Note: Descriptions are shown in the official language in which they were submitted.
CA 02337669 2001-02-23
Process for the preparation of atkylmercaptomethylergoline derivatives
The present invention relates to the preparation of pharmaceutical active
ingredients, and in particular to the preparation of rnedicaments active in
the
treatment of Parkinson's disease.
Prior Art
Alkaloids having an ergoline structure exhibit a wide spectrum of biological
effects which include both peripheral effects (vasoc:onstrictor and
contractile
effect on the smooth muscle of the uterus) and effects on the central nervous
system (various sites of action are located in vasomotor centres and cardiac
inhibitor centres found in the medulla oblongata and in sympathetic structures
found in the diencephalon).
Some of those alkaloids, such as ergotamine, ergometrine, ergosine,
ergocrystine
and ergocryptine, are entirely of natural origin because they can be isolated
from
the fungus Claviceps purpurea. That fungus is a member of the class of
Ascomycetes which is capable of infesting many cereals, such as rye, barley
and
wheat; its sclerotium contains a high percentage (0.5-0.8% by weight) of
alkaloids
having an ergoline structure which are responsible for its known toxic
properties.
Other compounds are of a semi-synthetic nature and are prepared by chemical
modification of naturally occurring alkaloids having an ergoiine structure.
Noteworthy among the above-mentioned semi-synthetic derivatives are
bromocryptine, [CAS 25614-03-3], lysuride [CAS 18016-80-3] and pergoiide
{Figure 1 ), namely (8 )-8-[(methylthio)methyl]-6-
propylergoline [CAS 66104-22-1 ]; this last-mentioned compound in particular
is a
semi-synthetic ergoline used in therapy for the treatment of Parkinson's
disease
CA 02337669 2001-02-23
2
H
9 71
10 6N _
~Z 11 5
vESI~ 4
2
Pergolide
Figure 1
The processes for the synthesis and purification of that molecule are
described in
United States patents US-4,166,182 and US-5,463,060; those patents, however,
describe synthetic approaches which, according to the authors themselves, are
not
entirely satisfactory from several points of view. The impurities which arise
during the synthesis processes described in US-4,166,182 and US-5,463,060 are
difficult to remove without significant losses in yield (J. Kennedy et _a~.,
Org.
Process Res. Dev. (1997), 1(1), 68-71); furthermore, the process described in
US-
4,166,182, has low yields and requires long operating times (J. W. Misner et
~.,
Book of Abstracts, 210th ACS National Meeting, Chicago, IL, August 20-24
(1995). Publisher: American Chemical Society, Wasl'nington, D.C.).
To be more precise, US-4,166,182 describes the synthesis of pergolide mesylate
with 22% yields starting from D-8 -methoxycarborrylergoline. The synthesis and
chromatographic purification steps make the process particularly complicated;
the
basic pergolide, obtained with a 38% ~rield starting from D-8 -
methoxycarbonylergoline, also requires a further purification step by
salification
using methanesulphonic acid.
US-5,463,060, on the other hand, describes the synthesis of the basic
pergolide
starting from 8,9-dihydroelymoclavine with 90.8"/o yields and with a titre of
94.1%. 8,9-dihydroelymoclavine (CAS 18051-16-6) is, however, a semi-synthetic
alkaloid derivative which is not readily available; because it is obtained
from
lysergic acid by means of numerous synthesis steps (see, for example: HU 89-
CA 02337669 2001-02-23
3
3223 890627; R.Voigt et ~. Pharmazie {1973), 2; S.Mirosiav e,~ ~.
Collect.Czech.Chem.Commun. (1968), 33(2), 577-82); the synthetic steps
necessary to carry out the above-mentioned conversion are also especially
onerous
because they require, inter a~,'~,.a, stereoselective hydrogenation of the
double bond
in the 9,10 position and the reduction of the 8 carboxylic function to an
alcoholic
function (upon conversion into methyl ester).
The object of the present invention is therefore to pro~ride an alternative
process
fvr the production of pergolide which permits yields and parities higher than
those
of US-4,166,182 and which uses a starting compound which is more readily
available than 8,9-dihydroelymaclavine.
Subject-matter of the invention
Medicaments active in the treatment of Parkinson's disease which can be
prepared
in accordance with the process of the present invention comprise products
which
have the following general formula VI:
H CHZSR4
wherein R~ may be, independently, a linear, branched or cyclic, saturated or
unsaturated C,_$ alkyl radical, such as, for example, the radicals methyl,
ethyl,
propyl, butyl, isobutyl, tent-butyl, pentyl, cyciopentyl, hexyl, cyclohexyl
and
octyl; the preferred compound includes, but is not limited only to, the
pergoiide
(R CH ).
The process far the synthesis of those compounds, which forms the main subject
of the present invention, uses as starting material the cornpound of formula I
given
below, wherein R, represents a linear, branched or cyclic, saturated or
unsaturated
C,_$ alkyl residue, preferably methyl, ethyl, propyl, butyl, isobutyl, tent-
butyl,
CA 02337669 2001-02-23
4.
pentyI, cyclopentyi, hexyi, cyclohexyl and octyl, and even more preferably
methyl, or the well known and readily available D-8 -methoxycarbonylergoline
[CAS 30341-92-5].
rT
I
In that process, the compounds of formula I are reacaed with 3-halo- and/or 2-
haio-propionyl chloride in an aprotic organic solvent in the presence of a
suitable
proton acceptor. Solvents that may be used in that :;tep are preferably
selected
from acetone, methyl ethyl ketone, tetrahydrofuran and dimethylformamide; the
proton acceptor is preferably selected from triethylarnine, pyridine and
lutidine.
Both the proton acceptor and the 3-halo- and/or 2-lhalo-propionyl chloride are
preferably used in equimolar amounts relative to the compound of formula I.
The compound or mixture of compounds IIa and iIb so obtained is then reacted
with calcium borohydride in an amount of preferably from 5 to 9 moles/mole of
substrate in tetrahydrofuran. The tetrahydrofuran ins preferably present in an
amount of from 2 to 8 mi per gram of substrate; optionally, it may be used in
admixture with protic organic solvents, such as methanol, ethanol or
isopropanol,
or with an aqueous-alcoholic solution thereof. The reaction is carried out at
a
temperature of from 10 to 6S°C, preferably at 60°C.
Compound III so obtained is then reacted in an aprotic organic solvent with an
alkylsulphonyl chloride in .the presence of ,a proton ;acceptor at a
temperature of
preferably from 10 to 30°C; the proton acceptors acre preferably
selected from
pyridine, triethylamine, lutidine; the alkyisulphon.yl chlorides are
preferably
selected from methanesulphonyl chloride, ethanesulphonyl chloride and p-
toluenesulphonyl chloride. The proton acceptor and the alkylsulphonyl chloride
CA 02337669 2001-02-23
are preferably used in amounts of from 20 to 30 and from 1.2 to 3 moles/mole
of
substrate, respectively.
Compound IV so obtained is then reacted in an apro~tic organic solvent with a
compound of the general formula R,SX, wherein R, is a linear, branched or
cyclic,
saturated or unsaturated C,_g alkyl residue, preferably methyl, and X is an
alkali
metal, preferably sodium. The compound R,SX is preferably used in an amount
equal to 4-8 equivalents relative to the substrate; the; apolar organic
solvent is
preferably dimethylformamide; the reaction is preferably carried out at a
temperature of from 90 to 100°C.
Finally, compound V so obtained is converted into t:he desired end product by
treatment with a reducing agent in an aprotic organic solvent at a temperature
of
preferably from 20 to 45°C. Reducing agents that may be used in that
step are
preferably selected from lithium aluminium hydride and sodium dihydro-bis(2-
methoxyethoxy) aluminate; aprotic solvents that may be used in that step are
preferably selected from tetrahydrofuran, dioxane and toluene.
For greater clarity, the novel process according to the present invention is
shown
in the following reaction schemes 1, 2 and 3.
CA 02337669 2001-02-23
6
Scheme 1
TT TT TT
uu ....
m
IT
v
CI VI
wherein R, represents a linear, branched or cyclic, saturated or unsaturated
C,_g
alkyl residue, such as, for example, the radicals methyl, ethyl, propyl,
butyl,
isobutyl, tent-butyl, pentyl, cyclopentyl, hexyl, cyciohexyl and octyl,
preferably a
methyl group; R, is a halogen (Cl, I, Br), preferably chlorine (Cl), X is an
iodine
molecule or a compound of the general formula R,;S03_ wherein RS is methyl,
ethyl or p-tolyl, preferably methyl; R4 is, independently, a linear, branched
or
cyclic, saturated or unsaturated C,_$ alkyl residue, such as, for example; the
I
CA 02337669 2001-02-23
7
radicals methyl, ethyl, propyl, butyl, isobutyl, tent=butyl, pentyl,
cyciopentyl,
hexyl, cyclohexyi, preferahly a methyl group.
Scheme 2
" I i
Rz
lia
LT
!11
~v
TT
TT
T1
wherein R" R" R, and ~ have been defined above.
ii
CA 02337669 2001-02-23
Scheme 3
TT
1 _
uu
TT
111
7T
TT
y vl
wherein R" RQ and X have been defined above.
The novel intermediates of formula II, III, IV and V, which are given
individually
below for greater clarity, constitute a further subject of the invention.
TS
n
,,~.
CA 02337669 2001-02-23
wherein R, and R3 may be a halogen (Ci, I, Br) and hydrogen (H), respectively;
. alternatively, R, and R, may be bonded to one another directly giving rise
to a
double bond; and R, represents a linear, branched or cyclic, saturated or
unsaturated C,_g ~kyl residue, such as, for example, the radicals methyl,
ethyl,
propyl, butyl, isobutyl, tent-butyl, pentyl, cyclopentyl; hexyl, cyclohexyl
and
octyl; the preferred molecules are represented by t'he compounds IIa (R3=H;
R,_--Cl; R,=CH3) and IIb (R3 and RZ ,joined together to give rise to a double
bond;
R,=CH3).
II,T
TT
wherein X is a halogen (X=I, compound IVb) or a compound of the general
formula R5SO3- wherein RS is methyl, ethyl or p-to:lyl; the preferred molecule
is
represented by the compound IVa(X=CH3S03-).
v
CA 02337669 2001-02-23
wherein R~ is, independently, a linear, branched or cyclic, saturated or
unsaturated
C,_a allcyi residue, such as, for example, the radicals methyl, ethyl, propyl,
butyl,
isobutyl, tent-butyl, pentyl, cyclopentyl; hexyi, cyclohexyl; the preferred
molecule
is represented by the compound Va (RQ CH3).
Detailed description of the invention
In order to obtain quantitative conversion of the 8 -methoxycarbonylergoline
into
the intermediate III, a series of acyiating agents, such as 3-halo- and 2-halo-
propionyl chlorides, were evaluated. The halogen derivatives tested were
chlorine,
iodine and bromine derivatives.
As is well known to experts in the field, the presence of an electron-
attracting
group (such as a chlorine, bromine or iodine atom) in the alpha or beta
position to
an acid chloride increases the latter's reactivity in acylation reactions.
During the research work which Ied to the present invention, it was hoped to
find,
by screening reducing agents, a reagent which exhibited a high degree of
chemoselectivity towards the intermediate chlorine derivative of formula II
(R,=halogen, R3=H or R,=H, R3 halogen). The reducing agent was intended to
replace the halogen in the alpha (or beta) position to the acyiamide function
with a
hydrogen atom and reduce the methoxycarbonyl function in the 8 position to an
alcoholic function without reducing the amide group in position 6.
We ascertained experimentally that by using an equimolar amount of 3-
chloropropionyl chloride in the presence of a proton acceptor in acetone
solution
under stirring at room temperature, D-8 -methoxycarbonylergoline gave, in
addition to the desired product (D-6-(3'-chloropropionyl)-
8 -methoxycarbonylergoline; compound IIa), a side product which was
subsequently identified ~cs D-6-(acryloyl)-
8 -methoxycarbonylergoline (compound ZIb). The presence of this side product
IIb
was initially regarded as a critical factor' for the industrial development of
the
process because, even if the presence of compound IIb could be contained by
suitably varying the experimental conditions (slow addition of the acylating
agent,
low reaction temperatures, low concentrations of tlne reagents) nothing was
known
CA 02337669 2001-02-23
11
of the possible influence of that secondary product on the subsequent
synthetic
steps.
Surprisingly, the screening carried out on a number of reducing agents under
various experimental conditions on a mixture constituted to the extent of 50%
by
compound IIb and compound IIa demonstrated not only that calcium borohydride
in tetrahydrofuran was capable of showing the desired chemoselectivity
(removal
of the chlorine in position 3' and reduction of the. 8 -methoxycarbonyl group
without reducing the amide in position 6) but ais~o that compound IIb was
converted into the desired compound of formula III.
The surprising reactivity of the double bond of compound IIb with calcium
borohydride in tetrahydrofuran gave us the possibility, which was not
foreseeable
from the literature, of using the reaction mixture obtained directly from the
acylation reaction of D-8 -methoxycarbonylergoline without purification in the
subsequent reaction step.
Thus, by reacting a mixture of D-8 -methoxycarlbonylergoline in an aprotic
solvent, in concentrations ranging from 8 to 18% weight/volume, under stizring
at
room termperature, with an equimolar amount of a suitable proton acceptor and
one equivalent of 3-halo- or 2-halo-propionyl chloride for a period ranging
from
30 minutes to 2 hours, we obtained, after dilution with water and filtration,
a
mixture of which approximately 50% was constituted by compound IIa and
compound IIb.
Aprotic solvents that may be used in that step are represented by acetone,
methyl
ethyl ketone; tetrahydrofizran, dimethylformamide" preferably acetone; proton
acceptors that may be used are triethylamine, pyridine and lutidine,
preferably
triethyiamine.
The mixture of compound IIa and compound Ilb is, dispersed in tetrahydrofuran
with sodium borohydride (from 5 to .9 moles per mole of substrate) and the
suspension so obtained is added, at a temperature hanging from 0 to
+15°C and
under vigorous stirring, to a tetrahydrofuran solution or to an alcoholic
solution
(methanol, ethanol or isopropanol) or an aqueous-alcoholic solution containing
calcium chloride (from 1.5 to 2 moles per mole of sodium borohydride). When
the
CA 02337669 2001-02-23
12
addition is complete, the temperature is increased to 60°C and the
reaction
mixture is maintained under stirring for a period ranging from 20 minutes to
60
minutes. The compound III so obtained is precipitated from the reaction
mixture
(after acidification of the reaction mixture, evaporation of the organic phase
and
treatment with aqueous carbonate) and recovered by filixation.
Alternatively, the calcium borohydride, instead of being produced "in situ",
can
be used already preformed in the commercially available forms (for example, as
a
bis-THF complex).
On the basis of the data obtained, compound III can be prepared in accordance
with Scheme 1 with total yields of 81°ro starting from D-8 -
methoxycarbonylergoline.
It was clear from the results obtained that, in order to synthesise the
compound of
formula III, it would have been equally advantageous to acylate compound I
directly with acryioyl chloride (Scheme 3) or to use the intermediate IIa with
a
high degree of chemical purity {obtainable by the acylation of compound I with
chloropropionyl chloride carried out at low temperatures (0-5°C) and
high
dilutions (0.05-0.2 molar); Scheme 2) and to reduce the intermediate IIb or
IIa so
obtained with calcium borohydride in the next step. An experimental check
carried out on those two variants confirmed total yields of compound III from
compound i superimposable on those obtained by synthesis Scheme 1, confrming
the validity thereof as alternatives for obtaining compound III.
Compound III was subsequently reacted, in solution with a proton acceptor,
with
an alkylsulphonyl chloride under stirring at room tempE;rature for a period
ranging
from 1 .to 2 hours to give compound IV (X=RSS03; wherein RS is methyl, ethyl
or
p-tolyl) with yields ranging from 88 to 95%. .
Suitable proton acceptors are represented by pyridine, .triethyiamine,
lutidine,
preferably pyridine. Alkylsulphonyl chlorides. that riiay be used are
represented
by, but not limited to, methanesulphonyl chloride, ethanesulphonyl chloride or
p-
toluenesulphonyl chloride, preferably methanesulphonyl chloride.
Compound IVa is then treated with from 4 to 8 equivalents of sodium alkyl
rnercaptide (compound of the general formula R,SNa; wherein R4 is,
CA 02337669 2004-06-22
13
independently, a linear, branched or cyclic, saturated or unsaturated C,~
alkyl
residue) in dimethylformamide with agitation at from 90 to 100°C for a
period
ranging from 2 to 5 hours to give compound V with yields ranging from 90 to
95°.'° and an HPLC titre of 97%.
If the R~ group of the allcyl mercaptide is an alkyl radical larger than
methyl or
ethyl, compound IVa (X=RSS03; wherein RS is methyl, ethyl or p-tolyl) can be
converted beforehand into a halogenated derivative IVb (preferably X=I) in
order
to facilitate nucleophilic substitution. That last step is carried out in
acetone
solution with agitation at reflux temperature in the presence of lithium
iodide to
dive compound IVb in quantitative yields.
Compound V is converted into the final compound VI by treating a heterogeneous
mixture of compound V in an aprotic solvent with a reducing agent at a
temperature ranging from 20 to 45°C for from 2 to 6 hours. Reducing
agents that
may be used in that step are lithium aluminium hydride or sodium dihydrido-
bis(2-methoxyethoxy) aluminate; the preferred reducing agent is sodium
dihydridro-bis(2-methoxyethoxy) aluminate. Aprotic solvents that may be used
in
that step are tetrahydrofuran, dioxane and toluene; the preferred solvent is
toluene.
The yields of that step are from 80 to 99%.
The physico-chemical characteristics of the product VI obtained (Ra=CH,) are
in
good agreement with the data reported in literature for this product; the HPLC
purity is 96%.
The high degree of purity of the pergolide base obtained (HPLC titre of 96% on
the crude reaction material), the high global yields of the process (66%)
starting
from D-8 -methoxycarbonylergoline and the ready availability of the primary
starting material make this process competitive compared with those known from
the prior art.
Several salts of compound VI (Pergolide) may 'be prepared, including acid
addiction salts of inorganic acids as well as salts derived from non toxic
organic
salts. The preparation of the above salts, and particularly the
methanesulfonate
(mesylate), may be easily realised following known literature procedures, as
for
example US-4, I66, I 82 and EP-0003667,
CA 02337669 2001-02-23
14
EXAMPLES
Example I
Prepararion of D-6-n-propionyi-8 -hydroxymethyiergoiine (compound III)
according to reaction scheme 1
A mixture of D-8 -methoxycarbonylergoline (compound I) (10.8 g; 0.04 mol) is
heated with vigorous agitation in acetone (100 ml) at: 40°C for 30
minutes, and
then at 55°C for a further 30 minutes. After cooling to ambient
temperature,
triethylarnine (0.04 mol) is added. After a few minutes, a solution of 3-
chloropropionyl chloride {5.08 g; 3.84 ml; 0.04 moI) in acetone (5 mI) is
added
dropwise while maintaining the reaction temperature at from 20 to 25°C.
When
the addition is complete, the reaction mixture is maint~uned under stirring at
room
temperature for 30 minutes, then it is poured into water (150 ml) and the
suspension so obtained is maintained under stirring for 30 minutes. After that
time, the precipitated solid is recovered by filtration, vvashed with water
(i00 ml)
and dried overnight under vacuum at a temperature of ti0°C to give 12.8
g of a 6/4
mixture of compound IIa and compound IIb.
For analysis purposes, the two compounds IIa and lib can be isolated by
chromatography on silica gel while eluting with dichloromethane/methanol =
9/1.
D-6-(3'-chloropropionyi)-8 -methoxyearbonyiergoiine (compound IIa):
TLC=Rf: 0.72 (eluant dichloromethanelmethanol = 911}
'H-NMR (60 MHz, DMSO-db) gives the diagnostic sig:aals (ppm):
0.50-1.50 (m); 2.I0-2.90 (m); 3.30 (s); 2.90-4.00 (m); Ei.30-6.75 (m, 4H,
aromatic)
Elemental analysis: calculated for C,9Hz,NzO,CI
theoretical- C: 63.24%; H:5.87%; N:7.76%; 0:13.30%:. CI:9.83%
found- C:63.29%; H:5.84%; N:7.67%; C1:9.88%
D-6-(acryloyi)-8 -methoxycarbonyiergoiine (compound IIb)
TLC=Rf:0.61 (eluant dichloromethane/methanol = 9/1}
MS(EI)- M+: mie=324
'H-NMR (60 MHz, DMSO-d6) gives the diagnostic signals (ppm):
CA 02337669 2001-02-23
2.15-2.40 {m, 3H); 2.40-3.20 {m, 3H); 3.25 (s, 3H, CO,CH3); 3.60-3.70 (m, 3H);
5.35-5.70 (m, 2H, CHI CH); 6.15 (m, IH, CHZ ~CI~; 6.30-7.i5 (m, 4H,
aromatic); 9.25-9.50 (sb, 1H, N-H)
Elemental analysis calculated for C,9H,oN~03
theoretical- C:70.35%; H:6.21%; N:8.64%; 0:14.80%
found- C:70.31 %; H:6.26%; N:8.73%.
The mixture of compounds IIa and LIb (1 g), which are obtained directly from
the
previous reaction, is dispersed in tetrahydrofuran (4 mI) with sodium
borohydride
(870 mg): The suspension so obtained is added, under vigorous stirring at a
temperature of 10°C, to a solution constituted by calcium chloride
(14.5 mmol) in
ethanol (16 ml). When the addition is complete, the temperature of the
reaction
mixture is slowly increased to 60°C and the mixture i:~ maintained
under stirring
at that temperature for 30 minutes. After that time, the reaction mixture is
concentrated under vacuum and the residue so obtainedl is acidified with 2N
HCl;
the suspension so obtained is maintained under stirrin;; for 1.5 hours at
ambient
temperature and then the precipitate is recovered b;y f ltration. The solid so
obtained is resuspended in methanol (8 ml); the heterogeneous mixture is
heated
to reflux temperature and is maintained at that temperature for 10 minutes:
When
the suspension has been cooled to 15°C, a 10% (I5 ml) potassium
carbonate
solution is added with vigorous stirring. The crystalline solid so obtained is
recovered by filtration, washed with a Iarge amount of water and dried under
vacuum at a temperature of 60°C to give 965 mg of compound IiI (81 %
total yield
from compound n.
TLC=Rf: 0.55 (eluant dichloromethane/methanol = 9/1)
Melting point: 2I4-216°C
MS{EI)- M': m/e=298
'H-NMR (60 MHz, DMSO-db) gives the diagnostic signals (ppm):
0.85-1.25 (t, 3H, CH,CH,C=O); 2.15-2.80 (rn); 2.85-4.00(m); 4.55-4.85 (sb, 1H,
O-H); 6.35-7.05 (m, 4H, aromatic); 10.25-10.50 (sb, 1H, N-H).
Example 2
Preparation of D-6-{propionyl)-8 -mesyoxymetf~ylergoline (compound IYa)
CA 02337669 2001-02-23
i6
Methanesulphonyl chloride (0.962 g) is added slowly to a solution of compound
III (0.984 g) and pyridine (5.900 g) under vigorous stirring and while
maintaining
the reaction temperature comprise between 15 and 20°C. When the
addition is
complete, the reaction mixture is maintained under stirring at room
temperature
for 1 hour, then it is worked up by adding a 10% aqueous solution of potassium
carbonate ( 1 S ml) and continuing agitation until a crystalline solid is
obtained
which is recovered by filtration, washed with a large ~unount of water and
dried
under vacuum at 60°C to give 1.091 g of compound IV (88% yields).
HPLC (column: LICHROCART 125x4 mm packed with LICHROSPHER RP-18,
m; mobile phase: 60% buffer 20 mM of K,HP04 adjn~sted to pH 6.5 using H3P0~
(85%) and 10 mM triethylamine; 40% acetonitrile; flow 1.2 ml/minute): rt
4'266".
Elemental analysis calculated for C,gFiz4NZO4S
theoretical- C:60.62%; H:6.43%; N:7.44%; 0:17.00%; 5:8.52%
found- C:60.66%; H:6.49%; N:7.45%; 5:8.48%
Example 3
Preparation of D-6-{propionyl)-8 -methylthiomethylf:rgoline (compound V)
Compound IV (1.091 g) is suspended in anhydrous dimethylformamide (6.825 g)
and the reaction mixture so obtained is heated (60-80°C) under stirring
until a
homogeneous solution is obtained. After cooling to ambient temperature, a 20%
solution of sodium methyl mercaptide (5.250 g) in nnethanol is added rapidly
under vigorous stirring. After 1 hour, the reaction mixti:~re is slowly heated
until a
temperature of 90-95°C is reached, distilling off alI of the methanol.
The reacrion
mixture then continues to be heated under vigorous stirring for 4 hours. The
reaction.mixture is cooled to 10°C and 7.5 ml of water are added under
stirring.
The precipitated product is recovered by f ltration, washed with water and
dried
under vacuum at a temperature of 60°C to give 0.905 g of compound V
(95%
yield).
TLC=Rt.:0.81 (eluant dichloromethane/methanol = 9/1 )
HPLC (same experimental conditions as in Example 2) == rt:l 1'070"
Melting point:268°C (decomposition)
Elemental analysis calculated for C,9H,4N~OS
CA 02337669 2001-02-23
17
theoretical- C:69.48%; H:7.36%; N:8.53%; 0:4.87%; 5:9.76%
found- C:69.51 %; H:7.31 %; N:8.48%; 5:9.78%.
Example 4
Preparation of D-6-n-propyi-8 -methylthiomethylerg;oline (compound VI)
4.0 g of a 70% solution of sodium dihydridro-bis(2-methoxyethoxy) aluminate in
toluene are added slowly to a suspension of compound V {0.905 g) in toluene
( 13.8 ml) undr stirring at room temperature. When the; addition is complete,
the
reaction is maintained under stirring for 1 hour then heating to a final
temperature
of 45°C; this temperature is maintained for 4 hours. At the end of that
time, the
reaction mixture is cooled to ambient temperature and acidified with 5% HCl
(25
ml). The two-phase mixture is distilled under vacuum until the organic phase
has
been eliminated; the aqueous suspension which remains is filtered under vacuum
and the solid so recovered is washed with water. The cmde material so obtained
is
resuspended in methanol (6 ml) and the suspension so obtained is heated under
reflex for 30 minutes, then cooled to room temperattu~e and treated with a 10%
aqueous solution of potassium carbonate (12 ml) under vigorous stirring. After
2
hours under stirring at room temperature, the suspension is filtered and the
solid
so recovered is washed with water and dried under vaicuum at a temperature of
60°C to give 0.826 g of compound VI (95% yield).
The physico-chemical characteristics of the product obtained are in goad
agreement with the literature data (as reported in US-4,166,182).
The HPLC titre (same experimental conditions as those given in Example 2) of
compound VI so obtained (rt 11'070"} is 96%.
Example 5
Preparation of D-b-(propionyl)-8 -hydroxymethylergoline (compound III}
according to reaction scheme 3
6 g ( 18.49 mmol) of D-8 -methoxycarbonyiergoline {nompound I) are dispersed
in
acetone (50 ml) and the reaction mixture is heated at 40"C for 30 minutes and
then
at 55°C for a further 30 minutes. After cooliirg to ambient
temperature,
triethylamine {2.24 g; 3.1 ml; 22.18 mmol) and a solutiion of acryloyl
chloride (2
g; I.8 ml; 22.18 mmol) in acetone (5 mi) are added in succession while
CA 02337669 2001-02-23
18
maintaining the reaction teriiperature comprise between 20 and 2S°C.
When the
addition is complete, the reaction mixture is maintained under stirring at
room
temperature for I hour. The reaction mixture is worked up by being poured into
water (I00 mi) and maintaining the resulting suspension under stirring for 30
minutes. After that time, the precipitated solid is recovered by filtration,
washed
with water (80 ml) and dried under vacuum at a temperature of 60°C to
give (S.4
g; I 6.64 mrnol; 90% yield) of compound IIb.
The physico-chemical characteristics of the resulting product IIb are the same
as
those of the product obtained by chromatographic purification in Example 1.
Compound IIb is then reduced using calcium borohydride produced "in situ", as
already described in Example l, to give compound ITl with total yields of 78%
starting from compound I.
Example 6
Preparation of D-b-(propionyl)-8 -hydroxymethylergoline (compound III)
according to reaction scheme 2
A mixture of D-8 -methoxycarbonylergoiine (compound I) (3.48 g; I2.9 mmol) is
heated, under vigorous stirring in acetone {6S ml) at 40"C for 30 minutes and
then
at SS°C for a further 30 minutes. When the reaction mixture has been
cooled to
5°C, triethylamine {13 mmol) is added and, while maintaining that
temperature., a
solution of 3-chioropropionyl chloride (1.64 g; 1.24 ml; 12.9 mol) in acetone
(6.S
mi) is added within a period of 30 minutes under vigorous stinting. When tt~e
addition is camplete, the reaction mixture is maintained under stirring at
room
temperature for 30 minutes and then it is poured into water (100 ml), the
resulting
suspension being maintained under stirring for 30 minutes. After that time,
the
precipitated solid is recovered by filtration, washed with water (35 ml) and
dried
overnight under vacuum at a temperature of .60°C to. dive 3.6 g of
compound IIa
(contaminated to the extent of S% with coiripound IIb). The crude product can
be
reduced using calcium borohydride produced "in situ" .as described in Example
1
to give compound III with total yields, starting from intermediate I, of 80%_
Example 7
CA 02337669 2001-02-23
19
Preparation of D-6-(propionyl)-$ -iodomethylergoline (IVb) starting from
compound IVa.
A mixture constituted by compound IVa (1 mmol; 376 mg) and lithium iodide (4
mmol; 455 mg) in acetone (20 ml) is stirred at reflux for 8 hours. After that
time,
the reaction mixture is worked up by diluting it with water {20 ml) and
recovering
the resulting solid by filtration, washing it with a large amount of water on
the
filter and drying it overnight under vacuum at 60°C. 392 mg (0.96 mmol)
of
compound IVb are recovered.
MS(EI)- M+: m/e = 408
Elemental analysis calculated for C,BH,,N,OI
theoretical- C:52.95%; H:5.18%; N:6.86%; 0:3.92%; I::31.08%
found- C:52.90%; H:5.12%; N:6.8I%; I:31.12%
