Aminoalkylation of 10-hydroxycamptothecin using methylene chloride under solid-liquid phase transfer catalysis: A new approach for the preparation of topotecan

Article abstract of DOI:10.1081/SCC-200026247

The use of dichloromethane as a reagent, for the preparation of Topotecan {(45)-10-(dimethylamino)methyl-4-ethyl-4,9-dihydroxy-1-H-pyrano[3′, 4′:6,7]indolizino-[1,2-b]quinoline-3,14(4H,12H)dione} from 10-hydroxy-camptothecin under solid-liquid phase transfer catalysis, which behaves both as a solvent and a reagent serving as for C-1 unit source for amino-alkylation of 10-hydroxy-(4S)-camptothecin.

Full text of DOI:10.1081/SCC-200026247

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Aminoalkylation of
10‐Hydroxycamptothecin
Using Methylene Chloride
Under Solid–Liquid Phase
Transfer Catalysis: A New
Approach for the Preparation
of Topotecan
S. C. Puri a , G. Handa a , K. L. Dhar a , O. P. Suri a
& G. N. Qazi a
a Natural Products Chemistry Division, Regional
Research Laboratory (CSIR), Jammu, 180004, India
Published online: 12 Jan 2011.
To cite this article: S. C. Puri , G. Handa , K. L. Dhar , O. P. Suri & G. N. Qazi
(2004) Aminoalkylation of 10‐Hydroxycamptothecin Using Methylene Chloride
Under Solid–Liquid Phase Transfer Catalysis: A New Approach for the Preparation
of Topotecan, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:15, 2857-2862, DOI: 10.1081/
SCC-200026247
To link to this article: http://dx.doi.org/10.1081/SCC-200026247
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 15, pp. 2857–2862, 2004
Aminoalkylation of
10-Hydroxycamptothecin Using
Methylene Chloride Under
Solid–Liquid Phase Transfer
Catalysis: A New Approach for
the Preparation of Topotecan#
*
S. C. Puri, G. Handa, K. L. Dhar, O. P. Suri,
and G. N. Qazi
Natural Products Chemistry Division, Regional Research Laboratory
(CSIR), Jammu, India
ABSTRACT
The use of dichloromethane as a reagent, for the preparation of
Topotecan f(4S)-10-(dimethylamino)methyl-4-ethyl-4,9-dihydroxy-1-H-
pyrano[30,40:6,7]indolizino-[1,2-b]quinoline-3,14(4H,12H)dioneg from
10-hydroxy-camptothecin under solid–liquid phase transfer catalysis,
#US Patent no. 6,660,861 December 9, 2003.
*
Correspondence: S. C. Puri, Natural Products Chemistry Division, Regional Research
Laboratory (CSIR), Jammu 180004, India; E-mail: purisc2004@yahoo.com or
scpuri2003@rediffmail.com.
2857
DOI: 10.1081/SCC-200026247
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2858
Puri et al.
which behaves both as a solvent and a reagent serving as for C-1 unit
source for amino-alkylation of 10-hydroxy-(4S)-camptothecin.
Key Words: Anticancer drugs; 10-Hydroxy-camptothecin; Mannich
reaction; Methylene chloride; Topotecan.
INTRODUCTION
Topotecan 9-[(dimethylamino)methyl]-10-hydroxy-(4S)-camptothecin
[I] (TPT) which is of the chemical structure (Fig. 1), is under clinical trials
and its chemotherapeutic efficacy appears to be very promising.[1] Topotecan
is one of the new class agents that target topoisomerase-I and stabilize the
DNA–topoisomerase-I complex, ultimately resulting in the cell death. The
rationale for the use of Topotecan in chronic lymphocytic leukemia (CLL)
is based on the finding that Top-I levels are elevated in the lymphocytes of
patients with this disease.[2]
FDA has approved Topotecan for the treatment of advanced ovarian
cancers, having developed resistance to other chemotherapeutic agents,
which worked as well or better than taxol in clinical trials.
The present report provides an improved process for the preparation of
TPT from 10-hydroxy-(4S)-camptothecin [II] (HCPT)[3] which comprises of
ortho-regioselective aminomethylation of HCPT using methylene chloride;
which behaves both as a solvent and a reactant with dimethylamine under
solid–liquid phase transfer catalysis. HCPT dissolved in an organic solvent
and stirred at room temperature in the suspension of a solid base (potassium
carbonate) and dimethylamine for the required time, then filtered and solid
extracted with ethyl acetate (20 mL). The solvent was evaporated in vacuo
Figure 1. Aminoalkylation of 10-hydroxy-(4S)-camptothecin.

New Apporach for the Preparation of Topotecan
2859
giving a residue which was purified by known methods and characterized by
physico-chemical techniques.
Methylene chloride was used for aminoalkylation of 10-HCPT to TPT.
Methylene chloride[4] has a double role to play where it can behave both as
a solvent and a reactant for rapid reaction with dimethylamine to form
Mannich adduct at atmospheric pressure. Methylene chloride and secondary
amine react rapidly at room temperature and atmospheric pressure in basic
conditions to form aminals (methylene-bisamines) as intermediates.
Our approach to the preformed methylene iminium salts (aminals), which
are better electrophiles to extend the reaction to complex and relatively inert
molecules, appears first of its kind. To the best of our knowledge, none of
Mannich products has been obtained at atmospheric pressure, even after
extended reaction time.
Solid–liquid transfer phase catalysis[5] is a straightforward route to the
desired products since use of preformed-iminium salts (Mannich reagents)
generally does not provide solution for aminoalkylation of indole, quinoline,
and isoquinoline alkaloids.[6,7] In the present approach high reactivity coupled
with minimized polyalkylation of comparatively inert substrates has been
attained. In addition the yields of the desired product are substantially
reduced in the absence of base which also helps in isolation of crude products
by simple filtration.
Anhydrous K2CO3, a solid base, was used as a catalytic support. It was
also observed that it is not necessary to work in anhydrous conditions.
Other solid bases such as sodium carbonate, lithium carbonate, and potassium
carbonate sesquihydrate have also been tried but the best results were obtained
with potassium carbonate (Table 1).
The methodology provides superior yields and faster reaction under
milder conditions with less undesired products for aminomethylation of
complex molecules. The conventional Mannich procedure relies on the gener-
ation of aminomethyl species through equilibria involving an amine and
formaldehyde which are only suitable for aminomethylation of electron-rich
aromatic species and has limited scope when extended to less reactive sub-
strates which are inert to classical Mannich conditions.[4,8]

2860
Puri et al.
Table 1. Aminomethylation of 10-hydroxy-(4S)-camptothecin (HCPT).
Yielda
(%)
S. no.
Solvent
Base (15 mmol)
K2CO3 (2.17 g)
K2CO3 (2.17 g)
1
2
3
4
5
6
7
8
9
Dichloromethane
Dibromomethane
Diiodomethane
65
60
34
60
34
54
31
41
14
K2CO3 (2.17 g)
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane/toluene
Dichloromethane/DMF
ꢁK2CO3, 1.5 H2O (2.17 g)
Na2CO3 (1.44 g)
K2CO3 (2.17 g)
K2CO3 (2.17 g)
Li2CO3 (2.17 g)
K2CO3 (2.17 g)
Note: For each reaction HCPT (0.364 g, 0.01 mmol), dimethylamine 12 mL, dihalo-
methane 50 mL and base 0.15 mmol ꢁexcept K2CO3, 1.5 H2O 20 mmol for 5 hr at
room temperature.
aYields are not theoretical but based on HPLC determination.
Though the yields, while using dibromo and diiodomethane, were slightly
lower, keeping in view the cost and the ease with which the reagents are
required to be handled, methylene chloride appears to be the best.
EXPERIMENTAL
General
All the reagents were purchased from E. Merck and Ranbaxy and used
without further purification. The solvents used were of commercial grade
and were doubly distilled. The yields reported are not theoretical but are on
the basis of HPLC determination. HPLC was recorded on Gilson HPLC
with 306 pump and 10 SC PUMP head 306 manometric module, 115 UV
detector set at 254 nm, Rheodyne injector 7725i with 50 mL sample loop
was used with Merck Lichrosphere 5 mm particle size, 4 mm ꢀ 100 mm size
RP-C18 column. The isocratic mobile phase used was 60% methanol/
water. IR spectra were recorded on a PC-16-FT Perkin Elmer Spectrophoto-
1
meter and UV on Perkin Elmer UV/VIS spectrophotometer Lambda 3b. H
NMR were recorded on INOVA-600 “eden” using CDCl3 as solvents.
SiMe4 was used as internal standard. Various splitting patterns were desig-
nated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; bs,

New Apporach for the Preparation of Topotecan
2861
broad signal. Chemical shifts were expressed in units (ppm) and coupling
constants in Hz.
General Procedure for Aminomethylation of 10-Hydroxy-(4S)-
camptothecin to 9-[(Dimethylamino)methyl]-0-hydroxy(4S)-
camptothecin (Topotecan)
A solution of HCPT (0.364 g 0.01 mmoL) and 40% aqueous dimethyl-
amine (12 mL) was added to methylene chloride (50 mL) containing anhy-
drous potassium carbonate (2.17 g, 15 mmoL) in suspension. The reaction
mixture was stirred at room temperature for 5 hr, then filtered and solid
extracted with ethylacetate (20 mL). The solvent evaporated in vacuo giving
a residue. The residue was triturated with 0.5% aqueous HCl (50 mL) to
dissolve the water-soluble adduct. Aqueous solution was partitioned with
petroleum ether (3 mL ꢀ 50 mL), followed by ethylacetate (3 mL ꢀ 50 mL).
The aqueous layer on lyophilization afforded white powder identified as Topo-
tecan hydrochloride (yield: 0.236 g, 65%) on the bases of the following:
C23H23N3O5 as HCl m.p. 2158 (dec.) (m/z 421.44); IR (KBr) 3400, 2960,
1740, 1650, 1590 cm21; 1H NMR (CDCl3) as its acetate 1.04 (t, 3, J ¼ 7 Hz,
C-18), 1.96 (q, 2, J ¼ 7 Hz, C-19), 2.01 (s, 3, CH3CO2), 2.50 (s, 6, (CH3)2NH),
4.20 (s, 2, ArCH2N), 5.28 (d, 1, J ¼ 19 Hz, C-17), 5.29 (s, 2, C-5), 5.50 (d, 1,
J ¼ 10 Hz, C-17), 7.42 (d, J ¼ 9 Hz, C-11), 7.67 (s, 1, C-14), 8.05 (d, J ¼ 9 Hz,
C-12), 8.51 (s, C-7).
ACKNOWLEDGMENTS
We thank Dr. M. C. Wani of Research Triangle Institute, Research
Triangle park, North Carolina 277709, USA for providing reference standard
of HCPT and Prof. Dr. M. Spiteller, Managing Director, INFU University of
Dortmund, Dortmund, Germany for high resolution NMR.
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Received in India April 5, 2004