PRODUCTION DE CABERGOLINE ET NOUVELLE FORME POLYMORPHIQUE DE CE COMPOSE

PRODUCTION OF CABERGOLINE AND NOVEL POLYMORPHIC FORM THEREOF

Abrégé français

L'invnetion concerne une nouvelle forme polymorphique de cabergoline contenant de la cabergoline et t-amylméthyléther, appelée cabergoline TAME, ainsi qu'un procédé de fabrication de cabergoline.

Abrégé anglais

The present application relates to a novel polymorphic form of cabergoline
comprising cabergoline and t-amyl methyl ether, designated Form TAME
cabergoline, together with a novel method of producing cabergoline.

Revendications

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CLAIMS
1. A solvate of cabergoline comprising cabergoline and t-amyl methyl ether,
designated Form TAME cabergoline.
2. Cabergoline Form TAME according to claim 1, which exhibits an X-ray
diffraction
pattern comprising peaks expressed in degrees two-theta at approximately
13.99, 15.63,
16.16, 16.68, 17.06, 17.78, 20.78, 21.68, 23.40, 23.48 and 25.88.
3. Cabergoline Form TAME according to claim 2 having the X-ray powder
diffraction
pattern substantially as shown in Figure 4b.
4. Cabergoline Form TAME according to any one of claims 1 to 3 comprising less
than 2 wt% of other polymorphs.
5. Cabergoline Form TAME according to claim 4 comprising less than 1 wt% of
other
polymorphs.
6. Cabergoline Form TAME according to claim 5 comprising less than 0.5 wt% of
other polymorphs.
7. Cabergoline Form TAME according to claim 6 comprising less than 0.1 wt% of
other polymorphs.
8. A method of preparing cabergoline Form TAME according to any one of claims
1
to 7, which comprises dissolving cabergoline in a solvent comprising t-amyl
methyl ether
and recovering cabergoline Form TAME from the solution formed.
9. A method according to claim 8, wherein the solution is cooled to a
temperature of
5°C or below.
10. A method according to claim 9, wherein the solution is cooled to a
temperature of
0 to 5°C.
11. A method according to any one of claims 8 to 10, wherein the solvent
comprises
at least 75% by volume of t-amyl methyl ether.

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12. A method according to claim 11, wherein the solvent comprises at least 95%
by
volume of t-amyl methyl ether.
13. A method according to claim 12, wherein the solvent comprises at least 98%
by
volume of t-amyl methyl ether.
14. A method according to any one of claims 8 to 14, wherein the cabergoline
Form
TAME is recovered by filtration.
15. A method according to any one of claims 8 to 15, wherein the recovered
cabergoline Form TAME is dried.
16. A method according to claim 15, wherein the recovered cabergoline Form
TAME
is dried in an inert gas atmosphere.
17. A method according to claim 15, wherein the recovered cabergoline Form
TAME
is dried under vacuum.
18. A method of preparing cabergoline, which comprises reacting a compound of
formula (II)
<IMG>
with EDAC
<IMG>
in a solvent, which comprises trifluoromethylbenzene.

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19. A method according to claim 18, wherein N-(3-dimethylaminopropyl)-N-ethyl
carbodiimide hydrochloride (EDAC.HCI) is combined with trifluoromethylbenzene
(BTF)
and aqueous alkali, and a solution of EDAC in BTF is recovered.
20. A method according to claim 19, wherein the solution of EDAC in BTF is
combined with a suspension of the compound of formula (II) in BTF.
21. A method for purifying cabergoline, which comprises extracting cabergoline
from
an aqueous solution utilising a solvent, which comprises t-amyl methyl ether.
22. A method according to claim 21 wherein the aqueous solution of cabergoline
is
the result of an aqueous work-up of the reaction of any one of claims 18 to
20.
23. A method of preparing Form I cabergoline, which comprises converting
cabergoline Form TAME into cabergoline Form I.
24. A method according to claim 23, wherein the cabergoline Form TAME is dried
to
remove the t-amyl methyl ether solvent and the cabergoline produced is then
converted
into cabergoline Form I.
25. A method according to either claim 23 or claim 24, wherein the cabergoline
Form
TAME or cabergoline is dissolved in a solvent comprising toluene,
ethylbenzene,
4-fluorotoluene, 1-chloro-4-fluorobenzene, 1,4-difluorobenzene, 1,3,5-
trimethylbenzene
or xylene and Form I cabergoline is recovered from the solution formed.

Description

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Production of Cabergoline and Novel Polymorphic Form Thereof
The present application relates to a novel polymorphic form of cabergoline.
The invention
further provides a novel method of producing cabergoline.
Cabergoline is an ergoline derivative with the systematic name 1-((6-
allylergolin-8P-yi)-
carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea and having the following
formula (I).
NMO2
Q iVy NIHEE
t?
$^r'tP4,ti
ki
H~F
(I)
It is known for treatment of a number of diseases, including CNS disorders,
reversible
obstructive airways disease, prolactin inhibition, and for controlling intra-
ocular pressure
and for treating glaucoma.
In the final step of the synthetic pathway leading to cabergoline, an allylic
acid
intermediate of Formula (II)
COOH
N.,,~,~="`~.'~`"'~.
H
N
H / p

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is reacted with N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (EDAC) to
produce
cabergoline, i.e.:
COOH
','I N
H +
cffi)
., I .~;..
H
{~)
O Ny P1HEt
C7
H
~
In a known procedure for producing cabergoline by this route, a mixture of the
intermediate of formula (II), EDAC (III) and triethylamine are reacted in the
presence of
dimethylformamide and then extracted with dichloromethane (see, e.g.
"Synthesis and
nidation inhibitory activity of a new class of ergoline derivatives",
Brambilla, E. et al.; Eur.
J. Chem. 24 (1989) 421-426.
The cabergoline so produced may then be subjected to purification procedures
(including
column chromatography and crystallisation from various solvents) and converted
to a
desired polymorph for incorporation into pharmaceutical preparations. Typical
purification
procedures include fractional crystallization from various solvents, as well
as solvent
extraction procedures. These are aimed at removing impurities, including an
unwanted
cabergoline isomer of Formula (IV), as well as producing a product consisting
essentially
of a desired cabergoline polymorph.

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Additionally, the procedures are often designed to produce a stable, pure form
of
cabergoline which is suitable for storage prior to being converted to a
desired polymorph
and/or formulated with excipients etc.
A number of different forms of cabergoline are known and, by way of example,
WO 01/72747 describes Form II cabergoline and WO 01/72746 describes Form VII
cabergoline.
Form I cabergoline is of particular interest, and its preparation is described
in
WO 01/70740, WO 03/078392 and WO 03/078433. It is known from WO 01/70740 to
prepare crystalline Form I cabergoline from a solvent comprising a
toluene/diethyl ether
mixture. From WO 03/078392 and WO 03/078433 it is known to prepare a solvate
of
cabergoline and toluene, and to obtain crystalline Form I cabergoline by
drying the
solvate.
Our WO 05/105796 describes and claims a process for producing Form I
cabergoline in
high yield and purity and with desirable particle size distribution utilising
ethylbenzene,
optionally in conjunction with n-heptane, as solvent. WO 05/105796 further
describes a
cabergoline ethylbenzene solvate. Our UK Patent Application Nos. 0505965.4 and
0515430.7 describe and claim processes for producing Form 1 cabergoline in
high yield
and purity and with desirable particle size distribution utilising 4-
fluorotoluene, 1-chloro-4-
fluorobenzene, 1,4-difluorobenzene or 1,3,5-trimethylbenzene as solvent,
again,
optionally in conjunction with n-heptane.
A series of polymorphs of cabergoline are also described in WO 2004/1 01 51 0.

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In more detail, in a typical procedure for producing cabergoline, the allylic
acid of Formula
(II) is reacted with EDAC in a suitable reaction medium. For example,
dimethylformamide
may be used as reaction medium (as in the procedure of Bramilla et al.) or as
an
alternative, acetonitrile may be used. After various solvent extraction steps,
a solution of
cabergoline is obtained, which may be used as starting material for further
purification
and for producing desired polymorphs for incorporation into pharmaceutical
preparations,
e.g. by the procedures of the above-mentioned International Patent Application
No. WO
05/105796 and UK Patent Application Nos. 0505965.4 and 0515430.7.
It is often not necessary to purify the solution resulting from the above
Reaction Scheme
and to convert it to desired polymorphs straight away, and it may be
convenient to store it
for eventual use. Clearly, it is inconvenient to store a solution in view of
its bulk and it is
advantageous for the cabergoline to be stored in solid form. However, where
the solution
is a solution of cabergoline in acetonitrile, it is impractical to obtain
cabergoline directly
from the solution, because only an oil is obtainable by simply evaporating off
the
acetonitrile. Also, evaporation and other available techniques for obtaining
solid
cabergoline from the acetonitrile solution often results in an impure product
being
obtained in which the cabergoline may be contaminated with impurities,
including
cabergoline isomers, e.g. the isomer of Formula (IV) above.
The present invention derives from research into the use of various solvents
in the
production of cabergoline and its polymorphs and solvates and especially
addresses the
problem of producing a novel form of cabergoline which has exceptionally high
chemical
and polymorphic purity, and has properties that make it especially useful for
storing in
bulk.
In the research program leading to the present invention, the synthetic
procedure
described above was modified by using trifluoromethyl benzene (BTF) as, or as
a
component of the reaction medium for the reaction of the intermediate of
formula (II) and
EDAC. It was found that by using BTF, the proportion of undesired cabergoline
isomers
was lower than when dimethylformamide is used (as per the procedure of
Brambilla et al.)
and that the environmental problems of using dichloromethane as extracting
solvent
could be avoided. Further, the cabergoline resulting from the process was
found to
contain a lower proportion of unwanted isomers (including the isomer of
formula (IV)) than

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in either of the prior processes referred to, i.e. the process of Bramilla et
al. using
dimethylformamide as reaction medium, and processes using acetonitrile.
In a further aspect of the invention, t-amyl methyl ether (TAME) was used as
extracting
solvent for the purification of relatively impure cabergoline. It was
surprisingly found that a
t-amyl methyl ether solvate could be readily isolated directly in a high state
of purity and
that this solvate could, if desired, be stored in preparation for transforming
it into desired
cabergoline polymorphs. It was also found that TAME was also useful in
preparing pure,
polymorphically homogeneous cabergoline from already partially purified
product.
Thus, the present invention, according to one aspect thereof, provides a
method of
preparation of a novel solid form of cabergoline having a high chemical and
polymorphic
purity which comprises forming a cabergoline solution in a solvent comprising
t-amyl
methyl ether and recovering said solid form from the solution.
The present invention further provides a novel t-amyl methyl ether solvate of
cabergoline.
Said solvate is distinct from known polymorphs of cabergoline and is
designated herein
as "Form TAME cabergoline".
According to a further aspect of the present invention, there is provided Form
TAME
cabergoline, which exhibits an X-ray diffraction pattern comprising peaks
expressed in
degrees two-theta, at approximately 13.99, 15.63, 16.16, 16.68, 17.06, 17.78,
20.78,
21.68, 23.40, 23.48 and 25.88.
According to another aspect of the present invention, there is provided Form
TAME
cabergoline, which exhibits an X-ray diffraction pattern of Table 1.
Also provided by the present invention is Form TAME cabergoline, which
exhibits an X-
ray powder diffraction pattern substantially the same as shown in Figure 4b.
Accordingly, the present invention provides cabergoline Form TAME comprising
less than
2 wt% of other polymorphs.
Preferably, the cabergoline Form TAME comprises less than 1 wt% of other
polymorphs.

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More preferably, the cabergoline Form TAME comprises less than 0.5 wt% of
other
polymorphs.
Most preferably, the cabergoline Form TAME comprises less than 0.1 wt% of
other
polymorphs.
In a method of the invention set out in more detail in the examples,
cabergoline may be
dissolved in a solvent which comprises t-amyl methyl ether, and the solution
cooled to a
temperature of 5 C or below. According to the first aspect of the invention,
the solvent
preferably comprises at least 75% by volume of t-amyl methyl ether, preferably
at least
95%, and more preferably, at least 98%. In a specific embodiment the solvent
consists
solely of t-amyl methyl ether.
Alternatively, for example as part of the preparative procedure for
synthesising
cabergoline, t-amyl methyl ether may be used as a solvent for extracting
cabergoline from
an aqueous phase. Thus, according to a further aspect of the present
invention, there is
provided a method of preparation of a novel solid form of cabergoline having a
high
chemical and polymorphic purity which comprises extracting cabergoline from an
aqueous solution thereof, using a solvent comprising t-amyl methyl ether and
recovering
said solid form from the t-amyl methyl ether phase.
Preferably, the solvent comprises at least 75% by volume of t-amyl methyl
ether, more
preferably at least 95%, and yet more preferably, at least 98%. In a specific
embodiment
the solvent consists solely of t-amyl methyl ether.
In embodiments of the invention set out in more detail in the examples below,
cabergoline
is dissolved in a solvent consisting of t-amyl methyl ether. This is
conveniently done
above room temperature, typically about 30 to 60 C, preferably about 40 to 50
C and the
resulting solution is preferably filtered to remove particulate material. The
temperature of
the solution is then lowered to 20 to 30 C or below, preferably 26 to 28 C and
a
precipitate of cabergoline/t-amyl methyl ether solvate formed. This can be
encouraged by
stirring and also by seeding, for example using crystalline Form I
cabergoline.
The resulting suspension may then conveniently be cooled further, for example
to 0 to
5 C and held at this temperature for a period of 10 to 20 hours.

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The resulting slurry may then be filtered to recover solid, which is
optionally washed, for
example with small quantities of t-amyl methyl ether, and then dried to yield
cabergoline/t-
amyl methyl ether solvate in high purity. The product may be optionally dried
under
vacuum or in an inert gas atmosphere. The product has been determined to be a
novel
polymorph, which we have designated "cabergoline Form TAME".
The cabergoline Form TAME can be utilised further in the production of other
forms of
cabergoline with the advantage that the method results in cabergoline having a
high
purity. The present invention accordingly provides a method of preparing
cabergoline
Form I, which comprises converting cabergoline Form TAME into cabergoline Form
I.
In one aspect of the invention, the cabergoline Form TAME is dried to remove
the t-amyl
methyl ether solvent and the cabergoline produced is then converted into Form
I
cabergoline.
In another aspect of the invention, the cabergoline Form TAME, or the
cabergoline
produced by drying thereof, is dissolved in a solvent comprising toluene,
ethylbenzene,
4-fluorotoluene, 1-chloro-4-fluorobenzene, 1,4-difluorobenzene, 1,3,5-
trimethylbenzene
or xylene and cabergoline Form I is recovered from the solution formed.
According to a further aspect of the present invention, there is provided a
method of
producing cabergoline, which comprises reacting a compound of formula (II):
CC3OH
N
~ ~.
H OU)
with EDAC
N=D~N-/
D
UI
in a solvent, which comprises trifluoromethylbenzene.

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Preferably, the N-(3-dimethylaminopropyl)-N-ethyl carbodiimide hydrochloride
(EDAC.HCI) is combined with trifluoromethylbenzene (BTF) and aqueous alkali,
and a
solution of EDAC in BTF is recovered.
More preferably, the solution of EDAC in BTF is combined with a suspension of
the
compound of formula (II) in BTF.
In a further aspect of the invention, the reaction mixture is heated to a
temperature of 35
to 38 C.
The invention will now be described in more detail in the following Examples
and with
reference to the accompanying drawings of which:
Figures 1 a and lb show 13C CPMAS spectra of the product of Example 2
(designated
Form TAME cabergoline) at -30 C and at ambient temperature, respectively;
Figure 2 shows a differential scanning calorimetry (DSC) trace of Form TAME
cabergoline;
Figure 3 shows a DRIFT IR scan of Form TAME cabergoline;
Figures 4a and 4b show X-ray diffraction patterns of Form TAME cabergoline;
Figures 5a and 5b show the results of particle size determinations for Form
TAME
cabergoline.
EXAMPLES
Example 1: Synthesis of Cabergoline
N-(3-Dimethylaminopropyl)-N-ethyl carbodiimide hydrochloride (EDAC.HCI) is
added to a
stirred mixture of trifluoromethylbenzene (BTF) and 25% w/w aqueous potassium
carbonate. The mixture is stirred until a clear two-phase solution is
obtained. The layers
are allowed to separate and the lower aqueous layer is discarded. The upper
organic
layer is stirred with anhydrous potassium carbonate and filtered to provide a
solution of
EDAC in BTF.
A suspension of a compound of formula (II) in BTF is stirred at 18 to 24 C and
the
required quantity of EDAC in BTF solution is charged. The resulting suspension
is then

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heated to a temperature of 35 to 38 C and maintained at this temperature until
the
reaction is complete. The solution is filtered and purified water added.
Glacial acetic acid
is then added to bring the pH to 5.0 to 5.5. The upper aqueous phase is
separated.
t-Butyl methyl ether is added to the upper aqueous phase and a 20% w/w
potassium
hydroxide solution is added to adjust the mixture to pH 9.5 to 10Ø
The layers are separated and the lower aqueous layer is extracted with t-butyl
methyl
ether. The two upper organic layers are combined and washed with 13% aqueous
sodium chloride. The upper organic layer is then separated and stirred with
charcoal. The
mixture is then filtered and concentrated under vacuum at 35 to 38 C to about
2 to 3
volumes. Acetonitrile is added and the solvent exchanged via distillation
under vacuum at
35 to 38 C to about 2 to 3 volumes.
The resulting acetonitrile solution may then be used as starting material for
producing
desired polymorphs for incorporation into pharmaceutical preparations, e.g. by
the
procedures of the above-mentioned International Patent Application No. WO
05/105796
and UK Patent Application Nos. 0505965.4 and 0515430.7.
Example 2 Formation of TAME solvate
Cabergoline (4.0g) was dissolved in 10mI of t-amyl methyl ether and placed on
a heating
mantle set for 50 C. A clear solution was obtained after 15 minutes when the
temperature had reached 41 C. The solution was filtered through a 0.45 micron
filter and
the resulting solution cooled to 20 to 26 C and seeded with 1% w/w of pure
Form I
cabergoline.
Crystallisation commenced at 27 C. and the resulting suspension was cooled to
0 to 5 C
and held at this temperature for over 16.5 hours. The resultant white solid
was filtered
under an atmosphere of nitrogen. The obtained product had a damp weight of
3.55g,
corresponding to a recovery of 88.8%.
Samples of the product were subjected to 13C mass spectrometry, differential
scanning
calorimetry (DSC), DRIFT IR, DSC, X-ray crystallographic analysis, gas
chromatography,
HPLC and particle size analysis and determined to be of a new crystalline
form. Further
the product was found to be of exceptionally high purity and to be free of the
cabergoline
isomer of formula (IV).

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RESULTS OF ANALYSES
1. 13C CPMAS spectra.
Two samples of the product of Example 2 were subjected to 13C CPMAS
spectroscopy at
-30 C and at ambient temperature. The results are shown in Figures 1 a and lb
respectively.
The samples were found to be exceptionally pure and there was no evidence of
the
presence of any isomers or other polymorphic forms. Narrow lines (labelled "s"
in the
ambient trace of Fig. lb are believed to derive from solvent (t-amyl methyl
ether).
Intensity differences between the -30 C and ambient temperature traces
(notably at 32
and 43.2 ppm) are considered to be due to a change in the motion of the
cabergoline
NMe2 side-chain.
2. X-ray crystallographic analysis
X-ray crystallographic analysis indicated that the product of Example 2
consisted of a
single polymorph.
Experimental
X-ray powder diffraction data were collected at room temperature on an
automated
Philips PW 1050/30 X-ray diffractometer, using Ni filtered CuKa radiation (,\
= 1.5418 A),
in flat plate 6/20 geometry. Data were collected in the range 5 to 70 2 0, in
steps of
0.05 , with a scan time of 2s per step and a 1 s delay time. The sample was
stored at
-20 C prior to the experiment.
The X-ray powder diffraction pattern for the sample examined is shown in Fig.
4a and 4b,
with measured peak data in Table 1.
The XRD pattern is strong, but showed peak broadening. This broadening is a
consequence of small particle size and reflects relatively low crystallinity.
The observed
data were compared to the diffraction patterns for the known polymorphs and
solvated

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forms. The data do not correspond to Form I, Form II or solvated Form V. The
data were
transformed to compare with those presented in patent application
PCT/US2004/014367
collected using CoKa radiation. No clear match is evident.
Table 1
20/0 d/A %
7.729 11.439 21
8.974 9.853 13
10.133 8.729 32
11.437 7.737 32
13.292 6.661 47
13.987 6.332 57
15.63 5.666 61
16.160 5.485 89
16.681 5.314 92
17.055 5.199 71
17.775 4.990 73
20.776 4.275 99
21.684 4.098 58
22.572 3.939 36
23.403 3.801 100
23.480 3.789 100
24.137 3.687 42
25.875 3.443 55
26.938 3.310 22
27.646 3.227 22
28.226 3.162 24
3. Gas Chromatography
The product of Example 2 was subjected to gas chromatography using the
following
apparatus and conditions.
Apparatus
GC system consisting of:
Regulated Helium, Nitrogen and air gas carrier

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Automated Injector
Thermostated column oven, injector port and FID detector
Reagents
Tert-amyl methyl ether
HPLC grade Dimethylformamide (DMF) (Dissolving solvent)
Chromatographic conditions
Column: ZB-624 (30M x 0.32MM x 1.8iaM) with 1 m deactivated
silica retention gap.
Inlet: 250 C, Split 40:1. He column head pressure 0.06 MPa (9.0 psi),
constant pressure mode.
Injection Volume: 5.OpL.
Oven: 85 C (5 min hold) then to 250 C at 120 C/min hold for
5.0 minutes.
Detector: FID at 250 C. N2 make-up at 45mI/min, H2 at 40mI/min
and air at 450m1/min.
Approximate Retention Times
Tert-amyl methyl ether 4.84 minutes
Standard preparation from O.Omg/mL to 2.724mg/mL
When plotted against concentration, the peak areas showed a high linearity.
The sample
contained 18.75% TAME.
4. DSC, DRIFT IR, Particle Size Analysis
The data in Figures 2, 3, 5a and 5b confirm the purity and excellent particle
size
distribution of cabergoline Form TAME. HPLC analysis showed the material to
have a
purity of 99.8%.