Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-16
2004-02-24
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S069000
Reexamination Certificate
active
06696568
ABSTRACT:
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&bgr;-carbonyl) ureas of formula [1]
wherein R
1
represents an alkyl group having from 1 to 4 carbon atoms, a cyclohexyl group or a phenyl group or a dimethylamino alkyl group —(CH
2
)
n
NMe
2
in which n is an integer, R
2
represents any of the groups which R
1
may represent, or a hydrogen atom or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl residue, R
3
represents a hydrocarbon group having from 1 to 4 carbon atoms, R
4
represents a hydrogen or a halogen atom or a methylthio or phenylthio group and R
5
represents a hydrogen atom or a methyl group; have shown potent dopamine agonist properties and have been useful as anti-Parkinson drugs and as prolactin inhibitors (U.S. Pat. No. 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-alkylergoline-8&bgr;-carbonyl)-1-[3-(dimethylamino)propyl]-3-ethylurea (international non-proprietary name Cabergoline) [1a] (Eur. J. Med. Chem., 1989, v.24, 421) which was firstly prepared by reaction of 6-alkylergoline-8&bgr;-carboxylic acid [7] with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (U.S. Pat. No. 4,526,892) (Scheme 1).
In this case both regioisomers [1a] and [8] were obtained and the yield of the isolated Cabergoline [1a] is low as a consequence of isolation difficulties.
Another method for Cabergoline preparation (Eur. J. Med. Chem., 1989, v, 24, 421 and BP 2,13,603) was based on the direct reaction of N-[3-(dimethylamino)propyl]-6-alkylergoline-8&bgr;-carboxamide [2a] with ethyl isocyanate (Scheme 2):
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 U.S. Pat. No. 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 or, the final step of the synthesis and decreasing chemoselectivity with increasing conversion of this reaction.
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 devise a new synthetic method, which avoids use of heavy metal salts, and which cleanly produces the desired Cabergoline [1a] under mild reaction conditions, avoiding tedious and expensive purification steps.
The present invention provides a commercially acceptable process for producing N-(ergoline-8&bgr;-carbonyl)ureas of formula [I]:
including their stereoisomers as well as acid addition salts thereof,
wherein R
1
is selected from alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, and (dimethylamino alkyl group —(CH
2
)
n
NMe
2
in which n is an integer,
R
2
is selected from hydrogen, alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, dimethylamino alkyl group —(CH
2
)
n
NMe
2
in which a is an integer, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl ,
R
3
represents a hydrocarbon group having from 1 to 4 carbon atoms, and
R
4
is selected from hydrogen halogen, methylthio and phenylthio group;
which process comprises silylating an ergoline-8-carboxamide of formula [2],
including stereoisomers as well as metal or ammonium salts or acid addition salts thereof,
wherein R
1
, R
2
, R
3
and R
4
are as defined above,
reacting the obtained product with isocyanate of the formula [5]:
R
1
—N═C═O [5]
Followed by Desilylation
This novel approach was used for the preparation of the known antiprolactinic and anti-Parkinson agent Cabergoline [1a] and related compounds.
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&bgr;-carbonyl)urea compounds of formula [I]. Particularly, the present invention utilizes the silylation of of ergoline-8&bgr;-carboxamide [2] in order to selectively activate it's amide group in the subsequent reaction with isocyanate.
This novel approach has the following advantages:
Silylated ergoline-8&bgr;-carboxamides react with isocyanates to give, after desilylation of intermediates, the desired N-(ergoline-8&bgr;-carbonyl)ureas [I] with high yield and purity.
Reagents used for silylation and desilylation are not toxic, commercially available and inexpensive.
Although any silylating agents, suitable for silylating amides, can be used for silylating ergoline-8&bgr;-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 thereof; intermediate [4] reacts with isocyanate of formula [5 ]:
wherein R
6
, R
7
and R
8
may be the same or different and are selected from the group consisting of alkyl having from 1 to 6 carbon atoms, aryl and aralkyl radicals;
Y is selected from the group consisting of chloro, bromo, iodo, (haloalkyl)-sulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, (trialkylsilyloxy)sulfonyloxy, imidazolyl, N-acyl-N-alkylamino, N-acyl-N-(trialkylsily) amino, (trialkylsilyl)-amino, N,N-dialkylamino, isopropenyloxy, 1-alkoxy-1-alkenyloxy and trichloroacetoxy radicals;
and R
1
, R
2
, R
3
and R
4
are as defined above, to give O-silylated N-[ergoline-8&bgr;-carbonyl]urea represented by formula [6]:
including, tautomers or mixtures thereof, stereoisomers, as well as addition salts thereof,
wherein R
1
, R
2
, R
3
, R
4
, R
6
, R
7
and R
8
are as defined above; following desilylation of the above compound(s) to obtain the desired N-(ergoline-8&bgr;-carbonyl)urea [I], which can be converted into acid addition salts thereof.
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&bgr;-carboxamide [2]. Preferably, silylating agents are selected from trimethylsilyl trifluoromethanesulfonate, trimethylsilyl methanesulfonate, trimethylsilyl benzenesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl chloride, bromide or iodide, trimethylsilyl trichloroacetate and trifluoroacetate, 1-(trimethylsilyl)imidazol, 1-(trimethylsilyl)-1,2,4-triazole, 1-(trimethylsilyl)-1H-benzotriazole, 1-(trimethylsilyl)-2-pyrrolidinone, N-methyl-N-(trimethylsilyl)trifluoroacetamide, methyl trimethylsilyl dimethylketene acetal, bis(trimethylsilyl)sulfate, N,O-bis(trimethylsilyl)acetamide and bis(trimethylsilyl)trifluoroacetamide.
The silylation reaction may be cared out from −50° C. to the reflux 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, 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.
Gutman Arie L.
Nisnevich Gennadiy
Pertsikov Boris
Ruchman Igor
Tishin Boris
Birch & Stewart Kolasch & Birch, LLP
Finetech Ltd.
Ford John M.
Liu Hong
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