Asymmetric Synthesis of Maraviroc (UK-427,857)
acetoxyborohydride (98 mg, 0.464 mmol) was added to the References
reaction mixture portionwise. The resultant slurry was
stirred at ambient temperature for 1.5 h. Then the reaction
mixture was treated with H2O (1 mL) followed by 2M
NaOH (1 mL). The aqueous layer was adjusted to pH 11–12
by addition of 10M NaOH. The layers were separated and
the aqueous phase was reextracted with dichloromethane.
The organic fractions were combined, washed with 1M
NaOH and brine, and dried over Na2SO4. The solvent was
removed. The residue was loaded upon a silica-gel column
and immediate chromatography (MeOH:EtOAc=1:6) fur-
nished the pure products as white solids.
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Typical Experimental Procedure for Deprotection
A solution of amine (134 mg) in methanol (3 mL) was
added palladium(II) hydroxide monohydrate on carbon
(10%) (13 mg, 10 wt%) under an N2 atmosphere. The resul-
tant slurry was stirred under an atmosphere of hydrogen at
90 psi for 16 h at room temperation. The reaction mixture
was filtered through celite and the filter pad was washed
with methanol. Then the solvent was removed giving the
product 7; yield: 86 mg (87%).
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Typical Experimental Procedure for the Synthesis of
Maraviroc and its Analogues by Modified Schotten–
Baum Conditions
Amine (0.23 mmol) was dissolved in CH2Cl2 (1.5 mL) at
room temperature, treated with a solution of saturated
aqueous sodium carbonate (1.5 mL) and water (0.5 mL) and
the mixture was cooled to 08C. 4,4-Difluorocyclohexanecar-
bonyl chloride (64 mg, 0.35 mmol, 1.5 equiv.) was added to
the reaction mixture dropwise at 08C and the resultant mix-
ture was stirred for 0.5 h at room temperature. Then the
mixture was separated and the aqueous phase was washed
with dichloromethane. The combined organic phases were
washed with 2M NaOH followed by water. The organic
phase was dried over Na2SO4 and the solvent was removed.
The residue was loaded upon a silica-gel column and imme-
diate chromatography (MeOH:EtOAc=1:6) furnished the
pure products 1 as white solids; Rf =0.52 (MeOH:EtOAc=
1:1).
Supporting Information
Experimental procedures, full spectroscopic data for all new
described compounds, NMR spectra, HPLC traces and HR-
mass spectra are available as Supporting Information.
Acknowledgements
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We thank VINNOVA (The Swedish Governmental Agency
for Innovation Systems) for support. Prof. Henri B. Kagan is
acknowledged for valuable suggestions with respect to the
À
SmI2-mediated N O reductions.
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Chem. Commun. 2007, 849.
Adv. Synth. Catal. 2010, 352, 2291 – 2298
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2297