Practical and efficient synthesis of the (R)-atropisomer of a 4-phenyl 1,2,4-triazole derivative as a selective GlyT1 inhibitor

Article abstract of DOI:10.1016/j.tetasy.2012.10.005

Herein we describe a novel and efficient method for synthesizing the (R)-atropisomer of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2- methylbenzonitrile 1, a novel GlyT1 inhibitor. The diastereomeric salt formation of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzoic acid 7 with (1R,2S)-(-)-2-amino-1,2-diphenylethanol afforded the desired (R)-atropisomer. We also report the determination of the absolute configuration of (R)-7 by powder X-ray diffraction.

Full text of DOI:10.1016/j.tetasy.2012.10.005

Tetrahedron: Asymmetry 23 (2012) 1528–1533
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Practical and efficient synthesis of the (R)-atropisomer of a 4-phenyl
1,2,4-triazole derivative as a selective GlyT1 inhibitor
⇑
Takashi Sugane , Noritaka Hamada, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno,
Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Shuichi Sakamoto, Shin-ichi Tsukamoto
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we describe a novel and efficient method for synthesizing the (R)-atropisomer of 3-[3-ethyl-5-(6-
phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile 1, a novel GlyT1 inhibitor. The diaste-
reomeric salt formation of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzoic
acid 7 with (1R,2S)-(ꢀ)-2-amino-1,2-diphenylethanol afforded the desired (R)-atropisomer. We also
report the determination of the absolute configuration of (R)-7 by powder X-ray diffraction.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 31 July 2012
Accepted 1 October 2012
Available online 8 November 2012
1. Introduction
observed for several months at ambient temperatures, we selected
(ꢀ)-1 as a candidate for further preclinical studies. It was therefore
In the central nervous system, specific sodium/chloride-depen-
dent transporters regulate glycine levels in the synapse. Glycine
activity here is terminated by reuptake via two high-affinity gly-
cine transporters: glycine transporters 1 (GlyT1) and 2 (GlyT2).1,2
GlyT1 is expressed in forebrain areas such as the hippocampus
important for us to establish a practical synthetic method to pro-
vide enough enantiomerically pure test samples for preclinical
studies.
Herein we report a concise method for synthesizing (ꢀ)-1,
including resolution via diastereomeric salt formation of interme-
diate 7 using (1R,2S)-(ꢀ)-2-amino-1,2-diphenylethanol (ADPE). In
addition, we have also determined the absolute stereochemistry
of these atropisomes via powder X-ray diffraction.
and cerebral cortex, and co-localized with the N-methyl-D-aspar-
tate (NMDA) receptors. Glycine acts as a co-agonist of the NMDA
receptor, where it has been suggested that GlyT1 modulates NMDA
receptor activity by regulating glycine concentration in the vicinity
of the NMDA receptors. As a result, agents which inhibit the activ-
ity of GlyT1 and thus activate the NMDA receptors may be useful
for treating schizophrenia, dementia, and related disorders.3–5
We have previously identified 3-[3-ethyl-5-(6-phenylpyridin-3-
2. Results and discussion
2.1. Synthesis of benzoic acid 7
yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile
1 as one such
In order to obtain enantiomerically pure (R)-1, we first focused
on the resolution via the diastereomeric salts of (RS)-1 with 15 dif-
ferent optically active carboxylic acids, but we found this approach
to be infeasible. We therefore considered utilizing carboxylic acid
(RS)-7 for the resolution (Scheme 1).
selective GlyT1 inhibitor.6 Compound 1 has a restricted rotation
between the triazole-4-yl and 3-cyano-2-methylphenyl groups,
resulting in two enantiomeric rotational isomers. In order to eval-
uate the thermal stability for interconversion, solutions of (+)-1
were maintained at various temperatures, and racemization was
monitored by HPLC. The barrier was found to be 30.5 kcal/mol,
which correlates with a half-life of 21 years under physiological
conditions (i.e. 37 °C).6 Subsequent biological studies revealed that
only the (ꢀ)-atropisomer (ꢀ)-1 showed potent GlyT1 inhibitory
activity, with the corresponding (+)-atropisomer (+)-1 exhibiting
far less potent activity (Table 1).6 Since nearly all of the inhibitory
activity resided in one rotational isomer and racemization was not
Before conducting the resolution, we investigated an efficient
synthetic route to intermediate 7. We have previously showed that
the cyclization of the triazole ring involves the addition of anilines
to 1,2,4-oxadiazoles or reactions of methyl thioimidates with acyl
hydrazides (Scheme 2).7,8 Although these methods were of great
use for preparing a wide variety of triazoles for structure optimiza-
tion, they required extreme thermal conditions (>160 °C) and chro-
matographic purification, neither of which are suitable for large-
scale synthesis. We therefore attempted the cyclization of the tri-
azole using the reaction of carboximidohydrazide 5 with Et-
9
⇑
C(OEt)3 under conditions that are milder than those shown in
Corresponding author. Tel.: +81 29 863 6678; fax: +81 29 852 5387.
E-mail address: takashi.sugane@astellas.com (T. Sugane).
Scheme 2.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.10.005

T. Sugane et al. / Tetrahedron: Asymmetry 23 (2012) 1528–1533
1529
Table 1
In vitro GlyT1 inhibitory activity
N
N
N
N
Et
Et
N
N
N
N
Me
Me
NC
(S)-(+)-1
CN
(R)-(-)-1
Selectivityc
a
b
½
a 2D5
ꢂ
(c 1.0, CHCl3),
Compound
Rat GlyT1 IC50
(l
M)
Rat GlyT2 IC50
(
lM)
(RS)-1
(S)-(+)-1
(R)-(ꢀ)-1
—
+213
ꢀ211
0.16 0.030
20 4.8
0.064 0.023
>30
>30
>30
>187
>1.5
>469
a
b
c
[3H]glycine uptake assay using rat C6 cells. Values are mean standard error for three experiments.
[3H]glycine uptake assay using rat brainstem cells.
Ratio of the IC50
(l
M) values rat GlyT2/rat GlyT1.
N
N
N
N
N
N
Me
Me
OH
Me
N
N
N
Resolution
Me
CN
Me
O
Me
O
N
N
N
OH
(R)-1
(R)-7
(RS)-7
Scheme 1. Approach for the synthesis of (R)-1.
N
N
N
N
EtOH/H2O (1:3), and after 4 h of stirring, the precipitated salt (R)-
7ꢁ(1R,2S)-ADPE was obtained in good diastereomeric purity (93%
de). A single recrystallization of the salt obtained in EtOH/H2O
(1:3) increased the enantiomeric purity to 99.5% de with good yield
(41% yield, E = 82%).11 Treatment of the diastereomeric salt (R)-
7ꢁ(1R,2S)-ADPE in ethanol with 1 equivalent of HCl, followed by fil-
tration of the resultant precipitate gave the desired optically active
benzoic acid (R)-7 (95% yield, 99.5% ee).
a
H2N R3
R1
N
R3
R2
+
O
R2
R1
SMe
N
N
b
R1CONHNH2
+
R2
N
R3
R2
R1
N
R3
Undesired (S)-7 can be recycled using the axially chiral nature
of 7. The salt containing 86% ee of undesired (S)-7 was dissolved
in N,N-dimethylacetamide (DMA) and then heated to 155 °C. Under
these conditions, racemization was completed in 9 h, yielding race-
mate 7. The undesired (S)-7 was almost quantitatively recycled to
the racemate (RS)-7 and could be used to prepare an additional
batch of desired (R)-7. This resolution process involving recycling
is valuable, as a large amount of the desired atropisomer can be
efficiently obtained without resorting to large-scale chiral HPLC
resolution.
Scheme 2. Reagents and conditions: (a) TsOHꢁH2O or (1S)-10-camphorsulfonic
acid, neat, >160 °C; (b) TsOHꢁH2O or (1S)-10-camphorsulfonic acid, DMF, >160 °C.
The preparation of 7 started with nicotinic acid 2 (Scheme 3).
Compound 2 was converted into the acid chloride by using SOCl2,
followed by reaction with aniline 3 to afford amide 4 in 77% yield.
Using SOCl2, the amide moiety of 4 was then converted into the
corresponding imidoyl chloride, which was further treated with
hydrazine hydrate to give carboximidohydrazide 5 in 70% yield.
Cyclization of the triazole ring proceeded smoothly using EtC(OEt)3
with carboximidohydrazide 5 in EtOH to give the desired triazole 6
in 80% yield. Finally, hydrolysis of the methyl ester of 6 afforded
benzoic acid 7 in 93% yield. It should be noted that no severe ther-
mal conditions were required for any of these 4 steps, and the de-
sired benzoic acid 7 was obtained without chromatographic
purification.
2.3. Determination of the absolute configuration of (R)-7
Since attempts to prepare single crystals of (R)-1 or (R)-7 suit-
able for X-ray diffraction were unsuccessful, we attempted to
determine the absolute configuration by powder X-ray diffraction
(PXRD)12 using the powder sample of the salt (R)-7ꢁ(1R,2S)-ADPE.
Generally PXRD can only determine relative stereochemistry. It
can, however, determine the absolute configuration by comparison
with the known absolute configuration of the compound in the
same crystal.12b,d
The PXRD data analysis was carried out using Accelrys Materials
Studio software packages (X-Cell, DMol3, Reflex Plus).13 The X-ray
powder diffraction data collected for (R)-7(1R,2S)-ADPE were in-
dexed by X-Cell.14 The intensities were integrated by Pawley meth-
od15 implemented within Reflex Plus.
2.2. Resolution of 7
The benzoic acid 7 was subjected to resolution via diastereo-
meric salt formation. We screened a panel of 36 commercially
available optically active amines and resolving conditions to max-
imize both the yield and enantiomeric purity (ee) and identified
(1R,2S)-(ꢀ)-2-amino-1,2-diphenylethanol (1R,2S)-ADPE as a suit-
able and the most efficient resolving agent for (R)-7 (Scheme 4).10
The (1R,2S)-ADPE salt formation with (RS)-7 was accomplished in

1530
T. Sugane et al. / Tetrahedron: Asymmetry 23 (2012) 1528–1533
NH2
N
O
O
HN
OH
NH
a
b
Me
O
c
Me
O
N
N
N
OMe
OMe
2
5
4
N
N
N
N
Me
OH
Me
N
N
e
d
Me
O
Me
N
N
OMe
O
6
7
Scheme 3. Reagents and conditions: (a) SOCl2, 60 °C; (b) methyl 3-amino-2-methylbenzoate 3, pyridine, THF, rt, 77%; (c) (i) SOCl2, 80 °C, (ii) hydrazine hydrate, EtOH, rt, 70%;
(d) EtC(OEt)3, EtOH, reflux, 80%; (e) 1 M NaOH, MeOH, rt, 93%.
N
N
N
N
N
N
Me
OH
Me
OH
Me
OH
N
N
N
a
b
Me
O
Me
O
Me
O
N
N
N
HO
NH2
(R)-7·(1R,2S)-ADPE
(RS)-7
(R)-7
99.5% de
99.5% ee
N
N
N
N
Me
OH
Me
N
N
Me
Me
c
N
N
OH
HO
NH2
O
O
(S)-7·(1R,2S)-ADPE
(RS)-7
86% de
Scheme 4. Resolution and recycling of atropisomer 7. Reagents and conditions: (a) (i) (1R,2S)-(ꢀ)-2-amino-1,2-diphenylethanol, EtOH/H2O (1:3); (ii) recrystallization from
EtOH/H2O (1:3), 41%; (b) 1 M HCl aq, 95%; (c) (i) DMA, 155 °C; (ii) 1 M HCl aq, 98%.
After initial geometrical optimization using DMol3, the struc-
ture solution was performed by a direct-space method using paral-
lel tempering method16 (Reflex Powder Solve). We used both (R)-7
and (S)-7 as initial structures for the structure refinement, where
the bond at the 4-position of the triazole (chiral axis) was able to
rotate freely in the structure solutions. As a result, both initial
structures with (R)-7 and (S)-7 yielded the same solution with an
(R)-configuration. The lattice constants after Rietveld refinement17
(Reflex Powder Refinement) corresponded to a primitive ortho-
rhombic cell (P212121, For Z = 4) with dimensions: a = 26.0848 Å,
b = 25.0880 Å, c = 6.1007 Å, V = 3992.39 Å3. The calculated density
was 1.00 g/cm3. The final Rietveld refinement was Rwp = 5.62%,
Rp = 3.82%. The molecular structure is represented in Figure 1,
and the (R)-configuration was determined by comparison with
the known absolute configuration of (1R,2S)-ADPE.
2.4. Conversion of (R)-7 to (R)-1
The conversion of (R)-7 to (R)-1 was carried out as shown in
Scheme 5. First, carboxylic acid (R)-7 was converted into the corre-
sponding carboxamide (R)-8 in 86% yield using N-ethyl-N0-(3-
Figure 1. The molecular structure of the salt composed of (R)-7 and (1R,2S)-ADPE.

T. Sugane et al. / Tetrahedron: Asymmetry 23 (2012) 1528–1533
1531
N
N
N
N
N
N
Me
Me
Me
OH
N
N
N
a
Me
O
b
Me
CN
Me
O
N
N
N
NH2
(R)-8
(R)-1
(R)-7
99.8% ee
Scheme 5. Reagents and conditions: (a) EDCIꢁHCl, HOBt, NH4Cl, Et3N, DMF, rt, 86%; (b) POCl3, DMF, 0 °C, 81%.
dimethylaminopropyl)carbodiimide hydrochloride (EDCIꢁHCl) and
1-hydroxybenzotriazole (HOBt) as the condensation agents. Car-
boxamide (R)-8 was then reacted with POCl3 in DMF at 0 °C to yield
the desired (R)-1 with 81% yield. No chromatographic purification
was required in these two steps, nor was racemization observed
with the (R)-1 obtained.
(50 mL) was added to a mixture of methyl 3-amino-2-meth-
ylbenzoate 3 (8.0 g, 48 mmol), pyridine (3.9 mL, 48 mmol), and
THF (150 mL) at 0 °C, and then stirred at room temperature for
1 h. Next, it was concentrated in vacuo, and the residue was
washed with water to give crude 4 as a solid. The solid was recrys-
tallized with EtOH/AcOEt/H2O to give the title compound 4 (13 g,
77%) as a pale yellow crystal. Mp 167–168 °C. 1H NMR (DMSO-
d6, 400 MHz): d 2.39 (3H, s), 3.86 (3H, s), 7.37 (1H, t, J = 8.0 Hz),
7.48–7.58 (4H, m), 7.68 (1H, d, J = 7.6 Hz), 8.16–8.22 (3H, m),
8.42 (1H, dd, J = 2.0, 8.4 Hz), 9.24 (1H, d, J = 2.0 Hz), 10.29 (1H, s).
13C NMR (DMSO-d6, 100 MHz): d 15.2, 52.1, 119.7, 125.8, 126.9,
127.6, 128.1, 128.8, 129.8, 130.5, 131.6, 134.6, 136.5, 137.1,
137.7, 148.8, 158.4, 163.9, 167.7. MS (FAB) m/z 347 [(M+H)+]. Anal.
Calcd for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C, 72.67; H,
5.29; N, 8.09.
3. Conclusion
In conclusion, we have developed a novel and efficient route for
synthesizing the (R)-atropisomer of 1, a potent and selective GlyT1
inhibitor. The resolution of the desired (R)-atropisomer was
achieved via the formation of a diastereomeric salt of 7 with
(1R,2S)-ADPE, and the opposite atropisomer could be recycled to
the racemate. It is noteworthy that neither column chromato-
graphic purification nor extreme thermal conditions were required
at any point during the procedure, with (R)-1 being obtained with-
out racemization. In addition, we have determined the absolute
stereochemistry of these analogues to be (R) via PXRD. By using
this route, we were able to obtain a sufficient amount of the com-
pound for further preclinical studies in pharmacology and drug
safety. We believe that this route could be applied for manufac-
ture-scale synthesis, and further optimization is currently under
investigation.
4.3. Methyl 3-{[hydrazino(6-phenylpyridin-3-yl)methylene]
amino}-2-methylbenzoate 5
A mixture of 4 (3.0 g, 8.7 mmol) and SOCl2 (30 mL) was stirred
at 80 °C for 1 h. After it was cooled to room temperature, the mix-
ture was concentrated in vacuo to give a chloro imidate as a pale
yellow solid (3.47 g, 100%). The solid obtained above (500 mg,
1.24 mmol) was added to
a solution of hydrazine hydrate
(0.30 mL, 6.2 mmol) in EtOH (10 mL), and then stirred at room
temperature for 1 h. After adding water, the mixture was extracted
with CHCl3 and washed with water. The organic layer was ex-
tracted with 1 M HCl aqueous solution, and the aqueous layer
was washed with CHCl3. The aqueous layer was then treated with
saturated NaHCO3 solution, extracted with CHCl3, dried over
MgSO4, and concentrated in vacuo to give the title compound 5
(314 mg, 70%) as a white solid. Mp 109–110 °C. 1H NMR (DMSO-
d6, 400 MHz): d 2.47 (3H, s), 3.83 (3H, s), 6.43 (1H, d, J = 8.0 Hz),
6.45–7.30 (3H, m), 7.01 (1H, t, J = 8.0 Hz), 7.13 (1H, d, J = 7.6 Hz),
7.38–7.49 (3H, m), 7.81 (1H, dd, J = 2.4, 8.8 Hz), 7.88 (1H, d,
J = 8.4 Hz), 8.04–8.09 (2H, m), 8.71 (1H, d, J = 1.6 Hz). 13C NMR
(DMSO-d6, 100 MHz): d 14.6, 51.9, 119.4, 120.7, 125.6, 125.7,
126.2, 126.9, 128.6, 128.9, 130.1, 131.8, 134.0, 135.4, 138.1,
141.8, 147.0, 154.4, 168.3. MS (FAB) m/z 361 [(M+H)+]. Anal. Calcd
for C21H20N4O2: C, 69.98; H, 5.59; N, 15.55. Found: C, 69.96; H,
5.65; N, 15.41.
4. Experimental
4.1. General
All commercial materials were used without further purifica-
tion. Uncorrected melting points (mp) were determined using
BÜCHI B-545 micro melting apparatuses. NMR spectra were re-
corded on a JEOL JMN-EX-400 at 400 MHz (1H) and 100 MHz
(
13C); the chemical shifts are expressed in d (ppm) values with tri-
methylsilane as an internal reference (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, and br = broad peak). Mass
spectra (MS) were recorded on a JEOL GCmate II or JEOL JMS-
LX2000 spectrometer. Elemental analyses were performed using
a Yanaco MT-6 and were within 0.4% of theoretical values. HPLC
analyses were conducted on Hitachi D-7500 system. Enantiomeric
excess (%ee) was determined using Chiralpak AD column
(4.6 ꢃ 250 mm, eluent:hexane/EtOH [1:1], flow rate: 0.5 mL/min,
UV detection: 254 nm) for compound 1, or Chiralcel OJ-RH column
(4.6 ꢃ 250 mm, eluent:CH3CN/phosphate buffer [20 mM, pH 2.3]
[3:7], flow rate: 0.5 mL/min, UV detection at 254 nm) for com-
pound 7.
4.4. Methyl 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-tria-
zol-4-yl]-2-methylbenzoate 6
To a solution of 5 (335 mg, 0.93 mmol) in EtOH (4.0 mL) was
added EtC(OEt)3, (0.37mL, 1.86mmol) and the mixture was re-
fluxed for 1 h. After cooling at room temperature, the mixture
was concentrated in vacuo to give a crude solid. This solid was trit-
urated with diethyl ether to give the title compound 6 (297 mg,
4.2. Methyl 2-methyl-3-{[(6-phenylpyridin-3-yl)carbonyl]am-
ino}benzoate 4
80%) as
a
white solid. Mp 184–185 °C. 1H NMR (DMSO-d6,
A mixture of 6-phenylnicotinic acid 2 (9.65 g, 48 mmol) and
SOCl2 (100 mL) was stirred at 60 °C for 1 h. After cooling at room
temperature, the mixture was concentrated in vacuo to give an
acid chloride as solid. The suspension of the acid chloride in THF
400 MHz): d 1.17 (3H, t, J = 7.6 Hz), 2.01 (3H, s), 2.46–2.55 (2H,
m), 3.84 (3H, s), 7.42–7.51 (3H, m), 7.60 (1H, t, J = 8.0 Hz), 7.78
(1H, dd, J = 2.4, 8.8 Hz), 7.87 (1H, d, J = 8.0 Hz), 7.99 (1H, d,
J = 8.8 Hz), 8.02 (1H, d, J = 7.6 Hz), 8.05–8.08 (2H, m), 8.60 (1H, d,

1532
T. Sugane et al. / Tetrahedron: Asymmetry 23 (2012) 1528–1533
J = 2.0 Hz). 13C NMR (DMSO-d6, 100 MHz): d 11.1, 14.4, 18.0, 52.3,
119.9, 121.8, 126.6, 127.7, 128.8, 129.6, 131.9, 132.3, 134.2,
135.5, 135.9, 137.3, 147.4, 150.6, 156.5, 156.7, 166.5. MS (FAB)
m/z 399 [(M+H)+]. Anal. Calcd for C24H22N4O2ꢁ0.1H2O: C, 72.02;
H, 5.59; N, 14.00. Found: C, 71.95; H, 5.65; N, 14.01.
EtOH/water (1:4), and dried in vacuo to give a crude solid
(1.47 g, 2.46 mmol, 93%, de). The crude solid was dissolved in
refluxing EtOH/water (1:3, 40 mL), and the mixture was then stir-
red overnight at room temperature. The resultant solid was col-
lected by filtration, washed with EtOH/water (1:4), and dried in
vacuo to give the salt (R)-7ꢁ(1R,2S)-ADPE (1.26 g, 2.11 mmol, 41%
4.5. 3-[3-Ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]
-2-methylbenzoic acid 7
yield, 99.5% de, E 82%) as a white solid. ½a D25
¼ ꢀ163 (c 1.0, MeOH).
ꢂ
Mp 110–111 °C. 1H NMR (DMSO-d6, 400 MHz): d 1.17 (3H, t,
J = 7.2 Hz), 1.99 (3H, s), 2.43–2.51 (2H, m), 4.30 (1H, d, J = 4.0 Hz),
5.02 (1H, d, J = 4.4 Hz), 7.09–7.22 (11H, m), 7.41–7.49 (4H, m),
7.56 (1H, d, J = 7.6 Hz), 7.77–7.82 (2H, m), 7.98 (1H, d, J = 8.8 Hz),
8.05–8.08 (2H, m), 8.62 (1H, d, J = 1.6 Hz). MS (FAB) m/z 385
[(M+H)+]. Anal. Calcd for C23H20N4O2ꢁC14H15NOꢁ1.5H2O: C, 71.13;
H, 6.13; N, 11.21. Found: C, 71.18; H, 6.37; N, 11.27. The filtrate ob-
tained from the above salt formation was collected, and evaporated
in vacuo to afford (S)-7ꢁ(1R,2S)-ADPE (1.66 g, 2.8 mmol, 86% de) as
a colorless amorphous solid.
To a solution of 6 (274 mg, 0.69 mmol) in MeOH (5.0 mL) was
added 1 M aqueous NaOH solution (1.38 mL, 1.38 mmol), and the
mixture was stirred for 17 h at room temperature. To the reaction
mixture was added 1 M aqueous HCl solution (1.38 mL,
1.38 mmol), followed by adding water (25 mL) to give a precipi-
tate. The precipitate was collected by filtration, washed with water,
and dried in vacuo to give the title compound 7 (246 mg, 93%) as a
white solid. Mp 257–258 °C. 1H NMR (DMSO-d6, 400 MHz): d 1.18
(3H, t, J = 7.3 Hz), 2.03 (3H, s), 2.45–2.52 (2H, m), 7.42–7.51 (3H,
m), 7.57 (1H, t, J = 7.8 Hz), 7.78 (1H, dd, J = 1.9, 8.3 Hz), 7.83 (1H,
d, J = 6.8 Hz), 7.99 (1H, d, J = 8.3 Hz), 8.03 (1H, dd, J = 0.9, 7.8 Hz),
8.05–8.10 (2H, m), 8.60 (1H, d, J = 1.9 Hz), 13.35 (1H, br s). 13C
NMR (DMSO-d6, 100 MHz): d 11.2, 14.6, 18.1, 120.0, 121.9, 126.6,
127.6, 128.8, 129.7, 131.9, 132.0, 133.5, 134.2, 135.6, 135.9,
137.4, 147.5, 150.6, 156.6, 156.8, 167.9. MS (FAB) m/z 385
[(M+H)+]. Anal. Calcd for C23H20N4O2: C, 71.86; H, 5.24; N, 14.57.
Found: C, 71.65; H, 5.30; N, 14.59.
4.8. Thermal racemization of (S)-7
The salt (S)-7ꢁ(1R,2S)-ADPE (1.66 g, 2.8 mmol, 86% de) was dis-
solved in DMA (10 mL), and the mixture was stirred at 155 °C for
9 h. After cooling to room temperature, 1 M aqueous HCl (2.8 mL,
2.8 mmol) was added, and the mixture was diluted with water.
The resulting precipitate was collected by filtration, washed with
water, and dried in vacuo to give racemic 7 (1.05 g, 98%, 0% ee).
4.6. Screening of optically active amines for the resolution of 7
4.9. (ꢀ)-(R)-3-[3-Ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-tria-
zol-4-yl]-2-methylbenzoic acid(R)-7
General procedure: A mixture of 7 (30 mg, 0.08 mmol) and an
optically active amine (0.08 mmol) was dissolved in CH3CN/water
(1:1, 4 mL). After the solution was kept at ambient temperature for
7–10 days, the precipitate was collected by filtration, washed with
CH3CN/water, and dried in vacuo to afford the corresponding dia-
stereomeric salt. The diastereomeric salts (R)-7ꢁ(1R,2S)-ADPE
(15%, 66% de) and (S)-7ꢁ(1S,2R)-ADPE (15%, 33% de) were obtained.
The following amines did not form solid diastereomeric salts with
7: (R)-(+)-1-methylbenzylamine, (S)-(ꢀ)-1-methylbenzylamine, (R)-
(ꢀ)-2-phenylglycinol, (S)-(+)-2-phenylglycinol, (1S,2S)-(+)-2-ami
no-1-phenyl-1,3-propanediol, (1R,2R)-(ꢀ)-2-amino-1-phenyl-1,3-
propanediol, (R)-(+)-1-(1-naphthyl)ethylamine, (S)-(ꢀ)-1-(1-naph
To a solution of diastereomeric salt (R)-7ꢁ(1R,2S)-ADPE (1.76 g,
2.8 mmol) in EtOH (15 mL) was added a 1 M aqueous HCl solution
(2.8 mL, 2.8 mmol). Water was then added, and the resulting pre-
cipitate was collected by filtration, washed with water, and dried
in vacuo to give the title compound (R)-7 (1.03 g, 95%) as a white
solid.
½
a 2D5
ꢂ
¼ ꢀ200 (c 1.0, CHCl3). Mp 235–236 °C. 1H NMR
(DMSO-d6, 400 MHz): d 1.18 (3H, t, J = 7.2 Hz), 2.03 (3H, s), 2.45–
2.52 (2H, m), 7.42–7.51 (3H, m), 7.57 (1H, t, J = 8.0 Hz), 7.78 (1H,
dd, J = 2.0, 8.4 Hz), 7.83 (1H, d, J = 7.6 Hz), 7.99 (1H, d, J = 8.8 Hz),
8.02 (1H, d, J = 7.6 Hz), 8.05–8.09 (2H, m), 8.61 (1H, d, J = 1.6 Hz),
13.33 (1H, br s). MS (FAB) m/z 385 [(M+H)+]. Anal. Calcd for
thyl)ethylamine,
D-phenylalaninol,
L-phenylalaninol, (1S,2S)-(+)-2-
C23H20N4O2: C, 71.86; H, 5.24; N, 14.57. Found: C, 71.62; H, 5.28;
amino-1-(4-nitrophenyl)-1,3-propanediol, (1R,2R)-(ꢀ)-2-amino-1
-(4-nitrophenyl)-1,3-propanediol, (1R,2R)-(+)-1,2-diphenyl-1,2-eth-
anediamine, (1S,2S)-(ꢀ)-1,2-diphenyl-1,2-ethanediamine, (1R,2S)-
(+)-cis-1-amino-2-indanol, (1S,2R)-(ꢀ)-cis-1-amino-2-indanol, (1R,
2R)-(ꢀ)-cyclohexanediamine, (1S,2S)-(+)-cyclohexanediamine, (R)-
1-(3-methoxyphenyl)ethylamine, (S)-1-(3-methoxyphenyl)ethyla
mine, (R)-1-(4-methoxyphenyl)ethylamine, (S)-1-(4-methoxy-
phenyl)ethylamine, (R)-1,2,3,4-tetrahydro-1-naphthylamine, (S)-1,
2,3,4-tetrahydro-1-naphthylamine, (1R,2S)-2-di-n-butylamino-1-
phenyl-1-propanol, (1S,2R)-2-di-n-butylamino-1-phenyl-1-propa-
N, 14.57. HPLC retention time (min): 11.1 [(R)-7], 16.3 [(S)-7].
4.10. (ꢀ)-(R)-3-[3-Ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-tria-
zol-4-yl]-2-methylbenzamide(R)-8
A
mixture of (R)-7 (800 mg, 2.1 mmol), NH4Cl (333 mg,
6.2 mmol), Et3N (0.43 mL, 3.1 mmol), 1-ethyl-3-(3-dimethylami-
nopropyl)carbodiimide hydrochloride (498 mg,
(EDCIꢁHCl)
2.6 mmol), and 1-hydroxy-1H-benzotriazole (HOBt) (351 mg,
2.6 mmol) in DMF (5.0 mL) was stirred at room temperature for
12 h. The reaction mixture was then diluted with EtOAc, washed
with saturated aqueous NaHCO3, and dried in vacuo to give a crude
solid. The solid was dissolved in refluxing EtOAc (10 mL), and the
mixture was then stirred overnight at room temperature. The
resultant solid was collected by filtration, washed with EtOAc,
and dried in vacuo to give the title compound (R)-8 (687 mg,
nol, (R)-(ꢀ)-1-aminoindane, (S)-(+)-1-aminoindane, (S)-(ꢀ)-
a,
4-dimethylbenzylamine, (R)-1-(4-methylphenyl)ethylamine, (S)-1-
phenyl-2-(p-tolyl)ethylamine, (R)-(ꢀ)-2-amino-1-phenylethanol,
(S)-(ꢀ)-3-amino-1,2-propanediol, and
D-threoninol.
4.7. (1R,2S)-2-Amino-1,2-diphenylethanol(ꢀ)-(R)-3-[3-ethyl-5-
(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methyl-
benzoate(R)-7ꢁ(1R,2S)-ADPE
86%) as a white solid. ½a D25
¼ ꢀ170 (c 1.0, CHCl3). Mp 207–208 °C.
ꢂ
1H NMR (DMSO-d6, 400 MHz): d 1.19 (3H, t, J = 7.2 Hz), 1.90 (3H,
s), 2.40–2.55 (2H, m), 7.42–7.53 (4H, m), 7.59–6.61 (2H, m), 7.67
(1H, d, J = 7.6 Hz), 7.82 (1H, dd, J = 2.0, 8.0 Hz), 7.96 (1H, br s),
7.99 (1H, d, J = 8.8 Hz), 8.05–8.09 (2H, m), 8.60 (1H, d, J = 2.4 Hz).
13C NMR (DMSO-d6, 100 MHz): d 11.2, 13.9, 18.0, 119.9, 121.9,
126.6, 127.3, 128.7, 129.0, 132.6, 133.6, 135.5, 137.4, 139.6,
147.3, 150.4, 156.5, 156.7, 169.6. MS (FAB) m/z 384 [(M+H)+]. Anal.
Racemic 7 (2.0 g, 5.2 mmol) and (1R,2S)-2-amino-1,2-diphenyl-
ethanol (1.1 g, 5.2 mmol) were dissolved in refluxing EtOH/water
(1:1, 44 mL). To this refluxing solution was added water (44 mL),
and the mixture was stirred at room temperature for 4 h. The
resultant white solid was collected by filtration, washed with

T. Sugane et al. / Tetrahedron: Asymmetry 23 (2012) 1528–1533
1533
Calcd for C23H21N5O: C, 72.04; H, 5.52; N, 18.26. Found: C, 71.89; H,
Acknowledgements
5.56; N, 18.26.
The authors thank the staff of the Analysis and Pharmacokinet-
ics Research Laboratories for performing the spectroscopic
measurements.
4.11. (ꢀ)-(R)-3-[3-Ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-tria-
zol-4-yl]-2-methylbenzonitrile(R)-1
To a solution of (R)-8 (300 mg, 0.78 mmol) in DMF (3.0 mL) was
added POCl3 (0.087 mL, 0.94 mmol) at 0 °C, and the mixture was
stirred for 20 min. The reaction was quenched by adding 1 M aque-
ous NaOH, and then extracted with EtOAc, washed with saturated
aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo to
give a crude solid. The solid was dissolved in refluxing EtOH/water
(1:4, 5 mL), and the mixture was stirred overnight at room temper-
ature. The resultant solid was collected by filtration, washed with
EtOH/water (1:4), and dried in vacuo to give the title compound
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(R)-1 (230 mg, 81%, 99.8% ee) as a white solid. ½a D25
¼ ꢀ211 (c
ꢂ
1.0, CHCl3), mp 162–163 °C. 1H NMR (DMSO-d6, 400 MHz): d 1.19
(3H, t, J = 7.4 Hz), 2.08 (3H, s), 2.41–2.59 (2H, m), 7.43–7.52 (3H,
m), 7.66 (1H, t, J = 7.8 Hz), 7.76 (1H, dd, J = 1.5, 8.3 Hz), 7.97–8.02
(2H, m), 8.05–8.12 (3H, m), 8.64 (1H, d, J = 1.9 Hz); 13C NMR
(DMSO-d6, 100 MHz): d 11.1, 15.6, 18.0, 114.4, 116.8, 119.9,
121.5, 126.6, 128.75, 128.78, 129.7, 133.7, 133.9, 134.9, 135.7,
137.4, 139.2, 147.7, 150.5, 156.7. MS (FAB) m/z 366. Anal. Calcd
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H, 5.23; N, 19.14. HPLC retention time (min): 22.7 [(R)-1], 33.1
[(S)-1].
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