Preparation of 5-(2-methoxy-4-nitrophenyl)oxazole: A key intermediate for the construction of VX-497

Article abstract of DOI:10.1021/op025546f

A process for the multigram preparation of 5-(2-methoxy-4-nitrophenyl)oxazole, a key intermediate for the preparation of the hepatitis C drug candidate VX-497 (merimepodib), has been achieved in good yield from a commercially available dye. Early studies focused on the preparation of the requisite aldehyde by the Beech reaction. A second approach utilized a palladium (0)-catalyzed formylation of an aryl diazonium species, which was followed by condensation of the aldehyde with tosylmethyl isocyanide (TosMIC) to provide the required oxazole. This two-step method has been carried out to provide multigram samples of this key intermediate in 75% overall yield and >95% purity from the commercially available Fast Red B tetrafluoroborate salt.

Full text of DOI:10.1021/op025546f

Organic Process Research & Development 2002, 6, 677−681
Preparation of 5-(2-Methoxy-4-nitrophenyl)oxazole: A Key Intermediate for the
Construction of VX-497
R. Jason Herr,*,† David J. Fairfax,† Harold Meckler,† and Jeffrey D. Wilson‡
Chemical DeVelopment Department, Albany Molecular Research, Incorporated., P.O. Box 15098,
Albany, New York 12212-5098, U.S.A., and Chemical DeVelopment Department, Vertex Pharmaceuticals Incorporated,
130 WaVerly Street, Cambridge, Massachusetts 02139, U.S.A.
Abstract:
formylation of the aryl diazonium species using Kikuwawa’s
method.5 Condensation of the resulting aldehyde with
TosMIC completed the assembly of 3 in 75% yield and
>95% purity (by HPLC analysis) for the two-step procedure.
A process for the multigram preparation of 5-(2-methoxy-4-
nitrophenyl)oxazole, a key intermediate for the preparation of
the hepatitis C drug candidate VX-497 (merimepodib), has been
achieved in good yield from a commercially available dye. Early
studies focused on the preparation of the requisite aldehyde
by the Beech reaction. A second approach utilized a palladium
(0)-catalyzed formylation of an aryl diazonium species, which
was followed by condensation of the aldehyde with tosylmethyl
isocyanide (TosMIC) to provide the required oxazole. This two-
step method has been carried out to provide multigram samples
of this key intermediate in 75% overall yield and >95% purity
from the commercially available Fast Red B tetrafluoroborate
salt.
Results and Discussion
The Beech Reaction and Related Work. The initial
research efforts centered around the synthesis of the oxazole
1 via aromatic oxime 6, obtained by a modification of the
Beech reaction (Scheme 1).3 In this method, aryl diazonium
intermediate 5, generated from commercially available
2-methoxy-4-nitroaniline (4),6 was decomposed with a copper
sulfate/sodium sulfite catalyst in the presence of formal-
doxime to produce the aryl oxime 6. Since aryl diazonium
species of many salt forms can be prepared from anilines
by a variety of literature methods,7 it was decided that aniline
4 would serve as a suitable starting material for the
exploration of this synthetic route. It was even more
fortuitous to find that a few appropriately substituted,
commercially available diazonium compounds 5 were offered
as technical-grade Fast Red B salts.8 Oxime 6 was anticipated
to be easily hydrolyzed to aromatic aldehyde 8, a precursor
in the Vertex synthesis of the corresponding oxazole 1, as
has been reported in the patent literature.2
An existing procedure for the synthesis of an isomeric
aldehyde, published by Woodward,4 describes the diazoti-
zation and oxime formation from the corresponding aniline.
The resulting oxime was then hydrolyzed with acid and
steam-distilled to obtain the corresponding aldehyde in 63%
yield.9 It was found that our aniline 4 was indeed converted
to the desired intermediate oxime 6, albeit in 24% yield and
in 88.5% purity (by HPLC analysis) for the 200-g scale
transformation. Additionally, it was found that the com-
mercially available diazonium salts 5, marketed as dyes under
Introduction
Recently a program was carried out to develop a synthetic
route for the multigram scale preparation of the hepatitis C
drug candidate VX-497 (3, merimepodib), which is currently
in phase II clinical research trials for the selective inhibition
of inosine monophosphate dehydrogenase (IMPDH).1 Our
process research efforts were directed toward the preparation
of 5-(2-methoxy-4-nitrophenyl)oxazole (1), which was orig-
inally reduced and coupled with aniline 2 in a convergent
synthesis of 3 (Figure 1).2 Our first synthetic approach to 1
involved the copper-catalyzed coupling of an aryl diazonium
species with formaldoxime, a variant of the Beech reaction3
that was highlighted as one key step in Woodward’s synthesis
of reserpine.4 Disappointing yields and purities on scale-up
led to a second-generation tactic in which the requisite
aldehyde was directly prepared by a palladium (0)-catalyzed
* To whom correspondence should be addressed. E-mail: rjasonh@
albmolecular.com.
† Albany Molecular Research, Incorporated.
(5) Kikuwawa, K.; Totoki, T.; Wada, F.; Matsuda, T. J. Organomet. Chem.
1984, 270, 283.
‡ Vertex Pharmaceuticals Incorporated.
(1) (a) Sorbera, L. A.; Silvestre, J. S.; Castan˜er, L. M. Drugs Future 2000, 25,
809. (b) Jain, J.; Almquist, S. J.; Shlyakhter, D.; Harding, M. W. J. Pharm.
Sci. 2001, 90, 625.
(6) (a) Rowe, F. M.; Cross, E. J. J. Chem. Soc. 1947, 461. (b) Spande, T. F.;
Glenner, G. G. J. Am. Chem. Soc. 1973, 95, 3400.
(7) (a) Colas, C.; Goeldner, M. Eur. J. Org. Chem. 1999, 1357. (b) Kloc, K.;
Mlochowski, J.; Mhizha, S. Synth. Commun. 1997, 27, 4049. (c) Dmowski,
W.; Piasecka-Maciejewska, K. Org. Prep. Proced. Int. 1992, 24, 194. (d)
Braish, T. F.; Fox, D. F. Org. Prep. Proced. Int. 1991, 23, 655. (e) Cleland,
G. H. Org. Synth. 1971, 51, 1. (f) Roe, A. In Organic Reactions; Adams,
R., Ed.; Wiley: New York, 1949; Vol. 5, p 194.
(8) At the present time, Fast Red B salts are also offered in 1,5-naphthalene-
disulfonate and diacetate salt forms that were not available at the time this
research was performed.
(2) (a) Armistead, D. M.; Badia, M. C.; Bemis, G. W.; Bethiel, R. S.; Frank,
C. A.; Novak, P. M.; Ronkin, S. M.; Saunders, J. O. (Vertex Pharmaceu-
ticals, Inc.). U.S. Patent 6,344,465, 2002. (b) Armistead, D. M.; Badia, M.
C.; Bemis, G. W.; Bethiel, R. S.; Frank, C. A.; Novak, P. M.; Ronkin, S.
M.; Saunders, J. O. (Vertex Pharmaceuticals, Inc.). U.S. Patent 6,054,472,
2000. (c) Armistead, D. M.; Badia, M. C.; Bemis, G. W.; Bethiel, R. S.;
Frank, C. A.; Novak, P. M.; Ronkin, S. M.; Saunders, J. O. (Vertex
Pharmaceuticals, Inc.), U.S. Patent 5,807,876, 1998.
(3) Beech, W. F. J. Chem. Soc. 1954, 1297.
(4) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W.
Tetrahedron 1958, 2, 1.
(9) The Beech reaction on a related system provided the aryl aldehyde in 35-
45% yield: Jolad, S. D.; Rajagopal, S. Organic Syntheses; Wiley & Sons:
New York, 1973; Collect. Vol. 5, p 139.
10.1021/op025546f CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/25/2002
Vol. 6, No. 5, 2002 / Organic Process Research & Development
•
677

Figure 1. Original synthetic approach to VX-497.
Scheme 1. Beech reaction and hydrolysis strategy
the trade name of Fast Red B salts, would also undergo the
transformation to 6 in comparable, best yields of 32% (for
the hemi-zinc chloride salt,10 150-g scale) and 31% (for the
tetrafluoroborate salt,11 25-g scale). In each case, an aqueous
solution of the aryl diazonium intermediate 5 was adjusted
to pH 5-6 with sodium acetate in water and the resulting
suspension added slowly to a solution of formaldoxime
(preformed from hydroxylamine hydrochloride and paraform-
aldehyde) and the critical copper sulfate/sodium sulfite
catalyst in water. Since this reaction also produced a
significant amount (10-40%) of the reduced 3-nitroanisole
byproduct, the workup conditions were modified. The
reaction mixture was extracted into aqueous sodium hydrox-
ide solution (oxime 6 was soluble in aqueous base), clarified
with decolorizing charcoal and acidified with concentrated
hydrochloric acid to afford oxime 6 as a tan powder in 98.7%
purity (by HPLC analysis).
To our surprise intermediate oxime 6 was found to be
resistant to hydrolysis by the literature procedures with
aqueous sodium metabisulfite,4,9 even after a series of
cosolvent mixtures and higher-temperature reaction condi-
tions to improve solubility was investigated. Hydrolysis of
aromatic oxime 6 to the corresponding aldehyde 8 was finally
achieved by formation of the bisulfite adduct 7 of the oxime
with sodium bisulfite, followed by acid hydrolysis to 8 using
the method of Pines and co-workers (Scheme 1).12 Thus, a
mixture of oxime 6 and sodium bisulfite in ethanol/water
(1:1) was heated at reflux for 1 h to provide the soluble
bisulfite adduct 7. The ethanol was removed under reduced
pressure, and the resulting orange suspension was acidified
with 2 N hydrochloric acid solution. This resulting solution
was diluted with methyl tert-butyl ether and the biphasic
mixture heated at reflux for 4 h to produce the crude aldehyde
8. Treatment of the aldehyde solution with Panther Creek
200 bentonite clay13 followed by filtration was effective in
providing relatively clean aldehyde 8 in a 37% isolated (best)
yield and in 83.9% purity (by HPLC analysis). It is worth
noting that the purification efficiencies of many bentonite
clays are affected by pH of both organic and aqueous
media,14 and thus, occasionally it is found that a survey of
available bleaching earths in a variety of solvents may
provide a convenient initial improvement in crude product
purity. We were thus gratified to find that this calcium
bentonite support was useful for the slurry purification of 8
in the biphasic aqueous acidic/MTBE solution to an initial
84% purity.14 Unfortunately, adsorption of product onto the
diatomaceous earth was also one likely (but unavoidable)
reason for the low product yield. Low mass recovery was
also due to the inefficient extraction of the product from the
aqueous phase. A few methods to claim further materials
from the acidic aqueous layer were examined (e.g., extraction
with other organic solvents, and at elevated temperatures),
but were not successful at improving product yields.
(13) Originally purchased from American Colloid Company (Arlington Heights,
Il), this material is now available from Rennecker Limited (Cleveland, OH).
(14) (a) Herr, R. J.; Meckler, H.; Scuderi, F., Jr. Org. Process Res. DeV. 2000,
4, 43. (b) See some additional commentary on the use of bentonite clays
in organic purifications: Herr, R. J. Technical Reports, Albany Molecular
Research, Inc., 1997; Vol. 1.; http://www.albmolecular.com/features/tekreps/
vol01/no02/(accessed June 2002).
(10) This technical-grade reagent is available from Sigma as approximately 20%
dye content and was used as received.
(11) This technical grade reagent is available from Aldrich as approximately
95% dye content and was used as received.
(12) (a) Pines, S. H.; Chemerda, J. M.; Kozlowski, M. A. J. Org. Chem. 1966,
31, 3446. (b) Von Pechmann, H. Ber. 1887, 20, 2539.
678
•
Vol. 6, No. 5, 2002 / Organic Process Research & Development

Scheme 2. Palladium-catalyzed formylation route
Formation of the aryl oxazole 1 was carried out in the
manner described by Vertex Pharmaceuticals,2 but with a
modification to the purification method. Thus, a mixture of
aldehyde 8, tosylmethyl isocyanide (TosMIC), and potassium
carbonate was heated at reflux in methanol for 12 h to
produce the crude oxazole. After an aqueous workup, the
residue was dissolved in methylene chloride and treated with
an acidic activated charcoal/Clarion 550 bentonite clay20/
silica gel mixture (1:1:2). After filtration and solvent removal,
oxazole 1 was produced as a yellow solid in 96% yield and
in 96.8% purity (by HPLC analysis).
To maximize the yield of 1, the two-step process was
carried out without purification of intermediate aldehydes
8. The carbonylation reaction was conducted as previously
described, except that methyl tert-butyl ether was substituted
for diethyl ether. The intermediate aldehyde 8 was isolated
by aqueous workup and used directly in the condensation
reaction. The crude reaction mixture was treated with the
charcoal/diatomaceous earth/silica gel mixture to produce the
oxazole 1 as a light orange solid in 85% yield and in >90%
purity (by proton NMR analysis) for the two-step operation.
Although much effort was expended to find conditions to
recrystallize the crude oxazole (to remove 3-nitroanisole
byproduct), no conditions were found that afforded 1 of
greater purity than was obtained by a simple plug filtration
of the material. Thus, this two-step process to provide 8 was
achieved from commercially available Fast Red B tetrafluo-
roborate salt in 75% overall isolated yield and in 97.1%
purity (by HPLC analysis).
Formylation and Oxazole Formation. Due to the
disappointing yield and purity results of the Beech reaction
route, the synthetic efforts were redirected to prepare the
aldehyde 8 directly by a modification of the reported
palladium-catalyzed carbonylation reaction of aryl diazonium
species developed by Kikuwawa (Scheme 2).5 Following the
literature precedent that this particular insertion reaction is
specific to crystalline diazonium salts (particularly for
tetrafluoroborate salt forms), the Fast Red B tetrafluoroborate
salt 5 was reacted with carbon monoxide (50 psi), triethyl-
silane, and 2 mol % of palladium (II) acetate in diethyl ether/
acetonitrile (1:1) at room temperature in a Parr Series 4842
stirred autoclave. After chromatographic purification, this
procedure afforded the desired aryl aldehyde 8 as an orange
solid in 78% isolated yield and >99% purity (by HPLC
analysis). The key feature of this process is that the
carbonylation reaction proceeded at a much lower carbon
monoxide pressure (50 psi versus 80-1200 psi) and a lower
molar catalyst loading (2 mol % versus 5-20 mol %) and
reaction temperature (ambient versus 80-150 °C) than is
reported in the literature for comparable palladium-catalyzed
methods.15-18 It should be noted at this point that the decision
to use the reducing reagent triethylsilane instead of poly-
(methylhydrosiloxane)15 was due to the necessity of HMPA
as a cosolvent in the latter case. Similarly, we decided against
the use of tributyltin hydride as a reducing agent16 due to
issues of toxic tin byproduct removal.
Conclusions
The development of a synthesis for the key intermediate
5-(2-methoxy-4-nitrophenyl)oxazole (1) amenable to mul-
tigram-scale preparation has been achieved in two steps from
a commercially available dye substance in 75% overall yield
and in >95% purity (by HPLC analysis). This compound is
one of two major components for the synthesis of the Vertex
Pharmaceuticals compound VX-497 (3, merimepodib).
Initially the crude formylation product was purified by
flash column chromatography to remove the 5-10% of
3-nitroanisole byproduct, but it was later found that filtration
through a short silica gel plug was useful to quickly provide
8 in >90% purity with no impurities greater than 3% (by
HPLC analysis). It was also found that the amount of the
reduction byproduct was minimized when the triethylsilane
was added in a slow, controlled fashion to the reaction
mixture rather than in one portion. This was achieved by
metering a solution of the reducing reagent in methyl tert-
butyl ether into the pressurized Parr vessel via a Waters
model 510 HPLC pump at a rate of 1.5 mL/min. By control
of the rate of addition, the amount of byproduct was reduced
to <5%, and the 20 °C exotherm produced by the oxidation/
reduction reaction was minimized.19
Experimental Procedures
General. All nonaqueous reactions were performed under
a dry atmosphere of nitrogen. Reagents and anhydrous
solvents were used as received from vendors, and no attempts
were made to purify or dry these components further. Thin-
layer chromatography was performed using 1 in. × 3 in.
Analtech GF 350 silica gel plates with fluorescent indicator.
Visualization of TLC plates was made by observation in
iodine vapors. The proton and carbon magnetic resonance
spectra were obtained on a Bruker AC 300 MHz nuclear
magnetic resonance spectrometer, using tetramethylsilane as
an internal reference. Melting points were obtained using
an electrothermal melting point apparatus and are uncor-
(19) The operation of this process has been described in preliminary form:
Fairfax, D. J.; Zettler, M. W. Technical Reports; Albany Molecular
Research, Inc., 1997; Vol. 1; http://www.albmolecular.com/features/tekreps/
vol01/no06 (accessed June 2002).
(20) Originally purchased from American Colloid Company (Arlington Heights,
IL), the comparable bleaching earth is available from Engelhard Corporation
(Iselin, NJ) as Engelhard F-105.
(15) Pri-Bar, I.; Buchman, O. J. Org. Chem. 1984, 49, 4009.
(16) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452.
(17) Ben-David, Y.; Portnoy, M.; Milstein, D. J. Chem. Soc., Chem. Commun.
1989, 1816.
(18) Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 7761.
Vol. 6, No. 5, 2002 / Organic Process Research & Development
•
679

rected. Infrared spectra were obtained as KBr pellets and
obtained on a Perkin-Elmer Spectrum 1000 FT-infrared
spectrophotometer. CI Mass spectroscopic analyses were
performed on a Shimadzu QP-5000 GC/mass spectrometer
(methane) by direct injection. Combustion analyses were
performed by Quantitative Technologies, Inc. of Whitehouse,
New Jersey. HPLC analyses were performed on a Waters
Symmetry C18 reverse phase column (150 mm × 3.9 mm,
5 µm particle size), mobile phase 5:95 acetonitrile/(0.05%
TFA in water) to 100:0 acetonitrile/(0.05% TFA in water)
over 25 min, flow rate ) 1.0 mL/min, detector at 254 nm,
column temperature ambient.
Preparation of 2-Methoxy-4-nitrobenzoxime (6) from
Fast Red B Hemi(Zinc Chloride) Salt (5). A solution of
hydroxylamine hydrochloride (11.0 g, 158 mmol) and
paraformaldehyde (4.7 g, 158 mmol) in water (100 mL) in
a 3-L, three-neck flask equipped with an overhead stirrer
and a reflux condenser was heated at gentle reflux until the
solution became clear and colorless (about 15 min). Sodium
acetate (13.0 g, 158 mmol) was added, and the solution was
heated at reflux for an additional 15 min. The solution was
cooled to room temperature, at which point copper (II) sulfate
pentahydrate (2.6 g, 10 mmol), sodium sulfite (0.4 g, 3
mmol), and sodium acetate (78.0 g, 840 mmol) in water (100
mL) were added, and the dark green mixture was stirred for
15 min.
temperature ambient) showed one peak, with a total purity
of 98.7% (area percent).
Preparation of 2-Methoxy-4-nitrobenzoxime (6) from
2-Methoxy-4-nitroaniline (4). In a 22-L, four-neck flask
equipped with an overhead stirrer, a thermocouple, a reflux
condenser, and a pressure-equalizing addition funnel, a
solution of hydroxylamine hydrochloride (124.0 g, 1.78 mol)
and paraformaldehyde (54.0 g, 1.78 mol) in water (800 mL)
was heated at gentle reflux until the solution became clear
and colorless (about 30 min). Sodium acetate (150.0 g, 1.78
mol) was added, and the solution was heated at reflux for
an additional 15 min. The solution was cooled to room
temperature, at which point copper (II) sulfate pentahydrate
(30.0 g, 119 mmol), sodium sulfite (4.5 g, 36 mmol),
additional sodium acetate (800.0 g), and additional water (500
mL) were successively added portionwise, and the dark green
mixture was vigorously stirred for 1 h.
In a separate 5-L, three-neck flask equipped with an
overhead stirrer, a thermocouple, and a pressure equilibrating
dropwise addition funnel, concentrated hydrochloric acid
(270 mL, 3.2 mol) was added dropwise over 15 min to a
solution of 2-methoxy-4-nitroaniline (4, 200.0 g, 1.19 mol)
in water (250 mL) at room temperature. The mixture was
cooled to 0 °C with an ice water bath, and a solution of
sodium nitrite (86.0 g, 1.25 mol) in water (100 mL) was
added dropwise over 30 min. The bright yellow mixture was
stirred at 0 °C for an additional 30 min and then warmed to
room temperature for the portionwise addition of solid
sodium acetate (150.0 g, 1.78 mol), at which time vigorous
off-gassing was observed. The mixture was then slowly
added via subsurface cannula with positive nitrogen pressure
to the formaldoxime solution at a rate that kept the excessive
foaming and exotherm (a 10-15 °C rise) to a minimum
(about 45 min). The reddish-brown suspension was stirred
at room temperature for 2 h, after which concentrated
hydrochloric acid (1.1 L) was added, and the mixture was
heated at reflux for 1 h. The orange solid was collected from
the cooled mixture by filtration, diluted in 1 M sodium
hydroxide solution (500 mL), and treated with decolorizing
charcoal (20 g). The mixture clarified by vacuum filtration
through a pad of Celite (200 g), washing the filter cake
sequentially with water (1 L). The filtrate was acidified with
6 N hydrochloric acid solution (200 mL) to precipitate the
product, which was collected by vacuum filtration and dried
overnight at 40 °C under reduced pressure to produce
2-methoxy-4-nitrobenzoxime (6) as an orange solid (56.2 g,
24%). The spectral data were consistent with the material
prepared by the previous route. HPLC analysis (reverse phase
Waters Symmetry C18 column, 150 mm × 3.9 mm, 5 µm
particle size, retention time ) 16.6 min, mobile phase 5:95
acetonitrile/(0.05% TFA in water) to 100:0 acetonitrile/
(0.05% TFA in water) over 25 min, flow rate ) 1.0 mL/
min, detector at 254 nm, column temperature ambient)
showed one peak, with a total purity of 88.5% (area %).
Preparation of 2-Methoxy-4-nitrobenzaldehyde (8)
from 2-Methoxy-4-nitrobenzoxime (6). A solution of
2-methoxy-4-nitrobenzoxime (6, 3.5 g, 17.8 mmol) and
sodium bisulfite (6.5 g, 62.4 mmol) in ethanol (25 mL) and
In a separate flask, a solution of Fast Red B hemi(zinc
chloride) salt (5,10 150.0 g, 105 mmol after correction for
assay) and sodium acetate (50.0 g, 610 mmol) in water (200
mL) was prepared. The insoluble zinc salts were removed
by filtration, and the filtrate was added via subsurface cannula
with positive nitrogen pressure to the formaldoxime solution
at a rate that kept the excessive foaming and exotherm (a
10-15 °C rise) to a minimum. The reddish-brown suspension
was cooled to room temperature, and stirring was continued
for a total of 1 h, after which the mixture was basified with
sodium hydroxide pellets (50 g) and treated with decolorizing
charcoal (10 g). The mixture was stirred for 15 min and
clarified by vacuum filtration through a pad of Celite (200
g), washing the filter cake sequentially with 1 N sodium
hydroxide solution (500 mL) and water (500 mL). The filtrate
was acidified with concentrated hydrochloric acid (200 mL)
to precipitate the oxime, which was collected by vacuum
filtration and dried overnight at 40 °C under reduced pressure
to produce 2-methoxy-4-nitrobenzoxime (6) as a tan powder
1
(6.7 g, 32%): mp 150-157 °C; H NMR (CDCl3) δ 8.50
(s, 1H), 7.91 (d, 1H, J ) 8.6 Hz), 7.85 (d, 1H, J ) 8.6 Hz),
7.77 (s, 1H), 7.53 (bs, 1H) and 3.97 (s, 3H) ppm; 13C NMR
(CDCl3) δ 163.6, 145.3, 135.3, 131.0, 127.3, 116.3, 106.6
and 56.6 ppm; IR (KBr) 3210, 2362, 1519, 1346 and 1255
cm-1; MS m/z 197 (M + H)+ Anal. Calcd for C8H8N2O4:
C, 48.98; H, 4.11; N, 14.28. Found: C, 48.71; H, 3.74; N,
13.93. HPLC analysis (reverse phase Waters Symmetry C18
column, 150 mm × 3.9 mm, 5 µm particle size, retention
time ) 16.6 min, mobile phase 5:95 acetonitrile/(0.05% TFA
in water) to 100:0 acetonitrile/(0.05% TFA in water) over
25 min, flow rate ) 1.0 mL/min, detector at 254 nm, column
680
•
Vol. 6, No. 5, 2002 / Organic Process Research & Development

water (25 mL) in a 250-mL flask equipped with a reflux
condenser was heated at reflux for 75 min. The solution was
cooled to room temperature, and the ethanol was removed
under reduced pressure. The resulting orange suspension of
bisulfite adduct 7 was diluted with 2 N hydrochloric acid
solution (100 mL) and methyl tert-butyl ether (50 mL). The
resulting biphasic mixture was heated at reflux for 4 h and
cooled to room temperature, and the organic phase was
collected. The aqueous phase was extracted with methyl tert-
butyl ether (2 × 50 mL), and the combined organic extracts
were washed with saturated sodium chloride solution (2 ×
100 mL). The organic solution was treated with Panther
Creek 200 bentonite clay13 (2 g), and the solids were removed
by vacuum filtration. The filtrate solvent was removed under
reduced pressure to produce 2-methoxy-4-nitrobenzaldehyde
(8) as a yellow powder (1.2 g, 37% yield). HPLC analysis
(reverse phase Waters Symmetry C18 column, 150 mm ×
3.9 mm, 5 µm particle size, retention time ) 17.1 min,
mobile phase 5:95 acetonitrile/(0.05% TFA in water) to 100:0
acetonitrile/(0.05% TFA in water) over 25 min, flow rate )
1.0 mL/min, detector at 254 nm, column temperature
ambient) showed one peak, with a total purity of 83.9% (area
%).
Preparation of 2-Methoxy-4-nitrobenzaldehyde (8)
from Fast Red B Tetrafluoroborate Salt (5). A suspension
of Fast Red B tetrafluoroborate salt (5, 25.0 g, 93.8 mmol)
in acetonitrile (50 mL) and methyl tert-butyl ether (50 mL)
in a Parr Series 4842 stir-equipped autoclave was sealed and
charged with carbon monoxide to a pressure of 50 psi. The
solution was vigorously stirred for 10 min after which the
pressure was released. This process was repeated twice after
which a suspension of palladium (II) acetate (0.40 g, 1.78
mmol) in acetonitrile (10 mL) was added through the
sampling port of the reactor. The reactor was then recharged
to 50 psi with carbon monoxide. A solution of triethylsilane
(10.6 g, 93.8 mmol) in acetonitrile (40 mL) and methyl tert-
butyl ether (50 mL) was added to the stirred reaction mixture
over 1.5 h through a Waters model 510 HPLC pump
plumbed to an inlet port on the autoclave head with stainless
steel connectors at a rate of 1.5 mL/min. During the addition,
a temperature increase of 25 °C (19-44 °C) and a pressure
increase of 40 psi (50-90 psi) were observed. Once the
addition was complete, the reaction was stirred for a further
30 min during which time the contents cooled to 35 °C
(monitored by an internal reaction temperature probe). The
pressure was released, the autoclave was opened, and the
dark solution was poured into saturated aqueous sodium
carbonate solution (250 mL). The organic layer was col-
lected, and the aqueous layer was extracted with ethyl acetate
(2 × 50 mL). The combined organic extracts were dried over
MgSO4, and the solvents were removed under reduced
pressure to produce a dark brown solid. This residue was
purified by flash column chromatography on silica gel,
eluting with ethyl acetate/hexanes (1:9), to provide 2-meth-
oxy-4-nitrobenzaldehyde (8) as a yellow solid (13.2 g, 78%
yield): mp 111-113 °C; 1H NMR (CDCl3) δ 10.53 (s, 1H),
7.97 (d, 1H, J ) 8.7 Hz), 7.87 (d, 1H, J ) 8.7 Hz), 7.85 (s,
1H) and 4.05 (s, 3H) ppm; 13C NMR (CDCl3) δ 188.4, 162.0,
152.4, 129.7, 128.8, 115.8, 107.4 and 56.7 ppm; MS m/z
182 (M + H)+. HPLC analysis (reverse phase Waters
Symmetry C18 column, 150 mm × 3.9 mm, 5 µm particle
size, retention time ) 17.1 min, mobile phase 5:95 aceto-
nitrile/(0.05% TFA in water) to 100:0 acetonitrile/(0.05%
TFA in water) over 25 min, flow rate ) 1.0 mL/min, detector
at 254 nm, column temperature ambient) showed one peak,
with a total purity of >99% (area %).
Preparation of 5-(2-Methoxy-4-nitrophenyl)oxazole (1)
from 2-Methoxy-4-nitrobenzaldehyde (8). To a solution
of 2-methoxy-4-nitrobenzaldehyde (8, 5.00 g, 27.5 mmol)
in methanol (50 mL) was added tosylmethyl isocyanide (5.37
g, 27.5 mmol) and potassium carbonate (10.0 g, 72.3 mmol),
and the resulting brown suspension was heated at reflux for
18 h, after which the dark brown solution was cooled to room
temperature. The mixture was concentrated under reduced
pressure, and the resulting black solid was partitioned
between methylene chloride (50 mL) and water (50 mL).
The organic layer was collected, and the aqueous layer was
extracted with methylene chloride (2 × 20 mL). The
combined organic extracts were dried over MgSO4, and the
dark green solution was treated with an activated charcoal/
Clarion 550-activated bentonite clay20/silica gel mixture (1:
1:2, 2 g). Clarification by vacuum filtration was followed
by concentration under reduced pressure to provide 5-(2-
methoxy-4-nitrophenyl)oxazole (1) as a yellow solid (5.82
1
g, 96% yield): mp 150-152 °C; H NMR (CDCl3) δ 8.03
(s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H)
and 4.10 (s, 3H); 13C NMR (CDCl3) δ 156.0, 151.2, 148.2,
146.6, 129.0, 126.4, 123.3, 116.7, 106.5 and 56.6 ppm; MS
m/z 221 (M + H)+. HPLC analysis (reverse phase Waters
Symmetry C18 column, 150 mm × 3.9 mm, 5 µm particle
size, retention time ) 18.0 min, mobile phase 5:95 aceto-
nitrile/(0.05% TFA in water) to 100:0 acetonitrile/(0.05%
TFA in water) over 25 min, flow rate ) 1.0 mL/min, detector
at 254 nm, column temperature ambient) showed one peak,
with a total purity of 97.1% (area %).
Acknowledgment
We acknowledge and thank Dr. Mark W. Zettler and Mr.
Chester J. Opalka of Albany Molecular Research, Inc. for
guidance and suggestions, and thank Maria D. Zimbal of
Albany Molecular Research, Inc. for assistance in retrieving
archived samples. We are also grateful to Vertex Pharma-
ceuticals Incorporated for permission to publish this body
of work.
Received for review May 6, 2002.
OP025546F
Vol. 6, No. 5, 2002 / Organic Process Research & Development
•
681