Synthesis of optically active N-(1-ethyl-3-methylhexahydro-1,3-diazin-5-yl)- and N-(1-ethyl-5-methyloctahydro-1,5-diazocin-3-yl)pyridine-3-carboxamides

Article abstract of DOI:10.1002/jhet.5570390417

As part of the structure-activity relationship of the dopamine D₂ and serotonin 5-HT₃ receptors antagonist 1, which is a clinical candidate with a broad antiemetic activity, the synthesis and dopamine D₂ and serotonin 5-HT

Full text of DOI:10.1002/jhet.5570390417

Jul-Aug 2002
Synthesis of Optically Active N-(1-Ethyl-3-methylhexahydro-
1,3-diazin-5-yl)- and N-(1-Ethyl-5-methyloctahydro-
1,5-diazocin-3-yl)pyridine-3-carboxamides
727
Yoshimi Hirokawa*, Hiroshi Yamazaki, and Shiro Kato
Medicinal Chemistry Group, Chemistry Research Laboratories,
Dainippon Pharmaceutical Co., Ltd., Enoki 33-94, Suita, 564-0053, Japan
Received December 18, 2001
As part of the structure-activity relationship of the dopamine D and serotonin 5-HT receptors antagonist
2
3
1, which is a clinical candidate with a broad antiemetic activity, the synthesis and dopamine D and serotonin
2
5-HT receptors binding affinity of (R)-5-bromo-N-(1-ethyl-3-methylhexahydro-1,3-diazin-5-yl)- and (R)-5-
3
bromo-N-(1-ethyl-5-methyloctahydro-1,5-diazocin-3-yl)-2-methoxy-6-methylaminopyridine-3-carboxam-
ides (2 and 3) are described. Treatment of 1-ethyl-2-(p-toluenesulfonyl)amino-3-methylaminopropane dihy-
drochloride (4a) with paraformaldehyde and successive deprotection gave the 5-aminohexahydro-1,3-
diazine 6 in excellent yield. 3-Amino-1-ethyl-5-methyloctahydro-1,5-diazocine (15) was prepared from 2-
(benzyloxycarbonyl)amino-3-[[N-(tert-butoxycarbonyl)-N-methyl]amino]-1-ethylaminopropane (9)
through the intramolecular amidation of (R)-3-[N-[(2-benzyloxycarbonylamino-3-methylamino)propyl]-N-
ethyl]aminopropionic acid trifluoroacetate (12), followed by lithium aluminum hydride reduction of the
resulting 6-oxo-1-ethyl-5-methyloctahydrodiazocine (13) in 41% yield. Reaction of the amines 6 and 15
with 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid furnished the desired 2 and 3, which
showed much less potent affinity for dopamine D receptors than 1.
2
J. Heterocyclic Chem., 39, 1 (2002).
(R)-5-Bromo-N-(1-ethyl-4-methylhexahydro-1,4-
and their biological evaluation was essential. This modifi-
diazepin-6-yl)-2-methoxy-6-methylaminopyridine-3-car-
cation of 1 may cause a change not only in the distance
between the nitrogen atom in the amine moiety (amide
group) and the pyridine ring but also in the preferred stable
conformations of the molecule. The present paper deals
boxamide difumarate (1) is a potent dopamine D and
2
serotonin 5-HT receptor dual antagonist and is considered
3
as clinical candidate with a broad antiemetic activity [1].
In order to gain insight into the pharmacological properties
of 1, synthesis of the pyridine-3-carboxamides 2 and 3
having respectively six-membered and eight-membered
heteroalicycles containing two nitrogen atoms (Figure 1)
with the synthesis, and serotonin 5-HT and dopamine D
3
2
receptors binding affinity of 5-bromo-N-(1-ethyl-3-
methylhexahydro-1,3-diazin-5-yl)- and 5-bromo-N-(1-
ethyl-3-methyloctahydro-1,5-diazocin-3-yl)-2-methoxy-6-
methylaminopyridine-3-carboxamides (2 and 3).
In this work, we first examined the synthesis of (R)-5-
amino-1-ethyl-3-methylhexahydro-1,3-diazine (6).
Reaction of 4a [2] with paraformaldehyde gave 5-(p-tolue-
nesulfonyl)amino-1-ethyl-3-methylhexahydro-1,3-diazine
(5a) in 94% yield. The structure of 5a was speculated from
1
H-nmr and ms spectra. On the other hand, treatment of the
5-(benzyloxycarbonyl)amino counterpart 4b with para-

728
Y. Hirokawa, H. Yamazaki, and S. Kato
Vol. 39
formaldehyde smoothly proceeded, however, the desired
product 5b was not isolated. The reason for this result is
unclear. The detosylation of 5a was carried out in refluxing
47% aqueous hydrobromic acid solution to afford the
desired amine 6 in quantitative yield (Scheme 1).
products were not obtained at all. Finally, the method
using intramolecular amidation of the 3-aminopropionic
acid derivative 7b was examined (Scheme 2). As shown in
Scheme 3, reaction of 9 [2] with methyl acrylate gave the
3-aminopropionic ester 10 in 65% yield. After removal of
the tert-butoxycarbonyl (Boc) group, intramolecular ami-
dation of the resulting aminoester with sodium methoxide
was unsuccessful. On the other hand, alkaline hydrolysis
of 10, followed by deprotection of Boc group of the resul-
tant 11 by trifluoroacetic acid afforded the aminoacid 12 in
excellent yield. Intramolecular amidation of 12 using ben-
zotriazol-1-yloxytris(dimethylamino)phosphonium hexa-
fluorophospate (BOP) proceeded smoothly to give the
desired 1-ethyl-5-methyloctahydro-1,5-diazocin-6-one 13
in 89% overall yield from 10. The structure of 13 was
Next, the formation of 1-ethyl-5-methyloctahydro-1,5-
diazocine ring was examined. Reaction of 4a with mal-
onyl dichloride did not afford the desired eight-membered
compound. In addition, treatment of the 3-aminopropionic
ester 7a, derived from 4a, with DIBAL-H at –70 °C, fol-
lowed by sodium borohydride reduction [3] did not pro-
duce the 1-ethyl-5-methyloctahydro-1,5-diazocin-6-one 8
(Scheme 2). Previously, we reported that reaction of 4a
with glyoxal in the presence of boran-triethylamine com-
plex directly produced the seven-membered product in
good yield [4]. The method was applied; 4a was treated
with malondialdehyde [5] instead of glyoxal in the pres-
ence of boran-triethylamine, but the eight-membered
1
deduced from H-nmr and ms spectra. Reduction of 13
with lithium aluminum hydride produced the 1-ethyl-5-
methyloctahydro-1,5-diazocine 14 in 71% yield.
Hydrogenolysis of 14 furnished 3-amino-1-ethyl-5-
methyloctahydro-1,5-diazocine (15).
Condensation of 5-bromo-2-methoxy-6-methyl-
aminopyridine-3-carboxylic acid [6] with the six-mem-
bered 5-amino-1,3-diazine 6 and the eight-membered 3-
amino-1,5-diazocine 15 by N,N'-carbonyldiimidazole
(CDI) gave the pyridine-3-carboxamides 2 and 3, respec-
tively (Scheme 4).
Pharmacological Results.
The affinities of 2 and 3 for serotonin 5-HT and
3
dopamine D receptors were determined using binding
2
assays. The affinity for serotonin 5-HT receptors was
3
3
evaluated using competition for [ H]GR65630 binding site

Jul-Aug 2002
Synthesis of Optically Active N-(1-Ethyl-3-methylhexahydro-1,3-diazin-5-yl)-
729
1
Hitachi M-1000 spectrometer. The H-nmr spectra were
recorded on a Varian Gemini-200 (200 MHz) or a JEOL JNM-
LA300 (300 MHz) spectrometer using dilute solution in deuteri-
ochloroform unless otherwise stated. Chemical shifts are
expressed as δ (ppm) values from tetramethylsilane as an internal
standard. Optical rotations were measured at 589 nm with a
Jasco P-1020 digital polarimeter. Organic extracts were dried
over anhydrous magnesium sulfate. The solvents were evapo-
rated under reduced pressure.
in rat cortical membranes, [7] while the affinity for
3
dopamine D receptors was evaluated using [ H]spiperone
2
in the rat striatum [8] (Table 1). For comparison, data for 1
are included in Table 1.
Table 1
Affinity of (R)-5-Bromo-N-(1-ethyl-3-methylhexahydro-1,3-diazin-5-
yl)- and (R)-5-Bromo-N-(1-ethyl-5-methyloctahydro-1,5-diazocin-3-yl)-
2-methoxy-6- methylaminopyridine-3-carboxamides (2 and 3) for
(R)-1-Ethyl-3-methyl-5-(p-toluenesulfonylamino)hexahydro-
1,3-diazine (5a).
Serotonin 5-HT and Dopamine D Receptors
3
2
Receptor Binding Affinity: IC (nM)
50
A mixture of 4a (5.0 g, 14 mmol), paraformaldehyde (0.5 g, 17
mmol), triethylamine (2.8 g, 28 mmol), and methyl alcohol (50
ml) was heated to reflux for 5 hours and cooled to room tempera-
ture. The solvent was then evaporated to leave a residue, which
was diluted with aqueous potassium carbonate solution and
extracted with chloroform. The extract was concentrated to give
a solid, which was chromatographed on silica gel with chloro-
form/methyl alcohol = 50/1 to afford 3.9 g (94%) of 5a. The
authentic sample was obtained by recrystallization from ethyl
Compound
Dopamine D [a]
Serotonin 5-HT [b]
3
2
2
3
1
698
595
2.5
47.5
1.6
1.1
3
[a] Determined in rat brain synaptic membranes using [ H]spiperone;
3
[b] in rat cortical membranes using [ H]GR65630.
1
acetate/hexane, mp 96—97 °C. H-nmr: δ 0.94 (t, J = 7.5 Hz,
The affinity of 2 and 3 for dopamine D receptors was
3H, CH Me), 2.11 (s, 3H, C H Me), 2.42 (s, 3H, NMe), 1.9—2.6
2
2
6 4
much less potent than that of 1. On the other hand, the
pyridine-3-carboxamide 3 with its eight-membered ring
(m, 7H), 3.42 (m, 1H), 3.54 (m, 1H, 5-CH), 5.52 (m, 1H, NH),
7.28 (d, J = 8.4 Hz, 2H, arom. H), 7.77 (d, J = 8.4 Hz, 2H, arom.
+
H); ms: m/z 298 (MH ); ir: 2795, 1475, 1464, 1335, 1165, 1094.
showed strong affinity for serotonin 5-HT receptors with
3
29
[α]
= + 0.95° (c = 1.0, MeOH).
D
an IC of 1.6 nM. This affinity for serotonin 5-HT
50
3
Anal. Calcd. for C H N O S: C, 56.54; H, 7.79; N, 14.13; S,
14 23
3 2
receptors was approximately equal to that of 1 (1.6 nM vs.
10.78. Found: C, 56.56; H, 8.06; N, 14.29; S, 10.51.
1.1 nM). The binding affinity for serotonin 5-HT recep-
3
(R)-5-Amino-1-ethyl-3-methylhexahydro-1,3-diazine (6).
tors of the pyridine-3-carboxamide 2 with its six-mem-
bered ring was less potent than that of the pyridine-3-car-
boxamide 1 with its seven-membered ring. From these
results, it is clear that 3 exhibits potent affinity for sero-
A solution of 5a (1.5 g, 5.1 mmol) in hydrobromic acid (15 ml
of 48% aqueous solution) was heated to reflux for 1 hour and
cooled to room temperature. The reaction mixture was washed
with chloroform, basified with 48% aqueous sodium hydroxide
solution, and extracted with chloroform. The extract was evapo-
rated to leave 0.7 g (quantitative yield) of 6 as a yellow oil, which
was used in the next amidation step without further purification;
tonin 5-HT receptors but not for dopamine D receptors
3
2
whereas 2 shows weak affinity for both receptors. It can,
therefore, be speculated that the dopamine D receptor site
2
has a narrow permissible area and that the serotonin 5-HT
1
H-nmr: δ 1.11 (t, J = 7.5 Hz, 3H, CH Me), 1.62 (br. s, 2H), 2.44
3
2
receptor site has a relatively broad permissible area. The
(s, 3H, NMe), 2.1—2.8 (m, 7H), 2.99 (m, 1H), 3.50 (m, 1H, 5-
+
CH); ms: m/z 144 (MH ).
conformational analysis for dopamine D and serotonin 5-
2
HT receptors binding sites are now in progress.
3
Methyl (R)-3-[N-[[2-Benzyloxycarbonylamino-3-(N-tert-
butoxycarbonyl-N-methyl)amino]propyl]-N-ethyl]aminopropi-
onate (10).
EXPERIMENTAL
A mixture of 9 (9.6 g, 26 mmol), methyl acrylate (2.8 g, 33
mmol), and methyl alcohol (50 ml) was stirred at room tempera-
ture for 16 hours and concentrated to dryness. The residue was
chromatographed on silica gel with chloroform/methyl alcohol =
All melting points were determined on a Yanagimoto
micromelting point apparatus without correction. The ir spectra
were recorded on a Shimadzu FTIR-8200PC spectrometer with
potassium bromide disks. Atmospheric pressure chemical ion-
ization and secondary ion mass spectra were obtained on a
1
100/1 to give 7.7 g (65%) of 10 as a pale yellow oil; H-nmr: δ
t
0.97 (t, J = 7.1 Hz, 3H, CH Me), 1.43 (s, 9H, Bu), 2.15—2.62
2

730
Y. Hirokawa, H. Yamazaki, and S. Kato
Vol. 39
(m, 6H), 2.65—2.96 (m, 2H), 2.88 (s, 3H, NMe), 3.1—3.7 (m,
2H), 3.64 (s, 3H, OMe), 3.81 (m, 1H), 5.08 (s, 2H, CH Ph), 5.65
tarate tetrahydrate solution. The organic layer was separated by
decantation, and the insoluble materials were washed with chlo-
roform. The combined organic solution was dried over anhy-
drous magnesium sulfate and concentrated to dryness. The
residue was chromatographed on silica gel with chloroform/
2
(br., 1H), 7.33 (m, 5H, arom. H); hrms: Calcd. for C H N O :
23 37
3 6
451.2681. Found: 451.2690.
(R)-3-[N-[[2-Benzyloxycarbonylamino-3-(N-tert-butoxycarbonyl-
N-methyl)amino]propyl]-N-ethyl]aminopropionic Acid (11).
methyl alcohol = 4/1 to give 0.95 g (71%) of 14 as a colorless oil;
1
H-nmr: δ 1.00 (t, J = 7.1 Hz, 3H, CH Me), 1.6—1.9 (m, 2H),
2
2.35 (s, 3H, NMe), 2.4—2.85 (m, 10H), 3.64 (m, 1H, 3-CH), 5.09
A mixture of 10 (7.7 g, 17 mmol), 2 N aqueous sodium
hydroxide solution (12.7 ml, 25 mmol), and ethyl alcohol (10 ml)
was heated to reflux for 2 hours and cooled to room temperature.
After evaporation of ethyl alcohol, the resulting aqueous solution
was washed with diethyl ether and then acidified (pH 3—4) with
aqueous citric acid solution and extracted with chloroform. The
extract was washed with brine and evaporated to give 6.7 g
(s, 2H, CH Ph), 5.52 (br., 1H, NH), 7.28—7.4 (s, 5H, arom. H);
2
hrms: Calcd. for C H N O : 305.2102 Found. 305.2101
17 27
3 2
(R)-3-Amino-1-ethyl-5-methyl-1,5-octahydrodiazocine (15).
A solution of 14 (0.8 g, 2.6 mmol) in ethyl alcohol (20 ml) was
hydrogenated over 10% palladium on carbon (0.2 g) under
atmospheric pressure at room temperature for 2 hours. The cata-
lyst was filtered off, and the filtrate was concentrated to dryness
to give 0.45 g (quantitative yield) of 15 as a colorless oil, which
1
(90%) of 11 as a colorless oil; H-nmr: δ 1.14 (t, J = 7.1 Hz, 3H,
t
CH Me), 1.43 (s, 9H, Bu), 1.8—2.3 (m, 3H), 2.5—2.75 (m, 3H),
2
2.88 (s, 3H, NMe), 2.75—3.1 (m, 4H), 4.03 (m, 1H, 2-CH), 5.06
(d, J = 6.4 Hz, 1H, PhCH ), 5.12 (d, J = 6.4 Hz, 1H, PhCH ), 6.08
was used in the next amidation step without further purification;
2
2
1
(m, 1H, NH), 7.1—7.4 (m, 5H, arom. H); hrms: Calcd. for
C H N O : 437.2525. Found: 437.2545.
H-nmr: δ 1.12 (t, J = 7.1 Hz, 3H, CH Me), 1.7—2.05 (m, 2H),
2
2.54 (s, 3H, NMe), 2.55—3.00 (m, 12H), 3.28 (br., 1H, 3-CH);
22 35
3 6
+
ms: m/z 172 (MH ).
(R)-3-Benzyloxycarbonylamino-1-ethyl-5-methyl-6-oxo-1,5-
octahydrodiazocine (13).
Preparation of the 5-Bromo-2-methoxy-6-methylaminopyridine-
3-carboxamides 2 and 3.
Trifluoroacetic acid (40 ml) was added to a solution of 11 (6.2 g,
14 mmol) in dichloromethane (80 ml) at room temperature. The
mixture was stirred at the same temperature for 3 hours and con-
centrated to dryness. The residue was dissolved in chloroform, and
then the volatiles were completely evaporated to give 8.0 g of (R)-
3-[N-[(2-benzyloxycarbonylamino-3-methylamino)propyl]-N-
ethyl]aminopropionic acid trifluoroacetate (12) as an oil, which
A solution of 5-bromo-2-methoxy-6-methylaminopyridine-3-
carboxylic acid (0.78 g, 3.0 mmol) and N,N'-darbonyldiimidazole
(CDI) (0.5 g, 3.1 mmol) in N,N-dimethylformamide (10 ml) was
stirred at room temperature for 4 hours. After addition of the
amines 6 and 15 (3.1 mmol), the mixture was stirred at the same
temperature for 16 hours. The solvent was evaporated to leave a
residue, which was dissolved in ethyl acetate. The solution was
washed successively with water, 2 N aqueous sodium hydroxide
solution, water, and brine. The solvent was evaporated, and the
residue was chromatographed on silica gel with chloroform to
chloroform + methyl alcohol to give the corresponding pyridine-
3-carboxamides 2 and 3. The oily compound 3 was converted to
the fumarate, which was recrystallized from ethyl alcohol.
1
was used in the next step without further purification; H-nmr
(dimethyl sulfoxide-d ): δ 1.20 (t, J = 7.1 Hz, 3H, CH Me), 2.60 (s,
6
2
3H, NMe), 2.74 (m, 2H), 2.4—2.8 (m, 8H), 4.22 (m, 1H, 2-CH),
5.07 (s, 2H, CH Ph), 7.3—7.5 (m, 5H, arom. H), 7.58 (d, 1H, J =
2
+
9.0 Hz), 8.69 (br. s, 2H); ms: m/z 338 (MH ).
To a mixture of 12 (8.0 g), benzotriazol-1-yloxytris(dimethy-
lamino)phosphonium hexafluorophospate (6.3 g, 14 mmol), and
dichloromethane (300 ml) was added dropwise triethylamine (5.7
g, 56 mmol) at room temperature. The whole was stirred at the
same temperature for 16 hours and washed successively with
water, 2 N aqueous sodium hydroxide solution, and brine. The
solvent was evaporated to leave a residue, which was chro-
matographed on silica gel with chloroform/methyl alcohol = 50/1
to give 4.5 g (99% from 11) of 13 as a white solid. The authentic
(R)-5-Bromo-N-(1-ethyl-3-methylhexahydro-1,3-diazin-5-yl)-2-
methoxy-6-methylaminopyridine-3-carboxamide (2).
1
Compound 2 has mp 131—132 °C (ethyl acetate/hexane); H-
nmr: δ 1.10 (t, J = 7.0 Hz, 3H, CH Me), 2.25 (s, 3H, NMe), 2.3—
2
2.8 (m, 7H), 3.06 (d, J = 5.0 Hz, 3H, NHMe), 3.41 (d, J = 10 Hz,
1H), 4.03 (s, 3H, OMe), 4.28 (m, 1H, 5-CH), 5.26 (d, J = 5.0 Hz,
1H, NHMe), 8.12 (br., 1H, CONH), 8.37 (s, 1H); ms: m/z 386,
sample was obtained by recrystallization from ethyl acetate, mp
1
+
102—104 °C; H-nmr: δ 1.01 (t, J = 7.1 Hz, 3H, CH Me), 2.4—
388 (MH ); ir: 3425, 3296, 2974, 2943, 2783, 1636, 1601, 1454,
2
29
2.8 (m, 8H), 2.94 (s, 3H, NMe), 2.94 (m, 1H), 3.62 (m, 1H), 3.86
1381, 1277, 1221; [α]
= -7.3° (C=1.0, MeOH).
D
(m, 1H), 5.09 (d, J = 12.2 Hz, 1H, PhCH ), 5.12 (d, J = 12.2 Hz,
Anal. Calcd. for C H BrN O : C, 46.64; H, 6.26; Br, 20.68;
2
15 24
5 2
1H, PhCH ), 5.18 (br., 1H, NH), 7.35 (s, 5H, arom. H); ms: m/z
N, 18.13. Found: C, 46.73; H, 6.24; Br, 20.48; N, 18.02.
2
+
29
320 (MH ); ir: 3271, 1707, 1618, 1533, 1248, 1036. [α]
=
D
(R)-5-Bromo-N-(1-ethyl-5-methylhexahydro-1,5-octahydrodia-
zocin-3-yl)-2-methoxy-6-methylaminopyridine-3-carboxamide
3/2Fumarate (3).
–15.5° (c = 1.0, MeOH).
Anal. Calcd. for C H N O : C, 63.93; H, 7.89; N, 13.16.
17 25
3 3
Found: C, 63.82; H, 7.83; N, 13.29.
1
Compound 3 has mp 188—189 °C; H-nmr (dimethylsulfox-
(R)-3-Benzyloxycarbonylamino-1-ethyl-5-methyl-1,5-octahy-
drodiazocine (14).
ide-d ): δ 1.02 (t, J = 7.0 Hz, 3H, CH Me), 1.90 (br., 2H), 2.49 (s,
6
2
3H, NMe), 2.71 (q, J = 7.0 Hz, 2H, CH Me), 2.93 (d, J = 4.6 Hz,
2
To a solution of 13 (1.4 g, 4.4 mmol) in anhydrous tetrahydro-
furan (15 ml) was added lithium aluminum hydride (0.39 g, 10.0
mmol) at 5 °C. The mixture was stirred at the same temperature
for 3 hours and excess lithium aluminum hydride was decom-
posed by addition of saturated aqueous potassium sodium tar-
3H, NHMe), 2.75—3.1 (m, 8H), 4.00 (s, 3H, OMe), 4.08 (m, 1H,
3-CH), 6.54 (s, 3H, fumaric acid), 7.03 (d, J = 4.6 Hz, 1H,
NHMe), 7.92 (d, J = 7.9 Hz, 1H, CONH), 8.08 (s, 1H); ms: m/z
+
414, 416 (MH ); ir: 3383, 2953, 1682, 1599, 1516, 1464, 1383,
29
1279; [α]
= +7.9° (C=1.0, MeOH).
D

Jul-Aug 2002
Synthesis of Optically Active N-(1-Ethyl-3-methylhexahydro-1,3-diazin-5-yl)-
731
34, 1469 (1997); [b] H. Harada and T. Morie, S. Kato, Chem. Pharm.
Anal. Calcd. for C
H BrN O •3/2C H O : C, 46.94; H,
17 28 5 2 4 4 4
Bull., 46, 1160 (1998).
[4] H. Harada, T. Morie, T. Suzuki, T. Yoshida and S. Kato,
Tetrahedron, 54, 10671 (1998).
5.82; Br, 13.58; N, 11.90. Found: C, 46.94; H, 5.90; Br, 13.39; N,
11.83.
[5] M. Fieser and L. Fieser, Reagents for Organic Synthesis,
John Wiley & Sons, Inc, 2, 257 (1969).
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[6a] Y. Hirokawa, T. Horikawa and S. Kato, Chem. Pharm.
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ibid., 49, 1621 (2001).
[7] G. J. Kilpatrick, B. J. Jones and M. B. Tyers, Eur. J.
Pharmacol., 159, 157 (1989).
[1a] S. Kato, I. Fujiwara and N. Yoshida, Med. Res. Rev., 19,
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[2] Y. Hirokawa, T. Horikawa, H. Noguchi, K. Yamamoto,
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[3a] S. Kato, H. Harada and T. Morie, J. Heterocyclic Chem.,