D. P. Walker et al. / Bioorg. Med. Chem. 14 (2006) 8219–8248
8243
bottle and hydrogenated at 50 psi for 48 h. The mixture
was filtered through Celite and concentrated in vacuo to
afford 15.1 g (99%) of (3R,4S)-3-(tert-butoxycarbonyla-
mino)-1-azabicyclo[2.2.1]heptane as a white solid: Rf
C14H15N3O2ÆC4H4O4: C, 57.91; H, 5.13; N, 11.25.
Found: C, 57.80; H, 5.19; N, 11.17.
5.1.67. N-[(3R,4S)-1-Azabicyclo[2.2.1]hept-3-yl]-1,3-ben-
zodioxole-5-carboxamideÆ4-methylbenzenesulfonate (9b).
The compound 9b (191 mg, 64%) was prepared from
1,3-benzodioxole-5-carboxylic acid (166 mg, 1.0 mmol)
and 15 (456 mg, 1.0 mmol), followed by subsequent
treatment with para-toluenesulfonic acid monohydrate
(133 mg, 0.70 mmol) in a manner similar to that de-
0.16 (chloroform–methanol–ammonium hydroxide,
25
D
tance) 2975, 2942, 2885, 1711, 1551, 1364, 1292, 1277,
90:9.5:0.5); ½aꢂ 20 (c 1.0, CHCl3); IR (diffuse reflec-
1
1270, 1248, 1171, 1078, 1005, 979, 827 cmꢀ1; H NMR
(300 MHz, CDCl3) d 5.60–5.50 (br s, 1H), 3.82–3.72
(m, 1 H), 3.33–3.15 (m, 4H), 2.82–2.70 (m, 2H), 2.00–
1.84 (m, 1H), 1.65–1.50 (m, 1H), 1.46 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 155.3, 79.59, 63.34, 57.41,
53.91, 53.22, 42.84, 28.41, 27.20; high-resolution MS
(FAB) Calcd for C11H21N2O2 [M+H] m/z 213.1603.
Found 213.1611. An analytical sample was prepared
via silica gel column chromatography (chloroform–
methanol–ammonium hydroxide, 95:4:1), followed by
crystallization from ethyl acetate: mp 165–166 ꢁC.
scribed for the preparation of 1b. White solid: mp
25
D
tance) 1650, 1539, 1485, 1350, 1303, 1259, 1240, 1217,
147–149 ꢁC; ½aꢂ 6 (c 0.74, methanol); IR (diffuse reflec-
1199, 1187, 1172, 1123, 1034, 1011, 682 cmꢀ1 1H
;
NMR (400 MHz, methanol-d4)
d
7.69 (d, 2H,
J = 8.30 Hz), 7.45 (dd, 1H, J = 7.88, 1.66 Hz), 7.32 (d,
1H, J = 1.66 Hz), 7.21 (d, 2H, J = 7.88 Hz), 6.85 (d,
1H, J = 8.30 Hz), 6.02 (s, 2H), 4.22–4.16 (m, 1H),
3.74–3.66 (m, 1H), 3.49 (d, 1H, J = 9.12 Hz), 3.41–3.37
(m, 2H), 3.29–3.20 (m, 2H), 3.01 (d, 1H, J = 4.56 Hz),
2.35 (s, 3H), 2.20–2.10 (m, 1H), 1.86–1.76 (m, 1H);13C
NMR (100 MHz, methanol-d4) d 168.3, 151.1, 148.2,
142.2, 140.6, 128.7, 127.4, 125.8, 122.6, 107.7, 107.4,
102.1, 60.00, 57.14, 52.09, 51.90, 40.93, 24.40, 20.12;
high-resolution MS (ESI) Calcd for C14H17N2O3
[M+H] m/e 261.1239. Found 261.1244. Anal. Calcd for
C14H16N2O3ÆC7H8O3S : C, 58.32; H, 5.59; N, 6.48.
Found: C, 57.99; H, 5.65; N, 6.44.
To a stirred solution of (3R,4S)-3-(tert-butoxycarbon-
ylamino)-1-azabicyclo[2.2.1]heptane (22.0 g, 104 mmol)
in ethyl alcohol (700 mL) was added p-toluenesulfonic
acid monohydrate (42.7 g, 224 mmol). The reaction
mixture was heated to reflux for 10 h, followed by
cooling to room temperature. The white solid that
formed was collected by vacuum filtration and washed
with cold ethyl alcohol to give 15 as a white, crystal-
25
D
line solid (40.7 g, 87%): ½aꢂ 2.4 (c 0.90, MeOH); IR
(diffuse reflectance) 3028, 2979, 2971, 2958, 2926,
2817, 2782, 1210, 1194, 1170, 1125, 1036, 1013, 813,
5.1.68.
N-[(3R,4S)-1-Azabicyclo[2.2.1]hept-3-yl]pyr-
686 cmꢀ1
;
1H NMR (400 MHz, D2O) d 7.54 (d,
rolo[1,2-c]pyrimidine-3-carboxamide sesquifumarate (9c).
The compound 9c (273 mg, 63%) was prepared from
pyrrolo[1,2-c]pyrimidine-3-carboxylic acid hydrochlo-
ride (202 mg, 1.01 mmol) and 15 (456 mg, 1.00 mmol),
followed by subsequent treatment with fumaric acid
(102 mg, 0.88 mmol) in a manner similar to that de-
J = 8.25 Hz, 2H), 7.22 (d, J = 8.09 Hz, 2H), 3.73–3.68
(m, 1H), 3.62 (dd, 1H, J = 7.70, 2.28 Hz), 3.45–3.33
(m, 3H), 3.22 (d, 1H, J = 10.26 Hz), 3.20–3.12 (m,
1H), 3.11 (d, 1H, J = 4.42 Hz), 2.25 (s, 6H), 2.20–
2.10 (m, 1H), 1.78–1.67 (m, 1H); 13C NMR
(100 MHz, CD3OD) d 143.1, 141.6, 129.6, 126.7,
58.29, 57.48, 52.89, 51.93, 40.85, 25.47, 21.03; high-res-
olution MS (FAB) Calcd for C6H13N2 [M+H] m/z
113.1079. Found 113.1078. An analytical sample was
prepared via re-crystallization from ethyl alcohol: mp
232–233 ꢁC. Anal. Calcd for C6H12N2. 2C7H8O3S: C,
52.61; H, 6.18; N, 6.14. Found: C, 52.62; H, 6.15;
N, 6.14.
scribed for the preparation of 1b. White solid: mp
25
D
tance) 3380, 3366, 2977, 2961, 1738, 1698, 1662, 1545,
140–145 ꢁC; ½aꢂ 0 (c 0.61, methanol); IR (diffuse reflec-
1491, 1428, 1421, 1354, 1318, 1299, 1270 cmꢀ1 1H
;
NMR (400 MHz, methanol-d4) d 9.01 (s, 1H), 8.10 (s,
1H), 7.72 (d, 1H, J = 3.32 Hz), 6.99 (dd, 1H, J = 3.73,
2.90 Hz), 6.78 (d, 1H, J = 3.73 Hz), 6.71 (s, 3H), 4.30–
4.25 (m, 1H), 3.72–3.68 (m, 1H), 3.55–3.38 (m, 3H),
3.30–3.20 (m, 2H), 3.03 (d, 1H, J 4.56 Hz), 2.22–2.12
(m, 1H), 1.90–1.80 (m, 1H); 13C NMR (100 MHz, meth-
anol-d4) d 169.0, 166.0, 138.3, 134.5, 132.0, 130.5, 117.5,
114.2, 113.9, 104.6, 59.51, 56.94, 51.97, 51.46, 41.41,
24.46; high-resolution MS (ESI) Calcd for C14H17N4O
[M+H] m/e 257.1402. Found 257.1393. Anal. Calcd for
C14H16N4OÆ1.5C4H4O4: C, 55.81; H, 5.15; N, 13.02.
Found: C, 55.51; H, 5.23; N, 12.81.
5.1.66. N-[(3R,4S)-1-Azabicyclo[2.2.1]hept-3-yl]furo[2,3-
c]pyridine-5-carboxamideÆfumarate (9a). The compound
9a (1.88 g, 85%) was prepared from furo[2,3-c]pyri-
dine-5-carboxylic acid (965 mg, 5.92 mmol) and 15
(2.70 g, 5.92 mmol), followed by subsequent treatment
with fumaric acid (615 mg, 5.30 mmol) in a manner sim-
ilar to that described for the preparation of 1b. White
25
D
(mull) 1683, 1673, 1659, 1605, 1579, 1527, 1516, 1492,
solid: mp 170–172 ꢁC; ½aꢂ 0 (c 0.98, methanol); IR
5.1.69.
N-[(3R,4S)-1-Azabicyclo[2.2.1]hept-3-yl]-2,3-
1
1349, 1337, 1291, 1277, 1172, 790, 640 cmꢀ1; H NMR
dihydro-1,4-benzodioxine-6-carboxamideÆ0.5fumarateÆ0.5
hydrate (9d). The compound 9d (200 mg, 65%) was pre-
pared from 2,3-dihydro-1,4-benzodioxine-6-carboxylic
acid (180 mg, 0.89 mmol) and 15 (400 mg, 0.89 mmol),
followed by subsequent treatment with fumaric acid
(101 mg, 0.88 mmol) in a manner similar to that de-
(400 MHz, methanol-d4) d 8.88 (s, 1H), 8.42 (s, 1H),
8.09 (d, 1H, J = 2.07 Hz), 7.09 (d, 1H, J = 1.66 Hz),
6.69 (s, 2H), 4.36–4.28 (m, 1H), 3.76–3.68 (m, 1H),
3.57–3.45 (m, 2H), 3.44–3.39 (m, 1H), 3.28–3.20 (m,
2H), 3.05 (d, 1H, J = 4.98 Hz), 2.22–2.13 (m, 1H),
1.90–1.80 (m, 1H); 13C NMR (100 MHz, methanol-d4)
d; high-resolution MS (API) Calcd for C14H16N3O2
[M+H] m/e 258.1242. Found 258.1249. Anal. Calcd for
scribed for the preparation of 1b. White solid: 185–
25
D
3236, 3060, 2991, 1644, 1609, 1583, 1550, 1499, 1372,
188 ꢁC; ½aꢂ 9 (c 0.57, methanol); IR (diffuse reflectance)