Journal of Medicinal Chemistry
Article
(m, 16H); 13C NMR (D2O) δ 135.0, 133.4, 53.5, 51.1, 49.7, 49.4, 35.6,
25.7, 25.62, 25.58, 25.5. HRMS (FAB) m/z calcd for C26H52N6 (M +
H)+ 449.4253; found 449.4326.
160 mmol) in 25% MeOH/CH2Cl2 (500 mL) at room temperature
was added salicylaldehyde (2.47 g, 20.3 mmol) dropwise over 5 min,
and the reaction was allowed to stir for 1 h. After H NMR (CDCl3)
1
4-Methylaminobutan-1-ol, 6.9a To a stirred solution of 4-
aminobutanol 5b (4.31 g, 48.4 mmol) in EtOH (50 mL) was added
ethylformate (5.86 mL, 75.5 mmol), and the mixture was stirred at
reflux for 18 h under N2. The solution was evaporated under reduced
pressure, and the crude formamide was used in the next step without
further purification. The reaction mixture was then dissolved in THF
(25 mL) and added to a suspension of LiAlH4 (5.50 g, 145 mmol) in
THF (50 mL) dropwise under a drying tube while stirring. The
reaction mixture was brought to reflux and monitored by TLC (20%
showed complete conversion to the imine, the reaction was cooled to
0 °C and di-tert-butyl dicarbonate (4.42 g, 20.3 mmol) was added as a
solid. The reaction was then stirred for 45 min at room temperature.
The volatiles were then removed under reduced pressure and the
residue was redissolved in absolute EtOH (400 mL) and cooled to 0
°C. A 1 M HCl (30 mL) solution was added dropwise, and then the
reaction was warmed to room temperature and allowed to stir for 2 h.
After hydrolysis of the imine was complete, the volatiles were removed
under reduced pressure. The residue was then redissolved in CH2Cl2
and washed three times with saturated aqueous Na2CO3 to generate
the free base. The free base was then purified by column
chromatography, Rf = 0.28 (1% NH4OH/10% MeOH/89%
CH2Cl2), to give 10 as a pale yellow oil (3.55 g, 47%). The lower-
than-expected yield here was likely due to the surprising partial
removal of Boc groups during the 2 h acid hydrolysis step. Note: an
alternative hydrolysis procedure under acid-free conditions was later
found to give higher yields in this type of transformation.11 1H NMR
(CDCl3) δ 3.18 (t, 6H), 2.82 (s, 3H), 2.71 (t, 2H), 1.25−1.65 (m,
26H); 13C NMR (CDCl3) δ 155.8, 155.5, 79.3, 79.2, 48.6, 48.0, 49.6,
41.0, 40.7, 34.1, 28.6, 28.4, 28.0, 25.8, 25.2, 24.8.
1
EtOH/80% CHCl3) and H NMR (CDCl3). After 2 h, the starting
material was consumed, and H2O (4.16 mL) was added to the cooled
reaction mixture, followed by 4 M NaOH (4.16 mL) and H2O (12.5
mL) with vigorous stirring. The precipitate was then removed by
filtration, and the filtrate was concentrated in vacuo. The residue was
redissolved in CHCl3, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to give 6 as a colorless oil (2.76
1
g, 56%). H NMR (CDCl3) δ 3.74 (br s, 2H), 3.57 (t, 2H), 2.62 (t,
2H), 2.43 (s, 3H), 1.50−1.75 (m, 4H), which matched literature
values.9a
(4-Hydroxybutyl)methylcarbamic Acid tert-Butyl Ester, 7.9b,21
A
solution of 6 (2.76 g, 26.8 mmol) in TEA/MeOH (1:7 v/v, 100 mL)
was stirred at 0 °C for 10 min. A solution of di-tert-butyl dicarbonate
(8.76 g, 40.2 mmol) in MeOH (20 mL) was added dropwise over 10
min. The mixture was stirred for 1 h under N2 atmosphere. The
temperature was allowed to gradually rise to room temperature, and
the solution was stirred overnight. The solution was evaporated under
reduced pressure, and the residue was dissolved in CH2Cl2 and washed
with deionized water. The organic layer was separated, dried over
anhydrous Na2SO4, filtered, and concentrated to give a colorless oil 7
that was used in the next step without further purification (4.54 g,
Di-tert-butyl {[{[Anthracene-9,10-diylbis(methylene)]bis-
( a z a n e d i y l ) } b i s ( b u t a n e - 4 , 1 - d i y l ) ] b i s { 4 - ( t e r t -
butoxycarbonylmethylamino)butyl}carbamate, 11. To a stirred
solution of amine 10 (600 mg, 1.61 mmol) in 25% MeOH/CH2Cl2
(25 mL) was added a solution of anthracene-9,10-dicarboxaldehyde
(172 mg, 0.73 mmol) in 25% MeOH/CH2Cl2 (20 mL). The reaction
was then stirred at room temperature under N2 overnight. After
1
complete imine formation was determined by H NMR, the solvents
1
were then removed in vacuo and the residue was redissolved in 50%
MeOH/CH2Cl2 (25 mL). The solution was then cooled to 0 °C,
followed by addition of NaBH4 (166 mg, 4.38 mmol) in small
portions, and the mixture was stirred at room temperature for 2 h.
After the reduction was complete, the solvents were removed in vacuo,
the residue was redissolved in CH2Cl2, and the organic layer was
washed three times with aqueous Na2CO3, separated, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo to give 11 as a
yellow oil (505 mg, 73%). Rf = 0.28 (6% MeOH/0.5% NH4OH/93.5%
84%). H NMR (CDCl3) δ 3.66 (t, 2H), 3.23 (t, 2H), 2.83 (s, 3H),
1.78 (br s, 1H), 1.51−1.60 (m, 4H), 1.44 (s, 9H), which matched
literature values.21
Methanesulfonic Acid 4-(tert-Butoxycarbonylmethylamino)butyl
Ester, 8.9b To a solution of the alcohol 7 (4.54 g, 22.24 mmol) and
TEA (15.5 mL, 111 mmol) in CH2Cl2 (60 mL) at 0 °C was added
methanesulfonyl chloride (12.73 g, 111 mmol) dropwise over 30 min
under a N2 atmosphere. The reaction mixture was stirred at 0 °C for 1
h and was slowly warmed to room temperature and stirred overnight
under N2. The reaction mixture was then cooled to 0 °C, and a 1 M
NaOH solution (500 mL) was added slowly with vigorous stirring.
The organic phase was separated and washed with deionized water.
The organic phase was again separated, dried over anhydrous Na2SO4,
filtered, and concentrated to give the product 8 as a colorless oil that
was used in the next step without further purification (6.03 g, 96%).
1H NMR (CDCl3) δ 4.25 (t, 2H), 3.28 (t, 2H), 3.02 (s, 3H), 2.84 (s,
1
CH2Cl2). H NMR (CDCl3) δ 8.37 (dd, 4H), 7.53 (dd, 4H), 4.70 (s,
4H), 3.19 (t, 12H), 2.89 (t, 4H), 2.81 (s, 6H), 1.57−1.44 (m, 52H);
13C NMR (CDCl3) δ 155.8, 155.6, 132.1, 130.1, 125.7, 124.9, 79.1,
50.4, 46.9, 46.0, 34.1, 28.5, 27.5. HRMS (FAB) m/z calcd for
C54H88N6O8 (M + H)+ 949.6664; found 949.6736.
Di-tert-butyl [{[{[Naphthalene-1,4-diylbis(methylene)]bis-
(azanediyl)}bis(butane-4,1-diyl)]bis[(tert-butoxycarbonyl)-
azanediyl]}bis(butane-4,1-diyl)]bis(methylcarbamate), 12. Com-
pound 12 was generated by the procedure described for compound
11, except that naphthalene-1,4-dicarboxaldehyde was used. Yellow oil
3H), 1.78 (m, 2H), 1.66 (m, 2H), 1.44 (s, 9H), which matched
literature values.9b
[4-(4-Aminobutylamino)butyl]methylcarbamic Acid tert-Butyl
Ester, 9. Putrescine (9.45 g, 107 mmol, 5 equiv) was dissolved in
acetonitrile (200 mL) with K2CO3 (14.79 g, 107 mmol) and the
mixture was stirred under N2. Mesylate 8 (6.03 g, 21.4 mmol)
dissolved in acetonitrile (60 mL) was added dropwise over 30 min
with stirring under N2. After 30 min, the reaction mixture was brought
to reflux and stirred overnight. The reaction mixture was then cooled,
solid K2CO3 was filtered off, and the filtrate was concentrated in vacuo.
The residue was redissolved in CH2Cl2 (200 mL) and washed six
times with saturated aqueous Na2CO3 to remove the unreacted
putrescine. The organic layer was then dried over anhydrous Na2SO4,
filtered, and concentrated to give the product 9 as a clear oil that was
used in the next step without further purification [yield 5.31 g (90%
1
(55%), Rf = 0.29 (10% MeOH/0.5% NH4OH/89.5% CH2Cl2). H
NMR (CDCl3) δ 8.21 (dd, 2H), 7.52 (dd, 2H), 7.71 (s, 2H), 4.22 (s,
4H), 3.19 (t, 12H), 2.81 (s, 3H), 2.75 (t, 4H), 1.31−1.62 (m, 52H);
13C NMR (CDCl3) δ 155.8, 155.6, 135.5, 132.2, 125.8, 125.6, 124.4,
79.2, 79.1, 51.8, 49.8, 46.9, 34.1, 28.5, 27.5. HRMS (FAB) m/z calcd
for C50H86N6O8 (M + H)+ 899.6507; found 899.6601.
Di-tert-butyl [{[1,4-Phenylenebis(methylene)]bis(azanediyl)}bis-
(butane-4,1-diyl)]-bis{[4-(tert-butoxycarbonylmethylamino)butyl]-
carbamate}, 13. Compound 13 was generated by the procedure
described for compound 11, except that benzene-1,4-dicarboxaldehyde
was used. Yellow oil (74%), Rf = 0.25 (7% MeOH/0.5% NH4OH/
92.5% CH2Cl2). 1H NMR (CDCl3) δ 7.27 (s, 4H), 3.76 (s, 4H), 3.20
(t, 12H), 2.83 (s, 6H), 2.64 (t, 4H), 1.53−1.45 (m, 52H); 13C NMR
(CDCl3) δ 155.7, 155.5, 138.9, 128.1, 79.0, 53.6, 49.0, 46.9, 34.0, 28.4,
27.3. HRMS (FAB) m/z calcd for C46H84N6O8 (M + H)+ 849.6351;
found 849.6423.
1
yield of crude mixture)]. H NMR (CDCl3) δ 3.21 (t, 2H), 2.84 (s,
3H), 2.71 (t, 2H), 2.62 (t, 4H), 1.40−1.60 (m, 17H). Note: this same
displacement chemistry has been performed with an amino alcohol.9b
t e r t - B u t y l N - ( 4 - A m i n o b u t y l ) - N - [ 4 - ( t e r t -
butoxycarbonylmethylamino)butyl]carbamate, 10. To a stirred
solution of 9 (5.54 g, 20.3 mmol) and anhydrous Na2SO4 (23 g,
H
dx.doi.org/10.1021/jm400496a | J. Med. Chem. XXXX, XXX, XXX−XXX