=
(41 mg, 0.050 mmol, 0.10 eq.) were mixed in dry deoxygenated
dioxane (2 mL). The mixture was heated to 80 ◦C under N2
for 5 h before adding water (20 mL) and EtOAc (20 mL). The
phases were separated and the aqeueos phase was extracted
(EtOAc). The combined organic phase was washed several times
with saturated aqeueos NaHCO3, dried (MgSO4), filtered and
concentrated in vacuo. The resultant syrup was exposed to
column chromatography (Rf = 0.11 in EtOAc) to give pure
aporphine 7a (155 mg, 73%) as a yellowish foam. dH(300 MHz,
CDCl3) 8.05 (br s, 1H, H1), 7.54–7.48 (m, 2H, 2-Ar), 7.27 (s, 1H,
H3), 7.13 (d, 1H, H8/H9, J(8,9) = 8.3 Hz), 6.98–6.92 (m, 2H,
2-Ar), 6.86 (d, 1H, H8/H9), 3.84 (s, 6H, 2xArOCH3), 3.38–3.04
(m, 4H), 2.80 (dd, 1H, J = 2.8 Hz, J = 16.2 Hz), 2.66–2.53
56.2 (ArOCH3), 52.8 (C5), 43.8 ( NCH3), 34.2 (C7), 29.1 (C4),
21.0 (ArOCOCH3). [a]D25 −213 (c 0.19, CHCl3). HRMS (EI):
417.1711 calc. for C26H24FNO3 417.1740.
(R)-(−)-11-Acetoxy-2-(4-trifluoromethylphenyl)-10-methoxy-
aporphine (7e). This compound was prepared in a similar
manner to 7a but using 4-trifluoromethylphenylboronic ester
6e as starting material which gave aporphine 7e as a yellowish
solid in a yield of 63%. Rf = 0.13 in EtOAc.
Mp decomp. 89–91 ◦C. dH(300 MHz, CDCl3) 8.06 (br s, 1H,
H1), 7.68 (br s, 4H, 2-Ar), 7.31 (br s, 1H, H3), 7.15 (d, 1H,
H8/H9, J(8,9) = 8.2 Hz), 6.89 (d, 1H, H8/H9), 3.85 (s, 3H,
ArOCH3) 3.33–3.02 (m, 4H), 2.82 (dd, 1H, J = 1.9 Hz, J =
=
15.2 Hz), 2.58 (s, 3H, NCH3), 2.65–2.50 (m, 2H), 2.25 (s, 3H,
=
(m, 2H), 2.58 (s, 3H, NCH3), 2.23 (s, 3H, –OCOCH3).
ArOCOCH3). dC(75 MHz, CDCl3) 168.7 (ArOCOCH3), 151.1,
144.7, 137.9, 137.1, 135.5, 134.2, 131.7, 129.5, 127.9, 127.3,
127.2, 126.2, 126.0, 125.9, 124.4, 111.5 (Ar), 62.4 (C6a), 56.4
dC(75 MHz, CDCl3) 168.3 (ArOCOCH3), 158.8, 150.6, 138.6,
136.6, 133.1, 132.9, 130.8, 128.8, 127.9, 127.7, 127.5, 126.2,
125.7, 123.6, 114.0, 110.8 (Ar), 61.9 (C6a), 56.1 (ArOCH3),
=
(ArOCH3), 53.0 (C5), 44.1 ( NCH3), 34.4 (C7), 29.3 (C4), 21.2
=
55.2 (ArOCH3), 52.7 (C5), 43.5 ( NCH3), 34.0 (C7), 28.8 (C4),
(ArOCOCH3). [a]2D5 −170 (c 0.19, CHCl3). HRMS (EI): 467.1702
21.0 (ArOCOCH3). [a]2D5 −127.0 (c 0.20, CHCl3). HRMS (EI):
calc. for C27H24F3NO3 467.1708.
429.1925 calc. for C27H27NO4 429.1940.
(R)-(−)-2-(4-Hydroxyphenyl)apomorphine hydromide bromide
(8a). Aryl methyl ether 7a (58 mg, 0.135 mmol, 1.0 eq.) was
dissolved in CH2Cl2 (2 mL). To this solution was carefully added
BBr3 (1.35 mL, 1 M solution in CH2Cl2, 1.35 mmol, 10 eq.) under
nitrogen. After 1.5 h the mixture was concentrated to dryness.
The residue was taken up in MeOH (10 mL) and refluxed
under nitrogen for 30 min before concentrating to dryness. After
dissolution of the resultant oil in MeOH (10 mL) and addition of
activated carbon, the mixture was heated to reflux and quickly
filtered through a pad of celite. Concentration of the mother
liquid followed by washing of the remaining oil with CH2Cl2
and CHCl3 gave pure apomorphine hydrobromide 8a (22 mg,
37%) as an off-white solid.
(R)-(−)-11-Acetoxy-2-(4-tolyl)-10-methoxyaporphine (7b).
This compound was prepared in a similar manner to 7a but
using 4-tolylboronic ester 6b as starting material which gave
aporphine 7b as a brown oil in a yield of 39%. Rf = 0.11 in
EtOAc.
dH(300 MHz, CDCl3) 8.06 (br s, 1H, H1), 7.48 (d, 2H, 2-
Ar, Jortho = 8.1 Hz), 7.29 (d, 1H, H3, J(1,3) = 1.7 Hz), 7.22
(d, 2H, 2-Ar), 7.12 (d, 1H, H8/H9, J(8,9) = 8.2 Hz), 6.85 (d,
1H, H8/H9), 3.38–3.04 (m, 4H), 2.80 (dd, 1H, J = 2.8 Hz,
=
J = 16.2 Hz), 2.65–2.52 (m, 2H), 2.57 (s, 3H, NCH3), 2.40
(s, 3H, ArCH3), 2.23 (s, 3H, ArOCOCH3). dC(75 MHz, CDCl3)
168.5 (ArOCOCH3), 150.9, 139.2, 137.9, 137.0, 136.9, 133.3,
133.1, 131.1, 129.5, 129.0, 127.9, 126.7, 126.6, 125.9, 124.1, 111.1
Mp > 250 ◦C. dH(300 MHz, DMSO-d6) 9.90 (br s, 1H,
disappears with D2O), 9.65 (br s, 1H, disappears with D2O),
9.60 (br s, 1H, disappears with D2O), 8.85 (br s, 1H, disappears
with D2O), 8.50 (br s, 1H, H1), 7.45 (d, 2H, 2-Ar, Jortho = 8.6
Hz), 7.35 (br s, 1H, H3), 6.35 (d, 2H, 2-Ar), 6.75 (d, 1H, H8/H9,
J(8,9) = 7.9 Hz), 6.68 (d, 1H, H8/H9), 4.35 (br s, 1H, H6a), 3.76
=
(Ar), 62.0 (C6a), 56.2 (ArOCH3), 53.8 (C5), 43.5 ( NCH3),
34.0 (C7), 28.7 (C4), 21.1, 21.0 (ArCH3 and ArOCOCH3). [a]D25
−107 (c 0.20, CHCl3). HRMS (EI): 413.1959 calc. for C27H27NO3
413.1991.
(R)-(−)-11-Acetoxy-2-phenyl-10-methoxyaporphine (7c).
This compound was prepared in a similar manner to 7a but
using phenylboronic ester 6c as starting material which gave
aporphine 7c as a brown oil in a yield of 85%. Rf = 0.11 in
EtOAc.
=
(br s, 1H, H5a), 3.20–3.00 (m, 4H, NCH3 + H4b), 2.68 (t, 1H,
H7b, J(7b,7a) = 13.5 Hz). Three signals (from H4a, H5b and
H7a) coincide with the water signal at 3.33 ppm. dC(75 MHz,
DMSO-d6) 158.1, 145.9, 144.1, 140.2, 133.5, 131.5, 131.0, 128.6,
127.6, 125.6, 125.3, 125.2, 120.6, 119.6, 116.6, 115.1 (Ar), 62.2
dH(300 MHz, CDCl3) 8.10 (br s, 1H, H1), 7.56 (dd, 2H, 2-
Ph, Jmeta = 1.5 Hz, Jortho = 7.1 Hz), 7.46–7.38 (m, 2H, 2-Ph),
7.37–7.30 (m, 2H, H3 + 2-Ph H), 7.14 (d, 1H, H8/H9, J(8,9) =
8.2 Hz), 6.87 (d, 1H, H8/H9), 3.84 (s, 3H, ArOCH3), 3.55–
3.10 (m, 5H), 2.86 (dd, 1H, J = 17.2 Hz), 2.80–2.72 (m, 2H),
(C6a), 52.2 (C5), 31.6 (C7), 26.7 (C4). Signal corresponding
25
=
to NCH3 coincides with DMSO. [a]D −183 (c 0.10, DMSO).
+
HRMS (EI): 358.1454, calc for C23H20NO3 (M-1 peak of free
amine) 358.1443.
=
2.68 (s, 3H, NCH3), 2.27 (s, 3H, ArOCOCH3). dC(75 MHz,
(R)-(−)-2-(4-Tolyl)-apomorphine hydromide bromide (8b).
Was prepared in a similar way as 8a except that 7b (35 mg, 0.0846
mmol) was used as starting material which gave 8b (23 mg, 62%)
as an off-white solid.
CDCl3) 168.8 (ArOCOCH3), 151.2, 141.0, 139.8, 137.2, 133.1,
131.4, 129.1 (2 signals), 128.9, 128.0, 127.6, 127.2, 127.0, 126.2,
124.6, 111.5 (Ar), 62.2 (C6a), 56.4 (ArOCH3), 52.9 (C5), 43.4
25
Mp > 250 ◦C. dH(300 MHz, DMSO-d6): 10.05 (br s, 1H,
disappears with D2O), 9.70 (br s, 1H, disappears with D2O),
8.85 (br s, 1H, disappears with D2O), 8.52 (br s, 1H, H1), 7.51
(d, 2H, 2-Ar, Jortho = 8.1 Hz), 7.40 (br s, 1H, H3), 7.30 (d, 2H, 2-
Ar), 6.85–6.60 (m, 2H, H8 + H9), 4.38 (br s, 1H, H6a), 3.78 (br s,
=
( NCH3), 33.9 (C7), 28.6 (C4), 21.2 (ArOCOCH3). [a]578 −225
(c 0.15, CHCl3). HRMS (EI): 399.1839 calc. for C26H25NO3
399.1834.
(R)-(−)-11-Acetoxy-2-(4-fluorophenyl)-10-methoxyaporphine
(7d). This compound was prepared in a similar manner to
7a but using phenylboronic ester 6d as starting material which
gave aporphine 7d as an off-white solid in a yield of 73%. Rf =
0.13 in EtOAc.
=
1H, H5a), 3.20–3.00 (m, 4H, NCH3 + H4b), 2.78–2.64 (m, 1H,
H7b). Three signals (from H4a + H5b + H7a) coincide with the
water signal at 3.33 ppm. dC(75 MHz, DMSO-d6) 145.9, 144.2,
140.1, 137.9 (2 signals), 133.7, 131.2, 130.5, 128.3, 127.3, 126.0,
125.7, 125.2, 120.5, 119.6, 115.2 (Ar), 62.2 (C6a), 52.2 (C5),
41.8 ( = NCH3), 31.5 (C7), 26.6 (C4), 21.6 (ArCH3). [a]2D5 −74.8
Mp decomp. at 77–79 ◦C. dH(300 MHz, CDCl3) 8.00 (br s,
1H, H1), 7.58–7.48 (m, 2H, 2-Ar), 7.25 (s, 1H, H3), 7.14 (d,
1H, H8/H9, J(8,9) = 7.9 Hz), 7.12–7.05 (m, 2H, 2-Ar), 6.87 (d,
1H, H8/H9), 3.85 (s, 3H, ArOCH3), 3.32–3.00 (m, 4H), 2.80
(dd, 1H, J = 2.6 Hz, J = 15.8 Hz), 2.63–2.49 (m, 2H), 2.55 (s,
+
(c 0.13, DMSO). HRMS (EI): 356.1646, calc for C24H22NO2
(M-1 peak of free amine) 356.1651.
=
3H, NCH3), 2.25 (s, 3H, ArOCOCH3). dC(75 MHz, CDCl3)
(R)-(−)-2-Phenylapomorphine hydromide bromide (8c). This
compound was prepared in a similar manner to 8a except that
7c (29 mg, 0.0726 mmol, 1.0 eq.) was used as starting material
which gave 8c (18 mg, 58%) as a slightly brown coloured oil.
168.5 (–OCOCH3), 162.4 (d, C–F, J(C,F) = 246 Hz), 150.9,
138.2, 137.1, 136.9, 134.2, 133.6, 131.2, 129.3, 128.4, 128.3,
127.9, 126.7, 125.9, 124.0, 115.8, 115.5, 111.2, (Ar), 62.1 (C6a),
4 0 8 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 0 7 7 – 4 0 8 1