CA2375234A1 - Process for the separation of the diastereomeric bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol - Google Patents
Process for the separation of the diastereomeric bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
Abstract
The invention relates to a method for separating the diastereomer bases of 2 - [(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol, whereby the separation of said diastereomer bases takes place by the formation of a base hydrate.
Description
G 2702-PCT As amended by submission of 21.06.2001 Process for the separation of the diastereomeric bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol This invention relates to a process for the purification and separation of the diastereomers of 2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol.
This compound and the salts thereof are of pharmaceutical interest. Tramadol hydrochloride, CA no. 36282-47-0 (~)-trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclo-hexanol hydrochloride has long been commercially available as a highly effective analgesic.
The above designation of the cis/trans isomers is not in accordance with IUPAC nomenclature. Compound CA no. 36282-47-0 is accordingly hereinafter designated the cis isomer or cis-tramadol in accordance with IUPAC nomenclature and taken to encompass the racemic mixture of (1R,2R)- and (1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclo-hexano1, while the racemic mixture of (1R,2S)- and (1S,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol is designated the trans isomer or trans-tramadol.
Known purification and separation processes, US 3,830,934 and DE-OS 4 330 240, for the above-stated tramadol hydrochloride are based on the reaction of the diastereoisomeric base mixture with mineral acids and subsequent fractional crystallisation from organic solvents. The disadvantage of this procedure is that it gives rise to two or more fractions which require further processing, so greatly reducing economic viability.
G 2702-PCT As amended by submission of 21.06.2001 Moreover, since concentrated mineral acids are sometimes used, this procedure inevitably gives rise to decomposition products due to the acid lability of the tertiary alcohol function. Furthermore, separation of the cis/trans isomers may only be achieved by means of the above-stated process if the isomer ratio of the base mixture to be separated is greater than 75:25 cis:trans.
WO 99/03820 describes a process for the production of pure cis-tramadol hydrochloride, in which a monohydrate of the corresponding cis-tramadol base is obtained from the Grignard bases by addition of water and is separated.
In all hitherto known processes, the trans:trans isomer ratio of the diastereomeric base mixtures to be separated is 80:20 and above. For example, according to DE-OS
4 330 240 or US 5,414,129, the ratio is 86:14.
However, there is also interest in separating the desired cis isomer from mixtures which contain the diastereomeric bases in an unfavourable isomer ratio, in order, for example, to be able to work up Grignard reaction mixtures obtained from deviant reaction conditions or also mother liquors. Mother liquors arising from a first precipitation of the desired isomer still contain the diastereomeric bases in a cis:trans isomer ratio of approx. 50:50.
The object of the invention is accordingly to provide a process which, without primary salt formation, permits separation of the diastereomers from a diastereomeric base mixture of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol over a wide isomer ratio range.
G 2702-PCT As amended by submission of 21.06.2001 ' It has surprisingly been found that diastereomer separation with 2-[(dimethylamino)methyl]-I-(3-methoxyphenyl)cyclo-hexanol advantageously proceeds by formation of a base hydrate by adding water or preferably organic solvent or solvent mixture and water to a diastereomeric base mixture of this compound with a cis:trans isomer ratio of below 80:20.
The invention accordingly provides a process for the separation of the diastereomeric bases of 2-[(dimethyl-amino)methyl]-1-(3-methoxyphenyl)cyclohexanol by treatment with water in at least stoichiometric quantities for complete conversion of the bases and subsequent separation of the precipitated hydrate of the cis diastereomer, which process is characterised in that a base mixture with a cis:trans isomer ratio of below 80:20, preferably of 60:40-75:25, is used.
When separating contaminated diastereomeric base mixtures, said mixtures are preferably dissolved in a water-miscible organic solvent or solvent mixture before the reaction with water, wherein solvents from the group of alcohols, ketones, esters, ethers, low molecular weight polyalcohols or aromatic hydrocarbons are used. The organic solvent or solvent mixture is here preferably used in a volume ratio to water of 10:2-10:5.
The water-miscible organic solvents used are preferably C1_8 alcohols, C3_$ ketones, CZ_$ esters, aliphatic, aromatic, open-chain and cyclic C9_$ ethers, CZ_6 polyalcohols or C5_g aromatics.
G 2702-PCT As amended by submission of 21.06.2001 ' The separated hydrate crystals of the cis diastereomer are finally washed with a mixture of the organic solvent and water in a volume ratio of 10:2-10:5 and then dried.
The water is used in at least stoichiometric quantities far complete conversion of the bases. Moreover, the water and also the solvent or solvent mixture may be used with the diastereomeric base mixture in a wide range of mixing ratios.
Separation of the diastereomers may proceed over a wide temperature range, provided that it is ensured that the reaction mixture does not freeze out at low temperatures.
At higher temperatures, the temperature of the reaction mixture is preferably maintained below the melting point of the base hydrate.
The process according to the invention is characterised in that, under the described conditions, the diastereomeric base mixture forms a hydrate and this hydrate, namely the cis diastereomer, preferably precipitates, so enabling easy separation of the diastereomers.
In comparison with hitherto described procedures, the process offers the advantages that diastereomer separation may proceed without salt formation (for example via the hydrochloride), that unwanted decomposition products are simply and effectively avoided by the formation of the base hydrate and that subsequent salt formation with numerous acids is possible directly via the base stage. Above all, however, the process makes it possible to separate G 2702-PCT As amended by submission of 21.06.2001 diastereomeric base mixtures, the cis:trans isomer ratio of which deviates greatly from that conventionally arising after the Grignard reaction. In particular, the process is suitable for working up mother liquors.
This compound and the salts thereof are of pharmaceutical interest. Tramadol hydrochloride, CA no. 36282-47-0 (~)-trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclo-hexanol hydrochloride has long been commercially available as a highly effective analgesic.
The above designation of the cis/trans isomers is not in accordance with IUPAC nomenclature. Compound CA no. 36282-47-0 is accordingly hereinafter designated the cis isomer or cis-tramadol in accordance with IUPAC nomenclature and taken to encompass the racemic mixture of (1R,2R)- and (1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclo-hexano1, while the racemic mixture of (1R,2S)- and (1S,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol is designated the trans isomer or trans-tramadol.
Known purification and separation processes, US 3,830,934 and DE-OS 4 330 240, for the above-stated tramadol hydrochloride are based on the reaction of the diastereoisomeric base mixture with mineral acids and subsequent fractional crystallisation from organic solvents. The disadvantage of this procedure is that it gives rise to two or more fractions which require further processing, so greatly reducing economic viability.
G 2702-PCT As amended by submission of 21.06.2001 Moreover, since concentrated mineral acids are sometimes used, this procedure inevitably gives rise to decomposition products due to the acid lability of the tertiary alcohol function. Furthermore, separation of the cis/trans isomers may only be achieved by means of the above-stated process if the isomer ratio of the base mixture to be separated is greater than 75:25 cis:trans.
WO 99/03820 describes a process for the production of pure cis-tramadol hydrochloride, in which a monohydrate of the corresponding cis-tramadol base is obtained from the Grignard bases by addition of water and is separated.
In all hitherto known processes, the trans:trans isomer ratio of the diastereomeric base mixtures to be separated is 80:20 and above. For example, according to DE-OS
4 330 240 or US 5,414,129, the ratio is 86:14.
However, there is also interest in separating the desired cis isomer from mixtures which contain the diastereomeric bases in an unfavourable isomer ratio, in order, for example, to be able to work up Grignard reaction mixtures obtained from deviant reaction conditions or also mother liquors. Mother liquors arising from a first precipitation of the desired isomer still contain the diastereomeric bases in a cis:trans isomer ratio of approx. 50:50.
The object of the invention is accordingly to provide a process which, without primary salt formation, permits separation of the diastereomers from a diastereomeric base mixture of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol over a wide isomer ratio range.
G 2702-PCT As amended by submission of 21.06.2001 ' It has surprisingly been found that diastereomer separation with 2-[(dimethylamino)methyl]-I-(3-methoxyphenyl)cyclo-hexanol advantageously proceeds by formation of a base hydrate by adding water or preferably organic solvent or solvent mixture and water to a diastereomeric base mixture of this compound with a cis:trans isomer ratio of below 80:20.
The invention accordingly provides a process for the separation of the diastereomeric bases of 2-[(dimethyl-amino)methyl]-1-(3-methoxyphenyl)cyclohexanol by treatment with water in at least stoichiometric quantities for complete conversion of the bases and subsequent separation of the precipitated hydrate of the cis diastereomer, which process is characterised in that a base mixture with a cis:trans isomer ratio of below 80:20, preferably of 60:40-75:25, is used.
When separating contaminated diastereomeric base mixtures, said mixtures are preferably dissolved in a water-miscible organic solvent or solvent mixture before the reaction with water, wherein solvents from the group of alcohols, ketones, esters, ethers, low molecular weight polyalcohols or aromatic hydrocarbons are used. The organic solvent or solvent mixture is here preferably used in a volume ratio to water of 10:2-10:5.
The water-miscible organic solvents used are preferably C1_8 alcohols, C3_$ ketones, CZ_$ esters, aliphatic, aromatic, open-chain and cyclic C9_$ ethers, CZ_6 polyalcohols or C5_g aromatics.
G 2702-PCT As amended by submission of 21.06.2001 ' The separated hydrate crystals of the cis diastereomer are finally washed with a mixture of the organic solvent and water in a volume ratio of 10:2-10:5 and then dried.
The water is used in at least stoichiometric quantities far complete conversion of the bases. Moreover, the water and also the solvent or solvent mixture may be used with the diastereomeric base mixture in a wide range of mixing ratios.
Separation of the diastereomers may proceed over a wide temperature range, provided that it is ensured that the reaction mixture does not freeze out at low temperatures.
At higher temperatures, the temperature of the reaction mixture is preferably maintained below the melting point of the base hydrate.
The process according to the invention is characterised in that, under the described conditions, the diastereomeric base mixture forms a hydrate and this hydrate, namely the cis diastereomer, preferably precipitates, so enabling easy separation of the diastereomers.
In comparison with hitherto described procedures, the process offers the advantages that diastereomer separation may proceed without salt formation (for example via the hydrochloride), that unwanted decomposition products are simply and effectively avoided by the formation of the base hydrate and that subsequent salt formation with numerous acids is possible directly via the base stage. Above all, however, the process makes it possible to separate G 2702-PCT As amended by submission of 21.06.2001 diastereomeric base mixtures, the cis:trans isomer ratio of which deviates greatly from that conventionally arising after the Grignard reaction. In particular, the process is suitable for working up mother liquors.
G 2702-PCT As amended by submission of 21.06.2001 Examples Example 1 50 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were dissolved in 100 ml of acetone. 20 ml of water were then added and the reaction mixture stirred at 20°C. Crystallisation began after approx. 30 minutes. The suspension was stirred for a further 90 minutes. The crystals were separated from the mother liquor using a filter, were washed twice with an acetone/water mixture (volume ratio 10:2) and suction filtered dry. The hydrate of the cis diastereomer was obtained at a yield of 67% and a purity of greater than 950. The isomer ratio in the crystal fraction was 98% cis isomer to 2o traps isomer.
Example 2 50 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were dissolved in 100 ml of isopropanol. 50 ml of water were then added and the reaction mixture stirred at 45°C. Crystallisation began after approx. 20 minutes. The suspension was stirred for a further 90 minutes. The crystals were separated from the mother liquor using a filter, were washed twice with an isopropanol/water mixture (volume ratio 10:5) and suction filtered dry. The hydrate of the cis diastereomer was obtained at a yield of 64°s and a purity of greater than G 2702-PCT As amended by submission of 21.06.2001 - 95%. The isomer ratio in the crystal fraction was 97% cis isomer to 3% trans isomer.
Example 3 50 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were dissolved in 50 ml of tetrahydrofuran (THF). 25 ml of water were then added and the reaction mixture stirred at 0°C. Crystallisation began overnight. The suspension was stirred for a further 90 minutes. The crystals were separated from the mother liquor using a filter, were washed twice with an THF/water mixture (volume ratio 10:5) and suction filtered dry. The hydrate of the cis diastereomer was obtained at a yield of 66% and a purity of greater than 950. The isomer ratio in the crystal fraction was 98o cis isomer to 2°s trans isomer.
Example 4 100 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were exposed to atmospheric humidity. After 3 days, a crystalline mass was obtained, which, after washing three times with cold ethanol/water, gave rise to the hydrate of the cis diastereomer at a yield of 45o and a purity of 95s. The isomer ratio in the crystal fraction was 98.1 cis isomer to 1.9o traps isomer.
G 2702-PCT As amended by submission of 21.06.2001 - Example 5 Conversion of a base hydrate obtained according to the invention into a salt:
20 g of the moist crystallisate obtained according to Example 1 were dissolved in 40 ml of isopropanol and stirred together with 36o hydrochloric acid until the measured pH value of the solution fell below 3. The solvent was then stripped out and the product recrystallised from isopropanol. Tramadol hydrochloride was obtained.
Example 6 50 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 63:37) were dissolved in 100 ml of acetone. 20 ml of water were then added and the reaction mixture stirred at 20°C. Crystallisation began after approx. 30 minutes. The suspension was stirred for a further 90 minutes. The crystals were separated from the mother liquor using a filter, were washed twice with an acetone/water mixture (volume ratio 10:2) and suction filtered dry. The hydrate of the cis diastereomer was obtained at a yield of 36o and a purity of greater than 95%. The isomer ratio in the crystal fraction was 97% cis isomer to 3o trans isomer.
Example 7 20 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol G 2702-PCT As amended by submission of 21.06.2001 - (cis:trans isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 20 vol.% of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration and washed twice with 10 ml portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is obtained at a yield of 34~ and a purity of greater than 95%. The isomer ratio in the crystal fraction was 98.80 cis isomer to 1.2o traps isomer.
Example 8 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol 15 (cis:trans isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 33 vol.o of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration and washed twice with 10 m1 portions of ethanol/water.
20 After drying, the hydrate of the cis diastereomer is obtained at a yield of 43% and a purity of greater than 95s. The isomer ratio in the crystal fraction was 99.40 cis isomer to 0.6o traps isomer.
Example 9 20 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 40 vol.~ of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration G 2702-PCT As amended by submission of 21.06.2001 ' and washed twice with 10 ml portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is obtained at a yield of 46o and a purity of greater than 95%. The isomer ratio in the crystal fraction was 99.80 cis 5 isomer to 0.2% trans isomer.
Example 10 g of a diastereomeric base mixture of (~)-cis/trans-2-10 [(dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 50 vol.% of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration 15 and washed twice with 10 ml portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is obtained at a yield of 50% and a purity of greater than 95%. The isomer ratio in the crystal fraction was 99.50 cis isomer to 0.5o traps isomer.
Example 11 20 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (trans:cis isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 60 vol.% of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration and washed twice with 10 m1 portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is obtained at a yield of 53% and a purity of greater than G 2702-PCT As amended by submission of 21.06.2001 - 950. The isomer ratio in the crystal fraction was 99.60 cis isomer to 0.4o trans isomer.
Example 2 50 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were dissolved in 100 ml of isopropanol. 50 ml of water were then added and the reaction mixture stirred at 45°C. Crystallisation began after approx. 20 minutes. The suspension was stirred for a further 90 minutes. The crystals were separated from the mother liquor using a filter, were washed twice with an isopropanol/water mixture (volume ratio 10:5) and suction filtered dry. The hydrate of the cis diastereomer was obtained at a yield of 64°s and a purity of greater than G 2702-PCT As amended by submission of 21.06.2001 - 95%. The isomer ratio in the crystal fraction was 97% cis isomer to 3% trans isomer.
Example 3 50 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were dissolved in 50 ml of tetrahydrofuran (THF). 25 ml of water were then added and the reaction mixture stirred at 0°C. Crystallisation began overnight. The suspension was stirred for a further 90 minutes. The crystals were separated from the mother liquor using a filter, were washed twice with an THF/water mixture (volume ratio 10:5) and suction filtered dry. The hydrate of the cis diastereomer was obtained at a yield of 66% and a purity of greater than 950. The isomer ratio in the crystal fraction was 98o cis isomer to 2°s trans isomer.
Example 4 100 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were exposed to atmospheric humidity. After 3 days, a crystalline mass was obtained, which, after washing three times with cold ethanol/water, gave rise to the hydrate of the cis diastereomer at a yield of 45o and a purity of 95s. The isomer ratio in the crystal fraction was 98.1 cis isomer to 1.9o traps isomer.
G 2702-PCT As amended by submission of 21.06.2001 - Example 5 Conversion of a base hydrate obtained according to the invention into a salt:
20 g of the moist crystallisate obtained according to Example 1 were dissolved in 40 ml of isopropanol and stirred together with 36o hydrochloric acid until the measured pH value of the solution fell below 3. The solvent was then stripped out and the product recrystallised from isopropanol. Tramadol hydrochloride was obtained.
Example 6 50 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 63:37) were dissolved in 100 ml of acetone. 20 ml of water were then added and the reaction mixture stirred at 20°C. Crystallisation began after approx. 30 minutes. The suspension was stirred for a further 90 minutes. The crystals were separated from the mother liquor using a filter, were washed twice with an acetone/water mixture (volume ratio 10:2) and suction filtered dry. The hydrate of the cis diastereomer was obtained at a yield of 36o and a purity of greater than 95%. The isomer ratio in the crystal fraction was 97% cis isomer to 3o trans isomer.
Example 7 20 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol G 2702-PCT As amended by submission of 21.06.2001 - (cis:trans isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 20 vol.% of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration and washed twice with 10 ml portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is obtained at a yield of 34~ and a purity of greater than 95%. The isomer ratio in the crystal fraction was 98.80 cis isomer to 1.2o traps isomer.
Example 8 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol 15 (cis:trans isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 33 vol.o of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration and washed twice with 10 m1 portions of ethanol/water.
20 After drying, the hydrate of the cis diastereomer is obtained at a yield of 43% and a purity of greater than 95s. The isomer ratio in the crystal fraction was 99.40 cis isomer to 0.6o traps isomer.
Example 9 20 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 40 vol.~ of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration G 2702-PCT As amended by submission of 21.06.2001 ' and washed twice with 10 ml portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is obtained at a yield of 46o and a purity of greater than 95%. The isomer ratio in the crystal fraction was 99.80 cis 5 isomer to 0.2% trans isomer.
Example 10 g of a diastereomeric base mixture of (~)-cis/trans-2-10 [(dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (cis:trans isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 50 vol.% of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration 15 and washed twice with 10 ml portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is obtained at a yield of 50% and a purity of greater than 95%. The isomer ratio in the crystal fraction was 99.50 cis isomer to 0.5o traps isomer.
Example 11 20 g of a diastereomeric base mixture of (~)-cis/trans-2-[(dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (trans:cis isomer ratio = 75:25) were dissolved in 20 g of ethanol at 22°C and combined with 60 vol.% of water. The solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration and washed twice with 10 m1 portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is obtained at a yield of 53% and a purity of greater than G 2702-PCT As amended by submission of 21.06.2001 - 950. The isomer ratio in the crystal fraction was 99.60 cis isomer to 0.4o trans isomer.
Claims (6)
1. Process for the separation of the diastereomeric bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclo-hexanol by treatment with water in at least stoichiometric quantities for complete conversion of the bases and subsequent separation of the precipitated hydrate of the cis diastereomer, characterised in that a diastereomeric base mixture with a cis:trans isomer ratio of below 80:20 is used.
2. Process according to claim 1, characterised in that the diastereomeric base mixture is used with a cis:trans isomer ratio in the range from 60:40-75:25.
3. Process according to claim 1 or 2, characterised in that, before the reaction with water, the diastereomeric base mixture is dissolved in a water-miscible organic solvent or solvent mixture, wherein solvents from the group of alcohols, ketones, esters, ethers, low molecular weight polyalcohols or aromatic hydrocarbons are used.
4. Process according to claim 3, characterised in that the organic solvent or solvent mixture is used in a volume ratio to water of 10:2-10:5.
5. Process according to claim 3 or 4, characterised in that C1-8 alcohols, C3-8 ketones, C2-8 esters, aliphatic, aromatic, open-chain and cyclic C4-8 ethers, C2-6 polyalcohols or C6-9 aromatics are used as organic solvents.
6. Process according to one or more of claims 1 to 5, characterised in that the separated hydrate crystals of the cis diastereomer are finally washed with a mixture of the organic solvent and water in a volume ratio of 10:2-10:5 and then dried.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP1999/004325 WO2000078705A1 (en) | 1999-06-22 | 1999-06-22 | Method for separating the diastereomer bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2375234A1 true CA2375234A1 (en) | 2000-12-28 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002375234A Abandoned CA2375234A1 (en) | 1999-06-22 | 1999-06-22 | Process for the separation of the diastereomeric bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US6521792B2 (en) |
| EP (1) | EP1187804A1 (en) |
| JP (1) | JP2003502400A (en) |
| AU (1) | AU4775699A (en) |
| CA (1) | CA2375234A1 (en) |
| CZ (1) | CZ20014669A3 (en) |
| HK (1) | HK1045301A1 (en) |
| HU (1) | HUP0201464A3 (en) |
| MX (1) | MXPA01013145A (en) |
| SK (1) | SK19002001A3 (en) |
| WO (1) | WO2000078705A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6579805B1 (en) * | 1999-01-05 | 2003-06-17 | Ronal Systems Corp. | In situ chemical generator and method |
| DE10108308A1 (en) | 2001-02-21 | 2002-08-29 | Gruenenthal Gmbh | Process for the isolation and purification of (1RS, 2RS) -2 [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol |
| EP1346978A1 (en) * | 2002-03-21 | 2003-09-24 | Jubilant Organosys Limited | Process for preparing tramadol hydrochloride and/or tramadol monohydrate |
| US7375035B2 (en) * | 2003-04-29 | 2008-05-20 | Ronal Systems Corporation | Host and ancillary tool interface methodology for distributed processing |
| US7429714B2 (en) | 2003-06-20 | 2008-09-30 | Ronal Systems Corporation | Modular ICP torch assembly |
| EP1785412A1 (en) * | 2005-11-14 | 2007-05-16 | IPCA Laboratories Limited | Tramadol recovery process |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3830934A (en) * | 1967-07-27 | 1974-08-20 | Gruenenthal Chemie | Analgesic and antitussive compositions and methods |
| IL103096A (en) * | 1992-09-08 | 1996-12-05 | Chemagis Ltd | Process for the purification of 2-[(dimethyllamino)methyl]-1-(3-methoxyphenyl) cyclohexanol and its salts |
| IL116281A (en) * | 1995-12-07 | 1999-06-20 | Chemagis Ltd | Process for the purification of (rr,ss)-2-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol and its salts |
| IL119121A (en) * | 1996-08-22 | 2000-11-21 | Chemagis Ltd | Process for the purification of (RR-SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride |
| AU730530B2 (en) * | 1997-07-15 | 2001-03-08 | Russinsky Limited | Tramadol, salts thereof and process for their preparation |
| US5877351A (en) * | 1997-12-24 | 1999-03-02 | Wyckoff Chemical Company, Inc. | Preparation and purification process for 2- (dimethylamino) methyl!-1-(3-methoxphenyl)-cyclohexanol and its salts |
| GB9800657D0 (en) * | 1998-01-14 | 1998-03-11 | Macfarlan Smith Ltd | Improved purification process |
-
1999
- 1999-06-22 CZ CZ20014669A patent/CZ20014669A3/en unknown
- 1999-06-22 CA CA002375234A patent/CA2375234A1/en not_active Abandoned
- 1999-06-22 EP EP99931139A patent/EP1187804A1/en not_active Ceased
- 1999-06-22 WO PCT/EP1999/004325 patent/WO2000078705A1/en not_active Application Discontinuation
- 1999-06-22 JP JP2001504875A patent/JP2003502400A/en not_active Withdrawn
- 1999-06-22 SK SK1900-2001A patent/SK19002001A3/en unknown
- 1999-06-22 MX MXPA01013145A patent/MXPA01013145A/en unknown
- 1999-06-22 HU HU0201464A patent/HUP0201464A3/en unknown
- 1999-06-22 AU AU47756/99A patent/AU4775699A/en not_active Abandoned
-
2001
- 2001-12-21 US US10/024,590 patent/US6521792B2/en not_active Expired - Fee Related
-
2002
- 2002-09-13 HK HK02106754.1A patent/HK1045301A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0201464A3 (en) | 2003-02-28 |
| US20020091287A1 (en) | 2002-07-11 |
| SK19002001A3 (en) | 2002-05-09 |
| HUP0201464A2 (en) | 2002-12-28 |
| US6521792B2 (en) | 2003-02-18 |
| HK1045301A1 (en) | 2002-11-22 |
| EP1187804A1 (en) | 2002-03-20 |
| CZ20014669A3 (en) | 2002-05-15 |
| MXPA01013145A (en) | 2002-06-04 |
| WO2000078705A1 (en) | 2000-12-28 |
| AU4775699A (en) | 2001-01-09 |
| JP2003502400A (en) | 2003-01-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |