F. Wan et al.
Synthesis of 1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane
(
5)
Method A [19] 1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclodode-
cane hydrobromide (4, 5.95 g, 10 mmol) was dissolved in water (250 mL) at 70 °C.
The solution was allowed to cool to 40 °C, after which 10 % aqueous KOH solution
(
11.2 mL, 20 mmol) was added. The reaction mixture was stirred at 40 °C for 30 min
and then extracted with hexanes (3 9 100 mL). The combined organic layers were
washed with water (3 9 100 mL), dried (Na SO ), filtered, and concentrated under
2
4
reduced pressure to give 5 as a colorless viscous oil which solidified upon storage at
0 °C (yield 4.10 g; 8.00 mmol, 95 %). Mp 44–47 °C.
2
Method B [2] Compound 4 (5.95 g, 10 mmol) was dissolved in 50 mL of dry
acetonitrile containing anhydrous K CO (20 mmol). The resulting mixture was
2
3
stirred at 50 °C for 24 h. After removal of the solids, the filtrate was concentrated
under reduced pressure. The residue was redissolved in CHCl and washed with
water thoroughly (3 9 100 mL). Evaporation of CHCl afforded 5 in quantitative
3
3
1
yield. Mp 43–45 °C (Fig. 3); H NMR (400 MHz, CDCl , d/ppm) 1.45 (s, 9 H),
3
1
Anal. calcd. for C H N O : C, 60.67; H, 9.79; N, 10.89. Found: C, 60.26; H,
.46 (s, 18 H), 2.56 (m, 4 H), 2.72–2.78 (m, 8 H), 2.81 (m, 4 H), 3.30 (s, 6 H);
26 50 4 6
9
.28; N, 10.80.
Synthesis of 1,4,7-Tris(tert-butoxycarbonylmethyl)-10-(adamantan-1-
ylcarbamoylmethyl)-1,4,7,10-tetraazacyclododecane (6)
To a suspension of 5 (2.57 g, 5 mmol) and anhydrous K CO (1.38 g, 10 mmol) in
2
3
6
0 mL of dry acetonitrile was added a solution of 2 (1.36 g, 5 mmol) in 20 mL of
acetonitrile. The resulting mixture was stirred vigorously at 80 °C under argon for
8 h. After removal of the solids and evaporation of the solvent, the residue was
4
redissolved in CHCl and washed thoroughly by water (3 9 30 mL). Evaporation of
3
CHCl afforded the crude product, which was purified by column chromatography
3
(
(
CHCl /CH OH, V:V = 10:1) to give 6 as yellow–white solid with yield of 2.68 g
3 3
-
1
7.6 mmol, 78 %). Mp 188.5–190.5 °C; FT-IR (KBr, cm ) 3,248, 2,980, 2,906,
,850, 2,827, 1,736, 1,668, 1,456, 1,423, 1,369, 1,309, 1,222, 1,171, 1,107, 756, 595
2
1
(
3
Fig. 4); H NMR (400 MHz, CDCl , d/ppm) 1.469 (s, 27 H, –CH ), 1.63 (t,
3
3
JH,H = 3.2 Hz, 4 H), 2.02 (s, 6 H), 2.07 (s, 3 H), 2.21–2.75 (m, 10 H, –CH N–),
2
2
3
.88–2.92 (s, 6 H, –CH N–), 3.10 (s, 2 H, –CH CONH–), 3.29 (s, 2 H, –CH COO–),
2 2 2
.34 (s, 2 H, –CH COO–), 3.38 (s, 2 H, –CH COO–), 7.01 (brs, 1 H, –CH CONH–).
2
2
2
1
3
C NMR (100 MHz, CDCl , d/ppm) 27.9, 28.1, 29.3, 29.4, 36.3, 36.4, 41.0, 41.1,
3
4
1
7
6
1.2, 41.4, 41.5, 52.0, 52.3, 52.6, 53.2, 56.3, 56.6, 58.3, 62.2, 81.6, 81.7, 81.8, 169.9,
?
70.6, 171.8, 172.3; MS (API, positive mode) m/z [M?H] calcd. 706.51, obsd.
06.30; Anal. calcd. for C H N O (w /%): C, 64.65; H, 9.57; N, 9.92. Found: C,
3
8
67
5
7
B
4.52; H, 9.65; N, 9.75.
1
23