A convenient synthesis of the immunosuppressive agent FTY720

Article abstract of DOI:10.1007/s00706-011-0582-7

This paper describes a practical synthetic approach to preparation of an immunosuppressant, FTY720. The key steps involve an iron-catalyzed cross-coupling reaction and a Wittig reaction. The advantages of this synthesis include readily available starting

Full text of DOI:10.1007/s00706-011-0582-7

Monatsh Chem (2012) 143:161–164
DOI 10.1007/s00706-011-0582-7
ORIGINAL PAPER
A convenient synthesis of the immunosuppressive agent FTY720
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•
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Xiangjun Feng Yuhua Mei Yu Luo
Wei Lu
Received: 6 May 2010 / Accepted: 12 July 2011 / Published online: 12 August 2011
Ó Springer-Verlag 2011
Abstract This paper describes a practical synthetic
approach to preparation of an immunosuppressant,
FTY720. The key steps involve an iron-catalyzed cross-
coupling reaction and a Wittig reaction. The advantages of
this synthesis include readily available starting materials,
inexpensive reagents, simple operations and good yields.
cross-coupling. Subsequently, this methodology was
applied to formal synthesis of FTY720 [4], but suffered
from the need for expensive reagents. Although each of
these reported methods has its own merits, each has such
disadvantages as long steps, low yield, expensive reagents/
starting materials, or inconvenient operations. Thus, it is
necessary to integrate the merits of the known methods to
develop a more convenient synthesis of FTY720.
Keywords FTY720 Á Immunosuppressant Á Synthesis Á
Iron-catalyzed Á Wittig reaction
Results and discussion
Introduction
Retrosynthetic analysis shown in Scheme 2 indicates that
FTY720 could be constructed from tris(hydroxymethyl)ami-
nomethane (3) and methyl 4-chlorobenzoate (2) via an iron-
catalyzed cross-coupling reaction and a Wittig reaction. The
advantages of this synthesis include inexpensive starting
materials, short reaction steps, simple work-up, and good
yields.
FTY720 (1), a synthetic analogue of sphingosine ISP-1
(myriocin) currently in phase III clinical trials [1, 2], has
had favorable immunosuppressive properties in numerous
investigations (Scheme 1).
It contains a hydrophilic head group (2-aminopropane-
1,3-diol) and a lipophilic hydrocarbon chain. Thus, syn-
thesis of FTY720 involves, mainly, the construction of the
two moieties. So far, a variety of methods of preparation of
FTY720 have been reported [3–9]. The hydrophilic head
group (2-aminopropane-1,3-diol) of FTY720 has com-
monly been prepared from diethyl acetamidomalonate
[3–5], nitrodiol [6], benzylamine [7] or tris(hydroxy-
methyl)aminomethane (TRIS) [8, 9]. The hydrocarbon
chain has traditionally been constructed via Friedel–Crafts
acylation and subsequent Wolff–Kishner reduction [3].
Recently, Fu¨rstner et al. [10, 11] developed a convenient
synthesis of alkylbenzene derivatives by iron-catalyzed
ThesyntheticroutetoFTY720isshowninScheme 3. First,
the hydrophilic head group and the lipophilic hydrocarbon
chain were synthesized separately. Coupling of methyl
4-chlorobenzoate (2) with octylmagnesium bromide in the
presence of catalytic amounts of Fe(acac)3 proceeded
smoothly to give compound 6 in 93% yield. Reduction of
compound 6 with KBH4/LiCl gave alcohol 7, which was
treated with PBr3 to afford bromide 8 in good yield. Reaction
of 8 with PPh3 provided the Wittig salt 9 in excellent yield.
The aldehyde moieties 5a and 5b can be obtained from
tris(hydroxymethyl)aminomethane (TRIS, 3) as the starting
substrate. N-Boc-protected aldehyde 5a was prepared in
two steps by the reported method [12]. N-Cbz-protected
aldehyde 5b was synthesized form the corresponding
alcohol 4a which could be accessed by a known procedure
[13] by using a Swern oxidation reaction.
X. Feng Á Y. Mei Á Y. Luo (&) Á W. Lu
Department of Chemistry, East China Normal University,
Shanghai 200062, People’s Republic of China
e-mail: yluo@chem.ecnu.edu.cn
123

162
X. Feng et al.
Finnigan MAT-95 mass spectrometer. All reagents were
used directly as obtained commercially, unless otherwise
noted.
HO
OH
NH2 HCl
5-(Cbz-amino)-2,2-dimethyl-1,3-dioxane-5-carbaldehyde
(5, C15H19NO5)
1
FTY720 ( )
To a cooled (-60 °C) solution of 5 cm3 DMSO in 20 cm3
CH2Cl2 was added a solution of 4.5 cm3 (COCl)2 in
20 cm3 CH2Cl2, and the mixture was stirred for 15 min. A
solution of 7.0 g 4 (24 mmol) in 20 cm3 CH2Cl2 was then
added dropwise, and stirring was continued for 30 min.
Then 30 cm3 triethylamine was added slowly. After
stirring for 15 min, the mixture was left to reach room
temperature and quenched with 15 cm3 aqueous HCl
(1 M). The organic layer was washed with brine, dried
with Na2SO4 and concentrated under vacuum to give crude
5. Crystallization from petroleum ether–ethyl acetate 8:1
gave pure 5 as a light yellow solid (5.2 g, 77% yield). M.p.:
80–82 °C; 1H NMR (500 MHz, CDCl3): d = 1.46 (s, 3H),
1.48 (s, 3H), 4.01–4.09 (m, 4H), 5.13 (s, 2H), 5.78 (s,
1H), 7.34–7.38 (m, 5H), 9.69 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3): d = 27.0, 39.5, 60.2, 62.5, 67.4, 98.8,
128.2, 128.4, 128.6, 135.7, 155.9, 199.1 ppm; MS (EI):
m/z = 293.
OH
HOOC
HO
NH2 OH
O
Myriocin
Scheme 1
HO
OH
NH2 HCl
1
FTY720 ( )
O
O
PPh3Br
OHC NHX
9
5
X = Boc, Cbz
4-Octylbenzoic acid methyl ester (6)
OH OH
A mixture of 17.0 g 2 (0.1 mol) and 1.8 g Fe(acac)3
(5 mmol) in 35 cm3 NMP and 250 cm3 anhydrous THF
was cooled to -5 °C. To the mixture was added a solution
of 150 cm3 octylmagnesium bromide (1 M in anhydrous
THF), over a period of 30 min, under nitrogen atmosphere.
After the solution had been stirred for 15 min, the reaction
was quenched with 20 cm3 aqueous HCl (1 M). THF was
evaporated under vacuum and the mixture was then
extracted with ethyl acetate (3 9 30 cm3). The organic
extract was washed with brine, dried over Na2SO4 and
evaporated to give crude 6 as a yellow oil (23.1 g, 93%),
which could be used in the next step without purification. A
small sample of 6 was purified by column chromatography
on silica gel eluted with petroleum ether (Rf = 0.4) and
characterized. 1H NMR and 13C NMR spectra were
identical with those reported in the literature [14].
Cl
COOMe
OH
H2N
2
3
Scheme 2
Then, heating of Wittig salt 9 with aldehydes 5a and 5b
in the presence of K2CO3 furnished the desired alkenes 10a
(83% yield) and 10b (78% yield), respectively, in an
E/Z mixture. Compound 10a can be converted to FTY720
by use of a reported method [8]. Simple hydrogenation
removed the Cbz group and reduced the double bond of
compound 10b in one step to give compound 11. Removal
of the acetonide groups afforded FTY720 in a yield of
81%.
In conclusion, a convenient strategy for synthesis of
FTY720 (1) was developed from readily available starting
materials in seven steps with 48% overall yield. This
approach provides an easy strategy for preparation of
FTY720 and its analogues.
4-Octylbenzyl alcohol (7)
A mixture of 24.8 g 6 (0.1 mol), 6.5 g KBH4 (0.12 mol),
and 5.0 g LiCl (0.12 mol) in 100 cm3 THF was heated
under reflux for 8 h, then cooled to room temperature and
quenched with 80 cm3 saturated NH4Cl solution. After
stirring for 2 h, THF was evaporated and the mixture was
extracted with ethyl acetate (3 9 30 cm3). The organic
phase was washed with brine, dried with Na2SO4 and
concentrated to give crude 7 as a colorless viscous oil
(19.8 g, 90% yield). A small sample of 7 was purified
by column chromatography on silica gel eluted with
Experimental
1H NMR spectra were recorded on a Bruker DRX-500
(500 MHz). 13C NMR spectra were obtained on a JNM-
EX400 (100 MHz). Mass spectra were determined on a
123

Synthesis of the FTY720
163
Scheme 3
HO
HO
a
CHO
O
O
4a, 5a
4b, 5b
O
: X = Boc
OH
OH
O
NH2
NHX
4a 4b
NHX
: X = Cbz
3
5a, 5b
,
OH
b
c
Cl
COOMe
C8H17
COOMe
C8H17
6
2
7
PPh3 Br
Br
e
f
d
C8H17
C8H17
9
8
NH2
NHX
g
h
C8H17
C8H17
O
O
O
O
10b
: X = Cbz
10a, 10b
11
Ref. 8
10a
: X = Boc
FTY720
1
Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, 77%; (b) C8H17MgBr (in THF),
Fe(acac)3, THF-NMP, 93%; (c) KBH4, LiCl, THF, reflux, 90%; (d) PBr3, CH2Cl2, 96%; (e) PPh3,
5a
5b
or , K2CO3, THF-DMF (3:1), reflux, (g) H2, Pd/C (10 wt%), MeOH,
toluene, 97%; (f) compound
r.t., 76% ( two steps); (h) aq. HCl (1 M), MeOH, 50 oC, 81%.
petroleum ether–ethyl acetate 20:1 (Rf = 0.3) and charac-
terized. 1H NMR and 13C NMR spectra were identical with
those reported in the literature [15].
under a nitrogen atmosphere for 6 h. The reaction mixture
was then cooled. The precipitated white solid was
collected, washed with 30 cm3 toluene and dried to give
pure 9 as white solid (35.4 g, 97%). M.p.: 162–163 °C; 1H
NMR (500 MHz, CDCl3): d = 0.87 (t, J = 7 Hz, 3H),
1.26–1.31 (m, 10H), 1.50–1.54 (m, 2H), 2.50 (t, J = 7 Hz,
2H), 5.33 (d, J = 14 Hz, 2H), 6.93 (d, J = 8 Hz, 2H), 6.98
(d, J = 6 Hz, 2H), 7.61–7.64 (m, 6H), 7.70–7.77 (m, 9H)
ppm; 13C NMR (100 MHz, CDCl3): d = 14.0, 22.6, 29.1,
29.2, 29.3, 30.3, 31.2, 31.8, 35.4, 128.8, 130.0, 130.1,
131.2, 131.3, 134.2, 134.3, 134.9 ppm.
1-Bromomethyl-4-octylbenzene (8)
To a solution of 30.8 g compound 7 (0.14 mol) in 65 cm3
CH2Cl2 at -10 °C was added 5.3 cm3 PBr3 (0.056 mol)
dropwise over a period of 20 min. The mixture was then
stirred for 4 h at room temperature and poured into 80 cm3
ice water. The solution was extracted with CH2Cl2
(3 9 20 cm3), washed with brine, dried over Na2SO4 and
concentrated to give crude 8 as a faint yellow viscous oil
(38 g, 96%). A small sample of 8 was purified by column
chromatography on silica gel with petroleum ether
(Rf = 0.8) and characterized. 1H NMR and 13C NMR
spectra were identical with those reported in the literature
[16].
2,2-Dimethyl-5-[2-(4-octylphenyl)ethyl]-1,3-dioxan-5-
amine (11, C22H39NO2)
A suspension of 1.5 g aldehyde 5b (5.6 mmol), 3.1 g
Wittig salt 9 (5.6 mmol), and 2.0 g K2CO3 (14 mmol) in a
mixture of 30 cm3 THF and 10 cm3 DMF was heated
under reflux for 20 h. After completion of the reaction,
THF was evaporated and the reaction mixture was
quenched with water and then extracted with ethyl acetate
(3 9 10 cm3). The combined organic layers were washed
with brine, dried with Na2SO4, and concentrated to give a
4-Octylbenzyl triphenylphosphonium bromide
(9, C33H38BrP)
A mixture of 19.0 g 8 (67 mmol) and 17.5 g PPh3
(67 mmol) in 100 cm3 toluene was heated under reflux
123

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X. Feng et al.
residue, which was purified by silica gel flash chromatog-
raphy with ether–ethyl acetate 8:1 (Rf = 0.4) to give alkene
10b in E/Z mixture. To a solution of the mixture in 20 cm3
methanol was added 0.2 g 10% Pd/C. The reaction mixture
was hydrogenated for 3 h at room temperature. The
mixture was then filtered. The filtrate was concentrated to
give compound 11 as a colorless oil (1.4 g, 76% from 9).
1H NMR (500 MHz, CDCl3): d = 0.86 (t, J = 7 Hz, 3H),
1.24–1.28 (m, 10H), 1.40 (s, 3H), 1.42 (s, 3H), 1.55–1.62
(m, 4H), 2.41 (s, 2H), 2.54 (t, J = 8 Hz, 2H), 2.60–2.63
(m, 2H), 3.47 (d, J = 11 Hz, 2H), 3.77 (d, J = 12 Hz, 2H),
7.01–7.14 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3):
d = 14.0, 22.6, 27.3, 28.2, 29.2, 29.3, 29.4, 29.6, 31.5,
31.8, 35.5, 37.5, 48.7, 65.9, 69.9, 98.2, 128.0, 128.4, 138.9,
140.5 ppm; HRMS-FAB: m/z calcd. for C22H39NO2 [M]?
347.2824, found 347.2825.
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2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol,
hydrochloride (FTY720, 1)
A solution of 0.7 g 11 (2.1 mmol) in 2 cm3 methanol and
2.5 cm3 aqueous HCl (1 M) was heated at 50 °C for 3 h.
The solvent was then evaporated to dryness to give crude
compound 1, which was crystallized from CH2Cl2–MeOH
(15:1) to give pure FTY720 (0.5 g, 81%). M.p.:
103–105 °C ([8] 105 °C).
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their use thereof. Patent WO2010043000, Apr 22, 2010
Free base of 1: M.p.: 122–124 °C ([8] 121–124 °C).
Acknowledgments We gratefully acknowledge financial support
for new century excellent talents in university (NCET). We also thank
Laboratory of Organic Functional Molecules, the Sino–French Insti-
tute of ECNU for support.
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