Water-soluble xanthobilirubinic acids?
167
pH = 4.0 using dilute HCl and extracted into CH2Cl2
(3 9 100 cm3). The organic phases were combined, dried
over anhyd. Na2SO4 and evaporated in vacuo (rotovap). The
crude product was purified by radial chromatography using
5% (vol/vol) CH3OH in CH2Cl2. The pure fractions were
collected and evaporated to obtain pure 1. Yield: 337 mg
(93%); mp 42–44 °C; 1H NMR: d = 2.1 (3H, s), 2.31 (3H,
s), 2.46 (2H, t, J = 7.5 Hz), 2.7 (2H, t, J = 7.5 Hz), 3.36
(3H, s), 3.37 (3H, s), 3.5–3.8 (20H, m), 4.26 (2H, m), 4.59
(2H, m), 6.26 (1H, s), 9.29 (1H, brs), 10.26 (1H, brs), 11.6
(1H, brs) ppm; 13C NMR: d = 9.8, 11.8, 20.3, 35.6, 59.22,
59.23, 70.2, 70.3, 70.70, 70.73, 70.76, 70.85, 70.87, 71.0,
71.4, 72.05, 72.12, 72.14, 101.1, 119.2, 119.8, 122.5, 124.9,
131.5, 147.9, 168.8, 177.9 ppm.
was then recovered by distillation, and the residue was
dissolved in *100 cm3 CH2Cl2, with cooling in ice bath,
and carefully neutralized with saturated aqueous NaHCO3.
The neutralized solution was then extracted with CH2Cl2
(5 9 100 cm3), dried, evaporated under vacuum to crude
product 8a, which was then purified by radial chromatog-
raphy using ethyl acetate–n-hexane (1:1 vol/vol) as eluent.
1
Yield: 6.7 g (79%); oil; H NMR: d = 3.35 (6H, s), 3.53
(4H, m), 3.63 (8H, m), 3.64 (4H, m), 3.68 (4H, m), 3.88
(6H, s), 4.29 (4H, m), 8.93 (1H, brs) ppm; 13C NMR:
d = 52.1, 59.2, 70.4, 70.75, 70.83, 70.88, 72.2, 74.0, 113.4,
141.5, 160.3 ppm.
Dimethyl 3,4-bis-(triethylene glycol methyl ether)-
1-benzylpyrrole-2,5-dicarboxylate (9a; C29H43NO12)
Following the procedure of [16], dihydroxypyrrole 11
(0.97 g, 3.18 mmol), K2CO3 (1.05 g, 7.5 mmol), and
triethylene glycol monomethyl ether-p-toluene sulfonate
(2.22 g, 2.2 equiv.) were dissolved in 30 cm3 dry acetoni-
trile, and the mixture was heated at reflux for 15 h, making
the entire solution turn yellow. The solution was cooled to
room temperature and the solids were removed by filtration
and washed with acetonitrile. The filtrate was evaporated
under vacuum to obtain the crude product, which was
purified using radial chromatography using ethyl acetate–
3,4-Bis-(triethylene glycol methyl ether)-3-pyrrolin-2-one
(6a; C18H35NO9)
Pyrrole 7a (200 mg, 0.500 mmol) was taken up into 2–
3 cm3 pyridine under an N2 atmosphere. To the solution
0.1 cm3 30% H2O2 was added, and the solution was heated
at reflux for 55 min. Pyridine was removed (rotovap) by
azeotroping with toluene. The residue was purified by
column chromatography followed by radial chromatogra-
phy using 5% (vol/vol) CH3OH–CH2Cl2 to obtain 6a as a
1
brown oil. Yield: 60 mg (29%); oil; H NMR: d = 3.34
1
n-hexane as eluent. Yield: 1.88 g (96%); oil; H NMR:
(6H, s), 3.5–3.72 (20H, m), 3.75 (2H, s), 4.21 (2H, m), 4.49
(2H, m), 6.41 (brs, NH) ppm; 13C NMR: d = 59.1, 63.9,
70.0, 70.6, 70.8, 71.1, 72.1, 101.7, 136.9 ppm.
d = 3.3 (6H, s), 3.5–3.7 (16H, m), 3.75 (4H, m), 3.8 (6H,
s), 4.20 (4H, m), 5.96 (2H, s), 6.87–6.90 (2H, m), 7.14–
7.21 (3H, m) ppm; 13C NMR: d = 49.0, 51.8, 59.2, 70.5,
70.7, 70.8, 70.9, 72.2, 74.0, 116.6, 126.1, 127.1, 128.6,
139.1, 142.4, 160.9 ppm.
3,4-Bis-(triethylene glycol methyl ether)-1H-pyrrole
(7a; C18H35NO8)
Following the procedure in [16], pyrrole ester 8a (0.81 g,
1.60 mmol) was placed in a 100-cm3 round-bottomed flask
and dissolved in 50 cm3 ethylene glycol. The solution was
degassed on a high-vacuum pump for 2 h. Then KOH
(0.36 g, 6.42 mmol) was added, and the mixture was
placed in a preheated oil bath at 190 °C and stirred for 3 h
under argon. After 3 h the reaction was cooled to 50 °C
before adding 100 cm3 H2O. The reaction mixture was
then extracted with CH2Cl2 (4 9 100 cm3). The combined
organic phases were washed with brine, dried, and
evaporated (rotovap) to give 6c as a brown oil. Yield:
2-Desmethyl-3-desethyl-2,3-bis-(diethylene glycol methyl
ether) xanthobilirubinic acid (2; C24H38N2O9)
and ethyl ester (2e; C26H42N2O9)
Dipyrrinone 2 and its ester 2e were prepared according to
the procedure for synthesizing 1 and 1e. Pure acid 2 is a
1
yellow solid. Yield: 248 mg (94%); mp 114–116 °C; H
NMR: d = 2.08 (3H, s), 2.25 (3H, s), 2.45 (2H, t,
J = 7.2 Hz), 2.78 (2H, t, J = 7.2 Hz), 3.35 (3H, s), 3.39
(3H, s), 3.58–3.9 (12H, m), 4.25 (2H, m), 4.6 (2H, m), 6.26
(1H, s), 9.2 (1H, s), 10.26 (1H, s) ppm; 13C NMR: d = 9.8,
11.6, 20.1, 35.5, 59.2, 59.3, 60.5, 62.0, 70.1, 70.4, 70.6,
70.9, 71.5, 72.0, 72.16, 72.22, 101.2, 119.3, 119.5, 122.4,
124.8, 125.0, 131.8, 148.0, 168.8, 173.5 ppm.
1
0.6 g (96%); oil; H NMR (CDCl3, 400 MHz): d = 3.37
(6H, s), 3.56 (4H, m), 3.60 (4H, m), 3.65 (4H, m) 3.70 (4H,
m), 3.78 (4H, m), 4.04 (4H, m), 6.24 (2H, d, J = 3.0 Hz),
7.21 (1H, brs), 6.23 (brm, NH); 13C NMR: d = 59.2, 70.4,
70.8, 70.9, 72.2, 74.0, 101.6, 137.3 ppm.
Pure ester 2e is a yellow solid. Yield: 0.3 g (35%); mp
64–68 °C; 1H NMR: d = 1.24 (3H, t, J = 7.2 Hz), 2.1 (3H,
s), 2.33 (3H, s), 2.41 (2H, t, J = 7.5 Hz), 2.70 (2H, t,
J = 7.5 Hz), 3.35 (3H, s), 3.39 (3H, s), 3.58–3.9 (12H, m),
4.11 (2H, q, J = 7.2 Hz), 4.27 (2H, m), 4.63 (2H, m), 6.32
(1H, s), 9.82 (1H, brs), 10.51 (1H, brs) ppm; 13C NMR:
d = 9.8, 11.6, 14.5, 20.1, 35.5, 59.24, 59.27, 62.0, 70.0,
70.4, 70.5, 70.7, 70.9, 71.5, 72.16, 72.22, 72.7, 101.2, 119.3,
119.5, 122.4, 124.9, 125.1, 131.8, 148.4, 168.5, 173.5 ppm.
Dimethyl 3,4-bis-(triethylene glycol methyl ether)-
1H-pyrrole-2,5-dicarboyxlate (8a; C22H37NO12)
According to a reported procedure [26] for debenzylation
of a different pyrrole, a mixture of 3 g (5.0 mmol) 9a,
8 cm3 TFA, 1 cm3 anisole, and 0.2 cm3 conc. H2SO4 was
heated in a preheated oil bath at 90 °C for 30 min. TFA
123