Journal of Medicinal Chemistry
Article
title compound was obtained as a pale-yellow solid (148 mg, 399
μmol, 55% yield); Rf 0.32 (EtOAc/heptane 5:1). 1H NMR (300 MHz,
CDCl3) δ: 7.43−7.21 (m, 10H), 4.97 (s, 3H), 4.18 (s, 1H), 4.25 (d, J
= 18.3 Hz, 2H), 3.94 (d, J = 17.7 Hz, 1H). 13C NMR (75 MHz,
CDCl3) δ: 189.6, 160.7, 157.3, 141.9, 133.4, 130.9, 130.8, 128.9, 128.8,
128.7, 127.7, 127.6, 127.3, 127.2, 118.3, 114.1, 62.5, 54.7, 41.5, 35.0;
mp 179−181 °C (decomposed). LC-MS (m/z) calcd for C22H17N3O3
[M + H+], 372.1; found, 372.1.
2.1, 16.5 Hz, 1H), 3.20 (dd, J = 1.5, 16.2 Hz, 1H), 3.01 (dd, J = 2.1,
16.5 Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ: 193.0, 161.8, 157.2, 142.3, 141.2, 128.7, 128.6, 127.7, 127.6, 127.4,
127.3, 118.4, 113.3, 63.8, 63.6, 58.0, 49.7, 34.9, 19.3; mp 102−104 °C
(decomposed). [α]28 −34.5° (c 0.23, abs EtOH). LC-MS (m/z)
D
calcd for C23H21N3O2 [M + H+], 372.2; found, 372.2.
Ethyl 2-(Phenylamino)acetate (14). Ethyl bromoacetate (2.43 mL,
22 mmol) was added dropwise over 2 h to a stirred solution of aniline
(2 mL, 22 mmol) and N,N-diisopropylethylamine (8 mL, 46 mmol) in
acetonitrile (20 mL) at 60 °C. The reaction mixture was stirred for an
additional 3 h at 60 °C and then concentrated to dryness. Addition of
H2O (5 mL) to the residue and the solid was filtered and washed with
H2O several times. Recrystallization from toluene afforded the title
2-Amino-5-oxo-4-phenyl-7-((S)-1-phenylethyl)-5,6,7,8-tetrahy-
dro-4H-pyrano[2,3-c]pyridine-3-carbonitrile (11a/11b). A suspen-
sion of potassium tert-butoxide (78 mg, 0.69 mmol) in dry THF (5
mL) was added dropwise to a solution of (S)-ethyl 2-((2-oxopropyl)-
(1-phenylethyl)amino)acetate (24) (122 mg, 0.46 mmol) in dry THF
(8 mL) at 0 °C under a N2 atmosphere. The reaction mixture was
stirred at rt for 2 h and quenched with satd NH4Cl (2 mL). After
concentration in vacuo, the crude product was dissolved in EtOH/
H2O (6.5 mL, 10:3) and 13 (71 mg, 0.49 mmol) were added. The
reaction mixture was stirred at rt for 18 h. After concentration with
silica gel in vacuo, the crude product was purified by column
chromatography on silica gel. This afforded the title compound as a
pale-yellow solid (69 mg, 189 μmol, 41% yield); Rf 0.24 (EtOAc/
heptane 1:1). The diastereoisomic mixture was separated by HPLC
using a Chiralpak AD column (n-heptane/2-PrOH 80:20) to give 11a
and 11b (1:1) in 88% yield. Analytical data for 11a (99.7% de): tR =
14.6 min (n-heptane/2-PrOH 80:20). 1H NMR (300 MHz, CDCl3) δ:
7.36−7.19 (m, 10H), 4.50 (s, 2H), 4.41 (s, 1H), 3.54 (q, J = 6.6 Hz,
1H), 3.44 (d, J = 16.5 Hz, 1H), 3.38 (d, J = 15.9 Hz, 1H), 3.18 (d, J =
16.5 Hz, 1H), 2.98 (d, J = 15.9 Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ: 193.0, 161.8, 157.2, 142.2, 141.5, 128.7,
128.6, 127.7, 127.6, 127.4, 127.3, 118.4, 113.3, 63.8, 63.5, 58.3, 49.7,
34.8, 19.6; mp 121−123 °C (decomposed). [α]28D +10.3° (c 0.12, abs
EtOH). LC-MS (m/z) calcd for C23H21N3O2 [M + H+], 372.2; found,
372.2. Analytical data for 11b (99.7% de): tR = 12.3 min (n-heptane/2-
1
compound as a beige solid (1.83 g, 10.1 mmol, 46% yield). H NMR
(300 MHz, CDCl3) δ: 7.23−7.13 (m, 2H), 6.74 (t, J = 7.2, 1H), 6.59
(dd, J = 7.8, 0.9 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.88 (s, 2H), 1.29
(t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 171.1, 147.0,
129.2, 118.1, 112.9, 61.3, 45.8, 14.2; mp 55−57 °C (decomposed).
LC-MS (m/z) calcd for C10H13NO2 [M + H+], 180.1; found, 180.1.
Ethyl 2-((2-Oxopropyl)(phenyl)amino)acetate (15). Ethyl 2-
(phenylamino)acetate (14) (1 g, 5.6 mmol) and K2CO3 (2.31 g,
16.7 mmol) were stirred in dry THF (30 mL) at rt under a N2
atmosphere. A solution of chloroacetone (489 μL, 6.14 mmol) in dry
THF (4 mL) was added dropwise to the reaction mixture and stirred
for 30 min. Sodium iodide (920 mg, 6.14 mmol) was added, and the
reaction mixture was stirred at 60 °C for 3 days. The crude reaction
was quenched with H2O (10 mL) and extracted with EtOAc (3 × 30
mL), and the combined organic phases were washed with H2O (1 ×
30 mL) and brine (1 × 20 mL). The organic phase was dried over
MgSO4. After concentration in vacuo, the crude product was purified
by column chromatography on silica gel. This afforded the title
compound as a pale-yellow oil (448 mg, 1.73 mmol, 31% yield); Rf
1
0.25 (EtOAc/heptane 1:2). H NMR (300 MHz, CDCl3) δ: 7.24−
1
PrOH 80:20). H NMR (300 MHz, CDCl3) δ: 7.35−7.17 (m, 10H),
7.16 (m, 2H), 6.76 (dt, J = 7.2, 0.6 Hz, 1H), 6.53 (dd, J = 7.8, 0.9 Hz,
2H), 4.19 (q, J = 7.2 Hz, 2H), 4.12 (s, 2H), 4.09 (s, 2H), 2.19 (s, 3H),
1.27 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 207.7, 170.8,
147.7, 129.3, 118.3, 112.4, 62.3, 61.1, 53.8, 27.0, 14.2. LC-MS (m/z)
calcd for C13H17NO3 [M + H+], 236.1; found, 236.1.
4.51 (s, 2H), 4.39 (s, 1H), 3.58 (q, J = 6.6 Hz, 1H), 3.55 (dd, J = 1.5,
16.2 Hz, 1H), 3.28 (dt, J = 2.1, 16.5 Hz, 1H), 3.20 (dd, J = 1.5, 16.2
Hz, 1H), 3.02 (dd, J = 2.1, 16.5 Hz, 1H), 1.41 (d, J = 6.6 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ: 192.9, 161.7, 157.2, 142.3, 141.2, 128.7,
128.6, 127.7, 127.6, 127.5, 127.3, 118.3, 113.3, 63.7, 63.6, 58.0, 49.7,
34.9, 19.2; mp 102−104 °C (decomposed). [α]28D +31.5° (c 0.13, abs
EtOH). LC-MS (m/z) calcd for C23H21N3O2 [M + H+], 372.2; found,
372.2.
Ethyl 2-(Benzylamino)acetate (17). A solution of ethyl bromoa-
cetate (924 μL, 8 mmol) in dry THF (4 mL) was added dropwise over
10 min to a cooled solution of benzylamine (2 mL, 18 mmol) in dry
THF (20 mL) at 0 °C under a N2 atmosphere. The reaction mixture
was stirred for 3.5 h at rt, where after it was concentrated and
resuspended in diethyl ether. The white solid was filtered off. The
crude was concentrated and purified by column chromatography on
silica gel. This afforded the title compound as a pale-yellow oil (1.45 g,
2-Amino-5-oxo-4-phenyl-7-((R)-1-phenylethyl)-5,6,7,8-tetrahy-
dro-4H-pyrano[2,3-c]pyridine-3-carbonitrile (12a/12b). A suspen-
sion of potassium tert-butoxide (93 mg, 0.82 mmol) in dry THF (5
mL) was added dropwise to a solution of (R)-ethyl 2-((2-
oxopropyl)(1-phenylethyl)amino)acetate (145 mg, 0.55 mmol) in
THF (5 mL) at 0 °C under a N2 atmosphere. The reaction mixture
was stirred at rt for 3 h and quenched with satd NH4Cl (1 mL). After
concentration in vacuo, the crude product was dissolved in EtOH/
H2O (6 mL, 5:1) and 13 (84 mg, 0.55 mmol) and piperidine (11 μL,
0.20 mmol) were added. The reaction mixture was stirred at rt for 22
h. After concentration with silica gel in vacuo, the crude product was
purified by column chromatography on silica gel. This afforded the
title compound as a pale-yellow solid (117 mg, 0.32 mmol, 58% yield);
Rf 0.33 (EtOAc/heptane 1:1). The diastereoisomic mixture was
separated by HPLC using a Chiralpak AD column (n-heptane/2-
PrOH 80:20) to give 12a and 12b (1:1) in 82% yield. Analytical data
1
7.50 mmol, 90% yield); Rf 0.26 (EtOAc/heptane 1:1). H NMR (300
MHz, CDCl3) δ: 7.34−7.20 (m, 5H), 4.18 (q, J = 7.2 Hz, 2H), 3.80 (s,
2H), 3.40 (s, 2H), 1.89 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ: 172.3, 139.5, 128.4, 128.2, 127.1, 60.7, 53.2, 50.1,
14.2. LC-MS (m/z) calcd for C11H15NO2 [M + H+], 194.1; found,
194.1.
Ethyl 2-(Benzyl(2-oxopropyl)amino)acetate (18). Ethyl 2-
(benzylamino)acetate (17) (165 mg, 853 μmol) and NaHCO3 (72
mg, 853 μmol) were stirred in abs EtOH (3 mL) at 60 °C under a N2
atmosphere. A solution of chloroacetone (68 μL, 853 μmol) in abs
EtOH (1 mL) was added dropwise to the reaction mixture and stirred
for 18 h. The crude reaction was quenched with H2O (5 mL) and
extracted with EtOAc (3 × 10 mL), and the combined organic phases
were washed with H2O (1 × 10 mL) and brine (1 × 10 mL). The
organic phase was dried over MgSO4. After concentration in vacuo, the
crude product was purified by column chromatography on silica gel to
afford the title compound as a pale-yellow oil (137 mg, 580 μmol, 68%
yield); Rf 0.51 (EtOAc/heptane 1:1). 1H NMR (300 MHz, CDCl3) δ:
7.34−7.20 (m, 5H), 4.15 (q, J = 6.9 Hz, 2H), 3.83 (s, 2H), 3.52 (s,
2H), 3.45 (s, 2H), 1.26 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ: 207.8, 171.0, 138.1, 128.9, 128.4, 127.4, 63.1, 60.4, 58.4,
54.3, 27.5, 14.2. LC-MS (m/z) calcd for C14H19NO3 [M + H+], 250.1;
found, 250.1.
1
for 12a (99.8% de): tR = 11.0 min (n-heptane/2-PrOH 80:20). H
NMR (300 MHz, CDCl3) δ: 7.36−7.17 (m, 10H), 4.58 (s, 2H), 4.40
(s, 1H), 3.53 (q, J = 6.6 Hz, 1H), 3.43 (d, J = 16.5 Hz, 1H), 3.37 (d, J
= 15.9 Hz, 1H), 3.17 (dt, J = 1.5, 16.5 Hz, 1H), 2.98 (dd, J = 2.4, 16.2
Hz, 1H), 1.39 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ:
193.0, 161.9, 157.3, 142.3, 141.5, 128.7, 128.6, 127.6, 127.4, 127.3,
118.5, 113.2, 63.8, 63.1, 58.3, 49.7, 34.8, 19.6; mp 121−123 °C
(decomposed). [α]28D +15.9° (c 0.23, abs EtOH). LC-MS (m/z) calcd
for C23H21N3O2 [M + H+], 372.2; found, 372.2. Analytical data for
1
12b (99.2% de): tR = 15.5 min (n-heptane/2-PrOH 80:20). H NMR
(300 MHz, CDCl3) δ: 7.35−7.17 (m, 10H), 4.55 (s, 2H), 4.38 (s, 1H),
3.57 (q, J = 6.6 Hz, 1H), 3.54 (dd, J = 1.5, 16.2 Hz, 1H), 3.27 (dt, J =
H
dx.doi.org/10.1021/jm300345z | J. Med. Chem. XXXX, XXX, XXX−XXX