The preparation of carbon-14 and tritium radio-labeled PD-72953

Full text of DOI:10.1002/jlcr.1298

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 602–604.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1298
Short Research Article
The preparation of carbon-14 and tritium radio-labeled
PD-72953y
YINSHENG ZHANG1,*, ZHIGANG JIAN2 and YANG HONG3
1 Radiochemical Synthesis, Chemical R&D, Groton Laboratories, Pfizer Global Research and Development, Groton, CT 06340, USA
2 Radiochemistry, Novartis Pharmaceuticals Corporation, NJ, USA
3 Radiochemistry, Department of Chemical Synthesis, Pharmaceutical Research Institute, NJ 08903, USA
Received 24 July 2006; Revised 22 January 2007; Accepted 31 January 2007
Keywords: radioactive isotope; carbon-14; tritium; alkylation; palladium; reduction
Introduction
(Scheme 1). In our trial experiment (2 mmol scale), it
was found that a large excess methyl iodide was needed
to draw the alkylation to completion, and the high
solubility of isobutyric acid in water made it difficult to
isolate the labeled compound with an acceptable yield.
With this result, we decided to introduce methyl
group in the later step (Scheme 2). When propionic acid
was treated with LDA in THF, a dianion was formed.
This dianion reacted readily with 4-chlorobutyl ether to
provide the non-labeled starting material, bis (a-
methylhexanoic acid) ether 4. The crude reaction
mixture still contained the un-reacted starting material
chlorobutyl ether, which can be removed by vacuum
distillation. When compound 4 was treated with 4
PD-72953 is a ligand for the peroxisomal proliferation
activated receptor alpha (PPARa) and PPARg.1 In order
to study its absorption, distribution, metabolism and
excretion (ADME), and protein binding, the C-14 and
tritium-labeled PD-72953 was required. This paper
describes the synthesis of each labeled form.
Ca++
O
O
O
O
O
PD-72953
equivalents of LDA, followed by methyl iodide,
a
mixture of un-reacted 4, mono-methylated compound
5 and the desired [14C] PD-72953 (3) was formed. By
adjusting the molar ratio of [14C]MeI and compound 4,
we were able to make a mixture with the desire [14C]
PD-72953 as the major product. After HPLC purifica-
tion, we were able to obtain 89 mCi of [14C]PD-72953
out of 175 mCi of methyl iodide (50.8%) with a radio-
Results and discussion
Synthesis of [14C] PD-72953
The initial synthesis of [14C] PD-72953 was tried
according to the original unlabeled synthetic approach
*
1) LDA
HMPA/THF
2) *MeI
*
1) LDA/HMPA/THF
2) 3,4-dichlorobutylether
OH
CO2H
2
HO
CO2H
O
3
O
O
35%
*
1
Scheme 1
*Correspondence to: Yinsheng Zhang, Pfizer Inc, Chemical R&D, 301
Henrietta St, Kalamazoo 49007, USA.
E-mail: yinsheng.zhang@pfizer.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.

PREPARATION OF CARBON-14 AND TRITIUM RADIO-LABELED PD-72953 603
1) LDA/HMPA/THF
2) 3,4-dichlorobutylether
1) LDA/HMPA/THF
OH
2) [14C]MeI
HO
CO2H
O
63.4%
O
O
68%
1
4
*
*
*
OH
HO
OH
HO
O
5
+
O
3
O
O
O
O
1) HPLC separation
2) LDA/HMPA/THF
3) MeI
1) CaO/EtOH
2) MeOtBu
3) H O
80%
2
*
*
O
Ca++
O
O
O
O
6 [14C] PD-72953
Scheme 2 This scheme is available in colour online at www.interscience.wiley.com
chemical purity >99%. The free acid 3 was then treated
with 1 equiv. of CaO in ethanol to give [14C]PD-72953
calcium salt. The final carbon-14-labeled material was
found to be 98.74% radiochemical pure with a specific
activity of 19.2 mCi/mmol.
mono-alkylated product 7 as the major product. The
alkylation of propionic acid with the chloride 7 afforded
the desired precursor 5 of PD-72953. However, the
methylation of the precursor 5 turned out to be very
unreliable under micro-scale and was not pursued. An
alternate approach to [3H]PD-72953 was developed
based on the catalytic reduction of the unsaturated
precursor 11 or 13 (Scheme 4).
Synthesis of [3H]PD-72953
By adapting a published procedure,2 the diol 9 was
easily prepared in 72% by the treatment of commercially
available alkyne 8 with excess formaldehyde in the
presence of n-BuLi. The bromination of the diol 9 with
PPh3/CBr4 in CH2Cl2 provided the desired di-bromide 10
in 81% yield. The alkylation of isobutyric acid with the
di-bromide 10 furnished the unsaturated precursor 11 of
PD-72953. Direct tritiation of the precursor 11 with two
triple bonds gave the desired [3H]PD-72953, which was
Our initial plan for preparing [3H]PD-72953 was to
methylate the intermediate 5 using [3H]MeI (Scheme 3).
The treatment of isobutyric acid with excess 4-chlor-
obutyl ether (2.5 equiv.) gave a mixture of mono-
alkylated product 7 (20%) and di-alkylated by-product
(30%). By increasing the mole ratio of 4-chlorobutyl
ether and isobutyric acid from 2.5/1 to 5/1, and
adding the pre-prepared isobutyric acid dianion solu-
tion to the 4-chlorobutyl ether, we were able to make a
2. Synthesis of [3H] PD-72953
1) LDA/HMPA/THF
2) propoinicacid
1) LDA/HMPA/THF
2) 3,4-dichlorobutylether
HO
Cl
CO2H
1
O
61%
O
52%
7
1) LDA/HMPA/THF
2) [ H]MeI
OH
3
HO
[3H] PD-72953
O
O
O
0%
5
Scheme 3
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 602–604
DOI: 10.1002.jlcr

604 Y. ZHANG ET AL.
PPh /CBr
3
4
CH O/nBuLi
2
HO
Br
OH
Br
O
8
O
9
O
81%
72%
10
O
O
1) LDA/HMPA/THF
2) isobutyric acid
10% Pd/C
Tn
Tn
T gas
2
HO
OH
OH
HO
O
12
O
65%
O
O
11
H2gas/ Linder's catalyst
95%
O
O
T
T
10% Pd/C
T gas
HO
OH
HO
OH
2
O
O
T
T
O
O
14[3H] PD-72953
13
Scheme 4 This scheme is available in colour online at www.interscience.wiley.com
not stable due to the high radiation effect. Therefore, the
precursor with triple bond was partially reduced to the
precursor 13 first in the presence of Linder’s catalyst, and
was then reduced to [3H]PD-72953 with tritium gas
(0.6 Ci) and 10% Pd/C. A total activity of 56 mCi was
obtained with a specific activity of 103 Ci/mmol.
REFERENCES
1. Bisgaier CL, Essenburg AD, Barnett BC. J Lipid Res
1998; 39(1): 17–30.
2. Gleiter R, Rittinger S, Langer H. Chem Ber 1991;
124(2): 357–363.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 602–604
DOI: 10.1002.jlcr