Labelling of S-0139 with [M+4]-fumaric acid

Full text of DOI:10.1002/jlcr.1240

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 526–527.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1240
Short Research Article
Labelling of S-0139 with ½M+4ꢀ-fumaric acidy
ALAN H. WADSWORTH and KENNETH W. M. LAWRIE*
GlaxoSmithKline, Isotope Chemistry, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Keywords: carbon-13; fumarate; selective hydrolysis
Introduction
diacid 2. Hydroxynitroaldehyde 6 was O-protected with
a Boc group in order to avoid selectivity problems
during the subsequent anilide formation.2 The catalytic
reduction of nitroaldehyde 7 needed to be carefully
controlled to minimize the reduction of the aldehyde
group. The Wittig–Horner–Emmons reaction of ketal-
phosphonate 10 with aldehyde 9 to give the protected
S-0139 11 was carried out with DBU as base.
De-protection required alkaline hydrolysis to saponify
the methyl ester group and strong acid hydrolysis to
cleave the ketal and O-Boc groups, followed by
chromatographic purification. Compound 12 was
found to contain no detectable level of unlabelled
material.
Shionogi’s S-0139 1 is a highly selective endothelin-A
receptor antagonist that was developed in a joint
venture with GSK. A stable isotope labelled version
12 was requested for use as a mass labelled internal
standard.
Results and discussion
Selective saponification of dimethyl fumarate to its
half-acid methyl ester is reported by Niwayama1 in 79%
yield, by portionwise addition of sodium hydroxide in
aqueous THF at 08C. The authors suggest that the high
selectivity of this reaction is due to effects at the
interface of the biphasic reaction medium. In our
hands the yield was only 50% and the reaction became
homogeneous towards the end. We found that addition
of ether and sodium chloride maintained the two
phases. As a result, we were able to obtain reproducibly
a yield of >75% half-ester 4 albeit containing ca. 20%
Conclusion
A synthesis of [M þ 4] S-0139 12 has been demon-
strated in eight steps with an overall yield of 28%, using
an efficient preparation of the half-ester half-acid
chloride of [13C4] fumaric acid.
*Correspondence to: Kenneth W. M. Lawrie, GlaxoSmithKline, Isotope
Chemistry, Medicines Research Centre, Gunnels Wood Road, Steve-
nage SG1 2NY, UK. E-mail: ken.w.lawrie@gsk.com
yProceedings 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.

LABELLING OF S-0139 WITH ½M+4ꢀ-FUMARIC ACID 527
NaOH, NaCl,
THF, Et2O,
H2O, 0-5˚
Me3SiCl,
MeOH, 20˚
O
O
13C
O
13C
13C
13C
13
13C
OMe
13C
13C
13C
MeO
13C
O
HO
C
13
OH
C
OMe
HO
13C
O
100%
O
2
3
78%
4
(COCl)2,
CH2Cl2, 20˚
95%
NO2
O
O
13C
NH2
H
NO2
OH
H
[ButOC(=O)]2O,
DMAP, MeCN, 20˚
H2, PtO2,
EtOAc, 20˚
13C
H
Cl
OMe
13C
O
13C
O
+
O
5
OBut
51%
6
O
OBut
89%
O
O
O
PhNMe2,
CH2Cl2, 20˚
7
66%,
8
O
13C
HN
13C
H
OMe
13C
13C
O
H
OH
O
O
+
H
O
O
OBut
73%
H
O
O
9
10
P
O
OEt
OEt
O
DBU, MeCN, 20˚
H
H
OH
O
13C
OH
O
13C13
HN
C
13C
O
OH
H
O
O
O
13C
13C
O
H
OMe
NaOH, HCl
80%
HN
13C
O
H
O
13C
O
O
H
O
12
11
(1, unlabelled)
OH
O
OBut
O
REFERENCES
2. Konoike T, Araki Y, Hayashi T, Sakurai K,
Tozyo T. European Patent 628569A1 Shionogi,
1994.
1. (a) Niwayama S. Tetrahedron Lett 2000; 41:
10163–10166; (b) Niwayama S. J Org Chem 2000;
65: 5834–5836.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 526–527
DOI: 10.1002.jlcr