Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 513–514.
Published online in Wiley InterScience
JLCR
Short Research Article
Synthesis of [14C]tert-butyl acetyleney
KARLA G. CUEVAS-LICEA*, NATHAN X. YU, STEVEN J. STASKIEWICZ and CONRAD E. RAAB
Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Received 23 June 2006; Revised 13 December 2006; Accepted 14 December 2006
Keywords: CYP P-450; tert-butyl acetylene; Weinreb ketone synthesis
Introduction
Results and discussion
The cytochromes P-450 (CYP) constitute a superfamily
of heme-containing enzymes that are involved in the
metabolism of a wide variety of endogenous and
exogenous compounds.1 Drug interactions involving
P-450 are common, and generally result from either
enzyme inhibition or induction. Understanding CYP
enzyme interactions might allow prescribers the ability
to better anticipate and manage each patient’s
response to a drug regimen.2
Several possible syntheses have been published for
tBA.4 To date, the most efficient way of preparing tBA is
by the method from Bartlett and Rosen.5 We therefore
decided to prepare [14C]pinacolone by Weinreb ketone
synthesis and then apply the method of Bartlett and
Rosen for formation of [14C]tBA.
Synthesis of the pivalamide 3 was easily accom-
plished by applying a previously published procedure
by Tillyer6 using Schotten-Baumann conditions. The
Recently, evidence has been found that tert-butyl
acetylene (tBA) can act as mechanism-based inactiva-
tor of cytochrome P-450 enzymes.3 We were therefore
interested in conducting the synthesis of labeled tBA to
perform enzyme inhibition studies and amino acid
residue identification on the active site. The synthesis
of [14C]tBA has not been previously reported.
[
14C]methyl Grignard was prepared using standard
vacuum-transfer procedures. The formation of [14C]-
pinacolone 4 was accomplished in 28% yield, with 82%
radiochemical purity.
The next step was initially carried out unsuccessfully
using modified Negishi conditions.7 The chlorination/
dehydrochlorination step was therefore based on work
14CH3I
O
Cl
TBME/H2O
K2CO3
O
N
.
NH HCl
O
+
O
Mg/Et2O
1
2
3
1. t-BuO-K+
DMSO
14CH3
14CH3
PCl5
O
Cl
Cl
14CH
Petroleum
Ether
2. Kugelrohr
Distillation
[
14C]tert-Butyl Acetylene
4
5
Figure 1 Synthesis of [14C]tBA.
*Correspondence to: Karla G. Cuevas-Licea, Department of Drug
Metabolism, Merck Research Laboratories, P.O. Box 2000, Rahway,
NJ 07065, USA. E-mail: karla cuevas licea@merck.com
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.