Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-14
2002-03-12
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S491000, C548S484000
Reexamination Certificate
active
06355809
ABSTRACT:
The present invention relates to a novel process for the preparation of (2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]pyrrolidine-2-carboxamide, of its solvates and/or of its hydrates.
(2S)-1-[(2R,3S)-5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]pyrrolidine-2-carboxamide, of formula:
hereinafter known as compound A, is to date the most powerful and the most selective nonpeptide antagonist of arginine-vasopressin V
1a
receptors in various species, in particular of human V
1a
receptors (C. Serradeil-Le Gal et al., J. Clin. Invest., 1993, 92, 224-231), and is consequently of use in particular in the treatment of ailments of the cardiovascular system, of the central nervous system, of the renal system or of the gastric system and as antiemetic or antiproliferative agent or, in women, for treating dysmenorrhea or premature labor.
The preparation of compound A is illustrated in Patent EP 0 526 348 or U.S. Pat. No. 5,338,755. According to these documents, compound A is prepared by the cyclization reaction, in basic medium, of the compound of formula:
hereinafter known as compound B.
This reaction, related to an aldolization reaction, results in the formation of the compound of formula:
which, because of the formation of two centers of chirality at the 2- and 3-positions of the 2,3-dihydro-1H-indole ring, is found, at the end of the reaction, in the form of a mixture in the reaction medium of the four optical isomers.
This mixture is composed of two optical isomers, conventionally referred to as cis isomers, having the H and OH substituents on the same side of the ring, and of two optical isomers, conventionally referred to as trans isomers, having the H and OH substituents on either side of the ring.
Each of the cis optical isomers is distinguished and characterized in accordance with the analytical methods and process disclosed in document EP 0 526 348. An X-ray analysis made it possible to define the absolute configuration of one of the cis optical isomers, that of the other cis optical isomer being deduced therefrom.
Likewise, each of the trans optical isomers was isolated and characterized. However, their absolute configuration was not determined.
Thus, the four optical isomers of the compound of formula (III) have the following physicochemical characteristics and their conventionally attributed names are shown.
Cis Isomer 1
M.p.=190° C.
&agr;
D
20
=+115° (c=0.305, chloroform)
absolute configuration.
Cis Isomer 2: Compound A
M.p.=154-162° C.
&agr;
D
20
=−216° (c=1.0, chloroform)
absolute configuration.
Trans Isomer 1
&agr;
D
20
=+91° (c=0.03, chloroform)
unattributed absolute configuration.
Trans Isomer 2
M.p.=159° C.
unattributed absolute configuration.
More specifically, the process for the preparation of compound A as disclosed in the prior art consists in reacting (2S)-1-{[[4-chloro-2-(2-chlorobenzoyl)phenyl](3,4-dimethoxybenzene-sulfonyl)amino]acetyl}pyrrolidine-2-carboxamide (compound B) with 1,8-diazabicyclo[5.4.0]undec-7-ene in methanol for 60 hours and at a temperature of −10° C. to provide the mixture of the four optical isomers of the compound of formula (III).
However, this process has disadvantages, sometimes sufficient to exclude it from any use on the industrial scale.
For example, compound A prepared by this process is obtained with yields which are not very high. During the implementation of this process, compound A has in fact been obtained with final yields of between 12 and 20%, calculated from compound B.
One of the main reasons for this low yield is the presence in the medium of the four optical isomers at the end of the cyclization reaction on compound B. The content, expressed as % by weight, of each of the four optical isomers present in the medium at the end of reactions carried out under the conditions of the process of the prior art was measured by High Performance Liquid Chromatography (HPLC). The mean values are as follows:
Cis 1 formed
Cis 2 formed
Trans 1 formed
Trans 2 formed
(%)
compound A (%)
(%)
(%)
20
40
20
20
These results thus show the not insignificant presence of the cis 1, trans 1 and trans 2 isomers.
Consequently, the separation of compound A from this mixture and then its purification require numerous stages which contribute, each time, to a decrease in the final yield of compound A.
Furthermore, this process uses 1,8-diazabicyclo[5.4.0]undec-7-ene as base for carrying out the cyclization, which base is expensive and furthermore toxic, ruling out its use on the industrial scale.
Finally, implementation of this process requires a very long reaction time (60 hours).
Consequently, the search for a process for the preparation of compound A which does not exhibit the disadvantages and drawbacks of the known process of the prior art is of indisputable interest.
A novel process for the preparation of compound A, by reaction of compound B with an alkali metal hydroxide in a polyethylene glycol as a mixture with water, which makes it possible to avoid the disadvantages and drawbacks of the known process of the prior art, has, surprisingly, now been found.
The implementation of the process according to the invention makes it possible, during the cyclization reaction, to greatly reduce the formation of the cis isomer 1 and to enhance the formation of compound A. Thus, at the end of the reaction, amounts of the cis isomer 1 of the order of 0.1 to 7% by weight and amounts of compound A of the order of 45 to 60% by weight are achieved.
The separation and the purification of compound A are found to be facilitated thereby and it has been possible to obtain compound A with final yields of the order of 35 to 55%, calculated with respect to compound B.
Furthermore, the process according to the invention employs cheap and nontoxic compounds and makes it possible to greatly reduce the reaction times.
According to one of its aspects, a subject matter of the present invention is a process for the preparation of (2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]pyrrolidine-2-carboxamide, of its solvates and/or of its hydrates of formula:
by cyclization reaction of (2S)-1-{[[4-chloro-2-(2-chlorobenzoyl)phenyl](3,4-dimethoxybenzenesulfonyl)-amino]acetyl}pyrrolidine-2-carboxamide of formula:
characterized in that the cyclization is carried out by an alkali metal hydroxide in a polyethylene glycol with an average molecular weight of between 200 and 600 as a mixture with water.
The polyethylene glycol (PEG) with an average molecular weight of between 200 and 600 used in the above process can be a polyethylene glycol with a given average molecular weight or alternatively a mixture of polyethylene glycols with varied average molecular weights.
Preference is given, among polyethylene glycols with an average molecular weight of between 200 and 600, to polyethylene glycol 200 or “PEG 200”, polyethylene glycol 400 or “PEG 400”, or polyethylene glycol 600 or “PEG 600”.
Preference is particularly given, according to the invention, to the use of polyethylene glycol 400 or “PEG 400”.
The polyethylene glycol/water mixture used in the process of the invention comprises from 0.1 to 1 volume of water per volume of polyethylene glycol. Use is preferably made of a mixture comprising from 0.4 to 0.5 volume of water per volume of polyethylene glycol.
The polyethylene glycol/water mixture is used in a proportion of 2 to 10 equivalents by volume per equivalent by weight of compound of formula (II). The mixture is preferably used in a proportion of 2 to 5 equivalents by volume per equivalent by weight of compound of formula (II).
The alkali metal hydroxide used to carry out the cyclization is chosen from sodium hydroxide, potassium hydroxide or lithium hydroxide. Sodium hydroxide is pr
Chantreux Dominique
Mercey Philippe
Alexander Micheal D.
Dupont Paul E.
Higel Floyd D.
Saeed Kamal
Sanofi-Synthelabo
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