A novel method for large-scale synthesis of lamivudine through cocrystal formation of racemic lamivudine with (S)-(-)-1,1′-Bi(2-naphthol) [(S)-(BINOL)]

Article abstract of DOI:10.1021/op800228h

A large-scale synthesis of (-)-[2R,5S]-4-amino-1- [2-(hydroxymethyl)- 1,3-oxathiolan-5-yl]-2(1H)-pyrimidin-2-one (lamivudine) through resolution of racemic lamivudine by cocrystal formation with (S)- BINOL has been demonstrated. Lamivudine of very high pu

Full text of DOI:10.1021/op800228h

Organic Process Research & Development 2009, 13, 450–455
A Novel Method for Large-Scale Synthesis of Lamivudine through Cocrystal
Formation of Racemic Lamivudine with (S)-(-)-1,1′-Bi(2-naphthol) [(S)-(BINOL)]
Bhairab Nath Roy,* Girij Pal Singh, Dhananjai Srivastava, Harishchandra S. Jadhav, Manmeet B. Saini, and Umesh P. Aher
Lupin Research Park, Lupin Ltd., 46A/47A Nande Village, Mulshi Taluka, Pune - 411042, India
Abstract:
reported for the synthesis of all the four stereoisomers of
lamivudine. We report here a large-scale cost-effective method
of lamivudine synthesis having high purity with enantiomeric
excess of >99.9% through cocrystal formation with (S)-BINOL.
The other three pure isomers were also obtained with high
enantiomeric excess during the process.
Optical resolution of cis-(()-enantiomer of lamivudine to
pure cis-(-) optical isomer through diastereomeric salt has been
reported to be unsuccessful by commonly used techniques of
formation of a diastereomeric salt with acids such as malic acid,
mandelic acid, dibenzoyl tartaric acid, 3-bromocamphor-8-
sulfonic acid, 10-camphorsulfonic acids, and di-p-toluoyltartaric
acid. 16
(S)-BINOL is a versatile chiral ligand and extensively used
for asymmetric synthesis17 and reported to form complexes.18
Resolution of omeprazole, an active pharmaceutical ingredient,
via host-guest complex formation is known.19a,b Earlier in our
laboratory we have demonstrated a resolution of omeprazole19c
using (S)-BINOL through host-guest complex formation20 from
its racemic mixture.
A large-scale synthesis of (-)-[2R,5S]-4-amino-1- [2-(hydroxym-
ethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidin-2-one (lamivudine)
through resolution of racemic lamivudine by cocrystal formation
with (S)- BINOL has been demonstrated. Lamivudine of very high
purity with an enantiomeric excess of more than 99.9% was
obtained. All four isomers of lamivudine have also been separated
and characterized. Interestingly, cis-(-)- and trans-(-)-enanti-
omers form cocrystals with (S)-BINOL.
1. Introduction
The nucleoside analogue cis-(()-4-amino-1-[2-(hydroxym-
ethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidin-2-one, displays very
interesting biological activity. Both the optical isomers, viz. cis-
(-) and cis-(+), inhibit human immunodeficiency virus 1 and
2 in vitro.1 However, the cis-(-)-enantiomer is considerably
less cytotoxic than the other optical isomers2,3 shown below.
In the present work we have found that (S)-BINOL
forms a cocrystal with cis-(-)-enantiomer resulting in an
efficient process for synthesis of lamivudine of very high
purity and yield. Interestingly, it has been observed that
only cis-(-) and trans-(-) optical isomers form cocrystal
with (S)-BINOL leaving behind cis-(+) and trans-(+)
optical isomers in the solution.
The characterization data of all the isomers of lamivudine
is summarized (Table 1) and Scheme 1depicts the synthetic
sequence for obtaining all the four optical isomers of lamivudine.
There are several methods reported1-15 for the synthesis of
A as a single enantiomer. However, there is no efficient method
* Corresponding author. Telephone: +91 2066749403. Fax: +91 2066749560.
E-mail: bnroy@lupinpharma.com.
2. Results and Discussion
(1) (a) Belleau, B.; Dixit, D.; Nguyen-Ba, N.; Kraus, J. Fifth International
Conference on AIDS, Montreal Canada, June 4-9, 1989; paper
T.C.O.1. (b) Belleau, B.; Nguyen-Ba, N. U.S. Patent 5,047,407, 1991.
(2) Coates, J.; Cammack, N.; Jenkinson, H.; Mutton, I.; Pearson, B.; Storer,
R.; Cameron, J.; Penn, C. Antimicrob. Agents Chemother. 1992, 36,
733.
In the present work (Scheme 1), compound 1 was prepared
as per reported method.22 Cis and trans isomers were separated
by preparing the salt of (S)-(+) mandelic acid. The mandelate
salt of cis-(()-2 was precipitated as solid leaving behind trans-
(()-3-(S)-(+)-mandelate salt in mother liquor. Compound 2 thus
obtained was treated with 15% methanolic ammonia at room
temperature to get cis-(()-5. Compound 5 was heated at 55-60
°C with S-(-)-BINOL in methanol to get the cocrystal of (S)-
BINOL with the cis-(-)-enantiomer as a crystalline solid 6 upon
slowly cooling to ambient temperature (yield 70-75%). The
stoichiometric ratio (S)-BINOL with cis-(-)-enantiomer was
(3) (a) Chu, C.; Beach, J.; Jeong, L.; Choi, B.; Comer, F.; Alves, A.;
Schinazi, R. J. Org. Chem. 1991, 56, 6503. (b) Jeong, L.; Alves, A.;
Carrigan, S.; Kim, H.; Beach, J.; Chu, C. Tetrahedron Lett. 1992, 33,
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33, 4625.
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1995, 6, 1903.
450
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10.1021/op800228h CCC: $40.75  2009 American Chemical Society
Published on Web 01/21/2009

Table 1. Characterization details of lamivudine and its stereoisomers
DSC @ 10 °C/min TGA
specific optical rotation
HPLC purity (deg) [R]D at 25 °C
moisture
content (%)
cmpd melting point (°C) peak (°C) ∆H (J/g) weight loss % temp range (°C)
(ee (%)
(c 0.5%, water)
trans-(-)
trans-(+)
cis-(+)
168.0
172.6
171.4
176.0-177.0
174.58
178.49
177.9
140.34 and 114.28 and
182.05 74.27
72.31
94.68
144.48
0.49
0.116
0.00
1.49
20-300
20-300
20-300
20-300
98.85
98.47
98.20
99.90
-120.57
+122.41
+98.85
-98.32
0.22
0.02
0.01
1.63
cis-(-)a
a Form-1.21
Table 2. Crystal data and structure refinement
sr. no.
crystal data
1
2
3
4
5
6
7
empirical formula
formula weight
temperature
C8H11N3O3S·C20H14O2
515.57
273(2) K
0.71073
orthorhombic
P212121
wavelength
crystal system
space group
unit cell dimensions
a ) 9.0929(9) Å; R ) 90°
b ) 2.3452(12) Å; ꢀ ) 90°
c ) 22.031(2) Å; γ ) 90°
2473.0(4) Å3
4
8
9
volume
Z
10 calculated density
11 absorption coefficient
12 F (000)
1.385 Mg/m3
0.176 mm-1
1080
13 crystal size
0.22 mm × 0.17 mm ×
Figure 1. ORTEP drawing of the (S)-BINOL cocrystal (6)
showing the cocrystal formation has taken place. Displacement
ellipsoids are drawn at the 30% probability level, and H atoms
are shown as small spheres of arbitrary radii. Dashed line
denotes hydrogen bonds.
0.12 mm
14 θ range for data collection 1.85 to 25.00°
15 limiting indices
10 e h e 10
-14 e k e 14
-26 e l e 26
16 reflections collected/unique 17528/4353 [R(int) )
found to be 1:1 in the cocrystal. The solid thus obtained was
treated with dilute hydrochloric acid to get lamivudine of very
high purity having ee >99.9%.
Interestingly the (+) isomer B which did not form the
cocrystal with (S)-BINOL was isolated from mother liquor 7
by merely washing with ethyl acetate to remove excess of (S)-
BINOL. The solid thus obtained was recrystallised with water
as well as with methanol.
The trans-(()-isomer was isolated from the mother liquor
obtained after filtering cis-mandalate salt 2. On treatment of
trans-(()-isomer, so obtained, with (S)-BINOL in methanol,
only trans-(-) optical isomer was observed to form a cocrystal
with (S)-BINOL 8. The solid thus separated was filtered and
dried. The cocrystal thus obtained was treated with dilute
hydrochloric acid to get the pure trans-(-) optical isomer C.
The trans-(+) optical isomer D was isolated from mother liquor
9 as per the procedure adopted for the isolation of optical isomer
B, which was crystallized either with water or methanol or a
suitable mixture thereof.
0.0293]
25.00; 100.0%
none
17 completeness to θ
18 absorption correction
19 refinement method
full-matrix least-squares
on F2
20 data / restraints / parameters 4353 / 0 / 354
21 goodness-of-fit on F2
1.052
22 final R indices [I > 2σ(I)] R1 ) 0.0292
wR2 ) 0.0770
23 R indices (all data)
R1 ) 0.0321
wR2 ) 0.0798
24 absolute structure parameter 0.02 (6)
25 largest diff. peak and hole 0.188 and -0.129 e ·Å-3
26 measurement
27 software used
Bruker Smart Apex CCD
diffractometer
SHELXTL-PLUS
isolated in desired purity by fractional crystallization in
commonly used solvents like methanol, ethanol, and
isopropanol. None of the isomers of compound A was
found to form cocrystals either with racemic BINOL or
with (R)-BINOL under identical conditions.
Moreover, when the mixture of four isomers was treated
with (S)-BINOL, a mixture of cocrystals of both cis-(-)-
and trans-(-)-isomers was obtained, leaving in the mother
liquor cis-(+) and trans-(+) as a mechanical mixture with
(S)-BINOL. Although the melting point difference between
the two cocrystals 6 (190.1-190.6 °C) and 8 (224.0-227.2
°C) was considerably high, these cocrystals were not
(15) (a) Woo, J.; Shin, H.; Kim, T.; Ghim, S.; Jeong, L.; Kim, J.; Song, B.
Biotechnol. Lett. 2001, 23, 131. (b) Storer, R.; Clemens, I.; Lamont,
B.; Noble, S.; Williamson, C.; Belleau, B. Nucleoside Nucleotides
1993, 12, 225. (c) Faury, P.; Camplo, M.; Charvet, A.; Chermann, J.;
Kraus, J. Nucleosides Nucleotides 1992, 11, 1481. (d) Huang, J.;
Rideout, J.; Martin, G. Nucleosides Nucleotides 1995, 14, 195. (e)
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Li, J.; Qiu, X.; Gao, L.; Ding, M. Chin. Chem. Lett. 2001, 12, 487.
(g) Shen, Y.; Xiang, L.; Deng, Y.; Zhong, Y. Chin. Chem. Lett. 2006,
17, 431.
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36, 6961.
(16) Liotta, D.; Schnazi, R.; Choi, W. U.S. Patent 6,703,396. Method of
resolution and antiviral activity of 1,3-oxathiolane nucleoside enan-
tiomers 2004.
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Sulphur Silicon Relat. Elem. 1997, 120/121, 367.
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451

Scheme 1a
a Reagents and conditions: (a) cytosine, HMDS, TMCS. (b) S-(+)-Mandelic acid, ethyl acetate, 70 °C then rt. (c) 25% methanolic ammonia, ethanol. (d) (S)-
BINOL, methanol, 65°C. (e) Ethyl acetate, water, aq. HCl, NaOH 25°C. (f) Ethyl acetate, water.
2.1. X-ray Diffraction Data of Cocrystal 6. Crystal data
of cocrystal 6 are given in Figure 1. Crystal structure was
measured on Bruker Smart Apex CCD diffractometer
having software SHELXTL-PLUS at temperature 273 (2)
K and wavelength 0.71073 Å and θ range for data
collection was 1.85-25°. Crystallographic data and
hydrogen bonding in compound 6 are given in Table 2
and Table 3, respectively.
3. Conclusion
A highly efficient and large-scale synthesis of lami-
vudine has been developed. The synthesis involved the
(19) (a) Kyba, E.; Gokel, G.; Jong, F.; Koga, K.; Sousa, L.; Siegel, M.;
Kaplan, L.; Sogah, G.; Cram, D. J. Org. Chem. 1977, 42, 4173. (b)
Cram, D.; Cram, J. Acc. Chem. Res. 1978, 11, 8. (c) Singh, G.;
Godbole, H.; Maddireddy, N.; Tambe, S.; Nehate, S.; Jadhav, H. WO/
2008/004245, Process for the Preparation of Optically Pure or Optically
Enriched Enantiomers of Sulphoxide Compounds 2008.
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Tetrahedron: Asymmetry 2000, 11, 1729.
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Staniforth, S. J. Chem. Soc. Perkin Trans. 2 1997, 2653. (b)
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1996, 85, 193.
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ReV. 2007, 107, 1. (c) Noyori, R. Asymmetric Catalysis in Organic
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Asymmetry 2003, 14, 3769.
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Table 3. Hydrogen bonds of compound 6 (BINOL cocrystal)
D-H· · ·A
d(D-H) (Å)
d(H· · ·A) (Å)
d(D· · ·A) (Å)
∠(DHA) (deg)
O(2)-H(2O)· · ·N(2)a
O(4-H(4O)· · ·O(3)b
O(5)-H(5O)· · ·O(2)
N(3)-H(3A)· · ·O(1)c
N(3)- H(3B)· · ·O(4)d
0.89(3)
0.75(3)
0.76(3)
0.87(4)
0.84(3)
1.92(3)
1.91(3)
1.99(3)
2.28(4)
2.32(3)
2.777(2)
2.642(2)
2.696(2)
2.988(3)
3.060(3)
162(3)
169(3)
156(3)
139(3)
147(3)
a Symmetry transformations used to generate equivalent atoms: -x, y + 1/2, -z + 1/2. b x + 1, y, z. c -x, y - 1/2, -z + 1/2. d -x + 1, y - 1/2, -z + 1/2.
separation of enantiomers by forming the cocrystal with
(S)-(-)-BINOL. All four isomers were separated. The
recovery and recycling of resolving agent (S)-BINOL has
also been established.
Interestingly, out of four isomers only cis-(-)-A and
trans-(-)-C formed the cocrystal with (S)-BINOL, whereas
cis-(+)-B and trans-(+)-D isomers did not form the
cocrystal. Moreover, it was difficult to separate the mixture
of cis-(-)- and trans-(-)-(S)-BINOL cocrystal by frac-
tional crystallization to the extent of obtaining cis-(-)-A
of ee > 99%. Therefore, separation of the cis- and trans-
isomers prior to cocrystal formation with (S)-BINOL was
necessary through (S)-(+)-mandelate salt formation.
IR spectra [Nujol Mull] (cm-1): 707, 963, 1060, 1252, 1376,
1459, 1586, 1707, 1719, 2724, 2855, 2923, 2951, 3315, and
3583.
4.3. cis-(()-2-Hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathi-
olane (Racemic Lamivudine) 4. The compound 2 (70 kg;
144.32 mol) was suspended in the 15% methanolic
ammonia (1400 L) and stirred for 8-10 h at ambient
temperature. After the completion of reaction, excess of
solvent was recovered under vacuum. The solid thus
obtained was recrystallized with ethanol (280 L) to get 4
(yield: 23.95 kg, 72.46%).
mp 186.3-186.8 °C (lit.15g mp 187-188 °C).
IR spectra [KBr] (cm-1) 790, 803, 1057, 1069, 1292, 1402,
1439, 1518, 1605,1660, 3251, 3311, and 3434.
DSC peak 186.4 °C.
4. Experimental Section
1H NMR (DMSO d6): δ 3.02-3.06 (dd, 1H,J ) 4.92,11.68
Hz), 3.34-3.42 (dd, 1H, J ) 5.24,11.98 Hz), 3.71-3.75 (m,
2H), 5.14 -5.18 (t, 1H,J ) 4.55 Hz), 5.30-5.33 (br s, 1H),
5.72-5.74 (d, 1H, J ) 7.44 Hz), 6.19-6.21 (t, 1H, J ) 5.15
Hz), 7.19 (br s,1H)-7.24 (br s,1H)-, 7.80-7.82 (d, 1H,7.43
Hz). MS: M+1 ) 230.
PXRD [2θ] (Cu KR1 ) 1.54060 Å, KR2 ) 1.54443 Å, Kꢀ )
1.39225 Å; 40 mA, 45 kV): 15.14, 16.23, 17.15, 18.49, 18.99,
21.53, 22.62, 23.13, 23.80, 24.68, 25.20, 25.46, 29.16, and
34.67.
4.4. cis-(-)-2-Hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathi-
olane (S)-BINOL Cocrystal 6. The mixture of 4 (30 kg 130
mol) and (S)-(-)-BINOL (60 kg, 200 mol) in methanol (360
L) was heated to reflux for 1-2 h. The mixture was then cooled
to ambient temperature. The solid thus separated was filtered
and washed with methanol (15 L) to get 6 (yield: 22.69 kg,
67.26%).
mp 190.1-190.6 °C. [R]D at 25 °C ) -77° (c ) 1, MeOH).
IR spectra [Nujol Mull] (cm-1): 722, 753, 827, 961, 1037,
1141, 1202, 1273, 1341, 1376, 1459, 1595, 1645, 2723, 2855,
2924, 3359, and 3583.
All commercially available reagents and solvents were
employed without prior purification. Reactions were monitored
by thin layer chromatography on silica gel plates (Merck 60F254
)
and stained by the use of 2,4-dinitrophenylhydrazine.
4.1. Analytical Methods. The enantiomeric excess (ee)
was determined by HPLC using a Shimadzu LC 2010
system equipped with a chiral column (Chiracel OJH, 4.6
mm × 250 mm, 5 µm), column oven temperature 15 °C,
and UV visible detector. Mobile phase is n-hexane (900
mL):ethanol (100 mL):diethyl amine (2 mL):gl. acetic acid
(1 mL), with 1.0 mL min-1flow rate, injection volume 20
µL having concentration of 1000 ppm. The retention time
for the optical isomer A is 24.5 min; NMR spectra were
obtained at 200 and 400 MHz Bruker instruments, with
CDCl3/DMSO as solvent. Chemical shifts (δ) are given
in ppm relative to tetramethylsilane (δ ) 0 ppm) or to
residual protons in the solvent as internal standard. IR
spectra were recorded with a Perkin-Elmer Spectrum
(model: Spectrum 100), and absorption bands are given
in cm-1. TGA were recorded on Perkin-Elmer model Pyris
1 at the rate of 10 °C/min, and weight loss is given in
percentage. DSC was recorded on Perkin-Elmer model
Diamond DSC at the rate of 10 °C/min, and endothermic
peak is reported in °C and ∆H is reported in J/g. Melting
point was recorded on Mettler Toledo apparatus with 1
°C/min heating rate. Moisture content was determined by
the Karl Fischer titration method with Metrohm instrument.
4.2. cis-(()-2-Benzoyloxymethyl-5-cytosin-1-yl-1,3-ox-
athiolane Mandalate 2. Compound 1 (70 kg, 0.14 mol) and
S-(+)-mandelic acid (40.96 kg; 0.26 mol) was dissolved in ethyl
acetate (420 L) at 65-70 °C and stirred for 1-2 h. The reaction
mixture was then cooled to ambient temperature. The solid thus
precipitated was filtered and washed with methanol (280 L) to
afford compound 2 (yield: 23.95 kg, 46.98%).
1H NMR (DMSO-d6): δ 2.99-3.08 (dd, 1H, J ) 2.4,2.4
Hz), 3.36 (dd, 1H), 3.73 (m, 2H), 5.14-5.19 (t, 1H J ) 4.47
Hz), 5.72-5.76(d, 1H J ) 7.44 Hz), 6.17-6.23 (t, 1H J )
4.936 Hz), 6.90-6.94 (d, 2HJ ) 7.80 Hz), 7.12-7.33(m, 8H),
7.82-7.87(m, 6H), 9.24 (bs, 2H).
PXRD [2θ] (Cu KR1 ) 1.54060 Å, KR2 ) 1.5444 Å, Kꢀ )
1.39225 Å; 40 mA, 45 kV): 8.02, 10.52, 12.73, 14.33, 14.51,
16.06, 17.06, 17.80, 20.12, 21.94, 22.36, 23.70, 24.06, and
25.05.
4.5. cis-(-)-2-Hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathi-
olane (Lamivudine) A. Compound 6 (24.80 kg, 108.29 mol)
was suspended in the mixture of water (99.2 L) and ethyl
acetate (99.2 L) and pH of the solution was adjusted to
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2-3 using dil. hydrochloric acid. The aqueous layer was
separated, washed with ethyl acetate, and neutralized to
pH 7. Excess of water was evaporated in vacuum. The
solid thus obtained, was recrystallized in ethanol-water
mixture (7.44 L) to get pure lamivudine form-I (yield:
7.85, 70.02%).
J ) 7.41 Hz), 6.30-6.34 (dd, 1H, J ) 2.68, 5.24 Hz), 7.15
(brs, 1 H) 7.19 (brs, 1 H) and 7.55-7.5 9 (d, 1H J ) 7.39 Hz).
PXRD [2θ] (Cu KR1 ) 1.54060 Å, KR2 ) 1.54443 Å, Kꢀ )
1.39225 Å; 40 mA, 45 kV): 11.68, 16.30, 19.11, 23.28, 29.44,
29.54, and 35.32.
4.8. trans-(-)- 2-Hydroxymethyl-5-(cytosin-1-yl)-1,3-ox-
athiolane (S)-BINOL Cocrystal (8). The mixture of 5 (25 g;
0.109 mol) and (S)-(-)BINOL (50.0 g; 0.17 mol) in methanol
(300 mL) was heated to reflux. The mixture was then cooled
to ambient temperature. The solid thus separated was filtered
and washed with methanol to get 8 (yield: 20.0 g, 71.11%).
mp 224-227.2 °C.
mp 176.0-1770 °C (lit.21a mp 126 and 178 °C).
ee ) 99.9%. [R]D at 25 °C ) -98.32° (c ) 5 water). MS:
M + H ) 230.
IR spectra [Nujol Mull] (cm-1): 722, 788, 844, 927, 976,
1044, 1106, 1135, 1155, 1193, 1226, 1296, 1676, 14610, 1522,
1600, 1640, 2854, 2923, 3160, and 3330.
IR spectra [Nujol Mull] (cm-1): 558, 756, 961, 1047, 1285,
1494, 1644, 2942, 3051, 3365, and 3479.
1H NMR (DMSO-d6): δ 2.99-3.07 (dd, 1H, J ) 4.86, 11.67
Hz), 3.35-3.38 (dd, 1H, J ) 4.86, 11.67 Hz), 3.72-3.74 (m,
2H), 5.14-5.18 (t, 1H J ) 4.44 Hz), 5.32-5.38 (t, 1H J )
5.14 Hz), 5.71-5.75 (d, 1H, J ) 7.43 Hz), 6.16-6.21 (t, 1H J
) 5.11 Hz), 7.22-7.27 (d, 2H J ) 8.70 Hz), 7.80-7.83 (d,
1H, J ) 7.41 Hz).
1H NMR (DMSO-d6): δ 3.05-3.12 (dd, 1H J ) 2.73, 11.89
Hz,), 3.34-3.58 (m, 4H), 5.15-5.21(t, 1H J ) 5.92 Hz),
5.47-5.52(t, 1H J ) 5.04 Hz), 5.69-5.73(d, 1H J ) 7.42 Hz),
6.32-6.36 (m, 1H), 6.90-6.94 (d, 2H J ) 7.82 Hz), 7.12-7.33
(m, 8H), 7.57-7.61 (d, 1H J ) 7.42 Hz), 7.82-7.87(m, 3H),
9.20 (bs, 2H).
PXRD [2θ] (Cu KR1 ) 1.54060 Å, KR2 ) 1.54443 Å, Kꢀ )
0.39225 Å; 40 mA, 45 kV): 5.20, 6.66, 8.53, 8.81, 9.65, 9.85,
10.15, 10.41, 11.27, 11.38, 11.63, 12.34, 12.60, 12.93, 13.22,
14.60, 15.01, 15.17, 15.67, 15.81, 16.51, 17.59, 17.98, 18.13,
18.72, 19.10, 19.30, 19.76, 21.79, 23.49, 23.71, 25.44, 25.90,
27.34, 29.46, and 31.00.
4.6. cis-(+)-2-Hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathi-
olane B. Mother liquor of compound 7 was concentrated
in vacuum to get solid. The solid thus obtained was
washed with ethyl acetate to get crude B which, upon
recrystallization in water and methanol, afforded com-
pound B; mp 171.4 °C.
PXRD [2θ] (Cu KR1 ) 1.54060 Å, KR2 ) 1.54443 Å, Kꢀ )
1.39225 Å; 40 mA, 45 kV): 7.96, 12.87, 14.79, 18.14, 20.10,
22.60, 25.26, 29.77, 31.65, 37.39, and 38.34.
4.9. trans-(-)-2-Hydroxymethyl-5-(cytosin-1-yl)-1,3-ox-
athiolane C. Compound 8 (10 g, 0.019 mol) was suspended
in a mixture of water (40 mL) and ethyl acetate (40 mL), and
the pH of the solution was adjusted to 2-3 using 25% aqueous
hydrochloric acid. The aqueous layer was separated, washed
with ethyl acetate, and neutralized to pH 7. Excess of water
was evaporated in vacuum. The solid thus obtained was
recrystallized in an ethanol/water mixture (3:1, 40 mL) to get
pure C (yield: 3.5 g, 80.4%).
mp 168.0 °C. ee ) 98.85%. MS: M + H ) 230. Moisture
content: 0.22%. [R]D 25 °C ) -120.57° (c, 0.5% water).
IR spectra [KBr] (cm-1): 713, 782, 962. 1069, 1100, 1192,
1287, 1398, 1491, 1633, 1674, 3085, and 3399.
ee ) 98.2%. [R]D at 25 °C ) +98.85° (c ) 5 water). MS:
M + H ) 230.
IR spectra [Nujol Mull] (cm-1): 592.80, 786.23, 918.13,
1059.50, 1286.69, 1496.21, 1651.60, 2836.27, 3075.57, 3203.72,
and 3327.26.
1H NMR (DMSO-d6): δ 2.97-3.06 (dd, 1H, J ) 4.93, 11.66
Hz), 3.34-3.43 (dd, 1H, J ) 4.93, 11.65 Hz), 3.68-3.77 (m,
2H), 5.12-5.17 (t, 1H J ) 4.49 Hz), 5.28-5.33 (t, 1H J )
5.87 Hz), 5.69-5.73 (d, 1H, J ) 7.44 Hz), 6.15-6.21 (t, 1H J
) 5.16 Hz), 7.21 (d, 2H), 7.78-7.82 (d, 1H, J ) 7.42 Hz).
PXRD [2θ] (Cu KR1 ) 1.54060 Å, KR2 ) 1.54443 Å, Kꢀ )
1.39225 Å; 40 mA, 45 kV): 10.73, 12.18, 13.42, 17.56, 20.63,
21.45, 24.45, 24.95, 26.52, and 31.47.
1H NMR (DMSO-d6): δ 3.04-3.10 (dd, 1H, J ) 3.45, 11.92
Hz), 3.34-3.43 (dd, 1H,, J ) 3.52, 11.95 Hz), 3.43-3.49 (m,
2H), 5.19 (t, 1H), 5.47-5.52 (t, 1H J ) 4.99 Hz), 5.68-5.72
(d, 1H, J ) 7.40 Hz), 6.32 (t, 1H), 7.16-7.20 (d, 2H J ) 9.26
Hz), 7.56-7.60 (d, 1H, J ) 7.36 Hz).
XRPD [2θ] (Cu KR1 ) 1.54060 Å, KR2 ) 1.54443 Å, Kꢀ )
1.39225 Å; 40 mA, 45 kV): 9.98, 14.39, 17.22, 18.31, 20.00,
20.99, 21.76, 25.45, 26.18, 27.01, 27.96, 30.28, 32.32, 33.34,
35.66, 36.67, and 39.76.
4.7. trans-(()-2-Hydroxymethyl-5-(cytosin-1-yl)-1,3-ox-
athiolane 5. The mother liquor of compound 3 was
concentrated in vacuum (35 g; 0.15 mol) and was
suspended in 700 mL of methanolic ammonia (25%) and
stirred for 8-10 h at ambient temperature. After the
completion of reaction, excess of solvent was recovered
under vacuum. The solid thus obtained was recrystallized
with water (350 mL) to get 5 (yield 14 g, 70.85%); mp
222 °C (lit.15g > mp 222 °C). IR spectra [Nujol Mull]
(cm-1): 581, 777, 923, 1025, 1292, 1481, 1660, 2915,
3122, 3316, and 3428.
4.10. trans-(+)-2-Hydroxymethyl-5-(cytosin-1-yl)-1,3-ox-
athiolane D. Mother liquor of compound 9 was concentrated
in vacuum to get solid. The solid thus obtained was washed
with ethyl acetate to get crude D which, upon recrystallization
in water as well as in methanol, afforded compound D.
mp 172.6 °C. ee ) 98.07%. [R]D at 25 °C ) +124.41° (c
0.5%, water). MS: M + H ) 230.
IR spectra [Nujol Mull] (cm-1): 608, 785, 925, 1057, 1192,
1282, 1401, 1486, 1646, 2924, 3191, and 3333.
IR spectra [KBr] (cm-1): 713, 782, 961. 1068, 1099, 1191,
1287, 1397, 1490, 1630, 1675, 3074, and 3396.
1H NMR (DMSO d6): δ 3.03-3.10 (dd, 1H, J ) 2.74, 11.91
Hz), 3.39 -3.49 (m, 1H,), 3.50 3.71(m, 2H), 5.15-5.21 (t, 1H
J ) 5.88,), 5.45-5.51(t, 1H J ) 5.20 Hz), 5.67-5.71 (d, 1H
1H NMR (DMSO-d6): δ 3.03-3.10 (dd, 1H, J ) 2.74, 11.89
Hz), 3.33-3.49 (dd, 1H, J ) 2.72, 11.87 Hz), 3.50-3.71 (m,
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Vol. 13, No. 3, 2009 / Organic Process Research & Development

2H), 5.15-5.21(t, 1H J ) 5.91 Hz), 5.28-5.31 (t, 1H),
5.46-5.71 (d, 1H, J ) 7.40 Hz), 6.18-6.34 (t, 1H), 7.15-7.19
(d, 2H, J ) 8.02 Hz), 7.55-7.59 (d, 1H, J ) 7.42 Hz).
XRPD [2θ] (Cu KR1 ) 1.54060 Å, KR2 ) 0.54443 Å, Kꢀ )
1.39225 Å; 40 mA, 45 kV): 10.02, 14.41, 17.24, 18.33, 20.04,
20.96, 21.81, 25.45, 26.23, 27.08, 28.00, 30.32, 32.36, 33.36,
35.72, 36.71, and 39.77.
Lupin Research Park, Pune, India, for providing valuable
analytical support and Dr. Vishvas D. Patil of Intellectual
Property Cell, Lupin Research Park, Pune, India, for the
entire literature search.
Supporting Information Available
Crystal structure data for cocrystal of (S)-Binol with optical
isomer A (PDF and CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment
We sincerely thank Prof. Gautam R. Desiraju, Univer-
sity of Hyderabad, for valuable discussion, Dr. K. Ravi-
kumar, IICT Hyderabad for providing single-crystal XRD
data, Dr. P. R. Upadhyay of Analytical Development,
Received for review September 16, 2008.
OP800228H
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