Practical route to a new class of LTD4 receptor antagonists

Article abstract of DOI:10.1021/jo952103j

A general approach to the synthesis of a new class of LTD₄ antagonists is presented. The key diarylpropane framework was prepared by Claisen-Schmidt condensation and selective reduction of the enone. Depending on the bridge to the 7-chloroquinaldine moiety, alkylation or Heck coupling methodology was developed. The chiral sulfides were introduced by asymmetric reduction of the diarylpropanone intermediates and subsequent inversion of the chiral center.

Full text of DOI:10.1021/jo952103j

3398
J . Org. Chem. 1996, 61, 3398-3405
P r a ctica l Rou te to a New Cla ss of LTD4 Recep tor An ta gon ists
Robert D. Larsen,* Edward G. Corley, Anthony O. King, J ames D. Carroll, Paul Davis,
Thomas R. Verhoeven, and Paul J . Reider
Department of Process Research, Merck Research Laboratories, Division of Merck & Company, Inc.,
P.O. Box 2000, Rahway, New J ersey 07065
Marc Labelle, J acques Y. Gauthier, Yi Bin Xiang, and Robert J . Zamboni
Merck Frosst Center for Therapeutic Research, Division of Merck & Company, Inc., P.O./ C.P. 1005,
Pointe Claire-Dorval, Quebec H9R 4P8, Canada
Received November 28, 1995X
A general approach to the synthesis of a new class of LTD4 antagonists is presented. The key
diarylpropane framework was prepared by Claisen-Schmidt condensation and selective reduction
of the enone. Depending on the bridge to the 7-chloroquinaldine moiety, alkylation or Heck coupling
methodology was developed. The chiral sulfides were introduced by asymmetric reduction of the
diarylpropanone intermediates and subsequent inversion of the chiral center.
Since the discovery of the role played by the leukotri-
of the synthesis the target became the diarylpropanol 3.
A classical synthesis of a 1,3-diarylpropenone is conden-
sation of an acetophenone and a benzaldehyde, the
Claisen-Schmidt reaction, producing an enone known
as a chalcone;6 selective 3,4-reduction then provides the
1,3-diarylpropanone (Scheme 1). In the synthesis of 1
and 2 coupling of the 3′-substituted acetophenone 4 with
a 2-carboxybenzaldehyde 5 afforded the backbone of 3
enes in asthma and associated inflammatory diseases the
search for specific antagonists or inhibitors of this portion
of the aracadonic acid cascade has been intensive.1 An
early candidate for the control of asthma was the LTD4
antagonist MK-0571/MK-0679.2,3 Elaboration of this
original structure has advanced a new class of LTD4
antagonists with the selection of L-691,698 (1) and
L-699,392 (2) as active agents.4 Here the 3-thiapropi-
onamide side chain has been replaced with an arylethyl
group, and in the case of the former, the trans-double
bond has been changed to a phenyl quinaldine ether.
(1) (a) Young, R. N.; Guindon, T. R.; J ones, T. R.; Ford-Hutchinson,
A. W.; Bellanger, P.; Champion, E.; Charette, L.; DeHaven, R. N.;
Denis, D.; Fortin, R.; Frenette, R.; Gauthier, J .-Y.; Gillard, J . W.;
Kakushima, M.; Letts, L. G.; Masson, P.; Maycock, A.; McFarlane, C.;
Piechuta, H.; Pong, S. S.; Rosenthal, A.; Williams, H.; Zamboni, R.;
Yoakim, C.; Rokach, J . Advances in Prostaglandin, Thromboxane, And
Leukotreine Research; Raven Press: New York, 1986; Vol. 16, p 37.
(b) J ones, T. R.; Zamboni, R.; Belley, M.; Champion, E.; Charette, L.;
Ford-Hutchinson, A. W.; Frenette, R.; Gauthier, J .-Y.; Leger, S.;
Masson, P.; McFarlane, C. S.; Piechuta, H.; Rokach, J .; Williams, H.;
Young, R. N.; DeHaven, R. N.; Pong, S. S. Can. J . Physiol. Pharmacol.
1989, 67, 17. (c) Shaw, A.; Krell, R. D. J . Med. Chem. 1991, 34, 1235.
(d) Musser, J . H.; Kreft, A. F. J . Med. Chem. 1992, 35, 2501 and
references cited therein.
(2) (a) Gauthier, J . Y.; J ones, T.; Champion, E.; Charette, L.;
Dehaven, R.; Ford-Hutchinson, A. W.; Hoogsteen, K.; Lord, A.; Masson,
P.; Piechuta, H.; Pong, S. S.; Springer, J . P.; Therien, M.; Zamboni,
R.; Young, R. N. J . Med. Chem. 1990, 33, 2841. (b) Zamboni, R.; Belley,
M.; Champion, E.; Charette, L.; DeHaven, R.; Frenette, R.; Gauthier,
J . Y.; J ones, T. R.; Leger, S.; Masson, P.; McFarlane, C. S.; Metters,
K.; Pong, S. S.; Piechuta, H.; Rockach, J .; Therien, M.; Williams, H.
W. R.; Young, R. N. J . Med. Chem. 1992, 35, 3832.
(3) McNamara, J . M.; Leazer, J . L.; Bhupathy, M.; Amato, J . S.;
Reamer, R. A.; Reider, P. J .; Grabowski, E. J . J . J . Org. Chem. 1989,
54, 3718. For the preparation of the chiral derivative (MK-0679) by
lipase-catalyzed asymmetric hydrolysis, see: Hughes, D. L.; Bergan,
J . J .; Amato, J . S.; Bhupathy, M.; Leazer, J . L.; McNamara, J . M.;
Sidler, D. R.; Reider, P. J .; Grabowski, E. J . J . J . Org. Chem. 1990,
55, 6252.
(4) (a) Labelle, M.; Prassit, P.; Belley, M.; Blouin, M.; Champion,
E.; Charette, L.; DeLuca, J . G.; Dufresne, C.; Frenette, R.; Gauthier,
J . Y.; Grimm, E.; Grossman, S. J .; Guay, D.; Herold, E. G.; J ones, T.
R.; Lau, C. K.; Leblanc, Y.; Leger, S.; Lord, A.; McAuliffe, M.;
McFarlane, C.; Masson, P.; Metters, K. M.; Ouimet, N.; Patrick, D.
H.; Perrier, H.; Pickett, C. B.; Piechuta, H.; Roy, P.; Williams, H.; Wang,
Z.; Xiang, Y. B.; Zamboni, R. J .; Ford-Hutchinson, A. W.; Young, R. N.
Bioorg. Med. Chem. Lett. 1992, 2, 1141. (b) Labelle, M.; Belley, M.;
Champion, E.; Gordon, R.; Hoogsten, K.; J ones, T. R.; Leblanc, Y.; Lord,
A.; McAuliffe, M.; McFarlane, C.; Masson, P.; Metters, K. M.; Nicoll-
Griffith, D.; Ouimet, N.; Piechuta, H.; Rochette, C.; Sawyer, N.; Xiang,
Y. B.; Yergey, J .; Ford-Hutchinson, A. W.; Pickett, C. B.; Zamboni, R.
J .; Young, R. N. Bioorg. Med. Chem. Lett. 1994, 4, 463. (c) Labelle, M.;
Belley, M.; Gareau, Y.; Gauthier, J . Y.; Guay, D.; Gordon, R.; Gross-
man, S. G.; J ones, T. R.; Leblanc, Y.; McAuliffe, M.; McFarlane, C.;
Masson, P.; Metters, K. M.; Ouimet, N.; Patrick, D. H.; Piechuta, H.;
Rochette, C.; Sawyer, N.; Xiang, Y. B.; Pickett, C. B.; Ford-Hutchinson,
A. W.; Zamboni, R. J .; Young, R. N. Bioorg. Med. Chem. Lett. 1995, 5,
283.
Our goal was the development of a general approach
to this new class of LTD4 antagonists.4,5 By incorporating
the quinaldine portion of the molecule at the later stages
X Abstract published in Advance ACS Abstracts, May 1, 1996.
S0022-3263(95)02103-7 CCC: $12.00 © 1996 American Chemical Society

Practical Route to LTD4 Receptor Antagonists
J . Org. Chem., Vol. 61, No. 10, 1996 3399
Sch em e 1
Sch em e 2
tive was explored. With the recent success of Comins
the ortho-lithiation of benzaldehydes has become more
practical;11 N,N,N′-Trimethylethylenediamine acts as a
combined aldehyde-protecting group11a and ortho-direct-
ing group11c,d (Scheme 2).
in one step. After coupling and hydrogenation of the
enone, chiral reduction completed the construction of the
diarylpropanol framework. The quinaldine portions of
the molecules were now incorporated by alkylation to
provide the ether linkage or by Heck coupling to install
the ethene bridge. Thiolation with inversion of the chiral
alcohol via the mesylate completed the enantioselective
syntheses of the LTD4 antagonists. We now wish to
disclose herein the efficient syntheses of these drug
candidates that are suitable to the preparation of mul-
tigram quantities for testing.
Ortho-carboxylation of 4-chlorobenzaldehyde would
provide a one-step preparation of 5b.12 Unfortunately,
in order to obtain suitable metalation of the R-ami-
noalkoxide 3 equiv of BuLi was required.11c Because of
the excess BuLi, carboxylation gave poor yields of 5b
(<30%). However, smooth metalation of the ortho-
position of the R-aminoalkoxide occurred with only 1.1
equiv of n-BuLi in combination with 1.1 equiv of
N,N,N′,N′-tetramethylethylenediamine (TMEDA). Ad-
dition of the anion to THF continually saturated with CO2
provided an 89% yield of 5b. The combination of the two
ethylenediamine reagents was critical: replacement of
trimethylethylenediamine with 1-methylpiperazine or
morpholine11b failed to give efficient metalation, and
omission of TMEDA gave incomplete lithiation.
Chalcone coupling of the phenol 4a with the hydroxy-
phthalides 5a and 5b proceeded in high yield using
ethanolic NaOH (Scheme 3).6a In the case of the des-
chloro derivative the enone was not isolated; rather, the
lactone species formed.13 Reduction of this intermediate
was not expected to be selective. This problem was
overcome after we observed that 6a exists as the enone
7a under basic conditions. Addition of 1.05 equiv of
Resu lts a n d Discu ssion
The key to the synthesis of diarylpropane-based LTD4
antagonists was the efficient preparation of the ketoester
9. The Claisen-Schmidt reaction is a highly effective
method to prepare the 1,3-diarylpropane framework from
simple starting materials. In order to use this route for
construction of the 1,3-diarylpropane intermediate of
L-691,698, the hydroxyphthalide 5b was required. The
only reported synthesis of 5b was carried out in five steps
by traditional methods from phthalide.7 Probably the
most suitable method in modern synthetic chemistry for
preparing complex aromatic structures is directed ortho
metalation (DOM).8 Such hydroxyphthalides have been
prepared by ortho-lithiation of benzamides and alkylation
with an aldehyde.8,9 In our case the problem of formation
of regioisomers from a 3-chlorobenzamide caused us to
consider metalation of a para-substituted system. Di-
rected ortho metalation of a benzyl alcohol followed by
carboxylation and subsequent oxidation of the phthalide
has been reported.10 In order to avoid the oxidation step,
the more direct ortho lithiation of a benzaldehyde deriva-
(10) Trost, B. M.; Rivers, G. T.; Gold, J . M. J . Org. Chem. 1980, 45,
1835.
(11) (a) Comins, D. L.; Brown, J . D. Tetrahedron Lett. 1981, 22, 4213.
(b) Comins, D. L.; Brown, J . D.; Mantlo, N. B. Tetrahedron Lett. 1982,
23, 3979. (c) Comins, D. L.; Brown, J . D. J . Org. Chem. 1984, 49, 1078.
(d) Comins, D. L.; Killpack, M. O. J . Org. Chem. 1987, 52, 104. (e)
Comins, D. L.; Brown, J . D. J . Org. Chem. 1989, 54, 3730. (f) Tamao,
K.; Yao, H.; Tsutsumi, Y.; Abe, H.; Hayashi, T.; Ito, Y. Tetrahedron
Lett. 1990, 31, 2925. (g) Comins, D. L. Synthesis Lett. 1992, 615.
(12) Directed ortho metalation of the cyclohexylimine of 4-chloroben-
zaldehdye only provided BuLi attack at the imine and no detectable
ortho lithiation. Ortho lithiation of the cyclohexylimines is reported
to work only with aryl groups with electron-donating groups present;
see: Ziegler, F. E.; Fowler, K. W. J . Org. Chem. 1976, 41, 1564. For a
list of other benzaldehyde-related ortho directing groups see ref 8.
(13) Since the dimethylamide was ultimately desired, the metala-
tion-carboxylation of 4-chlorobenzaldehyde was carried out with
dimethylcarbamoyl chloride. The dimethylcarbamide derivative was
obtained cleanly; however, upon subjecting the material to the coupling
reaction the amide was easily hydrolyzed in situ to provide only 7b.
(5) For an efficient approach to the ethenyl-bridged derivatives,
see: King, A. O.; Corley, E. G.; Anderson, R. K.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J .; Xiang, Y. B.; Belley, M.; Leblanc, Y.;
Labelle, M.; Prasit, P.; Zamboni, R. J . J . Org. Chem. 1993, 58, 3731.
(6) (a) Baldwin, J . E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J .
Org. Chem. 1977, 42, 3846. (b) Bousquet, E. W.; Moran, M. D.; Harmon,
J .; J ohnson, A. L.; Summers, J . C. J . Org. Chem. 1975, 40, 2208 and
references cited therein. (c) Wattanasin, S.; Murphy, W. S. Synthesis
1980, 647.
(7) (a) Biniecki, S.; Rylski, L. Ann. Pharm. Fr. 1958, 16, 21. (b) A
shorter approach could be the selective reduction of chlorophthalic
anhydride; no success was obtained with this procedure. For an
example of this method see: Taub, D.; Girotra, N. N.; Hoffsommer, R.
D.; Kuo, C. H.; Slates, H. L.; Weber, S.; Wendler, N. L. Tetrahedron
1968, 24, 2443.
(8) Snieckus, V. Chem. Rev. 1990, 90, 879.
(9) (a) Beak, P.; Brown, R. A. J . Org. Chem. 1977, 42, 1823. (b) Beak,
P.; Brown, R. A. J . Org. Chem. 1979, 44, 4463. (c) Beak, P.; Brown, R.
A. J . Org. Chem. 1982, 47, 34. (d) Mills, R. J .; Snieckus, V. Tetrahedron
Lett. 1984, 25, 483. (e) Zani, C. L.; de Oliveira, A. B.; Snieckus, V.
Tetrahedron Lett. 1987, 28, 6561. (f) Harvey, R. G.; Cortez, C. J . Org.
Chem. 1987, 52, 283. (g) Kaino, M.; Ishihara, K.; Yamamoto, H. Bull.
Chem. Soc. J pn. 1989, 62, 3736.

3400 J . Org. Chem., Vol. 61, No. 10, 1996
Larsen et al.
Sch em e 3
and 7b under the basic conditions suppressed the Michael
reaction. By adding 1.2 equiv of NaOH and aging the
reaction mixture at 0 °C for ∼10 h the formation of
adduct 11 was prevented and 10 was kept to ∼5%. The
lactone was then closed by the addition of sulfuric acid
and heating the mixture at 60 °C for 0.5 h. The resultant
lactone 6c was isolated in 82% yield. This material
reduced in the same fashion as the phenol analogues to
provide the 3′-bromo keto acid 8c in 96% isolated yield.
The acids 8a -c were then converted to the methyl esters
9a -c, respectively, by refluxing in a mixture of methanol
and sulfuric acid.
Sch em e 4
NaOH to an ethanol slurry of 6a converted the lactone
completely to the enone 7a as evidenced by NMR.
Hydrogenation of this mixture with Wilkinson’s catalyst14
provided the diarylpropanone 8a in 88% isolated yield.
Interestingly, with the chloro compound the isolated
product from the coupling of hydroxyacetophenone 4a
and 5b existed as a 16:84 mixture of the lactone 6b and
the enone 7b. The enone form could be completely
converted to the lactone by acidification and heating of
the mixture. Instead, the addition of base to the reduc-
tion mixture was obviated by modifying the workup of
the coupling: adjustment of the pH to 6.0-6.5 provided
the enone as the sodium salt 7b in 93% yield. Reduction
of this enone with Wilkinson’s catalyst at 40 psi gave the
diarylpropanone 8b in 88% isolated yield.
The introduction of the chiral center of L-691,698
(Scheme 4) proceeded via asymmetric reduction of the
keto ester 9b rather than the dimethylamide 9d . The
diphenylprolinol-based reducing agents15 have profoundly
improved the enantioselective reduction of acetophenone
derivatives. Because of the potential reduction of the
amide group with borane the keto ester was chosen.
Treatment of the ketone 9b with borane in the presence
of 10 mol % of (S)-tetrahydro-1-methyl-3,3-1H,3H-pyr-
rolo[1,2-c][1,3,2]oxazaborole-borane (12) gave the hy-
droxy ester 3b in 90% enantiomeric excess. An increased
benefit of using the methyl ester was its crystallinity
The bromo derivative 4b, however, gave a mixture of
products under the same conditions. This conversion was
plagued by the propensity of the resultant enone 7c to
undergo Michael reactions forming the acetophenone
adducts 10 and 11 as byproducts. Presumably, the
increased electron density of the phenolate moiety of 7a
(15) (a) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc.
1987, 109, 5551. (b) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C.-
P.; Singh, V. K. J . Am. Chem. Soc. 1987, 109, 7925. (c) Corey, E. J .;
Shibata, S.; Bakshi, R. K. J . Org. Chem. 1988, 53, 2861. (d) Mathre,
D. J .; J ones, T. K.; Xavier, L. C.; Blacklock, T. J .; Reamer, R. A.; Mohan,
J . J .; Turner J ones, E. T.; Hoogsteen, K.; Baum, M. W.; Grabowski, E.
J . J . J . Org. Chem. 1991, 56, 751. (e) Mathre, D. J .; Thompson, A. S.;
Douglas, A. W.; Hoogsten, K.; Carroll, J . D.; Corley, E. G.; Grabowski,
E. J . J . J . Org. Chem. 1993, 58, 2880. (f) For the application of
B-chlorodiisopinocampheylborane to these systems see ref 5.
(14) (a) Ojima, I.; Kogure, T. Organometallics 1982, 1, 1390. (b)
Nakamura, K.; Fujii, M.; Ohno, A.; Oka, S. Chem. Lett. 1984, 925. (c)
Malek, J . Org. React. 1985, 34, 1.

Practical Route to LTD4 Receptor Antagonists
J . Org. Chem., Vol. 61, No. 10, 1996 3401
Sch em e 5
Sch em e 6
which facilitated optical enrichment; as was later learned
the hydroxyamide 13 would not crystallize. The crude
hydroxy ester was dissolved in CH2Cl2 by heating. The
precipitated solid from the cooled solution was filtered,
which proved to be a 33:67 mixture of the R/ S enanti-
omers. Only a 4.7% loss of the available R-enantiomer
resulted with an 86% removal of the undesired S-
enantiomer. By concentration of the filtrate, addition of
hexanes to the slurry and filtration of the solid the (R)-
hydroxy ester 3b was obtained 98% optically pure and
in 83% yield. The methyl ester was then converted to
the amide by treatment with magnesium dimethylamide
in THF to provide the key intermediate 12 in 49% overall
yield in five steps from 4-chlorobenzaldehyde.
To complete the synthesis of L-691,698 alkylation of
the phenol and inversion at the chiral center with the
mercaptan were run successively. To introduce the
quinaldine moiety 7-chloroquinaldine was functionalized
as the R-chloro derivative 14 with tert-butyl hypochlorite
in chlorobenzene (Scheme 5). This reagent offered the
benefit of not requiring photochemical or free-radical
generation of the active chlorinating agent. To the best
of our knowledge this is the first use of tert-butyl
hypochlorite for this purpose. The monochlorinated
material was separated from the R,R-dichloro byproduct
and starting material by crystallization from chloroben-
zene as the HCl salt in 88% yield. The phenol 12 was
then alkylated with 14 in DMF at 70 °C with K2CO3 as
base.16 The amorphous quinaldine phenyl ether 15 was
purified by crystallization as the HCl salt from CH2Cl2
in 78% yield by addition of 1 M HCl in ethyl ether.
The thia side chain was then introduced with inversion
of the stereochemistry by a three-step nonisolation
process: First, the alcohol was activated as the mesylate
in toluene at -20 °C with methanesulfonyl chloride and
triethylamine as base. The reaction was followed by the
downfield shift of the methine proton from 4.5 to 5.45
ppm. The solvent was changed to CH3CN, and methyl
3-mercaptopropionate and cesium carbonate were added.
After 2 h the displacement was complete. The salts were
removed by filtration, and the ester was then hydrolyzed
directly by addition of aqueous LiOH. The amorphous
parent compound L-691,698 was converted to the crystal-
line hydrochloride salt in 70% overall yield from 15.
The synthesis of L-699,392 required a carbon-carbon
bond formation17 rather than the etherification. The
Heck reaction is an extremely efficient method for mixed
couplings of aryl and alkenyl carbon bonds.18 Either the
bromide 9c or phenol 9a could be used; the latter was
converted to the triflate 9e. For incorporation of the
ethenyl bridge preparation of a 2-ethenylquinoline was
required. The best approach to prepare 17 was through
a Mannich reaction of 7-chloroquinaldine followed by
Hofmann elimination of 16 via the quaternary salt
(Scheme 6).19
Palladium-catalyzed coupling of the vinyl group with
the bromide 9c or triflate 9e was run in DMF at 100 °C
using 3 mol % palladium(II) acetate. To couple the
bromide substrate 9c the addition of tri-o-tolylphosphine
was necessary. The reaction was complete in 1 h,
providing a 98% conversion to the keto ester 18. With
triphenylphosphine a more sluggish reaction resulted,
requiring 20 h to reach 78% conversion. The optimized
coupling was run with 3 mol % of Pd(OAc)2, 9 mol % of
(tri-o-tolylphosphine), and 1.5 equiv of triethylamine in
DMF at 100 °C for 1.5 h to provide the keto ester in 91%
isolated yield (>95% conversion). The product was
formed as >99% trans-isomer.
Similarly, the triflate 9e gave effective coupling. In
contrast to 9c, the addition of LiBr was necessary.
Without the LiBr the coupling only reached 63% conver-
sion after 18 h. Also, triphenylphosphine (9 mol %)
provided superior results to tri-o-tolylphosphine. Even
with the optimization the coupling reaction of the triflate
was slower, requiring 6 h to complete. The product
mixture was not as clean as with 9c, providing only a
66% isolated yield. Again, only the trans-isomer of the
keto ester 18 was detected.
(16) The alkylation of the hydroxy ester 3b gave the crystalline
product i. However, a major byproduct in the alkylation was the lactone
ii (38%) formed by intramolecular esterification. Although the mixture
of i and ii could be converted to 13, purification and isolation of the
reaction intermediate was compromised.
The resultant ketoester 18 has been previously con-
verted to L-699,392 in 53% overall yield over three steps.5
(17) For the preparation of the ethene bridge via the Wittig
olefination, see: Lau, C. K.; Dufresne, C.; Gareau, Y.; Zamboni, R.;
Labelle, M.; Young, R. N.; Metters, K. M.; Rochette, C.; Sawyer, N.;
Slipetz, D. M.; Charette, L.; J ones, T.; McAuliffe, M.; McFarlane, C.;
Ford-Hutchinson, A. W. Bioorg. Med. Chem. Lett. 1995, 5, 1615.
(18) (a) Heck, R. G. Palladium Reagents in Organic Syntheses;
Academic Press: San Diego, 1985. (b) Heck, R. F. Vinyl Substitutions
with Organopalladium Intermediates. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol.
4, Chapter 3, p 833. (c) References cited in ref 5.
(19) Kagan, E. S.; Ardashev, B. I. Chem. Abstr. 1968, 68, 114408.

3402 J . Org. Chem., Vol. 61, No. 10, 1996
Larsen et al.
NMR of 7a (DMSO-d6) δ 8.6 (d, J ) 15.7 Hz, 1 H), 7.8 (d, J )
7.4 Hz, 1 H), 7.6-7.2 (m, 7 H), 7.0 (dd, J ) 8.3, 1.85 Hz, 1 H);
13C NMR of 7a (DMSO-d6) δ 189.8, 172.0, 159.7, 145.0, 143.7,
139.2, 132.4, 129.5, 129.3, 128.8, 127.5, 126.2, 121.7, 120.6,
117.7, 115.3. Anal. Calcd for C16H12O4: C, 71.63; H, 4.52.
Found: C, 71.75; H, 4.45.
Su m m a r y
A practical approach to synthesis of the LTD4 antago-
nists L-691,698 and L-699,392 has been developed, which
hinges on the straightforward coupling and selective
enone reduction to prepare the key diarylpropane inter-
mediate. Subsequently, the quinoline heterocycle can be
joined to this framework by either alkylation or Heck
coupling, appropriately, providing a general approach to
this important new class of drug candidates.
3-[2-(3-H yd r oxyp h e n yl)-2-oxoe t h yl]-5-ch lor o-1(3H )-
isoben zofu r a n on e (6b). To a mixture of the chlorohydroxy-
phthalide 5b (23.9 g, 129.4 mmol) and 3′-hydroxyacetophenone
(4a ) (20.0 g, 142.3 mmol) in 95% ethanol (490 mL) cooled to
5-10 °C was added 5 N NaOH (181 mL, 0.906 mol) over 6
min. The mixture was then allowed to warm to rt and was
stirred for 18 h. The reaction mixture was diluted with water
(480 mL) and cooled to 5 °C. At 5-10 °C 6 N HCl (∼140 mL)
was added to bring the pH to 6.0-6.5. The yellow solid was
filtered, washed with ethanol-water (1:2; 200 mL) and water
(200 mL), and suction dried: 39 g, 93%; yield mp > 300 °C
(ethanol-water). The solid proved to be the sodium carboxyl-
ate of 7b. An analytical sample was obtained by treatment of
the salt with 2 N HCl in ethyl acetate-ethanol-water. The
organic layer was washed with water (2×) and concentrated
to a light-yellow solid. The solid was recrystallized from ethyl
acetate-cyclohexane. The solid was found to be the lactone
derivative 6b by 1H NMR: mp 195-197 °C; 1H NMR of 6b
(DMSO-d6) δ 9.85 (br s, 1 H), 7.9 (d, J ) 1.9 Hz, 1 H), 7.85
(dd, J ) 8.3, 1.9 Hz, 1 H), 7.75 (d, J ) 8.3 Hz, 1 H), 7.48-7.28
(m, 2 H), 7.31 (s, 1 H), 7.05 (dd, J ) 7.9, 1.9 Hz, 1 H), 6.1 (dd,
J ) 7.9, 4.2 Hz, 1 H), 3.84 (dd, J ) 18.0, 4.2 Hz, 1 H), 3.7 (dd,
J ) 18.0, 7.9 Hz, 1 H); 13C NMR of 6b (DMSO-d6) δ 196.1,
168.4, 157.6, 148.5, 137.4, 134.2, 133.9, 129.8, 127.7, 124.7,
Exp er im en ta l Section
Gen er a l. The reactions were assayed by high-pressure
liquid chromatography (HPLC) on a Microsorb C-8 column (4.6
mm × 15 cm) using CH3CN/H2O as eluents containing 0.1%
TFA with detection at 230 nm unless otherwise indicated.
Reactions were carried out under an atmosphere of nitrogen.
As necessary, CH2Cl2, THF, CH3CN, DMF, toluene, and DMI
were dried over 3 Å molecular sieves.
6-Ch lor o-3-h yd r oxy-1(3H)-isoben zofu r a n on e (5b).
A
solution of TMEDA (101.6 mL, 0.78 mol) in THF (1 L) was
cooled to -25 °C, and n-BuLi (75 mL, 10 M in hexanes, 0.75
mol) was added over 15 min at <-20 °C. The mixture was
aged for 15 min at -20 °C. 4-Chlorobenzaldehyde (100 g, 0.71
mol) in THF (1 L) was added over 20 min at -20 °C, and this
mixture was aged for 30 min. TMEDA (118 mL, 0.824 mol)
was added, followed by n-BuLi (78.4 mL, 10 M in hexanes,
0.78 mol) at -25 to -20 °C, and the mixture was stirred for 2
h. The reaction mixture was transferred via cannula to a
solution of 1,3-dimethylimidazolidinone (100 mL) in THF (1
L) at -30 °C over 30 min while carbon dioxide gas was
simultaneously bubbled through the solution at 0.32 mol/min
(15-20 equiv; 7213 mL/min using a Manostate flow meter).
The carbon dioxide addition was continued for 5 min. After
the mixture was stirred for 1 h at -20 °C, it was quenched
with 6 N HCl (860 mL), and the temperature was allowed to
warm to 5 °C. Ca u tion ! F oa m in g occu r s d u e to th e
r elea se of ca r bon d ioxid e. The mixture was stirred at rt
for 30 min, and water (860 mL) was added. The product was
extracted with isopropyl acetate (1 × 2 L; 1 × 1 L). The
product was extracted from the combined organic layers with
5% NaHCO3 (1 × 2 L; 2 × 1 L). The combined aqueous layers
were acidified with 6 N HCl (400 mL), and the product was
extracted with isopropyl acetate (1 × 1 L; 3 × 400 mL). The
combined organic layers were washed with brine (400 mL) and
dried (Na2SO4). The filtered solution was concentrated to 1
L. Cyclohexane (1 L) was added, and the mixture was
concentrated to 800 mL; the procedure was repeated once
again. To the resultant slurry was added cyclohexane (500
mL), and the mixture was cooled at 10 °C for 1 h. The solid
was filtered, washed with cold cyclohexane, and dried: 117.4
g, 89% yield. An analytical sample was obtained by recrys-
tallization (cyclohexane/ethyl acetate): mp 135.5-137 °C; 1H
NMR (DMSO-d6) δ 8.3 (br s, 1 H), 7.9 (d, J ) 1.85 Hz, 1 H),
7.85 (dd, J ) 1.85, 7.86 Hz, 1 H), 7.1 (d, J ) 7.86 Hz, 2 H), 6.7
(br s, 1 H). Anal. Calcd for C8H5O3Cl: C, 52.05; H, 2.73.
Found: C, 52.12; H, 2.75.
1
124.4, 120.7, 119.1, 114.1, 77.1, 42.3; H NMR of 7b (DMSO-
d6) δ 8.6 (d, J ) 15.7 Hz, 1 H), 7.93 (d, J ) 8.3 Hz, 1 H), 7.6
(d, J ) 15.7 Hz, 1 H), 7.55 (m, 1 H), 7.45 (m, 1 H), 7.47 (m, 1
H), 7.34 (s, 1 H), 7.05 (dd, J ) 7.9, 2.3 Hz); 13C NMR of 7b
(DMSO-d6) δ 189.4, 169.8, 158.0, 145.6, 143.6, 139.1, 133.8,
131.2, 129.6, 128.5, 128.4, 127.3, 122.2, 120.1, 119.1, 114.9.
Anal. Calcd for C16H11O4Cl: C, 63.48; H, 3.67. Found: C,
63.41; H, 3.60.
3-[2-(3-Br om op h en yl)-2-oxoeth yl]-1(3H)-isoben zofu r a -
n on e (6c). To a solution of 4b (10.0 g, 50.0 mmol) and 5a
(8.3 g, 55 mmol) in 95% EtOH (200 mL) cooled to 0 °C was
added 5 N NaOH (12.0 mL, 60.0 mmol). The reaction mixture
was aged at <5 °C for 10 h and was allowed to warm slowly
to 20 °C over another 10 h. Concentrated H2SO4 (15 mL) was
added while the internal temperature was maintained at <40
°C. The mixture was heated to 60 °C for 30 min to complete
the lactonization. After being aged for 30 min at rt, the
product was filtered, washed with cold EtOH/H2O (1:1; 150
mL), and suction dried to provide 17.1 g of 84 wt % lactone 6c
contaminated with sodium sulfate (14.4 g by HPLC assay) in
82% corrected yield. The bis-adduct 10 crystallizes more
slowly. In order to prevent its cocrystallization the mixture
should not be aged for >2 h at rt. An analytical sample was
prepared by filtration/recrystallization from ethyl acetate/
1
cyclohexane: mp 125.5-126 °C; H NMR (DMSO-d6) δ 8.18
(m, 1H), 8.0 (dd, J ) 1.16, 2.66 Hz, 1 H), 7.9-7.7 (m, 4 H), 7.6
(m, 1 H), 7.5 (m, 1 H), 6.1 (dd, J ) 4.2, 7.8 Hz, 1 H), 3.9 (dd,
J ) 4.2, 18.2 Hz, 1 H), 3.78 (dd, J ) 7.8, 18.2 Hz, 1H); 13C
NMR (DMSO-d6) δ 195.5, 169.8, 149.8, 138.2, 136.2, 134.3,
131.0, 130.8, 129.3, 127.1, 125.5, 124.9, 122.9, 122.2, 76.9, 42.8.
Anal. Calcd for C16H11BrO3: C, 58.02; H, 3.35. Found: C,
58.10; H, 3.37.
3-[2-(3-H yd r oxyp h en yl)-2-oxoet h yl]-1(3H )-isob en zo-
fu r a n on e (6a ). To a mixture of 3′-hydroxyacetophenone (4a )
(13.62 g, 100 mmol) and 2-carboxybenzaldehyde (5a ) (15.01
g, 100 mmol) in 95% ethanol (400 mL) was added 5 N NaOH
(140 mL, 700 mmol) at 5-10 °C over 30 min. The mixture
was stirred at rt for 20 h. Water (400 mL) was added followed
by 6 N HCl (140 mL) at <10 °C whereupon a solid precipitated.
The mixture was aged at 5 °C for 5 h. The solid was filtered,
washed with 3:1 water-ethanol (150 mL) and water (200 mL),
and suction dried. The product was isolated as the lactone
(24.3 g, 90% yield). An analytical sample was obtained by
recrystallization from ethyl acetate: mp 174-175.5 °C; 1H
NMR of 6a (DMSO-d6) δ 9.85 (s, 1 H), 7.9-7.3 (m, 7 H), 7.05
(m, 1 H), 6.1 (dd, J ) 7.9, 4.2 Hz, 1 H), 3.8 (dd, J ) 18.0, 4.2
Hz, 1 H), 3.68 (dd, J ) 18.0, 7.9 Hz, 1 H); 13C NMR of 6a
(DMSO-d6) δ 196.2, 169.7, 157.6, 149.8, 137.5, 134.2, 129.8,
A Gen er a l P r oced u r e for th e Red u ction of th e La c-
ton es of 3-(2′-Ca r boxy)ch a lcon es: 2-[3-(3-Hyd r oxyp h en -
yl)-3-oxop r op yl]ben zoic Acid (8a ). The keto lactone 6a
(500 mg, 1.86 mmol) was suspended in 100% ethanol (10 mL),
and 1 N NaOH (1.96 mL, 1.96 mmol) was added dropwise
whereupon the solid dissolved to provide a yellow solution of
the enone. The solution was treated with hydrogen at 40 psi,
rt in the presence of Wilkinson’s catalyst (15 mg). When the
reaction was complete 1 N NaOH (25 mL) and isopropyl
acetate (25 mL) were added. After the layers were well-mixed
and separated the basic layer was acidified with 2 N HCl. The
product was extracted into isopropyl acetate (25 mL). The acid
was again extracted into 1 N NaOH (20 mL). The basic layer
was treated with Darco G-60 (200 mg) and filtered through
1
129.2, 125.4, 124.8, 122.8, 120.6, 119.1, 114.0, 77.0, 42.7; H

Practical Route to LTD4 Receptor Antagonists
J . Org. Chem., Vol. 61, No. 10, 1996 3403
Solka-Floc. The filtrate was acidified with 2 N HCl (10 mL),
whereupon the product crystallized. The solid was filtered,
washed with water, and suction dried to provide 442 mg (88%)
of the keto acid 8a as an off-white solid. An analytical sample
was obtained by recrystallization from ethyl acetate-cyclo-
1 L and then 0.4 L). The combined organic layers were washed
with saturated NaHCO3 (500 mL), water (2 × 500 mL), and
brine (500 mL). The solution was concentrated to 200 mL.
The slurry was warmed to redissolve the solid, and the mixture
was filtered to remove particulates. The mixture was then
cooled, and hexanes (250 mL) was added whereupon the
methyl ester precipitated. The slurry was stirred in an ice
bath for 30 min. The solid was filtered, washed with cold 1:1
ethyl acetate/hexanes (50 mL), and suction dried (37.0 g). A
second crop was collected (5.6 g) by concentration of the
filtrates to 125 mL (81% combined yield). An analytical
sample was obtained by recrystallization from CH2Cl2-hex-
anes: mp 105-106.5 °C; 1H NMR (CDCl3) δ 7.9 (d, J ) 2.3
Hz, 1 H), 7.56-7.48 (m, 2 H), 7.4 (dd, J ) 8.3, 2.3 Hz, 1 H),
7.34-7.25 (m, 1 H), 7.3 (s, 1 H), 7.08 (m, 1 H), 6.4 (br s, 1 H),
3.9 (s, 3 H), 3.3 (s, 4 H); 13C NMR (CDCl3) δ 199.7, 166.7, 156.3,
141.7, 138.0, 132.9, 132.3, 132.1, 130.8, 130.6, 129.9, 120.64,
120.6, 114.6, 52.4, 40.4, 28.7. Anal. Calcd for C17H15O4Cl: C,
64.05; H, 4.75. Found: C, 63.94; H, 4.78.
1
hexane with Darco G-60 decolorization: mp 172-173 °C; H
NMR (DMSO-d6) δ 12.9 (br s, 1 H), 9.75 (br s, 1 H), 7.81 (dd,
J ) 6.5, 1.4 Hz, 1 H), 7.25-7.5 (m, 6H), 7.0 (dd, J ) 7.8, 2.3
Hz, 1 H), 3.25 (m, 4 H); 13C NMR (DMSO-d6) δ 198.9, 168.6,
157.5, 142.3, 137.8, 131.7, 130.9, 130.3, 130.2, 129.7, 126.1,
120.1, 118.8, 113.9, 39.9, 28.4. Anal. Calcd for C16H14O4: C,
71.09; H, 5.23. Found: C, 70.83; H, 5.11.
5-Ch lor o-2-[3-(3-h yd r oxyp h en yl)-3-oxop r op yl]b en zo-
ic Acid (8b). The crude enone 7b as the sodium salt (60.5 g,
0.2 mol) was stirred in methanol/DMF (960 mL; 2:1) until most
of the solid had dissolved. A small amount of an insoluble
solid (1.7 g) was removed by filtration. Wilkinson’s catalyst
[(PPh3)3RhCl] (1.6 g) was added, and the mixture was treated
with hydrogen under 40 psi pressure at rt until the hydrogen
uptake stopped. The reaction mixture was added to a mixture
of water (2 L), and the pH was adjusted to 10-11. The mixture
was then washed with isopropyl acetate (2 × 500 mL). The
aqueous layer was treated with Darco G-60 (5 g) and stirred
for 15 min. After the mixture was filtered through Super-Cel
the filtrate was acidified with 6 N HCl. The product precipi-
tated as a white solid. The solid was filtered, washed with
water (100 mL), and suction dried. Final drying under vacuum
at 40 °C provided 53.6 g (88%) of the propanone 8b as a white
solid. An analytical sample was obtained by recrystallization
from ethyl acetate: mp 218-221 °C; 1H NMR (DMSO-d6) δ
13.3 (br s, 1 H), 9.8 (br s, 1 H), 7.79 (d, J ) 2.3 Hz, 1 H), 7.55
(dd, J ) 8.3, 2.3 Hz, 1 H), 7.42 (dd, J ) 8.8, 2.3 Hz, 1 H), 7.32-
7.25 (m, 2 H), 7.3 (s, 1 H), 7.0 (dd, J ) 8.3, 2.3 Hz, 1 H), 3.2
(m, 4 H); 13C NMR (DMSO-d6) δ 198.6, 167.4, 157.5, 141.2,
137.7, 132.9, 132.4, 131.3, 130.5, 129.7, 129.5, 120.2, 118.8,
113.9, 39.6, 27.7. Anal. Calcd for C16H13O4Cl: C, 63.06; H,
4.31. Found: C, 63.11; H, 4.41.
2-[3-(3-Br om op h en yl)-3-oxop r op yl]ben zoic Acid (8c).
A mixture of 6c (8.7 g, 26.3 mmol), Wilkinson’s catalyst (0.3
g), and 5 N NaOH (5.0 mL, 25.0 mmol) in EtOH (200 mL) was
hydrogenated at 40 psi and rt for 16 h. The EtOH was
removed in vacuo, and the residue was triturated with
cyclohexane (50 mL). The slurry was further diluted with
hexane (50 mL) and then aged at rt for 1 h. The product was
filtered, washed with hexane, and dried to afford 8.44 g of 8c
in 96% yield. An analytical sample was prepared by recrys-
tallization from ethyl acetate/cyclohexanes: mp 120-121 °C;
1H NMR (CDCl3) δ 9.7-8.5 (br s, 1 H), 8.1 (d, J ) 2.0 Hz, 1
H), 8.08 (dd, J ) 1.5, 3.2 Hz, 1 H), 7.9 (m, 1 H), (ddd, J ) 1.0,
2.0, 7.8 Hz, 1 H), 7.5 (m, 1 H), 7.4-6.8 (m, 3 H), 3.5-3.4 (m,
2 H), 3.4-3.3 (m, 2 H); 13C NMR (CDCl3) δ 198.1, 172.6, 144.0,
138.5, 135.9, 133.4, 132.0, 131.7, 131.2, 130.2, 128.1, 126.7,
126.6, 123.0, 40.6, 29.3. Anal. Calcd for C16H13BrO3: C, 57.67;
H, 3.94. Found: C, 57.66; H, 4.09.
2-[3-(3-Hydr oxyph en yl)-3-oxopr opyl]ben zoic Acid Meth -
yl Ester (9a ). A solution of 8a (2.5 g, 9.25 mmol) in MeOH
(75 mL) and H2SO4 (2.5 mL) was heated at reflux for 17 h.
The volatiles were removed in vacuo at <30 °C. The residue
was diluted with water (10 mL), and the mixture was extracted
with EtOAc (2 × 20 mL). The EtOAc layer was dried (MgSO4)
and evaporated to dryness to give 2.3 g of 9a (88% yield). An
analytical sample was prepared by recrystallization from ethyl
acetate/cyclohexane: mp 88.5-90 °C; 1H NMR (CDCl3) δ 7.92,
(dd, J ) 1.3, 7.8 Hz, 1 H), 7.55 (m, 1 H), 7.5-7.4 (m, 2 H),
7.35-7.25 (m, 2 H), 7.1 (m, 1 H), 3.9 (s, 3 H), 3.35 (m, 4 H);
13C NMR (CDCl3) δ 199.9, 168.0, 156.2, 143.2, 138.1, 132.4,
131.5, 130.9, 129.8, 129.3, 126.4, 120.7, 120.4, 114.6, 52.1, 40.7,
29.4. Anal. Calcd for C17H16O4: C, 71.81; H, 5.68. Found:
C, 71.73; H, 5.45.
5-Ch lor o-2-[3-(3-h yd r oxyp h en yl)-3-oxop r op yl]b en zo-
ic Acid Meth yl Ester (9b). The keto acid 8b (50.0 g, 0.164
mol) was suspended in methanol (800 mL), and sulfuric acid
(8.0 mL) was added. The mixture was heated at reflux for
18-24 h. Water (1 L) was added to the cooled reaction
mixture, and the pH was adjusted to 8.0-8.5 with saturated
NaHCO3. The product was extracted with ethyl acetate (2 ×
2-[3-(3-Br om op h en yl)-3-oxop r op yl]ben zoic Acid Meth -
yl Ester (9c). A solution of 8c (8 g, 24.0 mmol) in MeOH (120
mL) and H2SO4 (8 mL) was refluxed for 24 h. The volatiles
were removed in vacuo at <35 °C, and the partially crystallized
residue was slowly diluted with water (50 mL) at rt. After
the slurry was aged at rt for 1 h, the product was filtered and
dried at 40 °C under vacuum to provide 7.66 g of the ester 9c
in 92% yield. An analytical sample was prepared by recrys-
tallization from ethyl acetate/heptane: mp 83.5-84 °C; 1H
NMR (CDCl3) δ 8.1 (m, 1 H), 7.9 (m, 2 H), 7.65 (dd, J ) 7.8,
1.0 Hz, 1 H), 7.45 (m, 1H), 7.35-7.25 (m, 3 H), 3.9 (s, 3 H),
3.4-3.3 (m, 4 H);
13C NMR (CDCl3) δ 198.0, 167.7, 143.1, 138.7,
135.8, 132.4, 131.5, 131.3, 130.9, 130.2, 129.4, 126.7, 126.5,
122.9, 52.1, 40.7, 29.3. Anal. Calcd for C17H15BrO3: C, 58.80;
H, 4.36. Found: C, 58.70; H, 4.39.
(R)-5-Ch lor o-2-[3-h ydr oxy-3-(3-h ydr oxyph en yl)pr opyl]-
ben zoic Acid Meth yl Ester (3b). The keto ester (20.72 g,
65 mmol) was dissolved in THF (200 mL), and a 0.86 M
solution of (8S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyr-
rolo[1,2-c][1,3,2]oxazaborole (12) in toluene (7.6 mL, 6.5 mmol)
was added. The mixture was cooled to 0 °C, and 2 M
borane‚dimethyl sulfide in THF (35.8 mL, 71.5 mmol) was
added. The reduction mixture was stirred at 0 °C for 18 h.
The reaction was quenched by the addition of 2 N HCl (100
mL). Ca u tion ! F oa m in g occu r s a n d th e tem p er a tu r e
in cr ea ses to 15 °C. Water (300 mL) was added, and the
product was extracted with ethyl acetate (1 × 250 mL; 1 ×
125 mL). The combined organic layers were washed with 1 N
HCl, water, and brine. After the solution was dried (Na2SO4),
a sample of the product was assayed for enantiomeric purity
by conversion to the bis-acetate derivative: acetic anhydride-
DMAP in CH2Cl2. Pirkle L-phenylglycine covalent column: 50:
3:1 hexanes/CH2Cl2/IPA; 2 mL/min; 254 nm; (S)-enantiomer,
10.5 min; (R)-enantiomer, 11.2 min. The crude product was
obtained as a 95:5 R/ S mixture. The filtrate was concen-
trated, and the residue was treated with CH2Cl2 (500 mL).
The mixture was heated to reflux, and the solids were
filtered: 2.7 g of a 67:33 S/ R mixture of enantiomers. The
filtrate was concentrated to 400 mL, and hexanes (300 mL)
was added. The mixture was stirred for 10 min, and the solid
was filtered: 14.8 g (71%) of a 99.2:0.8 mixture of the R/S-
enantiomers: mp 106-107 °C; [R]25D +10 (c 3, THF). A second
crop was collected by concentration of the filtrate to 300 mL:
2.5 g (83% overall yield) of 98:2 mixture:
1H NMR (DMSO-d6)
δ 9.25 (s, 1 H), 7.7 (d, J ) 2.3 Hz, 1 H), 7.55 (dd, J ) 8.3, 2.3
Hz, 1 H), 7.3 (dd, J ) 8.3 Hz, 1 H), 7.1 (m, 1 H), 6.7 (m, 1 H),
6.68 (s, 1 H), 6.6 (ddd, J ) 7.9, 2.3, 0.9 Hz, 1 H), 5.2 (d, J )
4.2, 1 H), 4.4 (m, 1 H), 3.8 (s, 3 H), 3.0-2.7 (m, 2 H), 1.85-1.7
(m, 2 H);
13C NMR (DMSO-d6) δ 166.3, 157.1, 147.4, 141.9,
132.6, 131.6, 131.4, 130.3, 129.2, 128.8, 116.3, 113.5, 112.5,
71.8, 52.2, 40.8, 29.5. Anal. Calcd for C17H17ClO4; C, 63.65;
H, 5.35. Found: C, 63.74; H, 5.20.
(R)-5-Ch lor o-2-[3-h ydr oxy-3-(3-h ydr oxyph en yl)pr opyl]-
N,N-d im eth ylben za m id e (13). To a solution of 2.2 M
dimethylamine in THF (50 mL, 100 mmol) was added 2.0 M
ethylmagnesium bromide (50 mL, 100 mmol) dropwise over
10 min at 15-25 °C. Ca u t ion ! F oa m in g fr om r elea sed

3404 J . Org. Chem., Vol. 61, No. 10, 1996
Larsen et al.
eth a n e occu r s. The thick mixture was allowed to stir for 25
min at 10-20 °C. A solution of the methyl ester 3b (9.62 g,
30 mmol) in THF (40 mL) was added over 12 min at 20-25
°C, maintaining the temperature with an ice bath. The
reaction was aged for 4.5 h at room temperature and was then
quenched with 2 N HCl (100 mL) with cooling to maintain the
temperature <25 °C. The layers were separated, and the
aqueous layer was washed with isopropyl acetate (100 mL).
The combined organic layers were washed with 2 N HCl (50
mL), water (50 mL), and brine (50 mL) and dried (Na2SO4).
The filtered solution was concentrated to provide a quantita-
tive yield of the hydroxy amide 13 as a gummy foam, which
did not crystallize under many attempts (10.2 g containing 8
mol % isopropyl acetate). The material was used directly in
the next step: 1H NMR (CDCl3) δ 7.6 (br s, 1 H), 7.3-7.05 (m,
4 H), 6.8 (s, 1 H), 6.8-6.65 (m, 2 H), 4.45 (br m, 1 H), 3.05 (s,
3 H), 2.8 (s, 3 H), 2.7-2.45 (m, 2 H), 2.05-1.9 (m, 2 H); 13C
NMR (CDCl3) δ 170.5, 156.5, 145.8, 137.4, 136.8, 131.9, 131.0,
129.4, 125.9, 117.6, 114.5, 112.8, 39.8, 38.8, 34.8, 28.3; high-
resolution mass spectrum of C18H20NO3Cl found 333.1131,
calcd 333.1132.
7-Ch lor o-2-(ch lor om eth yl)qu in olin e Mon oh yd r och lo-
r id e (14). A solution of 7-chloroquinaldine (53.17 g, 0.3 mol)
in chlorobenzene (530 mL) was treated with tert-butyl hy-
pochlorite (53.6 mL, 0.45 mol) at rt over 15 min. The mixture
was then heated at 40-45 °C for 20 h. An additional charge
of tert-butyl hypochlorite (16.1 mL, 0.135 mol) was added
carefully, and the reaction was heated for an additional 20 h.
The mixture was cooled to rt. The unreacted quinaldine was
extracted by vigorously stirring a mixture of the chlorobenzene
reaction solution with 2 N HCl (200 mL) for 30 min. The
layers were separated, and the organic phase was dried by
concentration to 380 mL. A 1.0 M HCl/ethyl ether solution
(300 mL) was added, whereupon the hydrochloride salt of
7-chloro-2-(chloromethyl)quinoline precipitated. The mixture
was stirred for 1 h. The solid was filtered, washed with
chlorobenzene (300 mL) and then ethyl ether (250 mL), and
suction dried. The product 14 was obtained as a white solid
(65.2 g) in 88% yield. An analytical sample was prepared by
recrystallization from 2-propanol-1.6% water: sublimation
point (vacuum-nitrogen purged tube) 158 °C. A sample of the
hydrochloride salt was broken in isopropyl acetate/concen-
trated ammonium hydroxide, and the dichloroquinaldine was
recrystallized from hexanes: mp 97.5-98.5 °C; 1H NMR
(CDCl3) δ 8.175 (d, J ) 8.8 Hz, 1H), 8.075 (d, J ) 2.3 Hz, 1H)),
7.75 (d, J ) 8.8 Hz, 1H), 7.125 (d, J ) 8.8 Hz, 1 H), 7.5 (dd, J
) 2.3, 8.8 Hz, 1 H), 4.8 (s, 3 H); 13C NMR (CDCl3) δ 157.81,
147.73, 137.06, 135.80, 128.72, 128.28, 128.00, 125.72, 120.62,
47.07. Anal. Calcd for C10H7NCl2‚HCl: C, 48.32; H, 3.25; N,
5.64. Found: C, 48.21; H, 3.01; N, 5.40.
131.9, 131.0, 129.4, 129.3, 128.9, 128.0, 127.5, 125.91, 125.88,
119.3, 118.7, 113.2, 112.4, 71.0, 40.6, 38.8, 34.8, 28.2. Anal.
Calcd for C28H26N2O3Cl2‚HCl: C, 61.60; H, 5.00; N, 5.13.
Found: C, 61.88; H, 4.99; N, 4.99.
(S)-3-[[1-[3-[(7-Ch lor o-2-qu in olin yl)m eth oxy]p h en yl]-
3-[4-ch lor o-2-[(d im eth yla m in o)ca r bon yl]p h en yl]p r op yl]-
th io]p r op a n oic Acid [L-691,698 (1)]. The quinaldine phenyl
ether-alcohol 15 as the hydrochloride salt (1.0 g, 1.96 mmol)
was slurried in toluene (20 mL), and the mixture was cooled
to -25 °C. Triethylamine (0.49 mL, 3.5 mmol) was added
followed by the dropwise addition of methanesulfonyl chloride
(0.21 mL, 2.7 mmol) at <-25 °C. The mixture was warmed
to 0 °C over 2 h and stirred until the mesylation was complete.
An aliquot was removed, and the toluene was evaporated. 1H
NMR indicated when the reaction was complete by disappear-
ance of the methine proton of the alcohol (4.5 ppm) and
appearance of the methine proton of the mesylate (5.5 ppm).
The reaction was quenched with cold (0 °C) 5% NaHCO3 (20
mL), and the mixture was stirred for 30 min at rt. The layers
were separated, and the organic phase was washed with 5%
NaHCO3 (20 mL) and brine (10 mL). The organic phase was
concentrated to provide the mesylate as an oil. The mesylate
was dissolved in CH3CN (20 mL), and the solution was vacuum
purged with nitrogen (3×). 3-Mercaptopropanoic acid methyl
ester (0.33 mL, 2.94 mmol) was added at rt followed by Cs2CO3
(0.96 g, 2.94 mmol). The reaction mixture was stirred for 2 h.
The solids were filtered and washed with CH3CN (10 mL).
Water (20 mL) was added to the filtrate, and this mixture was
cooled to <5 °C. Lithium hydroxide (0.25 g, 5.9 mmol) was
added, and the saponification mixture was vigorously stirred
for 5 h. Acetic acid (1 mL) was added, and the product was
extracted with isopropyl acetate (2 × 50 mL). The combined
organic layers were washed with brine (25 mL) and dried
(Na2SO4). The filtered mixture was concentrated to an oil. The
crude propionic acid was chromatographed on silica gel (ethyl
acetate-toluene; 1:1; followed by ethyl acetate-toluene-acetic
acid; 1:1:0.01; Rf ) 0.24) to provide L-691,698 (1) as a foam in
70% overall yield from the R-alcohol 15: [R]25D -72.2° (c 0.39,
THF); 1H NMR (CDCl3) δ 8.15 (d, J ) 8.3 Hz, 1 H), 8.08 (d, J
) 1.85 Hz, 1 H), 7.74 (d, J ) 8.8 Hz, 1 H), 7.68 (d, J ) 8.8 Hz,
1 H), 7.48 (dd, J ) 8.8, 1.9 Hz, 1 H), 7.25-6.85 (m, 7 H), 5.5
(s, 2 H), 3.8 (m, 1 H), 3.05 (s, 3 H), 3.0-2.8 (m, 2 H), 2.85 (s,
3 H), 2.6-2.4 (m, 4 H), 2.1 (br s, 2 H); 13C NMR (CDCl3) δ
175.6, 169.7, 158.9, 158.4, 147.4, 143.8, 137.6, 137.1, 136.1,
135.8, 132.0, 130.9, 129.7, 129.0, 128.9, 127.6, 127.5, 126.0,
125.9, 120.9, 119.4, 114.4, 113.6, 70.6, 49.3, 38.6, 37.2, 34.6,
34.4, 30.3, 30.2, 25.9; high-resolution mass spectrum of
C31H30N2O4SCl2 found 597.1365, calcd 597.1381.
2-[2-(N,N-Dieth yla m in o)eth yl]-7-ch lor oqu in olin e (16).
A mixture of 7-chloroquinaldine (53.22 g, 0.297 mol), formalin
(23.6 g of 37% by weight formaldehyde, 0.290 mol), triethyl-
amine (1 mL, 7.17 mmol), and ethanol (40 mL) was heated at
60 °C. To this was added a solution of diethylamine hydro-
chloride (33 g, 0.301 mol), triethylamine (2 mL, 0.0143 mol),
ethanol (15 mL), and H2O (15 mL) from a dropping funnel over
2.5 h. After 3 h the reaction solution was cooled to rt and the
ethanol was removed under reduced pressure. The volume
was brought to 250 mL with water, and this solution was
extracted with methyl tert-butyl ether (MTBE) (6 × 50 mL) to
remove most of the starting material. The aqueous solution
was made basic by adding 5 N NaOH (88 mL), and this product
was extracted with MTBE (100 mL; 2 × 50 mL). The combined
organic layers were washed with brine (50 mL) and then
concentrated in vacuo to leave 47.7 g of the crude amine 16.
This material was used as is in the next reaction.
2-Eth en yl-7-ch lor oqu in olin e (17). The amine 16 (20.22
g, 0.077 mol) was stirred in ethanol (200 mL) at rt, and methyl
iodide (11.6 mL, 0.0186 mol) was added over 5 min. The
temperature rose to 40 °C, and a precipitate formed. After 2
h the reaction mixture was concentrated in vacuo to remove
the ethanol. Water (112 mL), ethanol (24 mL), and triethyl-
amine (10 mL, 7.17 mmol) were added, and this mixture was
heated at reflux for 16 h. After being cooled to rt, the mixture
was diluted with MTBE (300 mL) and EtOAc (100 mL), and
the aqueous layer was adjusted to pH 4.5 with 2 N HCl. After
separation of the layers the organic phase was washed with
(R)-5-Ch lor o-2-[3-[3-[(7-ch lor o-2-qu in olin yl)m eth oxy]-
p h en yl]-3-h yd r oxyp r op yl]-N,N-d im eth ylben za m id e (15).
The crude amide 13 (5.0 g, 15 mmol) was dissolved in DMF
(55 mL), and 7-chloro-2-chloromethylquinoline monohydro-
chloride (14) (4.1 g, 16.5 mmol) was added. Finely powdered
K2CO3 (6.2 g, 45 mmol) was added, and the mixture was heated
at 70 °C for 3 h. The mixture was cooled to room temperature
and was partitioned between isopropyl acetate (160 mL) and
water (160 mL). The organic layer was washed with water (2
× 80 mL) and brine (100 mL) and dried (Na2SO4). The solvent
was removed under vacuum to give 8.8 g of a crude viscous
oil. The oil was dissolved in CH2Cl2 (20 mL), and 1 M HCl in
ether (20 mL) was added. The resultant slurry was stirred at
room temperature for 1 h. The solid was filtered, washed with
hexanes/CH2Cl2 (3:2; 20 mL), and suction dried under a
nitrogen sweep to give 6.4 g (80% overall yield from the
hydroxy ester 3b) of the quinaldine-phenyl ether as an off-
white solid. An analytical sample was recrystallized from 2-
propanol: mp 170-173 °C (nitrogen-purged sealed tube); [R]25
D
+16.2 (c 0.93, THF) (as free base); 1H NMR (CDCl3) δ 8.15 (d,
J ) 8.3 Hz, 1 H), 8.07 (d, J ) 2.3 Hz, 1 H), 7.75 (d, J ) 8.8 Hz,
1 H), 7.68 (d, J ) 8.8 Hz, 1 H), 7.5 (dd, J ) 8.8, 1.9 Hz, 1 H),
7.43 (dd, J ) 8.3, 1.9 Hz, 1 H), 7.26 (m, 3 H), 7.03 (m, 1 H),
6.95-6.85 (m, 2 H), 5.35 (s, 2 H), 4.5 (br s, 1 H), 3.15 (s, 3 H),
2.85 (s, 3 H), 2.7 (m, 2 H), 2.0 (m, 2 H); 13C NMR (CDCl3) δ
170.4, 159.2, 158.4, 147.9, 146.7, 137.8, 136.8, 136.7, 135.5,

Practical Route to LTD4 Receptor Antagonists
J . Org. Chem., Vol. 61, No. 10, 1996 3405
brine (50 mL) and concentrated to provide 11.89 g of the
vinylquinoline 17 as a solid (81% yield from 16; 45% overall
yield from 7-chloroquinaldine). An analytical sample was
prepared by Darco treatment in ethanol and crystallization
stirred at 0 °C. The product mixture was filtered through a
12-g plug of silica gel and eluted with CH2Cl2. The eluent was
concentrated to provide 0.67 g of triflate 9e in 92% yield. A
flask was charged with 2-ethenyl-7-chloroquinoline (17) (0.34
g, 1.77 mmol), the triflate 9e (0.67 g, 1.61 mmol), palladium(II)
acetate (11 mg, 0.05 mmol), triphenylphosphine (0.026 g, 0.1
mmol), lithium bromide (0.14 g, 1.6 mmol), and DMF (3.5 mL).
The suspension was degassed with three vacuum/nitrogen
purges, and triethylamine (0.33 mL, 2.4 mmol) was added. The
mixture was heated at 100 °C. After 6 h the reaction mixture
was cooled to room temperature and was assayed by HPLC to
contain 0.71 g (98% yield) of the coupled product 18. The
product could not be isolated directly by the addition of water
due to gumming. The reaction mixture was partitioned
between isopropyl acetate (10 mL) and water (5 mL). The
organic phase was passed through silica gel (10 g) with
isopropyl acetate elution. The eluent was treated with Darco
(100 mg) and concentrated. The solid was redissolved in DMF
(3.5 mL), and water (1.0 mL) was added. The product was
collected, washed with 20% water in DMF and water, and
vacuum dried under nitrogen to afford 0.48 g of the keto ester
(66% overall yield). The product agreed with authentic keto
ester5 by mp, 1H and 13C NMR, and HPLC analysis: mp 124-
126 °C (lit.5 mp 128-130 °C).
1
by addition of water (1:1): mp 78-79 °C; H NMR (CDCl3) δ
8.08 (d, J ) 8.6 Hz, 1 H), 8.05 (d, 0.7 Hz, 1 H), 7.7 (d, J ) 8.6
Hz, 1 H), 7.55 (d, J ) 8.6 Hz, 1 H), 7.45 (dd, J ) 2.0, 8.6 Hz,
1 H), 7.05 (dd, J ) 10.9, 17.7 Hz, 1 H), 6.3 (dd, J ) 0.7, 17.7
Hz, 1 H), 5.7 (dd, J ) 0.7, 10.9 Hz, 1 H); 13C NMR (CDCl3) δ
157.0, 148.4, 137.6, 136.1, 135.4, 128.6, 128.4, 127.3, 125.8,
120.6, 118.7. Anal. Calcd for C11H8NCl: C, 69.66; H, 4.26;
N, 7.39. Found: C, 69.53; H, 4.49; N, 7.29.
(E)-2-[3-[3-[2-(7-Ch lor o-2-qu in olin yl)eth en yl]p h en yl]-
3-oxop r op yl]ben zoic Acid Meth yl Ester (18). F r om br o-
m id e 9c. A flask was charged with the vinylquinoline 17
(0.536 g, 2.83 mmol), the bromide 9c (0.889 g, 2.56 mmol),
palladium(II) acetate (17.7 mg, 0.079 mmol), tri-o-tolylphos-
phine (72 mg, 0.24 mmol), and DMF (5 mL). The suspension
was degassed with three vacuum/nitrogen purges, and then
triethylamine (0.54 mL, 3.87 mmol) was added. The mixture
was heated at 100 °C for 1 h. The reaction mixture was cooled
to rt, and water (1.25 mL) was added slowly while the
temperature was maintained at <30 °C. The slurry was aged
at rt for 3 h and then filtered. The filtered product was washed
with ice-cold 20% aqueous DMF (3 mL) and water (6 mL). After
the product was dried under vacuum at 60 °C, 1.06 g of 18
was obtained (91% yield).
Ack n ow led gm en t. We thank David J . Mathre for
supplies of 12 and Lawrence F. Colwell for high-
resolution mass spectrometry.
F r om Tr ifla te 9e. The phenol 9a (0.5 g, 1.76 mmol) was
dissolved in CH2Cl2 (10 mL), and the solution was cooled to 0
°C. Triethylamine (0.35 mL, 2.5 mmol) was added followed
by triflic anhydride (0.43 mL, 2.5 mmol). The mixture was
J O952103J