A new efficient synthesis of the immunosuppressive agent FTY-720

Article abstract of DOI:10.1055/s-2000-6365

A new efficient five-step synthesis of the immunosuppressive agent FTY- 720 is described.

Full text of DOI:10.1055/s-2000-6365

SHORT PAPER
505
A New Efficient Synthesis of the Immunosuppressive Agent FTY-720
Philippe Durand,* Philippe Peralba, Frédérique Sierra, Patrice Renaut
Laboratoires Fournier S. A., 50 rue de Dijon, 21121 Daix, France
Fax +33(3)80447538; E-mail: p.durand@fournier.fr
Received 25 October 1999; revised 6 December 1999
Using this synthetic pathway, we faced a major difficulty
during the condensation step of 2-iodophenylethyl deriv-
ative 2 with the sodium salt of diethyl acetamidomalonate.
In some experiments, elimination leading to a styrene de-
rivative was the major reaction observed. To alleviate this
side reaction, we decided to use an a-haloacetophenone
such as 6 instead of the 2-halophenylethyl derivative 2.
Abstract: A new efficient five-step synthesis of the immunosup-
pressive agent FTY-720 is described.
Key words: FTY-720, immunosuppressive agent, acylations, re-
ductions
We are interested in studying the pharmacological profile
of FTY-720 4, a new immunosuppressive agent endowed
with an original mechanism of action.1 For this purpose a
multigram quantity of FTY-720 was required. We first
used the only synthetic scheme described in the patent lit-
erature,2 an eight step, 4% overall yield synthesis
(Scheme, path a).
In this article, we describe a shorter and more efficient
synthesis of FTY-720 (Scheme, path b). Friedel-Crafts
acylation of 1-phenyloctane with bromoacetyl chloride in
dichloromethane using AlCl3 afforded the a-bromoace-
tophenone derivative 6 in 68% yield. An alternative but
more expensive route to this a-bromoketone consists of
the bromination of 1-(4-octylphenyl)ethanone.3 Conden-
sation of 6 with the sodium salt of diethyl acetamidoma-
lonate afforded the new ketone derivative 7 in 84% yield.
For its full characterisation, this compound was purified
by flash chromatography. However, for large-scale prep-
arations it could be used after removal of the slight excess
of diethyl acetamidomalonate by precipitation in petro-
leum ether. The conversion of the ketone into methylene
moiety using Et3SiH and CF3CO2H4 failed under different
reaction temperatures and even in the presence of a large
excess of the silane reagent. Such a lack of reactivity of a
ketone carrying an aminoester function has already been
described by Yato et al.5 They solved the problem using
the more oxophilic Lewis acid TiCl4 instead of trifluoro-
acetic acid. Using the same conditions, we obtained the
desired intermediate 3 as a crystalline compound in 77%
yield. Completion of the synthesis of FTY-720 was per-
formed as described by Fujita et al.2
In conclusion, we have developed a new efficient multi-
gram synthesis of FTY-720 in five steps and in a 13%
overall yield, starting from commercially available
1-phenyloctane.
All chemicals were purchased from commercial sources and were
used without further treatment except when specified. Mps were un-
corrected. 1H NMR spectra were determined 300 MHz with TMS as
internal standard. 13C NMR spectra were recorded at 75 MHz. The
chemical shifts are expressed in d values relative to TMS. Elemental
analyses were performed with an elemental analyser Perkin-Elmer
2400 CHN.
2-Bromo-1-(4-octylphenyl)-1-ethanone (6)
Bromoacetyl chloride (28.2 g, 180 mmol) in CH2Cl2 (60 mL) was
added dropwise to a cooled solution (-10 °C) of 1-phenyloctane 5
(34.2 g, 180 mmol) and AlCl3 (24.0 g, 180 mmol) in CH2Cl2 (50
mL). The solution was then allowed to return to r.t. and stirred for a
further 3 h. The mixture was poured slowly onto ice (100 g), the
Scheme
Synthesis 2000, No. 4, 505–506 ISSN 0039-7881 © Thieme Stuttgart · New York

506
P. Durand et al.
SHORT PAPER
aqueous phase was extracted with CH2Cl2 (60 mL) and the organic
phases were collected, dried (MgSO4) and concentrated. The prod-
uct was crystallised twice (CH3OH:H2O) to give 6 (38.3 g, 68%) as
white crystals; mp 45-50 °C (Lit.3 mp 39-40 °C).
1H NMR (CDCl3): d = 0.88 (t, 3H, J = 6.5 Hz, CH3), 1.20-1.40 (m,
10H, CH2), 1.56-1.66 (m, 2H, CH2CH2Ar), 2.67 (t, 2H, J = 7.5 Hz,
CH2CH2Ar), 4.43 (s, 2H, CH2Br), 7.29 (d, 2H, J = 8.3 Hz, Harom),
7.90 (d, 2H, J = 8.3 Hz, Harom).
CH2Cl2 (200 mL) at r.t. under N2 atm. TiCl4 (32.4 g, 170 mmol) was
added with a syringe and the reaction mixture was stirred for 12 h
at r.t. The solution was poured slowly onto ice (100g) and the aque-
ous phase was extracted with CH2Cl2 (60 mL). The organic phases
were collected and dried (MgSO4). The solvent was removed under
vacuum and the product was then crystallised twice from petroleum
ether to yield 3 as a colourless solid (15.1 g, 77%); mp 53 °C (Lit.2
mp 49-50 °C).
1H NMR (CDCl3): d = 0.87 (t, 3H, J = 6.5 Hz, CH3), 1.20-1.40 (m,
16H, (CH2)5 and 2 CH3), 1.56 (m, 2H, CH2CH2Ar), 1.97 (s, 3H,
CH3CO), 2.45 (m, 2H, CH2C(COOEt)2NHAc), 2.55 (t, 2H, J = 7.5
Hz, CH2Ar), 2.68 (m, 2H, CH2CH2C(CO2Et)2NHAc), 4.14-4.25
(m, 4H, OCH2CH3), 6.75 (s, 1H, NH), 7.02-7.09 (m, 4H, CHarom).
13C NMR (CDCl3): d = 14.0, 22.6, 29.1, 29.2, 29.3, 30.9, 31.8, 36.0,
128.8, 129.0, 131.6, 149.9, 190.8.
Anal: C16H23BrO (311.27): Calc C, 61.74; H, 7.45. Found C, 62.07;
H, 7.46.
13C NMR (CDCl3): d = 13.8, 14.0, 22.5, 22.8, 29.1, 29.2, 29.3, 29.6,
31.3, 31.5, 31.7, 33.2, 35.4, 62.4, 66.3, 128.2, 128.3, 137.5, 141.1,
167.9, 168.9.
2-(Acetylamino)-2-[2-(4-octylphenyl)-2-oxo-ethyl]propanedio-
ic Acid Diethyl Ester (7)
To a solution of NaOEt (0.68 g, 10 mmol) in EtOH (10 mL) diethyl
acetamidomalonate (3.50 g, 16 mmol) was added in portions at
60 °C. The mixture was stirred for a further 40 min and a solution
of the bromo derivative 6 (1.00 g, 3.2 mmol) in EtOH (5 mL) was
added. The mixture was stirred further for 45 min at 60 °C, cooled
to r.t. and poured onto ice (60.0 g). The aqueous phase was extracted
with EtOAc (3 ¥ 50 mL), the organic phases were collected, washed
with brine, dried (MgSO4), and concentrated. Purification of the
residue by flash chromatography on silica gel (EtOAc/cyclohexane,
8:2) gave 7 as a colourless oil (1.20 g, 84%).
1H NMR (CDCl3): d = 0.87 (t, 3H, J = 6.5 Hz, CH3), 1.20-1.40 (m,
16H, (CH2)5, 2 CH3CH2O), 1.61 (m, 2H, CH2CH2Ar), 1.96 (s, 3H,
CH3CO), 2.65 (t, 2H, J = 7.5 Hz, CH2CH2Ar), 4.24 (s, 2H,
CH2CO), 4.26 (q, 4H, J = 6.5 Hz, 2 CH3CH2O), 7.10 (s, 1H, NH),
7.26 (d, 2H, J = 8 Hz, CHarom), 7.87 (d, 2H, J = 8 Hz, CHarom).
Anal: C25H39NO5 (433.59): Calc C, 69.25; H, 9.07; N, 3.23. Found
C, 68.65; H, 9.03; N, 3.30.
References
(1) Chiba, K. Drugs Future 1998, 23, 94; and references cited
therein.
Troncoso P.; Kahan B. D. Clin. Biochem. 1998, 31, 369.
(2) Fujita, T.; Sasaki, S.; Yoneta, M.; Mishina, T; Adachi, K.;
Chiba, K. European Patent EP 0627406, Dec 07, 1994; Chem.
Abstr. 1995, 122, 239193.
Adachi, K.; Kohara, T.; Nakao, N.; Arita, M.; Chiba, K.;
Mishina, T.; Sasaki, S.; Fujita, T. Bioorg. Med. Chem. Lett.
1995, 5, 853.
(3) Giroud, A. M.; Muemmer-Westerhoff, U. T. Mol. Cryst. Liq.
Cryst. 1977, 41, 11; and reference cited therein.
(4) Yamamura, S.; Nishiyamo, S. In Comprehensive Organic
Synthesis, Vol. 8; Trost, B.; Fleming, I., Eds.; Pergamon:
Oxford, U. K., 1991; p 307; and references cited therein.
(5) Yato, M.; Homma, K.; Ishida, A. Heterocycles 1995, 41, 17.
13C NMR (CDCl3): d = 13.9, 14.1, 22.6, 22.9, 29.2, 29.4, 31.1, 31.8,
36.0, 42.2, 62.8, 64.0, 128.4, 128.7, 133.9, 149.6, 167.4, 169.4,
196.5.
Anal: C25H37NO6 (447.58): Calc C, 67.09; H, 8.33; N, 3.13. Found
C, 66.96; H, 8.35; N, 3.23.
2-(Acetylamino)-2-[2-(4-octylphenyl)ethyl]propanedioic Acid
Diethyl Ester (3)
A solution of the ketone 7 (20.0 g, 45 mmol) in CH2Cl2 (70 mL) was
added dropwise to a solution of Et3SiH (19.8 g, 170 mmol) in
Article Identifier:
1437-210X,E;2000,0,04,0505,0506,ftx,en;H08799SS.pdf
Synthesis 2000, No. 4, 505–506 ISSN 0039-7881 © Thieme Stuttgart · New York