G.A. Barron et al. / European Journal of Medicinal Chemistry 45 (2010) 1430–1437
1435
cyclohexane protons). 13C NMR (CDCl3):
d
140–127 (aromatic
44.7 (N–CH2), 36.7–24.5 (–CH2–). HRMS (FAB): Calcd. for
carbons), 43 (2 ꢁ CH–N), 39 (CH2), 30.1–27.0 (cyclohexane carbons),
C42H52N4O4 Br2, 755.3166 [M ꢃ Br]þ, found: 755.3168 [M ꢃ Br]þ.
21.5 (CH3.Mts), 13.6 (CH3.Mts).
4.2.4.3. BNIPDaoxoct. (69%) 13C NMR (DMSO-d6):
d 161 (C]O),
4.2.1.5. N1,N10-Dimesityldecane 7. (75%), 1H NMR (CDCl3):
aromatic protons), 4.6 (t, NH), 2.9 (q, –CH2–N), 2.7 (s, CH3.Mts), 2.3
(s, CH3.Mts), 1.5 (t, –CH2–), 1.2 (s, –CH2–). 13C NMR (CDCl3):
140.0–
d
6.9 (s,
138–125 (aromatic carbons), 72 (O–CH2), 70 (O–CH2), 50–30
(–CH2–). HRMS (FAB): Calcd. for C36H40N4O6Br2, 702.6134
[M ꢃ 2H ꢃ Br]þ, found: 702.2589 [M ꢃ 2H ꢃ Br]þ.
d
127.0 (aromatic carbons), 40.7 (2 ꢁ CH2–NH), 30.0–26.0 (8 ꢁ CH2),
21.5 (CH3.Mts), 13.6 (CH3.Mts) (Scheme 1B).
4.2.4.4. BNIPDaCHM. (75%) 13C NMR (DMSO-d6):
d 161.0 (C]O),
136.0–122.0 (aromatic carbons), 51.0–27.0 (–CH2– and cyclohexane
carbons). HRMS (FAB): Calcd. for C43H50N4O4Br2, 685.3753
[M ꢃ H ꢃ 2Br]þ, found: 685.3748 [M ꢃ H ꢃ 2Br]þ.
4.2.2. Synthesis of toluenesulfonyloxypropylnaphthalimide (2)
(Scheme 1A)
Naphthalic anhydride (6.46 g, 32.58 mmol) was dissolved in
DMF (70 mL), followed by the addition of aminopropanol (2.45 g,
32.58 mmol) and DBU (7.45 mL). The solution was stirred at 85 ꢀC
for 4 h. The resulting residue was poured into icy water (200 mL) to
form a precipitate. The latter was filtered off and washed with
4.2.5. Synthesis of naphthalimidopropylamine, NPA (Scheme 1A)
4.2.5.1. Step 1 (Scheme 1A). 2 (0.5 g, 1.22 mmol) was dissolved in
DMF (7 mL) followed by the addition of Potassium phthalimide
(1.95 M excess) (0.44 g, 2.37 mmol). The solution was left stirring
for 12 h at 50 ꢀC. Reaction completion was monitored by thin layer
chromatography. The solution was poured into icy water (200 mL)
to form a precipitate. The precipitate was collected by filtration,
washed thoroughly with water and recrystallised with absolute
water. This compound, N-(3-hydroxypropyl) naphthalimide
(82.9%), was pure enough to be taken to the next step without
further purification. 1H NMR (CDCl3):
8.5–7.5 (m, aromatic
1
d
protons), 4.3 (t, CH2–O), 3.6 (t, N–CH2), 3.2 (broad, s, OH), 2.1 (m,
CH2). 13C NMR (CDCl3):
d
161 (C]O), 136–122 (aromatic carbons),
ethanol. 8 (65%) 1H NMR (CDCl3):
4.3 (t, CH2–N), 3.8 (t, N–CH2, naphthalimido), 2.1 (m, –CH2). 13C
NMR (CDCl3): 161.0 (C]O), 140.0–123.0 (aromatic carbons), 39.0
d 8.2–7.5 (m, aromatic protons),
58, 38, 31 (3 ꢁ CH2).
1 (5.10 g, 20 mmol) was dissolved in anhydrous pyridine
(80 mL). The solution was stirred for 15 min at 0 ꢀC. Tosyl chloride
(5.72 g, 30 mmol) was added, slowly, over 30 min. The solution was
left overnight at 4 ꢀC. The solution was poured into icy water
(200 mL) to form a precipitate. The latter was filtered off and
washed thoroughly with water. The crude product was recrystal-
lised with ethanol to form Toluenesulfonyloxypropylnaphthalimide
d
(CH2–N), 38.0 (N–CH2), 27.0 (–CH2–).
4.2.5.2. Step 2 (Scheme 1A). 8 (0.5 g, 1.3 mmol) was dissolved in
Ethanol (25 mL) followed by the addition of Hydrazine hydrate
(10 M excess) (650 mL, 13 mmol). The solution was left stirring for
12 h at 85 ꢀC. Reaction completion was monitored by thin layer
chromatography. The ethanol was evaporated followed by the
addition of dichloromethane (10 mL) giving rise to a precipitate.
The latter was filtered off and the filtrate was evaporated to dryness
to give a thick oil as naphthalimidopropylamine in quantitative
yield. The latter was immediately converted to its corresponding
hydrochloride salt by dissolving the amine in ethanol (2 mL), fol-
lowed by the addition of conc. HCl (3 mL) and ether (10 mL). The
white precipitate formed was filtered off, recrystallised (95%
ethanol) and dried under vacuo to give NPA (26%) as the hydro-
2 (75%). 1H NMR (CDCl3):
Tos aromatic protons), 4.2 (m, CH2–O, CH2), 2.3 (s, CH3), 2.0 (m,
CH2). 13C NMR (CDCl3):
161 (C]O), 138–125 (aromatic carbons),
d 8.6–7.6 (m, aromatic protons), 7.2 (m, O-
d
129–144 (O-Tos aromatic carbons), 70, 38, 29 (3 ꢁ CH2), 20 (CH3).
4.2.3. General N-alkylation reaction (Scheme 1A)
Dimesitylated polyamines (3–6) (0.5 g) were dissolved in DMF
(7 mL) followed by the addition of 2 (2.1 M excess) and caesium
carbonate (6 M excess). The solution was left stirring overnight at
85 ꢀC (3-4). For 5 and 6, the solutionwas left for 96h at 50 ꢀC. Reaction
completion was monitored by thin layer chromatography. The solu-
tion was poured into icy water (200 mL) to form a precipitate. HCl
(20 mL, 2 M) was added to neutralise the solution, the precipitate was
collected by filtration and washed thoroughly with water.
chloride salt. 13C (DMSO-d6):
carbons), 39 (CH2–NH2), 38 (N–CH2), 30 (–CH2–). HRMS (FAB):
d 165 (C]O), 140–125 (aromatic
Calcd. For C15H14N2O2 255.1131 [M
þ
H]þ, found: 255.1128
[M þ H]þ.
4.2.6. Synthesis of bisphthalimidopropyldiaminodecane
4.2.4. General deprotection reaction (Scheme 1A–B)
(BPHPDadec)
The fully protected polyamine derivatives were dissolved in
anhydrous dichloromethane followed by the addition of hydro-
bromic acid/glacial acetic acid. The solution was left stirring for 24 h
at room temperature. The precipitate formed was filtered off and
washed with dichloromethane (20 mL) and, ether (5 mL) (BNIP-
Dahex, BNIPDadodec and BNIPDaCHM). For BNIPDaoxoct, the
dichloromethane/hydrobromic acid/glacial acetic acid was
removed under vacuo and the residue was washed with dichloro-
methane (5 mL). The crude product recrystallised with absolute
ethanol.
4.2.6.1. N1,N10-Dimesityldecane 7. (0.5 g, 0.931 mmol) was dis-
solved in DMF (7 mL) followed by the addition of N-(3-bromo-
propyl) phthalimide (2.1 M excess) (0.52 g, 19.56 mmol) and
caesium carbonate (6 M excess) (1.81 g, 5.586 mmol). The solution
was left stirring overnight at 85 ꢀC. Reaction completion was
monitored by thin layer chromatography. The solution was poured
into icy water (200 mL) to form a precipitate followed by the
addition of HCl (20 mL, 2 M) The precipitate was collected by
filtration, washed thoroughly with water and dried under vacuo.
The fully protected polyamine derivative (0.2 g, 2.19 mmol) was
dissolved in anhydrous dichloromethane (5 mL) followed by the
addition of hydrobromic acid/glacial acetic acid (0.8 mL).
The solution was left stirring for 24 h at room temperature. The
precipitate formed was filtered off and washed with dichloro-
methane (20 mL), ether (5 mL) and dried under vacuo (BPHPDadec)
as its dihydrobromide salt.
4.2.4.1. BNIPDahex. (91%) 13C NMR (DMSO-d6): 24.5 (CH2), 25.2
(CH2), 25.4 (CH2), 36.7 (CH2), 44.8 (N–CH2), 46.5 (N–CH2), 122.0,
127.1, 130.6, 131.2, 134.3 (Aromatic Carbons), 163.6 (C]O). HRMS
(FAB): Calcd. for C36H40N4O4 Br2, 671.2227 [M ꢃ Br]þ, found:
671.2221 [M ꢃ Br]þ.
4.2.4.2. BNIPDadodec. (80%) 13C NMR (DMSO-d6):
134.3, 131.2, 130.6, 127.1, 122.0 (aromatic carbons), 46.6 (N–CH2),
d
163.6 (C]O),
4.2.6.2. BPHPDadec. (96%) 13C NMR (DMSO-d6):
122 (aromatic carbons), 46 (NH–CH2), 39 (N–CH2), 32–27 (–CH2–).
d 168 (C]O), 142–