Salutaridine and its derivatives as
thebaine-equivalents in the synthesis of aporphines
2.7. Acid-catalyzed
rearrangement
of
OCH3), 3.73 (s, 3H, OCH3), 3.61 (dd, 1H, H9, J=4.2, <2),
3.29 (d, 1H, H10α, J10α-10β= 15.6), 2.99 (m, 1H, H10β),
2.60-2.25 (m, 6H, H15β, H16α, H16β, NCH3), 1.80 (ddd,
1H, H15α, J=5.0, <2, <2). 13C-NMR (CD3OD) δ=158.3,
145.1, 143.7, 135.8, 128.4, 124.6, 121.2, 118.7, 109.8,
91.7, 76.4, 62.1, 56.3, 55.2, 48.0, 43.8, 40.7, 37.7,
31.4.
salutaridine (1) in the presence of alcohols
A mixture of 1 (233 mg, 0.71 mmol), methanesulfonic
acid (1 mL) and alcohol (200 μL) was stirred for 30 min
at 90oC. Then the reaction mixture was added dropwise,
with stirring and external ice-cooling, to a solution of
potassium hydrogen carbonate (2 g) in water (10 mL).
After extraction with dichloromethane (3×15 mL), the
combined extracts were washed with saturated brine,
dried (MgSO4), and concentrated under reduced
pressure. The purification was performed by means of
column chromatography (Silica Gel 40, eluent: DCM/
MeOH = 9/1).
2.3. Acid-catalyzed
rearrangement
of
salutaridine (1) and salutaridinols (2)
A mixture of
1 or 2 (0.71 mmol) and 99.5%
methanesulfonic acid (1 mL) was stirred for 30 min at
90oC. Then the reaction mixture was added dropwise,
with stirring and external ice-cooling, to a solution of
potassium hydrogen carbonate (2 g) in water (10 mL).
After extraction with dichloromethane (3×15 mL), the
2.8. (R)-11-Hydroxy-2,3,10-trimethoxyaporphine
(4)
combined extracts were washed with saturated brine, Yield: 78% starting from compound 1. Off-white solid.
25
dried (MgSO4), and concentrated under reduced M.p.: 114-116oC. [α]D -118 (c=0.2 in methanol);
pressure. The purification was performed by means of calculated for free base C20H23NO4: C, 70.36; H, 6.79;
column chromatography (Silica Gel 40, eluent: DCM/ found: C, 70.19; H, 6.89; MS (ESI) m/z 342.2 (M+H+),
MeOH = 8/2).
calculated for C20H24NO4+: 342.2; 1H-NMR (CDCl3)
δ=8.01 (s, 1H, H1), 6.71 (d, 1H, H8, J8-9=7.7), 6.68
(d, 1H, H9, J8-9=7.7), 5.15 (br s, 1H, OH), 3.94 (s,
3H, OCH3), 3.87 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
2.4. (R)-3,11-dihydroxy-2,10-dimethoxyaporphine
(3)
Yield: 88% starting from compound 1. Pale green 3.39 (dd, 1H, H6a, J=4.5, <2), 3.19-2.87 (m, 3H, H7α,
25
solid. M.p.: 132-134oC. [α]D -108 (c=0.2 in methanol); H7β, H5α), 2.67-2.39 (m, 6H, H4α, H4β, H5β, NCH3);
calculated for free base C19H21NO4: C, 69.71; H, 6.47; 13C-NMR (CDCl3) δ=149.7, 148.5, 147.3, 144.3, 135.2,
found: C, 69.67; H, 6.59; MS (ESI) m/z 327.2 (M+H+), 133.9, 127.6, 126.4, 126.2, 120.3, 111.7, 108.5, 66.2,
calculated for C19H22NO4+: 327.2; 1H-NMR (CDCl3) 61.1, 56.4, 56.2, 52.3, 43.5, 34.5, 28.1.
δ=7.95 (s, 1H, H1), 6.75 (d, 1H, H8, J8-9=7.4), 6.71 (d,
2.9.
(R)-2,10-Dimethoxy-3-ethoxy-11-
hydroxyaporphine (5)
1H, H9, J8-9=7.4), 5.20 (br s, 2H, 2 OH), 3.92 (s, 6H,
2 OCH3), 3.48 (dd, 1H, H6a, J=4.4, <2), 3.15-2.86 (m,
3H, H7α, H7β, H5α), 2.62-2.41 (m, 6H, H4α, H4β, H5β,
NCH3); 13C-NMR (CDCl3) δ=150.3, 147.4, 144.3, 140.2,
130.9, 128.6, 128.4, 127.2, 126.7, 119.8, 112.2, 110.5,
64.2, 56.4, 56.2, 52.4, 43.8, 34.7, 28.4.
Yield: 48% starting from compound 1. Off-white foam.
[α]D25 -101 (c=0.2 in methanol); calculated for free base
C21H25NO4: C, 70.96; H, 7.01; found: C, 70.77; H, 7.11;
MS (ESI) m/z 355.1 (M+H+), calculated for C21H26NO4+:
355.2; 1H-NMR (CDCl3) δ=8.07 (s, 1H, H1), 6.74 (d, 1H,
H8, J8-9=7.6), 6.70 (d, 1H, H9, J8-9=7.6), 5.09 (br s, 1H,
OH), 4.11 (dd, 2H, OCH2, J=5.8), 3.86 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 3.39 (dd, 1H, H6a, J=4.6, <2), 3.19-
2.83 (m, 3H, H7α, H7β, H5α), 2.59-2.39 (m, 6H, H4α,
H4β, H5β, NCH3), 1.35 (t, 3H, CH2CH3, J=6.8); 13C-NMR
(CDCl3) δ=148.9, 147.5, 144.3, 143.9, 132.9, 130.8,
127.0, 126.8, 126.2, 120.8, 110.6, 109.1, 65.1, 64.2,
56.3, 56.2, 51.7, 43.6, 35.2, 28.4, 17.3.
2.5. (R)-2,11-dihydroxy-10-methoxyaporphine
(morphothebaine, 9)
Yield from the equimolar mixture of 2 epimers: 31%,
yield from pure 7S-salutaridinol (2): 37%. M.p. as an HCl
salt: 257-258oC (lit.: 258-260oC [25]).All the physical and
spectral data were fully in agreement with previously
2.6. (R)-2,10-Dimethoxy-11-hydroxyaporphine
2.10. (R)-2,10-Dimethoxy-11-hydroxy-3-
(10)
propoxyaporphine (6)
Yield from the equimolar mixture of 2 epimers: 37%,
yield from pure 7S-salutaridinol (2): 41%. M.p.: 150-
151oC (lit.: 149-151oC [17]). All the physical and spectral
data were fully in agreement with previously published
Yield: 40% starting from compound 1. Pale grey
25
solid. M.p.: 121-123oC. [α]D -99 (c=0.2 in methanol);
calculated for free base C22H27NO4: C, 71.52; H, 7.37;
found: C, 71.67; H, 7.44; MS (ESI) m/z 370.2 (M+H+),
2024