Preparative resolution of a key intermediate for the synthesis of optically active m-phenylene PGI2 derivatives

Article abstract of DOI:10.1016/S0957-4166(99)00442-5

A key intermediate for the synthesis of optically active m-phenylene PGI₂ derivatives was efficiently resolved on a preparative scale by diastereomeric salt formation method using (+)-cis-N-benzyl-2- (hydroxymethyl)cyclohexylamine ((+)-cis-amine) as a resolving agent.

Full text of DOI:10.1016/S0957-4166(99)00442-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4099–4105
Preparative resolution of a key intermediate for the synthesis of
optically active m-phenylene PGI2 derivatives
Hisanori Wakita,a Hideo Yoshiwara,a Atsuko Tajima,a Yukishige Kitano b and
Hiroshi Nagase a,∗
aBasic Research Laboratories, Toray Industries, Inc., 1111 Tebiro, Kamakura, Kanagawa, 248-8555 Japan
bToray Research Center, 3-3-7 Sonoyama, Otsu, Shiga, 520-8567 Japan
Received 9 August 1999; accepted 6 September 1999
Abstract
A key intermediate for the synthesis of optically active m-phenylene PGI2 derivatives was efficiently
resolved on a preparative scale by diastereomeric salt formation method using (+)-cis-N-benzyl-2-
(hydroxymethyl)cyclohexylamine ((+)-cis-amine) as a resolving agent. © 1999 Elsevier Science Ltd. All
rights reserved.
1. Introduction
PGI2, one of the natural prostaglandins, has been focused on since its discovery due to biological
activities such as inhibition of platelet aggregation or vascular vasodilation. However, it readily decom-
poses in acidic or even neutral media because of the instability of its enol–ether linkage at C5–C6–O. We
have developed a new PGI2 analogue 1 with a m-phenylene skeleton at C5–C6–C7 in order to stabilize
the enol–ether part in natural PGI2 (Scheme 1).1–5 We have also developed the stable analogue named
Beraprost, whose sodium salt, Beraprost sodium, is now commercially available as an anti-platelet drug.
With regard to the synthesis of Beraprost, which is a mixture of diastereomers, synthetic methods to
racemic m-phenylene PGI2 have been mainly described so far.5 Synthetic methods to obtain optically
active Beraprost are scarcely described.3 In this report we will disclose the results of a study on the
resolution, especially on a preparative scale, of a key intermediate carboxylic acid 4 for the synthesis of
optically active m-phenylene PGI2 derivative 5 (Scheme 2).
∗
Corresponding author. Tel: +81-467-32-2111; fax: +81-467-32-4791; e-mail: hiroshi_nagase@nts.toray.co.jp
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00442-5

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Scheme 1. PGI2 and its derivatives
Scheme 2. Key intermediate 4 for the synthesis of optically active m-phenylene PGI2 derivatives
2. Results and discussion
We chose the carboxylic acid 4 as a suitable candidate towards synthesis of chiral Beraprost 5 for
resolution using chiral amines because the corresponding carboxyl group on 4 is closely located to the
asymmetric center C-3a. The racemic carboxylic acid 4 was prepared from the cyclopenta[b]benzofuran
derivative 6 by regioselective Grignard exchange reaction6 followed by carboxylation (Scheme 3). Treat-
ment of 4 with various chiral amines 8–13 as resolving agents gave the corresponding diastereomeric salts
7 (Fig. 1). Table 1 shows the results of recrystallization of the diastereomeric salts on a small scale. Based
on the resolution yields and the enantiomeric excesses, the resolving efficiency was calculated by their
multiplication. Both the values of (−)-cinchonidine 8 and brucine 9 were low. On the other hand, two re-
crystallizations using commercially available (+)-cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine ((+)-
cis-amine) 117 gave highly enantiomerically pure (−)-4 in moderate yield (76%). Thus (+)-cis-amine
11 proved to be the most efficient reagent for the resolution of 4. Next, resolution on a preparative
scale for racemic 4 (100 g) was carried out by three recrystallizations from aqueous methanol with (+)-
cis-amine 11 (77.9 g) to give enantiomerically pure (−)-4 (31.1 g). From the mother liquid of the first
recrystallization, (+)-4 (45 g, 84.2% ee) was recovered and was again recrystallized twice with (−)-cis-
amine to give enantiomerically pure (+)-4 (19.1 g). Synthesis of enantiomerically pure Beraprost has
already been reported by us using (−)-4.3
The absolute configuration of resolved (−)-4 was determined by X-ray analysis of the methyl ester of
(−)-4 obtained by CH2N2 treatment. Fig. 2 shows a perspective view of the structure of the methyl ester
of (−)-4 which reveals that the configuration at both C-3a and C-8b is S.
3. Conclusion
In summary, the resolution of carboxylic acid 4 was efficiently achieved by the diastereomeric salt
formation method using (+)-cis-amine 11 as the resolving agent, and highly enantiomerically pure (−)-4
was obtained as the key intermediate of enantiomerically pure Beraprost.

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Scheme 3. Preparation and resolution of the carboxylic acid 4
Figure 1. Optically active amines used for resolution of the carboxylic acid 4
4. Experimental
4.1. General
1H NMR spectra of CDCl3 solution were recorded with a Jeol GX270 spectrometer at 270 MHz.
Infrared spectra were recorded with a Jasco A-3 spectrometer. MS spectra were recorded with a Hitachi
RML 7-M or a Jeol JMS D-300 spectrometer. Melting points were determined on a Yanaco MP-500D
melting point apparatus and are uncorrected. Analytical TLC was performed with Merck precoated
(0.25 mm) silica gel plates. Specific rotations were measured with a Jasco DIP-140 polarimeter. Optical
rotations were recorded at 20°C.

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Table 1
Results of recrystallization of diastereomeric salts formed from the carboxylic acid 4 and a variety of
chiral aminesa
Figure 2. X-Ray structure of (−)-4. Selected bond distances (Å) and angles (°): Br(1)–C(5): 1.913(9); C(7)–C(9):
1.500(13); C(9)–C(10): 1.507(15); C(9)–C(13): 1.531(14); C(12)–C(13): 1.528(13); O(3)–C(13): 1.454(12); C(7)–C(9)–C(10):
114.7(8); C(7)–C(9)–C(13): 103.7(8); C(10)–C(9)–C(13): 104.8(8); C(9)–C(13)–C(12): 105.4(8); O(3)–C(13)–C(9): 106.3(7);
O(3)–C(13)–C(12): 109.7(8)
4.2. (ꢀ)-3a,8b-cis-Dihydro-3H-5-carboxy-7-bromocyclopenta[b]benzofuran (ꢀ)-4
To the solution of 3a,8b-cis-dihydro-3H-5,7-dibromocyclopenta[b]benzofuran 6 (711 g, 2.25 mol) in
THF (1.5 L) was added 2.25 M cyclohexylmagnesium chloride (1.1 L, 2.48 mol) below 40°C. The
solution was stirred at 30–40°C for 10 h. After the solution was cooled to below −20°C, CO2 was bubbled
through at the rate of ca. 1 L/min for 4 h. The mixture was poured into a mixture of ice (500 g) and 6N
HCl (500 mL, 3 mol), and cyclohexane (1 L) was added to the resulting mixture. The precipitate was
filtered and washed with EtOAc (2 L) and 2N HCl (2 L). The organic layer in the filtrate was separated

H. Wakita et al. / Tetrahedron: Asymmetry 10 (1999) 4099–4105
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and concentrated to recover 4. The combined 4 was washed with H2O (2 L×4) and EtOAc (2 L×3)
and dried under reduced pressure to give pure 4 (499.3 g, 1.78 mol, 79%): mp 205–206°C; 1H NMR δ
2.83–3.01 (2H, m), 4.34–4.46 (1H, m), 5.59–5.68 (1H, m), 5.68–5.74 (1H, m), 5.77–5.87 (1H, m), 7.45
(1H, dd, J=2.0, 1.0 Hz), 7.81 (1H, d, J=2.4 Hz); IR (neat) 3200–2500, 1690, 1460, 1430, 1290, 1210,
1200, 1180, 950 cm−1; LRMS m/e 282 (M+ for C12H9O381Br), 280 (M+ for C12H9O379Br); HRMS (EI)
calcd for C12H9O381Br: 281.9715, C12H9O379Br: 279.9735. Found: 281.9730, 279.9755.
4.3. Resolution on a small scale
A mixture of 4 (1–2 g) and chiral amine (1 equiv.) was dissolved in a mixture of MeOH and H2O
or MeOH or CH3CN by heating. The solution was cooled to rt and inoculated with a crystal of the salt
having high optical purity. The solution was allowed to stand at rt for 1 day. The precipitate was filtered
and dried. A part of the salt was treated with a mixture of EtOAc and 1N HCl. The organic layer was
separated, washed with H2O, and dried. The mixture was filtered and the obtained filtrate was evaporated
to give crystals. The crystals were dried under reduced pressure and the [α]D was measured.
4.4. (−)-3a,8b-cis-Dihydro-3H-5-carboxy-7-bromocyclopenta[b]benzofuran (−)-4
To the solution of 4 (100 g, 0.356 mol) and (+)-cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine 11
(77.9 g, 0.355 mol) in MeOH (2 L) was added warm water (2 L, 50–60°C) under reflux. The solution
was cooled to rt overnight. The precipitate was filtered and dried under reduced pressure to give the salt
(85.9 g, 48% yield). The enantiomeric excess of (−)-4 in the first crop was 88.4%, which was measured
by a chiral HPLC column.
The first crop was dissolved in MeOH (1.8 L) by heating, and warm water (1.8 L, 50–60°C) was added
to the solution. The solution was cooled to rt. The second crop was filtered and dried under reduced
pressure to give the salt (64.8 g, 75% yield). The enantiomeric excess of (−)-4 in the second crop was
98.6%. The same procedure was repeated by using the second crop (64.8 g, 0.129 mol), MeOH (1.3 L),
and warm water (1.3 L) to give the third crop (51.5 g, 0.103 mol, 80% yield). The enantiomeric excess
of (−)-4 in the third crop was >99.0%.
The third crop (55.4 g, 0.111 mol) was treated with diluted H2SO4, and recrystallization from EtOAc
gave (−)-4 (31.1 g, 0.111 mol, 31% yield): mp 210.0–211.0°C; 1H NMR δ 2.74–3.00 (2H, m), 4.43 (1H,
d, J=7.3 Hz), 5.60 (1H, t, J=6.1 Hz), 5.70–5.78 (1H, m), 5.78–5.85 (1H, m), 7.51 (1H, dd, J=2.4, 1.0
Hz), 7.72 (1H, d, J=2.0 Hz); IR (neat) 3450, 3000, 1690, 1440, 1265, 1205, 1160, 820 cm−1; LRMS m/e
282 (M+ for C12H9O381Br), 280 (M+ for C12H9O379Br); HRMS (EI) calcd for C12H9O381Br: 281.9715,
C12H9O379Br: 279.9735. Found: 281.9729, 279.9750; [α]D=−188.0 (c 0.5, EtOH).
4.5. Method for determination of the enantiomer excess of 4
A part (1–20 mg) of 4 or diastereomeric salt was suspended in CH3CN and treated with p-
nitrophenacylbromide and diisopropylamine to give p-nitrophenacyl ester of 4. The ester was analyzed by
use of chiral HPLC column (sumipack OA-1000 (4 mm I.D.×25 cm), n-hexane:CH2Cl2:EtOH=88:11:1,
detection at 285 nm). The peaks of (+)- and (−)-4 were detected at the retention times of 30.5 min and
27.2 min, respectively.

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4.6. (+)-3a,8b-cis-Dihydro-3H-5-carboxy-7-bromocyclopenta[b]benzofuran (+)-4
The mother liquid of the first crop described above was treated with diluted H2SO4, and recrystalliza-
tion from EtOAc gave 4 containing (+)-isomer more (45 g, enantiomeric excess of (+)-4 was 84.2%).
To the solution of thus obtained (+)-4 (45 g, 0.160 mol) and (−)-cis-N-benzyl-2-
(hydroxymethyl)cyclohexylamine (35.1 g, 0.160 mol) in MeOH (1.7 L) was added warm water
(1.7 L, 50–60°C) under reflux. The solution was cooled to rt. The precipitate was filtered and dried under
reduced pressure to give the salt (60.7 g, 76% yield). The enantiomeric excess of (+)-4 in the first crop
was 99.4%.
The diastereomeric salt was recrystallized twice from a mixture of MeOH and H2O to give the salt
(37.0 g, 61% yield). The enantiomeric excess of (+)-4 in the third crop was >99.5%.
The third crop (37.0 g, 73.9 mmol) was treated with diluted H2SO4 and recrystallization from EtOAc
1
gave (+)-4 (19.1 g, 67.9 mmol, 42% yield): mp 211.0–212.0°C; H NMR δ 2.74–3.00 (2H, m), 4.43
(1H, d, J=7.9 Hz), 5.61 (1H, t, J=6.1 Hz), 5.68–5.77 (1H, m), 5.77–5.83 (1H, m), 7.51 (1H, d, J=3.1
Hz), 7.72 (1H, d, J=2.4 Hz); IR (neat) 3450, 3000, 1690, 1440, 1265, 1205, 1160, 820 cm−1; LRMS m/e
282 (M+ for C12H9O381Br), 280 (M+ for C12H9O379Br); HRMS (EI) calcd for C12H9O381Br: 281.9715,
C12H9O379Br: 279.9735. Found: 281.9714, 279.9728; [α]D=+187.60 (c 0.5, EtOH).
4.7. Crystallography
The diffraction was measured at room temperature on an Enraf–Nonius CAD4 diffractometer using
graphite-monochromated Mo-Kα radiation (λ=0.71073 Å) with an ω–θ scan method. The data were
corrected for Lorenz polarization and absorption effects. The data were monitored by measuring three
standard reflections every 41 min of X-ray exposure time. The structure was solved by heavy-atom
method and Fourier methods and refined by full-matrix least squares. Non-hydrogen atoms were refined
with anisotropic temperature factors using atomic scattering factors from the International Tables for
X-ray Crystallography.8 Hydrogen atoms were partially located from a difference density map and the
rest were fixed at calculated positions.
4.8. Crystal data for methyl ester of (−)-4
The compound crystallized as needles. A crystal of the dimensions 0.25×0.15×0.1 mm was used
for X-ray study; it belonged to the triclinic space group P1. Accurate cell dimensions and crystal
orientation matrix were a=4.283(1) Å, b=10.970(2) Å, and c=13.593(3) Å, α=70.23(1)°, β=82.94(1)°,
γ=80.32(1)°, V=591.0(1) Å3, D=1.66 g/cm3 for Z=2, F(000)=296 and absorption coefficient µ=36.8
cm−1. A total of 2807 independent reflections were collected, 1318 observed for I greater than 3σ(I0).
The final discrepancy factors were R=0.038 and wR=0.043. Refinement of the other enantiomer yielded
significantly higher discrepancy indices (R=0.044, wR=0.050). All results reported herein refer to the
enantiomer which yielded the lower R-values.
Acknowledgements
We gratefully acknowledge the late Dr. K. Ohno for his leadership and passion. We would like to thank
Dr. T. Tajima, Ms. M. Kajita, and Mr. R. Hayashi for analytical support.

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