convenient preparation of substituted 5-amino oxazoles via a microwave- assisted cornforth...

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


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


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%


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.

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



Saponification



a

chromatography

Sequence a


Saponification



chromatography

Sequence



Saponification



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.


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

convenient preparation of substituted 5-amino oxazoles via a microwave- assisted cornforth...

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