Efficient chromatography-free synthesis of the oxy-analogue of fingolimod

Article abstract of DOI:10.1016/j.tetlet.2010.05.051

Fingolimod (FTY720) and its analogue derivatives are not only promising therapeutics in sphingolipid signaling but also valuable tools for understanding the roles of sphingolipids in (patho)physiological conditions. A practical method for the synthesis of the ether analogue of FTY720 is described. Our final synthetic approach allows high yield and efficient synthesis of O-FTY in only four steps without chromatographic purifications.

Full text of DOI:10.1016/j.tetlet.2010.05.051

Tetrahedron Letters 51 (2010) 3769–3771
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Tetrahedron Letters
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Efficient chromatography-free synthesis of the oxy-analogue of fingolimod
*
Aleksandra Zivkovic, Holger Stark
Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, ZAFES/CMP/ICNP, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Fingolimod (FTY720) and its analogue derivatives are not only promising therapeutics in sphingolipid sig-
naling but also valuable tools for understanding the roles of sphingolipids in (patho)physiological condi-
tions. A practical method for the synthesis of the ether analogue of FTY720 is described. Our final
synthetic approach allows high yield and efficient synthesis of O-FTY in only four steps without chro-
matographic purifications.
Received 17 March 2010
Revised 10 May 2010
Accepted 12 May 2010
Available online 20 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Dr. Dr. Dr. W.
Schunack on the occasion of his 75th
birthday
Keywords:
Sphingolipids
Fingolimod
Synthesis
Chromatography-free
The role of sphingolipids in chemical biology as important mod-
ulators of diverse body functions has raised increased therapeutic
interest. Within the sphingolipid pathways different important
potential targets such as S1P receptors, sphingosine kinases, and
ceramide synthases are actually widely explored.1 Fingolimod
(FTY720, GileniaÒ) as parent prodrug compound for S1P receptor
agonist is the most advanced drug in this group.
Numerous comparable synthetic approaches for FTY720 have
been described2–11 but in our hands none of those offered chemical
approaches was fast enough for derivatization of FTY720. There-
fore, for the development of FTY720 derivatives as a pharmacolog-
ical tool its oxy-analogue (R)-AAL can be taken as comparable lead
structure (Fig. 1).12 The goal of our approach was to provide easy
access to the ether analogues to FTY720 (O-FTY, Fig. 1).
of O-FTY (3) synthesis but failed to improve overall yield (main-
tained approximately 25%) and reduced a number of chromato-
graphic purifications that were necessary for almost each
reaction step for route A.
To overcome these difficulties we started the synthesis in routes
C and D from the 4-(2-bromoethyl)phenol (13) (Fig. 3). The reac-
tion to both Boc-protected aminomalonate (14, route C) and ace-
tamidomalonate compound (15, route D) was accomplished with
NaH in DMF using corresponding N-protected aminomalonate
compound. After varying reaction time and temperature we were
able to synthesize both compounds after 48 h at 45 °C with a yield
of about 75%. Compound 17 (route D) was isolated pure after
Route A in Figure 2 shows the original synthesis of the O-FTY3
and route B the first synthesis that we developed because of the
poor overall yield obtained with route A of about 25%. In our at-
tempts to develop a more practicable and more cost effective syn-
thesis of targeted compounds we combined different method
variations adopted to the literature in the synthesis of comparable
structural elements (Fig. 2).2–11 Synthesis started from p-hydroxy-
acetophenone (9) which was first alkylated (10) and then bromi-
nated (11). Compound 11 upon substitution of bromine with
diethyl acetamidomalonate, subsequent reduction, and following
deprotection gave O-FTY (3). Route B significantly reduced costs
* Corresponding author. Fax: +49 69 798 20258.
E-mail address: h.stark@pharmchem.uni-frankfurt.de (H. Stark).
Figure 1. Fingolimode (FTY720) and its analogues.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.051

3770
A. Zivkovic, H. Stark / Tetrahedron Letters 51 (2010) 3769–3771
Figure 2. Alternative synthesis routes of O-FTY—comparison of route A3 and novel route B. Reagents and conditions: (a) NaOEt, C7H15Br; (b) MsCl, TEA, DCM; (c) NaI, 2-
butanone; (d) NaOEt/EtOH, diethyl acetamidomalonate; (e) LiAlH4, THF; (f) Ac2O, Py; (g) LiOH, MeOH, H2O; (h) C7H15Br, K2CO3, CH3CN; (i) Br2, DCM; (k) NaH, diethyl
acetamidomalonate, DMF; (l) TiCl4/Et3SiH, DCM; (m) NaBH4, THF, MeOH; (n) LiOH/THF/MeOH.
compounds 17 and 7 is accomplished without a single purification
step and easier to achieve than in any of previously described syn-
thesis to best of our knowledge. Therefore, this synthetic approach
is the most promising one for obtaining O-FTY and O-FTY deriva-
tives as polyfunctionalized hydrophilic head groups (2-aminopro-
pan-1,3-diol functionality) in our hands.
In conclusion, we have developed a new efficient multigram
synthesis of the FTY720 analogue O-FTY in four steps and 50%
overall yield without any chromatographic purification (route D).
Acknowledgments
Support by the LOEWE Lipid Signaling Forschungszentrum
Frankfurt (LiFF) and Onkogene Signaltransduktion Frankfurt (OSF)
is gratefully acknowledged.
Figure 3. New synthesis of O-FTY (routes C and D). Reagents and conditions: (o)
NaH, diethyl acetamidomalonate, DMF, 15 or 16 (rt, 1 h and then 48 h at 90 °C); (p)
C7H15Br, K2CO3, CH3CN, reflux, 12 h; (q) NaBH4, CaCl2, EtOH/H2O; (r) LiOH/MeOH/
Supplementary data
H2O; (s) TFA/THF, rt.
Supplementary data (experimental details for the synthesis as
well as analytical data) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2010.05.051.
simple crystallization from EtOAc whereas the corresponding Boc-
protected compound 16 (route C) had to be additionally purified by
References and notes
chromatographic separation. Under these conditions
a small
amount of the styrene derivative (62%) could be isolated. No side
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compound 18 (route C) had to be purified by column
chromatography.
Compounds 18 and 7 were both reduced with NaBH4/CaCl2/
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acetyl group (7 to 3, route D) or TFA for Boc-protecting group (18
to 3, route C). After both reactions, product 3 could be purified
by re-crystallization from ethyl acetate.
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