Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7747
7.64-6.90 (m, 12H, ArH), 7.00 (d, 1H, J=2.0 Hz, H8), 6.52 (d,
1H, J=2.0 Hz, H6), 4.96 (d, 1H, J=8.0 Hz, H11), 4.83 (s, 2H,
OCH2CdO), 4.65 (s, 2H, OCH2CdO), 4.28 (m, 1H, H10), 3.78
(s, 3H, OCH3), 3.59 (m, 1H, H23a), 3.40 (m, 1H, H23b). MS
(ESI-) m/z 881 (M - H)þ.
(1.11 mmol) of butenyl bromide dropwise under argon. The
reaction mixture was stirred at 55 ꢀC for 3 h. The cooled mixture
was poured into ice-water (20 g) and worked up as above. The
yellowish residue was subjected to a column chromatography
over 10.0 g silica gel, using CHCl3/EtOAc/AcOH (20:1:0.1) as
eluent (Rf 0.45). Final major product (()-4b was purified over
Sephadex LH-20 column using CHCl3/MeOH (80:3) as eluent.
Yield: 32 mg (11%), yellowish solid, HPLC purity 95.13%. 1H
NMR (400 MHz, CDCl3) δ 12.64 (s, 1H, 5-OH), 7.77 (d, J=
1.6 Hz, 1H, H18), 7.76 (d, J=1.6 Hz, 1H, H13), 7.08 (d, 1H, J=
8.8 Hz, H21), 7.00 (br d, 1H, J=8.8 Hz, H22), 6.98 (br d, 1H,
J=8.4 Hz, H15), 6.94 (d, 1H, J=8.4 Hz, H16), 6.41 (d, 1H, J=
2.0 Hz, H8), 6.34 (d, 1H, J=2.2 Hz, H6), 5.78-5.92 (m, 2H,
H30,300), 5.05-5.21 (m, 4H, H40,400), 5.02 (d, 1H, J =8.2 Hz,
H11), 4.05-4.15 (m, 5H, H10,100,10), 3.95 (s, 3H, OCH3), 3.88
(m, 1H, H23b), 3.61 (br dd, 1H, J=8.8, 3.2 Hz, H23a), 2.50-
2.65 (m, 4H, H20,200). 13C NMR (100 MHz, CDCl3) δ 178.77 (C,
C4), 164.67 (C, C7), 161.85 (C, C5), 156.63 (C, C8a), 155.45 (C,
C2), 146.89 (C, C19), 146.43 (C, C12a), 145.59 (C, C16a), 143.60
(C, C20), 138.12 (C, C3), 134.43 (CH, C300), 133.7 (CH, C30),
127.50 (C, C17), 123.84 (C, C14), 122.76 (CH, C22), 120.75 (CH,
C15), 117.50 (CH, C21), 117.27 (CH, C16), 117.06 (CH2, C400),
116.97 (CH2, C40), 114.68 (CH, C18), 109.37 (CH, C13), 105.93
(C, C4a), 98.24 (CH, C6), 92.44 (CH, C8), 78.67 (CH, C10),
76.28 (CH, C11), 71.88 (CH2, C100), 67.66 (CH2, C10), 61.55
(CH2, C23), 55.98 (OCH3), 34.46 (CH2, C200), 33.20 (CH2, C20).
MS (ESIþ) m/z 589 (M þ H)þ.
Preparation of 7-OH Monoether 2. N,N-Diethyl-2-{2-[3-(3-
methoxy-4- hydroxyphenyl)-2-hydroxylmethyl-2,3-dihydro-ben-
zo[1,4]dioxin-6-yl]-3,5-dihydroxy-4-oxo-4H-chromen-7-yloxy}-
acetamide ((()-2). This compound was prepared by the general
method with silybin and 2-bromo-N,N-diethyl-acetamide (40 mg,
0.2 mmol) as starting materials and purified on silica gel
chromatography using CHCl3/MeOH (40:1) as eluent. Final
major product (()-2 was purified over Sephadex LH-20 column
using CHCl3/MeOH (80:3) as eluent. Yield: 25 mg (20%),
yellow solid, HPLC purity 97.71%. 1H NMR (400 MHz,
Me2CO-d6) δ 12.58 (1H, s, OH-5), 7.89-6.78 (m, 6H, ArH),
6.72 (br s, 1H, H8), 6.33 (br s, 1H, H6), 5.00 (d, 1H, J=8.0 Hz,
H11), 4.93 (s, 2H, OCH2CdO), 4.24 (m, 1H, H10), 3.78 (m, 1H,
H23a), 3.76 (s, 3H, OCH3), 3.56 (m, 1H, H23b), 3.42 (q, 2H, J=
7.2 Hz, OCH2CH3), 3.38 (q, 2H, J=7.2 Hz, OCH2CH3), 1.22 (t,
3H, J=7.2 Hz, OCH2CH3), 1.18 (t, 3H, J=7.2 Hz, OCH2CH3).
MS (ESIþ) m/z 594 (M þ H)þ.
Preparation of 2-[3-(4-Ethoxycarbonylmethoxy-3-methoxy-
phenyl)-2-hydroxylmethyl-2,3-dihydro-benzo[1,4]dioxin-6-yl]-3,-
5-dihydroxy-4-oxo-4H-chromen-7-yloxy-acetyl Ethyl Ester ((()-3).
To a solution of silybin (48 mg, 0.1 mmol), K2CO3 (11 mg),
and KI (2 mg) in dry DMF (6 mL) was added 22.5 mg of
chloroacetic acid ethyl ester (0.4 mmol) in 1 mL of DMF under
argon. The reaction mixture was stirred at 45 ꢀC for 12 h. The
cooled mixture was poured into ice-water (10.0 g). The yellow-
ish precipitates solid was then filtrated, washed by distilled
water, dried over Na2SO4, and subjected to a silica gel column
chromatography, using PET/EtOAc (1:1) as eluent. Final major
product (()-3 was purified over Sephadex LH-20 column using
CHCl3/MeOH (30:1) as eluent. Yield: 26 mg (26%), yellow
Preparation of (()-2-[3-(4-Isopentenyloxy-3-methoxy-phe-
nyl)-2-hydroxylmethyl-2,3-dihydro-benzo[1,4]dioxin-6-yl]-3,5-
dihydroxy-4-oxo-4H-chromen-7-yloxy-isopentenyl Ether ((()-4c).
To a solution of silybin (241 mg, 0.5 mmol) and 276 mg of
K2CO3 (2.0 mmol) in 5 mL of dry DMF was added 165.0 mg
(1.11 mmol) of isopentenyl bromide dropwise under argon. The
reaction mixture was stirred at 75 ꢀC for 3 h. The cooled mixture
was poured into ice-water (20 g) and worked up as above. The
yellowish residue was subjected to a column chromatography
over 10.0 g silica gel, using CHCl3/EtOAc/AcOH (7:1:0.1) as
eluent (Rf 0.49). Final major product (()-4c was purified over
Sephadex LH-20 column using CHCl3/MeOH (30:1) as eluent.
Yield: 49 mg (16%), yellowish solid, HPLC purity 96.69%. 1H
NMR (400 MHz, CDCl3) δ 12.69 (s, 1H, 5-OH), 7.79 (d, 1H,
J=8.0 Hz, H15), 7.75 (br s, 1H, H13), 7.08 (d, 1H, J=8.8 Hz,
H21), 6.92-7.01 (m, 3H, ArH16,18,22), 6.42 (br s, 1H, H8), 6.35
(d, 1H, J=1.6 Hz, H6), 5.44-5.53 (m, 2H, H20,200), 5.02 (d, 1H,
J=8.0 Hz, H11), 4.55-4.63 (m, 4H, H10,100), 4.15 (m, 1H, H10),
3.85 (s, 3H, OCH3), 3.75 (m, 1H, H23b), 3.60 (m, 1H, H23a),
1.81 (s, 3H, CH3), 1.79 (s, 3H, CH3), 1.75 (s, 6H, 2 CH3). MS
(ESIþ) m/z 617 (M þ H)þ.
1
solid, HPLC purity 97.27%. H NMR (400 MHz, CDCl3) δ
11.20 (1H, s, OH-5), 8.24-6.88 (m, 6H, ArH), 6.66 (br s, 1H,
H8), 6.20 (br s, 1H, H6), 4.88 (d, 1H, J=7.6 Hz, H11), 4.26 (q,
2H, J = 7.2 Hz, COCH2CH3), 4.22 (q, 2H, J = 7.2 Hz,
COCH2CH3), 4.93 (s, 2H, OCH2CdO), 4.24 (m, 1H, H10),
3.84 (m, 1H, H23a), 3.78 (s, 3H, OCH3), 3.58 (m, 1H, H23b),
3.42 (s, 2H, COCH2O), 3.39 (s, 2H, COCH2O), 1.30 (t, 3H, J=
7.2 Hz, COCH2CH3), 1.28 (t, 3H, J=7.2 Hz, COCH2CH3). MS
(ESIþ) m/z 653 (M þ H)þ.
Preparation of (()-2-[3-(4-Ethenylmethoxy-3-methoxy-phe-
nyl)-2-hydroxylmethyl-2,3- dihydro-benzo[1,4]dioxin-6-yl]-3,5-
dihydroxy-4-oxo-4H-chromen-7-yloxy-allyl Ether ((()-4a). To
a solution of silybin (241 mg, 0.5 mmol), 276 mg of K2CO3
(2.0 mmol) in 5 mL of dry DMF was added 150 mg of allyl bromide
dropwise under argon. The reaction mixture was stirred at 55 ꢀC
for 3 h. The cooled mixture was poured into ice-water (20 g)
and extracted with EtOAc (3ꢀ10 mL). The organic phase was
separated and washed with brine (2ꢀ10 mL), dried over Na2SO4,
and evaporated under reduced pressure. The yellowish residue
was subjected to a column chromatography over silica gel, using
CHCl3/EtOAc/AcOH (20:1:0.1) as eluent. Final major product
(()-4a was purified over Sephadex LH-20 column using CHCl3/
MeOH (80:3) as eluent. Yield: 77 mg, (27%), yellowish solid,
HPLC purity 95.84%. 1H NMR (400 MHz, Me2CO-d6) δ 11.65
(1H, s, OH-5), 7.12-6.68 (6H, m, ArH), 6.17 (1H, br s, H8), 6.11
(1H, br s, H6), 6.06 (1H, m, OCH2CHdCH2), 6.02 (1H, m,
OCH2CHdCH2), 5.28-5.06 (4H, m, OCH2CHdCH2), 4.92
(1H, d, J=7.6 Hz, H11), 4.26-4.21 (4H, m, OCH2CHdCH2),
4.21 (1H, m, H10), 3.89 (1H, m, H23a), 3.78 (3H, s, OCH3), 3.63
(1H, m, H23b). MS (ESIþ) m/z 561 (M þ H)þ.
Preparation of (()-2-[3-(4-Ethenylmethoxy-3-methoxy-phe-
nyl)-2-hydroxylmethyl-2,3- dihydro-benzo[1,4]dioxin-6-yl]-3-al-
lyloxy-5-hydroxy-4-oxo-4H-chromen-7-yloxy-allyl ether ((()-4d).
To a solution of silybin (241 mg, 0.5 mmol) and 276 mg of
K2CO3 (2.0 mmol) in 5 mL of dry DMF was added 200.0 mg
(1.65 mmol) of allyl bromide dropwise under argon. The reac-
tion mixture was stirred at 75 ꢀC for 3 h. The cooled mixture was
poured into ice-water (20 g) and worked up as above. The
yellowish residue was subjected to a column chromatography,
using petroleum ether/EtOAc (6:1) as eluent (Rf 0.33), over
10.0 g silica gel. Final major product (()-4d was purified over
Sephadex LH-20 column using CHCl3/MeOH (80:3) as eluent.
Yield: 40 mg (13%), yellowish solid, HPLC purity 95.55%. 1H
NMR (400 MHz, Me2CO-d6) δ 12.70 (s, 1H, 5-OH), 7.82 (dd,
1H, J=8.8, 2.0 Hz, H15), 7.75 (d, 1H, J=2.0 Hz, H13), 7.19 (d,
1H, J=8.0 Hz, H18), 7.03-7.10 (m, 3H, ArH16,21,22), 6.77 (d,
1H, J=2.0 Hz, H8), 6.35 (d, 1H, J=2.0 Hz, H-6), 6.10 (m, 3H,
H-20,200,2000), 5.17-5.48 (m, 6H, H-30,300,3000), 5.10 (d, 1H, J=
8.0 Hz, H11), 4.72 (d, 2H, J=5.2 Hz, H1000), 4.67 (d, 2H, J=
6.0 Hz, H100), 4.62 (d, 2H, J = 5.2 Hz, H10), 4.27 (m, 1H,
H10), 3.87 (s, 3H, OCH3), 3.54 (m, 2H, H23). MS (ESIþ) m/z
601 (M þ H)þ.
Preparation of (()-2-[3-(4-Allylmethoxy-3-methoxy-phenyl)-
2-hydroxylmethyl-2,3-dihydro-benzo[1,4]dioxin-6-yl]-3,5-dihy-
droxy-4-oxo-4H-chromen-7-yloxy-butenyl Ether ((()-4b). To a
solution of silybin (241 mg, 0.5 mmol) and 276 mg of K2CO3
(2.0 mmol) in 5 mL of dry DMF was added 150.0 mg