Multi-step polymer-assisted solution-phase (PASP) library synthesis of functionalized diaminobenzamides.
A parallel solution-phase library synthesis of functionalized diaminobenzamides is described. The four-step library synthesis is accomplished using polymer-assisted solution-phase (PASP) synthesis techniques. This high-yielding, multi-step sequence utilizes sequestering resins for the removal of reactants, reactant by-products, and employs a resin capture/release strategy as a key library synthesis step. Step one of the sequence relies on the displacement of an activated fluoro-group from the aromatic ring of 1a, b with a variety of primary amines to introduce the first diversity position. Step two is hydrolysis of the benzoate ester to a benzoic acid which is subsequently captured on a polyamine resin, washed, and released to give 4a, b in pure form. Step three utilizes PASP resins to mediate the amide coupling of a benzoic acid with a variety of primary amines to give the aminonitrobenzamides 5a, b and introduces the second diversity position. Step four is the parallel reduction of the aminonitrobenzamides 5a, b to the functionalized diaminobenzamides 6a, b. This library synthesis proceeds with high overall purities which average 80 % over the 4-step sequence.
South
M S
MS
Department of Combinatorial and Parallel Medicinal Chemistry, Searle Discovery Research, Monsanto Company, St. Louis, MO 63167, USA. michael.s.south@stl.monsanto.com
Case
B L
BL
Dice
T A
TA
Franklin
G W
GW
Hayes
M J
MJ
Jones
D E
DE
Lindmark
R J
RJ
Zeng
Q
Q
Parlow
J J
JJ
D000588:Amines / Q000138:chemical synthesis; D001549:Benzamides / Q000138:chemical synthesis*; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D013058:Mass Spectrometry; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry
D000588:Amines; D001549:Benzamides; D011108:Polymers