Synthesis of three alpha 7 agonists in labeled form.
In support of a program to develop an alpha 7 agonist as a treatment for Alzheimer's disease, three drug candidates, 1, 2, and 3, were prepared in labeled forms. Compound 1 was prepared in C-14 labeled form by lithiation of [2,6-(14)C2]2-chloropyridine and subsequent coupling with spirooxirane-2,3'-quinuclidine. When this same coupling was attempted using [3,4,5,6-(2)H4]2-chloropyridine, alcohol [(2)H6]-6 was the major product indicating that the primary isotope effect for the lithiation step was significant enough to shift the reaction pathway. Therefore, an alternate site of labeling was used to prepare [(2)H4]-1. [(13)C5]-2 was prepared in five steps from [(13)C5 ]2-furoic acid, but the C-14 labeled compound used [(14)C2]-1 as the starting material instead. [(14)C2]-3 was prepared in two steps from [carbonyl-(14)C]nicotinic acid.
Isotope Chemistry, DMPK, AstraZeneca Pharmaceuticals LP, 43183, Mölndal, Sweden.
Charles S
CS
Elmore
Scott
S
Landvatter
Peter N
PN
Dorff
Mark E
ME
Powell
David
D
Killick
Timothy
T
Blake
James
J
Hall
J Richard
JR
Heys
John
J
Harding
Rebecca
R
Urbanek
Glen
G
Ernst
D002247:Carbon Isotopes / Q000737:chemistry* / Q000302:isolation & purification*; D007553:Isotope Labeling; D009525:Niacin / Q000031:analogs & derivatives*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors*
D002247:Carbon Isotopes; D019275:Radiopharmaceuticals; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009525:Niacin
[13C5]2-furoic acid; [carbonyl-14C]nicotinic acid; alpha 7; deuterium isotope effect