4458 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 20
Andersen et al.
Step 2. 2-(Oxa lyla m in o)-6-p yr id in -4-ylm eth yl-4,5,6,7-
tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22g).
Yield 104 mg (28%) of 22g; mp 230-235 °C. 1H NMR (300
MHz, DMSO-d6): δ 3.0 (s, 2H), 3.13 (s, 2H), 3.96 (s, 2H), 4.15
(s, 2H), 7.55 (d, 1H), 8.65 (d, 1H), 12.3 (bs, 1H, NHCOCOOH).
Anal. (C16H15N3O5S‚1HCl, 1H2O) C, H, N.
2-(Oxa lyla m in o)-6-qu in olin -2-ylm eth yl-4,5,6,7-tetr a h y-
d r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22h ). Step 1.
2-(Eth oxyoxa lyla m in o)-6-qu in olin -2-ylm eth yl-4,5,6,7-tet-
r a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid Eth yl
Ester (21h ). Yield 1.23 g (39%) of 21h . 1H NMR (300 MHz,
CDCl3): δ 1.39 (t, 3H), 1.43 (t, 3H), 2.88 (t, 2H), 2.95 (d, 2H),
3.73 (s, 2H), 4.05 (s, 2H), 4.38 (q, 2H), 4.44 (q, 2H), 7.52 (t,
1H), 7.69 (q, 2H), 7.81 (d, 1H), 8.08 (d, 1H), 8.13 (d, 1H), 12.4
(s, 1H, NHCOCOOEt).
The following compounds were prepared by the method
described for the preparation of compound 22n .
6-(2-(4-Ben zyloxyp h en yl)eth yl)-2-(oxa lyla m in o)-4,5,6,7-
tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22l).
Step 1. 2-Am in o-6-[2-(4-ben zyloxyp h en yl)eth yl]-4,5,6,7-
tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid ter t-
Bu tyl Ester (16l). Yield 1.7 g (62%) of 16l. 1H NMR (300 MHz,
CDCl3): δ 1.54 (s, 9H), 2.69-2.84 (m, 8H), 3.49 (s, 2H), 5.04
(s, 2H), 5.89 (bs, 2H, -NH2), 6.90 (d, 2H), 7.13 (d, 2H), 7.29-
7.43 (m, 5H).
Step 2. 6-(2-(4-Ben zyloxyp h en yl)eth yl)-2-(ter t-bu toxy-
oxa lyla m in o)-4,5,6,7-tetr a h yd r oth ien o[2,3-c]p yr id in e-3-
ca r boxylic Acid ter t-Bu tyl Ester (17l). Yield 1.3 g (68%) of
1
17l. H NMR (300 MHz, CDCl3): δ 1.59 (s, 9H), 1.62 (s, 9H),
2.73-2.87 (m, 6H), 2.91 (m, 2H), 3.66 (s, 2H), 5.04 (s, 2H), 6.72
(d, 2H), 7.13 (d, 2H), 7.28-7.44 (m, 5H), 12,5 (s, 1H, NHCO-
COOt-Bu).
Step 2. 2-(Oxa lyla m in o)-6-qu in olin -2-ylm eth yl-4,5,6,7-
tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22h ).
1
Step 3. 6-(2-(4-Ben zyloxyph en yl)eth yl)-2-(oxalylam in o)-
4,5,6,7-tetr ah ydr oth ien o[2,3-c]pyr idin e-3-car boxylic Acid
Yield 92 mg (11%) of 22h ; mp >250 °C. H NMR (300 MHz,
DMSO-d6): δ 2.95 (bs, 2H), 3.07 (bs, 2H), 3.92 (bs, 2H), 4.24
(bs, 2H), 7.60 (t, 1H), 7.66 (d, 1H), 7.76 (t, 1H), 7.99 (t, 1H),
8.37 (d, 1H), 12.3 (bs, 1H, NHCOCOOH). Anal. (C20H17N3O5S‚
1H2O) C, H, N.
1
(22l). Yield 240 mg (68%) of 22l; mp >250 °C. H NMR (300
MHz, DMSO-d6): δ 3.0 (m, 2H), 3.11 (bs, 2H), 3.4 (m, 2H),
3.55 (bs, 2H), 4.47 (bs, 2H), 5.07 (s, 2H), 6.97 (d, 2H), 7.20 (d,
2H), 7.3-7.43 (m, 5H), 12.3 (bs, 1H, NHCOCOOH). Anal.
(C25H24N2O6S‚0.6TFA) C, H, N.
2-(Oxa lyla m in o)-6-(2-t h iop h en -3-ylet h yl)-4,5,6,7-t et -
r a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22n ).
Step 1. 2-Am in o-4,5,6,7-tetr a h yd r oth ien o[2,3-c]p yr id in e-
3-ca r boxylic Acid ter t-Bu tyl Ester (18). To a solution of
4-oxo-piperidine, hydrochloride mono hydrate (13a ) (20 g, 0.13
mol), tert-butyl cyanoacetate (20.2 g, 0.143 mmol), and sulfur
(4.6 g, 0.143 mmol) in EtOH (350 mL) was added N-methyl
morpholine (43 mL) followed by 4 Å molecular sieves (15 g).
The mixture was heated to 50 °C for 7 h and cooled, and the
precipitate was filtered off and washed with EtOH (50 mL).
The solvent was evaporated, and the residue was subjected to
flash column chromatography on silica gel (EtOAc (700 mL)
the 4% TEA in EtOAc). This afforded 5.8 g (18%) of 18. 1H
NMR (300 MHz, CDCl3): δ 1.56 (t, 9H), 2.70 (m, 2H), 3.05 (t,
2H), 3.77 (t, 2H), 5.91 (bs, 2H, -NH2).
Step 2. 2-(ter t-Bu toxyoxa lyla m in o)-6-(2-th iop h en -3-yl-
eth yl)-4,5,6,7-tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxy-
lic Acid ter t-Bu tyl Ester (17n ). To a solution of 18 (0.6 g,
2.36 mmol) and 2-thiophen-3-ylethanol (0.3 g, 2.48 mmol) in
propionitril (25 mL) was added (cyanomethyl)trimethylphos-
phonium iodine (0.69 g, 2.83 mmol) followed by DIPEA (0.53
mL, 3.07 mmol). The resulting mixture was heated at reflux
for 2 h, cooled, and filtered. The residue was submitted to flash
chromatography on silica gel (EtOAc/heptane, 1:3) to afford
0.5 g (58%) of 2-amino-6-(2-thiophen-3-ylethyl)-4,5,6,7-tetrahy-
dro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (16n ).
1H NMR (300 MHz, CDCl3): δ 1.53 (s, 9H), 2.78 (m, 3H), 2.90
(m, 2H), 3.50 (s, 2H), 5.89 (bs, 2H, -NH2), 6.95 (m, 1H), 6.99
(m, 1H), 7.22 (m, 1H).
To a solution of the above tert-butyl ester (0.5 g, 1.37 mmol)
in THF (40 mL) was added imidazol-1-yloxoacetic acid tert-
butyl ester (0.53 g, 2.74 mmol). The reaction mixture was
stirred at room temperature for 48 h and evaporated. The
residue was subjected to flash column chromatography on
silica gel (EtOAc/heptane, 1:3). This afforded 55 mg (81%) of
17n . 1H NMR (300 MHz, DMSO-d6): δ 1.60 (s, 9H), 1.62 (s,
9H), 2.83 (m, 4H), 2.92 (m, 4H), 3.66 (s, 2H), 6.96 (d, 1H), 7.00
(m, 1H), 7.23 (m, 1H), 12.5 (s, 1H, NHCOCOOt-Bu).
Step 3. 2-(Oxalylam in o)-6-(2-th ioph en -3-yleth yl)-4,5,6,7-
tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22n ).
To a solution of 17n (32.4 g, 0.099 mol) and TEA (20.7 mL,
0.15 mol) in THF (300 mL) was added dropwise a solution of
ethyl oxalyl chloride (13.3 mL, 0.12 mol) in THF (130 mL) at
0 °C. The reaction mixture was stirred at room temperature
for 16 h and evaporated. To the residue was added water (300
mL), and the mixture was extracted with EtOAc (3 × 100 mL).
The organic phases were washed with water (100 mL) and
brine (100 mL) and dried (MgSO4), and the solvent was
evaporated. This afforded 190 mg (34%) of 22n ; mp >250 °C.
1H NMR (300 MHz, DMSO-d6): δ 3.12 (m, 3H), 3.47 (bm, 6H),
4.47 (bs, 1H), 7.06 (d, 1H), 7.34 (s, 1H), 7.52 (m, 1H), 12.3 (bs,
1H, NHCOCOOH). Anal. (C16H16N2O5S2‚0.6TFA) C, H, N.
2-(Oxa lyla m in o)-6-(2-p yr id in -2-yleth yl)-4,5,6,7-tetr a h y-
d r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22o). Step 1.
2-Am in o-6-(2-p yr id in -2-yleth yl)-4,5,6,7-tetr a h yd r oth ien o-
[2,3-c]p yr id in e-3-ca r boxylic Acid ter t-Bu tyl Ester (16o).
1
Yield 0.5 g (59%) of 16o. H NMR (300 MHz, CDCl3): δ 1.52
(s, 9H), 2.80 (s, 4H), 2.92 (m, 2H), 3.05 (m, 2H), 3.52 (s, 2H),
5.91 (s, 2H, -NH2), 7.11 (dd, 1H), 7.19 (d, 1H), 7.59 (dt, 1H),
8.51 (d, 1H).
Step 2. 2-(ter t-Bu toxyoxa lyla m in o)-6-(2-p yr id in -2-yl-
eth yl)-4,5,6,7-tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxy-
lic Acid ter t-Bu tyl Ester (17o). Yield 0.6 g (88%) of 17o. 1H
NMR (300 MHz, CDCl3): δ 1.62 (s, 9H), 1.64 (s, 9H), 2.85-
3.01 (m, 6H), 3.07 (m, 2H), 3.68 (s, 2H), 7.11 (dd, 1H), 7.20 (d,
1H), 7.59 (dt, 1H), 8.53 (d, 1H), 12,5 (s, 1H, NHCOCOOt-Bu).
Step 3. 2-(Oxa lyla m in o)-6-(2-p yr id in -2-yleth yl)-4,5,6,7-
tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22o).
1
Yield 450 mg (75%) of 22o; mp >250 °C. H NMR (300 MHz,
DMSO-d6): δ 3.14 (bs, 2H), 3.27 (t, 2H), 3.63 (m, 4H), 4.55
(bs, 2H), 7.33 (dd, 1H), 7.38 (d, 1H), 7.80 (dt, 1H), 8.53 (d, 1H),
12.3 (bs, 1H, NHCOCOOH). Anal. (C17H17N3O5S‚1.5TFA) C,
H, N.
2-(Oxa lyla m in o)-6-(2-p yr id in -4-yleth yl)-4,5,6,7-tetr a h y-
d r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22p ). Step 1.
2-Am in o-6-(2-p yr id in -4-yleth yl)-4,5,6,7-tetr a h yd r oth ien o-
[2,3-c]p yr id in e-3-ca r boxylic Acid ter t-Bu tyl Ester (16p ).
1
Yield 0.6 g (88%) of 16p . H NMR (300 MHz, CDCl3): δ 1.54
(s, 9H), 2.74-2.89 (m, 8H), 3.50 (s, 2H), 5.91 (s, 2H, -NH2),
7.15 (d, 2H), 8.49 (d, 2H).
Step 2. 2-(ter t-Bu toxyoxa lyla m in o)-6-(2-p yr id in -4-yl-
eth yl)-4,5,6,7-tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxy-
lic Acid ter t-Bu tyl Ester (17p ). Yield 0.15 g (74%) of 17p .
1H NMR (300 MHz, CDCl3): δ 1.59 (s, 9H), 1.61 (s, 9H), 2.78-
2.90 (m, 8H), 3.66 (s, 2H), 7.15 (d, 2H), 8.49 (d, 2H), 12.5 (s,
1H, NHCOCOOt-Bu).
Step 3. 2-(Oxa lyla m in o)-6-(2-p yr id in -4-yleth yl)-4,5,6,7-
tetr a h yd r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22p ).
1
Yield 90 mg (60%) of 22p ; mp >250 °C. H NMR (DMSO-d6):
δ 3.15 (m, 4H), 3.53 (m, 4H), 4.50 (bs, 2H), 7.48 (d, 2H), 8.60
(d, 2H), 12.3 (bs, 1H, NHCOCOOH). Anal. (C17H17N3O5S‚
1.4TFA) C, H, N.
6-(3,3-Diph en ylp r op yl)-2-(oxa lyla m in o)-4,5,6,7-tetr a h y-
d r oth ien o[2,3-c]p yr id in e-3-ca r boxylic Acid (22r ). Step 1.
2-Am in o-6-(3,3-diph en ylpr opyl)-4,5,6,7-tetr ah ydr oth ien o-
[2,3-c]p yr id in e-3-ca r boxylic Acid ter t-Bu tyl Ester (16r ).
1
Yield 0.6 g (57%) of 16r . H NMR (300 MHz, CDCl3): δ 1.52
(s, 9H), 2.31 (m, 2H), 2.43 (m, 2H), 2.65 (t, 2H), 2.76 (m, 2H),
3.37 (s, 2H), 4.04 (t, 1H), 5.87 (s, 2H, -NH2), 7.16 (m, 2H),
7.25 (m, 8H).
Step 2. 2-(ter t-Bu toxyoxa lyla m in o)-6-(3,3-d ip h en ylp r o-
p yl)-4,5,6,7-t et r a h yd r ot h ien o[2,3-c]p yr id in e-3-ca r b oxy-