Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist

Article abstract of DOI:10.1021/jo991292t

An efficient, practical, asymmetric synthesis of the endothelin receptor antagonist 1 is reported. The key pyridine-fused cyclopentane ring bearing three consecutive chiral centers was constructed by first an auxiliary induced asymmetric conjugate addition of the bottom aryllithium from 19 to an unsaturated ester 21 in high diastereoselectivity. After a highly diastereoselective addition of the top aryl Grignard reagent to the aldehyde 22, the alcohol product then underwent a stereospecific intramolecular alkylation of the ester enolate by the phosphate of the alcohol, resulting in the desired trans-trans relative stereochemistry on the cyclopentane ring. The two key chiral centers that set the chirality of the molecule were both induced from cis-1-amino-2-indanol-derived chiral auxiliaries, one in the conjugate addition reaction, the other in setting the chiral center of the bottom side chain via chiral alkylation of an enolate. Oxidation of the primary alcohol to the carboxylic acid in the bottom side chain was carried out with the newly developed TEMPO/bleach-catalyzed oxidation by sodium chlorite (NaClO₂) or chromium oxide catalyzed oxidation by periodic acid. The overall process has been run successfully to make multikilograms of the drug in high purity.

Full text of DOI:10.1021/jo991292t

9658
J . Org. Chem. 1999, 64, 9658-9667
P r a ctica l Asym m etr ic Syn th esis of a n En d oth elin Recep tor
An ta gon ist
Zhiguo J . Song,* Mangzhu Zhao, Richard Desmond, Paul Devine, David M. Tschaen,
Richard Tillyer, Lisa Frey, Richard Heid, Feng Xu, Bruce Foster, J ing Li, Robert Reamer,
Ralph Volante, Edward J . J .Grabowski, Ulf H. Dolling, and Paul J . Reider
Process Research Department, Merck Research Laboratories, Merck & Co. Inc., P.O. Box 2000,
Rahway, New J ersey 07065
Shigemitsu Okada, Yoshiaki Kato, and Eiichi Mano
Process R & D, Banyu Pharmaceutical Co. Ltd. Okazaki, Aichi 444-0858, J apan
Received August 13, 1999
An efficient, practical, asymmetric synthesis of the endothelin receptor antagonist 1 is reported.
The key pyridine-fused cyclopentane ring bearing three consecutive chiral centers was constructed
by first an auxiliary induced asymmetric conjugate addition of the bottom aryllithium from 19 to
an unsaturated ester 21 in high diastereoselectivity. After a highly diastereoselective addition of
the top aryl Grignard reagent to the aldehyde 22, the alcohol product then underwent a stereospecific
intramolecular alkylation of the ester enolate by the phosphate of the alcohol, resulting in the
desired trans-trans relative stereochemistry on the cyclopentane ring. The two key chiral centers
that set the chirality of the molecule were both induced from cis-1-amino-2-indanol-derived chiral
auxiliaries, one in the conjugate addition reaction, the other in setting the chiral center of the
bottom side chain via chiral alkylation of an enolate. Oxidation of the primary alcohol to the
carboxylic acid in the bottom side chain was carried out with the newly developed TEMPO/bleach-
catalyzed oxidation by sodium chlorite (NaClO2) or chromium oxide catalyzed oxidation by periodic
acid. The overall process has been run successfully to make multikilograms of the drug in high
purity.
In tr od u ction
The structure of the target molecule 1 is shown in
Scheme 1. The key feature of this compound is the
cyclopentane ring fused with pyridine, which bears three
consecutive chiral centers. Substitution on the cyclopen-
tane ring includes the center carboxylic acid and the two
adjacent aryl groups, one of which has a side chain
bearing an additional chiral center. While the core
cyclopentane ring with three consecutive chiral centers
is common in this class of endothelin receptor antago-
nists, the synthesis of these compounds has been very
tedious. The enantiospecific preparation is even more
challenging and very few synthetic approaches have been
reported.1a,2 The two unique aryl side chains and the
fused pyridine structure make the synthesis of this
compound in large scale at low cost a uniquely challeng-
ing task. Scheme 1 shows the retrosynthetic analysis we
envisioned to construct this compound. The key steps
involve a chiral Michael addition reaction of the bottom
aryl piece organometallic species 5 into the conjugate
pyridine ester 3 which has been properly functionalized
on the pyridine. Introduction of the chirality would be
either through a chiral auxiliary or an external additive.
The top aryl group can be introduced by addition of the
arylmetal to the aldehyde. The cyclopentane ring can
then be closed via intramolecular alkylation of the ester
enolate. While the chiral conjugate addition reaction
based on chiral auxiliary is well precedent in the
literature,3-6 the subsequent steps are rather exploratory
in nature.
Endothelin receptor antagonists are useful therapeutic
agents which are being developed for possible indications
in congestive heart failure, hypertension, and some other
areas. Extensive work in medicinal chemistry has been
reported in the literature.1 Practical syntheses of some
compounds in development were also described.2 In this
paper, we report a practical, concise synthesis of one of
the endothelin receptor antagonists which is under
development jointly by Merck and Banyu.1a The objective
of this work was to develop an efficient, safe, cost-
effective, and environmentally friendly synthesis of this
compound suitable for scale-up so that kilogram quanti-
ties of this drug candidate could be made via this
chemistry for safety assessment and clinical studies. The
synthesis should also be suitable for eventual commercial
production if necessary.
(1) (a) Ishikawa, K.; Nagase, T.; Mase, T.; Hayama, T.; Masaki, I.;
Nishikibe, M.; Yano, M. PCT Int. Appl. WO 9505374, 1995. (b)
Berryman, K. A.; Edmunds, J . J .; Bunker, A. M.; Haleen, S.; Bryant,
J .; Welch, K. M.; Doherty, A. M. Bioorg. Med. Chem. 1998, 6, 1447. (c)
Tasker, A. S.; Boyd, S. A.; Sorensen, B. K.; Winn, M.; J ae, H.-S.; von
Geldern, T. M.; Henry, K. J . PCT Int. Appl. WO 9730046, 1997. (d)
Astles, P. C.; Brown, T. J .; Halley, F.; Handscome, C. M.; Harris, N.
V.; McCarthy, C.; McLay, I. M.; Lockey, P.; Majid, T.; Porter, B.; Roach,
A. G.; Smith, C.; Walsh, R. J . Med. Chem. 1998, 41, 2745. (e) Bagley,
S. W.; Broten, T. P.; Chakravarty, P. K.; Dhanoa, D. S.; Fitch, K. J .;
Greenlee, W. J .; Kevin, N. J .; Pettibone, D. J .; Rivero, R. A.; Tata, J .
R.; Wash, T. F.; Williams, D. L., J r. US Patent 5767310, 1998.
(2) (a) Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G.; K.; Pridgen,
L. N.; Olsen, M. A.; Mills, R. J .; Lantos, I.; Baine, N. H. J . Am. Chem.
Soc. 1998, 120, 4550. (b) Pridgen, L. N.; Huang, G. K. Tetrahedron
Lett. 1998, 39, 8421. (c) Bhagwat, S.; Gude, C.; Chan, K. Tetrahedron
Lett. 1996, 37, 4627.
10.1021/jo991292t CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/24/1999

Synthesis of an Endothelin Receptor Antagonist
J . Org. Chem., Vol. 64, No. 26, 1999 9659
Sch em e 1
Sch em e 2
P r ep a r a tion of th e Bottom Ar yl Br om id e. For the
synthesis of the chiral aryl bromide fragment, we turned
our attention to the use of cis-aminoindanol ketal as the
possible chiral auxiliary for alkylation of propionyl eno-
late by the benzyl chloride 14.9 (1R,2S)-cis-Aminoidanol
is readily available as part of the Merck AIDS drug
CRIXIVAN process and has been used as a chiral
auxiliary extensively.10 Thus, the propionyl amide of
aminoidanol ketal 15 was enolized and reacted with the
benzyl chloride 14 at -30 °C to give the product 16 in
excellent de (98/2). Subsequent hydrolysis gave the free
acid 17 as an oil in 60% overall yield. Thus, the ami-
noindanol ketal is a useful alternative as the chiral
auxiliary for enolate alkylation reactions because it is
readily available, easy to install and to remove, and can
be recycled easily if necessary.9 To protect the acid
against epimerization of the chiral center as well as
reaction toward organometallic species (e.g. aryllithium
compounds), the acid was reduced to the alcohol 18 with
borane in 95% yield. Crystallization of the alcohol
improved the ee to >99%. Subsequent protection of the
alcohol as the TBS ether 19 (99% yield) made this piece
ready for organometallic reactions.
Resu lts a n d Discu ssion
P r ep a r a tion of th e Mich a el Accep tor 12. There are
several possible approaches for the chiral Michael addi-
tion reaction. One approach was based on a preliminary
report by Alexakis et al.,4 where aryl-substituted unsat-
urated esters 6 bearing an o-aldehyde group can undergo
conjugate addition reactions with simple organocuprates.
When the aldehyde is protected as the chiral acetal (by
chiral diol) or chiral diaminoacetal (by chiral diamine),
the organocuprate addition products 7 were obtained in
high ee after removal of the protecting groups. Recent
work at Merck by Frey et al. has extended the application
of this strategy to Michael addition by aryllithium
species.5 To apply a similar strategy for our target
molecule, we needed to make compound 12 as the
Michael acceptor, which could also be used in an alter-
nate approach using an external chiral additive in the
conjugate addition.7
Con ju ga te Ad d ition . Two approaches for the chiral
Michael addition reaction were systematically explored.
The first involved installing a chiral auxiliary on the
aldehyde, similar to the reaction reported by Alexakis et
al. (eq 1) and the recent work by Frey et al.4,5 In the
Thus, as shown in Scheme 2, 3-cyano-6-methyl-2-
pyridone (8) was alkylated with propyl bromide under
basic conditions to the n-butylpyridine8 9 and then
converted to the bromide with P2O5/Bu4NBr in 64%
overall yield. DIBAL-H reduction of the cyano group to
the aldehyde 11 gave nearly quantitative yield. The tert-
butyl acrylate was installed by Heck reaction with tert-
butyl acrylate, using allyl palladium chloride dimer and
tri-o-tolylphosphine as catalyst to produce 12 in 83%
yield. It should be pointed out that all of these compounds
were oils and were used directly without any purification.
reaction of the compound 12, we found that both (1S,2S)-
(+)-pseudoephedrine (20B) and N-methyl-(1S,2R)-cis-1-
amino-2-indanol (20A) were good auxiliaries. Although
pseudoephedrine is readily available in the United
States, it is not so in J apan due to government regula-
tions on the substance. So we developed methods to use
either auxiliary. The crude aldehyde 12 from the Heck
reaction was treated with either amino alcohol in toluene
to give the N,O-acetal 21A or 21B in quantitative yield.
This compound was then treated with the aryllithium
generated from aryl bromide 19 and n-butyllithium at-
(3) For a review on conjugate addition reactions, see: Rossiter, B.
E.; Swingle, N. M. Chem. Rev. 1992, 92, 771.
(4) Alexakis, A.; Sedrani, R.;, Mangeney, P.; Normant, J . F. Tetra-
hedron Lett. 1988, 29, 4411.
(5) Frey, L. F.; Tillyer, R. D.; Caille, A.-S.; Tschaen, D. M.; Dolling,
U.-H.; Grabowski, E. J . J .; Reider, P. J . J . Org. Chem. 1998, 63, 3120.
(6) Takaya, T.; Ogasawara, M.; Hayashi, M., Sakai, M.; Miyura, T.
J . Am. Chem. Soc. 1998, 120, 5579.
(7) Xu, Feng; Tillyer, R. D.; Tschaen, D. M.; Grabowski, E. J . J .;
Reider, P. J . Tetrahedron: Asymmetry 1998, 9, 1651.
(8) Related method: Okada, S.; Ushijima, R.; Ishikawa, K. PCT Int.
Appl. WO 9825906, 1998.
(9) A similar alkylation reaction: Lee, J .; Choi, W.-B.; Lynch, J . E.;
Volante, R.; Reider, P. J . Tetrahedron Lett. 1998, 39, 3679.
(10) (a) Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Wells, K.
M.; Volante, R. P.; Reider, P. Tetrahedron Lett. 1994, 35, 673. (b)
Senanayake, C. H Aldrichimica Act. 1998, 31, 3.

9660 J . Org. Chem., Vol. 64, No. 26, 1999
Song et al.
Sch em e 3
to the crude aldehyde 22 in THF at low temperature (<-
65 °C). This reaction was stereoselective, i.e., it produced
one diatereoisomer over the other by a 94/6 ratio. On the
basis of the chemistry carried out in the later steps, the
stereochemistry was assigned as shown in 24. This
stereoselectivity became extremely critical for the ste-
reospecific ring closure reaction later on. Interestingly,
the selectivity became lower when more toluene was used
in the reaction or when the aryllithium was used instead
of Grignard reagent. This Grignard addition product was
again used without purification because it was an oil.
Cycliza tion . With the alcohol in hand, it was obvious
that the most straightforward route to the cyclopentane
ring was to convert the alcohol in 24 to a leaving group
and react that with the enolate of the tert-butyl ester.
Because the configuration at the alcohol center was not
known at the time, it was not clear whether retention or
inversion of configuration was needed at the alcohol
carbon in order to obtain the correct stereochmistry of
the cyclization product. (i.e. the trans,trans configuration
as in 25). Initial attempts to make the mesylate of the
alcohol using mesyl chloride gave the chloride instead of
the mesylate, as a 3/1 diastereomeric mixture at the
chloride center. Treatment of the chloride with LDA at
low temperature gave the cyclized product as a mixture
of the stereoisomers on the ring with the desired trans,-
trans-isomer as the minor product. Use of mesyl anhy-
dride in the preparation of the mesylate led to complex
undesired products, presumably through intramolecular
Friedel-Crafts reaction of the extremely reactive inter-
mediates. Similar results were observed when trying to
make the tosylate or trifluoromethane sulfonate. These
results indicated that the sulfonates of the benzylic
alcohol 24 are too reactive due to the extra activation
from the diaryl substitution as well as the p-alkoxyl
group on the top aryl moiety, which leads to decomposi-
tion of these compounds. We reasoned that a much less
active leaving group might solve the problem. A phos-
phate appears to be a good candidate due to its lower
reactivity as leaving group and rather low reactivity
toward nucleophiles at the phosphorus center. To our
delight, when we treated the alcohol 24 with 1.5 equiv
of diethyl chlorophosphate and 4.5 equiv of lithium bis-
(trimethylsilyl)amide at 0 °C, the desired cyclization
occurred, giving the desired trans,trans-isomer 25 in high
yield (85% with pure starting material). Presumably, the
diethyl phosphate ester of the chiral alcohol was formed
first which underwent intramolecular alkylation of the
enolate of the tert-butyl ester.
low temperature (<-65 °C). Optimal yield was observed
when the aryllithium was added to the ester 21 at low
temperature (<-50 °C). Use of mostly toluene with some
THF (4/1 ratio) as the solvent was also necessary for the
lithium bromide exchange reaction in large scale (long
time cycle) in order to avoid the side reaction between
the butyl bromide and the resulting aryllithium. After
acidic workup, the amino alcohol was removed to give
the free aldehyde 22 in 92% overall yield from 12 and
96/4 diastereomeric ratio. This crude product was used
for the next step without purification because it was an
oil. The amino alcohol auxiliary can be recovered easily.
Because of the easy installation, removal, and recycle of
the amino alcohol, this approach offers an economically
attractive method to install this strategic chiral center
in high yield and selectivity for this synthesis. Two as-
pects of this reaction greatly expand the scope of the
reactions reported by Alexakis et al. The first is the use
of the more readily available, easily recyclable amino al-
cohols as the auxiliaries compared to the less available
and more expensive chiral diamines. The other is the use
of only 1 equiv of organolithium as the nucleophile in-
stead of the organocuperate species, which would require
at least 2 equiv of the rather expensive aryl bromide 19.
The second approach to the chiral conjugate addition
reaction involved the use of external chiral additives.
Thus, the dimethyl acetal 27 of the aldehyde reacted with
the aryllithium derived from 19 in the presence of a
stoicheometric amount of (-)-sparteine. The product 28
was isolated in 67% de, as shown in Scheme 5. The
lithium bromide exchange had to be done with a mini-
mum amount of THF (0.3 equiv) in order to optimize the
de. A few other similar reactions under these conditions
were also investigated and the results were published.7
Gr ign a r d Ad d ition . To install the top aryl group (Ar2
in Scheme 5) the Grignard 23 of the commercially
available, corresponding bromide was added in high yield
To probe whether the cyclization reaction went through
stereospecific SN2 type displacement, we made the alcohol
24 as a 2/1 diastereomeric mixture at the alcohol center
(major isomer shown in Scheme 5). Under the cyclization
conditions, a mixture of stereoisomers 25, 29, and 30 was
produced with 25 as the major product. The assignment
of these structures was based on NOE data of the proton
NMR. The ratio was approximately 25/(29 + 30) ) 2/1,
consistent with SN2 type displacement of the phosphate
ester by the tert-butyl ester enolate.
After the cyclization reaction, crude product 25 was
then treated with concentrated HCl in acetonitrile to
remove both the TBS group and the tert-butyl ester
group. Salt formation with benzylamine afforded the salt
of 26 as the first crystalline intermediate over several
steps with an isolated yield of 70-75% from the Michael
addition product 22. This crystallization was important

Synthesis of an Endothelin Receptor Antagonist
J . Org. Chem., Vol. 64, No. 26, 1999 9661
Sch em e 4
Sch em e 5
in that it allowed purification of this penultimate inter-
mediate after more than six steps without any purifica-
tion. The purity of the isolated salt was over 95% by
HPLC.
Use of a RuCl3/H5IO6 protocol offered a low yield of the
desired product,11 which was probably due to the destruc-
tion of the electron rich aromatic ring. Swern oxidation
to the aldehyde followed by sodium chlorite (NaClO2)
oxidation to the acid gave a reasonably good yield but
could lead to epimerization of the neighboring chiral
center.12 TEMPO-catalyzed oxidation with bleach also
Oxid a tion . With the alcohol 26 in hand, the only step
left is to convert the alcohol to the acid. A survey of
several available methods from the literature showed
that an economical method which can tolerate electron-
rich aromatic rings as well as an adjacent chiral center
was needed. For example, oxidation with CrO3/H2SO4
gave the desired product in reasonable yield, but the use
of stoichiometric quantities of chromium is not practical
on large scale due to toxicity and waste disposal concerns.
(11) (a) Carlsen, P. H. J .; Katsuki, T.; Martin V. S.; Sharpless, K.
B. J . Org. Chem. 1981, 46, 3936. (b) Oxidation of alcohols to acids
catalyzed by Na2WO4 was reported recently: Sato, K.; Aoki, M.; Takagi,
J .; Noyori, R. J . Am. Chem. Soc. 1997, 119, 12386-12387.
(12) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888. (b) Dalcanale, E.; Montanari, F. J . Org. Chem. 1986, 51, 567. (c)
Ireland, R.; Norbeck, D. J . Org. Chem. 1985, 50, 2198.

9662 J . Org. Chem., Vol. 64, No. 26, 1999
Song et al.
gave a low yield due to significant chlorination of the
aromatic rings.13a Other oxidants (H2O2, MeCO3H,
t-BuO2H etc.) examined for the TEMPO-catalyzed oxida-
tions did not give satisfactory results.
pound 8 is 32% over 8-10 steps. The efficiency of the
chemistry was demonstrated by the fact that multiple
steps were carried out without the need for purification.
This process has been scaled up in the pilot plant to make
over 10 kg of the compound 1 to be used for safety
assessment and clinical studies for this important drug
candidate.
As part of this work, a new protocol of oxidizing
primary alcohols to the corresponding carboxylic acids
using sodium chlorite and catalytic amount of TEMPO
and bleach has been shown to be a generally applicable
method to a variety of different alcohols.14b Under
optimized conditions, the starting material alcohol 26 was
dissolved in acetonitrile and mixed with pH ) 6.7 buffer.
At 35 °C, a catalytic amount (5 mol %) of TEMPO was
added followed by simultaneous addition of NaClO2 and
a catalytic amount of bleach (3 mol %).14a The yield of
the acid 1 was over 90%. The reaction has been optimized
to minimize chlorination of the aryl ring and to enhance
the safety for scale-up. The reaction was faster at lower
pH, but it was accompanied by increased the amount of
chlorination products (up to 0.5% and difficult to remove).
It was slower at lower temperature, as expected, but
surprisingly, the chlorination level appeared to be slightly
elevated. Increasing the amount of TEMPO and bleach
increased the reaction rate, but the TEMPO/NaClO molar
ratio should be >2 to minimize chlorination. Thus, the
TEMPO-catalyzed oxidation of alcohol to has been proven
to be mild, economical, and environmentally benign.14b
Finally, the disodium salt of 1 was isolated in 85% overall
yield from the alcohol and over 99% purity by treatment
of the diacid of 1 with sodium ethoxide.
Exp er im en ta l Section
Gen er a l. All substrates and reagents were obtained com-
mercially and used without purification. Nuclear magnetic
resonance (NMR) chemical shifts (δ) are referenced on the
deuterated solvents. Elemental analyses were done by QTI at
Whitehouse Station, NJ . LC-MS were done on a HP series
1100 MSD mass spectrometer. Melting points were uncor-
rected. Anhydrous solvents were obtained commercially and
used as is or dried with molecular sieves. Moisture contents
in solvents or reaction mixtures were measured by Karl
Fischer titrators and are presented as KF values. HPLC
results are presented as area percent of the peak (A%) for a
particular compound relative to the total area of all the peaks
integrated.
6-Bu tyl-3-cya n o-2-p yr id on e (9). To a solution of diiso-
propylamine (413 mL, 3.15 mol) in THF (1 L) at -30 °C was
added n-BuLi (315 mL, 10 M). The resulting LDA was
cannulated into a solution of 2-hydroxy-6-methylpyridine (200
g, 1.83 mol) in THF (1 L) over 40 min while the temperature
was maintained at <-20 °C. The mixture was stirred for 2.5
h at 0-5 °C to form an orange slurry. 1-Bromopropane (140
mL, 1.54 mol) was added over 10 min and the mixture was
stirred for 3 h. Water (1 L) was added and the THF was
distilled off under vacuum. Toluene (1.5 L) was added in one
portion followed by slow addition of sulfuric acid (3.6 M, 300
mL). The layers were separated, and the toluene layer was
washed with brine (500 mL), filtered, and concentrated to a
total volume of 650 mL. Hexane (750 mL) was added dropwise
and the resulting slurry was cooled to 5 °C and filtered to
collect the solid product. The product was washed with hexane
(500 mL) and air-dried to yield 199 g the title compound as
We also developed a chromium oxide catalyzed oxida-
tion with periodic acid, and the general protocol was
published recently.15 With that method, the alcohol 26
can also be converted to the acid 1 with 2.5 equiv of
periodic acid and 1.5 mol % of CrO3 in wet acetonitrile
in over 90% yield. The disodium salt was isolated in 85%
yield in over 99% purity.
1
an orange solid (76% yield): mp 109 °C; H NMR (250 MHz,
CDCl3) δ 0.93 (t, 3H, J ) 7.3 Hz), 1.36 (m, 2H), 1.67 (m, 2H),
2.67 (t, 2H, J ) 7.5 Hz), 6.20 (d, 1H, J ) 7.5 Hz), 7.79 (d, 1H,
J ) 7.5 Hz); 13C (63 MHz, CDCl3 ) δ 163.3, 157.7, 148.5, 115.70,
105.80, 100.98, 33.40, 30.54, 22.07, 13.63; LC-EIMS m/z 177
(M+ + 1). Anal. Calcd for C8H8BrClO: C, 40.8; H, 3.42.
Found: C, 41.1; H, 3.3.
Con clu sion
We have developed a highly convergent synthesis of
the structurally complex endothelin receptor antagonist
1. The key steps involved the efficient chiral conjugate
addition reaction of an aryllithium to an unsaturated
ester in high diastereoselectivity and yield. The stereo-
selective Grignard addition and the novel, phosphate-
mediated stereospecific intramolecular cyclization build
the fused cyclopentane ring efficiently.16 The synthesis
was finished by an economical, environmentally benign
TEMPO-catalyzed oxidation of the alcohol to the acid.
The overall yield from the commercially available com-
2-Br om o-6-bu tyl-3-cya n op yr id in e (10). 6-Butyl-3-cyano-
2-hydroxypyridine (177 g, 1.01 mol), phosphorus pentoxide
(300 g, 1.06 mol), and tetrabutylammonium bromide (391
g,1.21 mol) were mixed in toluene (2L) and heated to reflux
for 4 h. The mixture was cooled to rt and water (1L) was added
carefully with stirring and cooling. The mixture was stirred
for 2 h and then filtered through a pad of Celite, and the layers
were separated. The toluene layer was washed with brine and
concentrated in vacuo. The product was passed through a pad
of silica gel (50 g) and eluted with ethyl acetate:hexane (10:1)
to give 202 g (84% yield) of product as a clear yellow oil: 1H
NMR (250 MHz, CDCl3) δ 0.93 (t, 3H, J ) 7.3 Hz), 1.30 (m,-
2H,) 1.70 (m, 2H), 2.82 (t, 2H, J ) 7.3 Hz), 7.22 (d, 1H, J )
7.9 Hz), 7.82 (d, 1H, J ) 7.9 Hz); 13C (63 MHz, CDCl3 ) 13.77,
22.26, 31.21, 37.98, 110.82, 116.05, 121.71, 142.29,142.79,-
168.21; LC-EIMS m/z 239 (M+ + 1), 290 (M+ + 1 + MeCN).
Anal. Calcd for C10H11N2Br: C, 50.23; H, 4.64; N, 11.72
Found: C, 50.61; H, 4.73; N, 11.68.
2-Br om o-6-bu tyl-3-for m ylp yr id in e (11). A solution of
2-bromo-6-butyl-3-cyanopyridine (202 g, 0.845 mol) in toluene
(1.3 L) was cooled to -60 °C. DIBAL solution (676 mL, 1.01
mol) was added dropwise over 45 min while the temperature
was maintained at -50 °C. The reaction mixture was aged
for 2.5 h and then carefully quenched into a mixture of 2 M
sulfuric acid (2 L), toluene (200 mL), and THF (100 mL). The
resulting mixture was stirred for 16h at rt, water (1.9 L) was
added, and the layers were separated. The organic layer was
washed with water (1 L) and concentrated in vacuo to a yellow
(13) (a) Miyazawa, T.; Endo, T.; Shiihashi, S.; Okawara, M. J . Org.
Chem. 1985, 50, 1332. (b) NaBrO2 has been reported in the literature
as the co-oxidant with TEMPO, but it is not readily available:
Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. J . Org. Chem.
1990, 55, 462.
(14) (a) For safety reasons, especially on larger scale, the bleach was
added slowly and simultaneously with NaClO2 to the batch at 35 °C,
with a slow nitrogen sweep over the reaction mixture, to prevent build
up of the oxidants and the risk of a runaway reaction. It should be
noted that mixing of bleach and NaClO2 prior to the addition is not
advised, since some toxic and potentially explosive chlorine dioxide
(ClO2) may be generated. (b) Zhao, M.; Li, J .; Mano, E, Song, Z.;
Tschaen, D. M.; Grabowski, E. J . J .; Reider, P. J .;. J . Org. Chem. 1999,
64, 2564.
(15) Zhao, M.; Li, J .; Song, Z.; Desmond, R.; Tschaen, D. M.;
Grabowski, E. J . J .; Reider, P. J . Tetrahedron Lett. 1998, 39, 5323.
(16) We could find only one related cyclization to form cyclopropane
ring from an ester enolate and a strained phosphate: Braschwitz, W.-
D.; Otten, T.; Rucker, C.; Fritz, H.; Prinzbach, H. Angew. Chem. 1989,
101, 1384.

Synthesis of an Endothelin Receptor Antagonist
J . Org. Chem., Vol. 64, No. 26, 1999 9663
1
oil (197 g, 96% yield); H NMR (250 MHz, CDCl3) δ 0.93 (t,
dropwise to the reaction mixture over a period of 30 min while
the temperature is maintained at <15 °C. The temperature is
controlled by cooling and monitoring the rate of addition. The
initial addition of water is highly exothermic. Using a large
excess of thionyl chloride results in a more exothermic quench.
If the quench temperature is not controlled, hydrolysis of the
benzyl chloride back to the alcohol may result. The resulting
thick white slurry is aged for 1 h at 0-5 °C. The benzyl
chloride is isolated by filtration. The cake is washed with (1:
1) DMF:H2O (100 mL) and then water (200 mL). The solid is
dried in vacuo to give 93 g of the benzyl chloride (94% yield,
96 A% by HPLC) as a white solid: mp 74 °C; HPLC assay:
column, Waters Symmetry C8, 4.6 × 250 mm; UV detection,
220 nm; column temp, 25 °C; flow rate, 1 mL/min; eluent, CH3-
CN:0.1% H3PO4 (70:30); tR for alcohol, 3.9 min; chloride, 7.3
min; DMF, 2.6 min. 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J )
8.8 Hz, 1 H), 7.01 (d, J ) 3.0 Hz, 1H), 6.73 (dd, J ) 8.8 Hz, 3.0
Hz, 1H), 4.63 (s, 2H), 3.78 (s, 3H); 13C (100 MHz, CDCl3) δ
159.2, 137.5, 133.7, 127.3, 116.3, 115.9, 114.3, 55.6, 46.3; GC-
EIMS m/z 234 (M+). Anal. Calcd for C8H8OBrCl: C, 40.8; H,
3.4. Found C, 41.1; H, 3.3.
3H, J ) 7.3 Hz), 1.39 (m, 2H), 1.69 (m, 2H), 2.82 (t, 2H, J )
7.3 Hz), 7.23 (d, 1H, J ) 7.9 Hz), 8.05 (d, 2H, J ) 7.9 Hz),
10.28 (s, 1H); 13C NMR (63 MHz, CDCl3 ) 13.77, 22.31, 31.35,
37.96, 122.46, 128.08, 137.98, 144.85, 169.65, 190.79; LC-
EIMS m/z 242 (M+ + 1). Anal. Calcd for C10H12NOBr: C, 49.61;
H, 5.00; N, 5.79 Found: C, 49.54; H, 4.79; N, 5.73.
ter t-Bu tyl (6-Bu tyl-3-for m ylp yr id in -2-yl)a cr yla te (12).
2-Bromo-6-butyl-3-formylpyridine 11 (30.2 kg, 125 mol), so-
dium acetate (30.7 kg, 374 mol), tris-O-tolylphosphine (3.8 kg,
12.5 mol), toluene (150 L), allylpalladium chloride dimer (1.83
kg, 5 mol), and tert-butyl acrylate (19.2 kg, 150 mol) were
mixed together, and the resulting slurry was heated under N2
atmosphere at 108-112 °C for 18.5 h. The reaction mixture
was cooled to ambient temperature, and the precipitates were
filtered off with a filter. Water (100 L) was mixed with the
filtrate and the organic layer was separated, washed with
saturated sodium bicarbonate and 1M aqueous citric acid, and
then dried (MgSO4). The mixture was filtered and concentrated
in vacuo. The resulting oil was quantitated by HPLC (29.8 kg
of 12, 82% yield) and used in the next step without isolation.
HPLC assay: column, YMC ODS AQ 302; eluent, acetonitrile:
water (70:30); flow rate, 1 mL/min; tR for bromide 11, 4.5 min;
unsaturated ester 12, 8.9 min. A pure sample of 12 was
isolated as an oil by column chromatography through silica
gel: 1H NMR (250 MHz, CDCl3) δ 0.86 (d, J ) 7.2 Hz, 3H),
1.23-1.38 (m, 2H), 1.46 (s, 9H), 1.60-1.72 (m, 2H), 2.76 (t, J
) 7.6 Hz, 2H), 7.03 (d, J ) 15.2 Hz, 1H), 7.20 (d, J ) 8.0 Hz,
1H), 7.97 (d, J ) 8.0 Hz, 1H), 8.28 (d, J ) 15.2 Hz, 1H), 10.30
(s, 1H); 13C NMR (63 MHz, CDCl3) δ 13.85, 22.38, 28.06, 31.28,
38.41, 80.91, 123.49, 127.07, 128.55, 136.83, 138.15, 153.06,
165.65, 167.58, 189.92; IR (cm-1) 2959, 2932, 2872, 1710, 1580,
1458, 1311; LC-EIMS m/z 290 (M+ + 1). Anal. Calcd for
Aceton id e 15. To a 5 L three-neck round-bottom flask
equipped with a mechanical stirrer, N2 inlet, thermocouple
probe, heating mantle, and addition funnel were charged
(1R,2S)-cis-aminoindanol (100 g, 0.670 mol), tetrahydrofuran
(1.2 L, KF ) 120 µg/mL), and triethylamine (96 mL, 0.69 mol,
KF ) 500 µg/mL). The resulting slurry was heated under a
N2 atmosphere to 40-45 °C, giving a yellow solution. Propionyl
chloride (59 mL, 0.679 mol) was charged to an addition funnel
and slowly added to the solution while the temperature was
maintained at 45-50 °C. The temperature was controlled by
the rate of addition and a cooling bath. After completion of
the amide formation, methanesulfonic acid (3 mL) was added
and then 2-methoxypropene (140 mL) was charged to an
addition funnel and added over 30 min at 50 °C. The reaction
slurry was stirred at 50 °C until the reaction was complete
(1-2 h as judged by HPLC). The reaction mixture was cooled
to 0-5 °C and quenched with Na2CO3 (1 L, 5% aqueous) and
heptane (1 L). The organic layer was separated, washed with
water (300 mL), and then concentrated to 700 mL at 50 °C
under reduced pressure. Heptane (1.0 L) was added and the
solution was again concentrated to 700 mL. The solution was
allowed to cool and seeded with the acetonide at 35-40 °C.
The thick slurry was stirred for 1 h at ambient temperature
then cooled to 0-5 °C and stirred for 1 h. The slurry was
filtered and the filter cake was washed with cold heptane (200
mL) and air-dried to yield the acetonide as a crystalline white
C
17H23NO3: C, 70.55; H, 8.02; N, 4.84. Found: C, 70.21; H,
7.96; N, 4.74.
4-Br om o-2-ch lor om eth yla n isole (14). Step 1: Red u c-
tion of th e Acid 13. Sodium borohydride (8.6 g, 0.23 mol)
was slurried in THF (150 mL of KF ) 150 µg/mL) in a round-
bottom flask equipped with a thermocouple, an addition
funnel, a nitrogen inlet, a mechanical stirrer, and a cooling
bath. 2-Bromo-5-methoxybenzoic acid 13 (50 g, 0.22 mol)
dissolved in THF (100 mL, KF ) 150 µg/mL) was added to
the sodium borohydride slurry over 45 min while the temper-
ature was maintained at 20-25 °C. Ca u tion : Hyd r ogen ga s
is evolved ! Exoth er m ic! The mixture was aged for 30 min
at 20-25 °C. Boron trifluoride etherate (36.9 g, 0.26 mol) was
added over a period of 30 min at 30-35 °C. (Ca u tion :
d ela yed exoth er m !). The resulting white slurry was aged for
1 h at 30-35 °C and then was cooled to 15 °C and carefully
quenched into a cold (10 °C) saturated aqueous ammonium
chloride solution (150 mL) while the temperature was main-
tained at <25 °C. (Ca u tion : Hyd r ogen ga s w a s gen er a ted !)
Ethyl acetate (500 mL) was added, and the layers were
separated. The organic layer was washed with water (100 mL)
and then transferred to a 1 L round-bottom flask equipped
for distillation. The solution was concentrated and charged
with fresh ethyl acetate. This was repeated until a solution
with a volume of 200 mL has KF < 200 µg/mL. The solvent
was then switched to DMF to give the final volume of 200 mL
with a KF < 200 µg/mL.
Step 2: Ch lor in a tion . A DMF solution of the benzyl
alcohol from the proceeding step(91.3 g, 0.42 mol, in 400 mL,
KF ) 300 µg/mL) was charged to a 2 L flask equipped with a
mechanical stirrer, thermocouple, N2 inlet, and cooling bath.
The solution was cooled to 0-5 °C and the addition funnel was
charged with thionyl chloride (55.0 g, 0.46 mol). The thionyl
chloride was added over a period of 45 min while the temper-
ature was maintained at 5-10 °C. The mixture was aged for
1 h at 5 °C and assayed by HPLC. The HPLC sample was
prepared by evaporating a sample of the DMF solution with a
N2 stream and then dissolving the sample in column eluent.
HPLC typically indicates <1% of the benzyl alcohol. Adding
the DMF solution directly into the column eluent could result
in some hydrolysis of the chloride to the alcohol. The addition
funnel is charged with water (400 mL), which is added
solid (141.1 g, 85% yield): mp 79 °C. [R]20 ) -163° (c 1.18,
D
MeOH); 1H NMR (250 MHz, CDCl3) δ 1.29 (t, J ) 7.4 Hz, 3H),
1.35 (s, 3H), 1.63 (s, 3H), 2.71, (m, 2H), 3.12 (d, 2H, J ) 1.7
Hz), 4.87 (m, 1H), 5.30 (d, 1H, J ) 4.5 Hz), 7.2-7.3 (bm, 4H);
13C NMR (63 MHz, CDCl3) 9.51, 24.23, 26.64, 29.40, 36.37,
65.90, 78.80, 96.44, 124.27, 125.92, 127.22, 128.52, 140.83,
141.03, 170.43; LC-EIMS m/z 246 (M+ + 1). Anal. Calcd for
C15 H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.45; H,
7.86; N, 5.64.
(S)-2-Met h yl-3-(2′-b r om o-5-m et h oxyp h en yl)p r op ion -
ic Acid (17). A solution of the acetonide 15 (252 g, 1.03 mol)
and the benzyl chloride 14 (255 g, 1.08 mol) in THF (2 L, KF
< 200 µg/mL) was cooled to -10 °C. Lithium bis(trimethylsi-
lyl)amide (1.45 L, 1.45 mol) was added dropwise over 5 h at
0-2 °C and the mixture was stirred for 1.5 h. After completion
of the reaction (HPLC), NH4Cl (saturated aqueous, 1 L) was
added. The quenched reaction mixture was then transferred
into a mixture of aqueous ammonium chloride (1.5 L), water
(0.5 L), and ethyl acetate (3 L) with stirring. The organic layer
was separated, washed sequentially with water (1 L) and brine
(0.5 L), and then concentrated to low volume. It was then
solvent switched to 1,4-dioxane by flushing with the latter
solvent (∼4 L total). The dioxane solution was adjusted to 1.8
L and 6 N HCl (1.5 L) was added. The mixture was heated to
reflux and the hydrolysis was monitored by HPLC. The
reaction mixture quickly becomes a thick slurry due to
precipitation of the amide intermediate. It then became a two-
phase solution as the amide was gradually hydrolyzed. Upon

9664 J . Org. Chem., Vol. 64, No. 26, 1999
Song et al.
the completion of the reaction (∼2 h), the reaction mixture was
cooled to 20 °C and MTBE (methyl tert-butyl ether, 3 L) was
added with stirring. The organic layer was separated and
washed with water (1 L). The product was then extracted into
aqueous phase by 0.6 N NaOH (2 L) solution. To the aqueous
layer was added MTBE (2.5 L) and the mixture was cooled to
10 °C and then acidified with 5.4 M sulfuric acid (250 mL)
with stirring. The organic layer was separated and washed
with water (0.5 L). The MTBE solution of the acid was dried
by distillation and then solvent switched to THF. The final
volume of the THF solution was 2 L with a KF < 250 µg/mL.
It was used directly for the next step. The purity of the acid
at this stage was >95 A% by HPLC. HPLC conditions: column,
Waters Symmetry C8; mobile phase, acetontrile/0.1% aqueous
H3PO4 (70:30); flow rate, 1.00 mL/min; tR for acetonide, 4.5
min; benzyl chloride, 7.5 min; alkylation product, 11.5 min;
aminoindanol, 1.7 min; acid 17 tR ) 4.5 min. A pure sample of
17 was isolated through silica gel column chromatography as
the completion of the reaction was confirmed by HPLC assay
(<1 A% alcohol). Toluene (156 mL) was added to the reaction
mixture along with water (235 mL) and the phases were
separated. The organic was washed with water (100 mL × 3)
and then concentrated (∼40 °C, 40 mmHg) to 150 mL to dry
the crude product solution (KF <100 µg/mL) (flush with more
toluene if necessary). The crude product was used directly for
the next step. It may be further purified by silica gel column
to give analytically pure samples as a colorless liquid. HPLC
assay: column, Zorbax SB-C8; mobile phase, 60-95% aceto-
nitrile in 15 min, 10 mM pH ) 7.0 Trizma buffer; flow rate,
1.50 mL/min; UV detection, 220 nm; tR for DMF, 1.8 min;
imidazole, 2.1 min; alcohol (SM), 3.5 min; product, 14.5 min.
[R]25D ) +14.3° (c 1.52, hexane); 1H NMR (250 MHz, CDCl3) δ
0.06 (s, 6H, SiMe2), 0.91 (d, J ) 7 Hz, 3H, Me), 0.93 (s, 9H,
CMe3), 1.17-2.08 (m, 1H, CH), 2.44 (dd, J ) 13.3, 8.3 Hz, 1H,
CH2), 2.88 (dd, J ) 13.3, 6.2 Hz, 1H, CH2), 3.49 (d, J ) 5.6
Hz, 2H, CH2), 3.77 (s, 3H, OMe), 6.62 (dd, J ) 8.7, 3.0 Hz, 1H,
ArH), 6.76 (d, J ) 3.0 Hz, 1H, ArH), 7.40 (d, J ) 8.7 Hz, 1H,
ArH); 13C NMR (63 MHz, CDCl3) δ -5.37 (q), -5.32 (q), 16.48
(t), 18.35 (s), 25.97 (q), 36.26 (q), 39.70 (t), 55.36 (d), 67.36 (t),
113.11 (d), 115.42 (s), 116.98 (d), 133.20 (d), 141.59 (s), 158.62
(s); IR (cm-1) 2955, 2856, 1570, 1472, 1250, 838; LC-EIMS
m/z 373 (M+ + 1). Anal. Calcd for C17H29O2BrSi: C, 54.82; H,
7.85. Found: C, 55.19; H, 7.92.
a colorless oil: [R]25 ) +19.4° (c 1.04, MTBE); 1H NMR
D
(CDCl3) δ 10.5-8.7 (br, 1 H), 7.41 (d, J ) 8.8 Hz, 1 H), 6.78 (d,
J ) 3.0 Hz, 1 H), 6.66 (dd, J ) 8.8, 3.0 Hz, 1 H), 3.75 (s, 3 H),
3.14 (dd, J ) 13.1, 6.7 Hz, 1 H), 3.20-3.06 (m, 1 H), 2.77 (dd,
J ) 13.1, 7.4 Hz, 1 H), 1.23 (d, J ) 6.9 Hz, 3 H); 13C NMR
(CDCl3) δ 182.32, 158.71, 139.33, 133.37, 116.86, 115.08,
113.88, 55.36, 39.42, 39.39, 16.72; IR (thin film) 3500-2500
(br), 1701 (s), 1473, 1294, 1241 cm-1. Anal. Calcd for C11H13O3-
Br: C, 48.37; H, 4.80. Found C, 48.33; H, 4.56.
N-F or m yl-(1S,2R)-1-a m in o-2-in d a n ol. (1S,2R)-1-Amino-
2-indanol (10 g, 0.067 mol) was dissolved in THF (100 mL) at
50 °C. Acetic acid (0.192 mL, 0.003 mol) was added followed
by ethyl formate (43.2 mL, 0.53 mol) and the mixture was
heated to 62 °C for 20 h. The mixture was then cooled to rt
and the solid filtered, washed with THF (2 × 15 mL), and air-
dried to yield (10.76 g, 91% yield) of title compound as a white
(2S)-(2′-Br om o-5′-m eth oxyp h en yl)-2-m eth ylp r op a n -1-
ol (18). A solution of the acid 17 (225 g, 0.82 mol) in THF (2
L) was added to a slurry of NaBH4 (33 g, 0.86 mol) in THF
(0.5 L KF ) 200 µg/mL) over 1 h while the temperature was
maintained at 20-25 °C. (Ca u tion : Hyd r ogen ga s evolu -
tion a n d exoth er m ic!) The mixture was stirred for 30 min
at 20-25 °C, then BF3‚Et2O (152 g, 1.07 mol) was carefully
added over 1 h while the temperature was maintained at 25-
35 °C. (Ca u tion : Dela yed exoth er m !) The resulting milky
white slurry was stirred for 1 h at 30 °C. HPLC assay indicated
completion of the reaction. The reaction mixture was cooled
to 15 °C and carefully quenched by transferring into cold (10
°C) saturated aqueous NH4Cl (1.5 L) while the temperature
was maintained at 25 °C. (Ca u tion : Hyd r ogen ga s!) Most
of the THF was removed by distillation in vacuo (crucial for
good crystallization) and the aqueous layer was extracted with
MTBE (1.5 L). The organic layer was dried by flushing with
additional MTBE and then solvent switched to hexanes and
adjusted to a volume of 350 mL. It was seeded and stirred for
2 h at 20 °C and then cooled to 0-5 °C and stirred for 1 h.
The product was collected by filtration and the filter cake was
washed with cold hexanes (200 mL). The solid was dried under
a nitrogen sweep. The isolated solid (164 g) was >99 A% and
>99% ee by reverse phase and chiral HPLC assays. Reverse
phase HPLC: Column, Waters Symmetry C8; mobile phase,
MeCN/0.1% aqueous H3PO4 (50:50); flow rate, 1.00 mL/min;
UV detection at 220 nm; acid tR ) 10.2 min, alcohol tR ) 10.7
min. Chiral HPLC: column, Chiracel OD-H; mobile phase,
hexane:2-propanol (97:3); flow rate, 1.00 mL/ min; UV detec-
tion at 220 nm; (R)-isomer tR ) 23.6 min, (S)-isomer tR ) 29.2
min. White solid, mp 59-60 °C; [R]25D ) -0.68° (c 1.03, MTBE);
1H NMR (CDCl3) δ 7.40 (d, J ) 8.8 Hz, 1 H), 6.75 (d, J ) 3.1
Hz, 1 H), 6.63 (dd, J ) 8.8, 3.1 Hz, 1 H), 3.76 (s, 3 H), 3.59-
3.46 (m, 2 H), 2.85 (dd, J ) 13.4, 6.5 Hz, 1 H), 2.48 (dd, J )
13.4, 8.1 Hz, 1 H), 2.12-1.95 (m, 1 H), 1.76 (s, 1 H), 0.95 (d, J
) 6.8 Hz, 3 H); 13C NMR (CDCl3) δ 158.63, 141.07, 133.24,
crystalline solid: mp 192 °C; [R]20 ) +83° (c 1.18, MeOH); 1H
D
NMR (250 MHz, CDCl3/DMSO-d6) δ 2.30 (dd, 1H, J ) 1.5, 16.4
Hz), 2.50 (dd, 1H, J ) 4.9, 16.4 Hz), 2.75 (s, 3H), 3.92 (m, 1H),
4.35 (d, 1H, J ) 4.6 Hz), 4.76 (dd, 1H, J ) 4.9, 8.9 Hz), 6.60
(m, 3H), 7.28 (m, 1H), 7.73 (s, 1H); 13C NMR (63 MHz, CDCl3/
DMSO) δ 39.59, 55.43, 71.97, 123.83, 124.59, 126.12, 127.17,
140.25, 141.09, 161.41; LC-EIMS m/z 133 (M+ + 1 -
HCONH2). Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N,
7.90. Found: C, 67.72; H, 6.23; N, 7.77.
N-Meth yl (1S,2R)-1-Am in o-2-in d a n ol (20A). N-Formyl-
(1S,2R)-1-amino-2-indanol (20 g, 0.112 mol) was added to a
slurry of sodium borohydride (6.4 g, 0.169 mol) in 150 mL of
THF. Boron trifluoride etherate (28.8 mL, 0.227 mol) was
slowly added over 30 min while the temperature was main-
tained at 25-35 °C using an ice bath to control the exotherm.
The mixture was aged at 29-32 °C for 6 h and then carefully
quenched by transferring over 15 min into 3 N HCl (240 mL)
using an ice bath to control the temperature (15-25 °C). After
stirring for 15 min, 50% NaOH (50-55 mL) was added to
adjust the pH to 12.5 using an ice bath to control the
temperature (20-30 °C). MTBE (100 mL) was added, the
layers were separated, and the aqueous layer was extracted
with MTBE (100 mL). The combined organic layers were then
distilled and switched into EtOH and concentrated to 40 mL.
Water was added (80 mL) over 20 min and the slurry was aged
for 2 h at rt and then cooled to 5 °C and aged for 1 h. The
product was collected by filtration and washed with a cold
EtOH:water mixture (40 mL of 1:4) and air-dried to yield 16.1
20
g (87% yield) of the title compound: mp 114 °C; [R]D ) -29°
(c 1.18, MeOH); 1H NMR (CDCl3, 250 MHz) δ 2.57 (s, 3H),
2.97 (bm, 4H CH2, NH,OH), 3.92 (d, 1H, J ) 5.2), 4.45 (m,
1H), 7.23 (m, 4H); 13C (63 MHz, CDCl3) 35.14, 39.67, 67.67,
70.53, 123.86, 125.63, 126.67, 128.01, 141.12, 142.22; LC-
EIMS m/z 164 (M+ + 1). Anal. Calcd for C10H13NO: C, 73.59;
H, 8.03; N, 8.58. Found: C, 73.63; H, 8.09; N, 8.54.
116.97, 113.16, 67.35, 55.36, 39.67, 36.32, 16.38; IR (cm-1
)
(KBr) 3431 (br), 1571, 1473, 1039; GC-EIMS m/z 258 (M+).
Anal. Calcd for C11H15O2Br: C, 50.98; H, 5.83. Found: C, 51.02;
H, 5.74.
(2S)-3-(2-Br om o-5-m eth oxyp h en yl)-1-(ter t-bu tyld im e-
th ylsilyoxy)-2-m eth ylp r op a n e (19). tert-Butyldimethylsilyl
chloride (30.45 g, 0.202 mol) was added to a solution of the
alcohol 18 (51.8 g, 0.200 mol) in dry DMF (104 mL, KF < 100
µg/mL) at 20 °C. A solution of imidazole (16.34 g, 0.24 mol) in
DMF (52 mL) was then added slowly, the temperature of the
reaction mixture being maintained between 20 and 30 °C. The
reaction mixture was aged at room temperature for 2 h and
N,O-Aceta l 21A fr om N-Meth yl-(1R,2S)-1-a m in o-1-in -
d a n ol. To a solution of the Heck reaction product 12 in toluene
(5.18 g in a total of 12.8 g, 17.9 mmol) was added solid (1R,2S)-
N-methyl 1-amino-1-indanol (2.92 g, 17.9 mmol), followed by
acetic acid (20 mg). The reaction mixture was then heated to
reflux to remove water by azeotrope with a Dean-Stark trap.
After HPLC assay indicated that the Heck product has been
consumed (<2 A%), the reaction was cooled to 20 °C and

Synthesis of an Endothelin Receptor Antagonist
J . Org. Chem., Vol. 64, No. 26, 1999 9665
poured into saturated aqueous NaHCO3 (15 mL) with stirring.
The organic layer was washed with water (20 mL × 2) and
concentrated to minimum volume under reduce pressure (40-
50 °C, 40 mmHg) and flushed with additional toluene if
necessary to dry the crude product by azeotrope until KF <
100 µg/mL. HPLC: column, Zorbax SB-C8, 4.6 × 250 mm;
mobile phase, acetonitrile/10 mM Trizma buffer (with 5%
MeCN), 60-95% MeCN in 15 min; flow rate, 1.50 mL/min;
UV detection at 220 nm; tR for toluene, 3.8 min; Heck product,
7.7 min; N,O-acetal, 12.0, 12.5 min (two diastereomers). 1H
NMR (250 MHz, CDCl3) (A mixture of two compounds in about
55/45 was observed; all peaks are listed and some peaks are
paired up if they appear to be from the same hydrogens of the
two diastereomers) δ 0.85-1.0 (m, 3H), 1.25-1.45 (m, 2H),
1.53, 1.54 (s, s, 9H), 1.6-1.8 (m, 2H), 2.18, 2.51 (s, s, 3H), 2.65-
2.80 (m, 2H), 3,21-3.24 (m, 2H), 4.88, 4.25 (d, J ) 5.1 Hz, d,
J ) 7.7 Hz, 1 H), 5.04-5.11 (m, 1 H), 5.13, 5.44 (s, s, 1H),
6.9-7.4 (m, 5H), 7.5-8.2 (m, 3H); 13C NMR (63 MHz, CDCl3)
δ 166.5, 166.2, 162.4, 162.1, 155.6, 155.0, 142.6, 142.1, 141.1,
139.7, 138.8, 138.7, 136.4, 135.9, 130.3, 128.7, 128.5, 128.3,
127.2, 126.9, 126.0, 125.4, 125.3, 125.03, 124.96, 123.3, 122.7,
95.7, 91.7, 81.5, 80.4, 80.2, 77.3, 76.0, 74.1, 39.4, 38.7, 37.9,
37.8, 37.0, 31.7, 31.6, 28.2, 27.0, 22.5, 22.4, 14.0.
N,O-Aceta l 21B fr om P seu d oep h ed r in e. The same pro-
cedure was used. One isomer was observed; 1H NMR (250
MHz, CDCl3) δ 0.94 (t, 3H, J ) 7.3), 1.25 (d, 3H, J ) 6.0 Hz),
1.39 (m, 2H), 1.55 (s, 9H), 1.72 (m, 2H), 2.18 (s, 3H), 2.55 (m,
1H), 2.79 (t, 2H, J ) 7.9), 4.79 (d, 1H, J ) 8.7 Hz), 5.30 (s,
1H), 7.0(d, 1H, J ) 15.3 Hz), 7.14 (d, 1H, J ) 8.0 Hz), 7.2-7.4
(bm, 4H), 7.85 (d, 1H, J ) 8.0), 8.24 (d, 1H, J ) 15.3 Hz); 13C
NMR (63 MHz, CDCl3) δ 13.97, 14.38, 22.44, 28.24, 31.72,
35.18, 37.96, 68.91, 80.33, 86.43, 95.89, 123.19, 125.22, 126.55,
128.02, 128.45, 130.50, 137.38, 139.02, 140.08, 151.22, 162.73,
166.44.
Con ju ga te Ad d ition To P r ep a r e 22. To a dry and
degassed (put under vacuum and nitrogen two or three times)
solution of aryl bromide 19 (3.80 g, 98 wt %, 10.0 mmol) in
toluene (20 mL, KF < 100 µg/mL) and THF (5.0 mL) at -78
°C was added a 2.5 M solution of n-BuLi in hexanes (4.0 mL,
10.0 mmol) in ∼15 min. The mixture was stirred at -78 °C
for 1 h. The cold solution was then cannulated into the cold
solution (-78 °C) of N,O-acetal from N-methyl-(1R,2S)-1-
amino-2-indanol (9.0 mmol) in THF (20 mL) rapidly. The
exotherm raises the temperature of the reaction mixture to
approximately -50 °C. It was stirred at -50 to -60 °C for 1
h and then quenched carefully with 2.85 mL of acetic acid.
(Ca u tion : Exoth er m ic r ea ction !) After warming to ∼0 °C,
aqueous citric acid solution (4.8 g of citric acid in 15 mL of
water) was added and the two-phase mixture was rapidly
stirred for 16 h at room temperature. HPLC assay indicates
that the N,O-acetal hydrolysis was complete. The organic layer
was separated and successively washed with 14 wt % NaCl
(20 mL), saturated aqueous NaHCO3 (30 mL), 14 wt % NaCl
(20 mL), and finally brine (20 mL). The NaHCO3 wash should
be slightly basic (pH ) 7.5-8.5), otherwise more bicarbonate
washes were done. The organic layer was dried by azeotropic
distillation under reduced pressure (40-50 °C, ∼40 mmHg)
to minimum volume. Flush with additional toluene if necessary
to achieve KF < 100µg/mL. HPLC assay indicated 90-95%
overall yield from the Heck reaction product. The de of the
product was determined by HPLC to be 90%. These steps have
been run on 10 kg scale. HPLC conditions were the same as
described in the N,O-acetal formation; tR for toluene, 3.8 min;
Ar1H, 12.9 min; Ar1Br, 14.5 min; Ar1Bu, 16.5 min; aldehyde
product 22, 17.7 min; N,O-acetal product, 20.9, 22.1 min (two
diastereomers epimeric at the acetal moiety). Chiral HPLC
assay: column, (R, R) Whelk-O; mobile phase, hexane:IPA 97:
3; flow rate, 1.00 mL/min; tR for major isomer, 6.3 min; minor
isomer, 7.1 min. A pure sample was isolated as an amorphous
(m, 3H), 3.73 (s, 3H), 5.45 (dd, J ) 11.2, 3.7 Hz, 1H), 6.57 (dd,
J ) 8.6, 2.6 Hz, 1H), 6.71 (d, J ) 2.6 Hz, 1H), 6.91 (d, J ) 8.6
Hz, 1H), 7.12 (d, J ) 7.9 Hz, 1H), 7.98 (d, J ) 7.9 Hz, 1H),
10.25 (s, 1H); 13C NMR (63 MHz, CDCl3) δ -5.33, 13.95, 16.74,
22.42, 25.97, 27.96, 31.06, 36.18, 38.28, 39.28, 41.23, 55.05,
67.87, 79.97, 111.49, 115.58, 120.77, 126.87, 129.96, 133.52,
137.43, 139.06, 157.77, 163.38, 166.38, 171.35, 191.18; IR
(cm-1) 2956, 2930, 2857, 1729, 1584, 1463. Anal. Calcd for
C
34H53NO5Si: C, 69.94; H, 9.15; N, 2.40. Found: C, 70.24; H,
9.27; N, 2.38.
Gr ign a r d Ad d ition . P r ep a r a tion of th e Gr ign a r d Re-
a gen t (Ar 2MgBr ). To a 22 L reaction flask equipped with an
efficient condenser were added Mg (240 g, 9.87 mol) and dry
THF (8.2 L, KF < 100 µg/mL). After degassing by two vacuum/
N2 cycles, the mixture was heated to 50 °C and then the
4-bromo-1,2-(methylenedioxy)benzene (1.89 kg, 9.40 mol) was
added carefully. (Ca u tion : Du e to th e in d u ction p er iod
a n d th e ver y exoth er m ic r ea ction , th e a r yl br om id e
sh ou ld be a d d ed ver y ca r efu lly! No m or e th a n 10%
sh ou ld be a d d ed befor e th e r ea ction is in itia ted a s
in d ica ted by th e color ch a n ge fr om color less to br ow n
a n d exoth er m .) Once the reaction was initiated, the remain-
ing aryl bromide was added slowly to maintain a gentle reflux.
The reaction mixture was then stirred at 50 °C for 2 h to give
a solution of ArMgBr (∼9.4 L, 1.0 M). The reaction was
monitored by HPLC: Column, Zorbax SB-C8 (4.6 × 250 mm);
column temperature, 30 °C; mobile phase, MeCN/0.1% aqueous
H3PO4 (40/60-70/30 in 15 min); flow rate, 1.50 mL/min; UV
detection, 220 nm; tR for Ar2Br, 6.2 min; Ar2H, 9.2 min.
Gr ign a r d Ad d ition to th e Ald eh yd e 22 To P r ep a r e 24.
To a 72 L flask were added a dry solution of the crude Michael
addition product 22 (4.22 kg in ∼4.7 L of toluene and 2.5 L of
THF, KF < 200 µg/mL) and more dry THF (20 L, KF < 100
µg/mL). The mixture was degassed by a vacuum/N2 cycle and
cooled to -75 °C with a dry ice-methanol bath. The Ar2MgBr
prepared was added slowly to maintain the reaction mixture
below -65 °C. The mixture was stirred at -70 °C for 3 h and
the completion of the reaction was confirmed by HPLC (<1
A% aldehyde). The reaction mixture was then pumped into
saturated aqueous NH4Cl (14 L, 20 wt %) to quench the
reaction. Toluene (14 L) was added and the mixture warmed
to 20 °C. The organic layer was separated and washed with
brine (14 L) to give a solution of the crude Grignard addition
product (50.11 kg). Assay by HPLC indicates the presence of
4.67 kg (91% yield) of the product 24 in the solution as a 93/7
mixture of two diastereomers. HPLC conditions: column,
Zorbax SB-C8, 4.6 × 250 mm; temperature, 30 °C; mobile
phase, CH3CN/ 0.1% aqueous H3PO4, 80:20 gradient to 100:0
over 15 min; flow rate, 1.5 mL/min; tR for aldehyde, 12.15 min;
major stereoisomer, 9.93 min; minor stereoisomer, 10.65 min.
The crude product solution was dried by azeotropic distillation
of toluene to a final volume of 15 L (∼40 °C, 40 mmHg). The
KF of the residue should be below 150 µg/mL (flush with
additional toluene if necessary). The crude product was used
directly for the cyclization. The analytical sample was obtained
as an amorphous solid by silica gel column purification. [R]25
D
1
) -38.3° (c 1.50, hexane); H NMR (250 MHz, CDCl3) δ 0.04
(s, 3H), 0.05 (s, 3H), 0.90 (s, 9H), 0.90-1.00 (m, 6H), 1.32 (s,
9H), 1.34-1.50 (m, 2H), 1.72-1.83 (m, 2H), 1.84 (d, J ) 3.3
Hz, 1H), 1.92-2.10 (m, 1H), 2.40 (dd, J ) 14.3, 8.8 Hz, 1H),
2.53 (dd, J ) 16.3, 4.0 Hz, 1H), 2.80 (t, J ) 7.6 Hz, 2H), 2.96
(dd, J ) 14.3, 6.0 Hz, 1H), 3.38-3.50 (m, 3H), 3.73 (s, 3H),
4.97 (dd, J ) 10.9, 3.9 Hz, 1H), 5.86 (d, J ) 2.4 Hz, 1H), 5.91
(d, J ) 2.3 Hz, 2H), 6.59 (dd, J ) 8.6, 2.8 Hz, 1H), 6.70-6.80
(m, 4H), 6.86 (d, J ) 8.6 Hz, 1H), 6.97 (d, J ) 7.9 Hz, 1H),
7.42 (d, J ) 7.9 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ -5.40,
13.97, 16.76, 18.30, 22.45, 25.92, 27.95, 31.36, 35.98, 36.23,
37.55, 40.28, 41.24, 54.98, 67.84, 70.47, 79.54, 100.85, 107.32,
107.86, 111.36, 115.73, 119.89, 120.49, 129.56, 133.93, 134.18,
136.28, 136.42, 139.26, 146.61, 147.50, 157.78, 158.10, 159.96,
171.50; IR (cm-1) 3451, 2857, 1731, 1608, 1573; LC-EIMS m/z
706 (M+ + 1). Anal. Calcd for C41H59NO7Si: C, 69.75; H, 8.42;
N, 1.98. Found: C, 69.99; H, 8.47; N, 1.93.
solid through silica gel column chromatography: [R]25
)
D
1
-116.4° (c 1.42, hexane); H NMR (250 MHz, CDCl3) δ 0.06
(s, 6H), 0.91 (s, 9H), 0.91-1.00 (m, 6H), 1.30 (s, 9H), 1.33-
1.48 (m, 2H), 1.73-1.86 (m, 2H), 1.98-2.12 (m, 1H), 2.46 (dd,
J ) 14.3, 9.0 Hz, 1H), 2.60 (dd, J ) 16.5, 3.5 Hz, 1H), 2.86 (t,
J ) 7.6 Hz, 2H), 3.07 (dd, J ) 14.3, 5.8 Hz, 1H), 3.49-3.61
Cycliza tion -Dep r otection . Diethyl chlorophosphate (1.65
kg, 9.6 mol, 1.45 equiv) was added to the dry Grignard addition

9666 J . Org. Chem., Vol. 64, No. 26, 1999
Song et al.
product 22 in toluene (∼15 L) at -15 °C. Then LiN(SiMe3)2
(1.0 M in THF, 28.75 L, 4.35 equiv) was added while the
reaction temperature was kept at <5 °C. The slurry was
stirred at 0-10 °C for 4 h. More diethyl chlorophosphate and
LiN(SiMe3)2 may be added to complete the reaction if required.
HPLC: Column, Zorbax SB C-8 (4.6 × 50 mm); mobile phase,
MeCN/0.1% aqueous H3PO4, gradient 80/20, 10 min 95/5, 20
min A/B 98/2; flow rate, 1.5 mL/min; UV detection, 220 nm; tR
for starting material, 10.9 min; intermediate, 11.7 min;
intermediate, 13.2 min; cyclization product, 12.2 min. After
the reaction was completed (SM < 1%), water (17 L) and acetic
acid (4.5 kg, exoth er m ic!) were added while the reaction
temperature was kept at <30 °C. The organic layer was
separated, washed with brine (14 L), concentrated under
vacuum to 10-12 L, mixed with acetonitrile (20 L), and then
cooled to 0 °C. Concentrated HCl (13.2 kg) was added slowly
while the reaction temperature was kept at <25 °C. The
mixture was stirred at 20-25 °C overnight to give a mixture
of the acid alcohol and the lactone. HPLC conditions: (same
column and eluents as above) gradient, time 0 A/B 50/50, 10
min A/B 90/10, 15 min 90/10; tR for tert-butyl ester alcohol,
6.4 min; lactone, 4.7 min; acid alcohol, 2.9 min. After the tert-
butyl ester alcohol was consumed (19 h), the reaction mixture
was cooled to 0 °C and neutralized with 40% NaOH until pH
) 3-5 (∼12.4 kg) while the temperature was kept at <25 °C.
Water (6 L) was also added to dissolve all the salt. The two
layers were separated and the top organic layer was mixed
with 3.3 kg of 40% NaOH (5 equiv) and 12 L of water. The
mixture was vigorously stirred for 3 h until all the lactone was
hydrolyzed (organic layer sample). The two layers were then
separated and then MTBE (20 L), water (20 L), and 40% NaOH
(200 g) were added to the organic layer with stirring. The two
layers were separated, and the organic layer was mixed with
NaOH (100 g, 40% NaOH), water (10 L), and heptane (20 L).
The layers were separated, and the organic layer was dis-
carded. Acetonitrile was mostly with the top layer in the first
separation but with the bottom layer in the second separation,
which was a difficult cut because both layers were dark brown.
The combined aqueous layers were mixed with MTBE (12 L)
and then neutralized with H3PO4 (85%, 4.6 kg, 6 equiv) until
pH ) 3-4 (exothermic, keep the temperature <25 °C). The
two layers were separated and the aqueous layer was extracted
with toluene (20 L). The combined organic layers were dried
by azeotropic distillation of toluene to a volume of 10 L. Flush
with more toluene if necessary to achieve KF < 500 µg/mL.
The residue was then diluted with 50 L of MTBE. Benzylamine
(0.85 kg, 1.2 equiv) was added as a solution in 3 L of MTBE in
an addition funnel. Only 1.5 L of this solution was added
initially and the batch was seeded and stirred for 1 h for the
salt to precipitate. The rest of the benzylamine solution was
added over 30 min. An additional 7 L of MTBE was used for
rinse of the addition funnel. The batch was stirred at ambient
temperature overnight. The solid was collected by filtration
and washed (3 × 4 L MTBE) until the wash was nearly
colorless. The batch was dried with nitrogen flow and suction.
The title compound was obtained as an off white solid (2.96
kg, 72% yield). HPLC showed ∼95 wt % pure and 98.5 A%:
mp 131-133 °C (dec); [R]25D ) +28.5° (c 0.98, MeOH); 1H NMR
(250 MHz, CDCl3) δ 0.83-0.89 (m, 6H), 1.21-1.36 (m, 2H),
1.51-1.63 (m, 2H), 1.89-2.00 (m, 1H), 2.54 (dd, J ) 14.2, 7.8
Hz, 1H), 2.66 (t, J ) 7.7 Hz, 2H), 2.77 (dd, J ) 14.2, 6.0 Hz,
1H), 3.04 (t, J ) 9.2 Hz, 1H), 3.20 (dd, J ) 10.7, 6.7 Hz, 1H),
3.36 (dd, J ) 10.7, 4.7 Hz, 1H), 3.47 (s, 2H), 3.67 (s, 3 H), 4.42
(d, J ) 9.0 Hz, 1H), 4.90 (d, J ) 9.2 Ha, 1H), 5.84 (s, 2H),
6.58-6.69 (m, 5H), 6.78 (d, J ) 8.5 Hz, 1H), 6.89-6.93 (m,
5H), 7.07-7.16 (m, 6H); 13C NMR (63 MHz, CDCl3) δ 13.9,
17.1, 22.3, 32.3, 36.7, 36.8, 37.5, 43.4, 50.3, 52.0, 54.9, 66.2,
66.9, 100.9, 108.2, 108.6, 111.6, 114.8, 120.6, 121.6, 128.1,
128.4, 128.6, 129.7, 132.7, 134.3, 135.4, 135.8, 137.7, 141.4,
146.3, 147.8, 157.4, 162.2, 165.1, 179.8; LC-EIMS m/z 518 (M+
+ 1). Anal. Calcd for C38H44N2O6: C, 73.05; H, 7.10; N, 4.48.
Found: C, 73.18, H, 7.09; N, 4.45.
g, 70 mmol) to a total volume of 160 mL. An aqueous solution
of CrO3 (0.16 mL, KF ) 200 µg/mL) was then added and the
mixture was stirred until all of the solid dissolves. The solu-
bility of H5IO6 in MeCN was limited and it may take 2 h to
dissolve it completely. The reaction was sensitive to the content
of water, and it appears that 0.5-1.0 vol % was optimal.
P r ep a r a tion of th e F r ee Acid 1. To a mixture of the
benzylamine salt of the hydroxy acid 26 (12.50 g, 20.0 mmol)
in MTBE (100 mL) and water (50 mL) was added 2.0 N HCl
(∼10 mL) until pH ) 3-4. The organic layer was washed with
water (3 × 50 mL) and brine (50 mL) and then concentrated
to ∼30 mL. It was flushed with acetonitrile (100 mL) and then
diluted with MeCN (to 100 mL). Water (0.75 mL) was then
added and the mixture was cooled to -5 °C. A portion of the
H5IO6/CrO3 solution (50 mL, 1.1 equiv) was added in 5-10
min. The remaining portion (110 mL) was added in 30-60 min
while the batch temperature was maintained at -3 to 0 °C.
No significant oxidation occurs until after the addition of the
first equivalent of the reagent. The mixture was stirred for
0.5 h at 0 °C and the completion of the reaction was confirmed
by HPLC. The reaction was quenched with Na2HPO4 solution
(8.52 g in 150 mL of H2O) and then brine (50 mL). Some
inorganic solid remains and was filtered off. The pH of the
aqueous layer should be 3-4. Toluene (150 mL) was added
and organic layer was separated and washed with 1/1 brine/
water mixture (2 × 100 mL). The organic layer was concen-
trated to 160 mL to remove most of the acetonitrile (40 mmHg,
30 °C bath). Loss in the aqueous washes was minimal (∼0.01
mg/mL). The acetonitrile should not be completely distilled in
order to avoid the appearance of some red brown gummy
material which may be the HCl salt of the product based on
HPLC. The mixture was treated with 0.30 N NaOH (150 mL)
for 0.5 h and the organic layer was separated and discarded.
MTBE was added (100 mL) to the aqueous layer and the
mixture was acidified with 2.0 N HCl (∼22.5 mL) to pH ) 3.5.
The organic layer was separated and washed with water (2 ×
50 mL) and brine (50 mL) and then concentrated to give the
crude product as a brown foam. HPLC indicates 9.5-10.9 g of
1 (90-95% yield) and 94-97 A% HPLC conditions: Column,
YMC-ODS AM, 4.6 × 250 mm; solvent: CH3CN:0.1% H3PO4
50:50 gradient to 80:20 over 15 min; flow rate, 1.0 mL/min;
temperature, 30 °C; UV detection, 220 nm; tR for hydroxy acid,
5.8 min; diacid, 7.8 min.
TEMP O/Na ClO-ca ta lyzed Oxid a tion To P r ep a r e 1. A
mixture of the benzylamine salt of the hydroxy acid 26 (6.60
kg by assay, 10.56 mol) in MTBE (66 L) and water (26 L) was
treated with 2.0 N HCl (5.5 L) until pH ) 3-4. The organic
layer was washed with water (2 × 26 L) and then extracted
with NaOH (37 L, 0.63 N NaOH). To the NaOH extract were
added MeCN (53 L) and NaH2PO4 (4.2 kg), and the mixture
was heated to 35 °C. The pH of the mixture should be 6.7.
TEMPO (165 g, 1.06 mol) was added followed by a simulta-
neous addition (over 2 h) of a solution of sodium chlorite
(NaClO2, 2.4 kg, 80%, 21 mol in 9.9 L of water) and a solution
of dilute bleach (550 g of 5.25% bleach diluted into 5.3 L of
water). The sodium chlorite solution and bleach should not be
mixed prior to the addition since the mixture appears to be
unstable. The addition was carried out as follows: with a slow
nitrogen sweep over the batch, approximately 20% of the
sodium chlorite solution was added followed by 20% of the
dilute bleach. Then the rest of the NaClO2 solution and dilute
bleach were added simultaneously over 2 h. The reaction was
slightly exothermic. The mixture was stirred at 35 °C until
the reaction was complete by HPLC (2-4 h). The batch was
cooled to room temperature, water (79 L) was added, and the
pH was adjusted to 8.0 with 2.0 N NaOH (12.7 L). The reaction
was quenched by pouring into cold (0 °C) Na2SO3 solution (3.22
kg in 53 L water) maintained at <20 °C. The pH of the aqueous
layer should be 8.5-9.0. After aging for 0.5 h at room
temperature, MTBE (53 L) was added with stirring. The
organic layer was discarded and the aqueous layer was
acidified with 2.0 N HCl (32.2 L) to pH ) 3-4 and extracted
with MTBE (80 L). The organic layer was washed with water
(2 × 26 L) and brine (40 L) to give a solution of the crude
Cr O3-Ca ta lyzed Oxid a tion To P r ep a r e 1. P r ep a r a tion
of th e Oxid a n t Solu tion . A solution of H5IO6/CrO3 was
prepared by adding water (1.1 mL) and MeCN to H5IO6 (15.95
dicarboxylic acid
1
(90-95% yield by HPLC assay).

Synthesis of an Endothelin Receptor Antagonist
J . Org. Chem., Vol. 64, No. 26, 1999 9667
P r ep a r a tion of th e Disod iu m Sa lt of 1. The organic layer
from last step was concentrated under vacuum and flushed
with dry ethyl acetate repeatedly (2 × 20 L) and the final
residue dissolved in 28 L of dry ethyl acetate. To this solution
was added a solution of sodium ethoxide (1.44 kg, 21.1 mol)
in 5.75 kg of ethanol over 10 min at 30-35 °C. After seeding,
additional ethyl acetate (140 L) was added over 2 h at 25 °C.
After aging for 16 h, the slurry was filtered and the cake
washed with 70 L of ethyl acetate. The crystals were dried in
a vacuum oven at 60 °C overnight to give the disodium salt as
a slightly hygroscopic, white solid (5.22 kg, 86% yield from the
NMR (250 MHz, H2O) δ 6.96 (d, J ) 7.8 Hz, 1 H), 6.80 (d, J )
2.3 Hz, 1 H), 6.75-6.56 (m, 6H), 5.68 (s, 2H), 4.88 (d, J ) 9.2
Hz, 1H), 4.47 (d, J ) 9.3 Hz, 1H), 3.68 (s, 3H), 3.00-2.74 (m,
3 H), 2.65-2.50 (m, 3H), 1.48-1.36 (m, 2H), 1.15-1.03 (m,
5H), 0.69 (t, J ) 7.3 Hz, 3H); 13C NMR (63 MHz, H2O) δ 186.34,
181.88, 165.21, 162.80, 157.85, 148.28, 146.84, 142.39, 138.02,
137.71, 135.05, 134.29, 130.51, 122.37, 122.13, 115.82, 112.93,
109.28, 108.96, 101.81, 69.39, 56.03, 53.12, 51.18, 46.13, 38.34,
37.26, 32.91, 22.48, 18.77, 14.26; LC-EIMS m/z 532 (M+
+
1).
alcohol): HPLC 99.1 A%. [R]25 ) +100° (c 1.135, H2O); 1H
J O991292T
D