6
temperature, the pH of the mixture was adjusted to 8~9 with an
aqueous solution of saturated NaHCO3, then the solution was
extracted with CH2Cl2 (3×10 mL) and the organic layers were
combined and evaporated by rotary evaporation to get pure PRII
(310.1 mg, 92% ). m.p., 123.1 °C; 1H NMR (600 MHz, CDCl3) ꢂ
6.98 – 6.67 (m, ArH, 10H), 6.00 (s, CONH, 1H), 5.18 (s, CONH,
1H), 4.56 (s, ArOCH2, 1H), 3.75 (td, ArCH2Ar&ArOCH3, J =
13.2, 8.8 Hz, 37H), 3.19 (d, NHCH2, J = 11.6 Hz, 2H), 2.93 (s,
NH2CH2, 2H), 2.58 (s, CONHCH2, 1H), 2.26 (s, COCH2, 2H),
1.72 (s, CONHCH2&CH2, 5H), 1.45 (s, CH2, 2H), 1.25 (s, CH2,
2H), 0.66(s, CH2, 2H), -0.19 (s, CH2, 2H), -1.14 (d, CH2, J = 80.1
ꢂ 168.62, 155.01, 151.68, 115.96, 115.14, 68.50, 55.99, 39.30,
33.43, 29.84, 29.62, 29.50, 27.08.
3.7.tert-butyl (6-((8-(2-(4methoxyphenoxy)acetamido)octyl)
amino) -6-oxohexyl) carbamate (4)
To a solution of compound 3 (308.30 mg, 1.00 mmol) and
6-((tert-butoxycarbonyl)amino)hexanoic acid (231.20 mg, 1.00
mmol) in anhydrous CH2Cl2 (5 mL), DCC (309.50 mg, 1.50
mmol) and DMAP (12.20 mg, 0.10 mmol) dissolved in
anhydrous CH2Cl2 (5 mL) were added dropwise at room
temperature and the mixture was stirred for 16 hours at room
temperature. After completion of the reaction, the white
precipitate was filtered off and the solvent was removed by rotary
evaporation. The crude product was purified by column
Hz, 2H), -1.48 (d, CH2, J = 24.1 Hz, 2H), -2.24 (s, CH2, 2H); 13
C
NMR (150 MHz, CDCl3) ꢂ 173.02, 167.66, 151.14, 150.97,
150.73, 150.65, 150.53, 1550.39, 147.63, 129.56, 129.39, 128.94,
128.70, 128.59, 128.46, 128.16, 127.68, 127.40, 1114.68, 114.51,
114.04, 113.13, 112.74, 66.32, 56.73, 56.44, 56.10, 55.99, 55.80,
55.45, 40.84, 40.27, 38.30, 36.69, 30.47, 29.59, 29.23, 28.99,
chromatography (SiO2, DCM:MeOH
= 30:1) to get the
compound 4 (285.00 mg, 55%) as a white power. m.p. 90.0
;
1H NNR (300 MHz, CDCl3) ꢂ 6.83 (s, ArH, 4H), 6.61 (s,
OCH2CONH, 1H), 5.64 (s, CONH, 1H), 4.62 (s,
(CH3)3COCONH 1H), 4.41 (s, ArOCH2, 2H), 3.75 (s, ArOCH3,
3H), 3.30 (dd, J = 13.3, 6.6 Hz, CONHCH2, 2H), 3.20 (dd, J =
13.0, 6.5 Hz, CONHCH2, 2H), 3.08 (dd, J = 11.8, 5.6 Hz,
CONHCH2, 2H), 2.14 (t, J = 7.4 Hz, COCH2, 2H), 1.62 (dt, J =
15.4, 7.8 Hz,CONHCH2CH2, 2H), 1.50 – 1.38 (m, t-but-H&CH2,
13H), 1.35 – 1.21 (m, CH2, 12H). 13C NMR (75 MHz, CDCl3) ꢂ
173.03, 172.95, 168.64, 155.05, 151.72, 116.00, 115.18, 77.78,
77.36, 76.93, 68.55, 56.00, 39.73, 39.26, 36.90, 30.10, 29.90,
29.78, 29.37, 27.08, 27.00, 26.71, 25.65. MS (m/z): HRMS (ESI)
calculated for [M+H]+ C28H48N3O6+, 522.3538; found 522.3561;
28.73, 28.48, 27.83, 26.54, 25.51, 24.01; MS (m/z): HRMS (ESI)
2+
, 517.7905; found
calculated for [M+2H]2+ C60H81N3O12
517.7950.
4.5. Compound R
A solution of compound PRII (51.68 mg, 0.05 mmol) and
compound 2 (13.66 mg, 0.05 mmol) in CDCl3 (0.5 mL) was
stirred for 18 hours at 60 then the reddish brown solution was
cooled to room temperature. Then NaBH4 (1.90 mg, 0.05 mmol)
in 0.5 mL CH3OH was added dropwise to the previous solution.
After stirring for 0.5 hour at room temperature, 20 µL of
deionized water was added to quench the reaction. After
completion of the reaction, the solvent was removed by rotary
evaporator and the pure product R (39.90 mg, 62%) was obtained
by silica gel column chromatography (CH2Cl2:MeOH = 30:1).
m.p. 96.9 °C; 1H NMR (600 MHz, CDCl3) ꢂ 7.25 – 6.69 (m, ArH,
24H), 5.81 (s, NHCOCH2O Ar, 1H), 5.22 (s, -CONH, 1H), 4.57
(s, OCH2, 2H), 3.81 – 3.68 (m, -OCH3, 37H), 3.19 (d, J = 34.8 Hz,
CONHCH2, 2H), 2.73 (t, J = 7.3 Hz, CONHCH2, 2H), 2.62 (s,
CONHCH2,1H), 2.25 (t, J = 7.5 Hz, COCH2, 2H), 1.76 – 1.70 (m,
CONHCH2&CH2, 3H), 1.69 – 1.63 (m, CH2, 2H), 1.49 – 1.42 (m,
CH2, 2H), 1.24 (dd, J = 13.0, 6.0 Hz, CH2, 4H), 0.62 (s, CH2, 2H),
-0.24 (s, CH2, 2H), -1.08 (d, J = 79.3 Hz, CH2, 2H), -1.52 (d, J =
32.4 Hz, CH2, 2H), -2.24 (s, CH2, 2H). 13C NMR (150 MHz,
CDCl3) ꢂ 172.95, 167.70, 154.83, 151.17, 151.00, 150.74, 150.67,
150.55, 150.40, 148.13, 147.60, 147.19, 130.08, 129.52, 128.98,
128.72, 128.61, 128.49, 128.17, 127.74, 127.40, 124.98, 124.42,
123.92, 122.99, 114.77, 114.54, 114.11, 113.14, 112.86, 112.70,
77.36, 66.33, 56.77, 56.50, 56.08, 56.02, 55.83, 55.76, 55.64,
55.44, 53.81, 49.50, 40.22, 38.30, 37.07, 30.55, 30.46, 29.93,
29.59, 29.25, 28.99, 28.76, 28.39, 27.81, 27.44, 27.10, 25.99,
23.98; MS (m/z): HRMS (ESI) calculated for [M+2H]2+
+
m/z calculated for [M-CO2-C4H8]+ C23H40N3O4 , 422.3013; found
422.3046.
3.8.6-amino-N-(8-(2-(4-methoxyphenoxy)acetamido)octyl)
hexanamide (5)
To a solution of compound 4 (52.14 mg, 0.10 mmol) in
anhydrous CH2Cl2 (0.4 mL), TFA (0.1 mL) was added dropwise.
The reaction mixture was stirred at room temperature for 0.5 hour
and the solvent was removed by rotary evaporator. The crude
product was recrystallized by diethyl ether to get the pure
1
compound 5 (28 mg, 66%) as a white power. m.p. 87.1 ; H
NMR (300 MHz, DMSO-d6) ꢂ 8.01 (t, J = 6.0 Hz, OCH2CONH,
1H), 7.74 (t, J = 5.6 Hz, CONH, 1H), 7.64 (s, NH2, 2H), 6.88 (d,
J = 4.0 Hz, ArH, 4H), 4.37 (s, ArOCH2, 2H), 3.69 (s, OCH3, 3H),
3.10 (dd, J = 13.4, 6.7 Hz, CONHCH2, 2H), 3.00 (dd, J = 13.0,
6.6 Hz, CONHCH2, 2H), 2.75 (dt, J = 12.0, 6.1 Hz, CONHCH2,
2H), 2.04 (t, J = 7.3 Hz, NHCH2, 2H), 1.57 – 1.44 (m, COCH2,
2H), 1.43 – 1.31 (m, CH2, 4H), 1.29 – 1.15 (m, CH2, 10H). 13C
NMR (75 MHz, DMSO-d6) ꢂ 172.58, 168.58, 116.63, 115.47,
68.67, 56.29, 40.45, 36.06, 30.10, 30.02, 29.64, 27.76, 27.34,
27.23, 26.44, 25.73. MS (m/z): HRMS (ESI) calculated for
+
[M+H]+ C23H40N3O4 , 422.3013; found 422.3043.
2+
C79H96N4O12 , 646.3507; found 646.3548; calculated for
[M+5H]5+ C79H99N4O125+ ,259.1446, found 258.1294.
3.9.6-((4-(diphenylamino)benzyl)amino)-N-(8-(2-(4-methoxyphen
oxy)acetamido) octyl)hexanamide (6)
3.6.N-(8-aminooctyl)-2-(4-methoxyphenoxy)acetamide (3)
To a solution of compound 5 (50.00 mg, 0.12 mmol) in
anhydrous CDCl3 (1.2 mL), 4-(diphenylamino)benzaldehyde
(32.77 mg, 0.12 mmol) was added. The reaction mixture was
To a solution of ethyl 2-(4-methoxyphenoxy)acetate (840.00
mg, 4.00 mmol) dissolved in ethanol (10.0 mL),
1,8-diaminooctane (1.73 g, 12.00 mmol) was added. After the
mixture was heated at reflux for 12 hours, the solvent was
removed by rotary evaporator. The crude product was purified by
column chromatography (SiO2, DCM:CH3OH = 10:1) to give a
stirred at 60
for 10 hours and the solvent was removed by
rotary evaporation. The mixture was dissolved in CHCl3 (0.5 mL)
and CH3OH (0.5mL), then NaBH4 (4.54 mg, 0.12 mmol) were
added and the reaction was stirred at room temperature for 10
min. After that, NaHCO3 aqueous solution (20.0 µL) was added
to quench the reaction and the solvent was removed by rotary
evaporation. The crude product was purified by column
chromatography (SiO2, DCM:MeOH = 10:1) to get the product 6
(18.60 mg, 23%) as a yellowish power. m.p. 107.6 ; Rf
1
white power (899.50 mg, 73 %). H NMR (300 MHz, CDCl3) ꢂ
6.85 (s, ArH, 4H), 6.64 – 6.51 (s, CONH, 1H), 4.43 (s,
CONHCH2, 2H), 3.77 (s, OCH3, 3H), 3.32 (dd, CONHCH2, J =
13.6, 6.8 Hz, 2H), 2.67 (t, NH2CH2, J = 6.9 Hz, 2H), 1.61 – 1.49
(m, CONHCH2CH2, 2H), 1.44 (d, NH2CH2CH2, J = 6.5 Hz, 2H),
1.38 (s, NH2, 2H), 1.29 (s, CH2, 8H). 13C NMR (75 MHz, CDCl3)
1
(DCM:MeOH = 10:1) 0.50; H NMR (600 MHz, CDCl3) ꢂ 7.21