1326
A. M. Palmer et al. / 19 (2008) 1310–1327
NMR (DMSO-d6, 200 MHz): d = 2.03 (mc, 1H), 2.24, 2.26 (mc, s, 4H),
2.36, 2.39 (2s, 6H), 2.55 (mc), 2.86, 2.92 (mc, s, 4H), 3.03 (s, 3H),
5.39 (dd, 1H), 6.63 (s, 4H), 7.26 (mc, 3H), 7.47 (mc, 1H), 7.86 (s,
1H). The salt of the title compound with fumaric acid was added
portionwise to a stirred mixture of sodium bicarbonate (10.5 g,
125 mmol), water (120 ml) and dichloromethane (200 ml). Stirring
was continued until a clear biphasic mixture was obtained. The
phases were separated and the aqueous phase was extracted with
dichloromethane (2 ꢀ 30 ml). The combined organic phases were
washed with water (2 ꢀ 30 ml), dried over sodium sulfate and con-
centrated under reduced pressure. The residue was dried in vacuo.
A foamy solid (8.8 g) was obtained which was treated with diethyl
ether (80 ml). The emulsion was warmed to 50 °C and, gradually,
crystallization of the title compound occurred. The slurry was stir-
red for 1 h at room temperature. The crystals were isolated by fil-
tration, washed with diethyl ether (15 ml) and dried in vacuo. The
title compound was isolated in the form of a colourless solid (7.8 g,
48% yield, 56% corrected yield, 99.3% ee): mp 178–180 °C (diethyl
ether); determination of the enantiomeric excess by HPLC (col-
4.27. (9S)-2,3-Dimethyl-9-thiophen-2-yl-7H-8,9-dihydro-
pyrano[2,3-c]-imidazo[1,2-a]pyridine-6-carboxylic acid
dimethylamide 55
In a flame-dried flask filled with argon, diol 47 (1.80 g, 4.8 mmol,
99.2% ee) was suspended in dry dichloromethane (30 ml). After the
addition of triphenylphosphine (1.90 g, 7.2 mmol) and the drop-
wise addition of DIAD (1.50 g, 7.4 mmol), a green solution was
obtained which was stirred for 45 min at room temperature. More
triphenylphosphine (0.60 g, 2.3 mmol) and DIAD (0.30 g, 2.5 mmol)
were added and stirring was continued for 20 min. The reaction
mixture was concentrated under reduced pressure to a volume of
15 ml and loaded on a column packed with silica gel (50 g). The
by-products were eluted with dichloromethane/methanol = 100:1
(v/v) and the polarity of the eluant was increased to 20:1 (v/v).
Evaporation of the corresponding fractions furnished a yellow-
brown solid (0.62 g), which was suspended in acetone (2 ml). After
a period of 1 h, the precipitate was isolated by filtration, washed
with acetone (0.5 ml) and diethyl ether (8 ml) and dried in vacuo.
The title compound was isolated in 22% yield (0.37 g of a colourless
solid, 84.0% ee): mp 237–238 °C; determination of the enantiomeric
excess by CE (method A): MT [(9R)-enantiomer] = 15.7 min/8.0
area-%; MT [(9S)-enantiomer] = 16.1 min/92.0 area-%; 84.0% ee;
1H NMR (DMSO-d6, 200 MHz): d = 2.25, 2.26, 2.34 (s, mc, s, 8H),
2.53 (mc), 2.73, 2.87 (mc, s, 4H), 3.01 (s, 3H), 5.56 (dd, 1H), 7.08
(dd, 1H), 7.23 (br d, 1H), 7.57 (dd, 1H), 7.79 (s, 1H); HRMS (ESI)
m/z C19H22N3O2S [M+H]+ calcd: 356.1427. Found: 356.1415. Anal.
Calcd for C19H21N3O2: C, 64.20; H, 5.95; N, 11.82; S, 9.02. Found:
C, 64.04; H, 6.02; N, 11.70; S, 8.93.
umn: 250 ꢀ 4.6 mm CHIRALPAKÒ AD-H 5
lm; mobile phase: etha-
nol/methanol = 1:1 (v/v) with 0.1% of diethylamine; flow rate:
1 ml/min; 35 °C, detection at 243 nm): RT [(9R)-enantiomer] =
3.7 min/0.3 area-%, RT [(9S)-enantiomer] = 4.4 min/98.1 area-%,
99.3% ee; 1H NMR (DMSO-d6, 200 MHz): d = 2.04 (mc, 1H), 2.25,
2.30, 2.35, 2.39 (s, mc, 2s, 10H) 2.56 (mc), 2.85, 2.91, 3.02 (mc, 2s,
7H), 5.37 (d, 1H), 7.28 (mc, 3H), 7.47 (mc, 1H), 7.79 (s, 1H); HRMS
(ESI) m/z C22H26N3O2 [M+H]+ calcd: 364.2020. Found: 364.2009.
Anal. Calcd for C22H25N3O2: C, 72.70; H, 6.93; N, 11.56. Found: C,
72.39; H, 7.16; N, 11.05.
4.26. (9S)-9-(4-Fluorophenyl)-2,3-dimethyl-7H-8,9-dihydro-
pyrano[2,3-c]-imidazo[1,2-a]pyridine-6-carboxylic acid
dimethylamide 54
Acknowledgements
We are grateful to Mr. V. Horn and Mrs. T. Ramisch of Nycomed,
Konstanz, for the determination of the enantiomeric excess of the
intermediates and target compounds. We thank Mr. B. Grobbel
(Nycomed, Konstanz), Dr. N. Caplan and Dr. L. Jafarpour (both of
Johnson Matthey, Cambridge) for technical assistance and Mr. Ian
Briggs of Johnson Matthey, Technology Centre, Sonning, UK, for
ruthenium analysis.
In
a flame-dried flask filled with argon, diol 46 (1.20 g,
3.1 mmol, 98.6% ee) was suspended in dry THF (18 ml). After the
addition of triphenylphosphine (1.22 g, 4.7 mmol) and the drop-
wise addition of DIAD (0.95 g, 4.7 mmol) a dark-green solution
was obtained which was stirred for 30 min at room temperature.
More triphenylphosphine (0.39 g, 1.5 mmol) and DIAD (0.30 g,
1.5 mmol) were added and stirring was continued for 15 min.
The reaction solution was concentrated under reduced pressure
and the crude product (5 g) was purified by column chromatogra-
phy [70 g of silica gel, eluant: dichloromethane/methanol = 100:1
(v/v)]. Evaporation of the corresponding fractions furnished a green
solid (1 g), which was suspended in acetone (1 ml) and diethyl
ether (15 ml). The precipitate was removed by filtration, washed
with diethyl ether and dried in vacuo. The title compound was iso-
lated in 48% yield (0.55 g of a colourless solid). The mother liquor
was concentrated and the obtained residue (400 mg) was purified
by column chromatography [15 g of silica gel, eluant: ethyl acetate,
then ethyl acetate/methanol = 10:1 (v/v)] and subsequent washing
with diethyl ether (5 ml). This yielded another 130 mg of the title
compound (60% overall yield, 98.2–98.4% ee). mp 258–260 °C;
determination of the enantiomeric excess by HPLC (column:
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