Post on 12-Nov-2014
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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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
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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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