Synthesis and crystal structure of pergolide sulfoxide

Article abstract of DOI:10.1135/cccc19980803

Pergolide sulfoxide (1), a metabolite of pergolide (2), has been prepared by oxidation of 2 with hydrogen peroxide. Its structure was determined by X-ray diffraction and compared with the structures of related ergot alkaloids. Two molecules of pergolide (S)-and (R)-sulfoxide crystallize with one molecule of water in the orthorhombic space group P2₁2₁2₁ with a = 12.216(3) A, b = 13.733(2) A, c = 22.186(6) A, Z = 4, V = 3 722(2) A³.

Full text of DOI:10.1135/cccc19980803

Pergolide Sulfoxide
803
SYNTHESIS AND CRYSTAL STRUCTURE OF PERGOLIDE SULFOXIDE
a1
b
a2
a3
Jan CEJKA , Zdenek HORAK , Svetlana PAKHOMOVA , Bohumil KRATOCHVIL ,
c1
c2
b
d,
Petr SEDMERA , Vladimir HAVLICEK , Ladislav CVAK , and Alexandr JEGOROV *
a
Department of Solid State Chemistry, Prague Institute of Chemical Technology, 166 28 Prague 6,
Czech Republic; e-mail: cejkaj@vscht.cz, pachomos@vscht.cz, kratochb@vscht.cz
Galena Co., 747 70 Opava-Komárov, Czech Republic
1
2
3
b
c
Institute of Microbiology, Academy of Sciences of the Czech Republic, 142 20 Prague 4,
1
2
Czech Republic; e-mail: sedmera@biomed.cas.cz, vlhavlic@biomed.cas.cz
Galena Co., Research Unit, Branisovska 31, 370 05 Ceske Budejovice, Czech Republic;
e-mail: husakm@marvin.jcu.cz
d
Received December 19, 1997
Accepted March 30, 1998
Pergolide sulfoxide (1), a metabolite of pergolide (2), has been prepared by oxidation of 2 with
hydrogen peroxide. Its structure was determined by X-ray diffraction and compared with the
structures of related ergot alkaloids. Two molecules of pergolide (S)- and (R)-sulfoxide crystallize
with one molecule of water in the orthorhombic space group P2 2 2 with a = 12.216(3) Å, b =
1
1 1
3
1
3.733(2) Å, c = 22.186(6) Å, Z = 4, V = 3 722(2) Å .
Key words: Ergot alkaloids; Pergolide sulfoxide; X-Ray crystal structure; NMR spectroscopy.
Pergolide (6-demethyl-8-[(methylsulfanyl)methyl]-6-propylergoline (2) is a semisyn-
1
–3
thetic ergot derivative used mainly in the treatment of Parkinson’s disease . It is a
4
potent agonist acting at D , D , and D dopamine receptors (see ref. for a review).
1
2
3
Some animal studies indicate that pergolide is significantly more potent and selective in
5
its central activity compared with some other dopamine agonists like bromokryptine (5).
Four pergolide metabolites have been characterized: pergolide sulfoxide (1), pergolide
6
–8
sulfone, N-depropylpergolide, and N-depropylpergolide sulfoxide . Oxidation of
xenobiotics often produces metabolites of different pharmacological activity. In con-
trast to any expectation, oxidation of the pergolide methylsulfanyl group either to sul-
foxide or sulfone does not alter significantly pharmacological properties of these
8
derivatives compared with the parent drug . However, the N-depropyl analogues are
8
devoid of any dopaminergic activity . A simple semisynthetic route to 1 and its detailed
structural comparison with related ergot alkaloid derivatives are described here. This
*
The author to whom correspondence should be addressed.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

8
04
Cejka et al.:
paper is our 19th communication on the structure and polymorphism of ergot alka-
9
–26
loids
.
EXPERIMENTAL
Synthesis
Pergolide (5.0 g, 16 mmol) was dissolved in mixture of dichloromethane (120 ml) and methanol (40 ml).
Hydrogen peroxide (4.3%, 35 ml) was added dropwise under vigorous stirring and the mixture was
stirred at ambient temperature for 10 h. Another portion of hydrogen peroxide (30%, 5 ml) was
added and stirring continued for another 10 h. The organic layer was separated, washed three times
with water (20 ml) and evaporated to dryness. The residue was purified by column chromatography
on a silica gel (Merck 100, 63–200 µm, 52 g) using a stepwise gradient elution with dichloro-
methane–methanol (0.25–3.5% of methanol). Pooled fractions were evaporated, dissolved in methanol,
decolourized with charcoal and methanol was partly evaporated. White crystals of pergolide sulfoxide
hemihydrate (0.6 g, 11%, m.p. 175 °C) were separated and dried at 50 °C.
H
CH SO CH
H
CH
S CH
3
2
3
2
H
H
N
H
CH2 CH2 CH3
N
H
CH2 CH2 CH3
HN
HN
pergolide sulfoxide
pergolide
1
2
CH2 CH2 CH2 NMe2
CO NH Et
H
CO
N
H
NH CO NEt
2
H
N
H
CH2 CH CH2
N
H
CH3
HN
HN
cabergoline
lisuride
3
4
H3C
CO NH
CH3
CH
OH
H
N
H
N
O
O
N
H
CH3
H
CH2
CH
H3C
CH3
HN
Br
bromokryptine
5
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Pergolide Sulfoxide
Characterization
805
Mass spectra were measured on a Finnigan MAT 90 spectrometer (double-focusing, BE geometry),
with positive-ion electron impact ionization, ionizing energy 70 eV, source temperature 200 °C,
emission current 0.5 mA, accelerating voltage 5 kV, direct inlet at 190 °C. EI-MS, m/z (rel. int. %):
+•
3
31 (5), 330.1764 (M , 330.1766 calculated for C H N OS, 21), 315 (7), 314 (25), 313.1735
19 26 2
(
313.1738 calculated for C H N S, 100), 301 (4), 268 (3), 267.1851 (267.1861 calculated for
19 25 2
C H N , 17), 266 (16), 265 (18), 252 (5), 251.1544 (251.1548 calculated for C H N , 12), 238 (4),
1
8
23
2
17 19
2
2
1
37.1391 (237.1392 calculated for C H N , 15), 223 (4), 196 (5), 194 (5), 181 (5), 168 (8), 167 (13),
16 17 2
55 (12), 154 (33), 127 (7), 43 (4), 41 (4). Collisionally-induced dissociation (CID) mass spectrum
of the molecular ion radical, m/z (rel. int. %): 313 (100), 267 (7), 266 (12), 265 (6), 251 (1), 237 (1),
1
94 (1), 168 (2), 167 (3).
A Varian VXR-400 spectrometer was used for 1H and 13C NMR measurements at 399.95 and
1
13
100.58 MHz for H and C, respectively, in CDCl at 25 °C. Residual solvent signal (δ 7.265, δ 77.00)
3
H
C
was used as an internal standard. Full assignment based on APT, HOM2DJ, COSY, delayed-COSY,
and HETCOR experiments is given in Table I.
Single-Crystal Structure Determination
Pergolide sulfoxide (1, 80 mg) was dissolved in butan-2-one (8 ml) by short refluxing and the solu-
tion was allowed to cool overnight. The formed crystals were separated, washed with a little cold
butan-2-one and dried on air. (C H N OS) ⋅H O, M = 678.98, orthorhombic system, space group
1
9
26
2
2
2
r
3
P2 2 2 (No. 19), a = 12.216(3) Å, b = 13.733(2) Å, c = 22.186(6) Å, V = 3 722(2) Å , Z = 4, D =
calc
.21 g cm , µ(CuKα) = 1.61 mm , F(000) = 1 464.
The structure of 1 was solved by direct methods. All non-H atoms were refined anisotropically by
1
1
1
–
3
–1
1
the full-matrix least-squares method based on F-values. The hydrogen atoms were set geometrically,
H811 and H812 were set to follow the O81–H811⋅⋅⋅O1 and O81–H812⋅⋅⋅O51 hydrogen bonds. Due to
lower quality of the measured crystal (R = 0.197), the empirical absorption correction routine DIFABS
int
2
7
(
ref. ) was used and the Friedel pairs were merged yielding thus a 6% lowering of R. Data collection
and refinement parameters are listed in Table II. Consecutive numbering of all individual C, N, O,
and S atoms was used for the independent (S)-sulfoxide molecule (Fig. 1). The same numbers larger
by 50 were used for the independent (R)-sulfoxide molecule (Fig. 2). Water molecule is denoted as
H811–O81–H812.
RESULTS AND DISCUSSION
6
–8
Pergolide sulfoxide (1) was recently reported as pergolide (2) metabolite or a product
2
8
of microbial oxidation of 2. It was also found as an impurity in 2, probably as the
2
9
result of degradation by oxygen . We report here a simple route to 1 by oxidation of 2
with hydrogen peroxide. Even if the yield of pure 1 is poor (11% based on final crys-
talline 1), this method is valuable. Because of many side and consecutive reactions
were observed (oxidation to N6-oxide, oxidation in position 2 of ergoline skeleton,
oxidation to sulfone), the conversion of peroxide was held low (50–60%) and the
desired pergolide sulfoxide was isolated by chromatography.
Electron impact mass spectrum of 1 afforded the molecular ion-radical of medium
intensity at m/z 330. The most intense peak (m/z 313) both in conventional and CID
+
•
mass spectra was assigned to the hydroxyl radical loss from the M ion. Although this
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

8
06
Cejka et al.:
TABLE I
13
1
H and C NMR data for pergolide sulfoxide (1)
Atom
δC
Multiplicity
δH
nH
Multiplicity
J, Hz
2
3
4
117.75
111.99
26.73
d
s
t
6.895
–
3.361
1
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
1
1
2
1
1
0
0
0
1
1
1
1
3
3
2
2
2
2
3
3
1
dd 1.6, 1.6
dd
ddd
dd
ddd
m
14.7, 4.0
14.7,11.1, 1.6
14.6, 4.0
2
.722
3.354
.718
2
6.68
t
2
14.6, 11.1, 1.6
5
7
63.48
3.44
55.17
d
d
t
2.536
2.536
3.190
6
m
ddd
dd
ddd
dd
m
11.3, 3.8, 2.1
11.3, 11.1
11.1, 3.6,2.2
11.1, 11.1
2
.283
3.255
.262
5
4.98
t
2
8
9
31.70
1.66
34.78
d
d
t
2.465
2.465
1.236
3
m
ddd
m
ddd
m
12.4, 12.1, 12.1
12.6, 12.2, 12.2
2
.913
1.315
.782
3
4.40
t
2
1
1
1
0
1
2
40.65
0.37
133.07
33.03
d
d
s
s
d
2.999
2.999
–
m
m
4
1
–
113.07
6.909
ddd
ddd
dd
6.6, 1.2, 1.2
6.6, 1.2, 1.2
8.2, 6.6
6.895
1
1
3
4
123.04
108.61
d
d
d
s
s
s
t
7.160
7.192
7.192
–
–
–
ddd
8.2, 1.2, 0.7
1
08.60
133.31
33.30
ddd
8.2, 1.2, 0.7
1
5
1
1
1
6
7
126.12
60.44
2.850
dd
dd
dd
dd
s
12.9, 5.8
12.9, 5.1
12.9, 5.8
12.9, 4.8
2
.604
2.818
.584
6
0.24
t
2
SCH3
39.35
9.31
58.69
q
q
t
t
t
2.651
2.641
2.803
2.803
1.542
1.524
0.916
0.912
8.052
3
s
α
m
m
m
m
t
5
1
1
8.40
7.29
7.19
β
γ
t
11.94
q
q
–
7.4
11.92
t
7.3
NH
–
d
unresolved
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Pergolide Sulfoxide
807
mechanism cannot be rationalized by a simple mechanistic interpretation, the nature of
this ion was confirmed by exact mass measurement. Ion m/z 267 arises by elimination
of the CH SO radical from the parent molecular ion. Other abundant ions (m/z 251,
3
3
0
2
37, 167, 154, 127) are common fragments present in EI mass spectra of ergolines .
Nearly all carbon signals in the C NMR spectrum of 1 were doubled (in the ratio
approximately 1 : 1). The same feature was apparent in the H NMR spectrum and
more clearly in the J-resolved (HOM2DJ) experiment. Protons forming such doublets
had similar or identical coupling patterns. Two three-proton singlets at 2.651 and 2.641 ppm
1
3
1
(
coupled to carbons resonating at 39.35 and 39.31 ppm) and changes in the environ-
ment of the original methysulfanyl group indicated the presence of the CH SO– moiety
3
3
1
(
CH SO: δ 2.50, δ 39.6; for comparison CH S in pergolide : δ 2.11, δ 16.29 and
3 H C 3 H C
CH S in pergolide mesylate: δ 2.132, δ 15.48, in (CD ) SO). Taking into account the
3
H
C
3 2
X-ray diffraction study, the two observed molecules were assigned to two diastereo-
mers which differ in the chirality of the sulfoxide group. The comparison of these two
compounds based on proton and carbon chemical shifts of the corresponding atoms
(
Fig. 3) shows an interesting pattern. Large effects observed on D-ring and N-propyl
atoms indicate probable preferred orientation of the CH SOCH – group (folded over
3
2
the ring so that the sulfoxide oxygen may interact with the nitrogen lone pair). Further
assignment was attempted using the molecular mechanics calculation based on structu-
ral parameters obtained from the X-ray diffraction study.
The X-ray crystal structure determination confirmed the presence of two independent
molecules of pergolide (S)- and (R)-sulfoxide in the crystal structure and one molecule
O1
C19
C16
C17
C69
O51
C68
C66
C65
C67
S1
C18
C56 C55
N52
C5
C15
N2
S51
C6
C7
C57
C54
C4
C58
C59
C8
C9
C53
C52
C3
C2
C14
C60
C64
C10
C51
N51
C1
C63
C62
C61
C11
C13
C12
N1
FIG. 1
FIG. 2
The ORTEP drawing of pergolide (S)-sulfoxide
The ORTEP drawing of pergolide (R)-sulfoxide
with atom numbering
with the atom numbering
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

8
08
Cejka et al.:
TABLE II
Data collection and refinement parameters
Crystal dimension
Diffractometer and radiation used
Scan technique
0.25 × 0.42 × 0.56 mm
Enraf–Nonius CAD4, CuKα, λ = 1.54056 Å
ω/2θ
Temperature
293 K
No. and θ range of reflections for lattice
20; 38 –40°
parameter refinement
Range of h, k, l
0→12, 0→14, –23→23
Standard reflections monitored in the interval;
intensity fluctuation
60 min; 3.21%
Total number of reflections measured; 2θ range
No. observed reflections
Criterion for observed reflections
Function minimized
4 850; 4–110°
2 095
I ≥ 1.96σ(I)
2
w(|Fo| – |Fc|)
33
Weighting scheme
Chebychev polynomial
425
Parameter refined
Value of R, wR, S
0.0752, 0.0856, 1.1109
Ratio of the maximum least-squares shift to e.s.d. 0.001
in the last cycle
–
3
Maximum and minimum heights in final ∆ρ map 0.74; –0.34 e Å
3
4
Source of atomic scattering factors
Programs used
ref.
CRYSTALS (ref. ), PARST (ref. ),
3
4
35
3
6
SIR92 (ref. )
0
32; 20
10
200
40
H
CH2 SO CH3
H
380
CH2 SO CH3
190
0
65; 21
40
80
131; 79
H
0
18
4
H
40
290
100
20
14
0
2
N
CH2 CH2 CH3
40 N CH2 CH2 CH3
0
0
0
0
H
H
10
7
; 4
0
50
1
0
0
0
HN
0
HN
0
a
b
FIG. 3
1
13
H NMR (a) and C NMR (b) chemical shift (ppb) differences between the two diastereomers of
pergolide sulfoxide
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Pergolide Sulfoxide
809
of water (the displacements of S1 and S51 are –0.707(4) and 0.620(4) Å from the
planes C18–C19–O1 and C68–C69–O51, respectively). The final positional and ther-
mal parameters of the non-H atoms of pergolide sulfoxide are deposited in the Cam-
bridge Crystallographic Data Base. The ergoline A and B rings, forming the indole
moiety, are nearly planar, ring C (C8, C9, C14, C2, C3, C4) possesses the E envelope
6
4
conformation, and ring D (C4, N2, C5, C6, C7, C8) has the C chair conformation. It
1
is generally assumed, that the ergoline skeleton is a rigid moiety the structural par-
ameters of which are nearly the same for all ergot derivatives. Whereas all structural
parametres of 2, pergolide mesylate and 1 are virtually nearly identical, a comparison
of some ergot alkaloid derivatives (Table III) indicates, that there are marked dif-
ferences in various puckering parameters even for related alkaloids, which seems likely
to explain their different spectra of pharmacological activity.
Apart from the ergoline skeleton which is almost rigid for all ergot alkaloids, the
sulfoxide side chain has fairly large conformation freedom. Single-point calculations
were carried out for torsion angles ω = C5–C6–C18–S1, ψ = C6–C18–S1–O1, ω =
S
S
R
C55–C56–C68–S51, and ψ = C56–C68–S51–O51 with 10° steps and the limit of con-
R
vergence set to 0.0001. The values of heat of formation were obtained using the semi-
3
2
empirical PM3 method (Figs 4 and 5). Three regions of low energy were found. The
flat global minima are located at ω = 130°, ψ = 130°, and ω = 130°, ψ = –130° for
S
S
R
R
(
S)- and (R)-sulfoxides, respectively. These global minima are separated by a 8 kJ/mol
barrier from another two broad local minima at ω = 130°, ψ = –50° and ω = 130°, ψ =
S
S
R
R
5
0°, and with a 24 kJ/mol barrier from sharp local minima at ω = ω = –60°, ψ = 130°,
S R S
TABLE III
Comparison of structrural parameters of ergot alkaloid derivatives exhibiting similar pharmacological
effects
Puckering
parameter
Pergolide
(S)-sulfoxide
38
Pergolide
mesylate
39
Lisuride
maleate
Bromokryptine
mesylate
4
0
Pergolide
38
Cabergoline
13
23
a
A/B , °
1.3(5)
1.23(19)
0.424(6)
1.16(16)
0.452(4)
–50.3(7)
53.4(5)
0.85(19)
0.465(6)
3.11(17)
0.357(6)
1.32(62)
0.42(2)
–66(3)
Ring C, Q, Å
0.47(1)
Ring C, ϕ2, ° –54(2)
–46(1)
–50.4(9)
–65(1)
Ring C, θ, °
50(1)
48.7(7)
0.586(6)
–91(15)
178.0(6)
51.2(7)
53.5(9)
0.484(6)
–91(1)
51(2)
Ring D, Q, Å
0.60(1)
0.593(4)
–146(10)
177.4(4)
0.595(5)
0.495(15)
–83(2)
Ring D, ϕ2, ° –150(13)
Ring D, θ, ° 175(1)
–107(6)
174.4(6)
130.2(7)
125(2)
a
The angle between the mean planes of the A and B ergolene rings.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

8
10
Cejka et al.:
ψ = –130°. Values ω = 64(1), ψ = 62(1)°, and ω = 169.3(7), ψ = –60(1)° were
R
S
S
R
R
found in the crystal structure. As follows from Figs 4 and 5, these values are very near
to the global minima for both diastereomers and a possible distortion caused by a H-bond
with the water molecule in the crystal structure is very low, if any. Although calculated
minima of energy are relatively broad, even a first inspection of Figs 4 and 5 clearly
indicates that the zig-zag conformation with opposite orientation of CH CH CH N6–
3
2
2
and CH SOCH C8– groups is preferred for (R)-sulfoxide, whereas that one which
3
2
brings these moieties to proximity is preferred for (S)-sulfoxide (see also Figs 1 and 2).
These differences make it possible to tentatively assign the molecule with up-field res-
onating protons of the N-propyl group and of C7 atom to (S)-sulfoxide, and with up-
field resonating protons of the C9 atom to (R)-sulfoxide.
Two neighbouring molecules of pergolide (S)- and (R)-sulfoxides are linked with
hydrogen bonds between the NH group of the indole moiety and free electron pair of
i
the N-propyl group forming infinite chains (N1–H1N⋅⋅⋅N52 , D⋅⋅⋅A = 2.95(1) Å, (i): –x + 1/2,
ii
–
y + 1, z + 1/2 and N51–H51N⋅⋅⋅N2 , D⋅⋅⋅A = 2.93(1) Å, (ii): –x – 1/2, –y + 1, z – 1/2).
Water molecule crosslinks individual chains thus creating a three-dimensional hydrogen
bond network, O81–H811⋅⋅⋅O1, D⋅⋅⋅A = 2.85(2) Å and O81–H112⋅⋅⋅O51, D⋅⋅⋅A = 2.95(2) Å.
This work was supported by the Grant Agency of the Czech Republic (grants No. 203/94/0135 and
No. 203/96/0111).
4
50
550
0
0
∆
cal
H
∆
H
f
f
cal
3
50
2
1
50
50
150
1
0
80
5
0
180
0
9
9
0
0
–
50
ωS, ° –50
ωR, °
–
90
–
90
–180
–180
–90
–90
0
0
–180
9
0
ψ
9
0
ψ
–180
180
, °
R
180
, °
S
FIG. 4
FIG. 5
The three-dimensional map of heat of forma-
The three-dimensional map of heat of forma-
tion vs torsion angles ωR and ψR for pergolide
(R)-sulfoxide (the arrow indicates the angle
combination found in the crystal structure)
tion vs torsion angles ω and ψ for pergolide
S
S
(
S)-sulfoxide (the arrow indicates the angle
combination found in the crystal structure)
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Pergolide Sulfoxide
811
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