic acid, was developed by Felix Hoffman
1875 In 1899 Heinrich
from the Bayer Company in 1875.
Dreser named the compound as "Aspirin"
Aspirin

á In 1933 Goldblatt was discovered Prostaglandin

activity.
8
 DISCOVERY OF MECHANISM OF ACTION
& History of NSAIDS and COX –2 Inhibitors

á In 1937 Von Eluer detected in semen and he named as

‘Prostaglandins’

áIn 1969 Piper and Vane demonstrated the first association

between prostaglandin production and the actions of aspirin- like
drugs.

á Arachidonic acid metabolism was discovered in 1971

á Prostaglandin was isolated in 1976 and cloned in 1988

9
 Arachidonic acid Cascade
Essential patty acid in diet

Esterified acid in cell lipid

Various stimuli
Activation of phopholipase
chemical & mechanical Of other acyl hydrolases

CO2H

ARACHIDONIC ACID 10
5,8,11,14-Ecosatetraenoic acid
CYCLOOXYGENASE PATHWAY
CO2H

ARACHIDONIC ACID
5,8,11,14-Ecosatetraenoic acid

COX - 1 / COX -2
Cyclooxygenase
O2 (PGH Synthase)

CO2H
O
O
O2

CO2H
O
O
O2

CO2H
O PGG2
O

HOO

CO 2 H
O
O PG H 2 11
HO
 HO
O CO
CO22H
H CO2H CO2H
O O
O O
O
HO HO
HO
HO
HO PGF TXA2
HO
HO PGI 2a
PGI22
Prostacycline
Prostacycline Synthase
Synthase PGF Synthase Tromboxine Synthase

ndoperoxide D - isomerase OH
HO CO2H CO2H
CO2H O
O O HO O
HO TXB
HO HO PGH 2
HO 2
6 Keto
PGF2a

PGE synthase PGD Synthase B-Oxdation

O HO
CO2H
CO2H CO2H
O
HO O
HO PGE2 HO HO
HO PGD 2,3-Dinor
2 TXB2

12
 Vasodilation, Fever
Inhibition of platelet
Aggregation, Reduction of TXA2
PGI2 gastric acid and etc.
Platelet activator &
aggregant, Vasoconstriction,
Bronchoconstriction
Platelets
Endothelium
Mast cells PGH2
Mast cells

Uterus
PGD2
PGE2

Vasodilation Vasodilation
Fever, Renin Release Mast cell activation
Reduction of Gastric Bronchoconstriction
acid secretion and etc. PGF2a

Vasoconstriction
Fever, Uterine contractions
Labour, Embryo implantation 13
 Expression of PGs in other Organs

COX –2
COX –2 strongly
High salt intake Constitutely
Control of the Expressed in
Induces, in renal in the β-cells
Autonomic Capillary body
papillary cells Nervous system

COX-1-Cytoprotected Complex integrative Intestine Lung Cancer

COX-2 –Inhibit the Functions.
Activation Of pathogenic
T-cells In the gut 14
 History of anti-inflammatory drugs
CO2H Ph O OH
CO2H N
HO NHCOCH3 O
OH Ph N C4H9 HO
OCOCH3 HO OH
OH
O
Salicylic Aspirin Acetaminophen SAu

acid Phenyl Aurothio

Butazone glucose
CO2H

MeO CO2H
H CO2H
N N CO2H
Cl
MeO
O

Ibuprofen Naproxen
Mefenamic acid
Indomethacin
SOCH3
CO2Na O
O COCO2H Cl O N

CO2H
CO2Na
Cl

Diclofenac Tolmetin Sulindac sodium

Ketoprofen 15
Sodium
 History of anti-inflammatory drugs
O O NHSO2CH3
S O
CO2H O
H
N N
Ph N CO2H
OH O H
F
NO2

Flurbiprofen Piroxicam Etodolac Nimuslide

H2NO2S
O O O
S N
H N N O O
N S CF3
NO2
OH O
H3CO2S H2NO2S

Meloxicam Rofecoxib Valdecoxib

Celecoxib
H2NO2S
N

N N N N N
A CF2
Na O
F O F
NH
H3CO2S O S O
O H2NO2S
O

Etoricoxib Parecoxib Sodium Tilmacoxib Deracoxib 16

Neck pain Teeth pain

Back pain
Muscle pain Ankylosing
spondylitis

Rheumatoid Osteoarthritis
arthritis

Post operation pain

Gout 17
Knee pain
Utilization of 1,2-diaryl ethanones in COX-2 inhibitors .
H2NO2S
MeO2S X H2NO2S

O
N S
N N
S

X = Me (Valdecoxib)
1 Merck
Compound
X = CH2OH (Searle compound) F
Merck
3 compound
2
MeO2S
4 N
Ar O
CF3
S Br
S
MeO2S
Ar1 5
Searle-Monsanto F
DuP 697
Compound

F
MeO2S MeO2S
6 N

O O O
7 O

MeO2S 8 O

Merck O
Compound F Merck
Compound
Pacific Corporation
18
Compound
 Utilization of 1,2-diaryl ethanones in some
other bioactive molecules.
OH OH
O R
OH
9 O
HO NO2 11
O
O
Human Nutrophil
Estrogen Recrptor- Catechol-O-methyltransferase
Elastase Inhibitors
beta Potency inhibitors, BIA 3 -202
Ono Pharma
selective ligand

10
N
MeO
N HO
N Ar O
N
S
X
13
12 Ar1
F
N
X = S, O, N, C
MeO Novartis active compounds
Platelet Aggrigation inhibitor p38 Map Kinase Inhibitors
Upjohan Company

N
N F
N
X N O
14 N S N
16
N Me
H N
Y
N
Smithline Becham F
IL-1 Bio synthesis inhibitors SB 203580 19
H2NO2S
Known methods to prepare 1,2-diaryl ethanones..

Ar
PhCH2CONEt3 CHO
ArMgBr Ph
ArH PhCH2COCl
LTA
AlCl3 CH2Cl2

CF3SO3H (5.0 eq) A O H2SO4, MeOH Ar

PhCH2CO2Me
Iodosobenzene Ph
ArH, 85 0C Ph
diacetate

ZnCl2 POCl3
P2O5 80 0C NaNH2

PhCH2CO2H ArH
PhCH2CO2H ArCOCH3 PhBr
ArH
20
Our new method to synthesis 1,2-diaryl ethanones.

O Ar O
Ph Ph
O Ar Ph
Minor traces Major

4 3

H3PO4, TFAA, ACN

500C, 30 - 180 min

PhCH2CO2H
+ 1

H3PO4, TFAA ArH

H3PO4, TFAA (excess)
250C, 60 sec 2 250C, 30 sec

Ar O K2CO3 / MeOH
F3C O
Ph
25 0C, 1.0 min. O Ar
Ph
21
3 5
 Our new method to synthesis of
2-(4-methoxyphenyl)-1-(methylsulfonylphenyl)-ethanone

MeO

SMe CH2CO2H O
H3PO4, TFAA (excess) O
CF3
+
250C, 30 sec, 60.0 %
OMe
SMe

H3PO4, TFAA K2CO3, MeOH

OMe
250C, 60 sec 250 C, 1.0 min,
97.0 %
95.0 %
O
SMe

22
 Reaction Mechanism
O O
F33C O CF33 O CF3 H
H33PO
PO44 O OCOCF
O OCOCF33
+ Ph Ph
Ph P
P
Ph O O TFAA
TFAA O O
O O OCOCF
OCOCF33
OH 6 77

O
O O ArH
Ph Ph OH
Ar Ar
O Ar
6 or 7
Ph Ph
Minor traces
3
4
TFAA
TFAA
(excess)
(excess) K2CO3, MeOH
1.0 min

FF33C
C O
O
Ph
Ph
O
O Ar
Ar
55 23
 Results
No Ph Ar Method B Method A Method
B1

01. Phenyl 2-methyl thioanisole 91.0 % 90.0 %

02. 4-Methoxy Thioanisole 97.0 % 92.0 % 93.0 %

phenyl

03. Phenyl Biphenyl 52.0 % 55.0 %

04. Phenyl Ethylbenzene 38.0 % 42.0 %

05. Phenyl Anisole 80.0 % 77.0 %

06. Phenyl Toluene 40.0 % 44.0 %

07. Phenyl Thioanisole 71.0 % 74.0 % 75.0 %

08. Phenyl 1,3-dimethoxy benzene 46.0 % 41.0 % 45.0 %

24
 Discussions

1660 – 1680 cm-1

R
O

R1

O
O
R CF3
O CF3
O
H
R1 R1
H
δ 6.77 –
6.71
δ 7.02 –
6.90 R
E - Isomer 25
Z - Isomer
 Preparation of 1,2,3-thiadiazole

CO2H Oxone NH2NHCO2Et

O O PTSA NNHCO2Et
MeS
MeS MeO2S
MeO2S

MeO2S

N SOCl2
N
S

26
 Preparation of Valdecoxib

i) ClSO3H
N ii) NH4OH N
O O

HO
H2NO2S

i)NH4OH HCl, NaOAc

ii) BuLi & EtOAc
Valdecoxib

i) ClSO3H
i) HCO2H, Et3N N
N ii) NH4OH N
O O O
i)NH4OH HCl, NaOAc Cl ii) NaOH
ii) BuLi & methyl HO OH
chloroacetate H2NO2S Cl H2NO2S

27
 Advantages
Features Friedel-Craft’s Our Method

Solvents Chlorinated Solvents Neat

Environmental Friendly

Reaction Time 3.0 To 12.0 or More Hours 30 – 60 Seconds

(High Speed)

Side products/ More possibility Negligible

Reactions

Starting materials Acid chlorides, Unstable Acids, Stable and

And Not easy to make Commercially Available

Functional Group Less More

Tolerability

Reaction setup Typical Very easy, User

Friendly
28
 Advantages / Conclusion
9 Ready availability of the starting materials and reaction
conditions.
9 Environmentally safe as the protocol is free from the use of
inorganic Lewis acids eg. AlCl3 & SnCl4 as well as chlorinated
hydrocarbons (CH2Cl2, CHCl3, EDC) as solvent.
9 Simple operational procedure.
9 The protocol is superior to the classical Friedel-Crafts
acylation technique and other multi step synthesis.
9 Acylation rate can be accelerated by omitting the use of
solvent thereby reducing the reaction time from hours to
minutes.
9 This high speed parallel transformation was utilized for the
parallel synthesis of 1,2-diaryl-1-ethanones to the biologically
29
importance compounds
30