Efficient synthesis of a GABA A alpha2,3-selective allosteric modulator via a sequential Pd-catalyzed cross-coupling approach.
A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-propan-2-ol (1), an oral GABA(A) alpha(2/3)-selective agonist, is described. The five-step process, which afforded 1 in 40% overall yield, included imidazopyrimidine 2 and pyridine boronic acid 4 as key fragments. The synthesis is highlighted by consecutive Pd-catalyzed coupling steps to assemble the final free base 1 in high yield and regioselectivity. A novel method for Pd removal in the final step is also described.
Jensen
Mark S
MS
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. mark_jensen@merck.com
Hoerrner
R Scott
RS
Li
Wenjie
W
Nelson
Dorian P
DP
Javadi
Gary J
GJ
Dormer
Peter G
PG
Cai
Dongwei
D
Larsen
Robert D
RD
D000494:Allosteric Regulation; D001897:Boronic Acids / Q000737:chemistry; D002384:Catalysis; D018755:GABA Agonists / Q000138:chemical synthesis*; D007093:Imidazoles / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010165:Palladium / Q000737:chemistry*; D020005:Propanols / Q000138:chemical synthesis*; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
C503524:2-(3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo(1,2-a)pyrimidin-7-yl)-propan-2-ol; D001897:Boronic Acids; D018755:GABA Agonists; D007093:Imidazoles; D020005:Propanols; D011725:Pyridines; D011743:Pyrimidines; D010165:Palladium; C029899:imidazole; C030986:pyrimidine; C023666:pyridine