Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-10
2001-06-05
Rotman, Alan L. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S074000, C549S076000, C562S443000, C562S448000, C562S449000
Reexamination Certificate
active
06242607
ABSTRACT:
The present invention relates to novel glutarimides 3,3-disubstituted with an aryl group and a carboxy (C
1
-C
2
)alkyl group, a method for their preparation via novel intermediates and use of said glutarimides for the preparation of the corresponding piperidines, which are 3,3-disubstituted with the same aryl group and a hydroxy (C
2
-C
3
)alkyl group.
The EP 512 901 document describes antagonists of neurokinines which are prepared from piperidines which are 3,3-disubstituted with an aryl group and a hydroxyalkyl group. These 3,3-disubstituted piperidines are prepared from nitriles by reduction to the amines and cyclisation.
The publications of X. Edmonds-Alt et al., European Journ. Pharmacol., 1993, 250, 403-413 and Life Sciences 1995, 56 (1), 27-32 respectively describe an NK
1
-antagonist, the chloride of (S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane or SR 140333 and an NK
3
-antagonist, (S)-N-[1-[3-{1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl}propyl]-4-phenylpiperidin-4-yl]-N-methylacetamide or SR 142801.
The preparation of these two products is described in EP 591 040 and EP 673 928, respectively. These documents describe 3,3-disubstituted piperidines as intermediates which can be represented by the following formula (A):
in which X is methylene or ethylene and Ar represents a phenyl non substituted or substituted one or more times with one of the substituents selected from a halogen atom, a hydroxyl, a (C
1
-C
4
)alkoxy, a trifluoromethyl, a (C
1
-C
4
)alkyl, said substituents being identical or different; a pyridyl group; a thienyl group.
According to EP 512 901, EP 591 040 and EP 673 928, the preparation of the final products in optically pure form comprises the separation of the optical isomers of the compounds of formula (A) above.
In EP 673 928, the preparation of a 3,3-disubstituted piperidine of formula (A) in which X is ethylene and Ar is 3,4-dichlorophenyl is carried out from 3,4-dichlorophenylacetonitrile (i) by the action of methyl acrylate, cyclising methyl 4-cyano-4-(3,4-dichlorophenyl)-heptanedioate (ii) to give 3-(3,4-dichlorophenyl)-3-(2-methoxy-carbonyl)ethyl-2-oxopiperidine (iii), saponifying this product in order to obtain the corresponding free acid (iv) and reducing the latter, according to the SCHEME A below.
It has now been found that in saponifying the compound (ii) above, the corresponding dicarboxylic acid is obtained which cyclises very easily with a very high yield giving a 3,3-disubstituted glutarimide.
It has also been found that this novel glutarimide can easily be resolved and converted into an optically pure compound of formula (A) by simple reduction.
It has also been found that, in the method of preparation of certain said glutarimides, it is possible to separate the optical isomers earlier when the intermediates possess an asymmetric carbon.
More generally, all a series of 3-carboxylalkyl-3-aryl-disubstituted glutarimides has been found which constitute useful intermediates for the preparation of 3,3-disubstituted piperidines of formula (A) above. Compared to the piperidine diones described in the WO94/21609 application, these 3,3-disubstituted glutarimides are interesting in that they may be resolved and used in the optically active form.
Thus, according to one of its aspects, the invention relates to a method of preparation of the glutarimides of formula (I):
in which Ar represents a phenyl non substituted or substituted one or more times with one of the substituents selected from a halogen atom, a hydroxyl, a (C
1
-C
4
)alkoxy, a trifluoromethyl, a (C
1
-C
4
)alkyl, said substituents being identical or different; a pyridyl group; a thienyl group; and X is methylene or ethylene; and their salts and enantiomers, said method being, according to a first alternative, characterised in that:
a compound of formula (III):
in which Ar and X are such as defined above for the formula (I) and Y is a cyano or carboxy group is cyclised;
and the compound thus obtained of formula (I) is isolated in the form of one of its salts or in its acid form which is optionally converted into one of its salts.
When it is desired to prepare a glutarimide of formula (I) in which X is methylene, the starting compound of formula (III) possesses a chiral carbon atom. It is therefore possible to use an optically active compound as starting material. In this case, said starting product can have the formula (III), in which X is methylene and Y is cyano and may be optically active. Such a starting compound is particularly advantageous for the preparation of the glutarimides of formula (I), in which X is methylene, and of their salts.
The intermediate compounds of formula (III), in which X is methylene, Y is cyano and Ar is 3,4-difluorophenyl or 3,4-dichlorophenyl are preferred.
In an advantageous aspect of the method according to the invention, the compound of formula (III) is obtained by saponification of the ester group(s) of an &agr;,&agr;-disubstituted arylacetonitrile of formula (II):
in which Ar and X are such as defined as above for the formula (I), Y
O
is a cyano or COOAlk group and Z is hydrogen or Alk, Alk being a (C
1
-C
3
)alkyl group.
The invention relates therefore, according to a second alternative, to a method of preparation of the glutarimides of formula (I) such as defined above, characterised in that:
(a) the ester group(s) of an &agr;&agr;-disubstituted arylacetonitrile of formula (II):
in which Ar and X are such as defined as above for the formula (I), Y
O
is a cyano or COOAlk group, Z is hydrogen or Alk, Alk being a (C
1
-C
3
)alkyl group, and at least one of the COOZ and Y
O
groups being COOAlk is (are) saponified;
(b) the compound of formula (III):
in which Ar and X are such as defined above and Y is a cyano or carboxy group is cyclised;
and the compound thus obtained of formula (I) is isolated in the form of one of its salts or in its acid form which is optionally converted into one of its salts.
According to this second alternative, when it is desired to prepare a glutarimide of formula (I) in which X is ethylene, which is the starting compound the most accessible, and therefore particularly advantageous, possesses the formula (II) in which X is ethylene, Y
O
is COOAlk and Z is Alk. In this case, the starting compound does not possess a chiral carbon atom.
The starting compounds of formula (II), in which X is ethylene, Y
O
is COOAlk and Z is Alk are particularly advantageous, those of formula (II) in which X is ethylene, Y
O
is COOCH
3
, Z is CH
3
and Ar is 3,4-difluorophenyl or 3,4-dichlorophenyl are preferred.
The method according to the present invention (1st and 2nd alternatives) is illustrated in the SCHEME 1 below.
Step (a) of the method of the present invention (2nd alternative) consists of a saponification of the ester group present in the compound of formula (II), especially, according to SCHEME 1, the saponification of a compound selected from those represented by the formulae (IIa), (IIb) and (IIc).
The saponification is carried out preferably using an alkaline hydroxide or carbonate. The reaction takes place in an aqueous-alcohol medium or in a tetrahydrofuran/water mixture.
The compound of formula (III) is isolated by acidification with a mineral or organic acid such as sulphuric acid, hydrobromic acid, methanesulphonic acid or, preferably, hydrochloric acid to an acid pH value which can vary between 0 and 3, the pH at which the product precipitates.
In step (b) which characterises the 1st alternative of the method of the present invention, the cyclisation of the compound (III) is effected by a hydration in the presence of an acid selected from phosphoric acid, hydrochloric acid or preferentially with concentrated sulphuric acid. An aprotic solvent may also be used such as for example toluene, in this case in the presence of a sulphonic acid such as for example paratoluenesulphonic acid monohydrate or methanesulphonic acid in the presence of water. The reaction is conducted in a p
Camus Philippe
Descamps Marcel
Radisson Joel
Alexander Michael D.
Desai Rita
Rotman Alan L.
Sanofi-Synthelabo
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