SYNTHESIS OF DEUTERIUM-LABELED POLYAMINES 669
1
N-(N-Boc-30-aminopropyl)-4-aminobutanol (3). Com-
pound 2 (0.79 g, 3.1 mmol) was added to 1.0 equivalent
(0.28g) of 4-aminobutanol in 5 mL dry dichloromethane.
After 5 h at 508C, the reaction mixture was cooled,
washed with saturated Na2CO3 and extracted with ether.
Flash silica gel chromatography using hexane–ethyl
acetate (9:1) as solvent gave 0.51 g (66%) N-(N-Boc-30-
aminopropyl)-4-aminobutanol 3. 1H NMR (CDCl3): d 7.40
(s, 1H), 2.55 (t, 2H), 1.75 (m, 2H), 2.60 (m, 2H), 2.55 (m,
2H), 1.81 (m, 2H), 1.72 (m, 2H), 3.75 (m, 2H), 1.35 (s, 9H).
described for 3 yielded 0.25g (62%) of compound 7. H
NMR (CDCl3): d 2.11 (s, 3H), 2.85–2.88 (m, 8H),
1.80–1.82 (m, 4H), 1.74–1.76 (m, 4H), 1.40 (s, 18H).
1; 1; 3; 3-2H4-N1-acetylspermine trihydrochloride. Com-
pound 7 (0.22 g, 0.5 mmol) was treated with 10 mL of
4 M HCl in dioxane (5 mL) with stirring at 25oC for 5 h.
Most of the solvent was evaporated in vacuo and the
sticky residue was then dissolved in distilled water
(50 mL) and extracted with ether (3 x 20 mL). The
aqueous layer was then passed through a C18 reverse-
phase column. The compound was eluted with 20%
ethanol–water. Fractions were collected and flushed with
N2 and lyophilized to afford 42mg (24%) of 1,1,3,3-2H4-
N1-acetylspermine trihydrochloride. 1H NMR (D2O): d
1.98 (s, 3H), 3.11 (m, 8H), 2.06 (m, 4H), 1.83 (m, 4H).
HRMS ðm þ HÞ theor.: 249.4121, found: 249.4130.
N-(N-Boc-30-aminopropyl)-N-Boc-4-aminobutanol
(4). Compound 3 (0.51 g, 2.07 mmol) was added to 1.0
equivalent (0.45 g) of (Boc)2O in 2.0 equivalent (0.6 mL,
4.14 mmol) of triethylamine in 10 mL of dry acetonitrile at
258C; the reaction was continued overnight. Pure N-(N-
Boc-30-aminopropyl)-N-Boc-4-aminobutanol 4 (0.325 g,
86%) was obtained following the procedure described
for 1. 1H NMR (CDCl3): d 2.60–2.66 (m, 6H), 1.78–1.82
(m, 6H), 3.72 (m, 2H), 1.40 (s, 18H).
Synthesis of N1-acetylspermidine dihydrochloride
N-Boc-4-aminobutanol (8). 4-Aminobutanol (1.02 g,
11.5 mmol) in 5 mL of dry acetonitrile was added to
1.1 equivalent (2.76 g) of (Boc)2O in 2.0 equivalent
(3.2 mL, 23 mmol) of triethylamine and kept stirring at
258C overnight. Further workup and purification as
described for 1 yielded 1.81 g (78%). 1H NMR (CDCl3): d:
2.88 (s, 1H), 3.67 (m, 2H), 1.63 (m, 2H), 1.58 (m, 2H),
2.95 (m, 2H), 1.31 (s, 9H).
N-(N-Boc-30-aminopropyl)-N-Boc-4-amino-1-metha-
nesulfonoxybutane (5). The reaction of
4 (0.33 g,
0.94 mmol) with 1.2 equivalent (0.13 g) methane sulfo-
nyl chloride as described above for the preparation of
2 yielded 0.33 g (85%) N-(N-Boc-30-aminopropyl)-N-
Boc-4-amino-1-methanesulfonoxy butane 5. 1H NMR
(CDCl3): d 2.40 (s, 3H), 2.82–2.86 (m, 6H), 1.68–1.75
(m, 6H), 4.23 (m, 2H), 1.39 (s, 18H).
N-Boc-4-amino-1-methanesulfonoxybutane (9). Methane
sulfonyl chloride (1.32 g, 11.5 mmol, 1.2 equivalent)
in anhydrous pyridine was added dropwise to the
Boc-protected aminobutanol 8 (1.81 g, 9.6 mmol). After
2h at 258C, workup and purification as described for
2 gave 1.9 g (69%). H NMR (CDCl3): d 2.37 (s, 3H), 3.81
(m, 2H), 1.69 (m, 2H), 1.60 (m, 2H), 2.97 (t, 2H), 1.35
(s, 9H).
N-Acetyl-1,1,3,3-2H4-1,3-diaminopropane (6). The syn-
thesis of
6 was adapted from the procedure of
Tabor et al.27 1,1,3,3-2H4-1,3-Diaminopropane (0.6 g,
7.69 mmol) was added to 45 mL of cooled glacial acetic
acid with magnetic stirring. The mixture was heated to
55–608C. A mixture of 0.36 mL of acetic anhydride (0.5
equivalent) in 10 mL of glacial acetic acid was added
dropwise with stirring during a 1 h period. The mixture
was stored at 258C overnight and then evaporated to
dryness. The residue was dissolved in hot water, cooled
and adjusted to acidic pH with 6 N HCl. After eva-
poration to dryness in vacuo, the resultant solid was
extracted twice with 50 mL 2-propanol, and the insoluble
residue (unreacted 1,3-diaminopropane hydrochloride)
was discarded. The combined filtrates were concentrated
and cooled to ꢁ108C. The crystals that formed were
collected by filtration and recrystallized from 100 mL of
1
N1-Acetyl-1,1,3,3-2H4-N8-Boc-spermidine
pound (0.3 g, 1.0 equivalent) in 5.0 mL of dry
(10). Com-
6
dichloromethane was added to 2.5 mmol (0.67 g)
9. After 5 h at 508C, workup as described for 3 gave
0.25 g (34%) of compound 10. 1H NMR (CDCl3): d 2.105
(s, 3H), 2.88–2.92 (m, 8H), 1.78–1.82 (m, 4H), 1.33
(s, 9H).
1
1,1,3,3-2H4-N1-acetylspermidine dihydrochloride. Com-
pound 10 (0.146 g, 0.5 mmol) was treated with 10 mL of
4M HCl in dioxane (5mL) with stirring at 258C for 5h.
Pure 1,1,3,3-2H4-N1-acetylspermidine hydrochloride
(50 mg, 38%) was obtained by following the procedure
described for 1,1,3,3-2H4-N1-acetylspermine hydrochlor-
ide. 1H NMR (D2O): d 1.99 (s, 3H), 3.150 (m, 4H), 2.12
hot 2-propanol. The yield of 6 was 0.48 g (73%). H NMR
(CDCl3): d 2.05 (s, 3H), 1.65 (s, 2H).
N1-Acetyl-1,1,3,3-(2H4)-N9,N12- Boc2-spermine (7). Com-
pound 5 (0.33g, 0.84mmol) was added to 1.3 equivalent
(0.13g, 1.09mmol) of 6 in 5.0 mL of dry dichloro-
methane. After 5 h at 508C, workup similar to that
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 666–670
DOI: 10.1002.jlcr