Syntheses of isotopomers of SK&F-S-104864, topotecan HCl

Full text of DOI:10.1002/jlcr.1245

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 530–531.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1245
Short Research Article
Syntheses of isotopomers of SK&F-S-104864, topotecan HCly
KENNETH W. M. LAWRIE1,*, J. RICHARD HEYS2, KEITH GARNES2,z, ANTHONY J. VILLANI2 and SCOTT LANDVATTER2
1 GlaxoSmithKline Isotope Chemistry, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
2 SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406 USA
Received 17 August 2006; Revised 20 December 2006; Accepted 22 December 2006
Keywords: carbon-14; carbon-13; tritium; nitrogen-15; topotecan
Introduction
ation of the dimethylaminomethyl side chain is a
known metabolic pathway,3 however, the exo-methy-
lene carbon remains untouched so we chose to label
with carbon-14 as shown in Scheme 2. 10-Hydroxy-
campothecin was suspended in glacial acetic acid,
dimethylamine added followed by [14C]formaldehyde.
The mixture was stirred at 758C until no further
reaction was observed (HPLC). The crude SK&F-
S-104864 was purified by reverse phase HPLC, the
relevant fractions pooled and c. HCl added. The
product was isolated by lyophilization giving
SK&F-S-104864-A 1, topotecan HCl, is a topo-isomer-
ase-I inhibitor marketed as Hycamtin.
Topotecan1 is a semi-synthetic derivative of campothe-
cin 2, an alkaloid first isolated2 in 1966. Campothecin1 is
converted into the 10-hydroxy derivative 3 by a reduc-
tion/oxidation sequence and a subsequent Mannich
reaction gives the desired SK&F-S-104864 (Scheme 1).
Results and discussion
[
14C]SK&F 104864-A in 68% yield from formaldehyde.
[3H]Topotecan was required for mechanistic studies
Carbon-14 labelled SK&F-S-104864 was required for
ADME studies. 10-Hydroxycampothecin 3 is readily
available from the synthesis of bulk drug. N-demethyl-
and is prepared in a directly analogous manner using
[3H]formaldehyde as the source of radiolabel. The
OH
HOAc, H2/PtO2
Pb(OAc)4, HOAc
HOAc, H2O
OH
N
O
N
O
N
O
N
O
HO
3
2
O
O
CH2O, Me2NH
HOAc, EtOH
HCl
OH
N
O
N
O
HO
O
1
N
.HCl
Scheme 1
crude product is purified by HPLC (C18, acetonitrile/
water/TFA) and isolated as the TFA salt by lyophiliza-
tion. The specific activity was 2.8 Ci/mmol.
*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
y
Stable isotope labelled topotecan was required as an
internal standard in LC/MS/MS assays. 10-Hydroxy-
campothecin 3 was reacted in glacial acetic acid
with aqueous formaldehyde and [2H6] dimethylamine
Proceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
z
Current address: Pfizer Research and Development, Groton CT 06340,
USA.
Copyright # 2007 John Wiley & Sons, Ltd.

SYNTHESES OF ISOTOPOMERS OF SK&F-S-104864, TOPOTECAN HCL 531
OH
14C or3H]CH2O,
N
O
[
OH
[2H6,or 15N]Me2NH
N
O
N
O
HO
HOAc, EtOH
HCl
N
O
O
HO
N
.HCl
1
3
O
14C
3H
15N
2H6
Scheme 2
hydrochloride (3 equivalents) at 558C until the reaction
was complete. The residue was purified by medium
pressure chromatography (RP18 silica, methanol/
water 1:4 (v/v)). The product was dissolved in DCM/
methanol (2:1 (v/v)) and a calculated amount of 10 M
HCl in IPA added. The product slowly precipitated.
Typical yields from 10-hydroxycampothecin were 50–
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60%.
[
15N]SK&F-S-104864 was required for NMR
studies in support of pharmaceutical formulation,
and was synthesised in a directly analogous manner
to [2H6]SK&F-S-104864.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 530–531
DOI: 10.1002.jlcr