4
04 Girreser et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 401–405
to 10 hours. After exposition to UV light a solution of 2
contained a large number of different oxidation products
Synthesis of 8 · I [8]:
0 ml of a 0.3 % solution of 3 in chloroform (150 mg, 0.42 mmol)
were irradiated with a low pressure mercury lamp “original
Hanau”TNN 1532 for 4 h while cooling the solution. After irradi-
ation, the solvent was evaporated and the remainder was dis-
solved in 5 ml of boiling methanol, then 0.2 ml of methyl iodide
5
(
3
for example up to ten isomers with a molecular weight of
55 Da were found). Only a comparatively small amount
of 8 and also 1, 3, and 5 could be detected.Photochemi-
cal reactions of 2 have been reported by Intestrosa et al.
(
Fluka, Buchs, Switzerland) was added. After cooling to room
[
15] only recently. Except for hydroxylated derivatives of
temperature, a few drops of water were added, the solution be-
came turbid and a precipitate formed upon storing at 5 °C for a
few hours.
papaverine they observed ring enlargement of the N-ox-
ide to a diazepine derivative in deoxygenated solvents.
The solid was collected by filtration and recrystallized from
methanol to form a black powder; yield 62 mg (0.13 mmol,
Therefore, we can not exclude that 8 ·Cl is formed
through the reaction cascade from 2 to 4 to 7 rather than
the proposed alternative way through 3 and 5.The high
reactivity of papaverinol to photooxygenation can also
be explained by the intermediate formation of 6, arising
from oxidation of the nitrogen atom with higher electron
density in 3 compared to 5, but 6 might have only a very
short lifetime under the reaction conditions.
3
1 %) with mp. 225 °C, decomp. Calculated for C20
5
H18NO I: C,
50.12;H, 3.79;N, 2.92;found C, 50.37, H, 3.96;N, 2.87.UV/Vis
–
1
–1
(MeOH, λmax, lg ε, ε in l · mol · cm ): 222 (4.5), 256 (4.3),
10 (4.6), 398 (4.1); in 0.1 M NaOH: 224 (4.8), 256 (4.5), 322
3
–
1
(
4.1). IR (KBr pellet): ν/cm 1719 (m), 1625 (m), 1589 (m),
1
495 (s), 1318 (s), 1206 (s). EI-MS of of 8 ·Cl: m/z 367 ([M +
+
+
Me] , 1), 352 (M , 22), 337 (10), 336 (9), 322 (8), 308 (5), 292
(4), 176 (4), 172 (4) 52 (Me Cl, 31), 50 (Me Cl, 100). EI-MS of
of 8 ·Cl:m/z 367 ([M + Me] , 1), 352 (M , 21), 337 (74), 336 (32),
3
3
7
35
+
+
The observed rate of formation of 8 can be given as 3 > 5
+
22 (69), 308 (14), 293 (25), 292 (23), 172 (32) 142 (MeI , 100),
+
>
1 > 2 ӷ 1 · HCl, not taking other side reactions like
127 (I , 30).
carbene insertion into account.In conclusion, the results
obtained from the above described experiments indicate
that the oxidation of 1 · HCl in aerobic chloroform solu-
tions occurs via 3 and 5 to 8 ·Cl.
ESI-MS in buffered ammonium acetate solution with enhanced
fragmentation afforded ions with m/z 352, 336, 322, 308, 292,
1
291. H NMR (300 MHz, DMSO-d
6
, TMS as internal standard)
), 7.16/
.34/7.47/8.28 (4 × s, 4 × 1 H, H-1/4/8/11) 8.53/9.57 (2 × d, 2 ×
of 8 ·Cl: δ 3.93/4.07/4.08/4.12 (4 × s, 4 × 3 H, 4 × OCH
3
7
The question of the importance of the yellowish hydro-
chlorides of 3 and 5 as photosensitizers for the reactions
discussed above in order to explain papaverine decom-
position at daylight conditions can not be answered with
the results obtained, requiring instead detailed kinetic
experiments. Furthermore, the regioselective ring clo-
sure of the two ring systems in 3 or 5 is of interest, only
the attack on position 6 of the 3,4-dimethoxyphenyl ring
is observed, only one isomer of 8 was found with all the
analytical methods employed.
1 H, J = 6.2 Hz, H-5/6).
1H NMR (300 MHz, DMSO-d
6
,TMS as internal standard) of 8 ·I:
δ 3.97/4.09/4.12/4.16 (4 × s, 4 × 3 H, 4 × OCH ), 7.50/7.82/
3
8
1
.14/8.27 (4 × br s, 4 × 1 H, H-1/4/8/11) 8.70/9.39 (2 × br s, 2 ×
H, J = 6.2 Hz, H-5/6). 13C NMR (75 MHz, DMSO-d
, TMS as
6
internal standard) of 8 ·I: δ 56.57, 56.64, 57.2, 57.3, 100.0,
01.4, 106.6, 107.4, 115.3, 121.3, 125.3, 126.7, 133.5, 140.8,
142.4, 150.6, 155.5, 156.3, 158.4, and 182.4.
1
1H NMR (300 MHz,TFA/D
O, sodium 3-trimethylsilylpropionate
2
as internal standard) of 8 ·CF CO : δ 4.03/4.15/4.19 (3 × s, 2 ×
3
2
3 H, 1 × 6 H, 3/9/10/2-OCH ), 7.49/7.49/7.60/8.48 (4 × s, 4 ×
3
1
H, H-11/H-4/H-8/H-1), 8.25/8.76 (2 × d, J = 6.9 Hz, 2 × 1 H,
13
H-6/5). C NMR (75 MHz, TFA/D
propionate as internal standard) of 8 ·CF
3-OCH ), 60.1 (9-OCH ), 60.3 (2/10-OCH , two overlapping
signals), 101.6 (C-8), 105.7 (C-1), 109.5 (C-11), 111.4 (C-4),
19.0 (C-11a), 126.5 (C-12b), 128.6 (C-6), 129.4 (C-5), 136.1
2
O, sodium 3-trimethylsilyl-
3
CO : δ 59.7
2
Experimental
(
3
3
3
Melting points were determined on a Boëtius microscope and
are not corrected. EI (70 eV) mass spectra were recorded on a
HP-MS engine 5989 A (Agilent Technologies, Waldbronn, Ger-
many). Electrospray mass spectra were recorded on an Bruker
1
(
(
C-4a), 146.0 (C-12a), 146.2 (C-11a), 155.0 (C-10), 160.5
C-9), 161.0 (C-2), 163.6 (C-3), and 186.3 (C-12).
1
13
Esquire LC. 300 MHz H- and 75 MHz C NMR spectra were
recorded on a Bruker ARX 300 spectrometer (Bruker, Ettlin-
gen, Germany).Chemical shifts are given in ppm andTMS was
used as an internal standard for the spectra obtained in DMSO-
References
d
6
. UV/Vis data were obtained with a HP 8452 UV/Vis spec-
trometer. IR spectra were recorded with a FT IR Raman Magna
60 spectrometer (Nicolet, Thermo-Nicolet, Madison, WO,
USA). Two Hanau Fluotest lamps with emission at 254 nm
15 Watt each) were used for the irradiation experiments.
[1] T. W. Hermann, U. Girreser, P. Michalski, K Piotrowska,
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 167–169.
7
[
[
[
2] J. Krepinskij, Ceskoslov. farm. 1958, 7, 13–16.
(
3] F. Machovi c¿ ovä, V. Parrak, Pharmazie 1959, 14, 10–12.
4] E. Pawelczyk, T. W. Hermann, Chem. Analit. (Warsaw)
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gether with UV detection at 255 nm with a HP 1050 VWD. A
Zorbax Eclipse XDB-C8 column 4.6 × 150 mm was used to-
gether with a precolumn (Agilent Technologies, Waldbronn,
Germany).The mobile phase consisted of a mixture of 35 % of
acetonitrile and 65 % (v/v) of 50 mM aqueous ammonium ace-
tate, pH 6.5 with a flow rate of 0.8 ml/min and a split ratio of 1:7
to the ESI mass spectrometer.
1
968, 13, 617–625.
[
5] S. Pfeifer, G. Behnsen, L. Kühn, Pharmazie 1972, 27,
6
39–647.
[6] S.Pfeifer, G.Behnsen, L.Kühn, R.Kraft, Pharmazie 1972,
27, 734–738.
©
2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim