Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 547–548.
Published online in Wiley InterScience
JLCR
Short Research Article
Synthesis of isotopically labeled 2-pyridinyloxyisobutanoic
acid, a building block for CB-1 inhibitors as drug candidates
for obesity treatmenty
JONATHAN Z. HO* and MATTHEW P. BRAUN
Department of Drug Metabolism, Merck & Co., Inc., 126 East Lincoln Ave, PO Box 2000, Rahway, NJ 07065, USA
Received 20 September 2006; Revised 8 January 2007; Accepted 20 January 2007
Keywords: Diels–Alder reaction; ozonolysis; deuterium; 2-(pyridinyloxy)-2,2-dimethylacetic acid
Introduction
Results and discussion
Substituted isobutanoic acids are widely used as
building blocks in the synthesis of pharmaceuticals
and various drug-like small molecules. The synthesis of
isotopically labeled variants of this motif is thus of
general interest. In the present case, we were particu-
larly interested in a stable isotope-labeled analog of a
2-pyridinyloxy-isobutanoic acid structure present in a
potential CB-1 inhibitor for the treatment of obesity.
This material was required for use as an internal
standard for LC/MS assays. Herein, we report a
synthetic protocol to make stable isotope-labeled 2-
pyridinyloxyisobutanoic acid. The strategy may be
extended to the synthesis of other labeled a-hydro-
xyacids and tertiary allylic alcohols.
The Lewis acid catalyzed Diels–Alder reaction of
anthracene with methyl acrylate gave the adduct,
which was reacted with Methyl-D3 Grignard reagent
in ether at reflux for 4 h affording tertiary alcohol 2
(Scheme 1). Six deuterium labels were thus introduced
in alcohol 2, and it was isolated in good yield after
recrystallization from methanol. Upon heating, a retro
Diels–Alder reaction of 2 released the allylic alcohol
which was collected in a cold (ꢀ788C) flask. Subse-
quent ozonolysis with a reductive work-up resulted in
the aldehyde. Oxidation with PCC followed by ester-
ification with ethanol gave the ester 3 in good yield
(Scheme 2). The one-step ozonolysis with oxidative
workup was explored but the resulting yield was
O
OMe
O
AlCl3, PhH, 80 oC, 4 h
96%
HO
+
CD3
OMe
CD3
1
ether
reflux, 4 h
D
D
91%
ether
reflux
2h
D
D
2
+ Mg
I
D
Mg
D
I
Scheme 1
*Correspondence to: Jonathan Z. Ho, Department of Drug Metabolism,
Merck & Co., Inc., 126 East Lincoln Ave, PO Box 2000, Rahway, NJ
y
Proceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
Copyright # 2007 John Wiley & Sons, Ltd.