Preparation of optically active (2RS,3SR)-2-amino-3-hydroxy-3- phenylpropanoic acid (threo-β-phenylserine) via optical resolutions by replacing and preferential crystallization

Article abstract of DOI:10.1248/cpb.54.1170

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by replacing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1·HCl] was examined based on the melting poi

Full text of DOI:10.1248/cpb.54.1170

1170
Chem. Pharm. Bull. 54(8) 1170—1174 (2006)
Vol. 54, No. 8
Preparation of Optically Active (2RS,3SR)-2-Amino-3-hydroxy-3-
b
phenylpropanoic Acid (threo- -Phenylserine) via Optical Resolutions
by Replacing and Preferential Crystallization
Tadashi SHIRAIWA,* Yuka KAWASHIMA, Atsushi IKARITANI, Yumiko SUGANUMA, and Reiichi SAIJOH
Unit of Chemistry, Faculty of Engineering and High Technology Research Center, Kansai University; Yamate-cho, Suita,
Osaka 564–8680, Japan. Received April 17, 2006; accepted May 22, 2006
To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by re-
placing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1·HCl]
was examined based on the melting point, solubility, and infrared spectrum. (2RS,3SR)-1·HCl was indicated to
exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. When,
in optical resolution by replacing crystallization, L-phenylalanine methyl ester hydrochloride (L-2) was used as
the optically active co-solute, (2R,3S)-1·HCl was preferentially crystallized from the supersaturated racemic so-
lution; the use of D-2 as the co-solute afforded (2S,3R)-1·HCl with an optical purity of 95%. In addition, optical
resolution by preferential crystallization was successfully achieved to give successively (2R,3S)- and (2S,3R)-
1·HCl with optical purities of 90—92%. The (2R,3S)- and (2S,3R)-1·HCl purified by recrystallization from 1-
propanol were treated with triethylamine in methanol to give optically pure (2R,3S)- and (2S,3R)-1.
Key words threo-b-phenylserine; optical resolution; conglomerate; replacing crystallization; preferential crystallization
2-Amino-3-hydroxy-3-phenylpropanoic acid (1; b-phen- fore, we have been screening for a simple derivative, such as
ylserine) that exists as four stereoisomers is a physiological- (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1·HCl], that exist as
ly important a-amino acid.1—3) (2RS,3SR)-1, DL-threo-b- conglomerate and attempted to optically resolve the found
phenylserine, is predominantly given by condensation of conglomerate by preferential and replacing crystallization
glycine with benzaldehyde under aqueous alkaline condi- (Chart 1).
tions.4—6) However, (2R,3S)- and (2S,3R)-1 enantiomers,
non-proteinogenic a-amino acids, are difficult to produce Results and Discussion
commercially in large quantities. Therefore, N-benzoyl
We examined the racemic structure of (2RS,3SR)-1·HCl
(2RS,3SR)-1 was optically resolved by separation of di- by comparing the melting point, solubility, and IR spectrum
astereoisomeric salts with (1S,2S)- and (1R,2R)-2-amino-1- of the (2RS,3SR)-1·HCl with those of (2R,3S)-1·HCl.6,7)
(4-nitrophenyl)-1,3-propanediol.6) In addition, benzylammo- (2RS,3SR)-1·HCl had a lower melting point (144—145 °C)
nium salt of N-benzoyl (2RS,3SR)-1, which was found to than (2R,3S)-1·HCl (150—151 °C). Although conglomerates
exist as a conglomerate, was subjected to optical resolution are known to have such melting point characteristics,6,7)
by preferential crystallization, with the aim of acquisition of the melting-point binary-phase diagram suggested that
(2R,3S)- and (2S,3R)-1.6) However, hydrolysis of the N-ben- (2RS,3SR)-1·HCl forms a racemic compound, as shown in
zoyl (2R,3S)- and (2S,3R)-1 obtained gave (2R,3S)- and Fig. 1. On the other hand, the IR spectrum of (2RS,3SR)-
(2S,3R)-1 in not a very high yields.6) Therefore, we at- 1·HCl was identical to that of (2R,3S)-1·HCl. In addition,
tempted to obtain (2R,3S)- and (2S,3R)-1 by more simple and (2RS,3SR)-1·HCl was more soluble than the (2R,3S)-1·HCl,
efficient optical resolution.
as summarized in Table 1. The solubility ternary-phase dia-
Optical resolutions by preferential and replacing crystal- gram also showed that (2RS,3SR)-1·HCl is expected to be a
lization are simple and useful procedures for separation of conglomerate, as shown in Fig. 2. The above results sug-
enantiomers from racemates. The optical resolution by pref- gested that (2RS,3SR)-1·HCl exists as a conglomerate at
erential crystallization is achieved by providing a small room temperature and forms a racemic compound at the
amount of one enantiomer as seed crystals in a supersatu-
rated racemic solution. On the other hand, the optical resolu-
tion by replacing crystallization is achieved by allowing an
optically active co-solute to coexist in a supersaturated
racemic solution without formation of diastereoisomers with
the co-solute. The optical resolution by replacing crystalliza-
tion does not require the enantiomer as seed crystals. How-
ever, although racemates exist in the form of racemic com-
pounds, racemic solid solutions, and conglomerates, only
conglomerates, which are defined as mechanical mixtures of
crystals of both enantiomers and are much less common than
(a) i) benzaldehyde (2 eq), OHꢀ, ii) recrystallization from water, iii) hydrochloric
racemic compounds, can be optically resolved by preferential
acid; (b) i) optical resolution by preferential and replacing crystallization, ii) re-
crystallization from 1-propanol, iii) triethylamine (pH 6), methanol.
and replacing crystallization. (2RS,3SR)-1 was concluded to
form a racemic compound which does not be optically re-
Chart 1. Preparation of Optically Active threo-2-Amino-3-hydroxy-3-
solved by preferential and replacing crystallization.6) There- phenylpropanoic Acid (1)
∗ To whom correspondence should be addressed. e-mail: shiraiwa@ipcku.kansai-u.ac.jp
© 2006 Pharmaceutical Society of Japan

August 2006
1171
Table 1. Solubilities of (2RS,3SR)- and (2R,3S)-2-Amino-3-hydroxy-3-phenylpropanoic Acid Hydrochloridesa)
L- or D-2c) as an optically
1·HClb)
Solubility
[g (100 cm3 of 1-propanol)ꢀ1
active co-solute (mmol)
]
(2R,3S)-1·HCl 6.06
(2S,3R)-1·HCl 6.06
d)
(2RS,3SR)-1·HCl
(2R,3S)-1·HCl
—
12.12
6.13
{
{
d)
—
(2R,3S)-1·HCl 7.50
(2S,3R)-1·HCl 8.14
(2RS,3SR)-1·HCl
L-2 45.0
15.64
(2R,3S)-1·HCl
(2R,3S)-1·HCl
L-2 45.0
D-2 45.0
7.39
7.97
a) Temperature, 10 °C. b) 1·HCl: threo-2-Amino-3-hydroxy-3-phenylpropanoic acid hydrochloride. c) 2: Phenylalanine methyl ester hydrochloride. d) None.
Fig. 3. Relationship between the Amount of Crystallization and Amount
of L-Phenylalanine Methyl Ester Hydrochloride (L-2) as Optically Active
Co-Solute in Optical Resolution of (2RS,3SR)-2-Amino-3-hydroxy-3-
phenylpropanoic Acid Hydrochloride [(2RS,3SR)-1·HCl]
Fig. 1. Melting-Point Binary-Phase Diagram of threo-2-Amino-3-hy-
droxy-3-phenylpropanoic Acid Hydrochloride (1·HCl)
ꢀ: beginning of melting. ꢁ: end of melting.
Conditions: (2RS,3SR)-1·HCl, 4.527 g (20.8 mmol); solvent, 20 ml of 1-propanol;
stirring time, 60 min; temperature, 10 °C. Amount of crystallization: ꢁ (2R,3S)-1·HCl;
ꢀ (2S,3R)-1·HCl.
was attempted by stirring a mixture containing 20.8 mmol
(4.527 g) of (2RS,3SR)-1·HCl and 6.00—10.0 mmol of L-2
in 20 ml of 1-propanol for 60 min at 10 °C. The yield
of enantiomer [YE (g)] and amounts of crystallization
[AC(2R,3S) (g) and AC(2S,3R) (g)] were calculated from
YE (g)ꢁyield (g)ꢂOP (%)/100
AC(2S,3R) (g)ꢁ(1/2)[yield (g)ꢀYE (g)]
AC(2R,3S) (g)ꢁYE (g)ꢃAC(2S,3R) (g)
Fig. 2. Solubility Ternary-Phase Diagram of threo-2-Amino-3-hydroxy-3-
phenylpropanoic Acid Hydrochloride (1·HCl)
where OP (%) is the optical purity of the obtained (2R,3S)-
1·HCl and was calculated based on the specific rotation
of optically pure (2R,3S)-1·HCl: [a]D20 ꢃ34.4° (cꢁ1.00,
methanol). The results are shown in Fig. 3.
Conditions: temperature, 10 °C; solvent, 1-propanol.
1
melting point.
The H-NMR spectra revealed that a trace of L-2 (below
Based on the above results, the optical resolution by re- 2.5 mol%) was present in the 1·HCl crystallized; the L-2
placing crystallization of (2RS,3SR)-1·HCl was first at- content was determined by the intensity ratio of the methine
tempted using various L-amino acid hydrochlorides and their proton signal (4.31 ppm) at the C-2 position of 1·HCl and
methyl esters as optically active co-solute. Of these co- methyl proton signal (3.84 ppm) of L-2 in the 1H-NMR spec-
solutes, only L-phenylalanine methyl ester hydrochloride (L- trum. However, the specific rotations of the 1·HCl obtained
2) gave a good result. When L-2 was present in the supersatu- are little affected by the presence of L-2 because of such low
rated solution of (2RS,3SR)-1·HCl, the solubilities summa- content and the specific rotation of L-2 ([a]D20 ꢃ15.9°
rized in Table 1 suggest that (2R,3S)-1·HCl is preferentially (cꢁ1.00, methanol)) which is half the specific rotation of
crystallized from the racemic solution. The optical resolution (2R,3S)-1·HCl.

1172
Vol. 54, No. 8
In the presence of 6.00—9.00 mmol of L-2, the amount of and (2S,3R)-1·HCl were free from L- and D-2, respectively.
crystallization of (2R,3S)-1·HCl slightly decreased with in- Next, we attempted the successive optical resolution by
creasing amount of L-2, whereas that of (2S,3R)-1·HCl rap- preferential crystallization of (2RS,3SR)-1·HCl by employ-
idly decreased. When a larger amount (10.0 mmol) of L-2 ing (2R,3S)- and (2S,3R)-1·HCl as the seed crystals:
was present in the racemic solution, the amount of crystal- (2R,3S)- and (2S,3R)-1·HCl were obtained by the optical res-
lization of (2R,3S)-1·HCl was rapidly decreased, and olution described above. The optical resolution was carried
(2S,3R)-1·HCl was hardly crystallized. In addition, (2R,3S)- out by stirring a racemic solution with a degree of supersatu-
1·HCl and (2S,3R)-1·HCl were not crystallized in the pres- ration of 140%, as the initial solution, for 30 min (Table 2).
ence of 11.0 mmol of L-2 by stirring for 60 min. Therefore, The degree of resolution [DR (%)] of the obtained (2R,3S)-
(2R,3S)-1·HCl with an optical purity of 92% was obtained in and (2S,3R)-1·HCl were calculated from
a degree of resolution [DR (%)] of 54% in the presence of
9.00 mmol of L-2: DR (%) was calculated from
[operation amount of (2R,3S)- or (2S,3R)-1·HCl (g)ꢀ1.212]
DR (%)ꢁ[(yield (g)ꢂOP (%)/100)ꢀ0.050]ꢂ100/
DR (%)ꢁYE (g)/[(4.527 (g)/2)ꢀ1.501 (g)]
where the operation amount is the amount of (2R,3S)- and
where the solubility of (2R,3S)-1·HCl is 1.501 g in the pres- (2S,3R)-1·HCl in the solution used in the optical resolution
ence of 9.00 mmol of L-2 in 20 ml of 1-propanol at 10 °C. and those in runs 2—4 in Table 2 were calculated based on
The degree of resolution [DR (%)] is defined as the yield (%) the yields and optical purities of the (2R,3S)- and (2S,3R)-
of (2R,3S)-1·HCl enantiomer, based on the supersaturating 1·HCl obtained in runs 1—3, respectively. Half of the solu-
portion of (2R,3S)-1·HCl in a racemic solution, and indi- bility of (2RS,3SR)-1·HCl is 1.212 g in 20 ml of 1-propanol
cates the efficiency of optical resolution; the supersaturating at 10 °C.
portion of (2R,3S)-1·HCl means the theoretical yield (g) of
(2R,3S)-1·HCl.
The optical resolution afforded (2R,3S)- and (2S,3R)-
1·HCl with optical purities of over 90% in degree of resolu-
When the supersaturated racemic solution was stirred for tions of 71—79%. The (2R,3S)- and (2S,3R)-1·HCl recrys-
40—170 min in the presence of 9.00 mmol of L-2, as shown tallized from 1-propanol were treated with triethylamine in
in Fig. 4, (2R,3S)-1·HCl was rapidly crystallized during the methanol to give optically pure (2R,3S)- and (2S,3R)-1.
first 40—80 min, and then the amount of crystallization of
Experimental
(2R,3S)-1·HCl for 80—170 min was approximately constant.
On the other hand, (2S,3R)-1·HCl was hardly crystallized
General Specific rotations were measured at 589 nm and 20 °C with a
under these conditions, although the amount of crystalliza-
tion of (2S,3R)-1·HCl tended to slightly increase with pro-
longed stirring. Therefore, (2R,3S)-1·HCl of an optical pu-
rity with 97% was obtained in the highest degree of resolu-
tion (65.5%) by stirring for 80 min: [a]D20 ꢃ33.5° (cꢁ1.00,
methanol). After collecting (2R,3S)-1·HCl by filtration,
(2S,3R)-1·HCl was not crystallized from the filtrate despite
vigorous stirring in an ice bath. Therefore, D-2 (9.00 mmol)
was employed as the optically active co-solute to obtain
(2S,3R)-1·HCl with an optical purity of 95% in a degree of
resolution of 64% by stirring the solution of (2RS,3SR)-
1·HCl (4.527 g) in 20 ml of 1-propanol for 80 min at 10 °C:
[a]D20 ꢀ32.7° (cꢁ1.00, methanol).
The (2R,3S)- and (2S,3R)-1·HCl partially resolved were
recrystallized from 1-propanol to give optically pure (2R,3S)-
and (2S,3R)-1·HCl, as described in the Experimental sec-
Fig. 4. Relationship between the Amount of Crystallization and Resolu-
tion. For example, optically pure (2R,3S)-1·HCl (2.45 g) was
obtained from (2R,3S)-1·HCl (5.00 g) with an optical purity
of 52%, and optically pure (2S,3R)-1·HCl (2.00 g) from
(2S,3R)-1·HCl (4.00 g) with an optical purity of 56%. The
tion Time in Optical Resolution (2RS,3SR)-2-Amino-3-hydroxy-3-phenyl-
propanoic Acid Hydrochloride [(2RS,3SR)-1·HCl]
Conditions: (2RS,3SR)-1·HCl, 4.527 g (20.8 mmol); L-phenylalanine methyl ester
hydrochloride (L-2), 1.941 g (9.00 mmol); solvent, 20 ml of 1-propanol; stirring time,
40—170 min; temperature, 10 °C. Amount of crystallization: ꢁ (2R,3S)-1·HCl; ꢀ
1H-NMR spectra indicated that the recrystallized (2R,3S)- (2S,3R)-1·HCl.
Table 2. Successive Optical Resolution by Preferential Crystallization of (2RS,3SR)-2-Amino-3-hydroxy-3-phenylpropanoic Acid Hydrochloridea)
Amount of
(2RS,3SR)-1·HCl added
(g)
Operation amount (g)
(2R,3S)-1·HCl (2S,3R)-1·HCl
Resolution time
(min)
Yieldb)
(g)
Run
Specific rotationc)
DRd) (%)
1
2
3
4
3.392
0.428
0.616
0.500
1.696
1.504
1.785
1.598
1.696
1.886
1.652
1.881
30
40
20
20
(2R,3S) 0.479
(2S,3R) 0.619
(2R,3S) 0.507
(2S,3R) 0.580
ꢃ31.0
ꢀ31.4
ꢃ31.6
ꢀ31.1
78.9
76.4
72.6
70.9
a) Conditions: Seed crystals of (2R,3S)- or (2S,3R)-1·HCl, 0.050 g; solvent, 20 ml of 1-propanol; temperature, 10 °C. b) The yield is the sum of the amounts of the crystal-
lized 1·HCl and seed crystals. c) [a]D20 (cꢁ1.00, methanol). d) DR, degree of resolution.

August 2006
1173
Horiba Seisakusho SEPA-300 auto polarimeter equipped with a quartz cell
with a 5.00 cm path length. IR spectra were obtained in the range of 4000—
2). Optical resolution was carried out at 10 °C by adding further (2RS,3SR)-
1·HCl to the filtrates in a way similar to that described above; the detailed
400 cmꢀ1 with a Perkin–Elmer Model 1600 FT-IR spectrometer by the conditions are shown in runs 3 and 4 in Table 2.
KBr disk method. 1H- and 13C-NMR spectra were recorded on a JNM-
(2R,3S)- and (2S,3R)-2-Amino-3-hydroxy-3-phenylpropanoic Acid
FX270 FT NMR system in deuterium oxide with sodium 3-(trimethyl- [(2R,3S)- and (2S,3R)-1] The partially resolved (2R,3S)- and (2S,3R)-
silyl)propane-1-sulfonate (DSS) as an internal standard. Chemical shifts 1·HCl were recrystallized from 1-propanol in the following manner:
were reported in d units downfield from DSS. Melting points were meas- (2R,3S)-1·HCl (5.00 g) ([a]D20 ꢃ17.9° (cꢁ1.00, methanol)) was added to 1-
ured with a Yanaco MP-500 D micro melting point apparatus.
propanol (20 ml). After vigorously stirring the mixture for 1 h at 50 °C, fol-
lowed by for 3 h at 10 °C, purified (2R,3S)-1·HCl was collected by filtration
and dried.
Glycine and L-2 ([a]D20 ꢀ3.75° (cꢁ2.00, water), [a]D20 ꢃ15.9° (cꢁ1.00,
methanol)) were purchased from Wako Pure Chemical Ind. Compound D-2
was prepared by a general procedure,8) namely, treatment of D-phenylalanine
(2R,3S)-1·HCl: Yield, 2.45 g; mp 149—151 °C; [a]D20 ꢃ34.4° (cꢁ1.00,
(19.8 g, 120 mmol), purchased from Wako Pure Chemical Ind., with thionyl methanol). Anal. Calcd for C9H12ClNO3: C, 49.67; H, 5.56; N, 6.44. Found:
chloride (13 ml) in methanol (100 ml); yield, 22.6 g (87.3%); [a]D20 ꢃ3.95° C, 49.59; H, 5.38; N, 6.52. IR and H- and 13C-NMR spectra were virtually
1
(cꢁ2.00, water), [a]D20 ꢀ16.7° (cꢁ1.00, methanol). 1H-NMR (270 MHz,
D2O, DSS) d: 7.44—7.28 (5H, m, arom. H), 4.45 (1H, dd, Jꢁ4.1, 5.1 Hz,
ꢄCH(NH3ꢃ)), 3.84 (3H, s, –CH3), 3.36 (1H, dd, Jꢁ4.1, 10.0 Hz, ꢄCHH),
3.24 (1H, dd, Jꢁ5.1, 10.0 Hz, ꢄCHH).
identical to those of (2RS,3SR)-1·HCl.
The partially resolved (2S,3R)-1·HCl (4.00 g) ([a]D20 ꢀ19.4° (cꢁ1.00,
methanol)) was purified by recrystallization from 15 ml of 1-propanol in a
manner similar to (2R,3S)-1·HCl described above.
(2RS,3SR)-2-Amino-3-hydroxy-3-phenylpropanoic Acid Hydrochlo-
(2S,3R)-1·HCl: Yield, 2.10 g; mp 150—151.5 °C; [a]D20 ꢀ34.4° (cꢁ1.00,
ride [(2RS,3SR)-1·HCl] (2RS,3SR)-1 was prepared by the reaction of methanol). IR and 1H- and 13C-NMR spectra were virtually identical to those
glycine with benzaldehyde in aqueous alkaline media.6) After dissolving of (2RS,3SR)-1·HCl.
90.6 g (500 mmol) of (2RS,3SR)-1 in 2.5 mol/l hydrochloric acid (200 ml),
the solution was evaporated to dryness in vacuo at 60 °C and then the
A solution of (2R,3S)- or (2S,3R)-1·HCl (1.50 g) in 15 ml of methanol
was adjusted with triethylamine to pH 6. After allowing the mixture to stand
residue was dissolved in 300 ml of ethanol at 60 °C. The solution was al- overnight at 5 °C, the precipitated (2S,3R)- or (2R,3S)-1 was collected by fil-
lowed to stand overnight at 5 °C. The precipitated (2RS,3SR)-1·HCl was col- tration, washed with a small amount of chloroform, and dried.
lected by filtration and dried.
1
(2R,3S)-1: Yield, 1.14 g; [a]D20 ꢃ50.4° (cꢁ0.500, 5 mol/l HCl). H-NMR
(2RS,3SR)-1·HCl: Yield, 98.7 g (90.6%); mp 144—145 °C. IR (KBr)
(270 MHz, D2O, DSS) dꢁ7.50—7.38 (5H, m, arom. H), 5.29 (1H, d,
1
cmꢀ1: 2907, 1738, 1564, 1504, 1454, 1207, 1028, 737, 700, 502. H-NMR Jꢁ4.3 Hz, ꢄCH(OH)), 3.91 (1H, d, Jꢁ4.3 Hz, ꢄCH(NH2)). 13C-NMR
(270 MHz, D2O, DSS) d: 7.49—7.41 (5H, m, arom. H), 5.45 (1H, d, (67.5 MHz, D2O, DSS) dꢁ174.3 (–COOH), 141.5 (arom. C), 131.4 (arom.
Jꢁ4.1 Hz, ꢄCH(OH)), 4.31 (1H, d, Jꢁ4.1 Hz, ꢄCH(NH3ꢃ)). 13C-NMR
(67.5 MHz, D2O, DSS) dꢁ170.5 (–COOH), 138.6 (arom. C), 129.7 (arom.
C), 129.6 (arom. C), 129.5 (arom. C), 126.5 (arom. C), 126.4 (arom. C),
71.3 (ꢄCH(OH)), 59.9 (ꢄCH(NH3ꢃ)). Anal. Calcd for C9H12ClNO3: C,
49.67; H, 5.56; N, 6.44. Found: C, 49.40; H, 5.40; N, 6.46.
C), 131.3 (arom. C), 131.0 (arom. C), 128.3 (arom. C), 128.2 (arom. C),
73.8 (ꢄCH(OH)), 63.4 (ꢄCH(NH2)).
(2S,3R)-1: Yield, 1.15 g; [a]D20 ꢀ50.5°(cꢁ0.500, 5 mol/l HCl) ([a]D
ꢀ50.3° (5 mol/l HCl)).9) 1H- and 13C-NMR spectra were virtually identical
to those of (2R,3S)-1.
Optical Resolution by Replacing Crystallization (2RS,3SR)-1·HCl
(4.527 g, 20.8 mmol) and L-2 (1.294—2.157 g, 6.00—10.0 mmol) were dis-
solved in 20 ml of 1-propanol at 60 °C. After cooling the solution to 10 °C
Solubility and Phase Diagrams (2RS,3SR)-1·HCl (4.535 g) or
(2R,3S)-1·HCl (3.00 g) was dissolved in 20 ml of 1-propanol at 60 °C. After
vigorously stirring the solution for 10 h at 10 °C, the precipitated (2RS,3SR)-
over a period of 40 min, followed by stirring by a magnetic stirrer for 60 min or (2R,3S)-1·HCl was rapidly collected by filtration and thoroughly dried.
at 100 rpm and 10 °C, the precipitated (2R,3S)-1·HCl was collected by fil- The solubility at 10 °C was calculated on the basis of the weight of the pre-
tration and dried.
cipitated (2RS,3SR)- or (2R,3S)-1·HCl. Solubility of (2RS,3SR)-1·HCl at
(2R,3S)-1·HCl obtained using 6.00 mmol of L-2: yield, 0.747 g; [a]D20
ꢃ13.7° (cꢁ1.00, methanol). (2R,3S)-1·HCl obtained using 8.00 mmol of L-
2: yield, 0.506 g; [a]D20 ꢃ26.9° (cꢁ1.00, methanol). (2R,3S)-1·HCl obtained
using 8.50 mmol of L-2: yield, 0.465 g; [a]D20 ꢃ30.0° (cꢁ1.00, methanol).
(2R,3S)-1·HCl obtained using 9.00 mmol of L-2: yield, 0.446 g; [a]D20
ꢃ31.8° (cꢁ1.00, methanol). (2R,3S)-1·HCl obtained using 10.0 mmol of L-
2: yield, 0.204 g; [a]D20 ꢃ29.3° (cꢁ1.00, methanol).
10 °C: 12.115 g (100 ml of 1-propanol)ꢀ1. Solubility of (2R,3S)-1·HCl at
10 °C: 6.125 g (100 ml of 1-propanol)ꢀ1
.
(2RS,3SR)-1·HCl (4.527 g) or (2R,3S)-1·HCl (3.00 g) was dissolved in a
solution containing 1.941 g of L- or D-2 in 20 ml of 1-propanol at 60 °C.
After vigorously stirring the solution for 10 h at 10 °C, the precipitated
1·HCl was rapidly collected by filtration and thoroughly dried. The solubil-
ity at 10 °C was calculated on the basis of the weight of 1·HCl. For the dis-
solution of (2RS,3SR)-1·HCl, the solubilities of (2R,3S)- and (2S,3R)-1·HCl
were estimated based on the optical purity of the 1·HCl obtained by filtra-
tion and its weight. The solubilities were summarized in Table 1.
Optical resolution was carried out for a solution of (2RS,3SR)-1·HCl
(4.527 g, 20.8 mmol) in 20 ml of 1-propanol in the presence of L-2 (1.941 g,
9.00 mmol) by stirring for 40—170 min at 10 °C in a manner similar to that
described above.
Preparing the solubility ternary-phase diagram, the solubilities of mix-
(2R,3S)-1·HCl obtained at 40 min: yield, 0.275 g; [a]D20 ꢃ32.6° (cꢁ1.00, tures of (2RS,3SR)- and (2R,3S)-1·HCl were measured at 10 °C similar to
methanol). (2R,3S)-1·HCl obtained at 50 min: yield, 0.289 g; [a]D20 ꢃ31.8° the method described above. The solid 1·HCl was filtered off and thor-
(cꢁ1.00, methanol). (2R,3S)-1·HCl obtained at 70 min: yield, 0.481 g; [a]D20
oughly dried and its specific rotation was measured. The amounts of
ꢃ32.0° (cꢁ1.00, methanol). (2R,3S)-1·HCl obtained at 80 min: yield, (2R,3S)- and (2S,3R)-1·HCl in the solution were calculated based on the
0.513 g; [a]D20 ꢃ33.5° (cꢁ1.00, methanol). (2R,3S)-1·HCl obtained at
90 min: yield, 0.531 g; [a]D20 ꢃ31.4° (cꢁ1.00, methanol). (2R,3S)-1·HCl ob-
tained at 120 min: yield, 0.575 g; [a]D20 ꢃ29.0° (cꢁ1.00, methanol). (2R,3S)-
solubility of 1·HCl and the specific rotation of the solid 1·HCl.
In preparation of the melting-point binary-phase diagram, the melting
points of the mixtures composed of (2RS,3SR)- and (2R,3S)-1·HCl were
1·HCl obtained at 170 min: yield, 0.566 g; [a]D20 ꢃ29.7° (cꢁ1.00, measured; after dissolving (2RS,3SR)- and (2R,3S)-1·HCl in an appropriate
methanol).
ratio in methanol, the mixtures were obtained by evaporating the solutions to
dryness in vacuo. The melting-point binary-phase diagram was prepared
from the temperatures at the beginning and end of melting.
Optical resolution was carried out using D-2 (1.941 g, 9.00 mmol) as the
optically active co-solute for a solution of (2RS,3SR)-1·HCl (4.527 g,
20.8 mmol) in 20 ml of 1-propanol by stirring for 80 min at 10 °C, in a man-
ner similar to that described above, to give (2S,3R)-1·HCl: yield, 0.512 g;
[a]D20 ꢀ32.7° (cꢁ1.00, methanol).
Acknowledgments This is a product of research which was financially
supported (in part) by the Kansai University Special Research Fund, 2005,
Successive Optical Resolution by Preferential Crystallization “Design and Application of Novel Chiral Supramolecular Hosts”.
(2RS,3SR)-1·HCl (3.392 g) was dissolved in 20 ml of 1-propanol at 60 °C to
prepare a 140% supersaturated solution at 10 °C. The solution was cooled to
10 °C over a period of 40 min and then seeded with 0.050 g of the (2R,3S)-
1·HCl. After stirring the mixture for 30 min at 10 °C, (2R,3S)-1·HCl
(0.479 g) was collected by filtration and dried (run 1 in Table 2). (2RS,3SR)-
1·HCl (0.428 g) was dissolved in the filtrate at 60 °C and the resulting solu-
tion was cooled to 10 °C. After adding (2S,3R)-1·HCl (0.050 g) as seed
crystals to the solution, followed by stirring the mixture for 40 min at 10 °C,
(2S,3R)-1·HCl (0.619 g) was collected by filtration and dried (run 2 in Table
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