Journal of Medicinal Chemistry
Article
(COOH), 176.42 (COOH), 158.9 (HNCOO), 139.7 (Ar), 131.1
(Ar), 130.6 (Ar), 130.2 (Ar), 68.2 (CH), 55.8 (CH2-Ar), 32.8 (CH2),
28.80 (CH2) ppm. MS [M + H+] calcd, 282.1; found, 282.0.
(CH2), 29.5 (CH2), 29.0 (CH2), 28.4 (CH2), 26.7 (N-CH3). MS [M +
H+] calcd, 423.4; found, 423.3; [M + Na+] found, 445.3.
N14-Methyl-7,14-diaza-8,15-dioxo-18-methyloxycarbonyl-
18-benzyloxycarbonylamino-18-(S)-octadecanoic Acid (6).
DCC (0.97 g, 0.00468 mol) and NHS (0.36 g, 0.00312 mol) were
added to a stirred solution of 5 (1.10 g, 0.0026 mol) in acetonitrile (20
mL) at room temperature. The resulting mixture was stirred for 16 h.
Then DCU was filtered off and washed several times with acetonitrile.
The organic solution was then dropped into a solution of 6-
aminohexanoic acid (0.51 g, 0.0039 mol) in water (5 mL), maintaining
the pH at 8 with 2 N NaOH. After the mixture was stirred for 4 h at
room temperature, the acetonitrile was removed under reduced
pressure and the aqueous solution was brought to pH 2 with 37% HCl.
The crude product was extracted with dichloromethane (3 × 50 mL).
The organic phase was dried over Na2SO4 and concentrated to give a
yellowish oil (1.6 g) that was purified by flash chromatography on
silica gel, eluting with 10:1 dichloromethane−methanol to yield the
desired product as a clear oil (0.88 g, 63%). 1H NMR (600
MHz,CDCl3, 25 °C, TMS): δ (ppm) = 7.34 (m, 5H, Ar-H), 5.09 (m,
2H, CH2-Ar), 4.34 (m, 1H, CH), 3.73 (s, 3H, COOCH3), 3.34 (m,
1H, CH2-NCH3), 3.27 (t, 2H, CH2NH), 3.20 (m, 1H, CH2-NCH3),
2.91 (s, 3H, N-CH3), 2.41 (t, 2H, CH2-COOH), 2.32 (m, 2H, CH2-
CONCH3), 2.21 (m, 1H, CH2-CH), 2.14 (t, 2H, CH2-CONH), 2.05
(m, 1H, CH2-CH), 1.61 (m, 4H, CH2), 1.52 (m, 4H, CH2), 1.35 (m,
2H, CH2), 1.25 (m, 2H, CH2). 13C NMR (150 MHz, CDCl3, 25 °C,
TMS): δ (ppm) = 178.9 (COOH), 175.6 (CONCH3), 174.9
(CONH), 174.3 (COOCH3), 158.5 (HNCOO), 138.5 (Ar), 131.2
(Ar), 103.9 (Ar), 130.7 (Ar), 69.2 (CH), 56.3 (COOCH3), 54.7 (CH2-
Ar), 51.6 (CH2-NCH3), 50.0 (CH2-COOH), 41.3 (CH2NH), 39.0
(CH2), 37.2 (CH2), 36.1 (CH2), 31.9 (CH2), 31.2 (CH2), 29.8 (CH2),
28.9 (CH2), 27.9 (CH2), 27.4 (CH2), 26.3 (N-CH3). MS [M + H+]
calcd, 536.6; found, 536.5; [M + Na+] found, 558.4; [M + K+] found,
574.4.
N-(Benzyloxycarbonyl)-L-glutamic Acid Anhydride (2). A
solution of N,N′-dicyclohexylcarbodiimide DCC (66.4 g, 0.32 mol)
in tetrahydrofuran (200 mL) was quickly dropped into a solution of 1
(82.05 g, 0.29 mol) in tetrahydrofuran (200 mL) under vigorous
stirring. The formation of a white precipitate was immediately
observed (N,N′-dicyclohexylurea DCU). After 6 days of stirring at
room temperature (room temperature), the suspension was filtered
and the solid was washed several times with tetrahydrofuran. The
solution was concentrated to afford a yellowish oil still containing
some DCU (85.5 g). The product was used in the following step
1
without any further purification. H NMR (600 MHz, CDCl3, 25 °C,
TMS): δ (ppm) = 7.36 (m, 5H, Ar-H), 5.14 (s, 2H, CH2-Ar), 4.45 (m,
1H, CH), 2.48 (m, 2H, HOOC-CH2), 1.93 (m, 1H, CH2-CH), 1.84
(m, 1H, CH2-CH) ppm.
N-(Benzyloxycarbonyl)-L-glutamic Acid Methyl α-Emiester
(3). Methanol (120 mL) was added to a solution of 2 (57.9 g, 0.22
mol) in dichloromethane (220 mL), and the solution was stirred at
room temperature overnight. The solution was concentrated to afford
a yellow oil (64.0 g) that was used in the following step without any
purification. The main impurities were the methyl ω-emiester (28%,
based on the HPLC area ratio), easier to remove in the next step
because it is much less reactive and the dimethyl ester (25%) is not
reactive at all. 1H NMR (600 MHz, CDCl3, 25 °C, TMS): δ (ppm) =
7.39 (m, 5H, Ar-H), 5.09 (s, 2H, CH2-Ar), 4.42 (m, 1H, CH), 3.73 (s,
3H, CH3), 2.44 (m, 2H, HOOC-CH2), 2.21 (m, 1H, CH2-CH), 1.99
(m, 1H, CH2-CH). 13C NMR (150 MHz, CDCl3, 25 °C, TMS): δ
(ppm) = 177.5 (COOH), 172.8 (COOCH3), 156.3 (HNCOO), 136.2
(Ar), 129.2 (Ar), 128.3 (Ar), 67.2 (CH), 53.1 (CH3), 51.9 (CH2-Ar),
30.0 (CH2), 28.4 (CH2). MS [M + H+] calcd, 296.3; found, 296.1.
6-N-Methylaminoesanoic Acid (4). A solution of N-methyl
caprolactam (8.12 g, 0.064 mol) in ethanol (80 mL) was dropped into
a solution of 85% KOH (80 mL). The solution was refluxed for 4 days
and then concentrated to eliminate ethanol and washed with
dichloromethane (2 × 60 mL) to eliminate the unreacted N-methyl
caprolactam. The aqueous solution was directly used in the following
step (8.8 g, 95%). 1H NMR (600 MHz, D2O, 25 °C, TMS): δ (ppm)
= 2.50 (t, 2H, CH2-NH), 2.27 (s, 3H, CH3), 2.17 (t, 2H, CH2-
COOH), 1.56 (m, 2H, CH2), 1.47 (m, 2H, CH2), 1.30 (m, 2H, CH2).
13C NMR (150 MHz, D2O, 25 °C, TMS): δ (ppm) = 186.3 (COOH),
1,5-Bis(trifluoroacetylamino)-3-azapentane (7). A solution of
ethyl trifluoroacetate (44.7 g, 0.315 mol) in tetrahydrofuran (50 mL)
was slowly dropped into a cooled solution (0−10 °C) of diethylenetri-
amine (18.0 g, 0.175 mol) in tetrahydrofuran (150 mL). The reaction
mixture was allowed to reach room temperature and stirred overnight.
The solvent was removed under reduced pressure and the crude oil
was stirred in diisopropyl ether (50 mL) to obtain a white solid, which
was then filtered off, washed with diethyl ether (2 × 50 mL), and dried
1
over P2O5, (33.2 g, 64%). H NMR (600 MHz, DMSO-d6, 25 °C,
TMS): δ (ppm) = 3.21 (t, 4H, CH2-NHCO), 2.82 (t, 2H, NHCO),
2.67 (t, 1H, CH2-NH-CH2), 2.62 (t, 4H, CH2-NH-CH2). 13C NMR
(150 MHz, DMSO-d6, 25 °C, TMS): δ (ppm) = 118.8 (q, CF3), 160.1
(q, CO), 49.8 (CH2-NHCO), 48.1 (CH2-NH-CH2). MS [M + H+]
calcd, 296.1; found, 296.1.
59.7 (CH2-NH), 52.6 (CH2-COOH), 36.8 (CH2), 30.4 (CH2), 27.9
(CH2), 19.1 (CH3). MS [M + H+] calcd, 146.1; found, 146.1.
N7-Methyl-7-aza-8-oxo-11-methyloxycarbonyl-11-benzylox-
ycarbonylamino-11-(S)-unecanoic Acid (5). DCC (2.83 g, 0.014
mol) and N-hydroxysuccinimide NHS (1.47 g, 0.013 mol) were added
to a stirred solution of 3 (4.7 g, 0.012 mol) in acetonitrile (60 mL) at
room temperature. The resulting mixture was stirred for 16 h. Then
DCU was filtered off and washed several times with acetonitrile. The
organic solution was then dropped into a solution of 4 (2.0 g, 0.016
mol) in water (30 mL), maintaining the pH at 8 with 2 N NaOH.
After 3 h at room temperature, the acetonitrile was removed under
reduced pressure, the aqueous solution was brought to pH 2 with 37%
HCl, and the desired product was extracted with dichloromethane (3
× 50 mL). The organic phase was dried over Na2SO4 and
concentrated to give a yellowish oil (5.4 g). The crude material was
purified by flash chromatography on silica gel, eluting with 95:5
dichloromethane−methanol to afford the title product as a clear oil
(1.84 g, 48%). 1H NMR (600 MHz, CDCl3, 25 °C, TMS): δ (ppm) =
7.33 (m, 5H, Ar-H), 5.07 (m, 2H, CH2-Ar), 4.32 (m, 1H, CH), 3.71
(s, 3H, COOCH3), 3.31 (m, 1H, CH2-NCH3), 3.19 (m, 1H, CH2-
NCH3), 2.87 (s, 3H, N-CH3), 2.40 (t, 2H, CH2-COOH), 2.32 (m, 2H,
CH2-CON), 2.19 (m, 1H, CH2-CH), 2.02 (m, 1H, CH2-CH), 1.61 (m,
2H, CH2), 1.50 (m, 2H, CH2), 1.28 (m, 2H, CH2). 13C NMR (150
MHz, CDCl3, 25 °C, TMS): δ (ppm) = 180.0 (COOH), 175.9
(CONCH3), 174.5 (COOCH3), 158.5 (HNCOO), 138.6 (Ar), 130.7
(Ar), 130. 5 (Ar), 130.3 (Ar), 69.2 (CH), 56.1 (COOCH3), 54.7
(CH2-Ar), 51.9 (CH2-N), 50.0 (CH2-COOH), 36.2 (CH2), 31.8
1,5-Bis(trifluoroacetylamino)-3-N-[6-bromohexanoyl]-3-aza-
pentane (8). 7 (11.8 g, 0.04 mol) was dissolved in dichloromethane
(100 mL), and K2CO3 (6.9 g, 0.05 mol) was added. The resulting
mixture was cooled at 4 °C, and 6-bromohexanoyl chloride (6.0 mL,
0.04 mol) was slowly added. After the mixture was stirred for 2 h at
room temperature, salts were filtered off and washed with dichloro-
methane (2 × 20 mL). The organic solution was washed with 5%
NaHCO3 (30 mL), water (30 mL), 0.1 N HCl (30 mL), water (30
mL), and brine (30 mL). The organic phase was dried over Na2SO4
1
and concentrated under reduced pressure (14.5 g, 76.8%). H NMR
(600 MHz, CDCl3, 25 °C, TMS): δ (ppm) = 3.60 (m, 4H, CH2-
NHCO), 3.53 (m, 4H, CH2NCO), 3.39 (t, 2H, CH2-Br), 2.33 (t, 2H,
CH2-CO), 1.85 (q, 2H, -CH2-), 1.60 (q, 2H, -CH2-), 1.44 (q, 2H,
-CH2-). 13C NMR (150 MHz, CDCl3, 25 °C, TMS): δ (ppm) = 171.8
(CON), 160.6 (q, COCF3), 160.4 (q, COCF3), 118.0 (q, CF3), 118.2
(q, CF3), 49.7 (CH2-NHCO), 47.6 (CH2-NHCO), 42.0 (CH2-NH-
CH2), 41.0 (CH2-NH-CH2), 35.8 (CH2), 34.9 (CH2), 34.6 (CH2),
29.9 (CH2), 26.6 (CH2). MS [M + H+] calcd, 474.2; found, 474.1.
1-[9-(Trifluoroacetylamino)-7-N-[2-(trifluoroacetylamino)-
ethyl]-6-oxo-7-azanonyl]-1,4,7,10-tetraazacyclododecane-
4,7,10-triacetic(1,1-dimethylethyl ester) (9). DO3A-tris-tert-butyl
ester47(10.3 g, 0.020 mol) was dissolved in acetonitrile (200 mL), and
K2CO3 (3.45 g, 0.025 mol) was added. A solution of 8 (9.5 g, 0.020
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dx.doi.org/10.1021/jm301831f | J. Med. Chem. 2013, 56, 2466−2477