874 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3
Gao et al.
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3H), 2.30-2.48 (m, 3H), 1.61-2.10 (m, 10H), 1.22 (t, J = 6.8
Hz, 3H). HRMS: calcd for C17H29N2O2 (M þ H)þ, 293.2229;
found, 293.2230.
47%); mp 156-158 °C. H NMR (CD3Cl, 400 Hz): δ 4.27 (s,
1H), 4.09-4.18 (m, 3H), 3.96 (s, 1H), 3.21 (t, J = 12.4 Hz, 1H),
2.80 (m, 2H), 2.60 (s, 1H), 2.38 (d, J = 13.2 Hz, 1H), 2.07 (m,
1H), 1.85-2.04 (m, 3H), 1.41-1.71 (m, 10H). HRMS: calcd for
C15H25N2O3 (M þ H)þ, 281.1865; found, 281.1882.
13-Benzyloxymatrine (6c). The title compound was prepared
from 3 and benzyl bromide in the manner as described above
(57%); mp 121-123 °C. 1H NMR (CDCl3, 400 Hz): δ 7.24-7.34
(m, 5H), 4.47-4.56 (m, 2H), 4.35 (dd, J = 4.0, 12.8 Hz, 1H),
3.99-4.05 (m, 1H), 3.84 (d, J = 4.0 Hz, 1H), 3.10 (t, J = 12.8
Hz, 1H), 2.76-2.84 (m, 2H), 2.45-2.65 (m, 2H), 2.16-2.23 (m,
1H), 2.09 (s, 1H), 1.82-1.98 (m, 3H), 1.33-1.77 (m, 10H).
HRMS: calcd for C22H31N2O2 (M þ H)þ, 355.2386; found,
355.2371.
13-Formyloxymatrine (6d). To a solution of 5 (1.0 g, 3.79
mmol) in anhydrous CH2Cl2 (10.0 mL) was added dropwise
benzoyl choride (0.48 mL, 4.17 mmol) with stirring, and then
KOH (0.42 g, 7.5 mmol) powder was added in portion. The
mixture was stirred at room temperature for 4 h. Inorganic salt
was removed via filtration, and the filtrate was concentrated
under reduced pressure. The residue was purified with flash
column chromatography on silica gel using CH2Cl2 and MeOH
as eluent to give white solid (0.51 g, 37%); mp 108-110 °C. 1H
NMR (CDCl3, 400 Hz): δ 7.96 (d, J = 7.2 Hz, 2H), 7.56 (t, J =
7.6 Hz, 1H), 7.41-7.45 (m, 2H), 5.38-5.39 (m, 1H), 4.32 (dd,
J = 4.4, 12.8 Hz, 1H), 4.05 (m, 1H), 3.10 (t, J = 12.8 Hz, 1H),
2.47-2.81 (m, 4H), 2.40-2.46 (m, 1H), 2.17 (s, 1H), 1.91-2.03
(m, 3H), 1.39-1.82 (m, 10H). HRMS: calcd for C22H29N2O3 (M
þ H)þ, 369.2178; found, 369.2188.
General Procedures for the Synthesis of Compounds 9a-b. To
a solution of 8 (3 mmol) in 50% KOH aqueous (2 mL) was
added dropwise halogenated hydrocarbon (6.5 mmol) with
stirring. The mixture was stirred at room temperature for 8 h.
After completion of the reaction, the resulting mixture was
neutralized with 3N HCl and then extracted with CH2Cl2. The
combined organic phase was washed with water and brine, dried
over Na2SO4, and then concentrated in vacuo. The residue was
purified with flash column chromatography on silica gel using
CH2Cl2 as eluent to give white solid.
13,14-Dimethoxymatrine (9a). The title compound was pre-
pared from 8 and methyl iodide in the same manner as described
above (35%); mp 77-79 °C. 1H NMR (CD3OD, 400 Hz): δ 4.16
(dd, J = 4.4, 12.8 Hz, 1H), 3.78-3.84 (m, 1H), 3.60-3.63 (m,
1H), 3.56-3.57 (m, 1H), 3.44 (s, 3H), 3.35 (s, 3H), 3.02 (t, J =
12.8 Hz, 1H), 2.74-2.81 (m, 2H), 2.14-2.20 (m, 2H), 1.91-2.02
(m, 3H), 1.21-1.76 (m, 10H). HRMS: calcd for C17H29N2O3 (M
þ H)þ, 309.2178; found, 309.2191.
13,14-Dibenzyloxymatrine (9b). The title compound was pre-
pared from 6 and benzyl bromide in the same manner as
1
described above (81%); mp 105-108 °C. H NMR (CD3OD,
400 Hz): δ 7.21-7.43 (m, 10H), 4.99 (d, J = 12.4 Hz, 1H), 4.66
(m, 3H), 4.45 (m, 2H), 3.30-3.90 (m, 6H), 2.69 (m, 2H),
2.07-2.27 (m, 3H), 1.59-1.89 (m, 8H), 1.39 (m, 1H). HRMS:
calcd for C29H37N2O3 (M þ H)þ, 461.2804; found, 461.2820.
General Procedures for the Synthesis of Compounds (9c-j). To
a solution of 8 (3 mmol) in anhydrous CH2Cl2 (5.0 mL) was
added dropwise corresponding acyl chloride (9 mmol) with
stirring. The mixture was stirred at room temperature for
1-24 h and then concentrated in vacuo to give crude products.
13,14-Diethoxyacyloxymatrine (9c). The title compound was
prepared from 8 and ethyl chloroformate in the same manner as
described above in the presence of KOH powder, stirred 8 h, and
the crude product purified with flash column chromatography
on silica gel using CH2Cl2 as eluent to give white solid (30%); mp
64-66 °C. 1H NMR (CD3OD, 400 Hz): δ 5.31 (d, J = 2.8 Hz,
1H), 5.23 (d, J = 2.8 Hz, 1H), 4.10-4.20 (m, 4H), 3.86-3.93 (m,
1H), 3.09 (t, J = 12.8 Hz, 1H), 2.73-2.80 (m, 2H), 2.46 (dt, J =
15.2, 5.6 Hz, 1H), 2.14 (s, 1H), 1.93-2.01 (m, 2H), 1.72-1.88 (m,
2H), 1.39-1.71 (m, 10H), 1.24 (m, 6H). HRMS: calcd for
C21H33N2O7 (M þ H)þ, 425.2282; found, 425.2325.
13-Nitromethylmatrine (7a). A solution of nitromethane
(1.08 mL, 20 mmol) and 3 (4.92 g, 20 mmol) in acetonitrile (10
mL) was mixed with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,
3.04 g, 20 mmol) at room temperature. The resulting solution
was kept at room temperature for 24 h and poured into water
(50 mL). The mixture was acidified with diluted hydrochloric acid
(pH 2) and then extracted with CH2Cl2. The combined CH2Cl2
extracts were washed with water, dried over Na2SO4, and evapo-
rated in vacuo. The residue was purified with flash column
chromatography on silica gel using EtOAc and MeOH as eluent
to give white solid (2.90 g, 47%); mp 80-82 °C. 1H NMR (CDCl3,
400 Hz): δ 4.28-4.39 (m, 3H), 4.04-4.09 (m, 1H), 3.12 (t, J = 12.4
Hz, 1H), 2.78-2.85 (m, 3H), 2.56 (dd, J = 5.2, 17.2 Hz, 1H),
2.16-2.24 (m, 2H), 1.91-2.01 (m, 5H), 1.82-1.90 (m, 3H),
1.51-1.78 (m, 3H), 1.38-1.48 (m, 3H). HRMS: calcd for
C16H26N3O3 (M þ H)þ, 308.1974; found, 308.1973.
13-Methylaminomatrine (7b). Na (0.46 g, 20 mmol) was added
to methylamine in EtOH (60 mL) in portion with stirring at 0 °C;
after the completion of the reaction, 3 was added (2.46 g, 10
mmol) at the same temperature. The reaction mixture was
stirred for 24 h at room temperature and concentrated in vacuo,
then soaked in ether. The mixture was filtered, and the solid was
washed with ether; the filtrate was concentrated under reduced
pressure to remove ether. The residue was purified with flash
column chromatography on silica gel using CH2Cl2 and MeOH
as eluent to give white solid 5b (1.1 g, 40%); mp 80-81 °C. 1H
NMR (CDCl3, 400 Hz): δ 4.34 (dd, J = 4.4, 12.8 Hz, 1H), 4.00
(br, 1H), 3.10 (t, J = 12.8 Hz, 1H), 2.94 (m, 1H), 2.83 (m, 2H),
2.56 (dd, J = 4.4, 16.8 Hz, 1H), 2.46 (s, 3H), 2.32 (dd, J = 5.6,
16.8 Hz, 1H), 2.12 (s, 1H), 1.89-1.97 (m, 4H), 1.63-1.77 (m,
5H), 1.37-1.54 (m, 6H). HRMS: calcd for C16H28N3O (M þ
H)þ, 278.2232; found, 278.2243.
13,14-Dihydroxymatrine (8). To a solution of 3 (6.15 g, 25
mmol) in water (20 mL) and acetone (20 mL) was added KMnO4
(5.93 g, 37.5 mmol) in portion over 1 h with stirring at 0 °C. After
confirming the completion of the reaction in TLC, the mixture
was stirred at 0 °C for another 1 h and then MeOH (50 mL) was
added. The mixture was filtered, and the solid was washed with
MeOH, and the filtrate was concentrated under reduced pres-
sure to remove MeOH and acetone. The resulting solution was
added 10% NaOH aqueous to adjust pH to 10-11, extracted
with CH2Cl2, dried over Na2SO4, and concentrated in vacuo,
soaked in ether, filtered, and dried to give white solid 6 (3.3 g,
13,14-Di(4-fluoro-3-nitro)benzoyloxymatrine (9d). The title
compound was prepared from 8, 4-fluoro-3-nitro-1-benzene-
carbonyl chloride, and K2CO3 anhydrous in the same manner as
described above, stirred 24 h, and the crude product was purified
with flash column chromatography on silica gel using CH2Cl2
and MeOH as eluent to give white solid (31%); mp 115-117 °C.
1H NMR (CD3OD, 400 Hz): δ 8.62 (dd, J = 7.2, 2.4 Hz, 1H),
8.48 (dd, J = 7.2, 2.0 Hz, 1H), 8.34-8.38 (m, 1H), 8.22-8.26 (m,
1H), 7.54-7.59 (m, 1H), 7.45-7.50 (m, 1H), 5.83-5.87 (m, 2H),
4.28 (dd, J = 13.2, 4.4 Hz, 1H), 4.09-4.16 (m, 1H), 3.23 (t, J =
12.8 Hz, 1H), 2.80-2.84 (m, 2H), 2.61-2.67 (m, 1H), 2.22
(s, 1H), 1.41-2.12 (m, 13H). HRMS: calcd for C29H29F2N4O9
(M þ H)þ, 615.1903; found, 615.1885.
14-Hydroxy-13-acetoxymatrine Hydrochloride (9e). The title
compound was prepared from 8 and acetyl chloride in the same
manner as described above, stirred 8 h, and the crude product puri-
fied with flash column chromatography on silica gel using CH2Cl2
and MeOH as eluent to give white solid (21%); mp 194-196 °C. 1H
NMR (CDCl3, 400 Hz): δ 12.22 (s, 1H), 5.19 (s, 1H), 5.00 (s, 1H),
4.63 (m, 1H), 4.56 (dd, J = 4, 14.4 Hz, 1H), 4.33-4.40 (m, 2H), 3.74
(t, J = 13.6 Hz, 1H), 3.51-3.59 (m, 2H), 3.13 (d, J = 9.2 Hz, 1H),
2.52-2.66 (m, 3H), 2.33-2.43 (m, 2H), 2.02-2.13 (m, 3H), 1.87-
1.90 (m, 1H), 1.63-1.75 (m, 6H). HRMS: calcd for C17H27N2O4
3
HCl (M - Cl)þ, 323.1971; found, 323.1966.