Efficient synthesis of the immunomodulating compound KRP-203

Article abstract of DOI:10.1055/s-2007-983721

A practical and concise synthesis of KRP-203 (1) was achieved by utilizing a palladium coupling reaction mediated by XantPhos and Pd₂(dba) ₃ as the key step. The coupling reaction of aryl bromide 5 with 3-hydroxythiophenol (6) proceeded chemoselectively to give phenol 7 in spite of the presence of a chlorine substituent on 5 and a hydroxyl group on 6. Phenol 7 was converted into KRP-203 by benzylation and removal of the protecting groups in high yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983721

SHORT PAPER
1927
Efficient Synthesis of the Immunomodulating Compound KRP-203
Synthesis of the
I
mmu
a
nomodulati
i
ng Com
k
pound KRP
o
-203 Hamada,* Masatoshi Kiuchi, Kunitomo Adachi
Chemistry Laboratory Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama,
Kanagawa 227-0033, Japan
Fax +81(45)9633529; E-mail: Hamada.Maiko@mc.m-pharma.co.jp
Received 6 March 2007; revised 27 April 2007
is considered that the effect of 2 on heart rate is also relat-
Abstract: A practical and concise synthesis of KRP-203 (1) was
ed to the agonism at S1P receptors, especially S1P3 in ro-
achieved by utilizing a palladium coupling reaction mediated by
dents.8 Interestingly, while
1
showed potent
XantPhos and Pd2(dba)3 as the key step. The coupling reaction of
aryl bromide 5 with 3-hydroxythiophenol (6) proceeded chemose-
immunomodulating effect comparable to 2, the effect on
lectively to give phenol 7 in spite of the presence of a chlorine sub- heart rate of 1 was weak in guinea pigs.4 Furthermore, the
stituent on 5 and a hydroxyl group on 6. Phenol 7 was converted into
potential of the monophosphate ester of 1, KRP-203-P (4),
KRP-203 by benzylation and removal of the protecting groups in
causing bradycardia in rats was ten-fold weaker than that
high yield.
of 3.9 These data show that 1 is a unique and useful com-
Key words: palladium, cross-coupling, synthesis, KRP-203,
FTY720
pound to investigate the physiological role of S1P recep-
tors. We present here a new concise synthetic approach to
1 using a Pd-catalyzed cross-coupling reaction.
In the previous preparations of 1, the construction of the
Diaryl sulfides are common functionalities found in bio-
diaryl sulfide moiety was accomplished by a traditional
logically active compounds.1 The traditional methods for
substitution reaction using 2-chloro-4-fluorobenzalde-
the construction of diaryl sulfides like Ullmann condensa-
hyde as the starting material.10 For the efficient proceed-
tion often need harsh conditions.2 Recently, mild and
ing of the substitution reaction, the aryl fluoride activated
highly selective methods for the formation of diaryl sul-
by the carbonyl group was required. However, the one-
fides using metal-catalyzed (Cu, Pd) coupling reactions
carbon elongation steps after the construction of the diaryl
were reported.3 These methods could shorten the synthetic
sulfide moiety were the main reason for the long synthetic
schemes using traditional substitution reaction for com-
schemes.
pounds possessing a diaryl sulfide moiety.
Our strategy for synthesis of 1 was to prepare the diaryl
KRP-203 (1, Figure 1) is a novel immunomodulating
sulfide moiety by a Pd-catalyzed cross-coupling reaction
compound with a diaryl sulfide moiety.4 The hydrophilic
of aryl bromide 5, which was easily accessible by an es-
part of 1, 2-aminopropane-1,3-diol, is the same as that of
tablished synthetic procedure11 from diethyl 2-[N-(tert-
FTY720 (2).5 Compound 2 is a synthetic immunomodu-
butoxycarbonyl)amino]malonate and 4-bromo-2-chlo-
lating agent with a sphingosine-like structure, and was ef-
robenzoic acid, with commercially available thiol 6. The
ficacious against multiple sclerosis and kidney transplant
synthesis of 1 is shown in Scheme 1.
rejection in clinical studies.6 For the immunomodulating
The first step was the formation of the diaryl sulfide. We
adopted the condition using Pd2(dba)3 in combination
with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(XantPhos) as the phosphine ligand reported by Itoh.12 Al-
though nonactivated aryl chlorides showed poor reactivity
under the condition, aryl–sulfur bonds were efficiently
mechanism of action is presumed that 2 is converted into
the monophosphate ester of 2, FTY720-P (3), in vivo, and
then 3 interacts with sphingosine 1-phosphate (S1P) re-
ceptor type-1 (S1P1), among five known S1P receptors
(S1P1–5), as an agonist.7 In the clinical trials of 2, transient
bradycardia was reported as a frequent adverse event.6 It
X
X
O
OH
O
OH
H2N
S
O
H2N
Cl
X = H (HCl salt): KRP-203 (1)
X = P(O)(OH)2 : KRP-203-P (4)
X = H (HCl salt): FTY720 (2)
X = P(O)(OH)2 : FTY720-P (3)
Figure 1
SYNTHESIS 2007, No. 13, pp 1927–1929
x
x.
x
x
.
2
0
0
7
Advanced online publication: 18.06.2007
DOI: 10.1055/s-2007-983721; Art ID: F04807SS
© Georg Thieme Verlag Stuttgart · New York

1928
M. Hamada et al.
SHORT PAPER
AcO
OAc
AcO
OAc
AcHN
Br
AcHN
S
OH
HS
OH
a
b
+
Cl
Cl
5
6
7
AcO
OAc
HO
OH
AcHN
S
O
H2N
S
O
c
HCl
Cl
Cl
8
KRP-203 (1)
Scheme 1 Reagents and conditions: (a) Pd2(dba)3 (2.5 mol%), XantPhos (5 mol%), DIPEA (2.0 equiv), 1,4-dioxane, 120 °C; (b) BnBr (1.3
equiv), K2CO3 (3 equiv), DMF, r.t.; (c) 1. LiOH·H2O (5 equiv), MeOH–H2O–THF, 80 °C, 2. 2 M HCl/EtOH, EtOH.
methylxanthene (665 mg, 1.2 mmol) and N,N-diisopropylethy-
lamine (8.0 mL, 46.0 mmol) in 1,4-dioxane (46 mL) was stirred at
120 °C for 9 h. After pouring into aq 1 M HCl (100 mL), the mixture
was extracted with EtOAc (3 × 200 mL). The combined organic lay-
ers were washed with brine (2 × 100 mL), dried (Na2SO4), and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (hexane–EtOAc) to give 7 (9.48 g, 86%) as a white
solid; mp 142–143 °C.
formed from aryl bromides and thiols. This selectivity to
bromide over chloride was favorable to our synthetic
strategy using bromo- and chloro-substituted aryl com-
pound 5 as the starting compound.
Under this condition we were able to obtain the desired
product 7 in 86% yield. The carbon–sulfur bond forma-
tion proceeded chemoselectively in spite of the presence
of a phenolic hydroxyl group.12 In addition, the reaction of
5 with the thiol group of 6 occurred at the bromine atom
exclusively. Triacetyl KRP-203 (8) was obtained by ben-
zylation of the phenol group of 7 by a standard method us-
ing benzyl bromide and potassium carbonate. Removal of
the acetyl groups was accomplished by treatment with
LiOH in an aqueous medium to give free base of 1. Final-
ly, the free base of 1 was converted into its HCl salt 1 by
treatment with 2 M HCl in EtOH. The three steps yield
from 7 was 91%, and the spectroscopic data well support-
ed the structure and high purity of compound 1 obtained
by this scheme.
IR (ATR): 3468, 3271, 3072, 1740, 1714, 1641 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.84 (s, 3 H), 1.92–1.97 (m, 2
H), 2.02 (s, 6 H), 2.62–2.66 (m, 2 H), 4.20 (d, J = 11.0 Hz, 2 H),
4.29 (d, J = 11.0 Hz, 2 H), 6.71–6.78 (m, 3 H), 7.18–7.33 (m, 4 H),
7.69 (s, 1 H), 9.70 (br s, 1 H).
MS (ESI): m/z = 480 [M + H].
Anal. Calcd for C23H26ClNO6S: C, 57.55; H, 5.46; N, 2.92. Found:
C, 57.46; H, 5.44; N, 2.86.
N-{3-[4-(3-Benzyloxyphenylthio)-2-chlorophenyl]-1,1-bis(acet-
oxymethyl)propyl}acetamide (8)
To a solution of 7 (9.48g, 19.8 mmol) in DMF (65 mL) were added
K2CO3 (8.20 g, 59.3 mmol) and benzyl bromide (3.0 mL, 25.2
mmol). The mixture was stirred at r.t. overnight. After pouring into
H2O (150 mL), the mixture was extracted with EtOAc (3 × 200 mL).
The combined organic layers were washed with H2O (3 × 150 mL)
and brine (2 × 100 mL), dried (Na2SO4), and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexane–EtOAc) to give 8 (10.9 g, 97%) as a white solid; mp 81–
82 °C.
In conclusion, we have developed a practical and concise
synthetic method for KRP-203 (1). The key step was the
chemoselective coupling reaction of thiol 6 with aryl bro-
mide 5. This route shortened the previously reported syn-
thetic schemes of 1, and makes it easier to utilize 1 for
pharmacological and biochemical studies.
IR (ATR): 3269, 3097, 1744, 1732, 1650 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.84 (s, 3 H), 1.93–1.97 (m, 2
H), 2.02 (s, 6 H), 2.62–2.66 (m, 2 H), 4.20 (d, J = 11.0 Hz, 2 H),
4.29 (d, J = 11.0 Hz, 2 H), 5.09 (s, 2 H), 6.89–7.00 (m, 3 H), 7.24
(dd, J = 8.0 Hz, 1.6 Hz, 1 H), 7.30–7.42 (m, 8 H), 7.69 (s, 1 H).
Silica gel column chromatography was performed using Fuji Silysia
PSQ100B. 1H NMR spectra were recorded on a Bruker Avance 400
(400 MHz) spectrometer. Chemical shifts are expressed in ppm rel-
ative to TMS as an internal standard. IR spectra were recorded on a
PerkinElmer FT-IR Spectrum One spectrometer. Mass spectra were
measured in a combination with a Waters Acquity UPLC system
(0.05% TFA in MeCN/0.05% TFA in H2O) and a Micromass ZQ
(ESI) spectrometer. Melting points were obtained on a Büchi 535
melting point apparatus and are uncorrected. Elemental analyses
were performed on a Yonako CHN coder MT-5 analyzer.
MS (ESI): m/z = 570 [M + H].
Anal. Calcd for C30H32ClNO6S: C, 63.20; H, 5.66; N, 2.46. Found:
C, 63.16; H, 5.61; N, 2.42.
2-Amino-2-{2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]eth-
yl}propan-1,3-diol Hydrochloride (KRP-203, 1)
N-{1,1-Bis(acetoxymethyl)-3-[2-chloro-4-(3-hydoxyphenyl-
thio)phenyl]propyl}acetamide (7)
A mixture of 5 (10.0 g, 23.0 mmol), 3-hydroxythiophenol (2.8 mL,
27.6 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform
adduct (600 mg, 0.58 mmol), 4,5-bis(diphenylphosphino)-9,9-di-
To a solution of 8 (10.9 g, 19.1 mmol) in MeOH (90 mL), THF (30
mL), and H2O (90 mL) was added LiOH·H2O (4.14 g, 100 mmol).
After stirring at 80 °C for 2 h, the organic solvents were removed in
vacuo. The solid obtained was collected by filtration to give the free
base of 1. The solid was dissolved in 2 M HCl in EtOH (30 mL) and
Synthesis 2007, No. 13, 1927–1929 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of the Immunomodulating Compound KRP-203
1929
EtOH (50 mL). After stirring, the precipitate formed was collected
by filtration to give 1 (8.6 g, 94%); white solid; mp 199–200 °C
(dec.).
IR (ATR): 3238, 3034, 2943 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.76–1.80 (m, 2 H), 2.71–2.76
(m, 2 H), 3.55 (d, J = 4.8 Hz, 4 H), 5.10 (s, 2 H), 5.42 (t, J = 4.8 Hz,
2 H), 6.90–7.01 (m, 3 H), 7.25 (dd, J = 7.9, 1.2 Hz, 1 H), 7.30–7.42
(m, 8 H), 7.91 (br s, 3 H).
Ohtsuki, M.; Hoshino, Y.; Teshima, K.; Chiba, K.; Sasaki,
S.; Fujita, T. J. Med. Chem. 2000, 43, 2946.
(6) (a) Kahan, B. D.; Karlix, J. L.; Ferguson, R. M.; Leichtman,
A. B.; Mulgaonkar, S.; Gonwa, T. A.; Skerjanec, A.;
Schmouder, R. L.; Chodoff, L. Transplantation 2003, 76,
1079. (b) Tedesco-Silva, H.; Mourad, G.; Kahan, B. D.;
Boira, J. G.; Weimar, W.; Mulgaonkar, S.; Nashan, B.;
Madsen, S.; Charpentier, B.; Pellet, P.; Vanrenterghem, Y.
Transplantation 2004, 77, 1826. (c) Kappos, L.; Antel, J.;
Comi, G.; Montalban, X.; O’Connor, P.; Polman, C. H.;
Haas, T.; Korn, A. A.; Karlsson, G.; Radue, E. W. N. Engl.
J. Med. 2006, 355, 1124.
(7) (a) Mandala, S.; Hadju, R.; Bergstrom, J.; Quackenbush, E.;
Xie, J.; Milligan, J.; Thornton, R.; Shei, G.; Card, D.;
Keohane, C.; Rosenbach, M.; Hale, J.; Lynch, C. L.;
Rupprecht, K.; Parsons, W.; Rosen, H. Science 2002, 296,
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MS (ESI): m/z = 444 [M + H].
Anal. Calcd for C24H27Cl2NO3S: C, 60.00; H, 5.66; N, 2.92. Found:
C, 59.83; H, 5.59; N, 2.90.
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