Microwave Synthesis Symposium - biotagedata.biotage.co.jp/pdf/presentations/3725.pdf · 2004.10.21...
Transcript of Microwave Synthesis Symposium - biotagedata.biotage.co.jp/pdf/presentations/3725.pdf · 2004.10.21...
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Microwave Synthesis Symposium:
San Francisco User Group Meeting
Embassy Suites HotelSouth San Francisco, CA 94080
October 21, 2004
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Matthew N. Mattson, Ph.D.Elan Pharmaceuticals, Inc.
800 Gateway Blvd. South San Francisco, CA 94080
Abstract: Using in situ generated carbon monoxide in a Microwave reactor, the amidation of aryl bromides was studied. An important acyl transfer step was improved in the Microwave-accelerated reaction. Formation of diverse amines for generating libraries of selective PTP inhibitors is presented.
Carbonylative Amidations Using Mo(CO)6 and Palladium Catalysis
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Protein Tyrosine Phosphatase Inhibitors
“Preparation of Oxoacetic Acids as Inhibitors of Protein Tyrosine Phosphatases (PTPs)”
Swinnen, D.; et al. PCT 2003, WO 2003064376, 346 pp.
“Protein Tyrosine Phosphatase Inhibition”
Ripka, W. C. Ann. Rep. Med. Chem. 2000, 35, 231-250.
• Oxalamides are potent reversible phosphate mimics. Multiple methodstoward diversification of these amidesare being pursued.
PTPNH
N
OR'''
NH
RHN
OR'''
RR'
R'
OH
O
O
• Phosphatases regulate many important biological pathways by specific de-phosphorylation of tyrosine-, as well as serine- and threonine-, phosphate groups on signaling proteins.
O P
O
O
O-O-NHH
NRAA
RAA'O
OH
O
NHHN
RAA
RAA'O
PTP
PTP-1B – insulin receptor/diabetes PTPalpha – cancer, osteoporosisPTP-SHP2 – proliferationPTP-CD45 – immune signaling
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Diverse Secondary Amines Needed:Selective PTP Inhibitors
PTPNH
N
OR'''
NH
RHN
OR'''
RR'
R'
OH
O
O
“Preparation of Oxoacetic Acids as Inhibitors of Protein Tyrosine Phosphatases (PTPs)”
Swinnen, D.; et al. PCT 2003, WO 2003064376, 346 pp.
• Need to form the amide second!
• May require novel chemistry with competing amine…
In this example, after first completing the amide formation, the reductive amination and catch+release yielded no amine.
NHN
O
NH
RHN
O
OHN
O
OHO
O
RR'
R'
OOH
O
1st 2nd
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Typical Literature: Carbonylative Amidation
Introducing Carbon Monoxide (CO) into regular apparatus… dangerous!
High Pressures Required!
Eur. Pat. Appl., 831095, 25 Mar 1998
Exotic catalyst required!
Introducing CO into vials in parallel – tricky, toxic
Journal of Molecular CatalysisA: Chemical, 212(1-2), 151-154; 2004
OOMe
BrPhNH2COg (1 atm)Bu3N
[PdCl2(As2L)]
Pd As
AsPh
Ph
Ph Ph
Si OEt
EtO OEt
ClCl
Catalyst:
OOMe
ONHPh
(Linked to silica resin)
77%
HN
NH
O
OBr
Br
PhNH2COg (10 atm)PdCl2(PPh3)2
120 oC, 24hAutoclave
HN
NH
O
OPhNH
NHPh
O
O88%
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Recent Literature: MicrowaveCarbonylative Amidation
5 mol% Pd(OAc)25 mol% DPPF4 eq. RR'NH1.5 eq. KOt-Bu1 eq. Imidazole
DMFMW 190oC - 15min
N
OR
BrG
GR'
70 - 94% yield
Carbonylation (CO) using Pd methods with DMF:
Hallberg, A.; et al. J. Org. Chem., 2002, 67, 6232-6235.
Requires excess of amine to compete against HNMe2
Successful only with DPPF ligand
Requires High Temp: 190 oC
Limited to electron-rich bromidesand iodides
Uses simple DMF!
H N
OMe
Me
1.5 eq. KO-tBu
1.0 eq. Imidazole MW - 190 oC
C O
HNMe
Me
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Recent Literature: MicrowaveCarbonylative Amidation
4 mol% Herrmann's Palladacycle10 mol% BINAP1.3 eq. RR'NH0.5 eq. Mo(CO)6
aq. K2CO3, diglyme MW 150oC - 15min
N
ORI
G GR'
(Br-)
Unhindered,nucleophilic amines
65 - 83% yield
Carbonylation (CO) using Pd methods with Mo(CO)6:
Larhed, M; et al. J. Comb. Chem., 2002, 4, 109-111.
Simply weigh in solid Mo(CO)6!
Works with electron-rich and electron-poor bromides and iodides
Aqueous base limits Molybdenum mirror averting potential vial hot spots/failure
Requires HOT Palladacycle catalyst (for bromides)
Limited to simple amines (No anilines!)
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Recent Literature: MicrowaveCarbonylative Amidation
10 mol% Pd(OAc)2 or 5 mol% Herrmann's Palladacycle3 eq. RR'NH3 eq. DBU1 eq. Mo(CO)6
THF/diglyme MW (I-) 100oC - 15min, (Br-) 150oC - 15min
N
ORI
G GR'
(Br-)53 - 92% yield
Carbonylation (CO) using Pd methods with Mo(CO)6:
Larhed, M; et al. JOC, 2003, 68, 5750-5753
Simply weigh in solid Mo(CO)6!
Works with alkyl and aryl amines!
Large excess of DBU and amine required
Requires HOT Palladacycle catalyst (for bromides)
Works best with electron-rich iodides and bromides
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Carbonylative Amidation: No Cylinder!
H N
OMe
Me
1.5 eq. KO-tBu
1.0 eq. Imidazole MW - 190 oC
C O
HNMe
Me
• CO from Dimethylformamide
Pd0
L
L
Carbonylation (CO) using Pd methods on Br-compounds:
Larhed, M; et al. JOC, 2003, 68, 5750-5753
Mo
C
CCC
C C O
OO
O
O
O
3.0 eq DBU
C O
(OC)6-nMo(DBU)n
ppt.
• CO from Mo(CO)6
PdII
X
LLAr
PdII
X
LL
Ar
O
PdII
X
LLH
Pd0
L
LBrAr
C O
K+ -O-tBuHO-tBuKX
Ar
ON
R1
R2
HNR1
R2
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Amine Model: Carbonylative Amidation10 mol% PdCl2(dppf)4 eq. BnNH23 eq. DBU1 eq. Mo(CO)6
diglyme, 170 oC
[Pd(OAc)2does not work!]
smallamount
NH
R R'HN
O
NH
R R'Br
“Palladacycles and a process for their preparation.”
Herrmann, W. A.; et al. 1998, US 5831107
Pd(OAc)2P
Pd
Ar Ar
OAc
"Herrmann's Palladacycle"
2
P
1.31 eq.
1.0 eq.Tol
+crystn
• Encouraging…5 mol% Herrmann's Palladacycle4 eq. BnNH23 eq. DBU1 eq. Mo(CO)6
diglyme, 170 oC 80%20% SMco-elute
NH
R R'HN
ONH
R R'Br
mixt.
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Breakthrough Conditions: Benzamide Synthesis
Lit: Larhed, M; et al. JOC, 2003, 68, 5750-5753
Br
NH
O
NH
O
5-10 mol% PdLn3 eq. RNH23 eq. DBU, [0.5 eq Imidazole]1 eq. Mo(CO)6
THF, MW 140-150oC
NH
O
difficult, electon-rich model bromide
Halide Amine PdLn Additive MW ToC-tmin % Amide4-MeOPh-Br BnNH2 Palladacycle 0 150-15 92
" PhNH2 " 0 150-15 684-CF3Ph-Br " " 0 150-15 53
4-AcNHPh-Br BnNH2 " 0 (Lit.) 150-12 40
Microwave carbonylationusing Mo(CO)6 - trials with added imidazole(by LC-MS) " " " 0.5 Imidazole 150-12 100
" " PdCl2(dppf) 0.5 eq 150-12 100" " Pd(OAc)2 0.5 eq 150-12 95" PhNH2 Palladacycle 0.5 eq 150-8 100" " PdCl2(dppf) 0.5 eq 150-8 100" " Pd(OAc)2 0.5 eq 150-8 100
• Direct comparison example produced 100% amide, while the Lit. conditions produced 40%.
• Works with aryl amines (aniline)!
• Only Pd(OAc)2 is needed!
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Improved Carbonylation, Amide Formation• CO from Mo(CO)6
Mo
C
CCC
C C O
OO
O
O
O
3.0 eq DBU
C O
(OC)6-nMo(DBU)n
ppt.
• Palladium Catalytic Cycle
PdII
X
LLAr
HNN
PdII
X
LL
Ar
O
PdII
X
LLH
Pd0
L
LBrAr
C O
Ar
ON N
Ar
ON
R1
R2
HNR1
R2
DBUHX-DBU
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Amidation of Various Bromides
Br
NH
O
NH
O
10 mol% Pd(OAc)23 eq. RNH23 eq. DBU, [0.5 eq Imidazole]1 eq. Mo(CO)6
THF, MW 150 oC - 15 min
NH
O
100%(LC-MS)
NH
ONH
O100%Br
NH
O same conditions
THF, MW 150 oC - 8 min
BrO
NH
O Osame conditions 90%(Lit. 68%) (para-OMe)THF, MW 150 oC - 12 min
Br
N NH
O
N
same conditions 100% (Lit. 0%) (failed for bromide and iodide)
THF, MW 150 oC - 6 min
Lit. for Br-compounds: Larhed, M; et al. JOC, 2003, 68, 5750-5753
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Improved Conditions: Challenging Substrate
• Using 3-4 eq of amine competes completely over nucleophilic secondary amine.
• Works in the presence of secondary amine and amides – No effect on catalyst!
[Prepared amine using MW method (Biotage) during time with the Initiator MW reactor.]
NH
Br
OMe
O
Br
1) MeOBnNH2 MeOH, 1h
2) PS-BH4 - MW 140-4min3) catch+release
Diversification
10 mol% Pd(OAc)24 eq. BnNH23 eq. DBU, 0.5 eq Imidazole1 eq. Mo(CO)6
THF, MW 150oC-12min
NH
OMe
HN
O
100%
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
PTP Inhibitors Revisited: Access to Diverse Amide Groups
Benzyl amine example:
NHHN
O
NH
Br
10 mol% Pd(OAc)24 eq. BnNH23 eq. DBU, 0.5 eq Im1 eq. Mo(CO)6
THF, MW-150oCR'RR'R
NHN
OR'R
ClOEt
O
O1)
2) NaOH
OH
O
O
Works in the presence of additional functional groups.
“Preparation of Oxoacetic Acids as Inhibitors of Protein Tyrosine Phosphatases (PTPs)”
Swinnen, D.; et al. PCT 2003, WO 2003064376, 346 pp.
Novel Chemistry: Can add Diversity outside of published compounds.
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
It takes more than COto make a “CO-catalyst”.…
Mo
C
CCC
C C O
OO
O
O
O
3.0 eq DBU
C O
(OC)6-nMo(DBU)n
ppt.NH
OMe
HN
O
NH
O
N
PdII
X
LLAr
HNN
PdII
X
LL
Ar
O
PdII
X
LLH
Pd0
L
LBrAr
C O
Ar
ON N
Ar
ON
R1
R2
HNR1
R2
DBUHX-DBU
2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
*Thank You*
Biotage (Personal Chemistry)
To all of you for your attention
…any questions?