CA2409614C - Separation of the enantiomers of piperidone derivatives with simultaneous racemisation in situ of the unwanted enantiomer - Google Patents
Separation of the enantiomers of piperidone derivatives with simultaneous racemisation in situ of the unwanted enantiomer Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
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) (see formula 1) wherein R1, R2, R3 and n may have the meanings given in the specification and claims, with simultaneous in situ racemisation of the unreacted enantiomer.
Description
Separation of the enantiomers of piperidone derivatives with simultaneous racemisation in situ of the unwanted enantiomer 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) R1 n HN
wherein R1r R2, R3 and n may have the meanings given in the specification and claims, with simultaneous racemisation in situ of the unreacted enantiomer.
According to one aspect of the present invention, there is provided process for dynamically separating the enantiomers of piperidone derivatives of general formula (1) R1 n HMN
wherein R1 denotes aryl, which is optionally mono- to polysubstituted, heteroaryl, which is linked to the piperidine ring via a carbon atom in the piperidine ring or a carbon atom belonging to the methylene bridge, C1-C$-alkyl, which is straight-chain or branched and is optionally mono-to polysubstituted by halogen;
R2 and R3, which are identical or different, denote C1-C6-alkyl, which is straight-chain or branched; and la n denotes 0, 1, 2 or 3, wherein:
a) an optically active organic acid and optionally catalytic amounts of a sulphonic acid are dissolved in a suitable solvent and this solution is kept at a temperature of between 35 and 70 C, b) a solution of the piperidone derivative is slowly metered into this solution, so that the desired enantiomer crystallises out as a salt of the optically active organic acid used, while at the same time the unwanted isomer is racemised in solution and the content of desired enantiomer thus formed is also precipitated as a salt in a dynamic process, and c) the salt of the desired enantiomer is separated off after crystallisation has ended.
Background to the invention Enantiomerically pure piperidone derivatives of general formula (1), wherein R1 denotes R4 , R2 and R3 each denote a methyl group, R4 denotes hydrogen, Cl-C6-alkyl, halogen, hydroxy, C1-C$-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 lb 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 C1-C6-alkyl, wherein the alkyl groups may be identical or different, -NH-acyl-(C1-C$-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 Case 1/1137 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 pharma-ceutically 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 racemised 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 crystallisation, separation of the crystals from the mother liquor, thermal re-racemisation, crystallisation, etc., is time-consuming and labour-intensive, however.
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 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 Case 1/1137 CA 02409614 2002-11-21 enantiomer and the racemisation 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 racemisation 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 be avoided; the advantage of having a yield of more than 50 % for the racemate separation, 1o 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) O
R~ n HN
(1), wherein R, denotes C,-CB-alkyl, preferably C,-Cg-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 [R4]m or heteroaryl, preferably pyridine, wherein the heterocyclic group is linked to the chiral centre by a carbon atom belonging to the ring or originating from the methylene bridge, R2 and R3, which may be identical or different, denote C,-C6-alkyl, which may be straight-chain or branched, preferably methyl or ethyl, particularly preferably methyl;
3o R4 independently of one another denote methoxy, ethoxy, isopropyloxy, halogen, hydroxy, C,-C6-alkyl, which may be partially or fully halogenated, such as e.g.
Case 1/1137 trifluoromethyl, amino, nitro, cyano, benzoyl, C,-Cs-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 crystallisation of the desired enantiomer as a salt of a suitable organic acid with simultaneous racemisation of the dissolved enantiomer.
In the process according to the invention for obtaining one enantiomer from a mixture lo 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 sulphonic acid, e.g. toluene- or camphorsulphonic 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) crystallises out as a salt of the optically active acid, whilst the other enantiomer remains in solution and racemises under the reaction conditions. In this way, the desired enantiomer is constantly being formed and precipitated in a dynamic process until equilibrium is 2o achieved.
The process according to the invention for dynamically separating the enantiomers of piperidone derivatives is thus characterised in that a) an optically active acid and optionally catalytic amounts of a sulphonic 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 crystallises out as a salt of the organic acid used, while at the same time the unwanted isomer is racemised 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 crystallisation 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-toluenesulphonic acid or camphorsulphonic acid. The reaction may be carried out, Case 1/1137 CA 02409614 2002-11-21 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.
wherein R1r R2, R3 and n may have the meanings given in the specification and claims, with simultaneous racemisation in situ of the unreacted enantiomer.
According to one aspect of the present invention, there is provided process for dynamically separating the enantiomers of piperidone derivatives of general formula (1) R1 n HMN
wherein R1 denotes aryl, which is optionally mono- to polysubstituted, heteroaryl, which is linked to the piperidine ring via a carbon atom in the piperidine ring or a carbon atom belonging to the methylene bridge, C1-C$-alkyl, which is straight-chain or branched and is optionally mono-to polysubstituted by halogen;
R2 and R3, which are identical or different, denote C1-C6-alkyl, which is straight-chain or branched; and la n denotes 0, 1, 2 or 3, wherein:
a) an optically active organic acid and optionally catalytic amounts of a sulphonic acid are dissolved in a suitable solvent and this solution is kept at a temperature of between 35 and 70 C, b) a solution of the piperidone derivative is slowly metered into this solution, so that the desired enantiomer crystallises out as a salt of the optically active organic acid used, while at the same time the unwanted isomer is racemised 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 crystallisation has ended.
Background to the invention Enantiomerically pure piperidone derivatives of general formula (1), wherein R1 denotes R4 , R2 and R3 each denote a methyl group, R4 denotes hydrogen, Cl-C6-alkyl, halogen, hydroxy, C1-C$-alkoxy, a benzoyl group bound via an oxygen or an alkylcarbonyl group having a straight-chain or branched lower alkyl group with 1 to 6 carbon atoms, wherein the lb alkyl group may optionally be substituted by one or more halogen atom(s), which may be identical to or different from one another, nitro, cyano, amino, amino mono- or disubstituted by C1-C6-alkyl, wherein the alkyl groups may be identical or different, -NH-acyl-(C1-C$-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 Case 1/1137 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 pharma-ceutically 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 racemised 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 crystallisation, separation of the crystals from the mother liquor, thermal re-racemisation, crystallisation, etc., is time-consuming and labour-intensive, however.
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 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 Case 1/1137 CA 02409614 2002-11-21 enantiomer and the racemisation 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 racemisation 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 be avoided; the advantage of having a yield of more than 50 % for the racemate separation, 1o 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) O
R~ n HN
(1), wherein R, denotes C,-CB-alkyl, preferably C,-Cg-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 [R4]m or heteroaryl, preferably pyridine, wherein the heterocyclic group is linked to the chiral centre by a carbon atom belonging to the ring or originating from the methylene bridge, R2 and R3, which may be identical or different, denote C,-C6-alkyl, which may be straight-chain or branched, preferably methyl or ethyl, particularly preferably methyl;
3o R4 independently of one another denote methoxy, ethoxy, isopropyloxy, halogen, hydroxy, C,-C6-alkyl, which may be partially or fully halogenated, such as e.g.
Case 1/1137 trifluoromethyl, amino, nitro, cyano, benzoyl, C,-Cs-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 crystallisation of the desired enantiomer as a salt of a suitable organic acid with simultaneous racemisation of the dissolved enantiomer.
In the process according to the invention for obtaining one enantiomer from a mixture lo 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 sulphonic acid, e.g. toluene- or camphorsulphonic 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) crystallises out as a salt of the optically active acid, whilst the other enantiomer remains in solution and racemises under the reaction conditions. In this way, the desired enantiomer is constantly being formed and precipitated in a dynamic process until equilibrium is 2o achieved.
The process according to the invention for dynamically separating the enantiomers of piperidone derivatives is thus characterised in that a) an optically active acid and optionally catalytic amounts of a sulphonic 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 crystallises out as a salt of the organic acid used, while at the same time the unwanted isomer is racemised 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 crystallisation 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-toluenesulphonic acid or camphorsulphonic acid. The reaction may be carried out, Case 1/1137 CA 02409614 2002-11-21 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.
5 By general formula (1) O
R- n HN
(1), is meant a racemic or optically active mixture of enantiomers which consists of the 1o two enantiomeric piperidone derivatives of general formulae (1a) and (1b) O O
R n_ R- n HN HN
(1 a) (1 b) A preferred process according to the invention is a process for isolating the enantiomer of general formuia (1 a) O
Ri n HN
(1a).
2o The (+)-piperidone (1 a) is precipitated, for example, by reaction with (+)-ditoluoyltartaric acid or (+)-dibenzoyltartaric acid and thus concentrated. With (-)-ditoluoyltartaric acid or (-)-dibenzoyltartaric acid, on the other hand, the opposite enantiomer is obtained, namely the (-)-piperidone (1b).
Particularly preferred is a process for obtaining the (+)-piperidone derivative of general formula (1a), wherein R' denotes 2-methoxyphenyl, R2 and R3 each denote methyl and Case 1/1137 n denotes 1, characterised in that the desired (R)-(+)-enantiomer is precipitated as the salt thereof by reacting with (+)-ditoluoyltartaric acid and at the same time, in the dissolved (S)-(-)-enantiomer, the chiral centre is epimerised by heating to a temperature of about 30-75 C, more preferably to 50-65 C. The solvent used may be acetonitrile, acetone, or mixtures thereof, preferably acetonitrile.
Also preferred according to the invention is a process which leads to a piperidone of general formula (1 a) or (1 b) with an enantiomeric excess of - 95 % ee, more lo preferably >- 97 % ee.
It is particularly preferred according to the invention to operate as follows:
a mixture of the enantiomeric piperidone derivatives of general formula (1) is dissolved in an inert solvent, e.g. acetonitrile, and added slowly to a solution of a suitable tartaric acid derivative, preferably (+)-ditoluoyltartaric acid, in the same solvent, which has been heated to about 35 to 75 C, preferably to 50 to 65 C. Stirring is continued for a further 0.5 to 36 hours at the same temperature until there is no more precipitate is being formed as far as the naked eye can tell. After cooling to ambient temperature, the crystals are suction filtered through a filter and the residue is washed with the cold solvent. After drying with gentle heating, the desired enantiomer is obtained in the form of the salt of the organic acid, from which the base can easily be liberated using known methods. The acid may be recovered in very good yields by simple extraction.
The separation of enantiomers of piperidone derivatives according to the invention by crystallisation with simultaneous racemisation of the unwanted enantiomer may be carried out starting from the free base of formula (1), which may also be used as the crude product containing up to 20 % impurities, or starting from an acid addition salt precipitated to purify it, e.g. a hydrochloride or hydrobromide, after previous liberation of the base.
The high yield of 85 % or more is certainly due to the following: the acidity of the acid used causes a racemisation equilibrium to be achieved. Since the desired isomer is of low solubility as its salt, it is precipitated and is thus withdrawn from the equilibrium. By constant re-adjustment of the equilibrium, the mixture is finally converted almost entirely into the salt of the desired enantiomer which is of low solubility and is precipitated.
Case 1/1137 ' CA 02409614 2002-11-21 = 7 Unless otherwise stated, the terms listed below have the following meanings within the context of the present invention: the term alkyl, both on its own and in conjunction with other groups, denotes a straight-chain or branched alkyl group with the specified number of carbon atoms, such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl or n-hexyl. Aryl denotes an aromatic hydrocarbon group having up to 10 carbon atoms, such as, for example, phenyl or naphthyl;
heteroaryl denotes a mono- or bicyclic aromatic group having up to 10 ring atoms which comprises, in addition to carbon atoms, one or more heteroatom(s) which are selected independently of one another from among N, 0 and S, such as e.g.
pyridine 1o or furan. Halogen denotes fluorine, chlorine or bromine.
The example which follows serves to illustrate one of the separation methods according to the invention, carried out by way of example, for obtaining enantiomerically pure piperidone derivatives of general formula (1). It should be regarded merely as a possible procedure, described by way of example, without restricting the invention to its contents.
Example 1: (+)-(R)-2-(2-Methoxyphenyl)methyl-3,3-dimethyl-4-piperidonium-hydrogenditoluoyitartrate 150 g (0.53 mol) of 2-(-methoxyphenyl)methyl-3,3-dimethyl-4-piperidonium-hydrochloride are first added to 320 ml of water. After the addition of 150 ml of toluene the pH is adjusted to 12.8 using 47.5 ml (0.53 mol) of sodium hydroxide solution (45% in water). The resulting mixture is stirred for about 40 minutes at ambient temperature, with thorough mixing of the phases, left to stand and then the aqueous phase is separated off. The organic phase is washed with 40 ml of water and then evaporated to dryness.
The oily residue (about 131 g, 0.53 mol) is dissolved in 131 ml of acetonitrile and measured into a solution of 204.2 g (0.53 mol) of (+)-ditoluoyltartaric acid in 102 mi of acetonitrile at 55-60 C over a period of 2 hours. After another 24 hours' stirring at this temperature the mixture is allowed to cool to ambient temperature over about 40 minutes and suction filtered through a filter. The residue is washed three times with 15 ml of acetonitrile and dried at 45-50 C in a drying cupboard until a constant weight is achieved. About 284 g(0.045 mol, 85 %) of the title compound with a optical rotation of ao20: +115 [c= 2; MeOH] are obtained.
R- n HN
(1), is meant a racemic or optically active mixture of enantiomers which consists of the 1o two enantiomeric piperidone derivatives of general formulae (1a) and (1b) O O
R n_ R- n HN HN
(1 a) (1 b) A preferred process according to the invention is a process for isolating the enantiomer of general formuia (1 a) O
Ri n HN
(1a).
2o The (+)-piperidone (1 a) is precipitated, for example, by reaction with (+)-ditoluoyltartaric acid or (+)-dibenzoyltartaric acid and thus concentrated. With (-)-ditoluoyltartaric acid or (-)-dibenzoyltartaric acid, on the other hand, the opposite enantiomer is obtained, namely the (-)-piperidone (1b).
Particularly preferred is a process for obtaining the (+)-piperidone derivative of general formula (1a), wherein R' denotes 2-methoxyphenyl, R2 and R3 each denote methyl and Case 1/1137 n denotes 1, characterised in that the desired (R)-(+)-enantiomer is precipitated as the salt thereof by reacting with (+)-ditoluoyltartaric acid and at the same time, in the dissolved (S)-(-)-enantiomer, the chiral centre is epimerised by heating to a temperature of about 30-75 C, more preferably to 50-65 C. The solvent used may be acetonitrile, acetone, or mixtures thereof, preferably acetonitrile.
Also preferred according to the invention is a process which leads to a piperidone of general formula (1 a) or (1 b) with an enantiomeric excess of - 95 % ee, more lo preferably >- 97 % ee.
It is particularly preferred according to the invention to operate as follows:
a mixture of the enantiomeric piperidone derivatives of general formula (1) is dissolved in an inert solvent, e.g. acetonitrile, and added slowly to a solution of a suitable tartaric acid derivative, preferably (+)-ditoluoyltartaric acid, in the same solvent, which has been heated to about 35 to 75 C, preferably to 50 to 65 C. Stirring is continued for a further 0.5 to 36 hours at the same temperature until there is no more precipitate is being formed as far as the naked eye can tell. After cooling to ambient temperature, the crystals are suction filtered through a filter and the residue is washed with the cold solvent. After drying with gentle heating, the desired enantiomer is obtained in the form of the salt of the organic acid, from which the base can easily be liberated using known methods. The acid may be recovered in very good yields by simple extraction.
The separation of enantiomers of piperidone derivatives according to the invention by crystallisation with simultaneous racemisation of the unwanted enantiomer may be carried out starting from the free base of formula (1), which may also be used as the crude product containing up to 20 % impurities, or starting from an acid addition salt precipitated to purify it, e.g. a hydrochloride or hydrobromide, after previous liberation of the base.
The high yield of 85 % or more is certainly due to the following: the acidity of the acid used causes a racemisation equilibrium to be achieved. Since the desired isomer is of low solubility as its salt, it is precipitated and is thus withdrawn from the equilibrium. By constant re-adjustment of the equilibrium, the mixture is finally converted almost entirely into the salt of the desired enantiomer which is of low solubility and is precipitated.
Case 1/1137 ' CA 02409614 2002-11-21 = 7 Unless otherwise stated, the terms listed below have the following meanings within the context of the present invention: the term alkyl, both on its own and in conjunction with other groups, denotes a straight-chain or branched alkyl group with the specified number of carbon atoms, such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl or n-hexyl. Aryl denotes an aromatic hydrocarbon group having up to 10 carbon atoms, such as, for example, phenyl or naphthyl;
heteroaryl denotes a mono- or bicyclic aromatic group having up to 10 ring atoms which comprises, in addition to carbon atoms, one or more heteroatom(s) which are selected independently of one another from among N, 0 and S, such as e.g.
pyridine 1o or furan. Halogen denotes fluorine, chlorine or bromine.
The example which follows serves to illustrate one of the separation methods according to the invention, carried out by way of example, for obtaining enantiomerically pure piperidone derivatives of general formula (1). It should be regarded merely as a possible procedure, described by way of example, without restricting the invention to its contents.
Example 1: (+)-(R)-2-(2-Methoxyphenyl)methyl-3,3-dimethyl-4-piperidonium-hydrogenditoluoyitartrate 150 g (0.53 mol) of 2-(-methoxyphenyl)methyl-3,3-dimethyl-4-piperidonium-hydrochloride are first added to 320 ml of water. After the addition of 150 ml of toluene the pH is adjusted to 12.8 using 47.5 ml (0.53 mol) of sodium hydroxide solution (45% in water). The resulting mixture is stirred for about 40 minutes at ambient temperature, with thorough mixing of the phases, left to stand and then the aqueous phase is separated off. The organic phase is washed with 40 ml of water and then evaporated to dryness.
The oily residue (about 131 g, 0.53 mol) is dissolved in 131 ml of acetonitrile and measured into a solution of 204.2 g (0.53 mol) of (+)-ditoluoyltartaric acid in 102 mi of acetonitrile at 55-60 C over a period of 2 hours. After another 24 hours' stirring at this temperature the mixture is allowed to cool to ambient temperature over about 40 minutes and suction filtered through a filter. The residue is washed three times with 15 ml of acetonitrile and dried at 45-50 C in a drying cupboard until a constant weight is achieved. About 284 g(0.045 mol, 85 %) of the title compound with a optical rotation of ao20: +115 [c= 2; MeOH] are obtained.
Claims (7)
1. Process for dynamically separating the enantiomers of piperidone derivatives of general formula (1) wherein R1 denotes aryl, which is optionally mono- to polysubstituted, heteroaryl, which is linked to the piperidine ring via a carbon atom in the piperidine ring or a carbon atom belonging to the methylene bridge, C1-C8-alkyl, which is straight-chain or branched and is optionally mono-to polysubstituted by halogen;
R2 and R3, which are identical or different, denote C1-C6-alkyl, which is straight-chain or branched; and n denotes 0, 1, 2 or 3, wherein:
a) an optically active organic acid and optionally catalytic amounts of a sulphonic acid are dissolved in a suitable solvent and this solution is kept at a temperature of between 35 and 70°C, b) a solution of the piperidone derivative is slowly metered into this solution, so that the desired enantiomer crystallises out as a salt of the optically active organic acid used, while at the same time the unwanted isomer is racemised 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 crystallisation has ended.
R2 and R3, which are identical or different, denote C1-C6-alkyl, which is straight-chain or branched; and n denotes 0, 1, 2 or 3, wherein:
a) an optically active organic acid and optionally catalytic amounts of a sulphonic acid are dissolved in a suitable solvent and this solution is kept at a temperature of between 35 and 70°C, b) a solution of the piperidone derivative is slowly metered into this solution, so that the desired enantiomer crystallises out as a salt of the optically active organic acid used, while at the same time the unwanted isomer is racemised 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 crystallisation has ended.
2. Process according to claim 1, wherein the enantiomer to be isolated is a piperidone derivative of general formula (1a)
3. Process according to claim 1 or 2, wherein R1 denotes R2 and R3, which are identical or different, denote methyl or ethyl;
R4 denotes methoxy, ethoxy, isopropyloxy, halogen, hydroxy, C1-C6-alkyl, which is partially or fully halogenated, trifluoromethyl, amino, nitro, cyano, benzoyl, C1-C6-alkylcarbonyl;
n denotes 1 and m denotes 0 or 1.
R4 denotes methoxy, ethoxy, isopropyloxy, halogen, hydroxy, C1-C6-alkyl, which is partially or fully halogenated, trifluoromethyl, amino, nitro, cyano, benzoyl, C1-C6-alkylcarbonyl;
n denotes 1 and m denotes 0 or 1.
4. Process according to any one of claims 1 to 3, wherein the optically active organic acid is ditoluoyltartaric acid or dibenzoyltartaric acid, optionally with the addition of catalytic amounts of toluenesulphonic acid or camphorsulphonic acid.
5. Process according to any one of claims 1 to 4, wherein the solvent is acetone, acetonitrile or a mixture thereof.
6. Process according to any one of claims 1 to 5, wherein the desired enantiomer is obtained with a purity of >= 95 % ee.
7. Process according to any one of claims 1 to 6, wherein R1 denotes 2-methoxyphenyl, R2 and R3 each denote methyl, n denotes 1, 1 equivalent of ditoluoyltartaric acid is used as the optically active organic acid and the reaction is carried out at 55 to 60°C in acetonitrile.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10029851A DE10029851A1 (en) | 2000-06-16 | 2000-06-16 | Optical resolution of 2-substituted 4-piperidone derivatives, for use as pharmaceutical intermediates, by simultaneous formation of salt with optically active acid and racemization |
| DE10029851.6 | 2000-06-16 | ||
| PCT/EP2001/006552 WO2001096306A1 (en) | 2000-06-16 | 2001-06-09 | Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2409614A1 CA2409614A1 (en) | 2001-12-20 |
| CA2409614C true CA2409614C (en) | 2008-08-05 |
Family
ID=7646064
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2409614 Expired - Fee Related CA2409614C (en) | 2000-06-16 | 2001-06-09 | Separation of the enantiomers of piperidone derivatives with simultaneous racemisation in situ of the unwanted enantiomer |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1305287A1 (en) |
| JP (1) | JP2004503539A (en) |
| KR (1) | KR100863922B1 (en) |
| AR (1) | AR028957A1 (en) |
| AU (1) | AU2001270563A1 (en) |
| CA (1) | CA2409614C (en) |
| DE (1) | DE10029851A1 (en) |
| IL (2) | IL153085A0 (en) |
| MX (1) | MXPA02012301A (en) |
| WO (1) | WO2001096306A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0736724B2 (en) * | 1992-08-07 | 1995-04-26 | 株式会社スリオンテック | Seeding and raising seedling sheet using ultraviolet curing adhesive and method for producing the same |
| KR100393133B1 (en) * | 1994-09-23 | 2003-11-17 | 다윈 디스커버리 리미티드 | Methods of racemization and asymmetry conversion used in the manufacture of levobupivacaine and its analogs |
| DE19528472A1 (en) * | 1995-08-03 | 1997-02-06 | Boehringer Ingelheim Kg | New process for the production of norbenzomorphan of an intermediate stage in the production of pharmaceutically valuable benzomorphan derivatives, in particular of (-) - (1R, 5S, S "R) -3'-hydroxy-2- (2-methoxypropyl -) - 5.9.9 -trimethyl-6.7 benzomorphan |
-
2000
- 2000-06-16 DE DE10029851A patent/DE10029851A1/en not_active Ceased
-
2001
- 2001-06-09 WO PCT/EP2001/006552 patent/WO2001096306A1/en active Application Filing
- 2001-06-09 JP JP2002510449A patent/JP2004503539A/en active Pending
- 2001-06-09 IL IL15308501A patent/IL153085A0/en active IP Right Grant
- 2001-06-09 EP EP01949395A patent/EP1305287A1/en not_active Withdrawn
- 2001-06-09 AU AU2001270563A patent/AU2001270563A1/en not_active Abandoned
- 2001-06-09 CA CA 2409614 patent/CA2409614C/en not_active Expired - Fee Related
- 2001-06-09 KR KR1020027016915A patent/KR100863922B1/en not_active IP Right Cessation
- 2001-06-09 MX MXPA02012301A patent/MXPA02012301A/en active IP Right Grant
- 2001-06-15 AR ARP010102869A patent/AR028957A1/en not_active Suspension/Interruption
-
2002
- 2002-11-26 IL IL153085A patent/IL153085A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004503539A (en) | 2004-02-05 |
| IL153085A (en) | 2008-11-26 |
| DE10029851A1 (en) | 2001-12-20 |
| MXPA02012301A (en) | 2003-04-25 |
| AR028957A1 (en) | 2003-05-28 |
| KR100863922B1 (en) | 2008-10-17 |
| IL153085A0 (en) | 2003-06-24 |
| EP1305287A1 (en) | 2003-05-02 |
| KR20030016288A (en) | 2003-02-26 |
| CA2409614A1 (en) | 2001-12-20 |
| AU2001270563A1 (en) | 2001-12-24 |
| WO2001096306A1 (en) | 2001-12-20 |
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