Synthesis of novel phosphoramide-tegafur derivatives containing aminopropylsilatrane

Article abstract of DOI:10.1080/104265090885039

A series of novel phosphoramide-tegafur derivatives containing γ-aminopropyl silatrane were synthesized via the condensation reactions of phosphoryl dichloride with N¹-(2-furanidyl)-N³- (hydroxyethyl)-5-fluorouracil, followed by condensation with γ-aminopropyl silatrane. The structures of the products were confirmed by ¹H NMR, ³¹P NMR, IR, MS, and elemental analysis. The results of preliminary bioassay showed that the new compounds had an inhibition effect against HCT-8 and Bel-7402 cell lines. Copyright Taylor & Francis Inc.

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Synthesis of Novel
Phosphoramide-Tegafur
Derivatives Containing
Aminopropylsilatrane
De Qing Shi a , Qi Chen a , Zhong Hua Li a & Xiao
Peng Liu a
a College of Chemistry, Central China Normal
University, Wuhan, P. R. China and Key Laboratory
of Pesticide and Chemical Biology, Ministry of
Education of China
Published online: 01 Feb 2007.
To cite this article: De Qing Shi , Qi Chen , Zhong Hua Li & Xiao Peng Liu
(2005) Synthesis of Novel Phosphoramide-Tegafur Derivatives Containing
Aminopropylsilatrane, Phosphorus, Sulfur, and Silicon and the Related Elements,
180:7, 1621-1627, DOI: 10.1080/104265090885039
To link to this article: http://dx.doi.org/10.1080/104265090885039
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Phosphorus, Sulfur, and Silicon, 180:1621–1627, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090885039
Synthesis of Novel Phosphoramide-Tegafur Derivatives
Containing Aminopropylsilatrane
De Qing Shi
Qi Chen
Zhong Hua Li
Xiao Peng Liu
College of Chemistry, Central China Normal University, Wuhan,
P. R. China and Key Laboratory of Pesticide and Chemical Biology,
Ministry of Education of China
A series of novel phosphoramide-tegafur derivatives containing γ -aminopropyl sila-
trane were synthesized via the condensation reactions of phosphoryl dichloride with
1
3
N -(2-furanidyl)-N -(hydroxyethyl)-5-fluorouracil, followed by condensation with
1
γ -aminopropyl silatrane. The structures of the products were confirmed by H NMR,
31
P NMR, IR, MS, and elemental analysis. The results of preliminary bioassay
showed that the new compounds had an inhibition effect against HCT-8 and Bel-
7402 cell lines.
Keywords Anti-tumor activity; γ -aminopropyl silatrane; phosphoramide; tegafur
INTRODUCTION
N1-(2-furanidyl)-5-fluorouracil 1 (tegafur) is a potent inhibitor of mam-
malian cell growth in clinical use. However, the undesirable side effects
such as hot sensations, pollakiuria syndrome,1 and low selectivity
between the normal cells and cancer cells has attracted the inter-
ests of many medical and chemistry scientists to develop better, new
anticancer drugs. There are many reports on synthesizing uracil deriva-
tives containing α-hydroxy phosphonates, phosphonopeptides, glyc-
erophospholipids, phosphoramides, and cyclic thiophosphonates.2−6
1-substituted silatrane compounds continue to attract considerable
Received June 6, 2004; accepted August 12, 2004.
We are grateful to the key project of the Chinese Ministry of Education‘(02140) and
the dawn plan of science and technology for young scientists of Wuhan city (2002501024)
for the financial support; we are also indebted to Prof. Guanhua Du who works at Beijing
Institute of Medicine in Academy of Medical Sciences of China for antitumor activities
test.
Address correspondence to De Qing Shi, College of Chemistry, Central China Normal
University, Wuhan, 430079 Hubei, China. E-mail: chshidq@yahoo.com.cn
1621

1622
D. Q. Shi et al.
attention due to their wide biological activities such as antitumor activ-
ity and special structures.7−9 In order to improve its antitumor activity
and lower its toxicity, we introduced γ -aminopropylsilatrane into tega-
fur, utilizing a phosphorylation reaction designed to synthesize a num-
ber of phosphoramide-tegafur derivatives 4 containing γ -aminopropyl
silatrane. The synthetic route is shown in Scheme 1.
SCHEME 1
The results of preliminary biological tests show that some of these
new compounds have certain selective anti-tumor activities.
RESULTS AND DISCUSSION
Preparation of the Title Compounds 4
The title compounds 4 were synthesized by the multi-step route out-
lined in Scheme 1. Most of phosphoramides were usually synthesized
by a one-pot method, but we found that this was not suitable to syn-
thesize this type of compounds because γ -aminopropyl silatrane is un-
stable and decomposes to acyclic compounds in acidic media (HCl was
formed when phosphoryl dichloride reacted with N1-(2-furanidyl)-N3-
(hydroxyethyl)-5-fluorouracil). However, the reaction went smoothly
when γ -aminopropyl silatrane was added dropwise and slowly to the
reaction mixtures with triethyl amine as a catalyst. Moreover, the re-
action was remarkably affected by the solvents used. When chloroform
and ethyl acetate were used, the yields of products were very low. On
the other hand, N,N-dimethyl formamide resulted in decomposing the

Phosphoramide-Tegafur Derivatives
1623
γ -aminopropyl silatrane. Finally, toluene was a suitable solvent for the
reaction; the reaction proceeded smoothly and the target compounds
4 were obtained in moderate yields without any byproducts being de-
tected by TLC.
The Structures of the Title Compounds 4
All the products 4 were purified by recrystalization or flash column chro-
matography on silica gel with a mixture of ethyl acetate and petroleum
ether as the eluent. The structure of compounds 4 was confirmed by
1H NMR, 31P NMR, IR spectra, MS, and elemental analysis.
For 1H NMR spectra, because of the formation of the nitrogen-
and silicon-coordinated bond and the shielded effects, the hydro-
gens of carbon nearest to the silicon atom appear upfield with the
chemical shifts at 0.4 in contrast of the corresponding protons of γ -
aminopropyl[triethoxy]silane at 0.65; moreover, the protons of methy-
lene linking with nitrogen in silatrane appear as triple peaks downfield
with the chemical shifts at 2.8 relative to the protons of trihydroxyethy-
lamine at 2.5. Because of coupling with the fluorine atom, the uracil pro-
ton exhibited a set of doublet peaks with a coupling constant of 7.6 ppm.
5-position protons of furanyl cycle (5ꢀ-H) appears as two sets of multiple
peaks. It is probably due to the two protons lying in different chemical
environments. For 31P NMR spectra, the phosphorus atom of all com-
pounds displayed one set of a single peak with the chemical shifts in
the range of 5–10 ppm.
The IR spectra of all compounds showed normal stretching absorp-
tion bands indicating the existence of the N-H (∼3285 cm−1), C O
(1680–1710 cm−1), P O (∼1260 cm−1), Si←O (∼1052 cm−1, 760 cm−1),
P O C (∼1000 cm−1), and Si←N (∼585 cm−1) moiety. The EI mass
spectra of compound 4 revealed the existence of the weak molecular ion
peaks, but the fragmentation peaks were in accordance with the given
structures of products 4.
Biological Activities
The cell toxicity experiments indicated that the title compounds had
some inhibition effect against HCT-8 and Bel7402 cell lines. For exam-
ple, the ratios of the inhibition against HC7-8 cell lines of compounds 4d
and 4c were, respectively, 29.33% and 12.36% at a mass concentration
of 5.0 × 10−6, and the inhibitory ratio of Bel7402 cell lines of compounds
4d was 20.26% at the same concentration. The cell toxicity experiments
show that the title compounds have little inhibition against A-549 cell
lines.

1624
D. Q. Shi et al.
EXPERIMENTAL
1H NMR and 31P NMR spectra were recorded with a VARIAN
MERCURY-PLUS400 spectrometer with TMS and 85% H3PO4 as the
internal and external reference, respectively, and CDCl3 as the sol-
vent. Mass spectra were obtained with a Finnigan TRACEMS2000
spectrometer using the EI method. IR spectra were measured by
a NICOLET NEXUS470 spectrometer. Elemental analysis was per-
formed with an ELEMENTAR Vario ELIIICHNSO elementary ana-
lyzer. Melting points were determined with a WRS-1B digital melting
point apparatus and were uncorrected.
The reagents and solvents were commercially available and pu-
rified according to conventional methods before use. Tegafur was
purchased from the Qilu medical factory in Sandong province, and
γ -aminopropyl[triethoxy]silane was purchased from the chemical fac-
tory in Wuhan University and redistillated before use. Phosphoryl
dichlorides were synthesized according to the literatures.10,11 N1-(2-
furanidyl)-N3-(hydroxyethyl)-5-fluorouracil 2 was prepared by the re-
action of Tegafur with chloroethanol according to literature.12
Synthesis of γ-Aminopropyl Silatrane
0.1 mol γ -aminopropyl[triethoxy]silane and 0.1 mol trihydroxyethyl
amine were added to 100 mL in a three-necked flask. The resulting
mixture was stirred under reflux, and the formed ethanol was distilled
during the reaction until no ethanol was produced. The reaction mix-
ture was cooled in a refrigerator and filtered, and a light yellow product
was obtained in 86% yield. (m.p. 87–88◦C,13 m.p. 87.2–87.9◦C).
General Procedure for the Synthesis of Phosphoramide-
Tegafur Derivatives Containing Aminopropyl Silatrane
5 mmol alkoxy(substituted phenoxy)phosphoryl dichloride and 10 mL
anhydrous toluene were added to a 50 mL three-necked reaction flask.
A solution of 5 mmol N1-(2-furanidyl)-N3-(hydroxyethyl)-5-fluorouracil
and 6 mmol triethylamine dissolved in 15 mL toluene was added drop-
wise with cooling in an ice bath. After the addition, the mixture was
then stirred at 0◦C for 1 h, and continued to stir at room temperature
for another 2 h. After removing the triethylammonium chloride, the
solution of phosphoryl chloride was added dropwise to the solution of
5 mmol γ -aminopropyl silatrane and 6 mmol triethylamine in 10 mL
anhydrous toluene at room temperature. After the addition, the mix-
tures were allowed to stir at room temperature for 2 h and 50◦C for 1 h;

Phosphoramide-Tegafur Derivatives
1625
the mixtures were cooled to room temperature, the solid was filtered,
and washed with water, and the crude product was recrystallized by
anhydrous ethanol or purified by silica gel-flash column chromatogra-
phy (petroleuom ether/ethyl acetate 1:2 as eluant) to give compounds
4a–h, yield: 41–67%.
4a (R CH3): colorless crystal, m.p. 166–167◦C, yield 41.2%; 1H NMR
(CDCl3) δ 0.40 (t, 2H, CH2Si), 1.60 (m, 2H, CH2CH2Si), 1.79–2.60
(m, 4H, 3ꢀ, 4ꢀ-H of furanyl), 2.78 (t, 6H, Si(OCH2CH2)3 N), 2.90 (m,
2H, PNHCH2), 3.45 (s, 1H, NH), 3.75 (t, 6H, Si(OCH2CH2)3 N), 3.80–
4.00 (m, 4H, NCH2CH2OP, 5ꢀ-H of furanyl), 4.18–4.38 (m, 5H, POCH3,
POCH2), 5.95 (d, br, 1H, 2ꢀ-H of furanyl), 7.42(d, 1H, 6-H of uracil,
3 J
= 7.2 Hz); IR (KBr) (υmax/cm−1) 3285 (N-H), 1717 and 1679 (C O),
H−F
1263 (P O), 1089 and 990 (P O C), 1065 and 760 (Si O), 585(Si←N);
MS, m/e (%) 552 (M+, 1.07), 174 (100), 156 (60.5), 130 (35.2), 71 (20.6),
58 (25.3); Anal. Calcd. For C20H34O9N4FPSi (552): C, 43.48; H, 6.16; N,
10.14. Found: C, 43.35; H, 6.20; N, 9.95.
1
4b (R C2H5): white solid, m.p. 160–162◦C, yield 51.3%; H NMR
(CDCl3) δ 0.41 (t, 2H, CH2Si), 1.30 (t, 3H, CH3), 1.61 (m, 2H, CH2CH2Si),
1.79–2.01 (m, 4H, 3ꢀ, 4ꢀ-H of furanyl), 2.80 (t, 6H, Si(OCH2CH2)3 N),
2.92 (m, 2H, PNHCH2), 3.50 (s, 1H, NH), 3.78 (t, 6H, Si(OCH2CH2)3
N), 3.83–4.05 (m, 4H, NCH2CH2OP, 5ꢀ-H of furanyl), 4.20–4.35 (m,
4H, POCH2CH3, POCH2), 5.94 (d, br, 1H, 2ꢀ-H of furanyl), 7.44(d, 1H,
6-H of uracil, 3 J
= 7.6 Hz); 31P NMR (CDCl3) δ = 5.78; IR (KBr)
H−F
(υmax/cm−1) 3280 (N-H), 1710 and 1680(C O), 1270(P O), 1090 and 980
(P O C), 1050 and 760 (Si O), 591(Si←N); MS, m/e (%) 567 (M + 1,
1.31), 174 (100), 156 (97), 130 (41), 71 (22), 58 (31.3); Anal. Calcd. for
C21H36O9N4FPSi (566): C, 44.52; H, 6.36; N, 9.89. Found: C, 44.61; H,
6.21; N, 10.24.
4c (R n-Pr): white solid, m.p. 156–157◦ C, yield 48.7%; H NMR
1
(CDCl3) δ 0.35 (t, 2H, CH2Si), 0.96 (t, 3H, CH3), 1.32 (m, 2H, CH2CH3),
1.58 (m, 2H, CH2CH2Si), 1.80–1.98 (m, 4H, 3ꢀ, 4ꢀ-H of furanyl), 2.80
(t, 6H, Si(OCH2CH2)3 N), 2.90 (m, 2H, PNHCH2), 3.48 (s, 1H, NH),
3.75 (t, 6H, Si(OCH2CH2)3 N), 3.80–3.95 (m, 4H, NCH2CH2OP, 5ꢀ-H of
furanyl), 4.20–4.37 (m, 4H, POCH2CH2CH3, POCH2), 5.96 (d, br, 1H,
2ꢀ-H of furanyl), 7.50 (d, 1H, 6-H of uracil, 3 JH−F = 7.4 Hz); IR (KBr)
(υmax/cm−1) 3280 (N-H), 1710 and 1675(C O), 1265(P O), 1085 and
988 (P O C), 1050 and 760 (Si O), 583(Si ← N); MS, m/e (%) 580 (M+,
1.16), 174 (100), 156 (54.2), 130 (40.6), 71 (34.6), 58 (23.4); Anal. Calcd.
for C22H38O9N4FPSi (580): C, 45.52; H, 6.55; N, 9.66. Found: C, 45.83;
H, 6.69; N, 9.57.
4d (R i-Pr): white solid, m.p. 152–154◦C, yield 47.5%; 1H NMR
(CDCl3) δ 0.40 (t, 2H, CH2Si), 1.18 (d, 6H, 2CH3), 1.60 (m, 2H,
CH2CH2Si), 1.78–2.00 (m, 4H, 3ꢀ, 4ꢀ-H of furanyl), 2.78 (t, 6H,

1626
D. Q. Shi et al.
Si(OCH2CH2)3 N), 2.90 (m, 2H, PNHCH2), 3.50 (s, 1H, NH), 3.78 (t,
6H, Si(OCH2CH2)3 N), 3.80–4.05 (m, 4H, NCH2CH2OP, 5ꢀ-H of fu-
ranyl), 4.22–4.40 (m, 3H, POCH(CH3)2, POCH2), 6.02 (d, br, 1H, 2ꢀ-
H of furanyl), 7.42 (d, 1H, 6-H of uracil, 3 J
= 7.6 Hz); IR (KBr)
H−F
(υmax/cm−1) 3278 (N H), 1715 and 1680 (C O), 1265(P O), 1087 and
990 (P O C), 1049 and 760 (Si O), 585(Si ← N); MS, m/e (%) 580 (M+,
1.21), 174 (100), 156 (50.2), 130 (20.2), 71 (40.35), 58 (28.3); Anal. Calcd.
for C22H38O9N4FPSi (580): C, 45.52; H, 6.55; N, 9.66. Found: C, 45.66;
H, 6.25; N, 9.61.
4e (R Ph): white solid, m.p. 147–149◦C, yield 50.1%; 1H NMR
(CDCl3) δ 0.42 (t, 2H, CH2Si), 1.58 (m, 2H, CH2CH2Si), 1.80–2.00 (m,
4H, 3ꢀ, 4ꢀ-H of furanyl), 2.80 (t, 6H, Si(OCH2CH2)3 N), 2.90 (m, 2H,
PNHCH2), 3.50 (s, 1H, NH), 3.75 (t, 6H, Si(OCH2CH2)3 N), 3.80–4.00
(m, 4H, NCH2CH2OP, 5ꢀ-H of furanyl), 4.20–4.30 (m, 2H, POCH2), 5.96
(d, br, 1H, 2ꢀ-H of furanyl), 7.22–7.50 (m, 6H, C6H5, 6-H of uracil); 31P
NMR (CDCl3) δ = 10.38; IR (KBr) (υmax/cm−1) 3282 (N H), 1710 and
1670 (C O), 1280(P O), 1110 and 995 (P O C), 1050 and 760 (Si O),
583(Si ← N); MS, m/e (%) 614 (M+, 0.05), 174 (100), 156 (57.3), 130
(10.5), 71 (14), 58 (20.1); Anal. Calcd. for C25H36O9N4FPSi (614): C,
48.86; H, 5.86; N, 9.12. Found: C, 48.96; H, 5.92; N, 9.25.
4f (R 4-ClPh): colorless crystal, m.p. 144–145◦C, yield 67.4%;
1H NMR (CDCl3) δ 0.38 (t, 2H, CH2Si), 1.60 (m, 2H, CH2CH2Si), 1.85–
2.10 (m, 4H, 3ꢀ, 4ꢀ-H of furanyl), 2.86 (t, 6H, Si(OCH2CH2)3 N), 2.91 (m,
2H, PNHCH2), 3.56 (s, 1H, NH), 3.75 (t, 6H, Si(OCH2CH2)3 N), 3.86–
4.12 (m, 4H, NCH2CH2OP, 5ꢀ-H of furanyl), 4.21–4.28 (m, 2H, POCH2),
5.93 (d, br, 1H, 2ꢀ-H of furanyl), 7.12–7.56 (m, 5H, C6H4, 6-H of uracil);
IR (KBr) (υmax/cm−1) 3285 (N H), 1710 and 1680 (C O), 1280(P O),
1050 and 990 (P O C), 1040 and 760 (Si O), 585 (Si ← N); MS, m/e
(%) 648 (M+, 0.1), 174 (100), 156 (34), 130 (27.5), 71 (46), 58 (12); Anal.
Calcd. for C25H35O9N4ClFPSi (648.5): C, 46.26; H, 5.40; N, 8.64. Found:
C, 46.14; H, 5.25; N, 8.97.
4g (R = 2, 4-Cl2Ph): white solid, m.p. 152–153◦C, yield 56.5%;
1H NMR (CDCl3) δ 0.40 (t, 2H, CH2Si), 1.58 (m, 2H, CH2CH2Si), 1.80–
2.05 (m, 4H, 3ꢀ, 4ꢀ-H of furanyl), 2.78 (t, 6H, Si(OCH2CH2)3 N), 2.90 (m,
2H, PNHCH2), 3.50 (s, 1H, NH), 3.75 (t, 6H, Si(OCH2CH2)3 N), 3.82–
4.10 (m, 4H, NCH2CH2OP, 5ꢀ-H of furanyl), 4.20–4.28 (m, 2H, POCH2),
6.02 (d, br, 1H, 2ꢀ-H of furanyl), 7.30–7.85 (m, 4H, C6H3, 6-H of uracil);
IR (KBr) (υmax/cm−1) 3290 (N H), 1705 and 1670 (C O), 1280 (P O),
1115 and 996 (P O C), 1050 and 760 (Si O), 580(Si ← N); MS, m/e (%)
683 (M+, weak), 174 (100), 156 (15), 130 (34), 71 (78), 58 (23); Anal.
Calcd. for C25H34O9N4Cl2FPSi (683): C, 43.92; H, 4.98; N, 8.20. Found:
C, 44.07; H, 5.20; N, 7.96.

Phosphoramide-Tegafur Derivatives
1627
4h (R = 3, 4-Cl2Ph): white solid, m.p. 163–165◦C, yield 45.7%;
1H NMR (CDCl3) δ 0.35 (t, 2H, CH2Si), 1.50 (m, 2H, CH2CH2Si), 1.82–
2.10 (m, 4H, 3ꢀ, 4ꢀ-H of furanyl), 2.84 (t, 6H, Si(OCH2CH2)3 N), 2.95 (m,
2H, PNHCH2), 3.45 (s, 1H, NH), 3.85 (t, 6H, Si(OCH2CH2)3 N), 3.80–
4.15 (m, 4H, NCH2CH2OP, 5ꢀ-H of furanyl), 4.20–4.30 (m, 2H, POCH2),
6.00 (d, br, 1H, 2ꢀ-H of furanyl), 7.35–7.88 (m, 4H, C6H3, 6-H of uracil);
IR (KBr) (υmax/cm−1) 3280 (N H), 1700 and 1670 (C O), 1277(P O),
1110 and 990 (P O C), 1050 and 760 (Si O), 560 (Si ← N); MS, m/e
(%) 683 (M+, 0.1), 174 (100), 156 (64), 130 (45), 71 (28), 58 (39.5); Anal.
Calcd. for C25H34O9N4Cl2FPSi (683): C, 43.92; H, 4.98; N, 8.20. Found:
C, 43.79; H, 5.11; N, 8.43.
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