Synthesis of imidazole based p38 MAP (mitogen-activated protein) kinase inhibitors under buffered conditions

Article abstract of DOI:10.1021/op060042t

This article describes chemistry that was developed to give access to multigram quantities of imidazole 479754 and several related analogues for Eli Lilly's p38 MAPK program targeting therapies to address inflammation. The molecules of interest have an is

Full text of DOI:10.1021/op060042t

Organic Process Research & Development 2006, 10, 556−560
Communication to the Editor
Synthesis of Imidazole Based p38 MAP (Mitogen-Activated Protein) Kinase
Inhibitors under Buffered Conditions
Nicholas A. Magnus,* William D. Diseroad, C. Richard Nevill, Jr., and James P. Wepsiec
Eli Lilly and Company, Chemical Product Research and DeVelopment DiVision, Indianapolis, Indiana 46285, U.S.A.
Abstract:
Results and Discussion
This article describes chemistry that was developed to give
access to multigram quantities of imidazole 479754 and several
related analogues for Eli Lilly’s p38 MAPK program targeting
therapies to address inflammation. The molecules of interest
have an isopropyl sulfonyl group present on the 2-aminobenz-
imidazole heterocycyle that was found to be labile when heated
in polar solvents and/or exposed to high or low pH. Due to this
instability issue, the syntheses of the target molecules required
optimizing Sonogashira reaction conditions, employing a buff-
ered oxidative method to produce r-diones, developing buffered
reaction conditions to generate imidazoles, and developing final
recrystallization conditions.
The imidazole 479754 had been prepared previously using
the chemistry illustrated in Scheme 1.2 The molecules 4, 6,
and 479754 in Scheme 1 contain isopropyl sulfonyl groups
that are labile if exposed to acid, base, and/or heat in polar
solvents such as DMSO or AcOH.
The Scheme 1 synthesis of imidazole 479754 presented
a few issues: (1) the expense of preparing the silyl-protected
Weinreb amide 3; (2) the Grignard chemistry gave about a
60% yield of the desired ketone 6 with 4 and des-iodo 4 as
the major impurities; (3) the oxidative imidazole formation
was plagued with competitive loss of the isopropyl sulfonyl
group to give 8, oxazole formation to give 9, and a
challenging purification by chromatography due to persistent
copper salts and poor separations. These issues motivated
us to develop alternative chemistry for the synthesis of
imidazole 479754.
Introduction
The inhibition of p38 MAP kinase has been targeted for
its potential therapeutic benefits with respect to inflamma-
tion.1 A series of compounds based upon a substituted
2-aminobenzimidazole showed promise as inhibitors of p38
MAP kinase thereby requiring the preparation of larger
quantities of both intermediates and final compounds.2
Imidazole 479754 was the lead molecule from the 2-amino-
benzimidazole series of compounds and was therefore our
initial focus. The technology we developed for the synthesis
of 479754 was also applied towards the synthesis of a series
of analogues needed on a multigram scale.
The hydroarylation/Sonogashira type chemistry described
by Mitchell et al. (Scheme 2) demonstrated that aryl iodide
4 is proficient in Sonogashira couplings.3
This led us to propose the retrosynthetic plan illustrated
in Scheme 3 for the synthesis of imidazole 479754. Phenyl-
acetylene 12 would serve as an inexpensive surrogate for
the Weinreb amide 3 (in the Scheme 1 synthesis), and
oxidation of the alkyne 13 to the R-dione 14 would give the
correct oxidation state for the imidazole preparation and
perhaps avoid the purification issues that the previously
mentioned copper salt chemistry had presented.
The Sonogashira reaction described by Mitchell (Scheme
2) involved dissolving aryl iodide 4 in DMSO at 23 °C,
adding catalytic Pd(PPh3)2(OAc)2 (bis(triphenylphosphine)
palladium(II) acetate), catalytic copper(I) iodide, and excess
triethylamine, followed by the addition of an excess of alkyne
10. After the reaction was deemed complete, solids were
precipitated from the reaction mixture by adding water. The
resulting crude solids were purified by slurrying in toluene,
followed by recrystallization from EtOAc.
We made only minor modifications to the aforementioned
Sonogashira reaction conditions when applying them to the
coupling of aryl iodide 4 and alkyne 12 (Scheme 4). (Note:
the isopropylsulfonyl group of aryl iodide 4 is thermally
* To whom correspondence should be addressed. E-mail: magnus_nicholas@
lilly.com.
(1) (a) Chakravarty, S.; Dugar, S. Inhibitors of p38a MAP Kinase. Ann. Rep.
Med. Chem. 2002, 37, 177. (b) Adams, J. L.; Badger, A. M.; Kumar, S.;
Lee, J. C. p38 Kinase: Molecular target for the inhibition of proinflammatory
cytokines. Prog. Med. Chem. 2001, 38, 1.
(2) de Dios, A.; Shih, C.; de Uralde, B. L.; Sa´nchez, C.; del Prado, M.; Cabrejas,
L. M. M.; Pleite, S.; Blanco-Urgoiti, J.; Lorite, M. C.; Nevill, R. C., Jr.;
Bonjouklian, R.; York, J.; Vieth, M.; Wang, Y.; Magnus, N. A.; Campbell,
R. M.; Anderson, B. D.; McCann, D. J.; Giera, D. D.; Lee, P. A.; Schultz,
R. M.; Li, L. C.; Johnson, L. M.; Wolos, J. A. J. Med. Chem. 2005, 48,
2270 and references therein.
(3) Hay, L. A.; Koenig, T. M.; Ginah, F. O.; Copp, J. D.; Mitchell, D. J. Org.
Chem. 1998, 63, 5050.
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10.1021/op060042t CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/15/2006

Scheme 1
Scheme 2
Scheme 3
Scheme 4
labile in DMSO, so the reagents were combined at 23 °C
and allowed to exotherm to 35 °C, but not physically heated
as this induced desulfonylation.) We examined reducing the
palladium catalyst load, as well as the equivalents of
phenylacetylene 12. The Pd(PPh3)2(OAc)2 charge was ex-
amined at the 1.0 mol % level (based on aryl iodide 4) and
was found to be too unreactive, with roughly a quarter of
the starting aryl iodide 4 remaining after an “overnight”
reaction. Eventually, 4.0 mol % of Pd(PPh3)2(OAc)2 was
found to give a complete reaction within 15 h. We also
reduced the charge of phenylacetylene 12 from the prescribed
3.5 equiv to 1.5 equiv. A fortunate observation was made in
the water addition after reaction completion. It was observed
that an initial portion of water caused a very fine dark
precipitate to form, which was filtered off and found to be
primarily catalyst. The resulting clarified filtrate was sub-
sequently treated with a further portion of water to induce
the alkyne 13 to precipitate in 86% yield. One impurity
typically remained with the alkyne 13, which was the dimer
of phenylacetylene 12. However, the dimer did not adversely
affect the subsequent chemistry. If a higher quality of alkyne
13 was required, it could be purified further by slurrying
the solids in hot toluene.
The alkyne 13 was oxidized to the R-dione 14 by
treatment with KMnO4 in buffered media.4 Other protocols
for this transformation, I2/DMSO/heat5 and PdCl2/DMSO/
(4) Khan, N. A.; Newman, M. S. J. Org. Chem. 1952, 17, 1063.
Vol. 10, No. 3, 2006 / Organic Process Research & Development
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557

heat,6 required heating in polar solvent which resulted in
significant to complete loss of the isopropylsulfonyl group.
We settled on reaction conditions described by Lee et al.,
which involved aqueous acetone with NaHCO3 and MgSO4
as a buffer mixture (initially pH 7.0 to 7.5) and KMnO4 as
the oxidant.7 The buffer mixture serves to neutralize hy-
droxide ions produced during the reduction of permanganate.
If the NaHCO3 was excessive with pH g 7.8 this would
result in oxidation of the solvent as well as lower yields of
the R-dione 14. The changes we made to the Lee procedure
were to reduce the volume (i.e., increase the throughput) and
modify the workup. The NaHCO3 and MgSO4 were dissolved
in water, and acetone was added causing the mixture to
become cloudy. The alkyne 13 was added to the reaction
mixture to give a slurry (∼30 °C), and KMnO4 was added
giving an exotherm to 40 °C. The reaction was typically
complete, if run at 40 °C, within 2 h. The reaction was clean,
but the workup was messy! The workup involved adding
EtOAc to the reaction mixture, followed by Na2SO3 and
aqueous sulfuric acid to reduce the unreacted KMnO4 and
give a phase separation. The organic phase was concentrated,
and after solvent removal, the R-dione 14 was obtained as a
yellow solid in 83% yield.
The conversion of R-diones into imidazoles is classically
conducted in aqueous or alcoholic ammonia with an aldehyde
present.8 There are also numerous examples of this reaction
type employing ammonium acetate in acetic acid.9 These
reaction types were investigated for the preparation of
imidazole 479754 and were found to induce considerable to
complete loss of the isopropylsulfonyl group. The use of
ammonium acetate in alcohols to affect the condensation of
ammonia, aldehyde 7, and R-dione 14 to give imidazole
479754 is a variation of the previously mentioned reaction
conditions that gave a form of buffering which retarded the
loss of the ispropylsulfonyl group. Indeed, it was found that
R-dione 14 could be converted into imidazole 479754
productively by reaction with 2,6-difluorobenzaldehyde 7 and
ammonium acetate, in MeOH, EtOH, IPA, or n-BuOH at or
below 55 °C (higher temperatures gave more desulfonyl-
ation). The eventual reaction that was developed to prepare
multigram quantities of imidazole 479754 employed n-BuOH
as the reaction solvent, due to improved workup character-
istics (i.e., n-BuOH facilitates phase separation from water).
The R-dione 14 was combined with ammonium acetate,
n-BuOH, and 2,6-difluorobenzaldehyde 7, and the resulting
slurry was heated to 55 °C and held at that temperature for
24 h to give an almost homogeneous mixture (some
ammonium acetate remained out of solution). The workup
consisted of removing salts from the reaction mixture with
water washes and concentrating the resulting organic phase
to an oil. The oil was taken up in MeOH and diluted with
MTBE to induce crystallization of the product, imidazole
479754. The crystals were filtered, washed with MTBE, and
dried to give imidazole 479754 that was contaminated with
<2 area% of the desulfonylated product 8 and <1 area% of
R-dione 14 by HPLC and percent levels of MTBE and
1
MeOH by H NMR. The crude imidazole 479754 was
dissolved in EtOAc, slurried with silica gel, and filtered
through a pad of silica gel to remove the desulfonylated
product 8 (Scheme 1), and afforded imidazole 479754 in
78% yield with >99 area% purity with R-dione 14 and
EtOAc as the only minor contaminants after solvent removal.
A large effort was put into selecting an appropriate salt
form of imidazole 479754 (see Experimental Section for the
preparation of the 479754 bis-mesylate salt). However, salts
of 479754 were found to be unstable during stability testing,
with considerable loss of the isopropylsulfonyl group. The
imidazole 479754 salt instability issues directed us towards
a free base form of the drug candidate. Eventually, the EtOH
solvated form of imidazole 479754 was discovered and
developed. The imidazole 479754 EtOH solvate has excellent
purity and stability and is a very tightly held solvate that
does not release the EtOH until it is melted. The solid
imidazole 479754 containing EtOAc that was produced from
the silica gel treatment was dissolved in EtOH, and the
solvent distilled off to remove the residual EtOAc. This was
done because EtOAc at low concentrations in EtOH would
preferentially solvate with imidazole 479754 over EtOH. This
protocol gave crystalline EtOH solvated imidazole 479754,
which was suspended in EtOH, and the resulting slurry was
brought to 55 °C momentarily and allowed to cool slowly
to 23 °C. This procedure gave imidazole 479754 EtOH
solvate in 84% yield (the mother liquor contained high
quality imidazole 479754 that was recovered).
The p38 MAPK program also required several other
analogues of 479754 be prepared on a multigram scale (Table
1). Aryl iodide 4 gave access to these analogues via the
chemistry utilized for the preparation of 479754 (Scheme
5). We found that the Songashira coupling of aryl iodide 4
with 2,4-difluorophenylacetylene could be run in neat
triethylamine without added CuI and with a catalyst loading
as low as 1.5 mol % of Pd(PPh3)2(OAc)2. The procedures
for the preparation of these analogues can be found in the
Supporting Information.
Conclusion
In conclusion, we developed chemistry that gave access
to multigram quantities of imidazole 479754 and several
related analogues for Eli Lilly’s p38 MAPK program. This
was accomplished by optimizing Sonogashira reaction condi-
tions, employing a buffered oxidative method to produce the
requisite R-diones, developing buffered reaction conditions
to generate imidazoles 479754 and related analogues, and
final recrystallization conditions.
(5) Yusybov, M. S.; Filimonov, V. D. Synthesis, 1991, 131.
(6) Chi, K. W.; Yusubov, M. S.; Filimonov, V. D. Synth. Commun. 1994, 24,
2119.
(7) Srinivasan, N. S.; Lee, D. G. J. Org. Chem. 1979, 44, 1574.
(8) Radziszewski, B. Ber. 1882, 15, 1493.
Experimental Section
(9) Japp and Wilson, J. Chem. Soc. 1886, 49, 825, recommended fused
ammonium acetate as more convenient than alcoholic ammonia. Davidson,
D.; Weiss, M.; Jelling, M. J. Org. Chem. 1937, 2, 319. Cook, A. H.; Jones,
D. J. J. Chem. Soc. 1941, 278.
Useful HPLC Method To Analyze Reactions for
Preparing 479754. Column: Zorbax SB-C8, 4.6 mm × 250
mm, 5 micron. UV ) 218 nm. Buffer: 1 L water + 1 mL
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Table 1
washed with 4 L of water. The solids were dried at 60 °C
under a vacuum to constant weight. The yield of alkyne 13
was 319 g (86%) of a light yellow granular solid. Mp
(recrystallized from toluene) 226.8 to 229.2 °C. IR (ATR)
3439, 3081, 1654, 1553 cm-1. 1H NMR (300 MHz, DMSO-
d6) δ 1.26 (6H, d, J ) 6.9 Hz), 3.92 (1H, sep, J ) 6.9 Hz),
7.14 (2H, bs), 7.22 (1H, d, J ) 7.9 Hz), 7.32-7.41 (4H, m),
7.49-7.57 (2H, m), 7.58 (1H, s). 13C NMR (126 MHz,
DMSO-d6) δ 16.3, 56.2, 88.6, 91.0, 114.3, 115.3, 116.8,
123.4, 129.0, 129.1, 129.4, 131.9, 133.1, 143.7, 154.6. MS
(ES+) calcd for (M + H)+, 339.4; found, 340.2, 234.3. MS
(ES-) calcd for (M - H)-, 339.4; found, 338.3, 232.4.
1-[2-Amino-3-(propane-2-sulfonyl)-3H-benzoimidazol-
5-yl]-2-phenyl-ethane-1,2-dione (14). Water (4 L), NaHCO3
(30 g, 0.357 mol), and MgSO4 (145 g, 1.205 mol) were
combined at 20 to 25 °C and stirred until homogeneous
(exotherm to 30.5 °C). Acetone (4 L) was added to the
reaction giving a cloudy mixture, followed by alkyne 13 (200
g, 0.590 mol). The resulting slurry was treated with KMnO4
(360 g, 2.278 mol) giving a gradual exotherm to 40 °C over
1 h. After an additional 1 h (35 °C), an aliquot of reaction
mixture was diluted with CH3CN for HPLC analysis. The
HPLC chromatogram indicated complete consumption of the
alkyne 13 with clean production of a slightly more polar
product. Na2SO3 (400 g) was added to the reaction mixture,
followed by EtOAc (3 L). 20% H2SO4 in water (300 mL)
was added to the reaction mixture over 25 min (temperature
range 30 to 40 °C, large amount of solid MnO2 produced).
The phases were allowed to separate, and an aliquot of the
top organic phase was collected for HPLC analysis (HPLC
chromatogram indicated clean product). The organic phase
was separated and clarified by filtration through Celite. The
aqueous phase (black and thick) was back extracted with
EtOAc (2 L), and the resulting organic phase was clarified
by filtration through Celite. EtOAc (1 L) was used to rinse
the Celite. The organic phases were combined and concen-
trated (7 L removed) at 40 °C under vacuum causing two
phases to form. EtOAc (2 L) was added to the mixture,
followed by water (0.5 L) and NaCl (30 g). The layers were
separated, and the aqueous phase was back extracted with
EtOAc (0.5 L). The organic phases were combined and dried
with MgSO4, and EtOAc (2 L) was used to wash the MgSO4.
The solvent was removed under a vacuum at 40 °C to give
compound R1 R2
R3
salt
yielda (%)
18
19
20
21
22
23
24
25
26
H
H
H
H
F
H
H
F
H
H
H
H
F
H
H
F
4-Cl-phenyl
2-CF3-phenyl
2-Cl-6-F-phenyl
2-F-6-CF3-phenyl MsOH
2-Cl-6-F-phenyl
i-propyl
MsOH
none
MsOH
58
61
24
58
68
46
50
76
63
MsOH
MsOH
none
MsOH
2MsOH
c-hexyl
t-butyl
t-butyl
H
H
a yield is calculated from the corresponding starting R-dione.
of 85% H3PO4 (pH ∼2.3). Gradient: T ) 0 min. 5% CH3CN
95% buffer, T ) 10 min. 80% CH3CN 50% buffer, T ) 15
min. 95% CH3CN 5% buffer, T ) 20 min. 95% CH3CN 5%
buffer, post-time ) 3 min. 5% CH3CN 95% buffer. Flow
rate 1.5 mL/min. Oven temp 40 °C. Retention times: aryl
iodide 4 ∼8.4 min, alkyne 13 ∼10.7 min, R-dione 14 ∼9.9
min, 479754 ∼7.1 min, imidazole 8 ∼5.1 min.
6-Phenylethynyl-1-(propane-2-sulfonyl)-1H-benzoimid-
azol-2-ylamine (13). Under a nitrogen atmosphere, aryl
iodide 4 (400 g, 1.095 mol), bis(triphenylphosphine) palla-
dium(II) acetate (32.8 g, 0.044 mol), and CuI (41.7 g, 0.219
mol) were combined, followed by DMSO (8.4 L) and
triethylamine (317 g, 3.133 mol). The resulting mixture was
stirred at 20 to 25 °C for 15 min, and phenylacetylene 12
(168 g, 1.645 mol) was added over 30 min giving a
temperature rise to 35 °C. The reaction cooled slowly to 20
to 25 °C, and after 15 h, an aliquot of the reaction was
quenched into water and diluted with CH3CN for HPLC
analysis. The HPLC chromatogram indicated complete
consumption of the aryl iodide 4 with the production of two
new less polar products (desired alkyne 13 and phenyl-
acetylene dimer). Water (4 L) was added to the reaction over
1 h giving a temperature rise to 40 °C and a dark precipitate
(mainly catalyst). The reaction was filtered through a thin
layer of Celite (24 cm diameter) with no washing of the
catalyst waste cake. The filtrate was returned to the reactor,
and an additional 4 L of water were added over 1 h giving
an ending temperature of 45 °C and a yellow slurry. The
mixture was left to cool overnight to 20 to 25 °C with
stirring. The solids were collected by vacuum filtration and
Scheme 5
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559

189 g of yellow solids. The solids were dried under a vacuum
at 60 °C to constant weight to give a final weight of 182 g
(83% yield, 14 could be further purified by slurrying in hot
IPA or concentrating the final EtOAc phase and letting the
R-dione 14 crystallize with excellent purity but poor recov-
ery). Mp (recrystallized from IPA) 172.8 °C. IR (ATR) 3469,
sulfonylated 479754 and was a precaution to remove metals
from earlier in the synthesis.
Preparation of 479754-EtOH solvate: 479754 (395 g)
was dissolved in EtOH (2 L) at 53 °C and vacuum distilled
to dryness (this procedure was repeated to remove residual
EtOAc from the 479754; confirmed by 1HNMR). The
resulting solids were slurried in EtOH (1.185 L) at 50 °C
for a few minutes and slowly cooled to 22 °C overnight.
The resulting slurry was cooled to -3 to 0 °C and held for
1 h. The crystals produced were filtered, washed with EtOH
(395 mL, 0 °C), and dried under a vacuum at 50 °C to
constant weight. 479754 EtOH solvate (324 g, 84%) was
isolated as a light pinkish solid. HPLC indicated the product
1
3440, 3065, 1678, 1668, 1646, 1598, 1539 cm-1. H NMR
(500 MHz, DMSO-d6) δ 1.27 (6H, d, J ) 6.8 Hz), 3.94 (1H,
sep, J ) 6.8 Hz), 7.33 (1H, d, J ) 8.8 Hz), 7.59-7.65 (5H,
m), 7.77 (1H, dd, J ) 1.5, 7.3 Hz), 7.97 (2H, dd, J ) 1.5,
8.3 Hz), 8.04 (1H, d, J ) 1.5 Hz). 13C NMR (100 MHz,
DMSO-d6) δ 15.4, 55.8, 111.9, 115.6, 124.2, 128.0, 129.2,
129.3, 131.8, 132.4, 135.1, 149.1, 155.8, 193.2, 195.0. MS
(ES+) calcd for (M + H)+, 371.4; found, 372.2. MS (ES-)
calcd for (M - H)-, 371.4; found, 370.3.
1
to be 99.5 area% pure, and H NMR confirmed a 1 to 1
ratio of 479754 to EtOH. Mp (DSC) (5 °C/min; peak melt
ambiguous, large shoulder) onset 128.18 °C, maximum
147.55 °C. IR (ATR) 3452, 2970, 1665, 1554 cm-1. 1H NMR
(300 MHz, DMSO-d6; EtOH omitted) δ 1.16 (3H, d, J )
5.27 Hz), 1.18 (3H, d, J ) 5.27 Hz), 3.50-3.75 (1H, m),
6.89 (1H, s), 7.01 (1H, s), 7.12-7.56 (11H, m), 12.74 (1H,
s). 13C NMR (75 MHz, methanol-d4) δ 16.1, 56.9, 110.0 (t,
J ) 18.5 Hz), 113.0 (dd, J ) 18.1, 7.3 Hz), 113.4, 117.0,
126.2, 127.1, 128.6, 129.5, 129.7, 132.3, 132.7 (t, J ) 10.4
Hz), 133.8, 136.7, 142.3, 155.3, 162.2 (dd, J ) 251.3, 8.0
Hz). MS (ES+) calcd for 493.5 (M + H)+, found 494.2.
MS (ES-) calcd for 493.5 (M - H)-, found 492.3. Metals
analysis: Mn nondetect and Pd < 10 ppm.
Preparation of 479754 Bismesylate salt. 479754 (428
mg, 0.87 mmol) was dissolved in EtOH/EtOAc (1:2, 8.56
mL) at 23 °C giving a yellow homogeneous solution.
Methanesulfonic acid (113 uL, 1.73 mmol) was added to
the reaction mixture, which removed the yellow color and
gave a temperature rise to 27 °C. After a few minutes,
nucleation was apparent. After 3 h at 23 °C, the crystals were
filtered and washed with EtOAc (10 mL). The white crystals
(540 mg, 90%, HPLC 100 area%) were dried under a vacuum
at 65 °C. 1H NMR indicated EtOAc inclusion that could not
be removed by drying. Mp (DSC) (5 °C/min) onset 165.68
°C, maximum 172.01 °C.
6-[2-(2,6-Difluoro-phenyl)-5-phenyl-1H-imidazol-4-yl]-
1-(propane-2-sulfonyl)-1H-benzoimidazol-2-ylamine
(479754). Under a nitrogen atmosphere, R-dione 14 (225
g, 0.606 mol), NH4OAc (700.4 g, 9.08 mol), n-BuOH (4.5
L), and 2,6-diflurorobenzaldehyde 7 (172.2 g, 1.212 mol)
were combined. The resulting mixture was heated to 55 °C
to give a yellow slurry. After 24 h, the reaction was almost
homogeneous, and an aliquot of the reaction was removed
for HPLC analysis (2.6 area% R-dione 14, 88.4 area%
479754, 8.8 area% desulfonylated 479754). The reaction
mixture was cooled to 15 °C, and water (2.5 L) was added.
After mixing for 15 min, the layers were separated, and the
organic phase was back extracted with water (2.5 L). The
organic phase was separated and concentrated under a
vacuum at 55 °C to give 513 g of a black oil. The oil was
dissolved in MeOH (505 mL) at 50 °C, and MTBE (2.25 L)
was added to the mixture over 1.5 h (crystals had begun
forming after the first liter of MTBE was added). The
resulting slurry was cooled slowly to 22 °C and stirred
overnight. The light brown solids were filtered and washed
with MTBE (750 mL). House vacuum was pulled on the
solids for 1.5 h to give 239 g of solid (DSC onset 106.65
°C, maximum 116.79 °C, 18.67 J/g). The solids were
dissolved in EtOAc (3.85 L) at 50 °C, and silica gel (250 g)
was added to the mixture. After 0.5 h, the mixture was
allowed to cool to 35 °C, vacuum filtered over silica gel
(250 g wet with EtOAc), and rinsed through with EtOAc (6
L). The resulting mixture was concentrated under a vacuum
at 50 °C to give a light brown solid (233.6 g, 78%; HPLC
Supporting Information Available
Synthetic procedures and characterization for compounds
16-26. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
Received for review February 23, 2006.
OP060042T
>99 area% 479754; H NMR indicates EtOAc included in
the solid). Note: the silica gel treatment removed de-
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