Oral, Direct Factor Xa Inhibitor
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 5907
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residue was dissolved in acetonitrile (70 mL), and potassium
phthalimide (2.6 g, 14.2 mmol) was added. In a sealed tube,
the reaction mixture was placed in the microwave apparatus
at 180 °C for 45 min. The reaction mixture was filtered, and
the filtrate was concentrated in vacuo. The residue (1.9 g) was
dissolved in methanol (35 mL), and hydrazine hydrate
(0.47 g, 9.37 mmol) was added. The reaction mixture was
refluxed for 2 h and cooled to room temperature. After addition
of saturated aqueous sodium bicarbonate and phase separa-
tion, the aqueous phase was extracted with dichloromethane.
The combined organic phases were dried (magnesium sulfate),
filtered, and evaporated in vacuo, yielding (5S)-5-(amino-
methyl)-3-[4-(2-oxopyrrolidin-1-yl)phenyl]-1,3-oxazolidin-2-
one.
N′-(3-Dimethylaminopropyl)-N-ethylcarbodiimide (0.29 g,
1.51 mmol) and diisopropylethylamine (0.40 mL, 2.32 mmol)
were added to a solution of (5S)-5-(aminomethyl)-3-[4-(2-
oxopyrrolidin-1-yl)phenyl]-1,3-oxazolidin-2-one (0.32 g,
1.16 mmol), 5-chlorothiophene-2-carboxylic acid (0.19 g,
1.16 mmol) and 1-hydroxy-1H-benzotriazol-hydrate (0.23 g,
1.51 mmol) in dimethylformamide (7.6 mL) at room temper-
ature. The reaction mixture was stirred at room temperature
overnight and evaporated in vacuo. The residue was dissolved
in dimethyl sulfoxide (3 mL) and purified by HPLC (acetoni-
trile/water/0.5% TFA gradient). From the combined fractions,
acetonitrile was removed and the formed precipitate was
filtered to give the title compound 11 (0.19 g, 39% yield) as a
colorless solid. mp: 229 °C; 1H NMR (DMSO-d6, 300 MHz):
8.99 (t, J ) 5.7 Hz, 1H), 7.69 (d, J ) 4.1 Hz, 1H), 7.67 (d, J )
9.3 Hz, 2H), 7.52 (d, J ) 9.3 Hz, 2H), 7.20 (d, J ) 4.0 Hz, 1H),
4.89-4.78 (m, 1H), 4.17 (t, J ) 9.1 Hz, 1H), 3.88-3.78 (m, 3H),
3.60 (t, J ) 5.7 Hz, 2H), 2.45 (m, 2H), 2.05 (m, 2H); MS
(ESIpos): 442 ([M + Na]+, 21%), 420 ([M + H]+, 72%), 145
(100%); HR MS ([M + H]+ for C19H18ClN3O4S): calcd 420.0780,
found 420.0786; degree of purity: HPLC: rt (method 1a):
4.54 min (98%), rt (method 4b): 3.92 min (100%).
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crystallography.
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Acknowledgment. The authors thank Ulrich Rester,
Peter Nell, and Axel Jensen for their molecular model-
ing work and helpful discussion, Axel Harrenga for his
support regarding the X-ray crystallography, and the
scientists of Proteros Biostructures GmbH in Planegg-
Martinsried, Germany, for crystallization, data collec-
tion, and structure solution of human FXa in complex
with derivative 5.
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A. L.; Mathieu, A. L.; Ritchie, R. B.; Wilson, D. W. J. Synthesis
and Antitumour Activity of New Derivatives of Flavone-8-acetic
Acid (FAA). Part 31: 2-Heteroaryl Derivatives. Arch. Pharm.
(Weinheim) 1998, 331, 405-411.
Supporting Information Available: Experimental de-
scription and analytical data for compounds 4, 6-10, 15-28.
This material is available free of charge via the Internet at
(15) The X-ray crystal structure of 5 in complex with human FXa
was performed by Proteros Biostructures GmbH in Planegg-
Martinsried, Germany.
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