A high speed parallel synthesis of 1,2A high speed parallel synthesis of 1,2--diaryldiaryl--11--ethanones :ethanones :Useful intermediates for the synthesis of COXIBSUseful intermediates for the synthesis of COXIBS

Venugopal Rao VeeramaneniVenugopal Rao Veeramaneni

Discovery Chemistry (Synthesis)Discovery Chemistry (Synthesis)

Ref: Venugopal rao VeeramaneniVenugopal rao Veeramaneni, Manojit Pal and Koteswar Rao Yeleswarapu; Tetrahedron, 59 (2003) 3283 - 3290

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Highlights of the presentationHighlights of the presentation

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

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Application of 1,2Application of 1,2--diaryldiaryl--11--ethanones.ethanones.

Versatile intermediates for the synthesis of alkaloids (Pavine, Versatile intermediates for the synthesis of alkaloids (Pavine, Isopavine & Protoberberine).Isopavine & Protoberberine).IntermediatesIntermediates for the synthesis of Bioactive molecules. for the synthesis of Bioactive molecules. i. i. CoxCox--2 inhibitors2 inhibitors

ii. tamoxifen analoguesii. tamoxifen analoguesiii. p38 Map kinase inhibitorsiii. p38 Map kinase inhibitorsiv. IL biosynthesis inhibitorsiv. IL biosynthesis inhibitorsv. Catecholv. Catechol--OO--methyl stransferase inhibitorsmethyl stransferase inhibitorsvi. Human vi. Human neutrophilneutrophil elastase inhibitorselastase inhibitorsvii. Platelet aggregation inhibitors. vii. Platelet aggregation inhibitors. viii. Active molecules in the treatment of Parkinson’s diseasviii. Active molecules in the treatment of Parkinson’s disease. e.

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Significance of parallel synthesisSignificance of parallel synthesis

• Parallel synthesis strategy has been shown to provide an attractive lead development tool for the refinementrefinement of biological activity.

• This strategy has been utilized successfully to generate a librarylibrary of heterocycles.

• This approach has been utilized for the synthesis of a number ofnovel compounds having potential potential biological activity as well as synthetic analogues of existingexisting bioactive molecules.

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Why we need COXIBSWhy we need COXIBS

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Why we need COXIBSWhy we need COXIBS

COXIBSCOXIBS are are NNon on SSteroidal teroidal AAntinti--inflammatory inflammatory DDrugsrugs

InflammationInflammation: : 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.

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How inflammation takes placeHow inflammation takes placeInflammation reactions to chemical, mechanical and thermal stimuli is significantly enhanced in the presence of ProstaglandinsProstaglandins (PGs) and LeucotrienesLeucotrienes (LTs).

PGs and LTs are enzymatically synthesized from Arachidonic AcidArachidonic Acid by three different pathways.

» Lipoxygenase pathway

» Cyclooxygenase pathwayCyclooxygenase pathway

» Monooxygenase pathway

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DISCOVERY OF MECHANISM OF ACTION DISCOVERY OF MECHANISM OF ACTION && History of NSAIDS and COX History of NSAIDS and COX ––2 Inhibitors2 Inhibitors

First anti-inflammatory drug was from Herbal, introduced by Reverend Edward StoneReverend Edward Stone in 1763 . First drug synthesized & introduced in 1860 by Kolbe

and Lautemann (Salicylic acid).Acetylsalicylic acid, was developed by Felix HoffmanFelix Hoffman

from the Bayer Bayer Company in 18751875. In 18991899 Heinrich Heinrich DreserDreser named the compound as "AspirinAspirin"

In 1933 Goldblatt Goldblatt was discovered Prostaglandin activity.

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DISCOVERY OF MECHANISM OF ACTION DISCOVERY OF MECHANISM OF ACTION && History of NSAIDS and COX History of NSAIDS and COX ––2 Inhibitors2 Inhibitors

In 19371937 Von EluerVon Eluer detected in semen and he named as ‘Prostaglandins’

In 1969 PiperPiper and VaneVane demonstrated the first association between prostaglandin production and the actions of aspirin- like drugs.

Arachidonic acid metabolism was discovered in 1971 1971

ProstaglandinProstaglandin was isolated in 1976 and cloned in 19881988

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Arachidonic acid CascadeArachidonic acid Cascade

Essential patty acid in diet

Esterified acid in cell lipidEsterified acid in cell lipid

Various stimuli Activation of phopholipasOf other acyl hydrolases

CO2H

ARACHIDONIC ACID5,8,11,14-Ecosatetraenoic acid

chemical & mechanicale

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CYCLOOXYGENASE PATHWAYCYCLOOXYGENASE PATHWAYCO2H

ARACHIDONIC ACID5,8,11,14-Ecosatetraenoic acid

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

CO2H

OO

O2

CO2H

OO

O2

OO

CO2H

HOO

PGG2

OO

CO 2H

HO

PGH2

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OO

CO2H

HO PGH2

CO2H

HOOO

TXA2

Tromboxine Synthase

CO2H

HOOHO

OH

TXB2

CO2H

HOOO

2,3-DinorTXB2

B-Oxdation

CO2H

HOHO

HO

PGF2a

PGF Synthase

HOHO

OO CO2H

PGI2

Prostacycline Synthase

HOHO

OO CO2H

PGI2

Prostacycline Synthase

CO2H

HOHO

HO

O

6 KetoPGF2a

ndoperoxide D - isomerase

CO2H

HO

O

HO PGE2

PGE synthase

CO2H

HOHO

HO

PGD2

PGD Synthase

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PGH2

PGI2

Endothelium

PGE2

Mast cells

PGF2a

Uterus

Vasodilation, FeverInhibition of platelet Aggregation, Reduction of gastric acid and etc.

TXA2

Platelets

Platelet activator & aggregant, Vasoconstriction, Bronchoconstriction

Mast cells

PGD2

VasodilationFever, Renin ReleaseReduction of Gastricacid secretion and etc.

VasoconstrictionFever, Uterine contractionsLabour, Embryo implantation

VasodilationMast cell activationBronchoconstriction

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Expression of PGs in other Organs

COX –2 stronglyExpressed in Capillary body

COX –2 Constitutely in the β-cells

Intestine

High salt intakeInduces, in renalpapillary cells

Control of the Autonomic Nervous system

Complex integrativeFunctions.

COX-1-Cytoprotected COX-2 –Inhibit the Activation Of pathogenic T-cells In the gut

Lung Cancer

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CO2H

OH

CO2H

OCOCH3

HO NHCOCH3 OHO

HOOH

OH

OH

SAu

NN

C4H9

O

OPh

Ph

N

CO2H

OCl

MeO HN

CO2H

CO2HMeO

CO2H

COCO2HOO

N

CO2HCO2Na

SOCH3

Salicylicacid

Aspirin AcetaminophenPhenyl Butazone

Aurothioglucose

Indomethacin Mefenamic acidIbuprofen Naproxen

Ketoprofen

O

Cl

ClCO2Na

DiclofenacSodium

Tolmetin Sulindac sodium

History of antiHistory of anti--inflammatory drugsinflammatory drugs

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History of antiHistory of anti--inflammatory drugsinflammatory drugs

PhF

CO2H

Flurbiprofen

SO O

OH

HN

O

N

Piroxicam

NH

O

CO2H

Etodolac

O

NO2

NHSO2CH3

Nimuslide

SO O

OH

HN

O

SNO2

Meloxicam

N NCF3

H2NO2S

Celecoxib

O

O

H3CO2S

Rofecoxib

ON

H2NO2S

Valdecoxib

N

N

H3CO2S

Etoricoxib

ON

SNH

OOO

Na

Parecoxib Sodium Tilmacoxib Deracoxib

O

N

H2NO2S

FA

N NCF2

O

H2NO2S

F

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Neck pain

Rheumatoid arthritis

Knee pain

Osteoarthritis

Ankylosingspondylitis

Muscle pain

Gout

Back pain

Post operation pain

Teeth pain

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Utilization of 1,2-diaryl ethanones in COX-2 inhibitors .

Ar1

Ar O

NO

XH2NO2S

X = Me (Valdecoxib)X = CH2OH (Searle compound)

SBr

MeO2S

F DuP 697

SN

N

Merck Compound

S

F

H2NO2S

Merck compound

O

F

MeO2S

O

Pacific Corporation Compound

Merck Compound

O

O

MeO2S

Merck Compound

O

S

NCF3

MeO2SSearle-Monsanto Compound

O

N

F

MeO2S

MeO2S

1122

33

44

55

6677 88

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SN

N

MeO

MeO

Platelet Aggrigation inhibitor Upjohan Company

OH

HO

Estrogen Recrptor-beta Potencyselective ligand

O

OHOH

NO2

Catechol-O-methyltransferase inhibitors, BIA 3 -202

O

O

Human Nutrophil Elastase Inhibitors Ono Pharma

R

O

NH

N

N

F

SMe

O

SB 203580

X

N

N

FN

HO

X = S, O, N, CNovartis active compoundsp38 Map Kinase Inhibitors

N

NX

N

YSmithline BechamIL-1 Bio synthesis inhibitors

Ar1

Ar O

NN

N

F

H2NO2S

Utilization of 1,2-diaryl ethanones in some other bioactive molecules.

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10

11

12 13

14 16

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Known methods to prepare 1,2-diaryl ethanones...

Ph

A O

PhCH2COCl

AlCl3 CH2Cl2

ArH PhCH2CO2H

ZnCl2 POCl380 0C

PhCH2CO2MeCF3SO3H (5.0 eq)

ArH, 85 0C Ph

ArH2SO4, MeOH

Iodosobenzenediacetate

Ph

ArCHO

LTA

ArMgBr PhCH2CONEt3

ArH PhCH2CO2H

P2O5

ArCOCH3 PhBr

NaNH2

ArH

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Our new method to synthesis 1,2Our new method to synthesis 1,2--diaryl ethanones.diaryl ethanones.

PhCH2CO2H

ArH

+ 1

2

Ph

OArPh

O

ArOPh

MajorMinor traces

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Ph

OAr

3

H3PO4, TFAA 250C, 60 sec

PhO

Ar

F3C

O

H3PO4, TFAA (excess) 250C, 30 sec

5

K2CO3 / MeOH

25 0C, 1.0 min.

H3PO4, TFAA, ACN 500C, 30 - 180 min

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Our new method to synthesis of 2-(4-methoxyphenyl)-1-(methylsulfonylphenyl)-ethanone

+

CH2CO2H

OMe

SMeH3PO4, TFAA (excess)

250C, 30 sec, 60.0 %

OCF3

O

MeO

SMe

O

OMe

SMe

H3PO4, TFAA 250C, 60 sec 97.0 %

K2CO3, MeOH 250 C, 1.0 min, 95.0 %

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Reaction MechanismReaction MechanismO

F3C O CF3

O

PhOH

O

+

O

F3C O CF3

O

PhOH

O

+ PhO CF3

O O6

H3PO4

TFAAPh O P OCOCF3

O O OCOCF37

H3PO4

TFAAPh O P OCOCF3

O O OCOCF37

H3PO4

TFAAPh O P OCOCF3

O O OCOCF37

ArHAr

O

Ph3

ArOH

Ph

PhO

ArOPh

Minor traces4

6 or 7

PhO

Ar

F3C

O5

TFAA(excess)

PhO

Ar

F3C

O5

TFAA(excess)

PhO

Ar

F3C

O5

TFAA(excess) K2CO3, MeOH

1.0 min

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ResultsResultsMethod Method

BB11Method AMethod AMethod BMethod BArArPhPhNoNo

90.0 %91.0 %2-methyl thioanisolePhenyl01.

93.0 %92.0 %97.0 %Thioanisole 4-Methoxy phenyl

02.

55.0 %52.0 %BiphenylPhenyl03.

42.0 %38.0 %EthylbenzenePhenyl04.

77.0 %80.0 %AnisolePhenyl05.

44.0 %40.0 %ToluenePhenyl06.

75.0 %74.0 %71.0 %Thioanisole Phenyl07.

45.0 %41.0 %46.0 %1,3-dimethoxy benzenePhenyl08.

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O

R1

R

DiscussionsDiscussions

1660 – 1680 cm-1

O

R1

RO

CF3

H

HO

R1

O

CF3

R

δ 6.77 –6.71

δ 7.02 –6.90 E - Isomer

Z - Isomer

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Preparation of 1,2,3Preparation of 1,2,3--thiadiazolethiadiazole

CO2H

MeSO

MeS

O

MeO2S

Oxone NH2NHCO2Et

PTSA NNHCO2Et

MeO2S

SOCl2

SN

N

MeO2S

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Preparation of ValdecoxibPreparation of Valdecoxib

O

i)NH4OH HCl, NaOAcii) BuLi & EtOAc

ON

HO

i) ClSO3Hii) NH4OH

ON

H2NO2S

i)NH4OH HCl, NaOAcii) BuLi & methyl chloroacetate

ON

HOCl

i) ClSO3Hii) NH4OH

ON

H2NO2S Cl

ON

H2NO2S OH

i) HCO2H, Et3N

ii) NaOH

ValdecoxibValdecoxib

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AdvantagesAdvantagesOur MethodOur MethodFriedelFriedel--Craft’sCraft’sFeaturesFeatures

NeatEnvironmental Friendly

Chlorinated SolventsSolvents

30 – 60 Seconds(High Speed)

3.0 To 12.0 or More HoursReaction Time

Negligible More possibility Side products/ Reactions

Acids, Stable and Commercially Available

Acid chlorides, Unstable And Not easy to make

Starting materials

MoreLessFunctional Group Tolerability

Very easy, UserFriendly

TypicalReaction setup

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

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