Note: Descriptions are shown in the official language in which they were submitted.
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Process and Intermediates for Production of Cabergoline
and Related Compounds
FIELD OF THE INVENTION
This invention relates to a new process for the preparation of dopamine
agonists such as Cabergoline, to some novel intermediates used in this process
and to their preparation.
BACKGROUND OF THE INVENTION
N-(Ergoline-8~3-carbonyl)ureas of formula [I]
R2
I H
O N~N~Rl
~'O
Hi.. N.R3
H
N
H ~R4 [I]
1o wherein RI represents an alkyl group having from 1 to 4 carbon atoms, a
cyclohexyl group or a phenyl group or a dimethylamino alkyl group -(CH2)"NMe2
in which n is an integer , R2 represents any of the groups which RI may
represent,
or a hydrogen atom or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl
or
thiadiazolyl residue, R3 represents a hydrocarbon group having from 1 to 4
Is carbon atoms, R4 represents a hydrogen or a halogen atom or a methylthio or
phenylthio group and RS represents a hydrogen atom or a methyl group; have
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shown potent dopamine agonist properties and have been useful as anti-
Parl~inson
drugs and as prolactin inhibitors (US 5,382,669 and Eur. J. Med. Chem., 1989,
v.
24, 421).
One of the most potent prolactin inhibitor of this class is
1-(6-allylergoline-8 [i-carbonyl)- I - [3 -(dimethylamino)propyl]-3 -ethylurea
(international non-proprietary name Cabergoline) [la] (Eur. J. Med. Chem.,
1989, v. 24, 421) which was firstly prepared by reaction of
6-allylergoline-8~i-carboxylic acid [7] with 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide (US 4,526,892) (Scheme 1):
to
H
N
~H
HN-J ~
EtN=C=N(CH~3NMe~
H~
EtHN~O Me~N~N~O
O ]N'~NMe~ O ]N'Et
H,~, I H,~ i
~ H~ I ~ H
i i
HN , HN
Cabergoline ( 1a ] By-product [ 8
Scheme 1
In this case both regioisomers [la] and [8] were obtained and the yield of
the isolated Cabergoline [la] is low as a consequence of isolation
difficulties.
Another method for Cabergoline preparation (Eur. J. Med. Chem., 1989, v.
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24, 421 and BP 2,103,603) was based on the direct reaction of
N [3-(dimethylamino)propyl]-6-allylergoline-8[i-carboxamide [2a] with ethyl
isocyanate (Scheme 2):
EtHN ~O
~'H
N~NMe~ f ~NMe2
EtNCo
H
[2a] a]
Scheme 2
to However, this approach required large amounts of ethyl isocyanate (up to
40 eq.) and reflux in toluene for several days. The use of large quantities of
toxic
isocyanate under drastic reaction conditions represented the major limitation
for
the large-scale preparation of Cabergoline by this route.
The method proposed in LTS 5,382,669 and Syn. Lett., 1995, 605 is based
is on copper salts catalyzed reaction of ethyl isocyanate with carboxamide
[2a]
using phosphorous ligands. Drawbacks of this approach are the use of heavy
metal ions on the final step of the synthesis and decreasing chemoselectivity
with
increasing conversion of this reaction.
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SUMMARY OF THE INVENTION
All the previously disclosed methods for the preparation of Cabergoline
present serious drawbacks for producing material suitable for use as a
pharmaceutical drug. A desirable goal, met by the present invention, has been
to
s devise a new synthetic method, which avoids use of heavy metal salts, and
which
cleanly produces the desired Cabergoline [la] under mild reaction conditions,
avoiding tedious and expensive purification steps.
The present invention provides a commercially acceptable process for
producingN-(ergoline-8~3-carbonyl)ureas of formula [I]:
Rz
I H
O N~N~Ri
~O
H,, . I
N~Rs
H
N
H Rø II1
including their stereoisomers as well as acid addition salts thereof,
wherein Rl is selected from alkyl having from 1 to 4 carbon atoms, cyclohexyl,
is phenyl, and dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer,
R2 is selected from hydrogen, alkyl having from 1 to 4 carbon atoms,
cyclohexyl, phenyl, dimethylamino alkyl group -(CH2)nNMe2 in which n is an
integer, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl
,
R3 represents a hydrocarbon group having from 1 to 4 carbon atoms, and
2o R4 is selected from hydrogen, halogen, methylthio and phenylthio group;
which process comprises silylating an ergoline-8-carboxamide of formula [2],
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H
~Ra
~R3
[~]
including stereoisomers as well as metal or ammonium salts or acid addition
salts
thereof,
wherein Rl, RZ, R3 and R4 are as defined above,
reacting the obtained product with isocyanate of the formula [5]
Rl N=C=O
[5]
followed by desilylation.
This novel approach was used for the preparation of the known
1o antiprolactinic and anti-Parkinson agent Cabergoline [la] and related
compounds.
O \ /NHEt
n ~r\~NMe2
[ la
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Other features and advantages will be apparent from the specification and
claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes a novel process for the preparation of
N (ergoline-8(3-carbonyl)urea compounds of formula [I]. Particularly, the
present
invention utilizes the silylation of of ergoline-8~i-carboxamide [2] in order
to
selectively activate it's amide group in the subsequent reaction with
isocyanate.
to This novel approach has the following advantages:
~ Silylated ergoline-8[i-carboxamides react with isocyanates to give, after
desilylation of intermediates, the desired N (ergoline-8 [i-carbonyl)ureas [I]
with
high yield and purity.
~ Reagents used for silylation and desilylation are not toxic, conunercially
is available and inexpensive.
Although any silylating agents, suitable for silylating amides, can be used
for silylating ergoline-8~i-carboxamide [2], a compound of formula [3] is
preferably used for this purpose to give intermediate N silylamide of the
formula
[4], tautomers or mixtures thereof, stereoisomers, as well as addition salts
2o thereof; intermediate [4] reacts with isocyanate of formula [5]
R2
I 6
R
.SI~R~
R8
R6 ~ R3
i
Y-Si RR Rl N=C=O
[3] [4] [5]
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wherein R6, R' and R8 may be the same or different and are selected from the
group consisting of all~yl having from 1 to 6 carbon atoms, aryl and aralkyl
radicals;
s Y is selected from the group consisting of chloro, bromo, iodo, (haloalkyl)-
sulfonyloxy, all~ylsulfonyloxy, arylsulfonyloxy,
(trialkylsilyloxy)sulfonyloxy,
imidazolyl, N acyl-N-alkylamino, N acyl-N (trialkylsilyl)amino,
(trialkylsilyl)-
amino, N,N dialkylamino, isopropenyloxy, 1-alkoxy-1-alkenyloxy and
trichloroacetoxy radicals;
1o and R2, R3 and R4 are as defined above, to give O-silylated
N [ergoline-8~i-carbonyl]urea represented by formula [6]:
R2
I 6
,R
~~.SI ~R~
N.RI R8
[6]
is including , tautomers or mixtures thereof, stereoisomers, as well as
addition salts
thereof,
wherein Rl, R~, R3, R4, R6, R~ and Rg are as defined above; following
desilylation
of the above compounds) to obtain the desired N (ergoline-8~i-carbonyl)urea
[I],
which can be converted into acid addition salts thereof.
2o The silylating agent may be used in a 0.5 to 10 fold molar amount,
preferably from 0.9 to 5 fold molar amount, relative to the amount of the
ergoline-8~i-carboxamide [2]. Preferably, silylating agents are selected from
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trimethylsilyl trifluoromethanesulfonate, trimethylsilyl methanesulfonate,
trimethylsilyl benzenesulfonate, trimethylsilyl chlorosulfonate,
trimethylsilyl
chloride, bromide or iodide, trimethylsilyl trichloroacetate and
trifluoroacetate,
1-(trimethylsilyl)imidazol, I-(trimethylsilyl)-1,2,4-triazole,
1-(trimethylsilyl)-1H-benzotriazole, 1-(trimethylsilyl)-2-pyrrolidinone,
N methyl-N (trimethylsilyl)trifluoroacetamide, methyl trimethylsilyl
dimethyll~etene acetal, bis(trimethylsilyl)sulfate, N,O-
bis(trimethylsilyl)acetamide
and bis(trimethylsilyl)trifluoroacetamide.
The silylation reaction may be carried out from -50 °C to the
reflux
to temperature of the reaction mixture. Preferably, the silylation is carried
out from
0° to 50 °C.
Organic or inorganic acids or salts may accelerate the silylation.
Examples of such acids include mineral acids such as sulfuric acid or hydrogen
halide. Examples of salts include metal halides, tertiary ammonium halides,
is ammonium halides, ammonium sulfate, pyridine or it's derivatives
hydrohalides.
However, preferably, organic or inorganic bases accelerate the silylation
reaction.
Examples of organic bases are tertiary amines, sterically hindered secondary
amines, pyridine or there derivatives, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or mixture thereof. Examples of
2o tertiary amines include I-ethylpiperidine, 1-butylpyrrolidine,
diisopropylethylamine, triethylamine, N,N,N,N-tetramethylethylenediamine,
1,4-diazabicyclo[2.2.2]octane or mixture thereof. Examples of sterically
hindered
secondary amines are diisopropylamine, dicyclohexylamine,
2,2,6,6-tetramethylpiperidine or mixture thereof. Examples of pyridine
25 derivatives axe 4-dimethylaminopyridine (DMAP),
4-(4-methylpiperidino)pyridine and 4-pyrrolidinopyridine or mixture thereof.
The solvent for the silylation reaction may be any suitable aprotic organic
solvent provided it does not inhibit the reaction. Examples thereof include
aromatic hydrocarbons such as benzene, toluene and xylene, chlorobenzene,
30 o-dichlorobenzene, m-dichlorobenzene and bromobenzene; hydrocarbon halides
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such as dichloromethane and chloroform; ether solvents such as ether,
isopropyl
ether, tent-butyl methyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane,
tetrahydrofuran (THF); ester-type solvents such as ethyl acetate, isopropyl
acetate, butyl acetate; or highly polar aprotic organic solvents such as
acetonitrile,
s N,N dimethylformamide (DMF), N,N dimethylacetamide or
1-methylpyrrolidinone (NMP).
The resultant silylated product may be used in the following step after
isolation from the reaction mass, or may be subjected to the subsequent step
without isolation.
1o After silylation, the resultant product is reacted with a compound of
formula [5], which may be used in a 1 to 10 fold molar amount, preferably 2 to
5
fold molar amount relative to the amount of the ergoline-8~i-carboxamide [2].
The reaction may be carried out at temperature from -50 °C to reflux
temperature
of the reaction mixture. Preferably, the reaction is carried out at 0 - 50
°C without
is isolating silylated ergoline-8(3-carboxamide from the reaction mass.
The reaction of silylated ergoline-8(3-carboxamide with isocyanate may be
carried out without solvent, but preferably, the reaction is carried out in
any
organic aprotic solvent which does not inhibit the reaction. Examples thereof
include aromatic hydrocarbons such as benzene, toluene and xylene,
2o chlorobenzene, o-dichlorobenzene, m-dichlorobenzene and bromobenzene;
hydrocarbon halides such as dichloromethane and chloroform; ether solvents
such as ether, isopropyl ether, tent-butyl methyl ether, 1,2-dimethoxyethane,
1,2-diethoxyethane, tetrahydrofuran (THF); ester-type solvents such as ethyl
acetate, isopropyl acetate, butyl acetate; or highly polar aprotic organic
solvents
2s such as acetonitrile, N,N dimethylformamide (DMF), N,N dimethylacetamide or
1-methylpyrrolidinone (NMP).
Optionally, the reaction of silylated ergoline-8(3-carboxamide with
isocyanate may be accelerated by transition metals) salts) and/or coordination
compounds) or fluoride-ions. Examples of the said transition metals include
3o copper or zinc. Preferably, the said transition metals) salts) are copper
and/or
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zinc halides. Preferably the said ligands in the coordination compounds) with
transition metals) contain phosphorous, nitrogen and/or oxygen atoms. Examples
of the ligands include triarylphosphines, pyridine or it's derivatives,
tertiary
amines, nitrites, amides and ether-type compounds.
The desilylation can be carried out by, for example, using fluoride salts
optionally in the presence of phase transfer catalysts. Examples of the said
fluoride salts include tetraalkylammonium fluoride, benzyltrialkylammonium
fluoride and alkali metal fluoride. Examples of the said phase transfer
catalysts
include tetraalkylammonium salts, benzyltrialkylammonium salts and crown
to ethers.
Cabergoline [la] may be prepared from amide [2a] according to Scheme
3:
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R6
R6 Rs_Si -R~
~, NMe2 Y_Si R~ n ~y/'~, NMe2
i8
R
[3]
[2a] [4a]
~, EtNCO
R~
6
O NHEt RS Si0 NEt
n ~.T~NMe2 n rr~NMe2
Desilylation
[ 6a ]
Cabergoline ( la ]
Scheme 3
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The invention will be further described in more detail with the following
non-limiting examples.
Example 1
Cabergoline [Ia]
O \ / NHEt
~'H
~ NMe2 ~ NMe2
1. TMSOTf/Et3N
EtN=C=O
2. Desilylation
[ ~a ] ~u~
Cabergoline [ Ia ]
to Scheme 4
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Typical procedure A.
A tree-necked round-bottom flask fitted with a reflux condenser
(optional), thermometer and septum was evacuated, dried and flushed with dry
nitrogen or argon. Solution of amide [2a] (3.00 g, 7.9 mmol) and triethylamine
s (1.11 g, 11.0 mmol) in dichloromethane (30 mL) was cooled to 0 =C and
trimethylsilyl trifluoromethanesulfonate ( 1.84 g, 8.3 mmol) was added
dropwise
during 5 min. The resulted mixture was stirred for 5 hours at 0 =C. Then ethyl
isocyanate (2.25 g, 31.6 mlnol) was added to the mixture. The resulted mixture
was stirred for 24 hours at 15 =C and evaporated under reduced pressure. The
to residue was dissolved in THF (30 rnL) and triethylamine trihydrofluoride
(1.40 g,
8.7 mmol) was added to the solution. The solution was stirred for 2-3 hours
(TLC monitoring) at room temperature. Diethyl ether (60 mL) and sat aq sodium
bicarbonate solution (50 mL, careful addition!) were added and the resulted
two-phase mixture was stirred for 20 min. Then the phases were separated and
is the aq phase was washed with diethyl ether. The combined organics were
washed
with water and brine, dried over sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified on a short silica gel column
followed
by crystallization from diethyl ether and vacuum desiccation to give 3.24 g
(90
%) of [la] as a white solid.
Typical procedure B.
The solution of amide [2a], triethylainine and ethyl isocyanate in
dichloromethane was cooled to 0 =C under argon and trimethylsilyl
trifluoromethanesulfonate (1.84 g, 8.3 mmol) in dichloromethane (5 mL) was
2s added dropwise. The resulted mixture was stirred for 20 min at 0 -C and for
additional 24 h at 15 ~C. Work-up and purification of the final product were
carried out as described in the procedure A.
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Examples 2-15
9
H R
O N~NMe~ O N~NMe~
1. TMSOTf
Et N
N~ Et.NCO H N
I ~ ~H I ~ H
HN-~ [ 2a ] 2. Desi~ylation RZON I
[ 1a ] R~ = EtNHCO, Rio = H,
Cabergoline;
[9] R~=H,Rl°=EtNHCO,
] R~ = R1o = EtNHCO
s
Scheme 5
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Table 1. Reaction between [2a] and ethyl isocyanate. Effect of solvent,
temperature and amounts of trimethylsilyl trifluoromethanesulfonate (TMSOTf)
and ethyl isocyanate on reaction yield and selectivity
Ex. TMSOTf EtNCO Solvent T, C Yield la/9/lOd
no. (eq.) (eq.) (procedure)a(time, of
h) la,
2 1.05 1 CHaCl2 (A) 0(5), rt(24)62 99.4:0.3
:0.3
3 1.05 2 CHzCl2 (A) 0(5), rt(24)70 99.0:0.3
:0.7
4 1.05 3-5 CH2C12 (A) 0(5), 90-95 99.7:0:0.3
15(24)
1.05 3-5 CH2C12 (B) 15(24) 88-92" 99.6:0:0.4
6 1.1 3-5 CH2C12 (A) 0(5), rt(24)86" 99.1:0. I
:0.7
7 1.1 3-5 CH2C12 (A) 0(5), 83U 94.0:0.5:5.2
40(24)
8 1.2 3-5 CH2Cl2 (A) 0(5), rt(24)78" 98.2:0.8:1.0
9 I .5 3-5 CH2C12 (A) 0(5), rt(24)69" 96.5:0.5:3.0
2.0 3-5 CH2C12 (A) 0(5), rt(24)64 85.0:1.0:13.7
11 2.5 3-5 CH2Cl2 (A) 0(5), rt(24)56 72.9:1.1:25.3
12 1.1 3 Et20 (A) 0(5), rt(24)65 99.3:0.3:0.4
13 1.1 3 Et20 (B) rt(24) 65 99.1:0.3:0.6
14 1.5 3 Et20 (A) 0(5), rt(24)58 95.5:1.0:3.5
1.1 3-5 Toluene(A) 0(5), rt(24)50 97.7:1.3:1.0
a Procedures A or B described in example 1;
b Crystallized from diethyl ether;
° Purified by short silica gel column;
d Monitored by HPLC of the crude product.
to
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Examples 16-23
9
H R
O N~NMe2 O N~NMe2
1. Me3SiY
H''~ N Et3N H'' N
\ H EtNCO I ~ H
i i
HN ~ [ ~a ] 2. Desilylation RloN I
[ 1a ] R~ = EtNHCO, Rlo = H,
Cabe~goline;
[ 9 ] R~ = H, R1° = EtNHCO,
[ 10 ] R~ = R1o = EtNHCO
Scheme 6
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Table 2. Reaction between [2a] and ethyl isocyanate with different silylating
agents according to method A of Example 1.
Ex. Silylating Solvent T C, (time, Yield Ia/9/10
No. agents (eq.) h) of
la,
16 HMDS (>2) CH2C12 0 (5), reflux no reaction
(24)
17 ~S (>2) Toluene 0 (5), reflux no reaction
(24)
18 TMSCI (>2) CH2Cl2 0 (5), reflux 17 99.0/0/1.0
(24)
19 TMSCl (>2) Toluene 0 (5), reflux 24" 99.0/0/1.0
(24)
20 TMSI (1.05) CH2C12 0 (5), 10 (24)92a 99.6/0/0.4
21 TMSBr (1.2) THF 50 (24) 94a 99.4/0.3/0.3
22 TMSOBs (1.2)THF 50 (24) 83" 98.7/0.4/0.9
23 MTDA (2.0) MeCN reflux (24) 89a 99.7/0/0.3
" Crystallized from diethyl ether
s b Purified by short silica gel column
Monitored by HPLC of the crude product
d Silylation agents: HMDS -1,1,1,3,3,3-hexamethyldisylazane, TMSCI -
trimethylsilyl chloride, TMSI - trimethylsilyl iodide, TMSBr - trimethylsilyl
bromide, TMSOBs - trimethylsilyl benzenesulfonate, MTDA - methyl
~o trimethylsilyl dimethylketene acetal.
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Example 24
1-Phenyl-3-[3-(dimethylamino)propyl]-3-(6-allylergoline-8(3-carbonyl)urea [1b]
O~ NHPh
~H
~ NMe2 ~ NMe2
I. Silylation
2.PhN=C=O
3. Desilylation
[2a] [1b]
Scheme 7
According to the method A of Example 1 compound [1b] was obtained
using phenyl isocyanate instead of ethyl isocyanate.
1o 1H NMR (CDCl3, ~, ppm) 9.81 (bs, 1H), 8.22 (s, 1H), 7.73 (d, 2H, J=8.0 Hz),
7.31 (t, 2H, J=8.0 Hz), 7.23-7.01 (m, 3H), 6.87 (m, 2H), 5, 92 (m, 1H), 5.23
(d,
1H, J=17.0 Hz), 5.21 (d, 1H, J=9.2 Hz), 3.84 (m, 2H), 3.54 (dd, 1H, J=13.0,
4.6
Hz), 3.32 (m, 2H), 3.15 (d, 1H, J=11.3 Hz), 3.00 (t, 1H, J=5.2 Hz), 2.72 (m,
2H),
2.61 (m, 2H), 2.49 (t, 2H, J=6.6 Hz), 2.14 (s, 3H), 1.83-1.74 (m, 3H).
is
