417
Hoveyda et al.
(dd, 3Hα, J = 6, 4 Hz), 9.79 (t, 3H, C(O)NH, J = 6 Hz), 12.20
(br s, 3H, OH). 13C NMR (DMSO-d6): 37.42 (C1), 53.46 (C2),
106.14 (Cb), 120.63 (Cγ), 139.30 (Cα), 143.77 (Cδ), 162.32
(C-OH), 163.36 (CTO). Anal. calcd. (found) for
C24H27N7O6 0.5H2O: C 55.60 (55.42), H 5.21 (5.33), N 18.90
(18.83).
product (150 mg, 73% recovery), equivalent to a 51% overall
yield; mp 115–117°C. TLC (eluant: 50% MeOH in EtOAc) Rf
= 0.3. IR: 3600–2600 (br,νOH), 3260 (m, νNH), 1675 (s, νCTO),
1605 (m, νCTC), 1560 (s, amide II), 1230, 775. 1H NMR (δ at
200 MHz in DMSO-d6): 1.3–1.9 (three overlapping m, 6
H3,7,8), 2.9–3.6 (partially obscured overlapping m, 8H2,4,6,9),
6.03–6.22 (m, 1Hβ), 6.40–6.51 (m, 2Hβ′,β′′), 7.24–7.45 (two
overlapping m, 2Hα,γ), 7.60–7.75 (m, 2Hγ′,γ′′), 8.22–8.38 (m,
2Hα′,α′′), 9.60–9.90 (m, 2H, C(O)NH), 11.85 (br s, 1H, OH),
12.45 (br s, 2H, OH). MS (FAB), m/z: 510 ± 1 (M+H)+. Anal.
calcd. (found) for C25H28N6O6 H2O: C 57.03 (57.13), H 5.74
(5.80), N 15.96 (15.82).
Method B: N-(2-Hydroxynicotinyl)-imidazole (HImNic)
To a mixture of 2-hydroxynicotinic acid (5.34 g, 38.4 mmol)
in THF (200 mL) was added CDI (6.43 g, 39.4 mmol) in one
portion. The mixture was refluxed for 19 h. After cooling the
reaction mixture to 20°C, the white precipitate was filtered,
washed with Et2O, and dried in vacuo to afford HImNic
(6.65 g, 98%). 1H NMR: 6.38 (t, 1Hβ, J = 6.6 Hz), 7.05 (dd,
1H4, J = 1.6, 0.8 Hz), 7.61 (t, 1H5, J = 1.6 Hz), 7.74 (dd, 1Hγ,
J = 6.3, 2.2 Hz), 7.93 (dd, 1Hα, J = 6.3, 2.2 Hz), 8.16 (t, 1H2, J
= 0.8 Hz), 12.32 (br s, OH). MS (EI), m/z: 189 (M+). Anal.
calcd. (found) for C9H7N3O2: C 57.14 (56.95), H 3.73 (3.81),
N 22.21 (22.15).
1
3
b
''
''
2
''
HN
O
O
OH
H
8
2
4
6
5
1
N
9
3
7
N
N
N
N
N
H
'
'
OH O
OH
O
'
N
OH
HpropylPic
H3NICSPERM
Tris{[(2-hydroxynicotinyl)carbonyl]-2-aminoethyl}amine
(H3NICTREN)
[(3-Hydroxypicolinyl)carbonyl]propylamine (HpropylPic)
To a mixture of HImNic (6.30 g, 33.3 mmol) in 1,4-dioxan
(400 mL) was added TREN (1.56 g, 10.67 mmol) in one por-
tion. The resulting mixture was refluxed for 18 h. After cooling
the reaction mixture to 20°C, the precipitate was filtered,
washed with THF and Et2O, and dried in vacuo to afford
To a mixture of 3-hydroxypicolinic acid (1.48 g, 10.6 mmol) in
THF (200 mL) was added CDI (1.92 g, 11.8 mmol) in one por-
tion. The mixture was refluxed for 2 h whereupon n-propylamine
(10.1 g, 0.12 mol) was added and the resultant mixture was
refluxed for a further 19 h. After cooling the reaction mixture
to 20°C, the volatiles were removed under reduced pressure
and the resultant oil was column chromatographed on silica gel
(eluant: 50% pentane in Et2O, Rf = 0.84) to afford Hpropylpic
(1.40 g, 74%) as a yellow-brown liquid. IR (neat on KBr
plates): 3600–2600 (br, νOH), 3380 (m, νN-H), 1650 (s, νCTO),
1580 (m, νCTC), 1535 (s, amide II), 1450 (m, νCTC), 1340,
1295, 1255, 1195, 810, 795. 1H NMR: 0.85 (t, 3H1, J = 7 Hz),
1.54 (m, 2H2), 3.25 (dt, 2H3, J = 8, 7 Hz), 7.36 (dd, 1Hγ, J = 8,
0.8 Hz), 7.48 (dd, 1Hβ, J = 8, 4 Hz), 8.12 (dd, 1Hα, J = 4,
1
H3NICTREN as a white solid (5.20 g, 95%). H NMR, 13C
NMR, IR, and MS spectra were identical to those reported for
the sample obtained by Method A. Anal. calcd. (found) for
C24H27N7O6 0.25H2O: C 56.08 (56.15), H 5.39 (5.57), N 19.07
(19.07).
1,1,1-Tris{[(2-hydroxynicotinyl)carbonyl]-2-aminomethyl}eth
ane (H3NICTAME)
To a mixture of HImNic (6.05 g, 32.0 mmol) in 1,4-dioxan
(400 mL) was added TAME (1.10 g, 9.39 mmol) in one por-
tion. The resulting mixture was refluxed for 19 h. After cooling
the reaction mixture to 20°C, the precipitate was filtered,
washed with THF and Et2O, and dried in vacuo to afford
H3NICTAME as an off-white solid (4.22 g, 89 %), mp 270°C
(dec.). IR: 3600–2600 (br, νOH), 3280 (m, νNH), 1665 (s,
νCTO), 1600 (m, νCTC), 1562 (s, amide II), 1480 (m, νCTC),
0.8 Hz), 9.14 (t, 1H, C(O)NH, J = 6 Hz), 12.70 (br s, OH). 13
C
NMR: 11.32 (C1), 22.27 (C2), 40.05 (C3), 125.84 (Cγ), 128.95
(Cβ), 131.49 (Cα), 139.66 (CC(O)NH), 157.37 (C-OH),
168.70 (CTO). Exact Mass calcd. (found) for C9H12N2O2:
180.0904 (180.0898). Anal. calcd. (found) for C9H12N2O2: C
59.99 (59.77), H 6.71 (6.78), N 15.55 (15.50).
1
1430, 1320, 1235, 1150, 790, 770. H NMR: 0.91 (s, 3H1),
3.14–3.47 (partially obscured d, 6H2, J = 6 Hz), 6.46 (t, 3Hβ J
= 6 Hz), 7.69 (dd, 3Hγ, J = 8, 1.2 Hz), 8.30 (dd, 3Hα, J = 8,
1.2 Hz), 10.01 (t, 3H, C(O)NH, J = 6 Hz), 12.38 (br s, 3H,
OH). MS (FAB), m/z: 481 (M+H)+. Anal. calcd. (found) for
C23H24N6O6 H2O: C 55.42 (55.68), H 5.22 (5.28), N 16.87
(16.55).
1,1,1-Tris{[(3-hydroxypicolinyl)carbonyl]-2-aminomethyl}-
ethane (H3PICTAME)
To a mixture of 3-hydroxypicolinic acid (5.34 g, 38.39 mmol)
in THF (150 mL) was added CDI (6.43 g, 39.65 mmol) in one
portion. The mixture was refluxed for 5 h whereupon TAME
(1.50 g, 12.80 mmol) was added and the solution was refluxed
for a further 26 h. After cooling the reaction mixture to 20°C,
the precipitate was filtered and the filtrate was concentrated in
vacuo to yield a dark reddish-brown residue. This residue was
redissolved in a minimum amount of hot MeOH (ca. 40 mL),
which, after cooling to room temperature, was triturated with
Et2O to yield the product as a brown solid (1.25 g, 20%), mp
165–167°C. X-ray quality crystals were obtained by slow
evaporation of a MeOH:Et2O (1:20) solution at room tempera-
ture (rt). IR: 3600–2600 (br, νOH), 3355 (m, νNH), 1650 (s,
νCTO), 1580 (m, νCTC), 1530 (s, amide II), 1448 (m, νCTC),
1355, 1315, 1295, 1245, 1200, 1160, 810, 695, 660. 1H NMR:
N1,N5,N10-Tris(2-hydroxynicotinyl)spermidine
(H3NICSPERM)
To a suspension of HImNic (2.639 g, 13.96 mmol) in 1,4-di-
oxane (200 mL) was added spermidine (0.658 g, 4.53 mmol)
in one portion. The resulting mixture was refluxed for 19 h.
After cooling the reaction mixture to 20°C, the brown-orange
precipitate was filtered, washed with Et2O, and dried in vacuo
to yield 1.611 g of the crude product; 205 mg of this was col-
umn chromatographed on lipophilic Sephadex LH-20™ (3 ×
120 cm column; eluant: 50% MeOH in EtOAc) to afford pure
© 1998 NRC Canada