Molecules 2009, 14
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4-(3’-Oxybutyloxycarbonyloxymethyleneoxy)acetanilide (2). Obtained using 2-methoxyethanol.
Purified after silica gel column chromatography eluting with acetone:hexane (20:80 to 35:65) to yield
an oil which solidified on standing. The solid was recrystallized from CH2Cl2:ethyl ether:petroleum
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ether to give colorless crystals. Yield = 11%, mp = 69-70 °C; H-NMR (400 MHz, CDCl3) δ 7.42 (d,
J = 9 Hz, 2 H), δ 7.09 (brs, 1 H), δ 7.03 (d, J = 9 Hz, 2H), δ 5.74 (s, 2 H), δ 4.33 (m, 2 H), δ 3.63 (m, 2
H), δ 3.39 (s, 3 H), δ 2.17 (s, 3 H); Anal. Calcd. for C13H17NO6: C, 55.12; H, 6.05; N, 4.94. Found: C,
54.95; H, 6.11; N, 4.98.
4-(3’-Oxy-1’-methylbutyloxycarbonyloxymethyleneoxy)acetanilide (3). Obtained using 1-methyl-2-
methoxyethanol. Purified after silica gel column chromatography eluting with acetone:hexane (20:80
to 30:70) to yield an oil which solidified on standing. The solid was recrystallized from CH2Cl2:ethyl
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ether:petroleum ether to give colorless crystals. Yield = 62%, mp = 80-82 °C; H-NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 9 Hz, 2 H), δ 7.18 (brs, 1 H), δ 7.03 (d, J = 9 Hz, 2H), δ 5.72 (dd, J = 0.8 Hz,
22 Hz, 2 H), δ 4.99 (m, 1 H), δ 3.45 (m, 2 H), δ 3.36 (s, 3 H), δ 2.16 (s, 3 H), δ 1.29 (d, J = 6 Hz, 3 H);
Anal. Calcd for C14H19NO6: C, 56.56; H, 6.44; N, 4.71. Found: C, 56.69; H, 6.45; N, 4.71.
4-(3’,6’,9’-Trioxydecyloxycarbonyloxymethyleneoxy)acetanilide (4). Obtained using triethylene glycol
monomethyl ether. Purified by silica gel column chromatography eluting with ethyl acetate:hexane
(50:50 to 90:10) followed by another column chromatography purification with acetone:hexane (30:70
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to 40:60) as the eluent to yield a colorless oil. Yield = 20%, H-NMR (400 MHz, CDCl3) δ 7.43 (d,
J = 9 Hz, 2 H), δ 7.30 (brs, 1 H), δ 7.01 (d, J = 9 Hz, 2 H), δ 5.73 (s, 2 H), δ 4.33 (m, 2 H), δ 3.72 (m, 2
H), δ3.63 (m, 6 H), δ 3.54 (m, 2 H), δ 3.37 (s, 3 H), δ 2.16 (s, 3 H); Anal. Calcd for C16H25NO8: C,
54.98; H, 6.79; N, 3.77. Found: C, 54.27; H, 6.95; N, 3.75.
3.2.2. Procedure for the synthesis of the NANAOCOM prodrug 5 [15]
(a) Methoxyethyloxycarbonylimidazole synthesis: 2-Methoxyethanol (0.01 mol) was reacted with
1,1’-carbonyldiimidazole (0.011 mol, 1.1 equivalents) in CH2Cl2 (50 mL) overnight at room
temperature. The clear solution was diluted with CH2Cl2 (50 mL), washed with 1N HCl (10 mL) and
water (2 × 10 mL). The CH2Cl2 layer was dried over Na2SO4 then concentrated to give
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methoxyethyloxycarbonylimidazole as an oil. Yield = 98%, H-0NMR (CDCl3): δ 3.4 (s, 3H), δ 3.73
(t, 2H), δ 4.55 (t, 2H), δ 7.08 (d, 1H), δ 7.45 (d, 1H), δ 8.15 (s, 1H).
(b) N-Methyl carbamic acid methoxyethyloxy ester: Methoxyethyloxycarbonylimidazole (0.01 mol)
was coupled with aqueous methylamine (0.013 mol, 1.3 equivalents) in 2-propanol (10 mL) at 50 °C
overnight. The reaction mixture was then concentrated using a rotavapor at 50 °C. The oily residue
obtained was dissolved in CH2Cl2 (50 mL) and washed with 1N HCl (10 mL) and water (5 × 3 mL).
The CH2Cl2 layer was dried over Na2SO4 and concentrated to give N-methyl carbamic acid
methoxyethyloxy ester as an oil: yield = 72%, 1H-NMR (CDCl3): δ 2.8 (d, 3H), δ 3.39 (s, 3H), δ 3.63
(t, 2H), δ 4.24 (t, 2H), δ 4.7 (s, 1H).
(c) N-Methyl-N-methoxyethyloxycarbonylaminomethyl chloride (NANAOCAM-Cl): A suspension
of N-methyl carbamic acid methoxyethyloxy ester (16 mmol), paraformaldehyde (1.7 eqvs.) and
trimethylsilyl chloride (13 eqvs.) was refluxed with a CaCl2 drying tube on top of a water condenser,
for 2.5 h over an oil bath. The suspension was diluted with CH2Cl2 and filtered to remove the