Y. Takeuchi et al. / Tetrahedron 59 (2003) 1639–1646
1645
7.33 (5H, s), 7.50 (1H, td, J¼7.3, 1.6 Hz), 7.69–7.81 (2H,
m), 7.97 (1H, brs), 8.28 (1 H, ddd, J¼8.1, 1.5, 0.6 Hz). MS
(FAB, positive ion mode) m/z: 450 (MHþ). Anal. Calcd for
C25H27N3O5: C, 66.80; H, 6.05; N, 9.35. Found: C, 66.66;
H, 6.02; N, 9.37.
less sands, mp. 205–2098C (dec.) (MeOH). IR (KBr) cm21
:
1
3390, 2800–2400, 1740, 1705, 1665. H NMR (500 MHz,
CD3COODþD2O) d: 1.56–1.66 (1 H, m), 1.77–1.88 (1H,
m), 2.01–2.11 (1H, m), 2.25–2.33 (1 H, m), 3.15 (1H, td,
J¼11.6, 3.5 Hz), 3.32 (1H, dd, J¼18.8, 7.3 Hz), 3.41–3.57
(3H, m), 3.47 (3H, s), 3.78 (1H, dd, J¼12.5, 7.0 Hz), 5.34
(2H, s,), 7.82 (1H, t, J¼7.5 Hz), 7.91 (1H, d, J¼8.0 Hz),
8.01 (1H, td, J¼7.8, 1.5 Hz), 8.36 (1H, dd, J¼8.0, 1.0 Hz),
9.03 (1H, s). MS (FAB, positive ion mode) m/z: 316
(MHþ22HCl). Anal. Calcd for C17H21N3O3·2HCl·5/4H2O:
C, 49.70; H, 6.26; N, 10.23. Found: C, 49.94; H, 6.06; N,
10.27.
3.1.12. 3-{3-[(2RS,3RS)-1-Benzyloxycarbonyl-3-meth-
oxy-2-piperidinyl]-2-oxopropyl}-4(3H)-quinazolinone
(cis-18) and 3-{3-[(2RS,3SR)-1-benzyloxycarbonyl-3-
methoxy-2-piperidinyl]-2-oxopropyl}-4(3H)-quinazoli-
none (trans-18). A mixture of cis-18 (0.60 g, 1.3 mmol) and
20% Pd(OH)2/C (0.06 g) in MeOH and THF (1:1, 8 ml) was
stirred at the room temperature for 3 h under H2 gas. The
mixture was filtered off and concentrated. A solution of the
residure in EtOH was heated at 808C for 1 h. The mixture
was concentrated. To a solution of the residue in CH2Cl2
(7 ml) was added dropwise Et3N (0.22 ml, 1.6 mmol) and
ClCOOCH2Ph (0.23 ml, 1.6 mmol) at 08C. The mixture was
stirred at the room temperature for 0.5 h under Ar gas. The
mixture was poured into water (50 ml) and extracted with
AcOEt (50 ml£2). The AcOEt layer was washed with brine
(50 ml), dried, and concentrated. The residue was subjected
to column chromatography (Al2O3; AcOEt/hexane¼1:1) to
give cis-18 (0.14 g, 24%) as colorless flakes. The next eluant
gave trans-18 (0.38 g, 63%) as amorphous solid. IR
3.1.15. 3-{3-[(2RS,3RS)-1-Ethoxycarbonyl-3-methoxy-2-
piperidinyl]-2-oxopropyl}-4(3H)-quinazolinone (cis-5).
A mixture of cis-18 (0.20 g, 0.44 mmol) and 20%
Pd(OH)2/C (0.02 g) in MeOH and THF (1:1, 10 ml) was
stirred at the room temperature for 1 h under H2 gas. The
mixture was filtered off and concentrated under the room
temperature. To a solution of the residue in CH2Cl2 (4 ml)
was added dropwise Et3N (0.076 ml, 0.55 mmol) and
ClCOOEt (0.052 ml, 0.54 mmol) at 08C. The mixture was
stirred at the room temperature for 0.5 h under Ar gas. The
mixture was poured into water (30 ml) and extracted with
AcOEt (30 ml£2). The AcOEt layer was washed with brine
(30 ml), dried, and concentrated. The residue was crystal-
lized from hexane to give cis-5 (0.12 g, 69%) as colorless
needles, mp 139–1418C (AcOEt). IR (KBr) cm21: 1725,
1
(CHCl3) cm21: 1735, 1680. H NMR (300 MHz, CDCl3)
d: 1.21–1.96 (4 H, m), 2.71–3.06 (3H, m), 3.23–3.46 (1H,
m), 3.38 (3H, s), 3.94–4.17 (1 H, m), 4.77–5.03 (2H, m),
5.14 (2H, s), 7.34 (5H, s), 7.51 (1H, td, J¼7.3, 1.7 Hz),
7.70–7.82 (2H, m), 7.90 (1H, brs), 8.26 (1H, d, J¼7.5 Hz).
MS (FAB, positive ion mode) m/z: 450 (MHþ). HRMS
(FAB) Calcd for C25H28N3O5 (MHþ): 450.2029. Found:
450.2028.
1
1690, 1680. H NMR (300 MHz, CDCl3) d: 1.25 (3H, t,
J¼6.9 Hz), 1.35–2.06 (4 H, m), 1.74 (1/2H), 2.38–3.15
(3H, m), 3.23–3.49 (1H, m), 3.37 (3H, s), 3.80–4.03 (1H,
m), 4.13 (2H, dd, J¼14.1, 6.9 Hz), 4.76–5.31 (3H, m), 7.50
(1H, td, J¼7.3, 1.7 Hz), 7.69–7.82 (2H, m), 8.00 (1H, brs),
8.28 (1H, dd, J¼7.7, 1.7 Hz, 5-H). MS (FAB, positive ion
3.1.13. 3-{3-[(2RS,3RS)-3-methoxy-2-piperidinyl]-2-oxo-
propyl}-4(3H)-quinazolinone dihydrochloride (cis-
6·2HCl). A mixture of cis-18 (0.20 g, 0.44 mmol) and
20% Pd(OH)2/C (0.02 g) in MeOH and THF (1:1, 4 ml) was
stirred at the room temperature for 2 h under H2 gas. The
mixture was filtered off and conc. HCl solution (0.50 ml)
was added to the filterate. The mixture was concentrated to
give cis-6·2HCl (0.17 g, 95%) as colorless sands, mp 134–
1368C (dec.) (AcOEt/cyclohexane). IR (KBr) cm21: 3410,
2720, 1740, 1705, 1665. 1H NMR (500 MHz, CD3COODþ
D2O) d: 1.67 (1H, t, J¼13.8 Hz), 1.75 (1H, d, J¼13.5 Hz),
1.90–2.15 (1H, m), 2.25 (1H, d, J¼14.0 Hz), 3.19 (1H, t,
J¼11.5 Hz), 3.38 (2H, d, J¼5.5 Hz), 3.44 (3H, s), 3.51 (1H,
d, J¼12.0 Hz), 3.71 (1H, brs), 3.92 (1H, brs), 5.41 (2H, dd,
J¼30.0, 18.0 Hz), 7.84 (1H, t, J¼15.0 Hz), 7.98 (1H, d,
J¼8.5 Hz), 8.10 (1H, t, J¼7.5 Hz), 8.24–8.58 (1 H, m), 9.41
(1H, s). MS (FAB, positive ion mode) m/z: 316
(MHþ22HCl). Anal. Calcd for C17H21N3O3·2HCl
8/5H2O: C, 48.95; H, 6.33; N, 10.07. Found: C, 48.65; H,
5.99; N, 10.11.
mode)
m/z:
388
(MHþ).
Anal.
Calcd
for
C20H25N3O5·1/4H2O: C, 61.29; H, 6.56; N, 10.72. Found:
C, 61.39; H, 6.43; N, 10.92.
3.1.16. 3-{3-[(2RS,3RS)-1-Ethoxycarbonyl-3-methoxy-2-
piperidinyl]-2-oxopropyl}-4(3H)-quinazolinone (cis-5)
and 3-{3-[(2RS,3SR)-1-ethoxycarbonyl-3-methoxy-2-
piperidinyl]-2-oxopropyl}-4(3H)-quinazolinone (trans-
5). A mixture of cis-18 (0.80 g, 1.8 mmol) and 20%
Pd(OH)2/C (0.08 g) in MeOH and THF (1:1, 10 ml) was
stirred at the room temperature for 2 h under H2 gas. The
mixture was filtered off and concentrated. A solution of the
residure in EtOH was heated at 808C for 1 h. The mixture
was concentrated. To a solution of the residue in CH2Cl2
(10 ml) was added dropwise Et3N (0.297 ml, 2.1 mmol) and
ClCOOEt (0.204 ml, 2.1 mmol) at 08C. The mixture was
stirred at the room temperature for 0.5 h under Ar gas. The
mixture was poured into water (80 ml) and extracted with
AcOEt (80 ml£2). The AcOEt layer was washed with brine
(80 ml), dried, and concentrated. The residue was subjected
to column chromatography (Al2O3; AcOEt/hexane¼3:1) to
give cis-5 (0.16 g, 23%) as colorless needles. The next
eluant gave trans-5 (0.41 g, 59%) as amorphous solid. IR
(CHCl3) cm21: 1730, 1680. 1H NMR (300 MHz, CDCl3) d:
1.25 (3H, t, J¼7.2 Hz), 1.35–1.97 (4H, m), 2.72–3.01 (3H,
m), 3.27–3.36 (1H, m), 3.39 (3H, s), 3.90–4.08 (1H, m),
4.13 (2H, dd, J¼14.1, 7.2 Hz), 4.87–5.10 (3H, m), 7.51
(1H, td, J¼7.5, 1.8 Hz), 7.68–7.81 (2H, m), 7.99 (1H, brs),
8.27 (1H, d, J¼8.4 Hz, 5-H). MS (FAB, positive ion mode)
3.1.14. 3-{3-[(2RS,3SR)-3-methoxy-2-piperidinyl]-2-oxo-
propyl}-4(3H)-quinazolinone dihydrochloride (trans-
6·2HCl). A mixture of trans-18 (0.19 g, 0.42 mmol) and
20% Pd(OH)2/C (0.019 g) in MeOH and THF (1:1, 4 ml)
was stirred at the room temperature for 2 h under H2 gas.
The mixture was filtered off and conc. HCl solution
(0.42 ml) was added to the filterate. The mixture was
concentrated to give trans-6·2HCl (0.13 g, 79%) as color-