Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-26
2002-12-17
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S192000, C546S207000, C546S208000
Reexamination Certificate
active
06495694
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process which can be used on an industrial scale for dynamically separating the enantiomers of piperidone derivatives of general formula (1)
wherein R
1
, R
2
, R
3
, and n have the meanings given in the specification and claims, with simultaneous racemization in situ of the unreacted enantiomer.
BACKGROUND OF THE INVENTION
Enantiomerically pure piperidone derivatives of general formula (1), wherein
R
1
denotes
R
2
and R
3
each denote a methyl group,
R
4
denotes hydrogen, C
1
-C
6
-alkyl, halogen, hydroxy, C
1
-C
8
-alkoxy, a benzoyl group bound via an oxygen or an alkylcarbonyl group having a straight-chain or branched lower alkyl group with 1 to 6 carbon atoms, wherein the alkyl group may optionally be substituted by one or more halogen atom(s), which may be identical to or different from one another, nitro, cyano, amino, amino mono- or disubstituted by C
1
-C
8
-alkyl, wherein the alkyl groups may be identical or different, —NH-acyl-(C
1
-C
8
-alkyl), wherein acyl denotes benzoyl or an alkylcarbonyl group having a straight-chain or branched lower alkyl group with 1 to 6 carbon atoms, whilst the alkyl group may optionally be substituted by one or more halogen atom(s), which may be identical to or different from each other, or a group which may be converted into one of the abovementioned groups by simple reactions known per se, and
n denotes 1,
are of major importance as intermediate products for the preparation of pharmaceutically valuable benzomorphan derivatives which may be used, for example, in the treatment of neurodegenerative disorders and cerebral ischaemias such as cardiac infarct or cerebral stroke.
Processes for preparing enantiomerically enriched piperidone derivatives are known from the prior art. Published German application DE 195 28 472 describes a process which is essential to the invention, in which the desired enantiomer is precipitated from the solution of a mixture of enantiomeric 3,3-dimethyl-4-piperidones by reacting with a suitable organic acid, e.g., tartaric acid, as a salt, i.e., as the tartrate, for example. After separation of the crystals formed, the unwanted enantiomer contained in the mother liquor can be racemized by heating. After various purification processes and changes of the solvent, the desired enantiomer thus formed is again precipitated as described above and isolated. The process can be repeated several times.
This procedure known from the prior art makes it possible to increase the yield to 75%, i.e., to values which are significantly higher than the maximum yield of 50%, which is the maximum theoretical yield for racemate separation. This reduces the waste of materials and increases the efficiency of the synthesis.
The procedure disclosed in DE 195 28 472 comprising crystallization, separation of the crystals from the mother liquor, thermal re-racemization, crystallization, etc., however, is time-consuming and labor-intensive.
To reduce the extra work involved in purification and isolation and to save time and money, it is, particularly for large-scale industrial manufacture, desirable to have a process which carries out enantiomer separation as a dynamic one-pot process.
It is therefore the aim and problem of the present invention to overcome the disadvantages of the known process as described above by providing a process which can be used on an industrial scale, enabling the precipitation of the desired enantiomer and the racemization of the other enantiomer to be carried out in one step.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has now been found that the separation of enantiomeric piperidone derivatives and the racemization of the unwanted enantiomer can be carried out simultaneously in one and the same reaction vessel and in one reaction step. The disadvantages of the process known from the prior art can thereby be avoided and the advantage of having a yield of more than 50% for the racemate separation, however, is unaffected or this yield may even be increased.
Consequently, the present invention relates to a process suitable for use on an industrial scale for separating the enantiomers of piperidone derivatives of general formula (1)
wherein
R
1
denotes C
1
-C
8
-alkyl, preferably C
1
-C
6
-alkyl, which may be straight-chain or branched and is optionally mono- to polysubstituted by halogen, aryl, which may optionally be mono- to polysubstituted, preferably optionally substituted phenyl or naphthyl, particularly preferably a group of general formula
heteroaryl, preferably pyridine, wherein the heterocyclic group is linked to the chiral center by a carbon atom belonging to the ring or originating from the methylene bridge,
R
2
and R
3
, which may be identical or different, denote C
1
-C
6
-alkyl, which may be straight-chain or branched, preferably methyl or ethyl, particularly preferably methyl;
R
4
independently of one another denote methoxy, ethoxy, isopropyloxy, halogen, hydroxy, C
1
-C
6
-alkyl, which may be partially or fully halogenated, such as, e.g., trifluoromethyl, amino, nitro, cyano, benzoyl, C
1
-C
6
-alkylcarbonyl, preferably methoxy;
n denotes 0, 1, 2 or 3, preferably 1, and
m denotes 0, 1, 2 or 3, preferably 0 or 1,
by crystallization of the desired enantiomer as a salt of a suitable organic acid with simultaneous racemization of the dissolved enantiomer.
In the process according to the invention for obtaining one enantiomer from a mixture of enantiomers of a piperidone derivative (1) a solution of an optically active organic acid is placed in a suitable solvent at a certain temperature, optionally with the addition of catalytic amounts of a sulfonic acid, e.g., toluene- or camphorsulfonic acid. A solution of the mixture of enantiomers of the piperidone derivative (1) is slowly added to this temperature-controlled solution. The optically active organic acid, the solvent or mixture of solvents and the reaction temperature are selected so that the desired enantiomer of the piperidone derivative (1) crystallizes out as a salt of the optically active acid, whilst the other enantiomer remains in solution and racemizes under the reaction conditions. In this way, the desired enantiomer is constantly being formed and precipitated in a dynamic process until equilibrium is achieved.
The process according to the invention for dynamically separating the enantiomers of piperidone derivatives is thus characterized in that
(a) an optically active acid and optionally catalytic amounts of a sulfonic acid are dissolved in a suitable solvent and this solution is kept at a specific temperature,
(b) a solution of the piperidone derivative is slowly metered into this solution, so that the desired enantiomer crystallizes out as a salt of the organic acid used, while at the same time the unwanted isomer is racemized in solution and the content of desired enantiomer thus formed is also precipitated as a salt in a dynamic process, and
(c) the salt of the desired enantiomer is separated off after crystallization has ended.
Suitable organic acids for the precipitation of the desired enantiomer include, for example, (+)- or (−)-ditoluoyltartaric acid or (+)- or (−)-dibenzoyltartaric acid. If desired, the reaction may be carried out in the presence of catalytic amounts of p-toluenesulfonic acid or camphorsulfonic acid. The reaction may be carried out, for example, in solvents such as acetone, acetonitrile, methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl acetate, water, toluene, methylcyclohexane, n-butyl acetate or mixtures thereof. Preferably, acetonitrile or acetone is used.
By general formula (1)
is meant a racemic or optically active mixture of enantiomers which consists of the two enantiomeric piperidone derivatives of general formulae (1a) and (1b)
A preferred process according to the invention is a process for isolating the enantiomer of general formula (1a)
The (+)-piperidone (1a) is precipitated, for example, by reaction with (+)-ditoluoyltartaric acid or (+)-dibenzoyltartaric acid and thus conc
Bressler Gerd-Rainer
Kreye Paul
Mueller-Boetticher Hermann
Boehringer Ingelheim Pharma KG
Desai Rita
Devlin Mary-Ellen
Raymond Robert P.
Rotman Alan L.
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