The improved synthesis of OPC-29030, a platelet adhesion inhibitor via diastereoselective oxidation of chiral non-racemic sulfide

Article abstract of DOI:10.1248/cpb.50.1511

An improved synthetic route of OPC-29030, the platelet adhesion inhibitor, was established via the diastereoselective oxidation of a chiral non-racemic sulfide (R)-5 to (S_S)-6 by the catalytic oxidation using VO(acac)₂ and cumene hydroperoxide (CHP) in the presence of MS4A. Under the current condition, the diastereoselectivity was not influenced by the presence of moisture, and moderate to high selectivity (72% de) was obtained at -30°C. The obtained sulfoxide, which diastereomeric excess was easily raised by the recrystallization, could successfully lead to OPC-29030.

Full text of DOI:10.1248/cpb.50.1511

November 2002
Notes
Chem. Pharm. Bull. 50(11) 1511—1513 (2002)
1511
The Improved Synthesis of OPC-29030, a Platelet Adhesion Inhibitor via
Diastereoselective Oxidation of Chiral Non-racemic Sulfide
Masato MATSUGI, ,a Rieko SHIMADA,a Shinji OHATA,a Masatomo NOJIMA,b Norio FUKUDA,c
*
d
Jun-ichi MINAMIKAWA,c and Yasuyuki KITA
a Department of Materials Chemistry, Graduate School of Engineering, Osaka University; b Department of Materials
Chemistry & Frontier Research Center, Graduate School of Engineering, Osaka University; 2–1 Yamada-oka, Suita, Osaka
565–0871, Japan: c BPC Division, Second Tokushima Factory, Otsuka Pharmaceutical Co., Ltd.; 224–18 Ebisuno,
Hiraishi, Kawauchi-cho, Tokushima 771–0182, Japan: and d Graduate School of Pharmaceutical Sciences, Osaka
University; 1–6 Yamada-oka, Suita, Osaka 565–0871, Japan. Received July 1, 2002; accepted September 4, 2002
An improved synthetic route of OPC-29030, the platelet adhesion inhibitor, was established via the diastere-
oselective oxidation of a chiral non-racemic sulfide (R)-5 to (SS)-6 by the catalytic oxidation using VO(acac)2 and
cumene hydroperoxide (CHP) in the presence of MS4A. Under the current condition, the diastereoselectivity was
not influenced by the presence of moisture, and moderate to high selectivity (72% de) was obtained at ꢀ30 °C.
The obtained sulfoxide, which diastereomeric excess was easily raised by the recrystallization, could successfully
lead to OPC-29030.
Key words oxidation; catalyst; sulfoxide; molecular sieve
mono-oxidation of sulfides (Table 1).13)
(S)-(ꢀ)-3,4-Dihydro-6-[3-(1-o-tolyl-2-imidazolyl)sulfinyl-
propoxy]-2(1H)-quinolinone (OPC-29030, Fig. 1)1) is known
as a sulfinyl derivative which exhibits potent inhibition of the
platelet adhesion by interfering with the release of 12(S)-hy-
droxyeicosatetraenoic acid (12-HETE) from platelets.2)
The first reported synthetic route3) to obtain the optically
pure OPC-29030 involves Sharpless–Kagan oxidation4—6) of
3-[1-(2-methylphenyl)imidazol-2-ylthio]propan-1-ol (1) as a
key step to introduce chirality to the molecule. However the
reaction proceeded with only 54% ee and the corresponding
sulfoxide 2 was isolated in 78% yield. To improve the low
stereoselectivity, previously we have reported a modified
Sharlpless–Kagan method for the sulfide 1 using (R)-man-
delic acid as a chiral auxiliary (Chart 2).7,8) The other
method, based on a kinetic resolution using an enzyme, was
also reported for introducing the chirality to the molecule.9,10)
In this note, we wish to report an alternative improved syn-
thetic route of OPC-29030 via a diastereoselective oxidation
by using a chiral non-racemic sulfide having an asymmetric
center at the neighboring position of the sulfur atom.11,12) The
improved synthetic route was established based on the as-
sumption that the use of the chiral sulfide (R)-5 would arise
high diastereoselective oxidation. Our hypothesis is that if
there is a hydroxyl group at the neighboring position to the
sulfur atom, metal catalyzed oxidation of the sulfide would
proceed in a stereoselective manner via rigid chelating inter-
mediate (Fig. 2).
Although the stereoselectivity of the oxidation was not
very high, we have found that oxovanadium(II) and tita-
nium(IV) gave the moderate result for the stereoselectivity of
the product among the metals used.
Next, we examined the possibility of the catalytic reaction
using oxovanadium(II), which is easier to handle compared
to titanium(IV). As clear from Table 2, both stereoselectivity
Fig. 1. Inhibitor of the Platelet Adhesion OPC-29030
Chart 1. First Synthetic Route of OPC-29030 via Modified Sharpless–
Kagan Oxidation
Since a favorable sulfide to our purpose has already been
reported by Uno et al., we synthesized the sulfide (R)-5 ac-
cording to their method as shown in Chart 3.3) In their report,
it also provided that a corresponding (SS)-sulfoxide, which
was isolated by the column chromatography after the
mCPBA oxidation of (R)-5, could effectively lead to OPC-
29030 via a reductive manner using a super Hydride®. This
information supported us to use (R)-5 as the substrate of the
diastereoselective oxidation.
First, we examined the stoichiometric oxidation of the sul-
fide (R)-5 using cumene hydroperoxide (CHP) along with
several kinds of metals that were claimed to be useful for the
Chart 2. Large Scale Synthesis of OPC-29030 via Asymmetric Oxidation
of 1 Using (R)-Mandelic Acid–Titanium Complex
∗ To whom correspondence should be addressed. e-mail: matsugi@ap.chem.eng.osaka-u.ac.jp
© 2002 Pharmaceutical Society of Japan

1512
Vol. 50, No. 11
Fig. 2. Strategy of the Effective Diastereoselective Oxidation
Chart 4. Diastereoselective Oxidation of (R)-5 Using mCPBA
Chart 3. Preparation of the Chiral Non-racemic Sulfide (R)-5
Chart 5. Derivation to OPC-29030 from (SS)-6
Table 1. Stoichiometric Diastereoselective Oxidation of (R)-5 Using Vari-
ous Metals
rather surprising, because in the usual Sharpless–Kagan oxi-
dation, even the presence of a small amount of water greatly
influences the stereoselectivity by changing the aggregation
state of the chiral titanium complex.15) The noted feature that
the presence of water does not affect the stereoselectivity of
the product is particularly useful for a large-scale synthesis.
In this oxidation, it is obvious that the metal salt plays an
essential role to exhibit high selectivity. Although the stereo-
selectivity of the mCPBA oxidation of (R)-5 was not men-
tioned in the previous report,3) we have confirmed that the m-
CPBA oxidation in methylene chloride provided the corre-
sponding sulfoxide with a lower stereoselectivity (only
4% de) and the sense of the chirality was opposite as shown
in Chart 4.
Entry
Metal
Yield (%)a)
De (%)b)
1
2
3
4
5
VO(acac)2
Ti(OiPr)4
MoO2(acac)2
Mn(acac)2
Ni(acac)2
50
40
21
3
trace
36
35
20
6
—
a) Calculated yield by HPLC. b) De was determined by HPLC.
In addition, when the substrate, whose hydroxyl function
was protected by the mesyl group was used in the VO(acac)2
oxidation, the reaction afforded the corresponding sulfoxide
with lower selectivity (78% yield, 9% de), suggesting that the
free hydroxyl function is also an essential feature to achieve
the high selectivity.
Table 2. Catalytic Diastereoselective Oxidation of (R)-5 Using VO(acac)2
Finally, we carried out the derivation of the sulfoxide to
the optically active OPC-29030 according to Uno’s report3)
(Chart 5). The recrystallization of the sulfoxide from ethanol
provided an almost optically pure sulfoxide (98% de) in a
good yield (61% from 5). Then the hydroxyl function was
converted to the corresponding mesylate function, followed
by reduction to methylene function by super Hydride® to af-
ford OPC-29030.
Entry
Additive
Yield (%)a)
De (%)b)
1
2
3
None
MS4A
MS4AꢀH2O (10 mol%)
81
91
93
46
72
68
a) Calculated yield by HPLC. b) De was determined by HPLC.
and product yield were higher than those in the reaction that
It is likely that the presented synthetic route is highly prac-
was carried out by a stoichiometric way (Table 2, Entries 1, tical, since the key reaction of the oxidation gives a good
2). It is noteworthy that the addition of the MS4A, which is yield of the product with moderate to high stereoselectivity,
an essential step to carry out the catalytic reaction in Sharp- and need not to care for the atmospheric moisture.
less–Kagan oxidation, made the stereoselectivity remarkably
high (72% de). At this moment, the role of the MS4A for the
Experimental
1
Melting points are uncorrected. H-NMR spectra were measured on 270
selectivity is not clear, but it is suggested that the MS4A,
which is known as the acid-base characteristic compound14)
participates in the formation of the active species in the tran-
sition-state.
Furthermore, we found that the presence of water in the
reaction medium had no significant influence on the stereose-
lectivity and also the yield (Table 2, Entry 3). This result is
or 500 MHz spectrometers with SiMe4 as the internal standard. E. Merck sil-
ica gel 60 (70—230 mesh ASTM) and YMC SIL 60A were used for column
chromatography. The de values of 6 were determined by HPLC on a TSK-
80TM column (eluent: MeCN/H2Oꢁ30/70) and ee values of OPC-29030
were determined by HPLC on a Ultoron ES-OVM (eluent: MeCN/20 mM
KH2PO4 aq.ꢁ10/90). Chiral non-racemic sulfide (R)-5 was prepared by the
published method.3)
(R)-6-[2-Hydroxy-3-(1-o-tolyl-1H-imidazol-2-ylsulfanyl)-propoxy]-3,4-

November 2002
1513
dihydro-1H-quinolin-2-one [(R)-5]3): Colorless crystals; mp 65.0—66.0 °C
(EtOH). [a]D24 ꢀ8.0° (cꢁ0.54, MeOH). 1H-NMR (CDCl3, 270 MHz) d: 2.10
(3H, s), 2.57—2.62 (2H, m), 2.89—2.94 (2H, m), 3.24—3.31 (1H, dd,
Jꢁ6.3, 15.0 Hz), 3.38—3.44 (1H, dd, Jꢁ2.6, 15.0 Hz), 3.94—4.00 (1H, m),
4.06—4.11 (1H, m), 4.35—4.37 (1H, m), 6.62—6.73 (3H, m), 6.98 (1H, d,
Jꢁ1.3 Hz), 7.11 (1H, d, Jꢁ1.3 Hz), 7.19—7.42 (4H, m), 7.62 (1H, br s).
Typical Procedure for the Diastereoselective Oxidation of (R)-5 To a
suspension of molecular sieves 4A in dry dichloromethane was added
vanadyl acetylacetonate (0.49 g, 1.8 mmol) at room temperature. To the
mixture was added 6-[2-hydroxy-3-(1-o-tolyl-1H-imidazol-2-ylsulfanyl)-
propoxy]-3,4-dihydro-1H-quinolin-2-one [(R)-5] (15.1 g, 36.8 mmol) and
then 80% cumene hydroperoxide (7.35 g, 38.6 mmol) was added to the
above mixture at ꢂ30 °C and the mixture was stirred for 24 h. After the fil-
tration of molecular sieves 4A, 8.3% sodium thiosulfate solution was added
and the mixture was stirred for 0.5 h at room temperature. The organic layer
was separated, dried (MgSO4) and concentrated in vacuo to give (SS)-6 of
72% de (14.2 g) in 92% yield.
2.06 (2H, m), 2.02 (3H, s), 2.39 (2H, t, Jꢁ7.3 Hz), 2.82 (2H, t, Jꢁ7.3 Hz),
3.38 (1H, ddd, Jꢁ13.8, 8.4, 6.5 Hz), 3.47 (1H, ddd, Jꢁ13.8, 8.4, 6.5 Hz),
4.00 (2H, t, Jꢁ6.1 Hz), 6.67 (1H, dd, Jꢁ8.6, 2.7 Hz), 6.72 (1H, d,
Jꢁ2.7 Hz), 6.75 (1H, d, Jꢁ8.6 Hz), 7.34—7.38 (2H, m), 7.36 (1H, d,
Jꢁ1.2 Hz), 7.47 (1H, ddd, Jꢁ7.4, 5.9, 2.4 Hz), 7.43 (1H, bd, Jꢁ7.4 Hz),
7.58 (1H, bd, Jꢁ1.2 Hz), 9.73 (1H, s). tR 24.5 min (flow rate, 1.0 ml/min).
References and Notes
1) Nishi T., Uno T., Shu Y., Tamura K., Okada M., Japan Patent 7-33765
(1995) [Chem. Abstr., 122, 160640z (1995)].
2) Kawasaki K., Komori K., Okazaki J., Ozeki Y., Sugimachi K., J. Car-
diov. Pharmacol., 36, 555—563 (2000).
3) Uno T., Ozeki Y., Koga Y., Chu G., Okada M., Tamura K., Igawa T.,
Unemi F., Kido M., Nishi T., Chem. Pham. Bull., 43, 1724—1733
(1995).
4) Gao Y., Hanson R. M., Klunder J. M., Ko S. Y., Masamune H., Sharp-
less K. B., J. Am. Chem. Soc., 109, 5765—5780 (1987).
5) Brunel J. M., Kagan H. B., Bull. Soc. Chim. Fr., 133, 1109—1115
(1996).
6) Pitchen P., Duñpach E., Deshmukh M. N., Kagan H. B., J. Am. Chem.
Soc., 106, 8188—8193 (1984).
7) Matsugi M., Fukuda N., Minamikawa J., Otsuka S., Tetrahedron Lett.,
39, 5591—5592 (1998).
8) Matsugi M., Fukuda N., Muguruma Y., Yamaguchi T., Minamikawa J.,
Otsuka S., Tetrahedron, 57, 2739—2744 (2001).
9) Morita S., Matsubara J., Otsubo K., Kitano K., Ohtani T., Kawano Y.,
Uchida M., Tetrahedron Asymmetry, 8, 3707—3710 (1997).
10) Kitano K., Matsubara J., Ohtani T., Otsubo K., Kawano Y., Morita S.,
Uchida M., Tetrahedron Lett., 40, 5235—5238 (1999).
11) Bortolini O., Di Furia F., Modena G., J. Catal., 19, 319—329 (1983).
12) Bortolini O., Di Furia F., Licini G., Modena G., Phosphorus Sulfur.,
37, 171—174 (1988).
13) Kagan H. B., “Catalytic Asymmetric Synthesis,” 2nd ed., ed. by Ojima
I., Wiley-VCH, New York, 2000, pp. 327—356.
14) Izumi Y., Onaka M., Adv. Catal., 38, 245—282 (1992).
15) Zhao S. H., Samuel O., Kagan H. B., Tetrahedron, 43, 5135—5144
(1987).
Recrystallization of (SS)-6 A solution of 14.2 g of (SS)-6 (33.4 mmol,
72% de) in 113.6 ml of ethylalcohol was heated to reflux. Then the solution
was cooled down to 2 °C by degrees under stirring and the stirring was con-
tinued for 30 min at 2 °C. The white precipitate was collected to give (SS)-6
of 98% de (9.55 g) in 67.3% yield.
(SS)-6-[2-Hydroxy-3-(1-o-tolyl-1H-imidazol-2-ylsulfinyl)-propoxy]-3,4-
dihydro-1H-quinolin-2-one [(SS)-6]3): Colorless solid; mp 128.0—130.0 °C.
1H-NMR (CDCl3, 270 MHz) d: 2.11 (3H, br s), 2.57—2.63 (2H, m), 3.54—
3.69 (2H, m), 4.05—4.16 (2H, m), 6.65—6.75 (3H, m), 7.18 (1H, m),
7.38—7.49 (4H, m), 8.06 (1H, m). tR 15.8 min (flow rate, 0.5 ml/min).
(SS)-Methanesulfonic Acid 1-(2-Oxo-1,2,3,4-tetrahydro-quinolin-6-yloxy-
methyl)-2-(1-o-tolyl-1H-imidazol-2-ylsulfinyl)-ethyl Ester [(SS)-7]3): Color-
less solid; mp 87.0—89.0 °C. [a]D25 ꢂ2.9° (cꢁ0.41, CHCl3). 1H-NMR
(CDCl3, 270 MHz) d: 2.11 (3H, s), 2.58—2.64 (2H, m), 2.90—2.98 (2H,
m), 3.07 (3H, s), 3.57 (1H, m), 4.23—4.33 (2H, m), 4.41—4.46 (1H, m),
5.32—5.40 (1H, m), 6.66—6.75 (3H, m), 7.20 (1H, m), 7.36—7.50 (5H, m),
7.97 (1H, br s). HR-MS Calcd for C23H26N3O6S2: 504.1263. Found:
504.1271.
(S)-(ꢀ)-3,4-Dihydro-6-[3-(1-o-tolyl-2-imidazolyl)sulfinylpropoxy]-
2(1H)-quinolinone (OPC-29030)3): Colorless solids; mp 124.0—126.0 °C.
[a]D20 ꢀ19.0° (cꢁ1.0, MeOH). 1H-NMR (DMSO-d6, 500 MHz) d: 1.93—