First practical resolution of a 3-(4-methoxyphenyl)glycidic acid ester by preferential crystallization and synthesis of diltiazem

Article abstract of DOI:10.1016/S0957-4166(98)00148-7

Among the various esters of 3-(4-methoxyphenyl)glycidic acid, 4-chloro- 3-methylphenyl ester (±)-3 was found to exist as a conglomerate, and could be alternately resolved into (+)- and (-)-3 of >98% ee by a preferential crystallization procedure. Furthermore, a 1,5-benzothiazepine derivative, (+)-6, a significant intermediate of diltiazem, was prepared in one pot in 76% overall yield through the treatment of enantiomerically pure (-)-3 with 2-aminothiophenol followed by a ring closing reaction.

Full text of DOI:10.1016/S0957-4166(98)00148-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1713–1721
First practical resolution of a 3-(4-methoxyphenyl)glycidic acid
ester by preferential crystallization and synthesis of diltiazem
Shin-ichi Yamada,a Katsuji Morimatsu,b Ryuzo Yoshioka,a,∗ Yasuhiko Ozaki a and
Hiroyasu Seko b
aPharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd, 16-89, Kashima-3-chome, Yodogawa-ku,
Osaka 532, Japan
bProduction Technology Division, Tanabe Seiyaku Co., Ltd, 16-89, Kashima-3-chome, Yodogawa-ku, Osaka 532, Japan
Received 5 March 1998; accepted 8 April 1998
Abstract
Among the various esters of 3-(4-methoxyphenyl)glycidic acid, 4-chloro-3-methylphenyl ester (ꢀ)-3 was found
to exist as a conglomerate, and could be alternately resolved into (+)- and (−)-3 of >98% ee by a preferential
crystallization procedure. Furthermore, a 1,5-benzothiazepine derivative, (+)-6, a significant intermediate of
diltiazem, was prepared in one pot in 76% overall yield through the treatment of enantiomerically pure (−)-3
with 2-aminothiophenol followed by a ring closing reaction. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Optically active glycidic acid esters are efficient synthetic sources, because epoxides are useful
electrophilic building blocks for making new bonds.1 As such, an epoxide, methyl (2R,3S)-3-(4-
methoxyphenyl)glycidate (−)-1 has been recently utilized to manufacture the coronary vasodilator,
diltiazem (+)-7,2 due to the minimum number of reaction steps and the reduction of raw materials.
Since optically active (−)-1 and its ester derivatives are such significant compounds, their economical
preparations have been tried using diastereomeric3 and enzymatic4 resolutions, asymmetric aldol5 and
Darzens6 reactions, and asymmetric reductions7 and epoxidations.8 However, there is no report on the
successful alternate resolution of (ꢀ)-1 by a preferential crystallization procedure, except for one that
was achieved under very limited conditions.9
Resolution via preferential crystallization is known to be practical and cost-effective in that it requires
no chiral reagent or enzyme, and can be applied to industrial scale preparations.10 Therefore, we
investigated the resolution of 3-(4-methoxyphenyl)glycidic acid ester derivatives using this procedure,
∗
Corresponding author. E-mail: yoshioka@tanabe.co.jp
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00148-7

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S. Yamada et al. / Tetrahedron: Asymmetry 9 (1998) 1713–1721
and fortunately found that the 4-chloro-3-methylphenyl ester (ꢀ)-3 can be alternately resolved. In
addition, we examined the synthesis of diltiazem from enantiomerically pure (−)-3, and also succeeded
in an effective one-pot synthesis. The present paper reports the first practical resolution of the racemic
glycidic acid ester (ꢀ)-3 and the efficient synthesis of diltiazem.
2. Results and discussion
2.1. Search for a conglomerate glycidic acid ester
(ꢀ)-1 itself is not a conglomerate appropriate for preferential crystallization, because the infrared
spectrum of (ꢀ)-1 is different from that of (+)- or (−)-1. Consequently, (ꢀ)-1 can not be successfully
resolved by this method. For this reason, we searched for a conglomerate ester derivative of (ꢀ)-1 and
prepared various racemic and optically active esters according to reported procedures. The hydrolysis of
the methyl ester 1 provided the potassium salt 2 in >90% yield,11 which was then reacted with another
alcohol in the presence of the 2-chloropyridinium salt and triethylamine to form an ester derivative in
about 50% yield12 (Scheme 1). As a result, most of the aliphatic ester derivatives were oily substances,
while half of the aromatic esters formed good crystals which have a high melting point.
Scheme 1. Synthesis of the racemic glycidic acid ester
Next, the glycidic acid substituted phenylesters were examined as to whether they were conglom-
erate crystals using a standard screening method.10 Of approximately 30 esters tested, only the 3-(4-
methoxyphenyl)glycidic acid 4-chloro-3-methylphenyl ester (ꢀ)-3 was found to exist as a conglomerate.
Table 1 shows the properties of the racemic and optically active 3. The melting point of (−)-3 is higher
than that of (ꢀ)-3, the solubility of (−)-3 in both THF and DMF is half that of (ꢀ)-3, and the infrared
spectra of (−)- and (ꢀ)-3 are identical. These results suggest that (ꢀ)-3 has typical conglomerate crystals
and can be resolved into its enantiomers by preferential crystallization.
2.2. Resolution of the glycidic acid ester by preferential crystallization
First, we employed THF as the solvent and attempted the resolution of (ꢀ)-3. A supersaturated solution
of (ꢀ)-3 including a small excess of (−)-3 was prepared by heating, and then cooled to 30°C. A small
number of seeds of (−)-3 was added and the stirred solution was allowed to crystallize for 20 min. The
Table 1
Properties of (ꢀ)- and (−)-3

S. Yamada et al. / Tetrahedron: Asymmetry 9 (1998) 1713–1721
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Table 2
Successive alternate resolution of (ꢀ)-3 by preferential crystallization in THFa)
Table 3
Successive alternate resolution of (ꢀ)-3 by preferential crystallization in DMFa)
weight of (−)-3 obtained after filtration was more than that of the (−)-3 introduced in excess at the
beginning of the experiment and the ee was almost 100%. To the mother liquor, (ꢀ)-3 was then added in
order that the quantity of (ꢀ)-3 in the solution could be recovered. The mixture was heated until the solid
was completely dissolved and then cooled to 30°C. After the solution had been seeded with (+)-3 and
stirred for 20 min, the precipitated (+)-3 was collected in a similar manner. These cycles of the procedure
were carried out six times to yield (+)- and (−)-3 of >91% ee with a 2.5–7.5% degree of resolution
(Table 2).
In the same manner as already described, alternate resolutions were done in DMF solvent, and (+)-
and (−)-3 of 74–94% ee could be repeatedly obtained in a 6–9% degree of resolution (Table 3). Crude
(+)- and (−)-3 could be easily purified into enantiomerically pure 3 by recrystallization.
In this way, we succeeded in the successive alternate resolution of (ꢀ)-3 in both THF and DMF
solvents. The degree of resolution is slightly low, but it might be improved by a detailed examination
of the resolution conditions.
2.3. Synthesis of diltiazem
Since (−)-3 is a new compound, diltiazem has not been previously prepared from it. With respect to
the preparation, we planned two routes as indicated in Scheme 2.

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S. Yamada et al. / Tetrahedron: Asymmetry 9 (1998) 1713–1721
Scheme 2. Synthesis of diltiazem
Table 4
Synthesis of (−)-1 from (−)-3 by transesterificationa)
We first investigated the transesterification of (−)-3 to (−)-1, because diltiazem is presently manu-
factured in high yield through the key intermediate (−)-1.13 As shown in Table 4, without a catalyst,
the reaction did not rapidly proceed even at the elevated temperature. Conversely, a catalytic amount of
base accelerated the reaction and (−)-1 could be isolated in 71% yield after 3 h at room temperature.
From (−)-1, another intermediate, (+)-6, with >99% ee was obtained in 80% yield, similar to a previous
report.13
Second, we explored the more straightforward route from (−)-3 to (+)-6. Initially, we attempted the
reaction of 2-aminothiophenol with (−)-3 using chlorobenzene or xylene as a solvent, and FeCl3·6H2O
as the catalyst14 (Table 5). In all cases, the cyclization product (+)-6 was recognized as well as (+)-5.

S. Yamada et al. / Tetrahedron: Asymmetry 9 (1998) 1713–1721
1717
Table 5
Reaction of (−)-3 with 2-aminothiophenola)
Fig. 1.
When the reaction was conducted at 100 or 110°C, the conversions into the two products were low.
In contrast, at the reflux temperatures of chlorobenzene or xylene, the total conversion into (+)-5 and
(+)-6 exceeded 90%. As for the catalyst, it was effective in xylene, but did not affect the conversions
in chlorobenzene. Eventually, (+)-5 could be isolated in 72% yield under the conditions indicated in
run 5. In this case, the cis-opening of the epoxy ring, that is, attack of the thiol group on the C-3
position from the same side of the epoxy oxygen is predominant, and thereby the threo isomer (+)-5
stereoselectively forms (Fig. 1).15 Next, we examined the intramolecular cyclization reaction of (+)-5 into
the 1,5-benzothiazepine derivative (+)-6. Fortunately, the enantiomerically pure (+)-6 was easily obtained
almost quantitatively by refluxing for 1 h in chlorobenzene with a catalytic amount of methanesulfonic
acid.
A one-pot synthesis is very attractive, in particular, for industrial scale operations, because two
reactions are performed in the same reactor and thus transferring contents to another vessel between
the two reactions is unnecessary.13 Therefore, we finally attempted to complete the successive procedure
from (−)-3 to (+)-6. The ester (−)-3 was reacted with 2-aminothiophenol in chlorobenzene at reflux
temperature for 30 min to give the intermediate (+)-5. Without being isolated, (+)-5 was cyclized in
the presence of methanesulfonic acid in the same vessel to give enantiomerically pure (+)-6 in 76%
overall yield. From (+)-6, diltiazem is readily prepared in high yield through N-alkylation6c,16 and O-
acetylation.6c
In conclusion, we have succeeded in the first practical resolution of the 3-phenylglycidic acid ester
by preferential crystallization, and developed effective procedures for the diltiazem synthesis. Epoxides
are generally reactive and susceptible to cleavage, and thus they are more difficult to be resolved. This
successive alternate resolution might be regarded as a rare case.

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S. Yamada et al. / Tetrahedron: Asymmetry 9 (1998) 1713–1721
3. Experimental section
Melting points are uncorrected. Optical rotations were measured on a Perkin–Elmer model 243
1
polarimeter. IR spectra were recorded on a Perkin–Elmer 1600 series FT-IR. H-NMR spectra were
measured at 200 MHz on a Bruker AC-200 instrument and chemical shifts are reported relative to
the tetramethylsilane (TMS) reference. Mass spectra were measured at 70 eV in the EI mode on a
Hitachi M-2000A mass spectrometer. Elemental analyses were performed on a Perkin–Elmer 2400 CHN
analyzer. All of the solvents and reagents were commercial products used without further purification.
An analytical TLC was performed on E. Merck precoated silica gel 60 F254 plates. Conversions from
(−)-3 to (+)-5 and (+)-6 were analyzed by reverse-phase HPLC [column: Waters Puresil 5 µm C18 120 Å
4.6×150 mm; mobile phase: CH3CN/10 mM KH2PO4 (pH 3)=60/40; flow rate: 1.0 mL/min; detection:
UV 254 nm; temperature: 40°C]. The optical purities of (+)- and (−)-3 were determined by a comparison
of the optical rotation with that of the optically pure compounds. The optical purity of (+)-6 was analyzed
by chiral HPLC [column: Daicel Chiralcel OD 4.6×250 mm; mobile phase: n-hexane/EtOH=85/15; flow
rate: 0.5 mL/min; detection: UV 250 nm; temperature: 35°C].
3.1. Potassium (ꢀ)-(2RS,3SR)-3-(4-methoxyphenyl)glycidate (ꢀ)-2
(ꢀ)-2 was prepared according to the reported procedure.11 To a solution of 85% potassium hy-
droxide (15.0 g, 0.227 mol) in EtOH (90 ml) was added a solution of methyl (ꢀ)-(2RS,3SR)-3-(4-
methoxyphenyl)glycidate (ꢀ)-116 (30.0 g, 0.144 mol) in EtOH (480 ml) under ice-cooling. After the
reaction mixture had been stirred for 3 h at room temperature, precipitated crystals were collected by
filtration, washed with EtOH (100 ml), and dried to give (ꢀ)-2 (31.9 g, 95.4%).
3.2. (ꢀ)-(2RS,3SR)-3-(4-Methoxyphenyl)glycidic acid 4-chloro-3-methylphenyl ester (ꢀ)-3
(ꢀ)-3 was prepared according to the reported procedure.12 A mixture of (ꢀ)-2 (40.7 g, 0.175 mol)
and triethylamine (17.7 g, 0.175 mol) in DMF (200 ml) was stirred at 40°C. To the mixture were added a
solution of 4-chloro-3-methylphenol (25.0 g, 0,175 mol) in DMF (100 ml) and a 1 M solution of 2-chloro-
1-methylpyridinium methyl sulfate in CH2Cl2 (193 ml) and then it was stirred for 30 min. The reaction
mixture was extracted with AcOEt, and the extract was washed with water and brine. After the extract had
been dried over MgSO4, it was concentrated under reduced pressure. Precipitated crystals were collected
by filtration, washed with cold AcOEt, and dried to give (ꢀ)-3 (28.1 g, 50.3%): mp 123–124°C; IR (KBr,
cm−1) 1750, 1612, 1517, 1476; 1H-NMR (CDCl3) δ: 2.38 (s, 3H), 3.71 (d, J=1.7 Hz, 1H), 3.83 (s, 3H),
4.19 (d, J=1.7 Hz, 1H), 6.9–7.4 (m, 7H); MS m/z 318 (M+).
3.3. (+)-(2S,3R)-3-(4-Methoxyphenyl)glycidic acid 4-chloro-3-methylphenyl ester (+)-3
(+)-3 was prepared from (+)-117 according to the above procedures: yield from (+)-2 50.0%; mp
138–140°C; [α]D +192.3 (c 1.0, THF); MS m/z 318 (M+); the IR and 1H-NMR spectra of the product
25
were identical with those of (ꢀ)-3.
3.4. (−)-(2R,3S)-3-(4-Methoxyphenyl)glycidic acid 4-chloro-3-methylphenyl ester (−)-3
(−)-3 was prepared from (−)-14c by using 2 equiv. of 4-chloro-3-methylphenol and 2 equiv. of 2-
chloro-1-methylpyridinium methyl sulfate, according to the above procedures: yield from (−)-2 81.6%;

S. Yamada et al. / Tetrahedron: Asymmetry 9 (1998) 1713–1721
1719
25
mp 139–141°C; [α]D −193.4 (c 1.0, THF); MS m/z 318 (M+). Anal. calcd for C17H15ClO4: C 64.06;
1
H 4.74. Found: C 64.07; H 4.59. The IR and H-NMR spectra of the product were identical with those
of (ꢀ)-3.
3.5. Optical resolution of (ꢀ)-3 by preferential crystallization in THF (Table 2)
(A) (ꢀ)-3 (8.58 g) and (−)-3 (0.40 g) were completely dissolved in THF (50 ml) by heating. After
the solution had been cooled to 30°C, the solution was seeded with crystals of (−)-3 (3 mg). The mixture
was stirred for 20 min while being cooled to 25°C. Precipitated crystals were collected by filtration,
25
washed with cold THF, and dried to give (−)-3 (0.51 g): [α]D −193 (c 1.0, THF); 100% ee. The IR
and 1H-NMR spectra of the product were identical with those of (ꢀ)-3.
(B) The amount of the mother liquor obtained by the above mentioned step (A) was adjusted to 50
ml. To the solution, (ꢀ)-3 (0.22 g) was added, which was completely dissolved by heating. After the
solution had been cooled to 30°C, it was seeded with crystals of (+)-3 (3 mg). The mixture was stirred
for 20 min while being cooled to 25°C. Precipitated crystals were collected by filtration, washed with
25
1
cold THF, and dried to give (+)-3 (0.35 g): [α]D +190 (c 1.0, THF); 98% ee. The IR and H-NMR
spectra of the product were identical with those of (ꢀ)-3. Subsequently, (+)- and (−)-3 were obtained by
repeated resolutions (4 times) in the same manner as already described.
3.6. Optical resolution of (ꢀ)-3 by preferential crystallization in DMF (Table 3)
(A) (ꢀ)-3 (8.10 g) and (−)-3 (0.31 g) were completely dissolved in DMF (50 ml) by heating. After
the solution had been cooled to 30°C, it was seeded with crystals of (−)-3 (3 mg). The mixture was stirred
for 20 min while being cooled to 25°C. Precipitated crystals were collected by filtration, washed with
25
1
cold DMF, and dried to give (−)-3 (0.62 g): [α]D −176 (c 1.0, THF); 91% ee. The IR and H-NMR
spectra of the product were identical with those of (ꢀ)-3.
(B) To the mother liquor obtained by the above mentioned step, (A), was added (ꢀ)-3 (2.26 g),
which was completely dissolved by heating. After the solution had been cooled to 30°C, the solution was
seeded with crystals of (+)-3 (3 mg). The mixture was stirred for 20 min while being cooled to 25°C.
Precipitated crystals were collected by filtration, washed with cold DMF, and dried to give (+)-3 (0.72
g): [α]D +181 (c 1.0, THF); 94% ee. The IR and 1H-NMR spectra of the product were identical with
25
those of (ꢀ)-3. Subsequently, (+)- and (−)-3 were obtained by repeated resolutions (4 times) in the same
manner as already described. The amount of DMF increased to 69 ml in the final crystallization.
3.7. General procedure for the synthesis of (−)-1 from (−)-3 by transesterification (Table 4)
A suspension of (−)-3 (0.5 g, 1.57 mmol) in MeOH (30 ml) with or without a catalyst was stirred
under the conditions indicated in Table 4. The solvent was evaporated under reduced pressure, the residue
was dissolved in diethyl ether (10 ml), and the solution was then seeded with a small amount of (−)-1.
Precipitated crystals were collected by filtration, washed with diethyl ether, and dried to give (−)-1. A
20
sample for analytical use was prepared by recrystallization from MeOH: mp 87–88°C; [α]D −207.1
(c 1.0, MeOH); IR (KBr) cm−1: 1750, 1520, 1450, 1210; 1H-NMR (DMSO-d6) δ: 3.73 (s, 3H), 3.76 (s,
3H), 3.82 (d, 1H, J=1.9 Hz), 4.10 (d, 1H, J=1.9 Hz), 6.94 (d, 2H, J=10 Hz), 7.29 (d, 2H, J=10 Hz); MS
m/z 208 (M+).

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3.8. General procedure for the synthesis of (+)-5 and (+)-6 (Table 5)
A suspension of (−)-3 (319 mg, 1.0 mmol) in chlorobenzene (5 ml) or xylene (5 ml) was heated to
100–140°C. 2-Aminothiophenol (138 mg, 1.1 mmol) with or without FeCl3·6H2O (0.027 mg, 1.0×10−4
mmol) in MeOH (0.1 ml) was added. The resulting mixture was stirred under the conditions indicated
in Table 5 and then cooled to room temperature. The conversions into (+)-5 and (+)-6 were analyzed by
HPLC.
3.9. (+)-(2S,3S)-3-(2-Aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionic acid 4-chloro-
3-methylphenyl ester (+)-5
A suspension of (−)-3 (319 mg, 1.0 mmol) in chlorobenzene (5 ml) was heated to reflux temperature.
2-Aminothiophenol (138 mg, 1.1 mmol) with FeCl3·6H2O (0.027 mg, 1.0×10−4 mmol) in MeOH (0.1
ml) was added. The resulting mixture was refluxed for 5 min and then cooled to room temperature.
Precipitated crystals were collected by filtration, washed with chlorobenzene, and dried to give a crude
product (320 mg, 72.1%), which was recrystallized from AcOEt to give (+)-5 (160 mg, 36.0%): mp
20
160–162°C; [α]D +242 (c 0.5, DMF); IR (KBr) cm−1: 1735, 1610, 1510, 1480; 1H-NMR (DMSO-d6)
δ: 2.26 (s, 3H), 3.72 (s, 3H), 4.42 (d, J=6.7 Hz, 1H), 4.61 (t, J=6.7 Hz, 1H), 5.36 (s, 2H), 6.60 (d, 1H),
6.31–7.41 (m, 11H); MS (SIMS) m/z 444 (M+). Anal. calcd for C23H22ClNO4S: C 62.23; H 4.99; N 3.16.
Found: C 62.35; H 4.85; N 3.06.
3.10. (+)-(2S,3S)-2,3-Dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (+)-6
A suspension of (+)-5 (1.33 g, 3.0 mmol) in chlorobenzene (6 ml) was heated to 110°C. Methane-
sulfonic acid (5.6 mg, 0.058 mmol) was added and the resulting mixture was refluxed for 1 h. After the
reaction mixture had been cooled to room temperature, precipitated crystals were collected by filtration,
25
washed with chlorobenzene, and dried to give (+)-6 (0.85 g, 94.0%): mp 199–200°C; [α]D +109.0 (c
1
0.5, DMF); IR (KBr) cm−1: 1680, 1510, 1475, 1250; H-NMR (DMSO-d6) δ: 3.76 (s, 3H), 4.29 (dd,
1H, J=6.4 Hz, 6.6 Hz), 4.74 (d, 1H, J=6.4 Hz), 5.05 (d, 1H, J=6.6 Hz), 6.87–7.62 (m, 8H), 10.31 (s, 1H);
MS m/z 301 (M+).
3.11. One-pot synthesis of (+)-6 from (−)-3
A suspension of (−)-3 (3.19 g, 10 mmol) in chlorobenzene (50 ml) was heated to reflux temperature.
2-Aminothiophenol (1.38 g, 11 mmol) with FeCl3·6H2O (0.27 mg, 10×10−4 mmol) in MeOH (0.1 ml)
was added, and the resulting mixture was refluxed for 30 min. Methanesulfonic acid (19 mg, 0.2 mmol)
was added and the solution was refluxed for an additional 1 h. After the reaction mixture had been cooled
to room temperature, the solvent was evaporated under reduced pressure and the residue was triturated in
MeOH (20 ml). Precipitated crystals were collected by filtration, washed with MeOH and dried to give
20
(+)-6 (2.30 g, 76.3%): mp 203–205°C; [α]D +114.4 (c 0.5, DMF); 100% ee; MS m/z 301 (M+). Anal.
calcd for C16H15NO3S: C 63.77; H 5.02; N 4.65. Found: C 63.83; H 4.93; N 4.55. The IR and 1H-NMR
spectra of the product were identical with those reported above.

S. Yamada et al. / Tetrahedron: Asymmetry 9 (1998) 1713–1721
1721
Acknowledgements
The authors thank the staff of the analytical department of our company for the spectral measurements.
We are also grateful to Drs. Takeji Shibatani, Kazuo Matsumoto, and Tetsuya Tosa, Managing Directors
of Tanabe Seiyaku Co., Ltd, for their encouragement and interest in this study.
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