Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2002-06-19
2004-02-03
Rotman, Alan L. (Department: 1625)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S195000, C435S196000, C435S198000
Reexamination Certificate
active
06686182
ABSTRACT:
The subject matter of the present invention is a lower alkyl ester of 3-(3,4-dihalophenyl)-2,6-dioxopiperidine-3-propionic acid. The invention also relates to a process for the preparation of this compound and to the use of said compound in preparing the corresponding acid.
3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid is disclosed in Patent Application WO 97/32852. According to this patent application, 3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid can be reduced, for example by borane, to give 3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine. The latter compound, disclosed in Patent Application EP-A-673 928, is an intermediate of use in the preparation of osanetant. Osanetant is a specific antagonist of NK
3
receptors described, in particular, by X. Emonds-Alt in Life Sci., 1995, 56 (1), 27-32.
The novel compound of formula:
in which:
X represents a halogen, preferably a chlorine or fluorine atom;
R
1
represents a linear C
1
-C
4
alkyl, preferably a methyl;
has now been found.
The present invention relates very particularly to the compound of formula (I) in which X=Cl and R
1
=CH
3
.
The invention comprises the compound of formula (I) in the racemic form and in the optically pure form.
The compound of S configuration corresponding to the formula:
in which R
1
and X are as defined above for (I), is particularly preferred.
According to the present invention, in order to prepare the compound of formula (I), an acid of formula:
in which X is as defined for (I), is esterified. The compounds of formula (III) are disclosed in Patent Application WO 97/32852.
The esterification is carried out by conventional means well known to a person skilled in the art. For example, by the action of an alcohol in an acidic and anhydrous medium or alternatively by the action of thionyl chloride, to prepare the chloride of the acid of formula (III) as an intermediate, and then by the action of an alcohol of formula R
1
OH, in which R
1
is as defined above for (I).
According to the process of the invention, the optical isomer of formula (II) can be prepared in the optically pure form by a process characterized in that an enantioselective enzymatic hydrolysis of the compound of formula:
is carried out.
Thus, the racemic compound of formula (I) is hydrolyzed by an enzyme chosen from lipases, proteases or esterases, lipases or esterases being preferred.
Mention may be made, as nonlimiting examples, of lipases or esterases of
Candida cylindracea, Candida rugosa, Pseudomonas flurorescens, Humilica lanuginosa
or
Candida lipolytica
, &agr;-chymotripsin or pig liver esterase.
Preference is given to the esterase or the lipase of
Candida rugosa
, or of
Candida cylindracea
, separately or as a mixture.
These enzymes are used in the purified form or in the form of crude extracts. The enzymes may or may not be attached to a support.
The hydrolysis reaction is carried out according to the following reaction scheme:
The enzymatic hydrolysis according to the invention is carried out in a medium comprising water and an organic solvent. The organic solvent can be nonpolar or moderately polar, such as a C
1
-C
10
ether, a C
1
-C
10
alkane, a C
1
-C
10
tertiary alcohol, a C
1
-C
10
ketone, a C
1
-C
10
sulfoxide or furan, or, in some cases, a chlorinated solvent, such as dichloromethane, these solvents being used pure or as a mixture.
Preferably, use is made of a C
1
-C
10
aliphatic ether, very particularly of methyl tert-butyl ether.
The water necessary for the hydrolysis can be dissolved in the reaction medium by a polar cosolvent or alternatively, preferably, the water constitutes a separate phase, the hydrolysis reaction then being carried out in a two-phase medium.
Thus, it is very particularly preferable to carry out the reaction in a two-phase medium composed of methyl tert-butyl ether (MTBE) and water. The MTBE/water ratio can vary from 1/99 to 99/1; a ratio of the order of 40/60 to 50/50, very particularly 44/56, is preferred.
The water used can be buffered or unbuffered and its pH can vary from 4 to 10 approximately; use is preferably made of water with a pH of the order of 5 to 8.
The concentration of diester in the reaction medium can vary in the proportions [lacuna] 1 to 500 g/l and preferably from 1 to 150 g/l, where the amount of enzyme varies in proportions from 0.0001 to 150 g/l and preferably from 1 to 50 g/l.
The temperature of the enzymatic hydrolysis reaction can vary between 0° C. and +50° C. and preferably between +16° C. and +35° C.
The duration of the reaction is between 3 hours and 36 hours, generally in the region of 10 hours.
The chiral ester of formula (II) is isolated by extraction, after having precipitated and then filtered off the enzyme used.
According to the present invention, a compound of formula (II) can also be prepared by a process consisting in carrying out a cyclization of the compound of formula:
in which R
1
and X are as defined above for (I)
The cyclization of the compound of formula (VI) is carried out either thermally or in the presence of a catalyst.
Thus, a thermal cyclization can be carried out between 170° C. and 250° C., either in a molten medium or in the presence of a solvent, for example,an inert solvent, such as toluene, DMSO, sulfolane or tetralin. The thermal cyclization is preferably carried out in a molten medium at a temperature in the region of 200° C.
The cyclization can also be carried out in the presence of a catalyst, such as an acid anhydride, for example acetic anhydride, phosphorus pentoxide, triflic anhydride, trifluoroacetic anhydride or methanesulfonic anhydride, or an acid, such as methanesulfonic acid or triflic acid, or a mixture of an acid anhydride and of an acid.
It is preferable to use, as catalyst, methanesulfonic anhydride and methanesulfonic acid or triflic anhydride and triflic acid.
The cyclization reaction is carried out at a temperature of between 20° C. and 130° C., preferably between 70° C. and 120° C.
Catalytic cyclization, which makes it possible to retain the optical purity, is preferably used in carrying out the cyclization of the compound of formula (VI).
The compound of formula (II) is isolated from the medium by extraction using conditions known to a person skilled in the art.
The compound of formula (VI) is obtained by a process consisting in treating, by an enzyme, a compound of formula
in which R
1
and XI are as defined above for (I).
The preparation of a compound of formula (V) is disclosed in Patent Applications EP-A-673 928 and WO 97/32852.
To convert the racemic diester of formula (V) to the chiral hemiester of formula (VI), an enantioselective enzymatic hydrolysis is carried out while choosing conditions similar to those described above.
The chiral hemiester of formula (VI) is isolated from the medium either by selective extraction or by precipitation after acidification of the aqueous phase.
The compound of the formula (VI) is novel and constitutes a further aspect of the present invention.
According to a further aspect, the present invention relates to the use of a compound of formula (II) in the preparation of a compound of formula:
in which X is as defined above;
the hydrolysis of an ester of formula (II) being carried out under conditions which make it possible to retain the stereochemistry of the 3-carbon of the piperidinedione. Thus, use may be made of the action of an acid, for example the action of a carboxylic acid in the presence of an inorganic acid, preferably acetic acid in the presence of hydrochloric acid.
Thus, the present invention relates to a process for the preparation of a compound of formula (VII) by hydrolysis of an ester of formula (II).
According to another aspect, the present invention relates to the use of a compound of formula (II) in the preparation of a compound of formula:
The reduction of the compound of formula (II) to a compound of formula (VIII) can be carried out by the action of a reducing agent.
The reducing agents used are borane complexes, such as, for example, borane-tetrahydrofuran
Castro Bertrand
Dormoy Jean-Robert
Rabion Alain
Alexander Michael D.
Dupont Paul E.
Robinson Binta
Rotman Alan L.
Sanofi-Synthelabo
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