Journal of Medicinal Chemistry
ARTICLE
Synthesis of tert-Butyl N-{4-[(2-{4-[2-(5-{[(tert-Butoxy)carbo-
nyl]amino}pentanamido)-5-tert-butylphenyl]phenyl}-4-tert-bu-
tylphenyl)carbamoyl]butyl}carbamate (14). By use of the same
procedure, but using N-Boc-5-aminovaleric acid instead of alanine,
compound 14 was synthesized with 60% yield. 1H NMR (300 MHz,
DMSO-d6) δ: 9.15 (s, 2H, NH), 7.44 (s, 4H, ArH), 7.39 (s, 4H, ArH),
7.30 (s, 2H, ArH), 6.80 (br s, 2H, NH), 2.90 (m, 4H, CH2), 2.18 (m,
4H, CH2), 1.50 (m, 4H, CH2), 1.35 (s, 22H, CH2 þ t-Boc), 1.32 (s, 18H, t-
Bu). 13C NMR (75 MHz, DMSO-d6) δ: 171.43, 155.31, 148.00, 137.90,
135.49, 132.14, 128.52, 126.92, 126.43, 124.44, 77.05, 54.67, 34.99, 33.96,
30.90, 28.86, 27.99, 22.19. m/z = 770.5 (calcd), 771.8 (obtained).
140.66, 139.21, 138.43, 132.52, 131.73, 127.13, 126.59, 126.47, 126.01,
125.90, 125.77, 125.68, 124.04, 123.61, 123.10, 122.41, 122.29, 122.07, 77.65,
37.93, 36.57, 36.47, 28.18, 28.13. m/z = 739.3 (calcd), 739.3 (obtained).
E. General Procedure for POCl3 Coupling. In a round-bottom flask
under nitrogen atmosphere, a specific diamine aryl oligomer (0.5 mmol,
1 equiv) and Boc-β-alanine (1.25 mmol, 2.5 equiv) were dissolved in dry
pyridine (5 mL). Once the temperature was cooled to 0 °C, POCl3 (1.25
mmol, 2.5 equiv) was added dropwise. The reaction mixture was stirred
at that temperature for 1 h. Ethyl acetate was added and the organic layer
washed with brine. Pyridine was removed by washing quickly with 1 M
HCl. The organic phase was then washed with a saturated solution of
NaHCO3 and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure, and the product was purified by flash column
chromatography with hexanes/ethyl acetate (60:40) eluent. According
to this procedure, the following compounds were obtained as solids.
Synthesis of tert-Butyl N-{2-[(2-{4-[2-(3-{[(tert-Butoxy)carbo-
nyl]amino}propanamido)-5-(trifluoromethyl)phenyl]phenyl}-
4-(trifluoromethyl)phenyl)carbamoyl]ethyl}carbamate (13b). Ac-
cording to the procedure described above, using compound 10b as
1
starting oligomer, compound 13b was obtained with 50% yield. H
NMR (300 MHz, DMSO-d6) δ: 9.45 (br s, 2H, NH), 7.93 (d, J = 8.6 Hz,
2H, ArH), 7.74 (d, J = 8.6 Hz, 2H, ArH), 7.63 (br s, 2H, ArH), 7.57 (s,
4H, ArH), 6.83 (m, 2H, NH), 3.17 (m, 4H, CH2), 2.40 (t, J = 6.9 Hz, 4H,
CH2), 1.35 (s, 18H, t-Boc). 13C NMR (75 MHz, DMSO-d6) δ: 170.19,
155.57, 138.79, 136.89, 135.19, 129.29, 126.82, 126.57, 125.99, 124.84,
122.34, 77.65, 36.50, 28.21. m/z = 738.3 (calcd), 739.3 (obtained).
F. General Procedure for Boc Deprotection. t-Boc protected oligomer
(0.16 mmol) was dissolved in dry DCM (1.5 mL), and trifluoroacetic
acid (TFA) was added (0.5 mL). After 1 h the product was precipitated
by a mixture of cold hexane and ethyl ether and filtrated. The pure
product, achieved as a salt with TFA, was dried under vacuum overnight.
The following compounds were obtained in a quantitative yield.
Synthesis of tert-Butyl N-{2-[(2-{6-[2-(3-{[(tert-Butoxy)carbo-
nyl]amino}propanamido)-5-(trifluoromethyl)phenyl]pyridazin-
3-yl}-4-(trifluoromethyl)phenyl)carbamoyl]ethyl}carbamate (11b).
According to the procedure described above, using compound 5b as starting
oligomer, compound 11b was obtained with a purity of about 90%. 1HNMR
(300 MHz, CDCl3) δ: 11.99 (br s, 2H, NH), 8.81 (d, J = 8.7 Hz, 2H, ArH),
8.16 (s, 2H, ArH), 7.92 (s, 2H, ArH), 7.78 (d, J = 8.7 Hz, 2H, ArH), 5.30 (br
s, 2H, NH), 3.52 (m, 4H, CH2), 2.74 (m, 4H, CH2), 1.35 (s, 18H, t-Boc).
Synthesis of Oligomer 1a. 1H NMR (300 MHz, DMSO-d6) δ: 10.58
(br s, 2H, NH), 8.09 (s, 2H, ArH), 7.78 (m, 10H, ArH þ NH), 7.59 (d, J
= 8.4 Hz, 2H, ArH), 3.02 (m, 4H, CH2), 2.63 (t, J = 6.5 Hz, 4H, CH2),
1.35 (s, 18H, t-Bu). 13C NMR (75 MHz, DMSO-d6) δ: 168.50, 158.45,
147.83, 133.29, 128.41, 127.77, 127.21, 126.72, 124.72, 35.02, 34.42,
33.22, 31.14. HRMS m/z = 517.3291 (calcd), 517.3293 (obtained).
Synthesis of tert-Butyl N-{2-[(2-{6-[2-(3-{[(tert-Butoxy)carbo-
nyl]amino}propanamido)-5-(trifluoromethyl)phenyl]pyridin-3-yl}-
4-(trifluoromethyl)phenyl)carbamoyl]ethyl}carbamate (12b). Ac-
cording to the procedure described above, using compound 9b as
1
starting oligomer, compound 12b was obtained with 50% yield. H
Synthesis of Oligomer 2a. 1H NMR (300 MHz, DMSO-d6) δ: 11.44
(br s, 1H, NH), 9.71 (br s, 1H, NH), 8.72 (s, 1H, ArH), 7.99 (m, 3H,
ArH), 7.74 (br s, 7H, ArH þ NH), 7.49 (m, 3H, ArH), 7.41 (s, 1H,
ArH), 3.06 (m, 2H, CH2), 2.98 (m, 2H, CH2), 2.69 (t, J = 6.6 Hz, 2H,
CH2), 2.55 (t, J = 6.9 Hz, 2H, CH2), 1.33 (s, 18H, t-Bu). 13C NMR (75
MHz, DMSO-d6) δ: 168.93, 168.2, 155.72, 148.99, 147.78, 146.76,
137.79, 133.95, 133.57, 132.32, 127.49, 127.07, 126.92, 126.51, 126.06,
NMR (300 MHz, DMSO-d6) δ: 12.30 (br s, 1H, NH), 9.74 (br s, 1H,
NH), 8.85 (br s, 1H, ArH), 8.59 (d, J = 8.7 Hz, 1H, ArH), 8.17 (d, J = 8.3
Hz, 2H, ArH), 8.09 (dd, J = 2.0, 8.3 Hz, 1H, ArH), 7.95 (d, J = 8.3 Hz,
1H, ArH), 7.80 (m, 3H, ArH), 6.91 (m, 1H, NH), 6.84 (m, 1H, NH),
3.27 (m, 2H, CH2), 3.14 (m, 2H, CH2), 2.55 (t, J = 6.8 Hz, 2H, CH2),
2.39 (t, J = 6.8 Hz, 2H, CH2), 1.33 (s, 9H, t-Boc), 1.29 (s, 9H, t-Boc).
13C NMR (75 MHz, DMSO-d6) δ: 170.11, 169.91, 155.54, 154.58, 147.81,
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dx.doi.org/10.1021/jm101410t |J. Med. Chem. 2011, 54, 2241–2254