Post on 22-Jul-2016
description
Convenient Preparation of Substituted 5-Amino oxazoles via a Microwave-Assisted Cornforth Rearrangement
M. Brad Nolt
Technology Enabled Synthesis Group, Department of Medicinal Chemistry, Merck Research Laboratories (WP), Merck & Co.
October 13, 2005
a
• Biologically active oxazole-containing compounds
• An established route involves a key thermal rearrangement and is conducive to microwave-assisted methodology
• Underrepresented in current literature
Trisubstituted 5-Aminooxazoles
N
O NR3R4
OOR2
R1
Biological Relevance a
Brown, P.; Davies, D. T.; O‘Hanlon, P. J.; Wilson, J. M. J. Med. Chem. 1996, 39, 446.
Psuedomonic acid derivative 1 has demonstrated growth inhibition of Gram-positive and -negative bacteria
32Streptococcus pneumoniae PU7
16Staphylococcus aureus
2Haemophilus influenzae Q1
MIC (ug / mL)
O
OHHO
OHO
N
ON
OO
1
Antibiotics
Biological Relevance a
Miller, D. J.; Ravikumar, K.; Shen, H.; Suh, J.-K.; Kerwin, S. M.; Robertus, J. D. J. Med. Chem. 2002, 45, 90.
Bicyclic oxazole 2 is an inhibitor of the enzymatic A chain of ricin (RTA) and a Shiga-like toxin Stx1A1, produced from pathogenic E. coli.
N
NHN
O
O
NH2
2
1.0 mM
Stx1A1 IC50
0.4 mM8-methyl-9-oxoguanine
RTA IC50
Toxin Antidotes
Biological Relevance a
Falorni, M.; Giacomelli, G.; Porcheddu, A.; Dettori, G. Eur. J. Org. Chem. 2000, 3217.
von Geldern, T. W.; Hutchens, C.; Kester, J. A.; Wu-Wong, J. R.; Chiou, W.; Dixon, D. B.; Opgenorth, T. J. J. Med. Chem. 1996, 39, 957.
Oxazole 3 is based on the C-terminal hexapeptideHis16-Trp21 of the endothelin-1 receptor. Peptidomimetics could attenuate specific protein binding pathogenic pathways
Protein Therapy
N
O
O
NHNH
Ph
Cbz
3
OMe
CO2Me
NH O
HN
O OMe
O
NH
RCbz
1) PPh32) I23) Et3N
DCMr.t. 12 h
NH O
Cbz NCO2Me
NHR
38%
Biological Relevance a
Smith, R. A.; Barbosa, J.; Blum, C. L.; Bobko, M. A.; Caringal, Y. V.; Dally, R.; Johnson, J. S.; Katz, M. E.; Kennure, N.; Kingery-Wood, J.; Lee, W.; Lowinger, T. B.; Lyons, J.; Marsh, V.; Rogers, D. H.; Swartz, S.; Walling, T.; Wild, H. Bioorg. Med. Chem. Lett. 2001, 11, 2775.
Urea oxazole 4 has demonstrated Rafkinase inhibition and may be instrumental in limiting Ras oncogeneactivity
Anti-neoplastic
N O
HN
O
HN
MeO O
4
5-Aminooxazole Synthesis a
Connell, R.; Scavo, F.; Helquist, P.; Akermark, B. Tetrahedron Lett. 1986, 27, 5559.
H3CO
O O
OCH3N2
CNN
O OCH3
O
OCH3Rh2(OAc)4
CHCl3 reflux
85%8 h
Sun, X.; Janvier, P.; Zhao, G.; Bienaymé, H.; Zhu, J. Org. Lett. 2001, 3, 877.
7
5
6
O
H2N
F
CN
Bn
O
NO
Ph
NHNMeOH
reflux
F
5-Aminooxazole Synthesis a
Dewar, M. J. S.; Turchi, I. J. J. Am. Chem. Soc. 1975, 40, 1521.Dewar, M. J. S.; Turchi, I. J. J. Am. Chem. Soc. 1974, 96, 6148.Dewar, M. J. S.; Spanninger, P. A.; Turchi, I. J. J. Chem. Soc., Chem. Commun. 1973, 925.
MeO2C CO2Me
NH2
Cl
O
OMe H2O/PhH0o C to r.t., 12 h
MeO2C CO2Me
HN
O
p-CH3OPh
85-95%
PCl5NaHCO3
CHCl3 reflux 1.5 h
N
O
CO2Me
OMeMeO
KOH N
O
CO2H
OMeMeODMSO/H2O
PCl5
CHCl3 reflux 30 min
N
O
COCl
OMeMeO
1) R1R2NH2) Et3N N
O
CONR1R2
OMeMeO
N
OMeO
CO2Me
NR1
R2
PhCH3 reflux 17 h
40-60% 50-60% 35-45%
80-90% > 95%
9 10
8
11
12 13
PhH, 0o C to r.t. 3h
100o C, 35 min.
5-Aminooxazole Synthesis a
Dewar, M. J. S.; Turchi, I. J. J. Am. Chem. Soc. 1975, 40, 1521.Dewar, M. J. S.; Turchi, I. J. J. Am. Chem. Soc. 1974, 96, 6148.Dewar, M. J. S.; Spanninger, P. A.; Turchi, I. J. J. Chem. Soc., Chem. Commun. 1973, 925.
MeO2C CO2Me
NH2
Cl
O
OMe H2O/PhH0o C to r.t., 12 h
MeO2C CO2Me
HN
O
p-CH3OPh
85-95%
PCl5NaHCO3
CHCl3 reflux 1.5 h
N
O
CO2Me
OMeMeO
KOH N
O
CO2H
OMeMeODMSO/H2O
PCl5
CHCl3 reflux 30 min
N
O
COCl
OMeMeO
1) R1R2NH2) Et3N N
O
CONR1R2
OMeMeO
N
OMeO
CO2Me
NR1
R2
PhCH3 reflux 17 h
40-60% 50-60% 35-45%
80-90% > 95%
9 10
8
11
12 13
PhH, 0o C to r.t. 3h
100o C, 35 min.
Cornforth Rearrangement a
Dewar, M. J. S.; Turchi, I. J. J. Am. Chem. Soc. 1974, 96, 6148.Dewar, M. J. S.; Spanninger, P. A.; Turchi, I. J. J. Chem. Soc., Chem. Commun. 1973, 925.
N
O
CONR1R2
OCH3
N
O
CO2CH3
NR1
R2
PhCH3 reflux 17 h
12 13
NO
NR1R2
OCH3
:
O
R3 R3
R3
Sequence
Rearrangement - Microwave Heating
Amide Formation Resin-Bound Reagents Microwave
Saponification
Cyclization/Dehydration
2-Aminomalonate + Acid Chloride
a
Sequence
Rearrangement - Microwave Heating
Amide Formation Resin-Bound Reagents Microwave
Saponification
Cyclization/Dehydration
2-Aminomalonate + Acid Chloride
a
Sequence
Rearrangement - Microwave Heating
Amide Formation Resin-Bound Reagents Microwave
Saponification
Cyclization/Dehydration
2-Aminomalonate + Acid Chloride
a
chromatography
Sequence a
Amide Formation Resin-Bound Reagents Microwave
Saponification
Cyclization/Dehydration
2-Aminomalonate + Acid Chloride
chromatography
Sequence
Rearrangement - Microwave Heating
Amide Formation Resin-Bound Reagents Microwave
Saponification
Cyclization/Dehydration
2-Aminomalonate + Acid Chloride
a
filtration
chromatography
Microwave-, Polymer-AssistedAmide Formation
a
Sauer, D. R.; Kalvin, D.; Phelan, K. M. Org. Lett. 2003, 5, 4721.
• Accelerated amide coupling (room temp. reaction times ~16 h)
• Complete conversion to product in excellent yield
• HOBt scavenging leaves material that is 98% pure
N
CO2H NH21) PS-carbodiimide (2 eq.), HOBt (1 eq.), DMA, 110o C for 5 min uwave
N
ONH
100% conversion
2) Si-Carbonate, MeOH 5 min., filter
(LC/MS)
Amide Formation - 1 a
• Aqueous workup removes impurities
• High yields
• Amides from amines and acids
EtO2C CO2Et
NH2
Cl
O
EtO2C CO2Et
HN
O
Ph
DCM0o C to r.t., 15 min 97%
Et3N14
Cyclization/Dehydration a
• Microwave heating decreases reaction time from ~1.5 h to 5 min
• Few byproducts by LC/MS
• Flash chromatography purification
EtO2C CO2Et
HN
O
Ph N
OPh OEt
CO2Et
TFAA (79%)
PhCF3 or CH3CN160o C, 5 minuwave
orPCl5 (25%)
14 15
Hydrolysis a
• Complete conversion to acid observed by LC/MS
• 48% yield of clean material by 1H NMR
• Can be used without purification
• Possibility of microwave heating
N
OPh OEt
CO2Et N
OPh OEt
CO2HKOH 1.5 eq
H2O100o C, 30 min.
15 16
Amide Formation - 2 a
• Shortened reaction time, complete conversion to product
• No excess reagents required
• Simple filtration and optional wash with MP-carbonate removes HOBt
N
OPh OEt
CO2H
1) pyrrolidine (1 eq.)2) PS-DCC (1 eq.)3) HOBt (1 eq.)
100o C, 5 min.
N
OPh OEt
O
N
PhCF3 orCH3CN
16 17
Microwave-Promoted Cornforth Rearrangement – Optimization Study
a
N
O OEt
O
N
Ph
N
O N
O
OEt
Ph
uwaveheating
solvent
99:1180° C, 10 min.acetonitrile4
1:1.3170° C, 10 min.acetonitrile3
1:2.2160° C, 10 min.acetonitrile2
1:99150° C, 10 min.acetonitrile1
product/starting materiala
rearrangement conditions
solvententry
a) determined by UV HPLC
17 18
a
• Dramatic decrease in reaction time - Microwave heating improves reaction time from 17 h to 5 min
• Good to excellent yields for two-step process
• Purity is typically > 93 % by 1H NMR
Microwave-Promoted Cornforth Rearrangement
180o C, 5 min.N
OPh OEt
O
N N
OPh N
O
OEt
PhCF3 97%CH3CN 35%
17 18
High-Speed Synthesis a
Amide Formation -1
15 min.
Cyclization/Dehydration
5 min.
Saponification
30 min.
Amide Formation - 2
5 min.
Cornforth Rearrangement
5 min.
• Total reaction time approximately one hour
• More than 30-fold time reduction in comparison to original procedure
a
N
OEtO
O
R2R1N N
OR2R1N
O
EtON
OEtO
O
HO
1) PS-carbodiimide2) HOBt3) R1R2NH4) filtration
PhCF3uwave
PhCF3uwave
100 C, 5 min 180 C, 5 min
994472
993981
yield (%)
productentryyield (%)
productentry
N
ON
OOEt
N
ON
O OEt
F
N
O
O OEt
NH
N
O
OOEt
NN
5-Aminooxazole-4-carboxylate Synthesis
PS-DIEA
a
829516
971076
7
998235
yield (%)
productentryyield (%)
productentry
N
O
O OEt
NH
OO
N
O
O OEt
NH S
N
O
O OEt
NH
O
O
N
O
O OEt
NH
NH
O
O
N
O N N
N
H
OOEt
N
O
OOEt
N
5-Aminooxazole-4-carboxylate Synthesis
PS-DIEA
PS-DIEA
Cornforth Rearrangement Confirmation a
• HPLC Retention Times• HMBC NMR Studies – Partial carbonyl shielding
causes a difference in proton shifts on the pyrrolidinering in the case of A, the rearranged product has equivalent methylene protons in the 2- and 5-positions of B
N
O
O
N
O
3.65
3.94
1.91
1.96
70.1 15.0
N
O N
O
O14.6
60.1
3.77
3.77
2.01
2.01
A B
Cornforth Rearrangement Confirmation a
• The thermal rearrangement was unequivocally confirmed by the characterization of the reduced product
N
O
OH
NPh
N
N
O
CO2Et
NPh
N
Dibal-H (3 eq.)
-78 C, 30 min.DCM
91%
aRetrosynthetic Strategy
O
OHHO
OHO
N
ON
OO
N
ON
OO
Wittig
N
ON
OO
HO
1
(EtO)2PO
O N
ON
OO
Br
halogenation
Arbuzov
N
ON
OO
BnOhydrogenation
aSynthesis
MeO2C
NH2
CO2Me Cl
OOBn MeO2C
HN
OO
97%
HCl
CO2Me
Et3N (2.5 eq.)
DCM
TFAA
PhCF3
180 C, 10 minMeO2C
HN
OO
CO2Me
N
O OMeBnO
O
OMe
3 : 1
inseparable by flash/reverse phase chromatography
• Optimization studies are in progress
Conclusions a
Products Reaction Development
Microwave as enabling technology
Microwave as driving force
• Microwave heating can significantly shortenreaction times versus conventional thermal conditions
• Microwave-assisted synthesis can be used effectively in combination with solid-phase reagents
• Microwave reactors have become an integral part ofmethod development in TES
Acknowledgments and Contributors a
Medicinal ChemistryGeorge HartmanSteve Young
Scott WolkenbergCraig Lindsley
Research NMRSandor Varga
TESBrian EastmanSteve SharikMark SmileyWilliam ShipeCorey ThebergeDavid D. WisnoskiF. Vivien YangZhijian Zhao
Ray McClainTodd Anderson