668
E. Rivero-Buceta et al. / European Journal of Medicinal Chemistry 92 (2015) 656e671
acid 31 (220 mg, 0.50 mmol) to give 121.9 mg (62%) of the OBn
protected derivative 34 as a white solid; m.p. 122e124 ꢁC. 1H NMR
[CDCl3, 300 MHz] d 1.09e1.23 (m, 8H, CH2), 1.23e1.35 (m, 4H, CH2),
ArH). 13C NMR [CD3OD, 75 MHz]
d 28.54 (CH2), 30.89 (CH2), 31.01
(CH2), 31.12 (CH2), 31.14 (CH2), 40.89 (CH2), 108.27 (ArC), 109.47
(ArC), 119.54 (ArC), 134.49 (ArC), 151.08 (ArC), 152.09 (ArC), 172.25
(CO). MS (ESþ): m/z 505.3 (MþH)þ. Anal. C26H36N2O8 (C, H, N, O).
3.19e3.28 (m, 4H, CH2NH), 5.09 (s, 4H, CH2Ph), 5.12 (s, 4H, CH2Ph),
5.17 (s, 4H, CH2Ph), 6.89 (d, 2H, J ¼ 9.1 Hz, ArH), 7.26e7.49 (m, 30H,
ArH), 7.86 (bs, 1H, NH), 7.93 (d, 2H, J ¼ 9.1 Hz, ArH). 13C NMR [CDCl3,
4.3.6. N,N0,N00-tris(2,3,4-trihydroxybenzoyl)spermidine (43)
75 MHz]
d
27.56 (CH2), 29.59 (CH2), 29.72 (CH2), 39.95 (CH2), 71.29
According to the general procedure spermidine (50 mg,
0.34 mmol) was treated with 2,3,4-tribenzyloxybenzoic acid 31
(500 mg, 1.13 mmol) to give 240 mg (75%) of the OBn protected
derivative 42 as a white solid; m.p. 68e70 ꢁC. 1H NMR [CDCl3,
(CH2Ph), 76.23 (CH2Ph), 109.67 (ArCH), 120.35 (ArC), 127.31 (ArCH),
128.00 (ArCH), 128.61 (ArCH), 128.81 (ArCH), 129.05 (ArCH), 129.09
(ArCH), 129.13 (ArCH), 136.67 (ArC), 136.81 (ArC), 137.55 (ArC),
141.46 (ArC), 152.17 (ArC), 156.02 (ArC), 165.14 (CO). Anal.
300 MHz]
d 1.00e1.20 (m, 1H, CH2), 1.30e1.42 (m, 2H, CH2),
C
64H64N2O8 (C, H, N, O).
Following the deprotection procedure, the OBn derivative 34
1.43e1.54 (m, 2H, CH2), 1.60e1.76 (m, 1H, CH2), 2.80e3.00 (m, 1H,
CH2), 3.02e3.20 (m, 4H, CH2), 3.20e3.40 (m, 2H, CH2), 3.60e3.80
(m, 1H, CH2), 4.96e5.30 (m, 18H, CH2Ph), 6.70e6.96 (m, 5H, ArH),
7.20e7.60 (m, 42H, ArH), 7.70e8.10 (m, 4H, ArH). Anal. C91H85N3O12
(C, H, N, O).
(112.2 mg, 0.113 mmol) gave a crude product which was then pu-
rified by triturating with dichloromethane to afford 25 mg (48%) of
39 as a white solid; m.p. 179e181 ꢁC. 1H NMR [CD3OD, 300 MHz]
d
1.36e1.44 (m, 8H, CH2), 1.55e1.67 (m, 4H, CH2), 3.27e3.36 (m, 4H,
Following the deprotection procedure, the OBn derivative 42
(128.7 mg, 0.09 mmol) gave a crude product which was then pu-
rified by triturating with diethyl ether to afford 23 mg (42%) of 43 as
a white solid; m.p. 185e187 ꢁC. 1H NMR [CD3OD, 500 MHz]
CH2NH, overlaps with CD3OD), 6.35 (d, 2H, J ¼ 8.8 Hz, ArH), 7.12 (d,
2H, J ¼ 8.8 Hz, ArH). 13C NMR [CD3OD, 75 MHz]
d 27.98 (CH2), 30.33
(CH2), 30.50 (CH2), 40.36 (CH2), 107.79 (ArC), 108.98 (ArCH), 119.05
(ArCH), 133.57 (ArC), 150.71 (ArC), 151.54 (ArC), 171.76 (CO). MS
(ESþ): m/z 449.6 (MþH)þ. Anal. C22H28N2O8 (C, H, N, O).
d
1.30e1.60 (m, 4H, CH2), 1.70e1.80 (m, 2H, CH2), 3.25e3.62 (m, 8H,
CH2NH), 6.22e6.31 (m, 3H, ArH), 6.43 (d, 1H, J ¼ 8.3 Hz, ArH), 7.01
(d, 2H, J ¼ 8.3 Hz, ArH). 13C NMR [CD3OD, 125 MHz]
d 26.30 (CH2),
4.3.4. N,N0-decamethylenebis(2,3,4-hydroxybenzamide) (40)
According to the general procedure 1,10-diaminodecane
(34.5 mg, 0.20 mmol) was treated with 2,3,4-tribenzyloxybenzoic
acid (220 mg, 0.50 mmol) to give 97.4 mg (51%) of the OBn pro-
tected derivative 35 as a white solid; m.p. 110e112 ꢁC. 1H NMR
28.10 (CH2), 36.03 (CH2), 38.37 (CH2), 48.20 (CH2), 54.62 (CH2),
106.39 (ArC), 106.51 (ArC), 106.82 (ArC), 107.34 (ArC), 107.47 (ArC),
115.67 (ArC), 117.55 (ArC), 117.60 (ArC), 117.64 (ArC), 132.54 (ArC),
132.56 (ArC), 132.94 (ArC), 143.02 (ArC), 147.04 (ArC), 149.22 (ArC),
149.26 (ArC), 150.20 (ArC), 150.24 (ArC), 170.41 (CO), 170.43 (CO),
171.81 (CO). MS (ESþ): m/z 602.2 (MþH)þ. Anal. C28H31N3O12 (C, H,
N, O).
[CDCl3, 300 MHz] d 1.17e1.23 (m, 12H, CH2), 1.25e1.35 (m, 4H, CH2),
3.21e3.29 (m, 4H, CH2NH), 5.08 (s, 4H, CH2Ph), 5.13 (s, 4H, CH2Ph),
5.17 (s, 4H, CH2Ph), 6.89 (d, 2H, J ¼ 9.2 Hz, ArH), 7.28e7.48 (m, 30H,
ArH), 7.92 (d, 2H, J ¼ 9.2 Hz, ArH). 13C NMR [CDCl3, 75 MHz]
d
27.35
4.3.7. Tris[2-(20,30,40-trihydroxybenzamide)ethyl]amine (45)
(CH2), 29.72 (CH2), 29.89 (CH2), 39.82 (CH2), 71.30 (CH2Ph), 76.01
(CH2Ph), 109.60 (ArCH), 120.18 (ArC), 127.30 (ArCH), 127.99 (ArCH),
128.61 (ArCH), 128.81 (ArCH), 129.11 (ArCH), 136.68 (ArC), 136.75
(ArC), 137.51 (ArC), 141.75 (ArC), 152.22 (ArC), 156.03 (ArC), 165.17
(CO). Anal. C66H68N2O8 (C, H, N, O).
According to the general procedure tris(2-aminoethyl)amine
(0.052 mL, 0.34 mmol) was treated with 2,3,4-tribenzyloxybenzoic
acid 31 (494 mg, 1.12 mmol) to give 478 mg (100%) of the OBn
protected derivative 44 as a colorless oil. 1H NMR (CDCl3, 300 MHz)
d
2.28e2.36 (m, 6H, CH2N), 3.08e3.21 (m, 6H, CH2NH), 4.98e5.20
(m, 18H, CH2Ph), 6.70e6.86 (m, 3H, ArH), 7.22e7.43 (m, 42H, ArH),
7.75e7.87 (m, 3H, ArH).13C NMR [CDCl3, 75 MHz]
36.92 (CH2),
Following the deprotection procedure, the OBn derivative 35
(90 mg, 0.088 mmol) gave a crude product which was then purified
by triturating with dichloromethane to afford 25.3 mg (61%) of 40
as a white solid; m.p. 177e179 ꢁC. 1H NMR [CD3OD, 300 MHz]
d
70.77 (CH2), 76.01 (CH2), 77.22 (CH2), 109.28 (ArC), 120.12 (ArC),
126.93 (ArC), 127.78 (ArC), 128.45 (ArC), 128.63 (ArC), 128.86 (ArC),
128.91 (ArC), 129.02 (ArC), 136.39 (ArC), 136.53 (ArC), 137.32 (ArC),
141.28 (ArC), 152.02 (ArC), 155.92 (ArC), 175.13 (CO). MS (ESþ): m/z
1413.1 (MþH)þ. Anal. C90H84N4O12 (C, H, N, O).
d
1.28e1.39 (m, 12H, CH2), 1.52e1.64 (m, 4H, CH2), 3.27e3.39 (m,
4H, CH2NH, overlaps with CD3OD), 6.35 (d, 2H, J ¼ 9.1 Hz, ArH), 7.12
(d, 2H, J ¼ 9.1 Hz, ArH). 13C NMR [CD3OD, 75 MHz]
d 28.02 (CH2),
30.35 (CH2), 30.50 (CH2), 30.54 (CH2), 40.36 (CH2), 107.77 (ArC),
108.96 (ArCH), 119.03 (ArCH), 133.96 (ArC), 150.57 (ArC), 151.56
(ArC), 171.74 (CO). MS (ESþ): m/z 477.5 (MþH)þ. Anal. C24H32N2O8
(C, H, N, O).
Following the deprotection procedure, the OBn derivative 44
(220 mg, 0.15 mmol) gave a crude product which was then purified
by triturating with diethyl ether to afford 32 mg (35%) of 45 as a
white solid. Characterization of this compound in the literature was
incomplete [29c] and NMR was made in D2O.. Missing data (melting
point) and NMR in methanol were now included; m.p.
4.3.5. N,N0-dodecamethylenebis(2,3,4-hydroxybenzamide) (41)
According
to
the
general
procedure
1,12-
154e156 ꢁC.1H NMR (CD3OD, 300 MHz)
CH2N), 3.49 (t, J ¼ 6.12 Hz, 6H, CH2NH), 6.26 (d, J ¼ 8.80 Hz, 3H,
ArH), 7.03 (d, J ¼ 8.81 Hz, 3H, ArH). MS (ESþ): m/z 603.7 (MþH)þ.
Anal. C27H30N4O12 (C, H, N, O).
d
2.83 (t, J ¼ 6.20 Hz, 6H,
dodecamethylendiamine (80.14 mg, 0.40 mmol) was treated with
2,3,4-tribenzyloxybenzoic acid (440 mg, 1 mmol) to give 417 mg
(100%) of the OBn protected derivative 36 as a white solid; m.p.
92e94 ꢁC. 1H NMR [CDCl3, 300 MHz]
d 0.90e1.00 (m, 4H, CH2),
1.17e1.40 (m, 16H, CH2), 3.20e3.40 (m, 4H, CH2eNH), 5.07 (s, 4H,
CH2Ph), 5.14 (s, 4H, CH2Ph), 5.19 (s, 4H, CH2Ph), 6.80e7.00 (m, 2H,
ArH), 7.28e7.51 (m, 28H, ArH), 7.80e8.00 (m, 4H, ArH). Anal.
4.4. General method for the synthesis of alkyl amides 50e52 and
57e59
C
68H72N2O8 (C, H, N, O).
Benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexa-
Following the deprotection procedure, the OBn derivative 36
fluorophosphate (pyBOP) (2.2 mmol) was added to a solution of
2,3-dimethoxybenzoic acid 46 (2.2 mmol) or 2-benzyloxysalicylic
acid 53 (2.2 mmol) in dry dichloromethane (20 mL). After 5 min,
triethylamine (TEA) (2 mmol) and the corresponding diamine
(1 mmol) were added. The mixture was stirred at room tempera-
ture overnight and then evaporated to dryness. The residue was
(106 mg, 0.102 mmol) gave a crude product which was then puri-
fied by triturating with dichloromethane to afford 24 mg (47%) of
41 as a white solid; m.p. 151e153 ꢁC. 1H NMR [CD3OD, 500 MHz]
1.20e1.47 (m, 16H, CH2), 1.52e1.58 (m, 4H, CH2), 3.30e3.40 (m,
4H, CH2NH), 6.34 (d, 2H, J ¼ 8.8 Hz, ArH), 7.12 (d, 2H, J ¼ 8.8 Hz,
d