Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-06-19
2002-05-21
Ramsuer, Robert W. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S158000
Reexamination Certificate
active
06392039
ABSTRACT:
This application is a 371 of PCT/FR99/03123 filed Dec. 14, 1999.
The present invention relates to a novel process for preparing (R)-(+)-3-{1-[2-(4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea and the salts, solvates and/or hydrates thereof.
(R)-(+)-3-{1-[2-(4-Benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea, of formula:
referred to hereinbelow as compound A, is a novel powerful and selective non-peptide antagonist of the NK
2
receptors of neurokinin A in various species, in particular of the human NK
2
receptors (X. Emonds-Alt et al., Neuropeptides, 1997, 31 (5), 449-458) and, consequently, may be useful especially in the treatment of complaints of the respiratory, gastro-intestinal, urinary, immune or cardiovascular system and of the central nervous system, and also for pain and migraine.
The preparation of compound A is illustrated in international patent application WO 96/23787. According to said document, compound A is prepared by reacting (+)-4-benzoyl-2-(3,4-difluorophenyl)-2-[2-(methanesulfonyloxy)ethyl]morpholine (compound B) with 3-(4-phenylpiperid-4-yl)-1,1-dimethylurea para-toluenesulfonate (compound C), in the presence of potassium carbonate, followed by conversion to its hydrochloride. However, this process has disadvantages and drawbacks, which are sufficient to exclude it from any use on an industrial scale.
For example, compound A prepared by this process is obtained in a relatively low yield, of about 38% calculated on the basis of compound B, according to the description of patent application WO 96/23787.
The main reason for this low yield is the formation, during the reaction of compound B with compound C, of numerous impurities in the reaction medium, leading to a low yield for conversion to compound A. It has been possible to isolate and identify these impurities, the main one of which (compound D) has the formula:
It has been found that the formation of these impurities, especially of compound D, is due to the instability of compound C in the form of the free base in solution. Thus, a stability study carried out on compound C at 50° C. in acetonitrile shows that it rapidly decomposes (about 5% per hour) and gives a multitude of products corresponding to a polymerization (dimer, trimer, etc.), thus excluding the use of compound C on an industrial scale.
Furthermore, the presence of these impurities, in particular of compound D, in the reaction medium, makes it difficult to separate out and purify compound A.
Consequently, the search for a process to prepare compound A which does not have the drawbacks and disadvantages of the known prior art process remains of unquestionable interest.
A novel process for preparing compound A which uses stable starting materials and intermediate compounds in the operating conditions, and which does not lead to the formation of the impurities present during the prior art process, has now been found.
Thus, according to one of its aspects, a subject of the present invention is a process for preparing (R)-(+)-3-{1-[2-(4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea, and the salts, solvates and/or hydrates thereof, of formula:
characterized in that:
(+)-4-benzoyl-2-(3,4-difluorophenyl)-2-(2-benzenesulfonyloxyethyl)morpholine of formula:
is reacted, in the presence of a base, with tert-butyl (4-phenylpiperid-4-yl)carbamate of formula:
to give tert-butyl (+)-(1-{2-[4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl]ethyl}-4-phenylpiperid-4-yl)carbamate, of formula
the compound of formula (V) thus obtained is deprotected by the action of an acid, to give (+)-[2-[2-(4-amino-4-phenylpiperid-1-yl)ethyl]2-(3,4-difluorophenyl)morpholin-4-yl]phenylmethanone, of formula
c) the compound of formula (VI) thus obtained is reacted first with a reactive derivative of carbonic acid, in the presence or absence of base, and then with dimethylamine to give the expected compound of formula (I);
d) the compound of formula (I) thus obtained is optionally converted into a salt thereof with pharmaceutically acceptable mineral or organic acids.
In the process according to the invention, it is possible to combine two or more steps.
Thus, for example, steps a) and b) may be combined in order to give compound (VI) directly from the compound of formula (III). Similarly, steps c) and d) may be combined. It is also possible to combine all the steps of the process according to the invention, which means that all the steps are carried out without isolating the intermediate compounds of formulae (V) and (VI), thereby simplifying the process.
Salts of the compounds of formula (V) or (VI) and also of the compound of formula (I) may be formed. These salts comprise not only those with mineral or organic acids which allow a suitable separation or crystallization of the compounds of formula (V), (VI) or (I), but also those which form pharmaceutically acceptable salts with the compound of formula (I), such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methane sulfonate, methyl sulfate, maleate, fumarate, succinate, 2-naphthalenesulfonate, glyconate, gluconate, citrate, isethionate, benzenesulfonate or para-toluenesulfonate.
Compound A thus obtained may be subsequently separated from the reaction medium according to the conventional methods.
Compound A obtained is isolated in the form of the free base or of a salt thereof, for example the hydrochloride, the fumarate or the succinate. It is also possible to isolate, for example, compound A in the form of the fumarate and to convert it into another of its salts, first by neutralizing it then by treating the free base with an acid, for example succinic acid.
When compound A is obtained in the form of the free base, the salification is carried out by treatment with the chosen acid in an organic solvent. By treating the free base, dissolved, for example, in an ether such as diethyl ether or in an alcohol such as methanol, ethanol or 2-propanol, or in acetone, or in dichloromethane or in ethyl acetate, with a solution of the chosen acid in one of the abovementioned solvents, the corresponding salt is obtained, which is isolated according to the conventional techniques.
Thus, the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methyl sulfate, benzenesulfonate, para-toluenesulfonate, oxalate, maleate, succinate, fumarate, 2-naphthalenesulfonate, glyconate, gluconate, citrate or isethionate is prepared, for example.
Preferably, the process according to the invention is used to prepare compound A in the form of the succinate or fumarate.
Thus, compound A in the form of the free base, dissolved in acetone, is treated at room temperature with succinic acid dissolved in acetone and the corresponding succinate is obtained, which is isolated according to the conventional techniques.
Similarly, compound A, in the form of the free base, dissolved in acetone, is treated under hot conditions with fumaric acid in acetone to give, after cooling to room temperature, the corresponding fumarate which is isolated according to the conventional techniques.
(R)-(+)-3-{1-[2-(4-Benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea succinate is novel and forms part of the invention.
(R)-(+)-3-{1-[2-(4-Benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperid-4-yl}-1,1-dimethylurea fumarate is novel and forms part of the invention.
When compound A is obtained in the form of a salt thereof, for example the hydrochloride or the fumarate, the free base may be prepared by neutralizing said salt with a mineral or organic base, such as sodium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate, such as sodium or potassium carbonate or bicarbonate, according
Aulombard Alain
Bernon Francoise
Bonnefoy Sabrina
Burgos Alain
Cabos Claude
Alexander Michael D.
Dupont Paul E.
Ramsuer Robert W.
Sanofi-Synthelabo
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