A practical procedure for the large-scale preparation of methyl (2R,3S)-3-(4-methoxyphenyl) glycidate, a key intermediate for diltiazem

Article abstract of DOI:10.1021/jo025647b

A practical synthesis of methyl (2R,3S)-3-(4- methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), was developed. Treatment of methyl (E)-4-methoxycinnamate 3 with chiral dioxirane, generated from chiral ketone 4, provided (-)-2 in 77% ee and 89% yield. The crude mixture of (-)-2 and 4 was efficiently separated by the use of novel and simple equipment performing a lipase-catalyzed transesterification and a continuous dissolution and crystallization to furnish the optically pure (-)-2 and recovery of 4 in 74% and 91% yield, respectively.

Full text of DOI:10.1021/jo025647b

J . Org. Chem. 2002, 67, 4599-4601
4599
A P r a ctica l P r oced u r e for th e La r ge-Sca le
P r ep a r a tion of Meth yl
(2R,3S)-3-(4-Meth oxyp h en yl)glycid a te, a
Key In ter m ed ia te for Diltia zem
Toshiyuki Furutani, Ritsuo Imashiro,
Masanori Hatsuda, and Masahiko Seki*
Product & Technology Development Laboratory, Tanabe
Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku,
Osaka 532-8505, J apan
m-seki@tanabe.co.jp
Received February 24, 2002
Abstr a ct: A practical synthesis of methyl (2R,3S)-3-(4-
methoxyphenyl)glycidate (-)-2, a key intermediate for dil-
tiazem (1), was developed. Treatment of methyl (E)-4-
methoxycinnamate 3 with chiral dioxirane, generated from
chiral ketone 4, provided (-)-2 in 77% ee and 89% yield. The
crude mixture of (-)-2 and 4 was efficiently separated by
the use of novel and simple equipment performing a lipase-
catalyzed transesterification and a continuous dissolution
and crystallization to furnish the optically pure (-)-2 and
recovery of 4 in 74% and 91% yield, respectively.
still unsatisfactory for a practical use. Herein we describe
a highly optimized and practical procedure for the
preparation of (-)-2 using an improved workup and
equipment that involves a lipase-catalyzed transesteri-
fication of the unwanted enantiomer (+)-2 [(2S,3R)
enantiomer].
The preparation of (-)-2 from 3 was conducted as
described in Scheme 1. Treatment of 3 with 5 mol % of 4
in the presence of Oxone (1 equiv) and NaHCO3 (3.1
equiv) in aqueous 1,4-dioxane at 5 °C for 24 h and at 27
°C for 2 h provided (-)-2 in 77% ee and 89% yield. There
are two significant improvements over the previously
reported procedure.9 The first modification is the workup
prior to the separation of (-)-2 and 4. We have previously
extracted the products by adding CHCl3 to the reaction
mixture. However, choice of a halogenated solvent such
as CHCl3 is not environmentally benign and makes it
difficult to recover 1,4-dioxane. Direct distillation of the
reaction mixture and extraction of the products with
toluene were thus performed. However, considerable ring
opening of (-)-2 to the corresponding diol was observed
in the workup whose scale was larger than 0.1 mol. To
avoid the decomposition of (-)-2, crystallization of (-)-2
and 4 by adding water to the reaction mixture was
attempted (Scheme 2). Addition of water (20 mL/g of
initially added 3) to the reaction mixture was found to
directly crystallize (-)-2 and 4. Although the resulting
solids contained an acceptable amount of (-)-2 (85% ee,
Catalytic asymmetric synthesis has recently been
recognized as one of the most expedient approaches to
enantiomerically pure chiral compounds, and consider-
able efforts have been devoted to enhance the enantiose-
lectivity as well as the catalytic activity.1 Quite few
examples2 are, however, found in technology that have
been applied to a practical large-scale preparation. Seri-
ous drawbacks of the method lie in the fact that they
largely need an expensive chiral catalyst, a quite low
temperature, or a costly workup to separate the product
and chiral catalyst. We have recently reported a synthesis
of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2,3
a key intermediate4 for diltiazem (1),5 by means of a
catalytic asymmetric epoxidation of methyl (E)-4-meth-
oxycinnamate 36 with chiral binaphthyl ketone 47,8 used
as the catalyst and subsequent separation of (-)-2 and
4 through continuous dissolution and crystallization.9
The synthesis is efficient in terms of mild reaction
conditions (5-27 °C) and high recovery of 4 (88%).
However, the yield of optically pure (-)-2 (64%) proved
(1) (a) Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH: New
York, 1993. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
J ohn Wiley & Sons: New York, 1994.
(6) For an economical synthesis of 3, see: Hatsuda, M.; Kuroda, T.;
Seki, M. Synth. Commun., in press.
(7) (a) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J .-
H.; Cheung, K.-K. J . Am. Chem. Soc. 1996, 118, 491. (b) Yang, D.;
Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J . Am. Chem. Soc.
1996, 118, 11311. (c) Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.;
Tang, M.-W.; Zheng, J .-H.; Cheung, K.-K. J . Am. Chem. Soc. 1998,
120, 5943.
(8) For a practical synthesis of 4, see: (a) Seki, M.; Furutani, T.;
Hatsuda, M.; Imashiro, R. Tetrahedron Lett. 2000, 41, 2149. (b)
Furutani, T.; Hatsuda, M.; Imashiro, R.; Seki, M. Tetrahedron:
Asymmetry 1999, 10, 4763. (c) Kuroda, T.; Imashiro, R.; Seki, M. J .
Org. Chem. 2000, 65, 4213. (d) Seki, M.; Yamada, S.; Kuroda, T.;
Imashiro, R.; Shimizu, T. Synthesis 2000, 1677. (e) Furutani, T.;
Hatsuda, M.; Shimizu, T.; Seki, M. Biosci. Biotechnol. Biochem. 2001,
65, 180. (f) Hatsuda, M.; Hiramatsu, H.; Yamada, S.; Shimizu, T.; Seki,
M. J . Org. Chem. 2001, 66, 4437.
(2) For example, see: (a) Knowles, W. S.; Sabacky, M. J .; Vineyard,
B. D.; Weinkauff, D. J . J . Am. Chem. Soc. 1975, 97, 2567. (b) Aratani,
T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1977, 2599. (c) Tani,
K.; Yamagata, T.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.;
Takaya, H.; Moyashita, A.; Noyori, R.; Otsuka, S. J . Am. Chem. Soc.
1984, 106, 5208. (d) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(e) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumoba-
yashi, H. J . Am. Chem. Soc. 1989, 111, 9134.
(3) For a recently published excellent catalytic asymmetric synthesis
of (-)-2, see: Nemoto, T.; Ohshima, T.; Shibasaki, M. J . Am. Chem.
Soc. 2001, 123, 9474.
(4) Hashiyama, T.; Inoue, H.; Konda, M.; Takeda, M. J . Chem. Soc.,
Perkin Trans. 1 1984, 1725.
(9) Seki, M.; Furutani, T.; Imashiro, R.;Kuroda, T.; Yamanaka, T.;
Harada, N.; Arakawa, Kusama, M.; Hashiyama, T. Tetrahedron Lett.
2001, 42, 8201.
(5) Nagao, T.; Sato, M.; Nakajima, H.; Kiyomoto, A. Chem. Pharm.
Bull. 1973, 21, 92.
10.1021/jo025647b CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/21/2002

4600 J . Org. Chem., Vol. 67, No. 13, 2002
Notes
Sch em e 1a
Sch em e 3
a
Reagents and yields: (a) (i) 4 (5 mol %), Oxone (1 equiv),
NaHCO3 (3.1 equiv), 1,4-dioxane/H2O, 5 °C, 24 h, 27 °C, 2 h, (ii)
NaCl, extraction with 1,4-dioxane, (iii) evaporation, (iv) separation
using equipment shown in Figure 1, 74% yield (>99% ee) with
91% recovery of 4.
Sch em e 2a
two vessels using a lab pump. After 23 h, 80% of the
unwanted enantiomer (+)-2 was selectively converted to
an oily n-butyl ester, and the circulation was further
continued for 2 h at lower temperature (10 °C for vessel
A and 5 °C for vessel B). Through these treatments were
obtained optically pure (-)-2 (74% based on 3) and 412
(91% based on initially added 4) both in excellent yields
from vessel B and A, respectively. It is worth noticing
that the equipment needs only a very small amount of
lipase SM (absorbed on Celite, 1.2 g for 1 mol scale
separation) since the amount of the substrate i.e. (+)-2
is vastly little (ca. 10% of the total amount of 2) and the
selectivity of the transesterification is unprecedentedly
high (E-value ) >100).13
In conclusion, a practical synthetic method of a key
intermediate (-)-2 for diltiazem was accomplished. The
present methodology, involving the dioxirane-mediated
asymmetric epoxidation of methyl (E)-4-methoxycin-
namate 3 and subsequent efficient separation of the
product (-)-2 and chiral catalyst 4, represents one of the
best approaches to (-)-2. Although it may have some
limitations on the generality of the substrates other than
3, the strategy used in this study would be of help for
the industrial chemists to apply the modern catalytic
asymmetric synthesis to their large-scale preparation of
chiral compounds.
a
The yields of (-)-2 and 4 shown in the scheme are based on 3
and 4 that were initially added for the asymmetric epoxidation.
80% based on 3), recovery of 4 was unsatisfactory (79%
based on initially added 4). An alternative procedure was
then undertaken which consisted of addition of NaCl to
the reaction mixture to separate phases and extraction
of the spent aqueous phase with another portion of 1,4-
dioxane (Scheme 3). The combined organic phases were
distilled to recover 1,4-dioxane in 83% yield. Then, to the
residue was added water to form a precipitate, which
upon filtration and subsequent washing with 1-butanol
afforded colorless water-free solids (water <1 wt %)
containing an acceptable amount of (-)-2 (79% ee, 87%)
and 4 (94%).
The second significant improvement was made on the
separation of (-)-2 and 4. We have previously developed
an efficient separating system based on continuous
dissolution and crystallization of the crude product.9 If
the unwanted enantiomer (+)-2 may selectively be con-
verted to an oily n-butyl ester concomitantly during the
separation, the yield of (-)-2 should be improved. Thus,
we designed a system that includes a lipase column for
the transesterification10 of unwanted (+)-2 (Figure 1).
The system has two vessels (A and B) initially kept at
25 and 18 °C, respectively, and fitted with a glass filter.
A column containing Celite-immobilized lipase SM (Ser-
ratia marcescens)11 was placed above the inlet of vessel
A. The crude mixture of (-)-2 and 4 was loaded into
vessel A with isopropyl ether containing 3.8 wt % of
1-butanol. The solvent was then circulated between the
Exp er im en ta l Section
Gen er a l Meth od . Melting points are uncorrected. 1H and 13C
NMR spectra were recorded with tetramethylsilane used as an
internal standard. Optical rotations were measured at the
indicated temperature with a sodium lamp (D line, 589 nm). All
solvents and reagents were used as received.
(10) Gentile, A.; Giordano, C.; Fuganti, C.; Ghirotto, L.; Servi, S. J .
Org. Chem. 1992, 57, 6635.
(11) Idei, A.; Matsumae, H.; Kawai, E.; Yoshioka, R.; Shibatani, T.;
Akatsuka, H.; Omori, K. Appl. Microbiol. Biotechnol. 2002, 58, 322.
(12) The recovered catalyst 4 could be used again for the asymmetric
epoxidation without any decrease in the chemical and optical yields.
(13) Matsumae, H. Ph.D. Thesis, Tottori University, J apan, 1995.

Notes
J . Org. Chem., Vol. 67, No. 13, 2002 4601
Sep a r a tion of P r od u ct (-)-2 a n d Ca ta lyst 4. The equip-
ment for separating (-)-2 and 4 used in this study has two
vessels (vessel A and B), an immobilized lipase column, and a
circulating pump as shown in Figure 1. The vessels (working
volume 0.5 L) are made of glass and are equipped with a water
jacket, a mechanical stirrer, and a glass filter (pore size 50 µm).
The lipase column (working volume 0.01 L) is made of glass.
The temperature of vessel A and B was initially kept at 25 and
18 °C, respectively. The crude mixture of (-)-2 (182 g, 79% ee)
and 4 (18.6 g) obtained by the asymmetric epoxidation (see
above) was loaded on vessel A with isopropyl ether (400 mL)
and 1-butanol (15 mL) and stirred. Celite-immobilized Lipase
SM (1.2 g) was used in the lipase column. When the inner
temperature of vessel A reached 25 °C, the suspension was
filtered through the glass filter to vessel B, and another portion
of isopropyl ether (400 mL) and 1-butanol (15 mL) was loaded
into vessel A. When the inner temperature of vessel B reached
18 °C, seed crystals (ca. 100 mg) of (-)-2 were added to vessel B
with stirring. Then, the filtrate was circulated by the lab pump
(30 mL/min) in a closed system for 23 h at these temperatures
and at lower temperatures [10 °C (vessel A) and 5 °C (vessel
B)] for 2 h. The crystals remaining in vessel A were collected
and washed by isopropyl ether (50 mL) to recover 4 (17.9 g, 91%
based on initially added 4), and the crystals formed in vessel B
were collected and washed with MeOH (50 mL) to give (-)-2
F igu r e 1. Separation of (-)-2 and 4.
Ca ta lytic Asym m etr ic Ep oxid a tion of 3. To a solution of
methyl (E)-4-methoxycinnamate 3 (192 g, 1 mol) and the catalyst
4 (19.8 g, 50 mmol) in a mixed solvent of 1,4-dioxane (2.4 L)
and H2O (1.44 L) were successively added Oxone (614.8 g, 1 mol)
and NaHCO3 (260.4 g, 3.1 mol) at 5 °C. The suspension was
mechanically stirred at 5 °C for 24 h. The mixture was then
warmed to 27 °C, and stirring was continued for 2 h. Into the
mixture was added NaCl (280 g), and the mixture was stirred
for 5 min. The organic phase was separated, and the aqueous
phase was extracted twice with 1,4-dioxane (2 × 500 mL). The
combined extracts containing (-)-2 (186 g, 89% yield, 77% ee)
and 4 (19.8 g, 100%) were distilled at 27 °C for 4 h under reduced
pressure (18 mmHg) to recover 1,4-dioxane [3.12 L (water
content 10%), recovery 83%]. Into the residue was added water
(1.5 L), and the mixture was stirred at 5 °C for 30 min. The
crystals formed were collected and washed with water (600 mL)
and n-BuOH (200 mL) to provide the crude mixture (water
content <1 wt. %) of (-)-2 (182 g, 87% yield, 79% ee) and 4 (18.6
g, 94%). The yield and the ee value of (-)-2 and 4 were
determined by HPLC (Chiralcel OD, hexane/i-PrOH ) 10:1, 220
nm, 40 °C; (-)-2, 8.1 min; (+)-2, 9.8 min).
(>99% ee, 155 g, 74% based on 3). (-)-2: mp 88 °C; [R]24 -205
D
(c, 1.0, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J ) 8.7
Hz, 2H), 6.89 (d, J ) 8.7 Hz, 2H), 4.05 (d, J ) 1.7 Hz, 1H), 3.82
(s, 3H), 3.80 (s, 3H), 3.51 (d, J ) 1.7 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 168.7, 160.2, 127.1, 126.9, 126.6, 114.3, 114.0,
57.8, 56.4, 55.2, 52.4; IR (KBr) ν 1748, 1613 cm-1; MS m/z 208
(M+). Anal. Calcd for C11H12O4: C, 63.45; H, 5.81. Found: C,
63.14; H, 5.50. The circulating fluid obtained after the separation
contained (-)-2 (6.1 g, 2.9%), (+)-2 (3.4 g, 1.6%), 4 (0.25 g, 1.3%),
and (+)-n-butyl ester (15.6 g, 6.2%) transesterified from (+)-2
(HPLC, Chiralcel OD, hexane/i-PrOH ) 10:1, 220 nm, 40 °C;
(-)-2, 8.1 min; (+)-2, 9.8 min, (-)-n-butyl ester, 6.0 min; (+)-n-
butyl ester, 6.4 min).
Celite-Im m obilized Lip a se SM.11 Aqueous Lipase SM
solution (30 mL) was thoroughly mixed in a 500 mL flask with
Celite (30 g), and the mixture was dried at 30 °C under reduced
pressure to give 36.5 g of the Celite-immobilized Lipase SM
having an activity of 8.2 U/mg (olive oil hydrolysis activity).
J O025647B