Amide-based atropisomers in tachykinin NK1-receptor antagonists: Synthesis and antagonistic activity of axially chiral N-benzylcarboxamide derivatives of 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one

Article abstract of DOI:10.1016/j.tet.2004.01.097

A series of novel N-benzylcarboxamide derivatives of bicyclic compounds, 3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one and 2,3,4,5-tetrahydro-6H- pyrido[2,3-b][1,5]oxazocin-6-one, were synthesized by cyclization of N-benzyl-2-chloro-N-(2-hydroxyethyl)-

Full text of DOI:10.1016/j.tet.2004.01.097

Tetrahedron 60 (2004) 4481–4490
Amide-based atropisomers in tachykinin NK1-receptor
antagonists: synthesis and antagonistic activity of axially chiral
N-benzylcarboxamide derivatives of 2,3,4,5-tetrahydro-6H-
pyrido[2,3-b][1,5]oxazocin-6-one
Yuji Ishichi,a Yoshinori Ikeuraa and Hideaki Natsugarib
,
*
aPharmaceutical Research Division, Takeda Chemical Industries, Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
bGraduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received 17 October 2003; revised 22 December 2003; accepted 5 January 2004
Abstract—A series of novel N-benzylcarboxamide derivatives of bicyclic compounds, 3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one
and 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one, were synthesized by cyclization of N-benzyl-2-chloro-N-(2-hydroxyethyl)-
[and -(3-hydroxypropyl)-] nicotinamides, respectively. Atropisomerism was observed in 5-[3,5-bis(trifluoromethyl)benzyl]-7-phenyl-
2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-ones due to steric hindrance of the carboxamide moiety and restriction of its rotation.
Cyclization of N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-[(2S)-3-hydroxy-2-methylpropyl]-5-methyl-4-phenylnicotinamide gave (3S)-
5-[3,5-bis(trifluoromethyl)benzyl]-3,8-dimethyl-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3b][1,5]oxazocin-6-one, which exists predomi-
nantly in the thermodynamically stable aR-conformer in CDCl3. This compound showed excellent NK1-antagonistic activity with IC50 value
(in vitro inhibition of [125I]-Bolton–Hunter-substance P binding in human IM-9 cells) of 0.47 nM, which is ca. 200-fold more potent than that
of its enantiomer, indicating that the atropisomer chirality affects NK1-receptor recognition.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
being more active (i.e., eutomer) [IC50, nM: aR, 0.24; aS,
1.4] (Scheme 1).2
In our previous papers,1–4 we described the synthesis of the
axially chiral 1,7-naphthyridine-6-carboxamide derivatives,
represented by 1 (Scheme 1)1,2 and TAK-637 (Scheme 2),3,4
as orally active tachykinin NK1-receptor antagonists.
Because the carboxamide moiety of these compounds exists
at the sterically hindered position, rotation around the
–C(6)[or (5a)]–C(vO)– bond is restricted, yielding separable
and stable atropisomers.
TAK-637 [(aR,9R)-3], which is an 8-membered cyclic
analogue of 1 with aR stereochemistry, was formed
atropodiastereoselectively by cyclization of the chiral (R)
methyl intermediate R-2 in preference to the aS-isomer
[(aS,9R)-3] in a ratio of ca. 98:2. The diastereomerically
pure aR-form (TAK-637) was obtained by a single
recrystallization of the crude product, and the minor
aS-isomer was isolated from the mother liquor by repeated
preparative HPLC (Scheme 2).
Compound 1, which has a trans-amide form,5 was separated
into aR- and aS-atropisomers by preparative high-perform-
ance liquid chromatography (HPLC) using a chiral column.
They have significant stability in solution, e.g., they were
not interconverted in dimethyl sulfoxide (DMSO) at 37 8C
for 16 h and underwent racemization only after storage at
50 8C for 6 days. The enantiomeric atropisomers differed in
activity at the tachykinin NK1-receptor, with aR isomer
The aR stereochemistry of TAK-637 was determined by
single-crystal X-ray structural analysis,3,4 which also
revealed the trans-conformation of the amide bond and a
stacking conformation between the C(5)-phenyl and the N(7)
-
benzylic phenyl groups. The relative spatial orientation of
the C(9)-methyl group and the N-benzyl group in TAK-637
(aR,9R) is important for high atropodiastereoselectivity;
these two groups are disposed in opposite directions, both in
the crystalline form (as observed in the X-ray analysis) and
Keywords: Atropisomer; Stereoselective synthesis; Tachykinin NK1
Pyrido[2,3-
antagonist;
b][1,5]oxazocin-6-one.
Pyrido[3,2-f][1,4]oxazepin-5(2H)-one;
in solution (i.e., the NOE was observed between the C(9)
-
proton and a benzylic methylene proton by NMR spectro-
scopic studies), whereas the same groups in the minor
*
Corresponding author. Tel./fax: þ81-3-5841-4775;
e-mail address: natsu@mol.f.u-tokyo.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.097

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Y. Ishichi et al. / Tetrahedron 60 (2004) 4481–4490
Scheme 1. Atropisomers of 1.
Scheme 2. Atropodiastereoselective formation of 3 from the chiral intermediates (R-2 and S-2).
isomer [(aS,9R)-3] are shown to be disposed in the same
orientation in solution as observed by the NOE between the
C(9)-methyl protons and a benzylic methylene proton.4 The
repulsion of these groups in (aS,9R)-3 may cause steric
instability, leading to the preferential formation of the
thermodynamically stable atropisomer (aR,9R)-3 in the
cyclization of the chiral intermediate R-2. The enantiomers
[(aS,9S)-3 and (aR,9S)-3] were similarly obtained starting
from the enantiomeric S-methyl intermediate (S-2).
dihydropyrido[3,2-f][1,4] oxazepin-5(2H)-one (4), 2,3,4,5-
tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one (5) and its
chiral derivatives (6) using the chemistry developed in our
previous studies. Those NK1-antagonistic activities are also
examined to obtain more simplified, bicyclic analogues of
TAK-637.
2. Synthetic chemistry
The NK1-antagonistic activity of these stereoisomers [IC50,
nM: (aR,9R)-3, 0.45; (aS,9R)-3, 20; (aS,9S)-3, 340; (aR,9S)-
3, 8.6] and X-ray analysis of (aR,9R)-3 indicate that the
pharmacophore of this class antagonists is A (Fig. 1), in
which the aR stereochemistry and the stacking confor-
mation between the two phenyl groups are important for
NK1-receptor binding.4
The synthesis of bicyclic compounds (4–6) is outlined in
Schemes 3 and 4. Key components are 2-chloro-4-phenyl-3-
pyridine carboxylic acids (11a–c), which were prepared
according to a procedure similar to that previously
reported.6 Thus, commercially available acetophenones
(7a and 7b) were condensed with ethyl cyanoacetate,
followed by reaction with dimethylformamide dimethyl
acetals to afford the enamines (9a–c). Formation of the
pyridine ring was achieved by reacting the enamines with
anhydrous hydrogen chloride to afford ethyl 2-chloro-4-
phenylpyridine-3-carboxylates (10a–c), which were hydro-
lyzed to give acids (11a–c). Other components (Schemes 3),
N-3,5-bis(trifluoromethyl) benzylamino-alkanols (15i–iv),
were prepared from 3,5-bis(trifluoromethyl) benzyl alcohol
(12) by mesylation, followed by displacement with amino-
alkanols (14i–iv).7Amidation of pyridine carboxylic acids
(11a–c) (via the acid chloride) with N-benzylamino-alkanols
(15i–iv) followed by intramolecular cyclization using sodium
hydride in tetrahydrofuran (THF) under reflux afforded the
desired 7- and 8-membered cyclic compounds (4–6). The
stereochemical features of the bicyclic compounds are
described in Section 4.
In this paper, we describe the amide-based atropisomerism
in the N-benzylcarboxamide derivatives of bicyclic 3,4-
Figure 1. Pharmacophore structure (A) required for NK1-receptor
recognition.

Y. Ishichi et al. / Tetrahedron 60 (2004) 4481–4490
4483
Scheme 3. Preparation of 2-chloro-3-phenyl-2-carboxylic acids 11a–c. Reagents: (a) NCCH2CO2Et, AcONa/AcOH/PhH (azeotropic); (b) for 9a and 9b:
Me2NCH(OMe)2, rt, for 9c: Me2NCMe(OMe)2, rt; (c) 4 N-HCL in AcOEt; (d) 4 N-NaOH(aq)/EtOH.
3. Biology
synthesized (Scheme 5), and those structures were analyzed
1
by H NMR spectroscopy since the pattern of N-benzylic
The compounds prepared were evaluated in vitro for
inhibition of [125I]-Bolton–Hunter (BH)-substance P bind-
ing in human IM-9 cells.1,8
methylene protons in the NMR spectrum is diagnostic for
the detection of the atropisomers. In compounds with a
7-membered ring (4a–c), the methylene protons appeared as
a singlet,9 whereas those of the compounds with an
8-membered ring (5a–c) appeared as an AB pattern
(J¼15.2–15.6 Hz) (Table 1). These data indicate that the
conformers (atropisomers) of 4 are rapidly interconverted9
even on the NMR timescale at room temperature, whereas
those of 5 are slowly interconverted, with the methylene
protons being diastereotopic.2,4 Thus, although the separ-
ation of the atropisomers of 5 has not been attempted, we
presume that compounds 5 exist as racemates.
4. Results and discussion
4.1. Atropisomerism
Since the carboxamide moiety of the compounds 4–6 exists
at a sterically hindered position, the presence of stable
atropisomers (aR- and aS-forms) was anticipated, as was
observed in 1 and TAK-637. First, the N-benzylcarbox-
amide derivatives of bicyclic 3,4-dihydropyrido[3,2-
f][1,4]oxazepin-5(2H)-one (4) and 2,3,4,5-tetrahydro-6H-
pyrido[2,3-b][1,5]oxazocin-6-one (5), which do not have a
methyl substituent on the 7- and 8-membered ring, were
Based on these data, we next synthesized the N-benzylcar-
boxamide derivatives of 7-phenyl-2,3,4,5-tetrahydro-6H-
pyrido[2,3-b][1,5]oxazocin-6-one (6), which bear a chiral
methyl group on the 8-membered ring, expecting the
Scheme 4. Preparation of bicyclic compounds. Reagents: (a) MsCl, Et3N/THF; (b) 14i–iv, THF; (c) acid chlorides of 11a or 11b, Et3N/THF; (d) NaH, THF,
reflux, 2 h; (e) for specification of the reside X in 4–6 including stereochemistry originating from atropisomerism, see Schemes 5 and 6.

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Y. Ishichi et al. / Tetrahedron 60 (2004) 4481–4490
Scheme 5. Cyclization of the intermediates (16 and 17) and interconversion between aR- and aS-isomers in the products (4 and 5).
enantioselective formation of the axial chirality induced by
the chirality at C(3), as was observed in the synthesis of
TAK-637 (Scheme 6).
The stereochemistry was deduced by detailed NMR
spectroscopic analysis in CDCl3 using (3S)-6b: the signals
of the major isomer were in good agreement with those of
TAK-637,4 revealing (aR,3S)10 stereochemistry [i.e., the
NOE observed between the C(3)-proton (H-3) and a benzylic
methylene proton (H-10a) (Fig. 2) indicates that the axial
chirality is aR, and the chemical shifts and coupling
constants of the 8-membered ring protons (–C(3)HMe–
Heating a THF solution of the chiral intermediates with the
S-methyl group (18Sa and 18Sb) under reflux for 2 h in the
presence of sodium hydride gave the cyclized compounds
(3S)-6a10 and (3S)-6b10 as colorless crystalline substances,
respectively. Similarly, the enantiomeric intermediates with
the R-methyl group, 18Ra and 18Rb, afforded (3R)-6a and
(3R)-6b, respectively, in satisfactory yields (Table 2,
Scheme 6).
C(4)H2–) together with long range coupling between a C(4)
-
proton (H-4b) and a benzylic methylene proton (H-10b)
(J¼1.4 Hz) also support the (aR,3S) structure]. On the other
hand, the signals of the minor isomer (see Section 6)
correspond well to those of the minor aS-isomer of TAK-
637, indicating that the minor peaks observed in the NMR
spectrum are those of the (aS,3S)-isomer.
1
The H NMR spectra (in CDCl3) revealed that all of these
compounds showed signals due to two diastereomers in a
ratio of ca. 98:211 as determined by the peak area of the
methyl group(s) at C(3) [for (3S)-6b; d, major 0.83 (d,
J¼6.6 Hz) and minor 1.31 (d, J¼7.3 Hz)] and/or C(8) [for
(3S)-6b; d, major 2.07 (s) and minor 1.98 (s)]. The ratio
(ca. 98:2) was not altered by repeated crystallization of
(3S)-6b or by heating (3S)-6b in toluene under reflux for
2 h. From these data, we assumed that (3S)-6b is a single
isomer in the solid state and exists as two conformers in
solution.12
In the NOESY spectrum of (3S)-6b, intersite exchange
peaks were observed between the two isomers at the
positions of CH3-3, CH3-8, H-4b, H-2a and H-2b,
demonstrating that these isomers are interconverted in
solution.13
Taking all this evidence into consideration, the structure of
(3S)-6b could reasonably be explained as (aR,3S) in the
Table 1. Physicochemical properties and NK1-antagonistic activity of 3,4-dihydrophyrido[3,2-f][1,4]oxazepin-5(2H)-ones (4a–c) and 2,3,4,5-tetrahydro-6H-
pyrido[2,3-b][1,5]oxazocin-6-ones (5a–c)
Compound no.
R1
R2
n
Yield (%)
Mp (8C)
1H NMRa ppm, d (Hz) (–CHaHb–)
NK1-antagonistic
activityb IC50 (nM)
4a
4b
4c
5a
5b
5c
H
Me
H
H
Me
H
H
H
Me
H
H
Me
1
1
1
2
2
2
86
80
83
82
64
77
200–201
179–181
151–153
188–189
180–182
164–165
4.88 (2H, s)
4.80 (2H, s)
4.87 (2H, s)
4.17, 5.50 (each 1H, d, J¼15.2 Hz)
4.05, 5.45 (each 1H, d, J¼15.6 Hz)
4.14, 5.49 (each 1H, d, J¼15.2 Hz)
4.3
1.1
3.3
7.1
1.6
2.5
TAK-637 showed IC50 value of 0.45 nM in this assay.
a
In CDCl3: s¼singlet, d¼doublet.
b
lnhibition of [125I]-BH-SP binding in human 1M-9 cells (lymphoblast cells).

Y. Ishichi et al. / Tetrahedron 60 (2004) 4481–4490
4485
Scheme 6. Cyclization of the intermediates with S-Me and R-Me (18S and 18R).
Table 2. Physicochemical properties and NK1-antagonistic activity of chiral 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-ones (6)
Compound no.
R1
Chirality
Yield
(%)
Mp
(8C)
[a]D
(in CHCl3)
1H NMRa ppm,d
NK1-antagonistic
activitya IC50 (nM)
(Hz) (–CHaHb–)b
At C(3)
At axial
( p )c
(3S)-6a
(3S)-6b
(3R)-6c
(3R)-6b
H
Me
H
S
S
R
R
R
R
S
82
65
74
68
142–143
147–148
142–143
147–149
275.1
2106.8
þ75.2
4.19, 5.49 (each 1H, d, J¼15.6 Hz)
4.06, 5.44 (each 1H, d, J¼15.3 Hz)
4.19, 5.49 (each 1H, d, J¼15.6 Hz)
4.06, 5.44
1.4
0.47
69
Me
S
þ102.5
96
a
See corresponding footnotes of Table 1.
The peaks for the major atropisomer are described.
ln solution (CDCl3), ca. 2% of the atropisomer exists as determined by 1H NMR.
b
c
solid state, and to be in an equilibrium state between the
(aR,3S)- and (aS,3S)-isomers in a ratio of ca. 98:2 in
solution,11 which may result from the low free energy of
activation.
7- or 8-position (4b and 5b) showed improved affinity
compared with compounds without a methyl group (4a, 4c,
5a and 5c), which presumably reflects the stacking
conformation desirable for receptor recognition, i.e., the
methyl group in 4b and 5b constricts the two phenyl rings so
as to take that conformation, as shown in Figure 3.14
The predominantly formed (aR,3S) structure determined for
(3S)-6b is also established for (3S)-6a. Consequently, the
enantiomers (3R)-6a and (3R)-6b should have an (aS,3R)
stereochemistry. The conformational preference at the axial
chirality is well explained by the thermodynamically stable
conformation in these isomers, i.e., the C(3)-methyl group
and the N-[3,5-bis(trifluoromethyl)-benzyl] group are dis-
posed in opposite direction as observed in TAK-637 (see
Fig. 2).
4.2. NK1-Antagonistic activity
The NK1-antagonistic activity of the bicyclic compounds
without a methyl substituent on the 7- and 8-membered ring
(4a–c and 5a–c) are shown in Table 1. The in vitro potency
is similar for both series of compounds. It is noteworthy that
the compounds with a methyl group on the benzene ring at
Figure 2. NOE correlation in (aR,3S)-6b.

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Y. Ishichi et al. / Tetrahedron 60 (2004) 4481–4490
6.1.1. Ethyl 2-cyano-3-phenylbut-2-enoate (8a). This
compound was prepared according to the published
method.6
6.1.2. Ethyl 2-cyano-3-phenylpent-2-enoate (8b).
A
mixture of 7b (33.6 g, 250 mmol), ethyl cyanoacetate
(28.3 g, 250 mmol), ammonium acetate (3.85 g, 50 mmol),
acetic acid (12 g), and benzene (50 mL) was refluxed for
10 h, while water was removed azeotropically using Dean–
Stark apparatus. After evaporation of the solvent, Et2O
(100 mL) was added to the residue. The mixture was washed
with H2O, 0.5 N HCl, H2O, saturated aqueous NaHCO3,
H2O, and brine successively. The organic layer was dried
and concentrated. The residue was distilled under reduced
pressure (3 mm Hg, 160 8C) to afford 8b as a pale yellow oil
Figure 3. Stacking conformation in 4b and 5b (right) caused by the 7- or
8-methyl group.
1
(37.0 g, 65%): H NMR 1.00–1.15 (3Hþ3H£1/2, m), 1.38
(3H£1/2, t, J¼7.2 Hz), 2.87 (2H£1/2, q, J¼7.6 Hz), 3.11
(2H£1/2, q, J¼7.4 Hz), 4.08 (2H£1/2, q, J¼7.4 Hz), 4.35
(2H£1/2, q, J¼7.2 Hz), 7.05–7.20 (1H, m), 7.30–7.55
(4H, m).
Table 2 shows the NK1-antagonistic activity of the optically
active compounds with an 8-membered ring (6). It was
clearly shown that the enantiomers differ in activity, i.e., the
(3S)-isomers which have a predominantly aR stereochem-
istry showed ca. 50–200-fold higher potency than the (3R)-
enantiomers, indicating that the axial chirality is recognized
by the NK1 receptor. The methyl substituent on the benzene
ring again improved the affinity by ca. 3-fold [(3S)-6a
versus (3S)-6b].13
6.1.3. Ethyl 2-cyano-5-(dimethylamino)-3-phenylpenta-
2,4-dienoate (9a). This compound was prepared according
to the published method.6
6.1.4. Ethyl 2-cyano-5-(dimethylamino)-4-methyl-3-phe-
nylpenta-2,4-dienoate (9b). N,N-Dimethylformamide
dimethyl acetal (9.40 mL, 70.2 mmol) was added dropwise
to 8a (13.4 g, 58.4 mmol) at 0 8C. After stirring at room
temperature for 2 h, the mixture was concentrated under
reduced pressure to afford 9b as a red oil (16.0 g, 96%). The
oil was used for next reaction without preparation and
further purification.
5. Conclusion
This study demonstrated that cyclization of the chiral
intermediates (18S and18R) gave thermodynamically stable
conformers at the amide-based axial bond, the chirality of
which was induced by the C(3) chirality. As observed in 1,7-
naphthyridine-6-carboxamide derivatives (TAK-637 and 1),
in these compounds the aR axial chirality and the stacking
conformation of the two phenyl rings are also important for
NK1-receptor recognition. Synthesis of NK1 antagonists
having other heterocycles based on the chemistry described
in this study will be the subject of the forthcoming paper.
6.1.5. Ethyl 2-cyano-5-(dimethylamino)-3-phenylhexa-
2,4-dienoate (9c). N,N-Dimetylacetamide dimethyl acetal
(containing 5–10% MeOH) (26.7 g, 180 mmol) was added
dropwise to 8a (30.0 g, 131 mmol) at 0 8C. After stirring at
room temperature for 2 h, the mixture was concentrated
under reduced pressure. The resulting solid was washed
with Et2O–AcOEt (1:1) to afford 9c as yellow crystals
1
(23.3 g, 63%); H NMR 1.12 (3H£1/5, t, J¼7.0 Hz), 1.33
(3H£4/5, t, J¼7.0 Hz), 1.39 (3H£4/5, s), 1.51 (3H£1/5, s),
3.12 (6H£1/5, s), 3.15 (6H£4/5, s), 4.00 (2H£1/5, q,
J¼7.0 Hz), 4.25 (2H£4/5, q, J¼7.0 Hz), 5.78 (1H£1/5, s),
7.12 (1H£4/5, s), 7.15–7.48 (5H, m).
6. Experimental
6.1. Chemistry
6.1.6. Ethyl 2-chloro-4-phenylnicotinate (10a). This
compound was prepared according to the published
method.6
Melting points were determined on a Yanagimoto micro
1
melting point apparatus and were uncorrected. H NMR
6.1.7. Ethyl 2-chloro-5-methyl-4-phenylnicotinate (10b).
A solution of 4 N HCl in AcOEt (150 mL) was added to 9b
(17.9 g, 62.9 mmol), and the mixture was stirred at room
temperature for 30 h. After evaporation of the solvent,
AcOEt was added to the residue. The mixture was washed
successively with H2O, 1 N HCl, H2O, saturated aqueous
NaHCO3, H2O, and brine. The organic layer was dried and
concentrated. The residue was subjected to chromatography
on silica gel using hexane–AcOEt (4:1) as eluant to afford
10b as colorless oil (8.23 g, 47%). Recrystallization from
spectra were taken on Varian Gemini 200 (200 MHz)
spectrometer in CDCl3 unless otherwise noted. Chemical
shifts were given in ppm with tetramethylsilane as the
internal standard and coupling constants (J) are given in
hertz (Hz). The following abbreviations are used: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad.
Mass spectra were obtained on a JEOL JMS-AX505W
spectrometer. Optical rotations were determined with a
JASCO DIP-370 digital polarimeter. Elemental analyses
were carried out by Takeda Analytical Laboratories, Ltd.
Extracted solutions were dried over anhydrous MgSO4 or
anhydrous Na2SO4. The yields reported are not optimized.
1
AcOEt–hexane gave colorless crystals: mp 89–908C; H
NMR 0.98 (3H, t, J¼7.2 Hz), 2.11 (3H, s), 4.06 (2H, q,

Y. Ishichi et al. / Tetrahedron 60 (2004) 4481–4490
4487
J¼7.2 Hz), 7.15–7.30 (2H, m), 7.37–7.50 (3H, m), 8.33
s), 7.82 (2H, s). Anal. Calcd C11H11F6NO: C, 46.00; H,
3.86; N, 4.88. Found: C, 46.01; H, 3.86; N, 4.89.
(1H, s).
6.1.8. Ethyl 2-chloro-6-methyl-4-phenylnicotinate (10c).
Compound 9c (6.61 g, 81.9 mmol) was treated according to
a procedure similar to that described for the preparation of
Similarly, compounds 15ii–iv were prepared from 13 and
the corresponding amino-alkanols 14ii–iv.
1
10b to afford 10c as a pale yellow oil (15.4 g, 68%); H
NMR 1.08 (3H, t, J¼7.0 Hz), 2.60 (3H, s), 4.18 (2H, q,
6.1.14. 3-{[3,5-Bis(trifluoromethyl)benzyl]amino}pro-
pan-1-ol (15ii). From 13 (6.65 g, 20.6 mmol) and 3-amino-
propanol 14ii (15.7 mL, 205 mmol). Colorless crystals
(4.10 g, 66%). Recrystallization from Et2O–hexane gave
colorless crystals: mp 57–58 8C; 1H NMR 1.77 (2H, quintet,
J¼5.8 Hz), 2.20–2.80 (2H, br), 2.89 (2H, t, J¼5.8 Hz), 3.82
(2H, t, J¼5.8 Hz), 3.93 (2H, s), 7.89 (3H, s). Anal. Calcd
C12H13F6NO: C, 47.85; H, 4.35; N, 4.65. Found: C, 47.76;
H, 4.32; N, 4.65.
J¼7.0 Hz), 7.13 (1H, s), 7.30–7.50 (5H, m).
6.1.9. 2-Chloro-4-phenylnicotinic acid (11a). This com-
pound was prepared according to the published method.6
6.1.10. 2-Chloro-5-methyl-4-phenylnicotinic acid (11b).
A mixture of 10b (8.20 g, 29.7 mmol), EtOH (10 mL) and
4 N aqueous NaOH solution (10 mL) was refluxed for 4 h,
and then concentrated under reduced pressure. The residue
was acidified with concentrated HCl, and the mixture was
extracted with AcOEt. The extract was washed with brine,
dried and evaporated to afford 11b as colorless crystals
(5.97 g, 81%). Recrystallization from AcOEt–isopropyl
ether (IPE) gave colorless crystals: mp 204–206 8C; 1H
NMR 2.18 (3H, s), 7.15–7.30 (2H, m), 7.37–7.60 (3H, m),
8.33 (1H, s). Anal. Calcd C13H10ClNO2: C, 63.04; H, 4.07;
N, 5.66. Found: C, 63.02; H, 4.09; N, 5.69.
6.1.15. (2S)-3-{[3,5-Bis(trifluoromethyl)benzyl]amino}-
2-methylpropan-1-ol (15iii). From 13 (1.20 g, 3.72
mmol) and (2S)-3-amino-2-methylpropan-1-ol 14iii7
1
(500 mg, 5.61 mmol). A colorless oil (635 mg, 56%); H
NMR 0.86 (3H, d, J¼6.8 Hz), 1.98 (1H, m), 2.63 (1H, dd,
J¼11.8, 9.4 Hz), 2.70–2.90 (2H, m), 2.86 (1H, ddd, J¼11.8,
4.0, 1.4 Hz), 3.56 (1H, dd, J¼10.6, 9.4 Hz), 3.71 (1H, ddd,
J¼10.6, 4.0, 1.4 Hz), 3.87 (1H, d, J¼13.8 Hz), 3.98 (1H, d,
J¼13.8 Hz), 7.79 (3H, s).
6.1.11. 2-Chloro-6-methyl-4-phenylnicotinic acid (11c).
Compound 10c (6.60 g, 25.2 mmol) was treated according
to a procedure similar to that described for the prepa-
ration of 11b to afford 11c as colorless crystals (4.70 g,
80%). Recrystallization from AcOEt–IPE gave colorless
6.1.16. (2R)-3-{[3,5-Bis(trifluoromethyl)benzyl]amino}-
2-methylpropan-1-ol (15iv). From 13 (2.40 g, 7.45
mmol) and (2R)-3-amino-2-methylpropan-1-ol 14iv7
(1.00 g, 11.2 mmol). A colorless oil (1.10 g, 47%); 1H
NMR spectrum was identical with that of 15iii.
1
crystals: mp 191–194 8C; H NMR 2.59 (3H, s), 7.16 (1H,
s), 7.45 (5H, s), 9.53 (1H, br.s). Anal. Calcd C13H10ClNO2:
C, 63.04; H, 4.07; N, 5.66. Found: C, 63.06; H, 4.06;
N, 5.65.
6.1.17. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
(2-hydroxyalkyl)-4-phenylnicotinamides (16, 17, 18S and
18R). A typical procedure is described for N-[3,5-bis(trifluor-
omethyl)benzyl]-2-chloro-N-(2-hydroxyethyl)-4-phenylnico-
tinamide 16a: Thionyl chloride (0.70 mL, 9.6 mmol) was
added dropwise to a solution of 11a (318 mg, 1.36 mmol) and
DMF (catalytic amount) in THF (10 mL), and the mixture was
refluxed for 4 h. The mixture was concentrated, and dissolved
in THF (5 mL). The solution was added dropwise to a mixture
of 15i (391 mg, 1.36 mmol), triethylamine (0.57 mL,
4.1 mmol) and THF (5 mL) at 0 8C. After stirring at room
temperaturefor 2 h,themixturewasconcentrated. Theresidue
was diluted with AcOEt, and washed with H2O and brine. The
organic layer was dried and concentrated. The residue was
subjected to chromatography on silica gel using hexane–
AcOEt (1:1) as eluant to give 16a as a colorless oil (551 mg,
81%, the ratio of cis–trans amide isomer: ca. 2:1); 1H NMR
2.00–2.40 (1H, m), 2.82–3.92 (4H, m), 4.16 (1H£1/3, d,
J¼16.0 Hz), 4.41 (1H£1/3, d, J¼16.0 Hz), 4.73 (1H£2/3, d,
J¼15.0 Hz), 4.87 (1H£2/3, d, J¼15.0 Hz), 7.20–8.85 (9H,
m), 8.43 (1H, m).
6.1.12. 3,5-Bis(trifluoromethyl)benzyl methanesulfonate
(13). Methanesulfonyl chloride (1.74 mL, 22.5 mmol) was
added dropwise to a solution of 3,5-bis(trifluoromethyl)-
benzyl alcohol 12 (5.00 g, 20.5 mmol) and triethylamine
(3.14 mL, 22.5 mmol) in THF (50 mL) at 08C. After stirring
at room temperature for 30 min, the mixture was concen-
trated. The residue was diluted with AcOEt (50 mL) and
washed with brine. The organic layer was dried and
concentrated to afford 13 as colorless crystals (6.28 g,
95%). Recrystallization from AcOEt–IPE gave colorless
1
crystals: mp 61–628C; H NMR 3.09 (3H, s), 5.33 (2H, s),
7.87 (2H, s), 7.91 (1H, s). Anal. Calcd C10H8F6O3S: C,
37.27; H, 2.50. Found: C, 37.25; H, 2.72.
6.1.13. 2-{[3,5-Bis(trifluoromethyl)benzyl]amino}alka-
nols (15i–iv). A typical procedure is described for
2-{[3,5-bis(trifluoromethyl)benzyl]amino}ethanol 15i: A
solution of 13 (1.89 g, 5.86 mmol) in THF (10 mL) was
added dropwise to a solution of 2-aminoethanol 14i
(3.6 mL, 59.6 mmol) in THF (30 mL) at 0 8C. After stirring
at room temperature for 1 h, the mixture was concentrated.
The residue was diluted with AcOEt (50 mL), and washed
with H2O and brine. The organic layer was dried and
concentrated to give 15i as colorless crystals (1.38 g, 82%).
Recrystallization from EtOH–Et2O gave colorless crystals:
mp 107–1088C; 1H NMR 1.38 (2H, s), 2.83 (2H, t,
J¼5.4 Hz), 3.72 (2H, t, J¼5.4 Hz), 3.96 (2H, s), 7.78 (1H,
Similarly, compounds 16b,c, 17a–c, 18Sa,b and 18Ra,b
were prepared from corresponding 3-pyridine carboxylic
acids 11a–c and 2-{[3,5-bis(trifluoromethyl)benzyl]ami-
no}alkanols 15i–iv.
6.1.18. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
(2-hydroxyethyl)-5-methyl-4-phenylnicotinamide (16b).
From 11b (300 mg, 1.21 mmol) and 15i (430 mg, 1.33
mmol). Colorless crystals (435 mg, 70%). Recrystallization

4488
Y. Ishichi et al. / Tetrahedron 60 (2004) 4481–4490
from AcOEt–IPE gave colorless crystals: mp 146–148 8C;
1H NMR 1.60–1.70 (1H, m), 2.09 (3H, s), 3.02 (1H, dt,
J¼15.0, 5.6 Hz), 3.25 (1H, dt, J¼15.0, 5.6 Hz), 3.60 (2H,
m), 4.57 (1H, d, J¼15.2 Hz), 4.79 (1H, d, J¼15.2 Hz),
7.05–7.50 (5H, m), 7.62 (2H, s), 7.76 (1H, s), 8.33 (1H, s).
Anal. Calcd C24H19ClF6N2O2: C, 55.77; H, 3.71; N, 5.42.
Found: C, 55.79; H, 3.73; N, 5.41.
6.1.24. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
[(2S)-3-hydroxy-2-methylpropyl]-5-methyl-4-phenylni-
cotinamide (18Sb). From 11b (513 mg, 2.07 mmol) and
15iii (653 mg, 2.07 mmol). A colorless oil (1.06 g, 94%); 1H
NMR 0.60–0.82 (3H, m), 1.50–2.00 (2H, m), 2.00–2.15
(3H, m), 2.15–3.92 (4H, m), 4.05–4.92 (2H, m), 7.00–7.85
(8H, m), 8.34 (1H, m).
6.1.19. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
(2-hydroxyethyl)-6-methyl-4-phenylnicotinamide (16c).
From 11c (2.00 g, 8.07 mmol) and 15i (2.86 g,
8.88 mmol). A colorless oil (4.07 g, 98%); the ratio of
6.1.25. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
[(2R)-3-hydroxy-2-methylpropyl]-4-phenylnicotinamide
(18Ra). From 11a (1.14 g, 4.88 mmol) and 15iv (1.84 g,
5.83 mmol). A colorless oil (2.14 g, 85%, the ratio of cis–
trans amide isomer: ca. 1:1); 1H NMR spectrum was
identical with that of 18Sa.
1
cis–trans amide isomer, ca. 3:2; H NMR 1.95–3.80 (5H,
m), 2.58 (3H, s), 4.15 (1H£2/5, d, J¼16.2 Hz), 4.41 (1H£2/
5, d, J¼16.2 Hz), 4.75 (1H£3/5, d, J¼15.0 Hz), 4.85
(1H£3/5, d, J¼15.0 Hz), 7.15 (1H£3/5, s), 7.17 (1H£2/5,
d, J¼15.0 Hz), 7.23–7.58 (5H, m), 7.74 (2H, s), 7.78 (1H, s).
6.1.26. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
[(2R)-3-hydroxy-2-methylpropyl]-5-methyl-4-phenylni-
cotinamide (18Rb). From 11b (824 mg, 3.49 mmol) and
15iv (1.10 g, 3.49 mmol). A colorless oil (1.73 g, 100%.);
1H NMR spectrum was identical with that of 18Sb.
6.1.20. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
(3-hydroxypropyl)-4-phenylnicotinamide (17a). From
11a (830 mg, 3.55 mmol) and 15ii (1.07 g, 3.55 mmol).
Colorless crystals (1.55 g, 84%, the ratio of cis–trans amide
isomer: ca. 3:1). Recrystallization from AcOEt–IPE gave
colorless crystals: mp 121–122 8C; 1H NMR 1.00–1.70
(2H, m), 2.75–3.20 (2H, m), 3.35–3.55 (3H, m), 4.06
(1H£1/4, d, J¼16.2 Hz), 4.31 (1H£1/4, d, J¼16.2 Hz), 4.65
(1H£3/4, d, J¼15.2 Hz), 4.76 (1H£3/4, d, J¼15.2 Hz),
7.20–7.55 (6H, m), 7.72 (2H, s), 7.80 (1H, s), 8.47 (1H, d,
J¼5.2 Hz). Anal. Calcd C24H19ClF6N2O2: C, 55.77; H,
3.71; N, 5.42. Found: C, 55.65; H, 3.70; N, 5.57.
6.1.27. 4-[3,5-Bis(trifluoromethyl)benzyl]-6-phenyl-3,4-
dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-ones (4a–c)
and 5-[3,5-bis(trifluoromethyl)benzyl]-7-phenyl-2,3,4,5-
tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-ones (5a–c).
A typical procedure is described for 4-[3,5-bis(trifluoro-
methyl)benzyl]-6-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxa-
zepin-5(2H)-one 4a: NaH (60% in oil) (60 mg, 1.5 mmol)
was added to a solution of 16a (348 mg, 0.69 mmol) in THF
(15 mL), and the mixture was refluxed for 2 h. The reaction
mixture was cooled to room temperature and diluted with
AcOEt, washed successively with 1 N HCl, H2O, saturated
aqueous NaHCO3, and brine. The organic layer was dried
and concentrated to afford 4a as colorless crystals (278 mg,
86%). Recrystallization from EtOH–hexane gave colorless
crystals: mp 200–201 8C; 1H NMR 3.70 (2H, t, J¼5.8 Hz),
4.47 (2H, t, J¼5.8 Hz), 4.88 (2H, s), 7.24 (1H, d, J¼5.2 Hz),
7.25–7.55 (5H, m), 7.80 (2H, s), 7.86 (1H, s), 8.44 (1H, d,
J¼5.2 Hz). MS (electron impact) m/z 466 (Mþ)
[(C23H16F6N2O2)þ].
6.1.21. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
(3-hydroxypropyl)-5-methyl-4-phenylnicotinamide
(17b). From 11b (300 mg, 1.21 mmol) and 15ii (400 mg,
1.33 mmol). A colorless oil (626 mg, 97%, the ratio of cis–
1
trans amide isomer: ca. 1:1); H NMR 1.10–1.80 (2H, m),
1.85–2.00 (1H, m), 2.06 (3H£1/2, s), 2.08 (3H£1/2, s),
2.80–3.30 (3H, m), 3.35–3.70 (1H, m), 4.08 (1H£1/2, d,
J¼16.4 Hz), 4.39 (1H£1/2, d, J¼15.0 Hz), 4.47 (1H£1/2, d,
J¼16.4 Hz), 4.70 (1H£1/2, d, J¼15.0 Hz), 6.90–7.62 (7H,
m), 7.72 (1H£1/2, s), 7.77 (1H£1/2, s), 8.28 (1H£1/2, s),
8.31 (1H£1/2, s).
Similarly, 4b, 4c and 5a–c were prepared from 16b, 16c and
17a–c, respectively.
6.1.22. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
(3-hydroxypropyl)-6-methyl-4-phenylnicotinamide
(17c). From 11c (938 mg, 4.02 mmol) and 15ii (1.33 g,
4.42 mmol). A colorless oil (1.95 g, 96%, the ratio of cis–
6.1.28. 4-[3,5-Bis(trifluoromethyl)benzyl]-7-methyl-6-
phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one
(4b). From 16b (100 mg, 0.19 mmol). Colorless crystals
(74 mg, 80%). Recrystallization from AcOEt–IPE gave
1
trans amide isomer: ca. 3:2); H NMR 1.15–1.65 (2H, m),
1
2.59 (3H, s), 2.75–3.20 (2H, m), 3.25–3.55 (3H, m),
4.06 (1H£2/5, d, J¼15.4 Hz), 4.31 (1H£2/5, d, J¼15.4 Hz),
4.65 (1H£3/5, d, J¼15.2 Hz), 4.74 (1H£3/5, d, J¼
15.2 Hz), 7.16 (1H, s), 7.20–7.60 (5H, m), 7.72 (2H, s),
7.78 (1H, s).
colorless crystals: mp 179–181 8C; H NMR 2.13 (3H, s),
3.57 (2H, t, J¼5.8 Hz), 4.42 (2H, t, J¼5.8 Hz), 4.80 (2H, s),
7.16 (2H, m), 7.47 (3H, m), 7.65 (2H, s), 7.81 (1H, s), 8.32
(1H, s).
6.1.29. 4-[3,5-Bis(trifluoromethyl)benzyl]-8-methyl-6-
phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one
(4c). From 16c (2.16 g, 4.18 mmol). Colorless crystals
(1.66 g, 83%). Recrystallization from AcOEt–IPE
gave colorless crystals: mp 151–153 8C; 1H NMR 2.58
(3H, s), 3.69 (2H, t, J¼5.4 Hz), 4.47 (2H, t, J¼5.4 Hz),
4.87 (2H, s), 7.11 (1H, s), 7.17–7.56 (5H, m), 7.80 (2H,
s), 7.86 (1H, s). Anal. Calcd C24H18F6N2O2·1/4H2O:
C, 59.44; H, 3.85; N, 5.78. Found: C, 59.42; H, 3.82; N,
5.84.
6.1.23. N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-
[(2S)-3-hydroxy-2-methylpropyl]-4-phenylnicotinamide
(18Sa). From 11a (850 mg, 3.64 mmol) and 15iii (1.37 g,
4.35 mmol). A colorless oil (1.40 g, 74%, the ratio of cis–
1
trans amide isomer: ca. 1:1); H NMR 0.53 (3H£1/4, d,
J¼7.0 Hz), 0.63 (3H£1/4, d, J¼7.0 Hz), 0.75 (3H£1/4, d,
J¼6.8 Hz), 0.81 (3H£1/4, d, J¼6.8 Hz), 1.50–1.90 (1H, m),
2.42–3.80 (5H, m), 4.00–4.95 (2H, m), 7.10–7.90 (9H, m),
8.42 (1H, m).

Y. Ishichi et al. / Tetrahedron 60 (2004) 4481–4490
4489
6.1.30. 5-[3,5-Bis(trifluoromethyl)benzyl]-7-phenyl-
2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one
(5a). From 17a (1.00 g, 1.93 mmol). Colorless crystals
(763 mg, 82%). Recrystallization from AcOEt–IPE gave
colorless crystals: mp 188–189 8C; 1H NMR 1.65–1.88
(1H, m), 2.18–2.45 (1H, m), 3.36 (1H, dd, J¼15.2, 3.8 Hz),
3.73 (1H, m), 4.17 (1H, d, J¼15.2 Hz), 4.32 (1H, dt,
J¼12.6, 3.6 Hz), 4.67 (1H, ddd, J¼12.6, 5.6, 3.6 Hz), 5.50
(1H, d, J¼15.2 Hz), 7.16 (1H, d, J¼5.2 Hz), 7.20–7.45 (5H,
m), 7.71 (2H, s), 7.83 (1H, s), 8.41 (1H, d, J¼5.2 Hz). Anal.
Calcd C24H18F6N2O2: C, 60.00; H, 3.78; N, 5.83. Found: C,
59.92; H, 3.76; N, 5.89.
Ar), 7.78 (1H, s, Ar), 8.29 (1H, s, H-9); NOEs taken on a
Bruker DPX 300 (300 MHz) spectrometer in CDCl3, were
observed between a benzylic methylene-Ha and H-3, CH3-3
and H-2a, CH3-3 and H-4b, and H-4a and a benzylic
methylene-Ha (Fig. 2); long range couplings between H-4b
and a benzylic methylene-Hb (J¼1.4 Hz), and H-2b and H-
4a (J¼1.0 Hz) were also observed. The minor isomer
assigned as (aS,3S)-6b showed the following peaks in the 1H
NMR spectrum, which are corresponding well to those of
the minor isomer of TAK-637:3,4 1.31 (3H, d, J¼7.3 Hz,
CH3-3), 1.98 (3H, s, CH3-8), 3.35 (1H, dd, J¼15.0, 4.5 Hz,
H-4a), 3.65 (1H, dd, J¼15.0, 6.0 Hz, H-4b), 4.23 (1H, dd,
J¼13.5, 4.5 Hz, H-2b), 4.35 (1H, dd, J¼13.5, 4.5 Hz, H-2a),
8.23 (1H, s, H-9). Other peaks of the minor isomer could not
be assigned because of overlapping with those of the major
isomer. In the NOESY spectrum of (3S)-6b, intersite
exchange peaks were observed between the two isomers at
the positions of CH3-3, CH3-8, H-4b, H-2a and H-2b.
6.1.31. 5-[3,5-Bis(trifluoromethyl)benzyl]-8-methyl-7-
phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazo-
cin-6-one (5b). From 17b (550 mg, 1.03 mmol). Colorless
crystals (324 mg, 64%). Recrystallization from AcOEt–IPE
gave colorless crystals: mp 180–182 8C; 1H NMR 1.71 (1H,
m), 2.07 (3H, m), 2.28 (1H, m), 3.24 (1H, dd, J¼15.2,
3.8 Hz), 3.64 (1H, dd, J¼15.2, 12.0 Hz), 4.05 (1H, d,
J¼15.6 Hz), 4.27 (1H, dt, J¼12.6, 3.8 Hz), 4.63 (1H, ddd,
J¼12.6, 5.4, 2.0 Hz), 5.45 (1H, d, J¼15.6 Hz), 6.6–7.4 (2H,
m), 7.37 (3H, br.s), 7.54 (2H, s), 7.78 (1H, s), 8.29 (1H, s).
Anal. Calcd C25H20F6N2O2: C, 60.73; H, 4.08; N, 5.67.
Found: C, 60.69; H, 4.05; N, 5.63.
6.1.34. (3S)-5-[3,5-Bis(trifluoromethyl)benzyl]-3-methyl-
7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazo-
cin-6-one [(3S)-6a]. Compound 18Sa (1.40 g, 2.63 mmol)
was treated according to a procedure similar to that
described for the preparation of (3S)-6b to afford (3S)-6a
as colorless crystals (1.06 g, 82%). Recrystallization from
AcOEt–IPE gave colorless crystals: mp 142–143 8C;
6.1.32. 5-[3,5-Bis(trifluoromethyl)benzyl]-9-methyl-7-
phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazo-
cin-6-one (5c). From 17c (1.95 g, 3.67 mmol). Colorless
crystals (1.40 g, 77%). Recrystallization from AcOEt–IPE
gave colorless crystals: mp 164–165 8C; 1H NMR 1.79
(1H, m), 2.30 (1H, m), 2.56 (3H, s), 3.35 (1H, m), 3.77
(1H, m), 4.14 (1H, d, J¼15.2 Hz), 4.31 (1H, m), 4.65 (1H,
m), 5.49 (1H, d, J¼15.2 Hz), 7.02 (1H, s), 7.20–7.50 (5H,
m), 7.72 (2H, s), 7.83 (1H, s). Anal. Calcd C25H20F6N2O2:
C, 60.73; H, 4.08; N, 5.67. Found: C, 60.43; H, 4.04; N,
5.74.
[a]2D0¼275.18
(c¼0.381,
CHCl3).
Anal.
Calcd
C25H20F6N2O2: C, 60.73; H, 4.08; N, 5.77. Found: C,
60.60; H, 4.00; N, 5.77; 1H NMR (taken on Varian Mercury
300) [(aR,3S):(aS,3S)¼ca. 98:2]; for (aR,3S), 0.87 (3H, d,
J¼6.9 Hz), 2.45 (1H, m), 3.10 (1H, d, J¼15.3 Hz), 3.58
(1H, dd, J¼15.3, 10.5 Hz), 3.91 (1H, dd, J¼12.7, 10.5 Hz),
4.19 (1H, d, J¼15.6 Hz), 4.63 (1H, dd, J¼12.7, 5.1 Hz),
5.49 (1H, d, J¼15.6 Hz), 7.17 (1H, d, J¼5.0 Hz), 7.20–7.50
(5H, m), 7.71 (2H, s), 7.83 (1H, s), 8.42 (1H, d, J¼5.0 Hz),
and for (aS,3S), following peaks were assigned;1.36 (3H, d,
J¼7.8 Hz, CH3-3), 3.64 (1H, dd, J¼15.0, 6.6 Hz, H-4b),
4.34 (1H, dd, J¼13.5, 4.5 Hz, H-2a), 7.06 (1H, d, J¼5.0 Hz,
H-8), 8.36 (1H, d, J¼5.0 Hz, H-9).
6.1.33. (3S)-5-[3,5-Bis(trifluoromethyl)benzyl]-3,8-
dimethyl-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-
b][1,5]oxazocin-6-one [(3S)-6b]. NaH (60% in oil) (61 mg,
1.53 mmol) was added to a solution of 18Sb (417 mg,
0.76 mmol) in THF (40 mL), and the mixture was refluxed
for 2 h. The reaction mixture was cooled to room
temperature and diluted with AcOEt, washed successively
with 1 N HCl, H2O, saturated aqueous NaHCO3, and brine.
The organic layer was dried and concentrated to afford (3S)-
6b as colorless crystals (251 mg, 65%). Recrystallization
from AcOEt–hexane gave colorless crystals: mp 147–
148 8C; [a]2D0¼2106.88 (c¼0.257, CHCl3). Anal. Calcd
C26H22F6N2O2: C, 61.49; H, 4.36; N, 5.51. Found: C, 61.30;
H, 4.52; N, 5.70. In the 1H NMR spectrum (CDCl3) taken on
Varian Mercury 300 (300 MHz), a set of major and minor
peaks were observed in a ratio of ca. 98:2, which was
calculated from the peak area of CH3-3 and CH3-8. The
major isomer assigned as (aR,3S)-6b showed the following
peaks, which are corresponding well to those of TAK-637:3,
4 0.83 (3H, d, J¼6.6 Hz, CH3-3), 2.07 (3H, s, CH3-8), 2.40
(1H, m, H-3), 2.97 (1H, d, J¼15.5 Hz, H-4a), 3.48 (1H, dd,
J¼15.5, 10.5 Hz, H-4b), 3.87 (1H, dd, J¼12.6, 10.5 Hz,
H-2a), 4.06 (1H, d, J¼15.3 Hz, –CHaHb-Ar), 4.59 (1H, dd,
J¼12.6, 5.1 Hz, H-2b), 5.44 (1H, d, J¼15.3 Hz, –CHaHb-
Ar), 6.6–7.4 (2H, m, Ar), 7.37 (3H, br.s, Ar), 7.53 (2H, s,
6.1.35. (3R)-5-[3,5-Bis(trifluoromethyl)benzyl]-3-
methyl-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-
b][1,5]oxazocin-6-one [(3R)-6a]. Compound 18Ra (2.14 g,
4.14 mmol) was treated according to a procedure similar to
that described for the preparation of (3S)-6b to afford (3R)-
6a as colorless crystals (1.52 g, 74%). Recrystallization
from AcOEt–IPE gave colorless crystals: mp 142–143 8C;
1H NMR spectrum was identical with that of (3S)-6a.
[a]2D0¼þ75.28(c¼0.724,
CHCl3).
Anal.
Calcd
C25H20F6N2O2: C, 60.73; H, 4.08; N, 5.67. Found: C,
60.60; H, 3.86; N, 5.77.
6.1.36. (3R)-5-[3,5-Bis(trifluoromethyl)benzyl]-3,8-
dimethyl-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-
b][1,5]oxazocin-6-one [(3R)-6b]. Compound 18Rb
(843 mg, 1.55 mmol) was treated according to a procedure
similar to that described for the preparation of (3S)-6b to
afford (3R)-6b as colorless crystals (533 mg, 68%).
Recrystallization from AcOEt–hexane gave colorless crys-
tals: mp 147–149 8C; 1H NMR spectrum was identical with
that of (3S)-6b. [a]2D0¼þ102.58 (c¼0.573, CHCl3). Anal.
Calcd C26H22F6N2O2: C, 61.49; H, 4.36; N, 5.51. Found: C,
61.26; H, 4.33; N, 5.69.

4490
Y. Ishichi et al. / Tetrahedron 60 (2004) 4481–4490
6.2. [125I]-BH-substance P binding in human IM-9 cells
1441–1453. (b) Miyazaki, M.; Matsuzawa, M. Jpn. Kokai
Tokkyo Koho. H6-41116 (February 15, 1994).
7. (a) Shimazaki, M.; Nagashima, N.; Suga, K.; Ohashi, T,
Watanabe, K. Jpn. Kokai Tokkyo Koho S57-142960
(September 3, 1982). (b) Shimazaki, M.; Nagashima, N.;
Ohashi, T.; Watanabe, K. Jpn. Kokai Tokkyo Koho JP57-
165357 (October 12, 1982). (c) Shimazaki, M.; Nagashima,
N.; Murakami, H.; Ohashi, T.; Watanabe, K. Jpn. Kokai
Tokkyo Koho JP61-271258 (December 1, 1986).
The binding activity was determined according to the
protocol previously reported.1,8
Acknowledgements
We thank Dr. Takenori Ishimaru for in vitro screening, and
Ms. Fumiko Kasahara and Ms. Mika Murabayashi for NMR
analysis.
8. Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.; Basal, A.;
Swain, C.; Seward, E.; Frances, B.; Burns, D.; Strader, C. D.
Mol. Pharmacol. 1992, 42, 458–463.
9. It should be noted that the N-benzylic methylene protons of
7-membered ring analogues of TAK-637 appeared as an AB
pattern in the NMR spectrum,4 suggesting that the confor-
mation of the 7-membered ring in compounds 4a–c changes
more rapidly than that in TAK-637 derivatives.
References and notes
1. Natsugari, H.; Ikeura, Y.; Kiyota, Y.; Ishichi, Y.; Ishimaru, T.;
Saga, O.; Shirafuji, H.; Tanaka, T.; Kamo, I.; Doi, T.; Otsuka,
M. J. Med. Chem. 1995, 38, 3106–3120.
10. For the stereochemistry at C(3) of 6, note that the sequence of
priority is different from that of TAK-637; the methyl group
exists in b-configuration for both compounds.
11. The ratio in the NMR spectrum changed slightly depending on
the solvent used; i.e., in CD3OD, it was ca. 96:4, in DMSO-d6,
ca. 97:3, and in pyridine-d5, ca. 97:3.
2. Ikeura, Y.; Ishichi, Y.; Tanaka, T.; Fujishima, A.; Murabayashi,
M.; Kawada, M.; Ishimaru, T.; Kamo, I.; Doi, T.; Natsugari, H.
J. Med. Chem. 1998, 41, 4232–4239.
3. Ikeura, Y.; Ishimaru, T.; Doi, T.; Kawada, M.; Fujishima, A.;
Natsugari, H. Chem. Commun. 1998, 2141–2142.
12. Coexistence of the two conformers (ca. 98:2) in the solid state
of (3S)-6b may not be ruled out.
4. Natsugari, H.; Ikeura, Y.; Kamo, I.; Ishimaru, T.; Ishichi, Y.;
Fujishima, A.; Tanaka, T.; Kasahara, F.; Kawada, M.; Doi, T.
J. Med. Chem. 1999, 42, 3982–3993.
13. For a recent NOESY (EXSY) experiment in atropisomers, see:
Gibson, K. R.; Hitzel, L.; Mortishire-Smith, R. J.; Gerhard, U.;
Jelley, R. A.; Reeve, A. J.; Rowley, M.; Nadin, A.; Owens,
A. P. J. Org. Chem. 2002, 67, 9354–9360.
14. In the 1H NMR spectra, the C(7)-phenyl protons of 5b, (3S)-6b
and (3R)-6b were observed as a broad signal (2H at 6.6–
7.4 ppm) and a broad singlet (3H at 7.37 ppm), whereas those
of 5a, 5c, (3S)-6a and (3R)-6a were observed as multiplets
with sharp peaks, suggesting that rotation of the phenyl ring is
moderately restricted for 5b, (3S)-6b and (3R)-6b.
5. Compound 1 (trans-amide) reached an equilibrium state of
trans- and cis-amide (¼ca. 7:1) in solution (e.g., CDCl3) in
about ca. 6 h at room temperature. The cis-form of 1, which
was separated and isolated in a crystalline form by column
chromatography, has weaker NK1-antagonistic activity
(IC50¼7.0 nM) than 1. The presence of atropisomers in the
cis-form was also shown by HPLC analysis using a chiral
column.1,2
6. (a) Prager, R. H.; Were, S. T. Aust. J. Chem. 1983, 36,