Practical enantioselective synthesis of endothelin antagonist S-1255 by dynamic resolution of 4-methoxychromene-3-carboxylic acid intermediate

Article abstract of DOI:10.1021/jo0261092

A practical multikilogram-scale synthesis of enantiomerically pure S-1255 (1), a potent and orally active ETA receptor antagonist, is described. Utilizing readily available starting materials and reagents, the entire sequence of reactions starting from 2,5-dihydroxyacetophenone 8 proceeded under mild conditions to give 1 in an excellent chemical yield (8 steps, 41% overall yield) and in a high enantiopurity (98% ee). The crucial step of the synthesis is a dynamic resolution of key intermediate 16. (R)-Methoxy acid (R)-16 having 97-99% ee was obtained in 83-84% yield from racemic 16 as a crystalline (1S,2R)-(+)-norephedrine or (+)-cinchonine salt by the dynamic resolution comprising concurrent crystallization and in situ racemization. A mechanism of the dynamic resolution through a ring-opened zwitterionic intermediate is discussed. In the final synthetic step, an effective carbon - carbon bond formation between the C4 carbon and the p-anisyl group was accomplished by a conjugate addition - elimination reaction of Grignard reagent 3 to (R)-16 to give 1 having 98% ee. Owing to high efficiencies of functional group transformations, carbon - carbon bond formations, and the dynamic resolution, the synthesis required no chromatographic purification and was amenable to a multikilogram-scale preparation. Several kilograms of 1 for clinical trials were successfully prepared by this process.

Full text of DOI:10.1021/jo0261092

P r a ctica l En a n tioselective Syn th esis of En d oth elin An ta gon ist
S-1255 by Dyn a m ic Resolu tion of 4-Meth oxych r om en e-3-ca r boxylic
Acid In ter m ed ia te
Toshiro Konoike,*,† Ken-ichi Matsumura,‡ Tadahiko Yorifuji,† Shoji Shinomoto,†
Yutaka Ide,† and Takashi Ohya†
Shionogi Research Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-chome,
Amagasaki, Hyogo 660-0813, J apan
toshiro.konoike@shionogi.co.jp.
Received J une 27, 2002
A practical multikilogram-scale synthesis of enantiomerically pure S-1255 (1), a potent and orally
active ETA receptor antagonist, is described. Utilizing readily available starting materials and
reagents, the entire sequence of reactions starting from 2,5-dihydroxyacetophenone 8 proceeded
under mild conditions to give 1 in an excellent chemical yield (8 steps, 41% overall yield) and in a
high enantiopurity (98% ee). The crucial step of the synthesis is a dynamic resolution of key
intermediate 16. (R)-Methoxy acid (R)-16 having 97-99% ee was obtained in 83-84% yield from
racemic 16 as a crystalline (1S,2R)-(+)-norephedrine or (+)-cinchonine salt by the dynamic resolution
comprising concurrent crystallization and in situ racemization. A mechanism of the dynamic
resolution through a ring-opened zwitterionic intermediate is discussed. In the final synthetic step,
an effective carbon-carbon bond formation between the C4 carbon and the p-anisyl group was
accomplished by a conjugate addition-elimination reaction of Grignard reagent 3 to (R)-16 to give
1 having 98% ee. Owing to high efficiencies of functional group transformations, carbon-carbon
bond formations, and the dynamic resolution, the synthesis required no chromatographic purification
and was amenable to a multikilogram-scale preparation. Several kilograms of 1 for clinical trials
were successfully prepared by this process.
In tr od u ction
prepared in 10 steps from 2,5-dihydroxyacetophenone 8
and in overall yield of 5%.3 Although this route facilitated
the SAR studies and led to a rapid optimization of lead
derivatives, it had several drawbacks for a multikilo-
gram-scale preparation of 1. The most serious problem
resided in the optical resolution of the racemic 1 (rac-1)
in the last step, where the yield was as low as 25% and
no practical method for recycling the undesired (S)-
isomer by racemization was available. The original route
also required several expensive reagents such as a
palladium complex in the Suzuki coupling reaction, and
chromatographic purification was used in most of the
reaction steps.
Endothelins (ET), endogenous vasoconstrictive pep-
tides consisting of 21 amino acids, have been implicated
in various cardiovascular disorders.1 Three isopeptides,
ET-1, ET-2, and ET-3, have been identified, which exert
the biological actions by binding the G-protein-coupled
receptors, ETA and ETB. Because of a promising thera-
peutic potential of an ETA receptor antagonist, a number
of peptide and nonpeptide ETA receptor antagonists have
been developed for treating various cardiovascular dis-
eases.2
In a previous paper,3 we have reported a synthesis, the
biology, and the structure-activity relationships (SAR)
of a novel ETA receptor antagonist, S-1255 (1), which is
an optically active 2H-chromene-3-carboxylic acid bearing
substituted phenyl groups on the 2- and 4-positions. The
absolute configuration of the 2-position was determined
to be R by X-ray analysis.3 In a discovery route, 1 was
Since identification of 1 as a promising drug candidate,
we have investigated a more efficient enantioselective
synthesis of 1 that is amenable to a multikilogram-scale
† Manufacturing Technology R & D Laboratories.
‡ Drug Discovery Laboratories, Shionogi Research Laboratories,
Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-
0002, J apan.
(1) Yanagisawa, M.; Kurihara, H.; Kimura, S.; Tomobe, Y.; Koba-
yashi, M.; Mitsui, Y.; Yasaki, Y.; Goto, K.; Masaki, T. Nature 1988,
332, 411.
(2) Wu, C. Exp. Opin. Ther. Patents 2000, 10, 1653 and references
therein.
(3) Ishizuka, N.; Matsumura, K.; Sakai, K.; Yamamori, T.; Mihara,
S.; Fujimoto, M. J . Med. Chem. 2002, 10, 2041.
preparation to supply a sufficient amount of 1 for
10.1021/jo0261092 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/09/2002
J . Org. Chem. 2002, 67, 7741-7749
7741

Konoike et al.
SCHEME 1
SCHEME 2a
a
Reagents and conditions: (a) i-PrBr, K2CO3, MeCN, reflux;
(b) 7, 2 N NaOH, MeOH, rt, 78% (2 steps); (c) POCl3, DMF, rt,
99%.
a small amount when other alkylation conditions were
used. This crude material of 6 was used for the next
reaction without further purification. The regioselective
isopropylation on the 5-position can be explained by an
intramolecular hydrogen bonding between the 1-acetyl
oxygen and the 2-hydroxy hydrogen, which retards the
alkylation of the 2-hydroxy group.
toxicological and clinical studies. In this paper, we report
the development of a practical multikilogram-scale syn-
thesis of S-1255 (1) via a new dynamic resolution of the
key intermediate 16, and the mechanism of the dynamic
resolution is discussed.
Synthesis of chromanone 5 from 6 was conducted under
conventional basic conditions.4 Stirring of a MeOH solu-
tion of crude 6, piperonal 7, and 2 N NaOH at room
temperature followed by collection of the precipitated
crystals by filtration gave 5 containing 4% of chalcone 9
in 78% overall yield from 8. The choice of the solvent
proved to be crucial for this reaction. When EtOH or
MeCN was used as the solvent, none of the crystals were
precipitated out and a complex mixture of 5, 9, and aldol
products was obtained. These results show that chro-
manone 5 is in equilibrium with chalcone 9 in the
reaction solution,5 and crystallization of 5 from MeOH
(not from EtOH or MeCN) shifts the equilibrium to give
5 in good yield.
The next step involving formylation of chromanone 5
at the 3-positon and a concurrent enol chlorination at the
4-position to form chloroaldehyde 4 was accomplished in
a single step by a Vilsmeier-Haack-type reaction.6
Reaction of 5 with POCl3 in DMF at room temperature,
followed by addition of H2O and collection of the precipi-
tates, gave 4 in 99% yield and 95% purity.
Resu lts a n d Discu ssion
Retr osyn th esis. Our retrosynthetic analysis of 1 is
shown in Scheme 1. The retrosynthetic disconnection of
the alkenyl-aryl bond at the 4-position furnished chro-
mene (R)-2 having a leaving group X at the 4-position.
The conjugate addition-elimination reaction of Grignard
reagent 3 to (R)-2 was planned for this alkenyl-aryl bond
formation. (R)-2 would be prepared by an optical resolu-
tion of racemic carboxylic acid 2 (R ) H) via a diaster-
eomeric salt with an optically active amine. The racemic
2 could be synthesized from aldehyde 4 via chromanone
5, which could be prepared by the coupling of piperonal
7 with 2-hydroxy-5-isopropoxyacetophenone 6 that could
be readily available from inexpensive 2,5-dihydroace-
tophenone 8. An efficient optical resolution of the racemic
2 (R ) H) with facile racemization of the unwanted (S)-2
(R ) H) should be developed.
Syn th esis of Ch lor oaldeh yde 4. As shown in Scheme
2, commercially available 2,5-dihydroxyacetophenone 8
was treated with 2-bromopropane and K2CO3 in refluxing
MeCN. Simple filtration and concentration of the reaction
mixture gave 5-isopropoxy-2-hydroxyacetophenone 6 con-
taining 2% of 8 and 9% of 2,5-diisopropoxy compound 10
(HPLC). 2-Isopropoxy compound 11 also was detected in
(4) Reichel, L.; Mu¨ller, K. Chem. Ber. 1941, 74, 1741.
(5) Draper, R. W.; Radha, B. H.; Iyer, R. V.; Li, X.; Lu, Y.; Rahman,
M.; Vater, E. J . Tetrahedron 2000, 56, 1811.
(6) Litkei, G.; Patonay, T.; Szila´gyi, L.; Dinya, Z. Org. Prep. Proced.
Int. 1991, 23, 741.
7742 J . Org. Chem., Vol. 67, No. 22, 2002

Synthesis of Endothelin Antagonist S-1255
SCHEME 3a
TABLE 1. Ad d ition -Elim in a tion Rea ction of 16 or 17
w ith Gr ign a r d Rea gen t 3
conditions
yield (%)a
3
T
time
(h)
16
or 17
rac-1
or 14
entry reactant (equiv) (°C)
18
1
2
3
4
5
6
16
16
17a
17a
17b
17b
3.0
4.0
1.1
3.0
3.0
3.0
0
0
0
0
0
2
2
3
0.5
0.5
4
6
0
34
0
0
4
81
0
0
9
87 (84b)
57
64c
82
64
30c
9
-78
18
a
Determined by HPLC analysis of the crude reaction mixture
unless otherwise stated. The yield was presented as an area
percentage of the compound peak relative to the total area of all
b
the peaks integrated. Isolated yield after recrystallization.
c Isolated yield after chromatography.
As the methoxy group has been known to be a better
leaving group than the chloro group for this type of
Grignard reaction,8,9 we determined to try the reaction
for methoxy acid 16 and methoxy esters 17. Preparation
of these compounds is shown in Scheme 3. The reaction
of chloro acid 12 or chloro ester 13 with NaOMe to give
16 or 17a was unsuccessful, recovering unchanged 12 and
13. Alternatively, the reaction of chloroaldehyde 4 with
NaOMe proceeded smoothly to give methoxyaldehyde 15,
which was isolated by aqueous workup and used for the
next step without further purification. Oxidation of 15
with an acidic reagent of NaClO2-NH2SO3H resulted in
decomposition of the starting material 15, whereas mild
NaClO2-DMSO oxidation in a weakly acidic medium10
gave highly pure methoxy acid 16 (HPLC, 99% purity)
in 69% overall yield from 4 after aqueous workup and
crystallization from toluene. The esterification of 16 with
MeI or 2-bromopropane with K2CO3 as the base and DMF
as the solvent provided methyl ester 17a or isoporpyl
ester 17b, respectively, in good yield.
a
Reagents and conditions: (a) NaClO2, NH2SO3H, toluene, H2O,
0 °C, 91%; (b) MeI, K2CO3, DMF, rt, 100%; (c) 3, THF, 0 °C or 3,
CuI, THF, 0 °C; (d) 28% NaOMe, MeOH, reflux; (e) NaClO2,
NaH2PO4, DMSO, H2O (pH 5), 25 °C, 69% (2 steps); (f) MeI, K2CO3,
DMF, rt, 88%; (g) i-PrBr, K2CO3, DMF, rt, 96%.
Syn th esis of Ra cem ic S-1255 (r a c-1). Ca r bon -
Ca r bon Bon d F or m a tion a t th e C4 P osition . Conver-
sion of chloroaldehyde 4 into S-1255 (1) requires oxidation
of the formyl group to the carboxylic acid at the 3-posi-
tion, substitution of chlorine with the p-anisyl group at
the 4-position, and introduction of the chirality at the
2-position. To optimize the oxidation and substitution
conditions, synthesis of the racemic 1 (rac-1) was initially
examined. Having failed in the reaction of 4 with Grig-
nard reagent 3 under a variety of conditions, we next
tried the Grignard reaction of 3-carboxy derivatives
(Scheme 3). Chloroaldehyde 4 was treated with NaClO2
in the presence of NH2SO3H as an HOCl scavenger7 to
give chloro acid 12 in 91% yield. The esterification of 12
with MeI afforded methyl ester 13 in quantitative yield.
The conjugate addition-elimination reaction of 12 or 13
with Grignard reagent 3 was then examined to form the
carbon-carbon bond at the 4-position giving compound
rac-1 or 14a . But, the reaction for 12 or 13 failed, giving
unchanged starting materials or 1,2-addition product.
The addition of CuI to the reaction mixture was also
ineffective.
The results of the conjugate addition-elimination
reaction with Grignard reagent 3 are summarized in
Table 1. The reaction of 4-methoxy acid 16 with 3
proceeded smoothly to give rac-1 in excellent yields
(entries 1 and 2). Coordination of the methoxy group and
the carbonyl group on the metal center of 3 would be
responsible for this smooth substitution.9 To complete the
reaction, 4.0 equiv of the Grignard reagent was required
(entry 2 vs entry 1). Although the crude product of rac-1
(7) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
J . Org. Chem, Vol. 67, No. 22, 2002 7743

Konoike et al.
already has been assigned to be R on the basis of the
single-crystal X-ray structure,3 that of (+)-16 is reason-
ably assigned to be R. This conclusion was further
supported by the experimental result that (+)-16 was
converted into 1 by the reaction with 3 (vide infra), which
should rationally proceed with retention of configuration
at the 2-position.
As the maximum theoretical yield of the desired (R)-
salt 22 in the above conventional resolution is only 50%,
the resolution conditions should be modified to improve
the yield of 22. Two important observations for the
modification were found during the conventional resolu-
tion. First, the unwanted (S)-16‚(+)-NE salt (21) in the
filtrate was rapidly epimerized by heating to give a 1:1
mixture of (S)-salt 21 and (R)-salt 22. Second, the desired
(R)-salt 22 is less soluble in many organic solvents,
whereas (S)-salt 21 is more soluble and tends to remain
in solution or as an oil in a concentrated solution. These
observations suggested that a dynamic resolution of
methoxy acid 16 could be achieved by modifying the
resolution conditions. A dynamic resolution is a meth-
odology in which a racemic or diastereomeric compound
is transformed into a single stereoisomer by a preferential
crystallization of one stereoisomer coupled with an in situ
racemization of the other, thereby offering the potential
of 100% conversion to the desired stereoisomer.12
The optimal condition for the dynamic resolution of 16
with (+)-NE was first investigated. The first crop of the
desired (R)-salt 22 was isolated in 54% yield and 96% ee
by heating a solution of acid 16 and (+)-NE in MeOH at
40 °C (Scheme 4). The yield of over 50% indicated that
the dynamic resolution occurred. To recycle the unwanted
(S)-salt 21 in filtrate through racemization, the filtrate
was heated under reflux conditions. After concentration,
the mixture was stirred at 40 °C to give the second crop
(22% yield, 99% ee). A similar resolution-racemization
process was repeated by using the second filtrate to give
the third crop (8% yield, 99% ee). Thus, (R)-salt 22 of
97% ee was isolated in 84% total yield. The fourth crop
(6% yield, 99% ee) obtained in a similar manner was
contaminated with chromanone 5, which presumably
formed by a hydrolysis of the vinylic methoxy moiety at
the 4-position in 16 followed by decarboxylation of the
resulting 4-oxo-3-carboxylic acid.
F IGURE 1. CD spectra of (R)-(+)-16 (a solid line) and 1 (a
dotted line) in MeOH.
was contaminated with anisole 19 and homodimer 20
arising from the Grignard reagent, these byproducts were
readily removed by the simple acid-base extraction
method. The overall yield of rac-1 from chloroaldehyde
4 was 58% in three steps, in which no chromatographic
purification was required. Thus, an efficient synthetic
route applicable to a multikilogram-scale production of
1 was established.
The reaction for methoxy esters 17 was also examined
to minimize the amount of Grignard reagent 3 (Table 1,
entries 3 to 6). The reaction of methyl ester 17a with 1.1
equiv of 3 resulted in recovery of 17a and formation of
ketone 18, excessive addition byproduct (entry 3). When
3.0 equiv of 3 was used, the starting material 17a was
completely consumed, but the formation of 18 was
significantly increased (entry 4). The use of 17b having
a bulkier isopropyl group in an attempt to avoid the
formation of 18 was not fruitful (entries 5 and 6). In
addition, the protection of the carboxyl group (17 vs 16)
is not beneficial from the viewpoint of brevity.
Dyn a m ic Resolu tion of Meth oxy Acid 16. Our
attention was next directed to the enantioselective syn-
thesis of S-1255 (1) via the resolution of methoxy acid
16, the precursor of rac-1, using optically active amines.
A conventional optical resolution of 16 by the diastereo-
meric salt formation with (1S,2R)-(+)-norephedrine ((+)-
NE) in MeOH/MeCN (1/1) gave (+)-16‚(+)-NE salt (22)
in 42% yield and 99% ee.
The absolute configuration of the salt 22 obtained was
determined from a CD spectrum of a pure sample (100%
ee) of free acid (+)-16 prepared from 22 by the method
in the next section, followed by recrystallization from
acetone/isopropyl ether. Compound (+)-16 exhibits a
positive Cotton effect around 240 nm arising from the
styrene chromophore similar to that of 1 (Figure 1),
indicating that both compounds have the same stereo-
chemistry.11 Because the absolute configuration of 1
While carrying out a multikilogram-scale preparation
of 1 by this method, several optically active amines other
than (+)-NE were screened for the dynamic resolution.
(+)-Cinchonine was found to be the most suitable. After
a solution of acid 16 and an equimolar amount of (+)-
cinchonine in MeOH/i-PrOH (1/1) was stirred at 70 °C
and then at 45 °C, the precipitates were collected to give
(12) (a) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J . M.;
Pippel, D. J .; Weisdenburger, G. A. Acc. Chem. Res. 2000, 33, 715. (b)
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. J pn. 1995,
68, 36. (c) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475. (d)
Reider, P. J .; Davis, P.; Hughes, D. L.; Grabowski, E. J . J . J . Org. Chem.
1987, 52, 955. (e) Shi, Y.-J .; Wells, K. M.; Pye, P. J .; Choi, W.-B.;
Churchill, H. R. O.; Lynch, J . E.; Maliakal, A.; Sager, J . W.; Rossen,
K.; Volante, R. P.; Reider, P. J . Tetrahedron 1999, 55, 909. (f) Alabaster,
R. J .; Gibson, A. W.; J ohnson, S. A.; Edwards, J . S.; Cottrell, I. F.
Tetrahedron: Asymmetry 1997, 8, 447. (g) Hagmann, W. K. Synth.
Commun. 1986, 16, 437. (h) Sohda, T.; Mizuno, K.; Kawamatsu, Y.
Chem. Pharm. Bull. 1984, 32, 4460. (i) Shieh, W.-C.; Carlson, J . A.;
Zaunius, G. M. J . Org. Chem. 1997, 62, 8271. (j) Cooper, J .; Humber,
D. C.; Long, A. G. Synth. Commun. 1986, 16, 1469. (k) Kemperman,
G. J .; Zhu, J .; Klunder, A. J . H.; Zwanenburg, B. Org. Lett. 2000, 2,
2829.
(8) J alander, L. Synth. Commun. 1988, 18, 343.
(9) Hattori, T.; Hotta, H.; Suzuki, T.; Miyano, S. Bull. Chem. Soc.
J pn. 1993, 66, 613.
(10) Dalcanale, E. J . Org. Chem. 1986, 51, 567.
(11) (a) Kikuchi, T.; Mori, Y.; Yokoi, T.; Nakazawa, S.; Kuroda, H.;
Masada, Y.; Kitamura, K.; Kuriyama, K. Chem. Pharm. Bull. 1983,
31, 106. (b) Wipf, P.; Weiner, W. S. J . Org. Chem. 1999, 64, 5321.
7744 J . Org. Chem., Vol. 67, No. 22, 2002

Synthesis of Endothelin Antagonist S-1255
SCHEME 4
F IGURE 2. Racemization rates of 1 and (R)-16 in MeOH at
40 °C.
late anion at the 3-position (addition of base) play crucial
roles in the racemization.
The racemization of 16 can be explained by a mecha-
nism via the ring-opened zwitterionic intermediate (Fig-
ure 3, A-D) as reported in the C2 epimerization of a 2H-
chromene compound.14 The existence of the zwitterionic
intermediate is supported by an experimental result that
the C2 proton of (R)-16 was not exchanged with deute-
rium when its (+)-NE salt 22 was refluxed in CD3OD.
This indicates the O1-C2 bond cleavage in a racemizing
process and denies the double bond isomerization mech-
anism involving protonation-deprotonation on C3-C4
and isomerized C2-C3 olefins of 16 in CD3OD. Both the
electron-donating mesomeric effect of the C4 methoxy
group (σR ) -0.58,15 B) and the electron-donating induc-
tive effect of the C3 carboxylate anion (σI ) -0.19,15 C)
will stabilize the C2 carbocation in the zwitter-
ionic intermediate, facilitating the racemization of 16.
This proposed racemization mechanism can explain the
successful dynamic resolution of methoxy acid 16 with
(+)-NE or (+)-cinchonine.
The racemization rate was also enhanced by the
addition of a catalytic amount of H2SO4. In this case,
protonation at the O1 atom prompts the O1-C2 bond
cleavage, leading to the rate enhancement of the race-
mization (Figure 3, D).
Syn t h esis of E n a n t iom er ica lly P u r e S-1255 (1).
Liberation of free acid (R)-16 from (+)-NE salt 22 was
carried out by using aqueous H3PO4 buffered with NaH2-
PO4 at pH 4 to minimize the acid decomposition of (R)-
16 (Scheme 5). Crude acid (R)-16 obtained in 97% ee was
used for the next step without further purification. (+)-
NE was easily recovered from the aqueous layer by
treatment with aqueous NaOH followed by toluene
extraction.
the desired (R)-16‚(+)-cinchonine salt (23) in 83% yield
and 99% ee (eq 1). It was significant that 23 was obtained
in excellent yield in a single crystallization step with-
out recycling the (S)-isomer. Among a number of dyna-
mic resolutions reported,12 our method especially using
(+)-cinchonine exceeds others in several respects: excel-
lent yield and high enantiopurity of the product, the mild
conditions, the simple operation, the use of an inexpen-
sive resolving reagent, and no requirement of an auxil-
iary to accelerate the racemization.
Although the dynamic resolution of rac-1 with some
chiral amines13 was also attempted under several condi-
tions, the yield of 1 did not exceed 50% owing to a
sluggish racemization of the antipode of 1 under the
resolution conditions.
A facile racemization of (R)- and (S)-16 under the
resolution conditions is crucial for our successful dynamic
resolution. To clarify the mechanism of the dynamic
resolution, the racemization rates of 1 and (R)-16 were
compared in MeOH at 40 °C in the presence or absence
of Et3N, NaOH, or H2SO4 (Figure 2). The order of the
racemization rate was found to be 1 < (R)-16 < (R)-16/
Et3N ) (R)-16/NaOH < (R)-16/H2SO4. These data indi-
cate that the existence of the methoxy group at the
4-position (1 vs (R)-16) and the formation of the carboxy-
The reaction of (R)-16 with Grignard reagent 3 was
accomplished by using a procedure similar to that
(14) Harie´, G.; Samat, A.; Gulielmetti, R.; Parys. I. V.; Saeyens, W.;
Keuleleire, D. D.; Lorenz, K.; Mannschreck, A. Helv. Chim. Acta 1997,
80, 1122.
(13) (1S,2R)-(+)-Norephedrine, (+)-cinchonine, (-)-cinchonidine, (R)-
(+)-R-methylbenzylamine, (R)-(+)-R-amino-ꢀ-caprolactam, and (R)-(+)-
1-(1-naphthyl)ethylamine were examined.
(15) Hansch, C.; Leo, A.; Hoekuan, D. Exploring QSAR. Hydropho-
bic, Electronic, and Steric Constant; Heller, S. R., Ed.; ACS Professional
Reference Book; American Chemical Society: Washington, DC, 1995.
J . Org. Chem, Vol. 67, No. 22, 2002 7745

Konoike et al.
F IGURE 3. Proposed racemization mechanism.
SCHEME 5a
NE salt (22), it is obvious that the (R)-16‚(+)-cinchonine
salt (23) obtained more simply can be equally used for
the kilogram-scale synthesis of 1.
Con clu sion
We have established the practical multikilogram-scale
synthesis of S-1255 (1), which provides a shorter route
and higher overall yield than the original synthesis (8
steps and 41% overall yield vs 10 steps and 5% overall
yield). To achieve the efficient enantioselective synthesis,
the highly efficient dynamic resolution of the key inter-
mediate 16 with (+)-NE or (+)-cinchonine as the resolv-
ing reagent was newly developed. A mechanistic inves-
tigation has shown that the methoxy group at the
4-positon as well as the carboxylate anion at the 3-posi-
tion play important roles in the successful dynamic
resolution. The formation of the carbon-carbon bond
between the C4 atom and the p-anisyl group was suc-
cessfully accomplished by the addition-elimination reac-
tion of (R)-16 with Grignard reagent 3 without loss of
enantiopurity. The short-step synthesis of 1 described
herein required no chromatographic purification and thus
can be easily applicable to the kilogram-scale prepara-
tion. In fact, this process has been scaled up in the pilot
plant to make over 10 kg of compound 1 for clinical
evaluations.
a
Reagents and conditions: (a) H3PO4, NaH2PO4, EtOAc, H2O
(pH 4); (b) 4.0 equiv of 3, THF, 0 °C, 92% (2 steps).
employed for the synthesis of rac-1. The reaction pro-
ceeded cleanly without racemization at the C2 position.
After workup for removing anisole 19 and dimer 20, the
product was crystallized from MeOH/H2O (1/1) with
stirring at room temperature to give the crude 1. Recrys-
tallization of the crude 1 from MeOH/H2O (4/1) at room
temperature gave purified 1 having 98% ee and >99%
purity in 92% yield (41% overall yield from 8). Although
1 was prepared on a kilogram scale via the (R)-16‚(+)-
7746 J . Org. Chem., Vol. 67, No. 22, 2002

Synthesis of Endothelin Antagonist S-1255
reaction mixture was stirred at room temperature for 24 h and
then poured into a mixture of NaOAc (7.18 kg, 12.5 mol),
EtOAc (1.37 L), and ice-water (27.4 L). The resulting pre-
cipitate was collected by filtration, washed with H2O (55 L),
and air dried to give 4 (2.58 kg, 99%) as yellow crystals: Mp
Exp er im en ta l Section
Gen er a l Meth od s. Chromatography was done on silica gel
(70-230 mesh). Melting points are uncorrected. 1H NMR and
13C NMR spectra were recorded at 300 and 75 MHz, respec-
tively, and signals are given in ppm with TMS as an internal
standard. J values are given in hertz. Optical rotations were
measured in a 10-cm cell. HPLC analysis was performed under
the following conditions. Condition A: Cosmosil 5C18R AR 4.6
mm × 150 mm; solvent, MeCH/H2O/TFA; flow rate, 1.0 mL/
min; detection, 254 nm. Condition B: CHIRALCEL OJ -R 4.6
mm × 150 mm; solvent, MeCN/H2O/TFA or MeCN/0.2 M H3-
PO4-KH2PO4 (pH 2.2); flow rate, 0.5 mL/min; detection, 286
nm. HPLC results are presented as an area percent of the peak
for a particular compound relative to the total area of all the
peaks integrated.
5-Isop r op oxy-2-h yd r oxya cetop h en on e (6). A mixture of
2,5-dihydroxyacetophenone 8 (1.52 kg, 10.0 mol), 2-bromopro-
pane (3.08 kg, 25.0 mol), K2CO3 (325 mesh, 3.46 kg, 25.0 mol),
and MeCN (15.2 L) was stirred under reflux for 10 h. An
insoluble material was removed by filtration and the filtrate
was concentrated under reduced pressure. Toluene (6 L) was
added to the residue and the resulting suspension was
concentrated to 4 L. An insoluble material was removed by
filtration and the filtrate was concentrated under reduced
pressure to give crude 6 (2.00 kg) as a dark brown oil, which
contained 2% of 8 and 9% of dialkoxy compound 10 (HPLC).
This crude product was used in the next reaction without
further purification. Analytically pure samples of 6 and 10
were obtained by silica gel chromatography (EtOAc/hexane,
1/5). 6: Yellow oil. 1H NMR (CDCl3) δ 1.32 (6H, d, J ) 6.1),
2.60 (3H, s), 4.34-4.52 (1H, m), 6.89-7.23 (3H, m). 13C NMR
(CDCl3) δ 22.4, 27.1, 71.9, 117.7, 119.3, 119.7, 126.5, 149.9,
156.9, 204.1. Anal. Calcd for C11H14O3: C, 68.02; H, 7.27.
1
126-127 °C. H NMR (CDCl3) δ 1.33 (6H, d, J ) 6.0), 4.38-
4.57 (1H, m), 5.90 (2H, s), 6.23 (1H, s), 6.60-7.26 (6H, m),
10.26 (1H, s). 13C NMR (CDCl3) δ 22.4, 22.5, 71.3, 75.0, 101.4,
107.8, 108.4, 113.1, 118.6, 120.8, 121.1, 123.2, 127.3, 132.0,
144.0, 148.0, 148.1, 148.9, 152.8, 188.2. Anal. Calcd for C20H17
-
ClO5: C, 64.44; H, 4.60; Cl, 9.51. Found: C, 64.36; H, 4.53;
Cl, 9.28. HPLC, condition A ((MeCN/H2O/TFA (75/25/0.1)): tR
5.5 min.
2-(Ben zo[1,3]d ioxol-5-yl)-4-ch lor o-6-isop r op oxy-2H -
ch r om en e-3-ca r boxylic Acid (12). A solution of NH2SO3H
(57.6 g, 593 mmol) in H2O (346 mL) was added to a stirred
solution of chloroaldehyde 4 (92.0 g, 247 mmol) in toluene (1.38
L). Thereto was added dropwise a solution of NaClO2 (55.9 g,
618 mmol) in H2O (346 mL) over 1 h at 0 °C, and stirring was
continued for 20 min at the same temperature. The reaction
was quenched successively with aqueous 24% Na2SO3 (131 g)
and aqueous 5.5% NaOH (740 g). After removing the toluene
layer, the aqueous layer was acidified with concentrated HCl
to pH 2. The resultant precipitate was collected by filtration,
washed with H2O, and air dried to give 12 (87.5 g, 91%) as
1
yellow crystals: mp 177 °C. H NMR (CDCl3) δ 1.33 (6H, d, J
) 6.0), 4.36-4.54 (1H, m), 5.91 (2H, s), 6.25 (1H, s), 6.26-
7.26 (6H, m). 13C NMR (CDCl3) δ 22.4, 22.5, 71.2, 76.5, 101.5,
108.2, 108.4, 114.0, 118.3, 120.2, 121.6, 121.9, 122.1, 131.7,
139.4, 147.8, 148.0, 148.2, 152.7, 168.8. Anal. Calcd for C20H17
-
ClO6: C, 61.78; H, 4.41; Cl. 9.12. Found: C, 61.84; H, 4.12;
Cl, 8.84.
Meth yl 2-(Ben zo[1,3]dioxol-5-yl)-4-ch lor o-6-isopr opoxy-
2H-ch r om en e-3-ca r boxyla te (13). A mixture of chloro acid
12 (7.00 g, 18.0 mmol), MeI (3.83 g, 27.0 mmol), K2CO3 (3.73
g, 27.0 mmol), and DMF (70 mL) was stirred at room
temperature for 3 h. The reaction mixture was poured into
ice-water and extracted with toluene, and the extract was
concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (EtOAc/hexane, 1/3)
to give 13 (7.25 g, 100%) as a yellow oil. 1H NMR (CDCl3) δ
1.31 (6H, d, J ) 6.3), 3.78 (3H, s), 4.42-4.49 (1H, m), 5.91
(2H, s), 6.23 (1H, s), 6.674-6.72 (2H, m), 6.78-6.84 (3H, m),
7.22 (1H, d, J ) 2.7). 13C NMR (CDCl3) δ 22.4, 22.5, 52.5, 71.2,
76.8, 101.4, 108.2, 108.3, 113.9, 118.0, 121.3, 121.5, 121.6,
121.9, 131.9, 136.2, 147.4, 148.0, 148.1, 152.7, 164.3. Anal.
Calcd for C21H19ClO6‚0.1EtOAc: C, 62.44; H, 4.85; Cl, 8.61.
Found: C, 62.13; H, 4.81; Cl, 8.67.
2-(Ben zo[1,3]d ioxol-5-yl)-6-isop r op oxy-4-m eth oxy-2H-
ch r om en e-3-ca r ba ld eh yd e (15). Chloroaldehyde 4 (2.42 kg,
6.50 mol) was added portionwise to a stirred mixture of
NaOMe (28 wt % solution in MeOH, 1.38 kg, 7.15 mol) and
methanol (7.3 L). After being stirred at 40 °C for 1.5 h, the
reaction mixture was allowed to cool to room temperature and
then poured into a mixture of EtOAc (24 L) and ice-water
(24 L). The organic layer was separated and an aqueous layer
was extracted with EtOAc (6 L). After each layer was washed
with brine (24 L), the organic layer and the extract were
combined and concentrated. Toluene (2.4 L) was added to the
residue, and the resulting suspension was concentrated to
remove EtOAc. This procedure was repeated twice to give
crude 15 (2.68 kg), which was used for the next step without
further purification. An analytically pure sample of 15 was
obtained by recrystallization from acetone/isopropyl ether.
Yellow crystals. Mp 82-83 °C. 1H NMR (CDCl3) δ 1.32 (6H,
d, J ) 6.0), 4.06 (3H, s), 4.35-4.53 (1H, m), 5.88 (2H, s), 6.24
(1H, s), 6.64-7.26 (6H, m), 10.21 (1H, s). 13C NMR (CDCl3) δ
22.4, 22.5, 64.0, 71.2, 74.1, 101.3, 107.9, 108.2, 111.2, 118.5,
118.9, 119.1, 121.0, 122.5, 133.0, 147.8, 147.8, 150.8, 152.5,
165.0, 186.9. Anal. Calcd for C21H20O6: C, 68.47; H, 5.47.
Found: C, 68.42; H, 5.50. HPLC, condition A ((MeCN/H2O/
TFA (75/25/0.1)): tR 3.5 min.
1
Found: C, 67.97; H, 7.43. 10: Yellow oil. H NMR (CDCl3) δ
1.30 (6H, d, J ) 6.0), 1.37 (6H, d, J ) 6.0), 2.62 (3H, s), 4.44-
4.61 (2H, m), 6.87 (1H, d, J ) 9.0), 6.98 (1H, dd, J ) 3.3 and
9.0), 7.26 (1H, d, J ) 3.3). 13C NMR (CDCl3) δ 22.4, 22.5, 32.5,
71.1, 71.5, 115.7, 116.6, 122.7, 129.9, 151.5, 151.8, 200.0. Anal.
Calcd for C14H20O3‚0.1H2O: C, 70.62; H, 8.55. Found: C, 70.32;
H, 8.44. HPLC, condition A (MeCN/H2O/TFA (75/25/0.1)): tR
8, 1.8 min; tR 6, 3.0 min; tR 10, 4.0 min.
2-(Be n zo[1,3]d ioxol-5-yl)-6-isop r op oxych r om a n -4-
on e (5). To a stirred mixture of crude 6 (2.00 kg), piperonal
(1.35 kg, 9.00 mol), and MeOH (2.25 L) was added 2 N NaOH
(9.00 L, 18.0 mol) at room temperature, and the stirring was
continued for 2 days. The precipitated product was collected
by filtration, washed with H2O (60 L), and air dried to give 5
(2.54 kg, 78% yield from 8) as yellow crystals, which contained
4% of chalcone 9 (HPLC). An analytically pure sample of 5
was obtained by recrystallization from acetone/isopropyl ether.
Mp 125-126 °C. 1H NMR (CDCl3) δ 1.33 (6H, d, J ) 6.1), 2.76-
3.11 (2H, m), 4.44-4.62 (1H, m), 5.34 (1H, dd, J ) 3.2, 13.0),
5.99 (2H, s), 6.81-7.36 (6H, m). 13C NMR (CDCl3) δ 22.3, 22.3,
44.9, 71.0, 79.8, 101.6, 107.0, 108.6, 110.4, 119.6, 120.2, 121.0,
127.2, 132.9, 148.1, 148.2, 152.5, 156.1, 192.2. Anal. Calcd for
C
19H18O5: C, 69.93; H, 5.56. Found: C, 70.16; H, 5.46. 9:
1
Yellow crystals. Mp 164-166. H NMR (CDCl3) δ 1.34 (6H, d,
J ) 5.7), 4.43-4.51 (1H, m), 6.04 (2H, s), 6.86 (1H, d, J ) 8.1),
6.96 (1H, d, J ) 9.0), 7.12-7.18 (3H, m), 7.39-7.44 (2H, m),
7.84 (1H, d, J ) 15.3), 12.44 (1H, s). 13C NMR (CDCl3) δ 22.5,
72.0, 102.0, 107.0, 109.0, 117.1, 118.3, 119.4, 120.2, 126.0,
126.1, 129.3, 145.6, 148.7, 149.8, 150.5, 158.1, 193.3. Anal.
Calcd for C19H18O5: C, 69.93; H, 5.56. Found: C, 69.59; H,
5.42. HPLC, condition A ((MeCN/H2O/TFA (75/25/0.1)): tR 5,
3.8 min; tR 9, 5.6 min.
2-(Ben zo[1,3]d ioxol-5-yl)-4-ch lor o-6-isop r op oxy-2H -
ch r om en e-3-ca r ba ld eh yd e (4). Phosphoryl oxychloride (2.68
kg, 17.5 mol) was added dropwise to DMF (6.85 L) with stirring
at 0 °C over 1.5 h and the mixture was additionally stirred at
room temperature for 30 min. To the resulting mixture was
added chromanone 5 (2.28 kg, 7.00 mol) in one portion. The
J . Org. Chem, Vol. 67, No. 22, 2002 7747

Konoike et al.
2-(Ben zo[1,3]d ioxol-5-yl)-6-isop r op oxy-4-m eth oxy-2H-
ch r om en e-3-ca r boxylic Acid (16). A solution of NaH2PO4
(1.95 kg, 16.3 mol) in H2O (4.9 L) was added to a stirred
solution of crude 15 (2.68 kg) in DMSO (29 L) at room
temperature over 15 min. Thereto was added a solution of
NaClO2 (80% purity, 1.91 kg, 16.9 mol) in H2O (7.64 L) in 10
portions over 3.5 h at a rate to keep the temperature at 25 °C.
After being stirred at room temperature for 20 min, the
mixture was poured into H2O (57.5 L) and the resulting
precipitate was collected by filtration. The crystals obtained
were dissolved in EtOAc (21 L), and the resulting solution was
washed with brine (5 L × 2). After evaporation of the solvent,
toluene (4 L) was added to the residue, and the suspension
was concentrated to remove EtOAc. Toluene (4 L) was added
and the resulting suspension was allowed to stand at 0 °C for
1.5 h. The precipitated product was collected, washed with cold
toluene (2 L), and air dried to give 16 (1.73 kg, 69% yield from
4) as yellow crystals: Mp 134 °C. 1H NMR (CDCl3) δ 1.31 (3H,
d, J ) 6.1), 1.32 (3H, d, J ) 6.1), 4.01 (3H, s), 4.34-4.52 (1H,
m), 5.89 (2H, s), 6.25 (1H, s), 6.65-6.92 (6H, m). 13C NMR
(CDCl3) δ 21.8, 21.9, 62.0, 70.7, 75.3, 100.8, 107.6, 107.7, 109.6,
110.9, 117.5, 118.5, 120.8, 121.2, 131.8, 147.3, 147.4, 150.0,
152.0, 159.6, 165.2. Anal. Calcd for C21H20O7: C, 65.62; H, 5.24.
Found: C, 65.53; H; 5.39. HPLC, condition A ((MeCN/H2O/
TFA (75/25/0.1)): tR 2.6 min.
Meth yl 2-(Ben zo[1,3]d ioxol-5-yl)-6-isop r op oxy-4-m eth -
oxy-2H-ch r om en e-3-ca r boxyla te (17a ). To a stirred solution
of methoxy acid 16 (7.00 g, 18.2 mmol) in DMF (70 mL) were
added MeI (3.87 g, 27.3 mmol) and K2CO3 (3.77 g, 27.3 mmol),
and the stirring was continued for 1.5 h at room temperature.
The mixture was poured into ice-water and extracted with
EtOAc, and the extract was concentrated. The residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1/4) to give 17a (6.40 g, 88%) as pale yellow crystals:
Mp 112 °C. 1H NMR (CDCl3) δ 1.30 (6H, d, J ) 6.0), 3.77 (3H,
s), 3.95 (3H, s), 4.37-4.48 (1H, m), 5.89 (2H, s), 6.16 (1H, s),
6.65-7.03 (6H, m). 13C NMR (CDCl3) δ 22.4, 22.5, 52.1, 62.2,
71.1, 76.3, 101.3, 108.2, 108.3, 108.6, 111.6, 118.2, 120.2, 121.1,
121.4, 133.3, 147.8, 149.3, 152.4, 160.2, 164.8. Anal. Calcd for
(20 mL) were added with stirring. The aqueous layer was
separated and washed with toluene. After being acidified with
35% HCl, the aqueous layer was extracted with EtOAc. The
extract was washed with H2O, dried with Na2SO4, and
concentrated. The residue was crystallized from EtOAc/toluene/
isopropyl ether to give rac-1 (2.02 g, 84%) as yellow crystals:
Mp 179-181 °C. 1H NMR (CDCl3) δ 1.15 (3H, d, J ) 6.0), 1.18
(3H, d, J ) 6.0), 3.87 (3H, s), 4.19 (1H, m), 5.91 (2H, s), 6.15
(1H, s), 6.25 (1H, m), 6.69-6.74 (3H, m), 6.87-6.97 (4H, m),
7.15-7.19 (2H, br). 13C NMR (CDCl3) δ 22.2, 22.4, 55.6, 70.8,
74.9, 101.3, 108.3, 108.4, 113.9, 116.4, 117.9, 120.2, 120.3,
121.5, 125.1, 128.6, 130.3, 132.8, 147.5, 147.9, 152.1, 159.7,
170.3. Anal. Calcd for C27H24O7: C, 70.43; H, 5.25. Found: C,
70.28; H, 5.30. HPLC, condition A ((MeCN/H2O/TFA (75/25/
0.1)): tR 5.4 min.
(R)-2-(Ben zo[1,3]d ioxol-5-yl)-6-isop r op oxy-4-m eth oxy-
2H -ch r om en e-3-ca r b oxylic Acid (1S,2R)-(+)-Nor ep h e-
d r in e Sa lt (22). Dyn a m ic R esolu t ion w it h (1S,2R)-(+)-
Nor ep h ed r in e. (1S,2R)-(+)-Norephedrine (617 g, 4.08 mol)
was added to a stirred mixture of methoxy acid 16 (1.57 kg,
4.08 mol) and MeOH (6.56 L). The resulting slurry was
dissolved on heating at 70 °C and then stirred at 40 °C for 8
h. After cooling to 0 °C, the precipitate was collected by
filtration and washed with cold MeOH (3 L) to give the first
crop of salt 22 as crystals (1.18 kg, 54%, 96% ee). The filtrate
was diluted with MeOH to 15 L, refluxed for 4 h, concentrated
to 3.4 kg, stirred at 40 °C for 8 h, and cooled to 0 °C. The
precipitate formed was filtered off and washed with cold MeOH
(1.5 L) to give the second crop (473 g, 22%, 99% ee). The filtrate
was again diluted with MeOH to 4 L, refluxed for 7 h,
concentrated to 1.8 kg, stirred at 40 °C for 3 h, and cooled to
0 °C. The precipitate was filtrated off and washed with cold
MeOH (1 L) to give the third crop (170 g, 8%, 99% ee). These
three crops were combined to give 22 (1.82 kg, 84%, 97% ee)
1
as colorless crystals: Mp 158-161 °C. H NMR (DMSO-d6) δ
0.87 (3H, d, J ) 6.6), 1.21 (6H, d, J ) 6.2), 3.25-3.36 (1H, m),
3.89 (3H, s), 4.35-4.53 (1H, m), 4.86 (1H, d, J ) 3.2), 5.93
(2H, s), 6.04 (1H, s), 6.67-7.35 (11H, m). 13C NMR (DMSO-
d6) δ 12.8, 22.8, 22.9, 52.7, 61.2, 70.7, 72.4, 77.8, 101.7, 108.5,
108.7, 110.9, 117.4, 117.8, 118.3, 121.9, 122.8, 126.7, 127.8,
128.9, 135.4, 142.6, 147.5, 147.7, 148.1, 150.5, 152.3, 169.7.
C
22H22O7: C, 66.32; H, 5.57. Found: C, 66.28; H, 5.51. HPLC,
condition A ((MeCN/H2O/TFA (75/25/0.1)): tR 5.9 min.
[R]22 +51.0 (c 1.00, MeOH). Anal. Calcd for C30H33NO8: C,
D
Isop r op yl 2-(Ben zo[1,3]d ioxol-5-yl)-6-isop r op oxy-4-
m eth oxy-2H-ch r om en e-3-ca r boxyla te (17b). To a stirred
solution of methoxy acid 16 (3.00 g, 7.80 mmol) in DMF (30
mL) were added 2-bromopropane (1.92 g, 15.6 mmol) and K2-
CO3 (2.16 g, 15.6 mmol), and the stirring was continued for
17 h at 50 °C. The mixture was poured into ice-water and
extracted with EtOAc, and the extract was concentrated. The
residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1/4) to give 17b (3.20 g, 96%) as pale yellow
crystals: mp 77-78 °C. 1H NMR (CDCl3) δ 1.18-1.32 (12H,
m), 3.94 (3H, s), 4.37-4.50 (1H, m), 5.05-5.18 (1H, m), 5.89
(2H, s), 6.15 (1H, s), 6.65-7.26 (6H, m). 13C NMR (CDCl3) δ
22.1, 22.3, 22.4, 22.5, 62.1, 68.3, 71.1, 76.6, 101.3, 108.1, 108.3,
109.8, 111.5, 118.1, 120.3, 120.9, 121.4, 133.6, 147.7, 149.3,
152.4, 159.4, 163.9. Anal. Calcd for C24H26O7: C, 67.59; H, 6.15.
Found: C, 67.20; H, 6.24. HPLC, condition A ((MeCN/H2O/
TFA (75/25/0.1)): tR 6.1 min.
Rea ction of Meth oxy Acid 16 w ith Gr ign a r d Rea gen t
3 (r a c-1, Ta ble 1, en tr y 2). A solution of 4-bromoanisole (18.7
g, 100 mmol) in THF (15 mL) was added dropwise to a stirred
mixture of Mg (2.43 g, 100 mmol), I2 (2 crystals), and THF (15
mL), and then the resulting mixture was refluxed for 2.5 h.
After cooling to room temperature, the mixture was diluted
with THF to a total volume of 100 mL. A portion (20.8 mL,
20.8 mmol) of this Grignard reagent was added dropwise to a
stirred solution of 16 (2.00 g, 5.20 mmol) in THF (14 mL) at
-30 °C. After the reaction mixture was stirred at 0 °C for 2 h,
ice and 2 N HCl (13 mL) were successively added. The
resulting mixture was extracted with EtOAc, and the extract
was washed with H2O and concentrated. The residue was
dissolved in toluene (50 mL), and 1 N NaOH (10 mL) and H2O
67.18; H, 6.21; N, 2.62. Found: C, 67.25; H, 6.27; N, 2.91.
HPLC, condition B (MeCN/0.2 M H3PO4-KH2PO4 (50/50)): tR
22, 11.3 min; tR (S)-salt 21, 13.1 min.
(R)-2-(Ben zo[1,3]d ioxol-5-yl)-6-isop r op oxy-4-m eth oxy-
2H-ch r om en e-3-ca r boxylic Acid Cin ch on in e Sa lt (23).
Dyn a m ic Resolu tion w ith (+)-Cin ch on in e. (+)-Cinchonine
(>98% purity, 800 mg, 2.71 mmol) was added to a mixture of
16 (1.00 g, 2.60 mmol), MeOH (5 mL), and i-PrOH (5 mL).
The resulting slurry was dissolved on heating at 70 °C and
stirred at 70 °C for 20 h and then at 45 °C for 5 h. The
precipitate was collected by filtration, washed with i-PrOH (5
mL), and air dried to give 23 (1.47 g, 83%, 99% ee) as colorless
1
crystals: Mp 178-180 °C. H NMR (DMSO-d6) δ 1.22 (6H, d,
J ) 6.0), 1.58 (2H, br), 1.78 (1H, br), 2.03-2.10 (1H, m), 2.34-
2.42 (1H, m), 2.73-2.83 (1H, m), 2.93-3.01 (2H, m), 3.19-
3.26 (1H, m), 3.42-3.49 (1H, m), 3.94 (3H, s), 4.43-4.51 (1H,
m), 5.11-5.17 (2H, m), 5.75-5.77 (1H, m), 5.93-5.94 (2H, m),
6.02-6.11 (1H, m), 6.12 (1H, s), 6.70-6.93 (6H, m), 7.54-7.62
(2H, m), 7.72-7.77 (1H, m), 8.04 (1H, d, J ) 8.4), 8.31 (1H, s,
J ) 8.4), 8.87 (1H, d, J ) 4.5). 13C NMR (DMSO-d6) δ 21.6,
22.7, 22.7, 25.4, 28.2, 39.1, 48.4, 49.3, 60.6, 61.8, 69.4, 70.6,
77.0, 101.7, 108.4, 108.4, 111.0, 113.5, 116.0, 118.0, 119.4,
119.5, 121.6, 121.8, 124.5, 126.1, 127.1, 129.6, 130.3, 134.6,
140.4, 147.6, 147.7, 148.3, 148.4, 149.6, 150.7, 152.3, 154.3,
168.1. [R]26D +98.7 (c 1.01, MeOH). Anal. Calcd for C40H42N2O8‚
0.5H2O: C, 69.85; H, 6.30; N, 4.07. Found: C, 69.88; H, 6.13;
N, 4.06. The enantiopurity was determined by HPLC with the
same conditions as for 22.
(R)-2-(Ben zo[1,3]d ioxol-5-yl)-6-isop r op oxy-4-m eth oxy-
2H-ch r om en e-3-ca r boxylic Acid ((R)-16). Salt 22 (1.61 kg,
7748 J . Org. Chem., Vol. 67, No. 22, 2002

Synthesis of Endothelin Antagonist S-1255
3.00 mol) was suspended in a mixture of aqueous 1 M NaH2-
PO4 (7.5 L) and EtOAc (16 L). Thereto was added dropwise
aqueous 10% H3PO4 (3.5 L) with stirring over 10 min at 20
°C. The organic layer was separated and the aqueous layer
was extracted with EtOAc (3 L). After each layer was washed
with H2O, the organic layer and the extract were combined
and concentrated. Toluene (7 L) was added to the residue, and
the resulting suspension was concentrated to remove the
remaining EtOAc to afford crude (R)-16 (1.20 kg, 97% ee) as
yellow crystals, which contained 7% of toluene. This crude
product was used in the next reaction without further purifica-
tion. An analytically pure sample of (R)-16 (100% ee) was
obtained by recrystallization from acetone/isopropyl ether: Mp
136-137 °C. 1H NMR (CDCl3) δ 1.31 (3H, d, J ) 6.1), 1.32
(3H, d, J ) 6.1), 4.01 (3H, s), 4.34-4.52 (1H, m), 5.89 (2H, s),
6.25 (1H, s), 6.65-6.92 (6H, m). 13C NMR (CDCl3) δ 21.8, 21.9,
62.0, 70.7, 75.3, 100.8, 107.6, 107.7, 109.6, 110.9, 117.5, 118.5,
120.8, 121.2, 131.8, 147.3, 147.4, 150.0, 152.0, 159.6, 165.2.
concentrated to remove EtOAc. The residue was dissolved in
toluene (13.5 L) and mixed with H2O (3 L). To the resulting
mixture was added dropwise 0.5 N NaOH (9 L) at 25 °C. The
basic aqueous layer was separated and the organic layer was
extracted with 0.25 N NaOH (6 L). After each layer was
washed with toluene (6 L), the basic aqueous layer and the
basic extract were combined. Thereto, 35% HCl (0.23 L), EtOAc
(12 L), and 35% HCl (0.3 L) were successively added with
stirring. The organic layer was separated, and the aqueous
layer was extracted with EtOAc (6 L). After each layer was
washed with H2O (9 L), the organic layer and the extract were
combined and concentrated. The residue was dissolved in
MeOH (8.7 L) on heating at 50 °C, allowed to cool to room
temperature, and then mixed with H2O (6.5 L). After the
mixture was left standing at room temperature for 1 h, the
precipitated crystals were filtered off and washed with cold
MeOH/H2O (1/1, 4.7 L) to give crude 1 (1.34 kg, 97%, 98% ee)
as pale yellow crystals.
[R]24 +42.6 (c 1.00, MeOH). Anal. Calcd for C21H20O7: C,
D
P u r ifica tion of S-1255. The crude 1 (3.50 kg, 7.60 mol)
was dissolved in MeOH (28 L) on heating, and the solution
was allowed to cool to room temperature and mixed with H2O
(7 L) at 25 °C. The precipitated crystals were collected by
filtration, washed with cold MeOH/H2O (4/1, 3 L), and air dried
to give pure 1 as pale yellow crystals (3.34 kg, 95% yield, 98%
ee, >99% purity): Mp 170-172 °C. 1H NMR (CDCl3) δ 1.15
(3H, d, J ) 6.2), 1.18 (3H, d, J ) 6.2), 3.87 (3H, s), 4.09-4.27
(1H, m), 5.90 (2H, s), 6.14 (1H, s), 6.24-7.18 (10H, m). 13C
NMR (CDCl3) δ 21.8, 22.0, 55.2, 70.5, 74.6, 101.0, 108.0, 108.1,
113.6, 116.2, 117.7, 120.0, 120.1, 121.3, 124.9, 128.5, 130.1,
65.42; H, 5.24. Found: C, 65.45; H, 5.28. The enantiopurity
was determined by HPLC with the same conditions as for 22.
Recycle of (1S,2R)-(+)-Nor ep h ed r in e. The aqueous layer
containing (1S,2R)-(+)-norephedrine phosphate obtained in the
previous step was concentrated and then added portionwise
to aqueous 25% NaOH over 45 min, and the resulting mixture
was stirred at 35 °C for 2 h. The resultant slurry was filtered
to remove Na3PO4, and the filtrate was mixed with toluene
(4.3 L). The organic layer was separated, dried with Na2SO4,
and concentrated. Hexane (4 L) was added to the residue and
the precipitate was collected by filtration to give (1S,2R)-(+)-
norephedrine (390 g, 86%) as colorless crystals: Mp 51 °C.
132.6, 147.4, 147.7, 152.0, 159.5, 170.6. [R]24 +178.8 (c 1.00,
D
MeOH). Anal. Calcd for C27H24O7: C, 70.43; H, 5.25. Found:
C, 70.20; H, 5.23. HPLC, condition A ((MeCN/H2O/TFA (55/
45/0.1)): tR 16.9 min. HPLC, condition B (MeCN/H2O/TFA (68/
32/0.1)): tR 1, 6.3 min; tR (S)-form, 12.9 min.
[R]24 +41.5 (c 5.00, 1 N HCl) (reported in the Aldrich
D
catalog: mp 51-54 °C; [R]20 +40 (c 7, 1 N HCl)).
D
(R)-2-(Ben zo[1,3]d ioxol-5-yl)-6-isop r op oxy-4-(4-m et h -
oxyp h en yl)-2H-ch r om en e-3-ca r boxylic Acid (1). A solu-
tion of 4-bromoanisole (2.25 kg, 12.0 mol) in THF (5 L) was
added dropwise to a stirred mixture of Mg (292 g, 12.0 mol),
I2 (1.00 g, 3.93 mmol), and THF (1 L) at a rate to keep the
temperature at 40-45 °C, and the stirring was continued at
40 °C for 3 h. The Grignard reagent was added dropwise to a
solution of crude (R)-16 (1.20 kg, 97% ee) in THF (7.5 L) at
-35 °C, and the stirring was continued at 0 °C for 2 h. To the
reaction mixture was added dropwise 6 N HCl (0.5 L) over 30
min under ice cooling, and the resulting mixture was poured
into a stirred mixture of 6 N HCl (1.7 L), ice-water (4.4 L),
and EtOAc (8 L). The organic layer was separated, and the
aqueous layer was extracted with EtOAc (6 L). After each layer
was washed with brine (12 L × 2), the organic layer and
extract were combined and concentrated. Toluene (1.5 L) was
added to the residue, and the resulting suspension was
Ack n ow led gm en t. The authors are grateful to
Messrs. I. Matsumura, K. Oda, T. Masui, T. Kobayashi,
and K. Sakai for their contribution to the improvement
of the multikilogram-scale preparation. We also thank
Dr. N. Ishizuka and Dr. H. Kondo for helpful discussion.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for reactions of 17a and 17b with 3 (Table 1, entries 4
1
and 5), melting point, H and 13C NMR, analytical data, and
HPLC data for 11, 1H NMR spectra of 6, 13, and 23 which
supplement the elemental analysis. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0261092
J . Org. Chem, Vol. 67, No. 22, 2002 7749