Synthesis of C-nucleosidic ATP mimics as potential FGFR3 inhibitors

Article abstract of DOI:10.1002/ejoc.200500999

Receptor tyrosine kinases (RTKs) play an important role in signal transduction pathways, and in particular, FGFR3 is one of the four RTKs related to the fibroblast growth factor family. This paper describes the synthesis of C-nucleosidic ATP mimics, as po

Full text of DOI:10.1002/ejoc.200500999

FULL PAPER
DOI: 10.1002/ejoc.200500999
Synthesis of C-Nucleosidic ATP Mimics as Potential FGFR3 Inhibitors
Patricia Busca,[a] Isabelle McCort,[a] Thierry Prangé,[b] and Yves Le Merrer*[a]
Keywords: Nucleosides / Tyrosine-kinase inhibitors / Heterocycles / -Mannitol
Receptor tyrosine kinases (RTKs) play an important role in
signal transduction pathways, and in particular, FGFR3 is
one of the four RTKs related to the fibroblast growth factor
family. This paper describes the synthesis of C-nucleosidic
ATP mimics, as potential FGFR3 inhibitors, by nucleophilic
epoxide ring-opening followed by in situ O-heterocyclization
of 1,2:5,6-dianhydro-3,4-di-O-benzyl-D-mannitol or L-iditol.
Cesium carbonate [Cs2CO3] was found to be the best catalyst
for the reaction of purine derivatives with these bis-epoxides.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
In this context, we became interested in the synthesis of
ATP mimics as potential FGFR3 inhibitors. We have pre-
Introduction
FGFRs consist of four (FGFR1–4) related receptor tyro- viously reported the synthesis of enantiopure polyhy-
sine kinases (RTKs) coupled with the fibroblast growth fac- droxylated tetrahydrofuran skeletons A bearing an aromatic
tor family. These receptors are involved in biological events moiety in the pseudo-anomeric position.[5] The general
that include mitogenic and angiogenic activity with a conse- strategy (Figure 1, path a) relies on a one-pot tandem alky-
quent and crucial role in cell differentiation and/or prolifer- lation-O-cyclization of enantiopure C2-symmetrical bis-ep-
ation.[1] Among them, FGFR3 has been identified to be oxide 1 derived from -mannitol by action of aromatic car-
particularly implicated in different malignant tumours, be- bon nucleophiles followed by hydrogenolysis.
nign tumours[2] and genetic diseases[3] through its constitu-
We have previously shown[5] that the intermediate al-
tive activation. Within the large number of different struc- lowed the reaction to proceed through either the expected
tural classes of RTK inhibitors reported, small molecules 5-exo-tet (path a) pathway or the 6-endo-tet O-cyclization
competing with ATP are considered to be of great inter- (path b), or by double nucleophilic attack on the primary
est.[4]
carbon atoms.
Figure 1. General strategy for the synthesis of C-glycosides.
[a] Université Paris Descartes, UMR 8601-CNRS, Laboratoire de
Chimie et Biochimie Pharmacologiques et Toxicologiques,
45 rue des Saints-Pères, 75270 Paris Cedex 06, France
Fax: + 33-142868387
As a continuation of our ongoing program, we wished to
broaden the scope of our methodology to aromatic nitrogen
nucleophiles such as purine derivatives in order to synthe-
size adenosine-like C-nucleosides B (Figure 2). These com-
pounds could be used to interfere with cell signalling de-
rived from TK activation.
E-mail: Yves.Le-Merrer@univ-paris5.fr
[b] Université Paris Descartes, UMR 8015-CNRS, Laboratoire de
Cristallographie et RMN Biologiques,
4 avenue de l’Observatoire, 75270 Paris Cedex 06, France
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P. Busca, I. McCort, T. Prangé, Y. Le Merrer
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Figure 2. Synthesis of adenosine-like C-nucleosides.
Results and Discussion
ity was observed in favour of the N9-alkylated derivative,
as the N7 regioisomer 8 was isolated as a byproduct only
when the reaction was scaled up to 1.5 mmol. The chemical
shift patterns of the N9 (compound 7) and N7 (compound
Adenosine mimics are generally prepared by alkylation
of adenine either with activated polyhydroxy derivatives[6]
or through nucleophilic opening of the polyhydroxylated
epoxide,[7] or they can be obtained from methylaminopen-
tofuranose with subsequent construction of the nucleo-
base.[8]
Usually, nucleophilic opening of the epoxide by adenine
or purinyl derivatives is carried out by heating under basic
conditions with sodium hydride or cesium carbonate.[7] The
latter condition was more efficient since the use of NaH led
to complex mixtures. Thus, ring opening of -ido bis-epox-
ide 1[9] by commercially available adenine (3), 2,6-diami-
nopurine (4) and 2-aminopurine (5) as nucleophiles
(Scheme 1) afforded the desired -gluco-homonucleosides 6,
7 and 9, respectively, with an average yield of 55%. It is
well known that N9- and N7-alkylated compounds are both
products of the purine alkylation process; their ratio usually
depends on the nature and the position of the substituents
of the purine moiety.[10] In our case, excellent regioselectiv-
1
8) regioisomers were consistent in both H- and 13C NMR
spectra with those observed for related compounds.[11]
Starting from the diastereoisomeric bis-epoxide 2[9] of -
manno configuration, the above-mentioned conditions led
to the adenosine analogs 10 and 11 in the -gulo configura-
tion with no significant variation of yields. In both series,
these conditions allowed the reaction to proceed only
through the expected 5-exo-tet pathway (Figure 1, path a).
Subsequent hydrogenolysis of the benzyl protecting
groups has been achieved in standard conditions (Pd black
in acetic acid) for adenine and guanine derivatives,[12] or by
catalytic transfer hydrogenation (HCO2NH4, Pd/C 10%).
The latter conditions were always more efficient and fur-
nished the debenzylated products in better yields (86% yield
for 12, for example). Nevertheless, with these conditions,
the reaction required a longer time (up to four days in re-
Scheme 1. Reagents, conditions and yields: purine 3, 4 or 5 (1 equiv.), Cs2CO3 (3 equiv.), DMF, 2 h, 20 °C, then bis-epoxide 1 or 2
(1 equiv.), DMF, 15–20 h, 110 °C, 6: 49%, 7: 49%, 8: 3%, 9: 66%, 10: 45%, 11: 56%.
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Synthesis of C-Nucleosidic ATP Mimics as Potential FGFR3 Inhibitors
FULL PAPER
fluxing methanol) and additional catalyst (up to 200wt.-%)
to reach completion (Scheme 2).
Finally, we applied the same strategy for the synthesis of
2,6-disubstituted analogs (Scheme 3) which could be inter-
In order to confirm both cyclization mode and regiose- esting from a biological point of view, for example for the
lectivity, an X-ray analysis of compound 13 was made. The investigation of the hydrophobic pocket of the binding site
resulting structure depicted in Figure 3 is consistent with an of ATP in kinases.[4] Starting from 2,6-dichloropurine (18),
N9–C linkage, in a cis relationship for the 1Ј and 4Ј substit- aniline was introduced in position 6 under standard SNAr
uents of the furanose-type heterocycle.
conditions.[16] Either an aliphatic side chain known to im-
In the course of our study, Hanessian and coworkers[14] prove solubility or benzylamine was introduced through a
reported the synthesis of 10 and 16 following an analogous second SNAr reaction.
strategy, but the epoxide opening was carried out by tri-
The resulting 2,6-disubstituted purines 20 and 21 were
methylsilylated adenine under Lewis acid catalysis used to open bis-epoxide 1 by applying the above-men-
[Mg(ClO4)2]. However, the 1H- and 13C NMR spectro- tioned conditions. In this series, the amount of N7 regioiso-
scopic data of compounds 10 and 16 were not in agreement mers was found to be more important (up to 15%), slightly
with those reported herein.[15]
lowering the overall yields of 22 and 23. Hydrogenolysis
Scheme 2. Reagents, conditions and yields: (a) H2, Pd/C, AcOH; (b) NH4·HCO2, Pd/C 10%, MeOH, 1–4 d, reflux, 12: 86%, 13: 70%,
14: 50%, 15: 53%, 16: 77%, 17: 60%.
Figure 3. X-ray structure of compound 13 solved with SHELXS and anisotropically refined with SHELXL.[13]
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P. Busca, I. McCort, T. Prangé, Y. Le Merrer
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Scheme 3. Reagents, conditions and yields: (a) Ph–NH2 (5 equiv.), Et3N (5 equiv.), nBuOH, 3 h, 80 °C, 95%; (b) Et2N(CH2)3NH2 or
BnNH2 neat, 20 h, 110 °C, 20: 97%, 21: 50%; (c) purine (1 equiv.), Cs2CO3 (3 equiv.), DMF, 2 h, 20 °C, then bis-epoxide 1 (1 equiv.),
DMF, 15–20 h, 110 °C, 22: 55%, 23: 34%; (d) H2, Pd/C, AcOH 24: 38%, 25: 35%.
was carried out in cyclohexane/EtOAc = 1:1. After hydrolysis, the
crude mixture was extracted twice with ethyl acetate, and the com-
bined organic layers were washed with brine, dried (MgSO4), fil-
tered and concentrated in vacuo. The residue afforded by flash
chromatography the protected C-nucleosides with 53% average
yield.
was performed under the previously mentioned conditions,
leading to 24 and 25.
Conclusion
The synthesis of 1Ј-homo-N-nucleosidic ATP analogs
was efficiently achieved by nucleophilic epoxide ring-open-
ing followed by in situ O-heterocyclization of 1,2:5,6-
dianhydro-3,4-di-O-benzyl--manno or -ido bis-epoxides.
This flexible strategy combines a ribose mimic bearing ami-
nopurines with various substituents in order to explore pos-
sible interactions with the different regions of the ATP
binding sites. These structures should be promising leads in
the development of FGFR3 inhibitors. Exploration of their
inhibitory activity is currently in progress and will be pre-
sented in due course.
1-(6-Amino-9H-purin-9-yl)-2,5-anhydro-3,4-di-O-benzyl-1-deoxy-D-
glucitol (6): Rf = 0.66 (CH2Cl2/MeOH, 10:1), 49% yield (303 mg)
from 1 (437 mg); yellowish solid. [α]D = +5.0 (c = 0.9, CH2Cl2);
1
m.p. 118 °C. H NMR (CDCl3): δ = 3.62 (dd, J = 2.8, 12.6 Hz, 1
H, 6a-H), 3.79 (dd, J = 2.6, 12.6 Hz, 1 H, 6b-H), 3.90–3.99 (m, 1
H, 5-H), 4.17–4.29 (m, 3 H, 1a-H, 2-H, 3-H), 4.30–4.43 (m, 2 H,
1b-H, 4-H), 4.48 (AB, J = 11.7 Hz, 1 H, CHPh), 4.54–4.69 (m, 2
H, CH2Ph), 4.73 (AB, J = 11.7 Hz, 1 H, CHPh), 6.04 (br. s, 2 H,
NH2), 7.27–7.41 (m, 10 H, 2 Ph), 7.59 (s, 1 H, 8Ј-H-Ade), 8.29 (s,
1 H, 2Ј-H-Ade) ppm. 13C NMR (CDCl3): δ = 44.8 (C-1), 61.5
(C-6), 72.5, 72.7 (CH2Ph), 78.6, 81.2, 83.6, 83.7 (C-2, C-3, C-4,
C-5), 119.4 (Cq), 127.6, 127.9, 128.2, 128.3, 128.5, 128.7 (CH-Ar),
137.3, 137.9 (Cq), 140.7 (C-8Ј), 150.1 (Cq), 152.6 (C-2Ј), 155.7 (Cq)
ppm. MS (ESI): m/z = 462 [M + H]+.
Experimental Section
2,5-Anhydro-1-(2,6-diamino-9H-purin-9-yl)-3,4-di-O-benzyl-1-de-
oxy-D-glucitol (7): Rf = 0.44 (EtOAc/MeOH/NH4OH, 5:1:0.1), 49%
1
Methods: H- and 13C NMR were recorded with a Bruker AM250
yield (2.259 g) from 1 (3.15 g); white solid. [α]D = –3.8 (c = 0.5,
CH2Cl2); m.p. 165 °C. H NMR (CDCl3): δ = 3.59 (dd, J = 2.4, 1
spectrometer at 250 and 63 MHz respectively. Compound 13 was
only obtained as microcrystals (max size 20 microns); X-ray diffrac-
tion data were recorded at the ESRF synchrotron facility (Greno-
ble) on the BM14 beam-line, at a wavelength of 0.972 Å, by using
a MAR CCD detector. The sample was kept at 100 K with an
Oxford Cryosystem nitrogen gas cooler. Optical rotations were
measured with a Perkin-Elmer 241C polarimeter with a sodium
(589 nm) lamp at 20 °C. Melting points were determined with a
Büchi 530 apparatus and are uncorrected. High resolution mass
spectra (HRMS) were recorded by the service de spectrometrie de
masse, Ecole Normale Supérieure, Paris. All reactions were carried
out under an argon atmosphere (except for hydrogenolysis), and
monitored by thin-layer chromatography with Merck 60 F254 pre-
coated silica on aluminium sheets. The visualisation of spots was
carried out by staining TLC with an ethanolic phosphomolybdic
acid solution followed by heating. Flash chromatography was per-
formed with Merck Kieselgel 60 (0.2–0.5 mm).
1
H, 12.8 Hz, 6a-H), 3.82 (dd, J = 2.8, 12.8 Hz, 1 H, 6b-H), 3.90–
3.99 (m, 2 H, 1a-H, 5-H), 4.15–4.22 (m, 2 H, 1b-H, 2-H), 4.28 (t,
J = 5.9 Hz, 1 H, 3-H), 4.47 (t, J = 5.9 Hz, 1 H, 4-H), 4.55–4.68
(AB, J = 12.0 Hz, 2 H, CH2Ph), 4.48–4.78 (AB, J = 11.8 Hz, 2 H,
CH2Ph), 4.83 (s, 2 H, NH2), 5.57 (s, 2 H, NH2), 7.24–7.38 (m, 11
H, 2 Ph, 8Ј-H-Ade) ppm. 13C NMR (CDCl3): δ = 44.8 (C-1), 61.1
(C-6), 72.7, 73.0 (CH2Ph), 78.5, 80.6, 83.0, 83.9 (C-2, C-3, C-4,
C-5), 114.6 (Cq), 127.6, 127.9, 128.2, 128.5, 128.7 (CH-Ar), 137.5
(Cq) 137.9 (Cq, C-8Ј), 152.6, 156.1, 159.6 (Cq) ppm. HRMS (ESI):
calcd. for C25H29N6O4 [M + H]+ 477.2257; found 477.2245.
2,5-Anhydro-1-(2,6-diamino-7H-purin-9-yl)-3,4-di-O-benzyl-1-de-
oxy-D-glucitol (8): Rf = 0.35 (EtOAc/MeOH/NH4OH, 5:1:0.1), 3%
yield (138 mg) from 1 (3.15 g); orange foam. [α]D = +13.5 (c = 1.1,
1
CH2Cl2); m.p. 109 °C. H NMR (CDCl3): δ = 3.47 (s, 1 H, 5-H),
3.64 (s, 1 H, 2-H), 3.80–3.85 (m, 3 H, 6-H, 3-H), 4.01–4.12 (m, 3
H, 1-H, 4-H), 4.34–4.68 (m, 5 H, 2 CH2Ph, OH), 5.17 (s, 2 H,
NH2), 6.19 (s, 2 H, NH2), 7.29 (m, 10 H, 2 Ph), 7.45 (s, 1 H, 8Ј-H-
Ade) ppm. 13C NMR (CDCl3): δ = 44.4 (C-1), 66.6 (C-2), 68.9
(C-6), 71.1 (C-3), 72.1, 72.5 (CH2Ph), 73.4, 74.5 (C-4, C-5), 113.8
(Cq), 127.7, 128.0, 128.4, 128.5, 128.7 (CH-Ar), 136.7, 137.5 (Cq),
Typical Procedure for Nucleophilic Opening: A suspension of purine
(1 equiv.) and cesium carbonate (3 equiv.) in dry DMF (5 mL/mmol
purine) was stirred at room temperature for 2 h. A solution of bis-
epoxide (1 equiv.) in dry DMF (5 mL/mmol epoxide) was added,
and the mixture was stirred at 110 °C overnight. TLC monitoring
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Synthesis of C-Nucleosidic ATP Mimics as Potential FGFR3 Inhibitors
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138.9 (C-8Ј), 156.8, 156.1, 160.0 (Cq) ppm. MS (ESI): m/z = 477
H, H-Ar), 7.64 (s, 1 H, 8-H), 7.81 (d, J = 7.9 Hz, 2 H, H-Ar), 8.49
(br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 11.0 (Cε), 26.3 (Cβ),
41.1 (Cα), 46.5 (Cδ), 51.1 (Cγ), 113.7 (Cq), 119.9, 122.7, 128.8 (CH-
Ar), 135.8 (C-8), 139.7, 152.0, 152.3, 159.7 (Cq) ppm. MS (ESI):
m/z = 338 [M – H]+.
[M + H]+.
1-(2-Amino-9H-purin-9-yl)-2,5-anhydro-3,4-di-O-benzyl-1-deoxy-D-
glucitol (9): Rf = 0.14 (CH2Cl2/MeOH, 9:5), 66% yield (102 mg)
from 1 (109 mg); yellowish solid. [α]D = +41.0 (c = 2.0, CH2Cl2);
m.p. 68 °C. 1H NMR (CDCl3): δ = 3.62 (dd, J = 2.2, 12.5 Hz, 1
H, 6a-H), 3.77 (dd, J = 2.2, 12.5 Hz, 1 H, 6b-H), 3.90–3.98 (m, 1
H, 5-H), 4.08 (d, J = 11.6 Hz, 1 H, 1a-H), 4.14–4.31 (m, 3 H, 1b-
H, 2-H, 3-H), 4.37 (t, J = 4.4 Hz, 1 H, 4-H), 4.47 (AB, J = 11.7 Hz,
1 H, CHPh), 4.56–4.70 (m, 2 H, CH2Ph), 4.73 (AB, J = 11.7 Hz,
1 H, CHPh), 4.85–5.10 (br. s, 1 H, OH), 5.15 (br. s, 2 H, NH2),
7.27–7.42 (m, 10 H, 2 Ph), 7.51 (s, 1 H, 8Ј-H-Ade), 8.64 (s, 1 H,
6Ј-H-Ade) ppm. 13C NMR (CDCl3): δ = 44.2 (C-1), 61.4 (C-6),
72.6, 72.8 (CH2Ph), 78.3, 80.9, 83.3, 83.6 (C-2, C-3, C-4, C-5),
127.6, 127.9, 128.2, 128.4, 128.5, 128.7 (Cq, CH-Ar), 137.3, 137.7
(Cq), 142.5 (C-8Ј), 150.2 (C-6Ј), 153.3, 159.5 (Cq) ppm. MS (ESI):
m/z = 462 [M + H]+.
2-Benzylamino-6-phenylamino-purine (21): A solution of 19
(170 mg, 0.60 mmol, 1 equiv.) in benzylamine (5 mL) was stirred at
110 °C for 17 h and concentrated in vacuo. The residue was taken
up in EtOAc (10 mL) and washed with H2O (20 mL) and brine
(20 mL). The organic layer was dried (MgSO4), filtered and concen-
trated in vacuo. Purification by flash chromatography (EtOAc then
EtOAc/MeOH, 9:1) afforded 21 in 50% yield (109 mg) as a pinkish
solid. Rf = 0.17 (EtOAc); m.p. 287 °C. 1H NMR ([D6]DMSO): δ =
4.50 (s, 2 H, CH2), 4.51 (s, 1 H, NH), 6.92 (t, J = 7.1 Hz, 1 H, H-
Ar), 7.10–7.20 (m, 2 H, H-Ar), 7.30 (m, 5 H, H-Ar), 7.77 (s, 1 H,
8-H), 7.90 (m, 2 H, H-Ar), 9.26 (s, 1 H, NHPh), 12.33 (s, 1 H, NH)
ppm. 13C NMR ([D6]DMSO): δ = 44.7 (CH2Ph), 113.7 (Cq), 120.0,
121.8, 126.4, 126.9, 128.1, 128.4 (CH-Ar), 136.3 (C-8), 140.4, 141.3,
152.0, 152.6, 159.7 (Cq) ppm. MS (ESI): m/z = 315 [M – H]+.
1-(6-Amino-9H-purin-9-yl)-2,5-anhydro-3,4-di-O-benzyl-1-deoxy-L-
gulitol (10): Rf = 0.35 (CH2Cl2/MeOH, 9:1), 45% yield (177 mg)
1
from 2 (278 mg); colourless oil. [α]D = +43.0 (c = 1.0, CHCl3). H
2,5-Anhydro-3,4-di-O-benzyl-1-[2-(N,N-diethylamino-3-propyl-
NMR (CDCl3): δ = 3.74–4.46 (m, 10 H, 1-H, 2-H, 3-H, 4-H, 5-H,
6-H, CH2Ph), 4.51 (s, 2 H, CH2Ph), 5.95 (br. s, 2 H, NH2), 7.10–
7.31 (m, 10 H, 2 Ph), 7.59 (s, 1 H, 8Ј-H-Ade), 8.28 (s, 1 H, 2Ј-H-
Ade) ppm. 13C NMR (CDCl3): δ = 45.5 (C-1), 61.2 (C-6), 71.8,
72.1 (CH2Ph), 81.4, 82.0, 83.3, 83.6 (C-2, C-3, C-4, C-5), 119.0
(Cq), 127.7, 127.8, 128.1, 128.6 (CH-Ar), 137.0, 137.2 (Cq), 141.8
(C-8Ј), 150.2 (Cq), 152.9 (C-2Ј), 155.4 (Cq) ppm. HRMS (ESI):
calcd. for C25H28N5O4 [M + H]+ 462.2136; found 462.2147.
amino)-6-phenylamino-9H-purin-9-yl]-1-deoxy-D-glucitol (22): Rf =
0.22 (EtOAc/MeOH/NEt3, 2:1:0.1), 55 % yield (189 mg) from 1
1
(180 mg); orange foam. [α]D = –22.5 (c = 1.0, CH2Cl2). H NMR
(CDCl3): δ = 1.04 (t, J = 7.0 Hz, 6 H, 2 CH3ε), 1.79 (m, 2 H,
CH2β), 2.56 (m, 6 H, CH2γ, 2 CH2δ), 3.50 (m, 2 H, CH2α), 3.64
(dd, J = 2.4, 12.0 Hz, 1 H, 6a-H), 3.80 (dd, J = 2.8, 12.0 Hz, 1 H,
6b-H), 3.97 (m, 1 H, 4-H), 4.09 (m, 2 H, CH2Ph), 4.23 (m, 2 H,
CH2Ph), 4.41 (m, 2 H, 3-H, 5-H), 4.48 (m, 1 H, 1a-H), 4.65 (m, 1
H, 2-H), 4,71 (m, 1 H, 1b-H), 5.66 (m, 1 H, NH), 7.02 (t, J =
7.3 Hz, 1 H, H-Ar), 7.29 (m, 10 H, 2 Ph), 7.80 (d, J = 7.9 Hz, 2
H, H-Ar), 7.97 (s, 1 H, 8Ј-H-Ade) ppm. 13C NMR (CDCl3): δ =
11.4 (Cε), 26.6 (Cβ), 41.1 (Cα), 44.2 (C-1), 46.7 (Cδ), 51.0 (Cγ),
61.3 (C-6), 72.4, 72.6 (CH2Ph), 78.5, 81.1, 83.3, 83.6 (C-2, C-3,
C-4, C-5), 114.0 (Cq), 119.7, 122.5, 127.5, 127.7, 128.0, 128.1,
128.3, 128.5 (CH-Ar), 137.4, 137.5 (Cq), 137.8 (C-8Ј), 139.4, 151.7,
152.2, 159.4 (Cq) ppm. MS (ESI): m/z = 666 [M + H]+.
2,5-Anhydro-1-(2,6-diamino-9H-purin-9-yl)-3,4-di-O-benzyl-1-de-
oxy-L-gulitol (11): Rf = 0.6 (EtOAc/MeOH, 5:1), 56 % yield
(230 mg) from 2 (280 mg); white solid. [α]D = +15.5 (c = 2.0,
1
DMSO); m.p. 165 °C. H NMR ([D6]DMSO): δ = 3.55–3.70 (m, 2
H, 6-H), 3.90–4.00 (m, 3 H, 3-H, 4-H, 5-H), 4.12 (m, 3 H, 1-H, 2-
H), 4.37 (s, 2 H, CH2Ph), 4.50 (AB, J = 12.0 Hz, 2 H, CH2Ph),
4.70 (t, J = 5.2 Hz, 1 H, OH), 5.69 (br. s, 2 H, NH2), 6.62 (br. s, 2
H, NH2), 7.26 (m, 10 H, 2 Ph), 7.63 (s, 1 H, 8Ј-H-Ade) ppm. 13C
NMR ([D6]DMSO): δ = 45.0 (C-1), 59.2 (C-6), 70.7, 70.8 (CH2Ph),
81.2, 81.9, 82.2, 89.9 (C-2, C-3, C-4, C-5), 113.0 (Cq), 127.5, 127.6,
128.2, 128.3 (CH-Ar), 137.7, 137.8 (Cq), 138.2 (C-8Ј), 151.7, 156.1,
160.2 (Cq) ppm. MS (ESI): m/z = 477 [M + H]+.
2,5-Anhydro-3,4-di-O-benzyl-1-(2-benzylamino-6-phenylamino-9H-
purin-9-yl)-1-deoxy-D-glucitol (23): Rf = 0.50 (EtOAc), 34% yield
(165 mg) from 1 (250 mg); yellowish oil. [α]D = +16.5 (c = 1.0,
1
CH2Cl2). H NMR (CDCl3): δ = 3.62 (dd, J = 2.5, 12.7 Hz, 1 H,
6a-H), 3.80 (dd, J = 2.3, 12.7 Hz, 1 H, 6b-H), 3.94–4.77 (m, 12 H,
1-H, 2-H, 3-H, 4-H, 5-H, 3 CH2Ph), 5.48 (br. s, 1 H, OH), 7.01 (t,
J = 7.3 Hz, 1 H, H-Ar), 7.22–7.36 (m, 17 H, H-Ar), 7.63 (d, J =
7.3 Hz, 2 H, H-Ar), 7.70 (s, 1 H, 8Ј-H-Ade) ppm. 13C NMR
(CDCl3): δ = 44.5, 46.0 (C-1, NCH2Ph), 61.4 (C-6), 72.6, 72.8
(CH2Ph), 78.5, 80.9, 83.2, 83.7 (C-2, C-3, C-4, C-5), 114.3 (Cq),
119.9, 126.9, 127.2, 127.6, 127.8, 127.9, 128.1, 128.5, 128.7 (CH-
Ar), 137.4 (Cq), 137.7 (C-8Ј), 139.0, 139.8, 151.5, 152.3, 159.1 (Cq)
ppm. MS (ESI): m/z = 644 [M + H]+.
2-Chloro-6-phenylamino-purine (19): To a solution of 2,6-dichlo-
ropurine (500 mg, 2.65 mmol, 1 equiv.) in butanol (45 mL) were
added triethylamine (1.8 mL, 13.23 mmol, 5 equiv.) and aniline
(1.21 mL, 13.23 mmol, 5 equiv.). After stirring for 3 h at 80 °C, the
mixture was concentrated. To the residue was added H2O (50 mL),
the precipitate was then filtered and washed with H2O, affording
1
19 in 95% yield (617 mg) as a white solid; m.p. 298 °C. H NMR
([D6]DMSO): δ = 7.07 (t, J = 7.3 Hz, 1 H, H-Ar), 7.35 (t, J =
7.6 Hz, 2 H, H-Ar), 7.83 (d, J = 7.8 Hz, 2 H, H-Ar), 8.29 (s, 1 H,
8-H), 10.15 (m, 1 H, NHPh) ppm. MS (ESI): m/z = 244
[M – H]+.
Typical Procedure for Hydrogenolysis
Method A: A mixture of benzylated C-nucleoside and palladium
black (100 wt.-%) in AcOH (10 mL/mmol) was stirred under a hy-
drogen atmosphere. After completion of the reaction monitored by
TLC, the crude mixture was filtered through Celite before concen-
tration under reduced pressure. Purification by flash chromatog-
raphy afforded the corresponding C-nucleoside.
2-(N,N-Diethylamino-3-propylamino)-6-phenylamino-purine (20): A
solution of 19 (170 mg, 0.69 mmol, 1 equiv.) in diethylaminopro-
pylamine (5 mL) was stirred at 110 °C for 17 h and then concen-
trated in vacuo. The residue was taken up in EtOAc (10 mL) and
washed with H2O (10 mL) and brine (10 mL). The organic layer
was dried (MgSO4), filtered and concentrated in vacuo to yield 20
in 97 % yield (228 mg) as an orange solid; Rf = 0.20 (EtOAc/
Method B: A mixture of benzylated C-nucleoside, ammonium for-
MeOH/NEt3, 85:15:1); m.p. 140 °C. 1H NMR (CDCl3): δ = 1.02 mate (16 equiv.) and Pd/C (100 wt.-%) in MeOH was heated at re-
(t, J = 6.9 Hz, 6 H, 2 CH3ε), 1.82 (quint, J = 6.5 Hz, 2 H, CH2β), flux for two days. The reaction was monitored by TLC. If neces-
2.58 (m, 6 H, CH2γ, 2 CH2δ), 3.46 (br. s, 2 H, CH2α), 6.25 (br. s,
1 H, NH), 7.01 (t, J = 7.2 Hz, 1 H, H-Ar), 7.29 (t, J = 7.7 Hz, 2
sary, more ammonium formate (16 equiv.) and Pd/C (100 wt.-%)
were added, and the mixture was heated at reflux again for two
Eur. J. Org. Chem. 2006, 2403–2409
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2407

P. Busca, I. McCort, T. Prangé, Y. Le Merrer
FULL PAPER
days. After completion, methanol was added, and the crude mix-
ture was sonicated for 30 min, filtered through Celite and concen-
trated under reduced pressure. Purification by flash chromatog-
raphy afforded the corresponding C-nucleoside.
82.3, 82.9 (C-2, C-3, C-4, C-5), 118.7 (Cq), 141.5 (C-8Ј), 149.7 (Cq),
152.5 (C-6Ј), 156.1 (Cq) ppm. HRMS (DCI): calcd. for
C11H16N5O4 282.1203; found 282.1198.
2,5-Anhydro-1-deoxy-1-(2,6-diamino-9H-purin-9-yl)-L-gulitol (17):
1-(6-Amino-9H-purin-9-yl)-2,5-anhydro-1-deoxy-D-glucitol (12):
Method A, Rf = 0.30 (CH2Cl2/MeOH/NH4OH, 7:3:0.1), 60% yield
(56 mg) from 11 (150 mg); yellow powder. [α]D = +25.0 (c = 0.5,
Method B, Rf = 0.31 (CH2Cl2/MeOH, 7:3), 86% yield (146 mg)
from 6 (278 mg); yellowish solid. [α]D = –1.5 (c = 0.5, H2O); m.p.
185 °C. 1H NMR (D2O): δ = 3.69–3.81 (m, 2 H, 6-H), 3.82–3.92
(m, 1 H, 5-H), 4.17 (t, J = 4.0 Hz, 1 H, 4-H), 4.24–4.56 (m, 4 H,
1-H, 2-H, 3-H), 8.15 (s, 2 H, 2Ј-H-Ade, 8Ј-H-Ade) ppm. 13C NMR
(D2O): δ = 46.8 (C-1), 64.2 (C-6), 79.4, 80.4, 81.8, 87.5 (C-2, C-3,
C-4, C-5), 120.9 (Cq), 145.5 (C-8Ј), 151.6 (Cq), 154.7 (C-2Ј), 157.8
(Cq) ppm. HRMS (ESI): calcd. for C11H16N5O4 [M + H]+
282.1197; found 282.1203.
1
H2O); m.p. 250 °C (dec.). H NMR (D2O): δ = 3.73 (dd, J = 6.5,
12.1 Hz, 1 H, 6a-H), 3.84 (dd, J = 4.2, 12.1 Hz, 1 H, 6b-H), 4.08
(dd, J = 2.6, 3.8 Hz, 1 H, 3-H), 4.18 (m, 2 H, 2-H, 5-H), 4.25 (dd,
J = 2.6, 4.4 Hz, 1 H, 4-H), 4.35 (d, J = 5.1 Hz, 2 H, 1-H), 7.87 (s,
1 H, 8Ј-H-Ade) ppm. 13C NMR (D2O): δ = 47.9 (C-1), 63.0 (C-6),
79.7, 81.5, 84.0, 85.2 (C-2, C-3, C-4, C-5), 115.5 (Cq), 143.5 (C-8Ј),
154.0, 158.9, 162.8 (Cq) ppm. MS (ESI): m/z = 297 [M + H]+.
2,5-Anhydro-1-[2-(N,N-diethylamino-3-propylamino)-6-
phenylamino-9H-purin-9-yl]-1-deoxy-D-glucitol (24): Method A, Rf
2,5-Anhydro-1-deoxy-1-(2,6-diamino-9H-purin-9-yl)-D-glucitol (13):
Method B, Rf = 0.36 (CH2Cl2/MeOH/NH4OH, 9:1:0.1), 70% yield
(130 mg) from 7 (418 mg); white solid. [α]D = –14.0 (c = 2.0,
DMSO); m.p. 206 °C. 1H NMR ([D6]DMSO): δ = 3.48 (m, 2 H, 6-
H), 3.59 (m, 1 H, 5-H), 3.75 (m, 1 H, 3-H), 3.88 (s, 1 H, 4-H),
4.03–4.15 (m, 3 H, 1-H, 2-H), 4.98 (t, J = 7.5 Hz, 1 H, 6-OH), 5.13
(d, J = 4.0 Hz, 1 H, 4-OH), 5.58 (d, J = 4.9 Hz, 1 H, 3-OH), 5.80
(s, 2 H, NH2), 6.68 (s, 2 H, NH2), 7.67 (s, 1 H, 8Ј-H-Ade) ppm.
13C NMR ([D6]DMSO): δ = 42.4 (C-1), 61.8 (C-6), 76.4 (C-3), 77.7
(C-4), 78.8 (C-2), 86.1 (C-5), 113.0 (Cq), 138.1 (C-8Ј), 151.6, 156.2,
160.1 (Cq) ppm. HRMS (DCI): calcd. for C11H17N6O4 297.1311
[M + H]+; found 297.1318. X-ray diffraction data: Space group
P212121 (Z = 4) with cell parameters a = 5.095(1), b = 10.363(1)
and c = 25.535(2) Å. Final R factor = 6.25% (880 observed F) and
R = 6.5% (958 F, all data). CCDC-293495 contains the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
= 0.20 (CH2Cl2/MeOH/NEt3, 9:1:0.1), 38% yield (50 mg) from 22
(179 mg); orange solid. [α]D = –31.0 (c = 0.6, CH2Cl2); m.p. 99 °C.
1H NMR (CDCl3): δ = 0.98 (t, J = 6.5 Hz, 6 H, CH3ε), 1.74 (m,
2 H, CH2β), 2.56 (m, 6 H, CH2γ, 2 CH2δ), 3.34 (m, 2 H, CH2α),
3.69 (m, 2 H, 6-H), 3.89 (m, 1 H, 4-H), 4.00–4.10 (m, 2 H, 3-H, 5-
H), 4.21 (m, 3 H, 1-H, 5-H), 5.95 (m, 1 H, NH2), 6.97 (t, J =
7.0 Hz, 1 H, H-Ar), 7.20 (m, 10 H, 2 Ph), 7.47 (s, 1 H, 8Ј-H-Ade),
7.73 (d, J = 7.4 Hz, 2 H, H-Ar), 8.11 (s, 1 H, NH) ppm. 13C NMR
(CDCl3): δ = 10.4 (Cε), 25.7 (Cβ), 40.6 (Cα), 42.7 (C-1), 46.3 (Cδ),
50.6 (Cγ), 61.9 (C-6), 76.6, 77.5, 79.7, 85.7 (C-2, C-3, C-4, C-5),
113.7 (Cq), 119.9, 122.6, 128.6 (CH-Ar), 138.1 (C-8Ј), 139.2, 151.1,
152.3, 159.2 (Cq) ppm. MS (ESI, MeOH): m/z = 486 [M + H]+.
1-(2-Amino-6-phenylamino-9H-purin-9-yl)-2,5-anhydro-1-deoxy-D-
glucitol (25): Method A, Rf = 0.10 (CH2Cl2/MeOH, 8:2), 35% yield
(42 mg) from 23 (200 mg); yellowish foam. [α]D = –31.0 (c = 1.6,
1
MeOH). H NMR (CD3OD): δ = 3.71 (t, J = 4.0 Hz, 1 H, 6-H),
3.81 (t, J = 3.6 Hz, 1 H, 5-H), 4.01 (t, J = 3.3 Hz, 1 H, 3-H), 4.10
(t, J = 3.3 Hz, 1 H, 4-H), 4.23–4.39 (m, 3 H, 1-H, 2-H), 7.04 (t, J
= 7.4 Hz, 1 H, H-Ar), 7.33 (t, J = 7.5 Hz, 1 H, H-Ar), 7.81 (d, J
= 7.6 Hz, 2 H, H-Ar), 7.85 (s, 1 H, 8Ј-H-Ade) ppm. 13C NMR
(CD3OD): δ = 44.4 (C-1), 63.1 (C-6), 78.2, 79.2, 80.8, 87.3 (C-2,
C-3, C-4, C-5), 114.8 (Cq), 121.4, 124.0, 129.7 (CH-Ar), 140.3
(C-8Ј), 140.8, 152.5, 154.0, 161.7 (Cq) ppm. MS (ESI): m/z = 373
[M + H]+.
1-(2-Amino-9H-purin-9-yl)-2,5-anhydro-1-deoxy-D-glucitol (14):
Method B, Rf = 0.24 (CH2Cl2/MeOH/NH4OH, 7:3:0.1), 50% yield
(17 mg) from 9 (56 mg); yellow solid. [α]D = +13.5 (c = 1.4,
1
MeOH); m.p. 172 °C. H NMR (D2O): δ = 3.70–3.81 (m, 2 H, 6-
H), 3.83–3.92 (m, 1 H, 5-H), 4.10–4.20 (m, 1 H, 4-H), 4.24–4.33
(m, 2 H, 1a-H, 3-H), 4.38–4.51 (m, 2 H, 1b-H, 2-H), 8.14 (s, 1 H,
8Ј-H-Ade), 8.54 (s, 1 H, 6Ј-H-Ade) ppm. 13C NMR (D2O): δ =
45.9 (C-1), 64.2 (C-6), 79.4, 80.2, 81.4, 87.7 (C-2, C-3, C-4, C-5),
129.5 (Cq), 147.8 (C-8Ј), 151.7 (Cq), 151.8 (C-6Ј), 162.4 (Cq) ppm.
MS (ESI): m/z = 282 [M + H]+.
Acknowledgments
2,5-Anhydro-1-(2,6-diamino-7H-purin-9-yl)-1-deoxy-D-glucitol (15):
Method B, Rf = 0.20 (CH2Cl2/MeOH, 7:3), 53% yield (52 mg) from
8 (158 mg); white powder. [α]D = –40.0 (c = 1.0, MeOH); m.p.
232 °C. H NMR ([D6]DMSO): δ = 3.4–3.8 (m, 5 H, 3-H, 4-H, 5-
We are grateful to GIS - Maladies rares for financial support. The
authors also thank Mrs Sophie Rougnon-Glasson for her partici-
pation in this work.
1
H, 6-H), 3.91 (m, 1 H, 2-H), 4.01 (dd, J = 4.8, 14.0 Hz, 1 H, 1a-
H), 4.14 (dd, J = 8.8, 14.0 Hz, 1 H, 1b-H), 4.96 (d, J = 7.5 Hz, 1
H, OH), 5.06 (br. s, 1 H, OH), 5.25 (br. s, 1 H, OH), 5.79 (br. s, 2
H, NH2), 6.61 (br. s, 2 H, NH2), 7.60 (s, 1 H, 8Ј-H-Ade) ppm. 13C
NMR ([D6]DMSO): δ = 43.5 (C-1), 67.4 (C-6), 68.2, 68.8, 69.1
(C-3, C-4, C-5), 72.9 (C-2), 113.2 (Cq), 138.5 (C-8Ј), 152.1, 156.3,
160.5 (Cq) ppm. MS (ESI): m/z = 297 [M + H]+.
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Eur. J. Org. Chem. 2006, 2403–2409

Synthesis of C-Nucleosidic ATP Mimics as Potential FGFR3 Inhibitors
FULL PAPER
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Received: December 21, 2005
Published Online: March 9, 2006
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Eur. J. Org. Chem. 2006, 2403–2409
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