New route for conversion of camptothecin to 7-ethylcamptothecin and 7-propylcamptothecin

Article abstract of DOI:10.1080/00397910601038723

In this article, a new route for conversion of camptothecin to 7-ethylcamptothecin and 7-propylcamptothecin is described. Compared with previous reports, the reaction time of the new synthetic route was greatly shortened to 30 min, and the products were obtained in high yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601038723

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New Route for Conversion of
Camptothecin to 7‐Ethylcamptothecin and
7‐Propylcamptothecin
Xin Wang a , Xiaojing Wu b , Ning Cheng b , Huiqing Zhao a , Zhihong Gu a &
Xiang Shen c
a Department of Chemistry , College of Basic Medicine, Anhui Medical
University , Hefei, Anhui, China
b School of Chemical Engineering, Hefei University of Technology , Hefei,
Anhui, China
c First Affiliated Hospital, Anhui Medical University , Hefei, Anhui, China
Published online: 06 Feb 2007.
To cite this article: Xin Wang , Xiaojing Wu , Ning Cheng , Huiqing Zhao , Zhihong Gu & Xiang Shen (2007)
New Route for Conversion of Camptothecin to 7‐Ethylcamptothecin and 7‐Propylcamptothecin, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:3,
519-523, DOI: 10.1080/00397910601038723
To link to this article: http://dx.doi.org/10.1080/00397910601038723
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Synthetic Communicationsw, 37: 519–523, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601038723
New Route for Conversion of Camptothecin
to 7-Ethylcamptothecin and
7-Propylcamptothecin
Xin Wang
Department of Chemistry, College of Basic Medicine, Anhui Medical
University, Hefei, Anhui, China
Xiaojing Wu and Ning Cheng
School of Chemical Engineering, Hefei University of Technology,
Hefei, Anhui, China
Huiqing Zhao and Zhihong Gu
Department of Chemistry, College of Basic Medicine, Anhui Medical
University, Hefei, Anhui, China
Xiang Shen
First Affiliated Hospital, Anhui Medical University,
Hefei, Anhui, China
Abstract: In this article, a new route for conversion of camptothecin to 7-ethylcamp-
tothecin and 7-propylcamptothecin is described. Compared with previous reports, the
reaction time of the new synthetic route was greatly shortened to 30 min, and the
products were obtained in high yield.
Keywords: camptothecin, 7-ethylcamptothecin, high yield, new route,
7-propylcamptothecin
Received May 16, 2006
Address correspondence to Xiaojing Wu, School of Chemical Engineering,
Hefei University of Technology, Hefei, Anhui 230009, China. E-mail: wuxiaojing@
ustc.edu
519

520
X. Wang et al.
INTRODUCTION
Camptothecin (CPT), a cytotoxic alkaloid first isolated from Camptotheca
acuminata by Wall and his coworkers in 1966, was shown to have strong
antitumor activity against L1210 leukemia and Walker 256 carcinosarcoma
models.[1,2] The unique mechanism of action that camptothecin inhibits, topoi-
somerase I, has revived the interest in CPT and its analogues as antitumor
agents.[3] A lot of analogues and derivates of CPT were prepared. Among
these, Topotecan and Irinotecan received FDA approval, and some other are
in clinical development.[4]
7-Ethyl-10-hydroxycamptothecin (SN-38) and 7-proply-10-hydroxy-
camptothecin were synthesized by Sawada et al.[5,6] SN-38 is a metabolite
of Irinotecan, which undergoes deesterification in vivo[5] 7-Propyl-10-hydro-
xycomptothecin was also more potent than CPT.[6] The route of synthesizing
7-ethycamptothecin is important in the synthesis of SN-38: 7-propylcamp-
tothecin to 7-propyl-10-hydroxycamptothecin.
According to the method of Sawada et al.[5,6] CPT was treated with
.
FeSO4 7H2O, CH3CH2CHO (or CH3CH2CH2CHO), and H2O2 in H2SO4 to
obtain the product of 7-ethylcamptothecin (or 7-propylcamptothecin). But it
was pointed out by You et al.[7] that the yield was low when this method
was used to synthesize 7-ethylcamptothecin.
To improve the yield, You et al. added acetic acid to obtain a homo-
geneous system (yield: 54%). Lei et al.[8] also studied this reaction; the
yield only reached 70%. Wang et al.[9] studied the reaction of synthesizing
7-propylcamptothecin, and the product was obtained in 65% yield.
We found a new route for conversion of camptothecin to 7-ethylcamp-
tothecin and 7-propylcamptothecin; hydroperoxide was used instead of
CH3CH2CHO (or CH3CH2CH2CHO) and H2O2. The present procedure
offers several advantages including much higher yield (7-ethylcamptothecin
in 83.3% and 7-propylcamptothecin in 73.6% yields), short reaction time
(within 30 min to complete the reaction), and the near completeness of the
reaction.
Hydroperoxide has been prepared with ordinary method as shown in
Scheme 1. Then compounds 1, 2 were used to get 7-ethylcamptothecin and
7-propylcamptothecin (Scheme 2).
EXPERIMENTAL
General Procedure
Camptothecin (0.2 g, 0.58 mmol) was suspended in a mixture of acetic acid
(2.0 ml) and H2SO4 (0.6 ml). After several minutes, a homogeneous system
.
was obtained. Then FeSO4 7H2O (0.42 g, 1.5 mmol) and H2O (1.8 ml)
were added successively. After cooling to 28C, hydroperoxidively (0.8 ml)

New Route for Conversion of Camptothecin
521
Scheme 1.
was added dropwise. The mixture was stirred for 30 min at 08C and was then
poured into ice water. The suspension was extracted with CHCl3 (4 ꢀ 20 ml),
and the solvent was removed under reduce pressure. The residue was purified
through column chromatography of silica gel with CHCl3 as elute.
Data
7-Ethylcamptothecin: Yellow powder (0.18 g), yield: 83.3%, mp: 259–
1
2618C. IR (KBR): Vmax: 3430, 1750, 1653, 1598 cm21. H NMR (CDCl3):
d: 1.03 (3H, t, J ¼ 6.90 Hz, C18-methyl protons), 1.43 (3H, t, J ¼ 6.90 Hz,
CH3CH2–), 1.89 (2H, m, C19-methylene protons), 3.20 (2H, q, CH3CH2–),
5.26 (2H, s, C5-methylene protons), 5.28–5.77 (2H, dd, J ¼ 16.20 Hz, C-17
methylene protons), 7.71 (1H, t, J ¼ 7.59 Hz, C10-H), 7.82 (1H, s, C14-H),
7.80 (1H, t, J ¼ 7.50 Hz, C11-H), 8.13 (1H, d, J ¼ 7.80 Hz, C9-H), 8.23,
(1H, d, J ¼ 8.10 Hz, C12-H). Anal calcd. for C22H20N2O4: C, 70.20; H,
5.36; N, 7.44%. Found: C, 70.10; H, 5.30; N, 7.40%. HRMS (EIþ): m/z
calcd. for C22H20N2O4; 376.1423; found: 376.1419.
7-Prpylcamptothecin: Yellow power (0.165 g), yield: 73.6%, mp: 232–
1
2338C. IR (KBr): vmax: 3430, 1745, 1650, 1600 cm21. H NMR (CDCl3)
d: 0.88–1.13 (8H, C19-methyl protons, CH3CH2CH2–), 1.92 (2H, m, C18-
methylene protons), 3.18 (2H, t, J ¼ 7.56 Hz, CH3CH2CH2–), 5.28 (2H, s,
C5-methylene protons), 5.29–5.79 (2H, dd, J ¼ 16.32 Hz, C-17 methylene
protons), 7.71 (1H, t, J ¼ 7.59 Hz, C10-H), 7.72 (1H, s, C14-H), 7.81 (1H,
t, J ¼ 7.29 Hz, C11-H), 8.12 (1H, d, J ¼ 8.34 Hz, C9-H), 8.26 (1H, d,
J ¼ 8.4 Hz, C12-H). Anal calcd. for C23H22N2O4: C, 70.75; H, 5.68; N,
Scheme 2.

522
X. Wang et al.
7.18%. Found: C, 70.60; H, 5.60; N, 7.10%. HRMS (EIþ): m/z calcd. for
C23H22N2O4: 390.1580; found: 390.1587
DISCUSSION
[8,10]
According to the literature,
media is probably a radical mechanism.
alkylation in position 7 of CPT in acidic
When hydroperoxide was used with transition-metal salt, the correspond-
ing triple-alkoxyl radicals were produced[11]
As a common fragmentation, triple-alkoxyl radical can split into alkyl
radical and acetone.[12]
The ethyl (propyl) radical formed acted with CPT to generate the 7-ethyl-
camptothecin (7-propylcamptothecin) species as shown in 3.[8,10]
In addition, it is very important to add acetic acid to the solvent system
because that will improve the solubility of CPT remarkably and accordingly
result in a much higher yield. The order of adding materials and the usage
.
of H2SO4 and FeSO4 7H2O are important too and deeply affect the
.
reaction course. For example, when we added 0.15 g of FeSO4 7H2O to

New Route for Conversion of Camptothecin
523
.
the system, the yield was low. In contrast, when 0.42 g of FeSO4 7H2O was
added to the system, the reaction finished completely.
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loidal leukemia and tumor inhibitor from Camptotheca acuminate. J Am. Chem.
Soc. 1966, (88), 3888–3890.
2. Muggia, F. M.; Creaveh, D. J.; Hansen, H.; Cohen, M. H.; Selawry, O. S. Phase I
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Sugino, E.; Yamaguchi, K.; Miyasaka, T. Synthesis and antitumor activity of
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Miyasaka, T. Synthesis and antitumor activity of 20 (S)-camptothecis derivatives:
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