CA2316991A1 - Purification of tramadol - Google Patents
Purification of tramadol Download PDFInfo
- Publication number
- CA2316991A1 CA2316991A1 CA002316991A CA2316991A CA2316991A1 CA 2316991 A1 CA2316991 A1 CA 2316991A1 CA 002316991 A CA002316991 A CA 002316991A CA 2316991 A CA2316991 A CA 2316991A CA 2316991 A1 CA2316991 A1 CA 2316991A1
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- Prior art keywords
- tramadol
- preparation
- salt
- crude
- hydrochloride
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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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the preparation of Tramadol according to a Grignard reaction of 2(dimethylaminomethyl)cyclo-hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base which is then introduced to a solvent, comprises contacting the crude base with hydrobromic or hydriodic acid to form a salt thereof, and subjecting the salt to a re-crystallisation step to obtain the product Tramadol hydrobromide or Tramadol hydriodide respectively, from which purified Tramadol base is obtainable for optional conversion to a pharmaceutically preferred form e.g. Tramadol hydrochloride.
Description
Purification of Tramadol Technical Field This invention relates to the production of a pharmaceutical product obtained through a process which initially produces a crude base as a mixture of isomers together with side products from which a selected isomer is to be separated. In particular the invention is concerned with the separation and purification of the selected isomer to achieve a substantially increased yield of same.
Background Art The desired product (~)-traps-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, (Tramadol) is difficult to isolate by distillation because the mixed geometric cis and traps isomers boil around 138°C - 140°C. However the target compound can be obtained through subsequent re-crystallisation steps by converting the crude base to the hydrochloride salt as described in US-A-3,652,589 and GB-A-997,399.
The production of Tramadol hydrochloride as described in GB-A-997,399 involves a Grignard reaction to produce mixed cis-and traps-isomers of 2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol and side products. The crude mixed isomer base is obtainable by distilling the complex mixture obtained from the Grignard reaction under a high vacuum. The distilled isomer mixture is dissolved in diethyl ether and treated with gaseous hydrogen chloride. The resulting crude mixture of cis- and traps-isomer hydrochlorides is precipitated and filtered. This procedure yields an isomer mixture with a relatively high content of cis-isomer. The isomer mixture is then refluxed with a five-fold volume of moist dioxane, and the resulting suspension is filtered while still hot. The filter cake is boiled once more with dry dioxane and filtered; the residue obtained consists of the target traps hydrochloride.
Background Art The desired product (~)-traps-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, (Tramadol) is difficult to isolate by distillation because the mixed geometric cis and traps isomers boil around 138°C - 140°C. However the target compound can be obtained through subsequent re-crystallisation steps by converting the crude base to the hydrochloride salt as described in US-A-3,652,589 and GB-A-997,399.
The production of Tramadol hydrochloride as described in GB-A-997,399 involves a Grignard reaction to produce mixed cis-and traps-isomers of 2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol and side products. The crude mixed isomer base is obtainable by distilling the complex mixture obtained from the Grignard reaction under a high vacuum. The distilled isomer mixture is dissolved in diethyl ether and treated with gaseous hydrogen chloride. The resulting crude mixture of cis- and traps-isomer hydrochlorides is precipitated and filtered. This procedure yields an isomer mixture with a relatively high content of cis-isomer. The isomer mixture is then refluxed with a five-fold volume of moist dioxane, and the resulting suspension is filtered while still hot. The filter cake is boiled once more with dry dioxane and filtered; the residue obtained consists of the target traps hydrochloride.
The commercial production of Tramadol is believed to have always followed the process described in GB-A-997,399 but certain disadvantages of the process described have caused the acceptability of such a process to be questioned. One such disadvantage lies in that the solvent used in that process is dioxane which is now considered as an unacceptable toxic compound for which the tolerance set for its residual content in the product is extremely low, of the order of several parts per billion. Furthermore dioxane is considered to be a health risk which is toxic by inhalation or through skin absorption as a carcinogen, central nervous system depressant and an agent causing necrosis of the liver and kidney. It is also considered to be a hazardous material by its flammability, and ability to form explosive peroxides.
There is also the need to improve the original method because the high vacuum distillation of the isomers prior to their isolation is undesirable.
A further method for purification and separation of Tramadol hydrochloride is proposed in US-A-5,414,129 wherein it is suggested that Tramadol hydrochloride is obtainable from the Grignard reaction mixture containing the isomers and side products by combining the mixture with a solution of hydrochloric acid in a low molecular weight alcohol or with gaseous hydrogen chloride in the presence of an organic solvent selected from medium molecular weight alcohols, ketones, esters, and ethers or aromatic ethers, to effect the selective precipitation of Tramadol hydrochloride.
Although suggesting that alternative solvents to dioxane are very hard to find, a large number of solvents, including alcohols, ketones, esters, ethers and aromatic ethers are suggested as being found suitable. Repetition of the work as described therein suggests that it is unlikely that the effective isomer separation of the hydrochlorides is achievable/improved under the conditions described.
There is also the need to improve the original method because the high vacuum distillation of the isomers prior to their isolation is undesirable.
A further method for purification and separation of Tramadol hydrochloride is proposed in US-A-5,414,129 wherein it is suggested that Tramadol hydrochloride is obtainable from the Grignard reaction mixture containing the isomers and side products by combining the mixture with a solution of hydrochloric acid in a low molecular weight alcohol or with gaseous hydrogen chloride in the presence of an organic solvent selected from medium molecular weight alcohols, ketones, esters, and ethers or aromatic ethers, to effect the selective precipitation of Tramadol hydrochloride.
Although suggesting that alternative solvents to dioxane are very hard to find, a large number of solvents, including alcohols, ketones, esters, ethers and aromatic ethers are suggested as being found suitable. Repetition of the work as described therein suggests that it is unlikely that the effective isomer separation of the hydrochlorides is achievable/improved under the conditions described.
Separation may be achievable during the subsequent two re-crystallisation steps mentioned therein, the conditions for which are not described in the patent, but the unwanted isomer still-remains at 2.2%. Even so it is considered that results might be achievable on a laboratory scale but the process, at least as described in the patent, would create processing problems if the method were to be attempted for full scale production.
More recently published EP-A-0 778 262 proposes an improved method of purification of Tramadol base reliant again on the use of the hydrochloride for this purpose which is based on treating mixtures otherwise difficult to resolve by simple hydrochloride salt formation in a solvent with acid to selectively dehydrate the unwanted isomer. Subsequently the hydrochloride salt formation allows for better resolution and re-crystallisation. Therefore, this dehydration stage allows resolution of mixtures by hydrochloride formation and re-crystallisation more efficiently than previously. Published EP-A-0-778 262 also comments on and confirms that the hydrochloride salt of Tramadol is not an efficient method for resolving the isomers and indicates that this additional dehydration step is necessary in order to achieve a resolution which is workable.
Therefore currently, it remains the position that as for approximately the last 20 years or so, the commercial production of Tramadol relies essentially on the process of GB-997,399 whereby the purification of the Tramadol base is by re-crystallisation of the hydrochloride with an improvement made by the dehydration stage above.
An object of the present invention is to provide a method which obviates or mitigates the aforesaid disadvantages of the prior art methods and does not require the dehydration stage.
More recently published EP-A-0 778 262 proposes an improved method of purification of Tramadol base reliant again on the use of the hydrochloride for this purpose which is based on treating mixtures otherwise difficult to resolve by simple hydrochloride salt formation in a solvent with acid to selectively dehydrate the unwanted isomer. Subsequently the hydrochloride salt formation allows for better resolution and re-crystallisation. Therefore, this dehydration stage allows resolution of mixtures by hydrochloride formation and re-crystallisation more efficiently than previously. Published EP-A-0-778 262 also comments on and confirms that the hydrochloride salt of Tramadol is not an efficient method for resolving the isomers and indicates that this additional dehydration step is necessary in order to achieve a resolution which is workable.
Therefore currently, it remains the position that as for approximately the last 20 years or so, the commercial production of Tramadol relies essentially on the process of GB-997,399 whereby the purification of the Tramadol base is by re-crystallisation of the hydrochloride with an improvement made by the dehydration stage above.
An object of the present invention is to provide a method which obviates or mitigates the aforesaid disadvantages of the prior art methods and does not require the dehydration stage.
Disclosure of Invention Surprisingly it is now found that remarkable improvements in production of Tramadol are obtainable by forming salts using hydrobromic or hydriodic acids.
Thus according to one aspect of the invention there is provided a process for the preparation of Tramadol according to a Grignard reaction of 2-(dimethylaminomethyl)cyclo-hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base which is then introduced to a solvent, characterised by contacting the crude base with hydrobromic acid to form a salt thereof, and subjecting the salt to a re-crystallisation step to obtain the product Tramadol hydrobromide.
According to another aspect of the invention there is provided a process for the preparation of Tramadol according to a Grignard reaction of 2-(dimethylaminomethyl)cyclo-hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base which is then introduced to a solvent, characterised by contacting the crude base with hydriodic acid to form a salt thereof, and subjecting the salt to a re-crystallisation step to obtain the product Tramadol hydriodide.
The Grignard reagent mentioned above for use in forming the crude base prior to salt formation may be of the traditional type wherein the halogen "X" is a matter of convenient choice, such as the chloride, bromide or iodide.
However, the bromide is found to be very suitable for the purposes of the invention and is preferred.
A variety of solvents for the crude base are available, but alcohols, such as isopropanol are found to be suitable for the present purpose.
Preferably the salt is recovered as a precipitate, e.g.
by filtering before the re-crystallisation step.
WO 99/3b390 PCT/GB99/00013 Preferably the salt forming process from the crude Tramadol free base is operated at very low pH i.e. at about pH 1.0, using acid solutions of about 40 to 60% strength of the appropriate acids, preferably 45 to 50%, especially 48%
Thus according to one aspect of the invention there is provided a process for the preparation of Tramadol according to a Grignard reaction of 2-(dimethylaminomethyl)cyclo-hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base which is then introduced to a solvent, characterised by contacting the crude base with hydrobromic acid to form a salt thereof, and subjecting the salt to a re-crystallisation step to obtain the product Tramadol hydrobromide.
According to another aspect of the invention there is provided a process for the preparation of Tramadol according to a Grignard reaction of 2-(dimethylaminomethyl)cyclo-hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base which is then introduced to a solvent, characterised by contacting the crude base with hydriodic acid to form a salt thereof, and subjecting the salt to a re-crystallisation step to obtain the product Tramadol hydriodide.
The Grignard reagent mentioned above for use in forming the crude base prior to salt formation may be of the traditional type wherein the halogen "X" is a matter of convenient choice, such as the chloride, bromide or iodide.
However, the bromide is found to be very suitable for the purposes of the invention and is preferred.
A variety of solvents for the crude base are available, but alcohols, such as isopropanol are found to be suitable for the present purpose.
Preferably the salt is recovered as a precipitate, e.g.
by filtering before the re-crystallisation step.
WO 99/3b390 PCT/GB99/00013 Preferably the salt forming process from the crude Tramadol free base is operated at very low pH i.e. at about pH 1.0, using acid solutions of about 40 to 60% strength of the appropriate acids, preferably 45 to 50%, especially 48%
5 hydrobromic acid or 47% hydriodic acid.
Modes for Carrying out the Invention The invention will now be further described by way of the following illustrative examples.
Examples:
Tramadol base In the present invention firstly a preparation of a crude Tramadol base is necessary. This follows traditional Grignard conditions which are well understood in the art. Here the Grignard reaction is between 2-(dimethylaminomethyl) cyclotnexanone and 3-methoxyphenylmagnesium bromide to achieve the target base. The quality of the crude base is typically 74.8%(RR,SS) . 15.6%(RS,SR).
Secondly resolution of the base using hydrobromic or hydriodic acid is carried out by conducting the following steps.
Tramadol hydrobromide 1 Charge Tramadol base (crude, 65g) to vessel with isopropanol (150m1).
2 Charge 48% hydrobromic acid to pH 1.0 and stir until crystallisation begins.
3 Stir mixture at 15°C to 25°C for a period of 1 hour.
4 Cool to 2°C to 5°C and stir for a further period of 1 hour.
5 Filter and wash with isopropanol (50m1) and acetone (50m1), to obtain damp cake typically 99.1%(RR,SS) .
0.4%(RS,SR). This forms the crude damp hydrobromide.
Modes for Carrying out the Invention The invention will now be further described by way of the following illustrative examples.
Examples:
Tramadol base In the present invention firstly a preparation of a crude Tramadol base is necessary. This follows traditional Grignard conditions which are well understood in the art. Here the Grignard reaction is between 2-(dimethylaminomethyl) cyclotnexanone and 3-methoxyphenylmagnesium bromide to achieve the target base. The quality of the crude base is typically 74.8%(RR,SS) . 15.6%(RS,SR).
Secondly resolution of the base using hydrobromic or hydriodic acid is carried out by conducting the following steps.
Tramadol hydrobromide 1 Charge Tramadol base (crude, 65g) to vessel with isopropanol (150m1).
2 Charge 48% hydrobromic acid to pH 1.0 and stir until crystallisation begins.
3 Stir mixture at 15°C to 25°C for a period of 1 hour.
4 Cool to 2°C to 5°C and stir for a further period of 1 hour.
5 Filter and wash with isopropanol (50m1) and acetone (50m1), to obtain damp cake typically 99.1%(RR,SS) .
0.4%(RS,SR). This forms the crude damp hydrobromide.
6 Take damp cake up in isopropanol (155m1) and water (8m1).
7 Stir the mixture until crystallisation starts and continue at 15°C to 25°C for a period of 1 hour.
8 Cool to -10°C to -15°C and stir for a further period of one hour.
9 Filter and wash with isopropanol (40m1) and acetone (40m1), and dry product.
Typical yield is 53g of Tramadol hydrobromide, [99,7$(RR,SS) . 0.03$(RS,SR)).
Typical yield is 53g of Tramadol hydrobromide, [99,7$(RR,SS) . 0.03$(RS,SR)).
10 This represents a recovery of >80$ of recoverable (RR,SS) isomer.
Tramadol hydriodide The above described resolution procedure is repeated using 47$ hydriodic acid in place of hydrobromic acid to again achieve excellent resolution.
Optional processing steps The thus highly purified Tramadol hydrobromide or hydriodide can then be readily converted to a preferred pharmaceutically acceptable form for example Tramadol hydrochloride. For producing the hydrochloride the product of the purification process is converted to the. base, mixed with absolute alcohol, diisopropyl ether and hydrochloride gas. It will be understood that no additional resolution benefits are achieved on converting to the hydrochloride, since a remarkably high resolution is already achieved using the hydrobromide or hydriodide. Therefore, this is simply formation of the hydrochloride salt for sale using a well established method in literature for forming hydrochloride salts of organic compounds in solvent and hydrochloride gas.
Whereas for many years the method of choice for purifying (~)-cis,traps-2-dimethylaminomethyl-1-(3-methoxyphenyl)-WO 99/3b390 PCT/GB99/00013 _ 7 cyclohexanol free base to selectively obtain the target Tramadol trans isomer has been via formation of the hydrochloride, the resolution has not been particularly good and several re-crystallisation steps were necessary to obtain any useful product at all.
Therefore the advantages offered by this invention are that use of the Tramadol hydrobromide and hydriodide salt dispense with the need for repeated re-crystallisation steps and removes the variations found in the yield and quality associated with the hydrochloride under similar conditions.
In fact a high resolution of product can surprisingly be obtained by only one re-crystallisation step. Furthermore the present invention obtains at least 80~ of the desired isomer with no re-crystallisation step whereas the prior art methods only obtain about 50~a and that is only obtained by re-crystallising at least two times and still contains circa 2~
of unwanted isomer. The fact that the prior art methods require multiple re-crystallisation means that the overall recovery is dramatically reduced, to about 40~ in order to achieve a material with an unwanted isomer of (< 0.3$).
Industrial Applicability This invention is applicable in the production of Tramadol which is useful therapeutically as a non-additive analgesic.
Tramadol hydriodide The above described resolution procedure is repeated using 47$ hydriodic acid in place of hydrobromic acid to again achieve excellent resolution.
Optional processing steps The thus highly purified Tramadol hydrobromide or hydriodide can then be readily converted to a preferred pharmaceutically acceptable form for example Tramadol hydrochloride. For producing the hydrochloride the product of the purification process is converted to the. base, mixed with absolute alcohol, diisopropyl ether and hydrochloride gas. It will be understood that no additional resolution benefits are achieved on converting to the hydrochloride, since a remarkably high resolution is already achieved using the hydrobromide or hydriodide. Therefore, this is simply formation of the hydrochloride salt for sale using a well established method in literature for forming hydrochloride salts of organic compounds in solvent and hydrochloride gas.
Whereas for many years the method of choice for purifying (~)-cis,traps-2-dimethylaminomethyl-1-(3-methoxyphenyl)-WO 99/3b390 PCT/GB99/00013 _ 7 cyclohexanol free base to selectively obtain the target Tramadol trans isomer has been via formation of the hydrochloride, the resolution has not been particularly good and several re-crystallisation steps were necessary to obtain any useful product at all.
Therefore the advantages offered by this invention are that use of the Tramadol hydrobromide and hydriodide salt dispense with the need for repeated re-crystallisation steps and removes the variations found in the yield and quality associated with the hydrochloride under similar conditions.
In fact a high resolution of product can surprisingly be obtained by only one re-crystallisation step. Furthermore the present invention obtains at least 80~ of the desired isomer with no re-crystallisation step whereas the prior art methods only obtain about 50~a and that is only obtained by re-crystallising at least two times and still contains circa 2~
of unwanted isomer. The fact that the prior art methods require multiple re-crystallisation means that the overall recovery is dramatically reduced, to about 40~ in order to achieve a material with an unwanted isomer of (< 0.3$).
Industrial Applicability This invention is applicable in the production of Tramadol which is useful therapeutically as a non-additive analgesic.
Claims (21)
1. A process for the preparation of Tramadol according to a Grignard reaction of 2-(dimethylaminomethyl)cyclo-hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base which is then introduced to a solvent, characterised by contacting the crude base with hydrobromic acid to form a salt thereof, and subjecting the salt to a re-crystallisation step to obtain the product Tramadol hydrobromide.
2. A process for the preparation of Tramadol according to a Grignard reaction of 2-(dimethylaminomethyl)cyclo-hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base which is then introduced to a solvent, characterised by contacting the crude base with hydriodic acid to form a salt thereof, and subjecting the salt to a re-crystallisation step to obtain the product Tramadol hydriodide.
3. A process for the preparation of Tramadol according to Claim 1 wherein the halogen (X) is bromide.
4. A process for the preparation of Tramadol according to Claim 2 wherein the halogen (X) is bromide.
5. A process for the preparation of Tramadol according to Claims 1, 2, 3 or 4 wherein the salt is recovered as a precipitate.
6. A process for the preparation of Tramadol according to Claim 5 wherein the salt is recovered by filtering before the re-crystallisation step.
7. A process for the preparation of Tramadol according to any one of claims 1 to 4 wherein the salt forming process from the crude Tramadol free base is operated at or about pH 1Ø
8. A process for the preparation of Tramadol according to Claim 6 wherein the salt forming process from the crude Tramadol free base is operated at or about pH 1.0, using acid solutions of about 40 to 60% strength of the appropriate acids.
9. A process for the preparation of Tramadol according to Claim 6 wherein the salt forming process from the crude Tramadol free base is operated at or about pH 1.0, using acid solutions of about 45 to 50% strength of the appropriate acids.
10. A process for the preparation of Tramadol according to Claims 1, 3, 5, 6, 7 or 8 wherein the salt forming process from the crude Tramadol free base is operated at or about pH 1.0, using an acid solution of 48% hydrobromic acid.
11. A process for the preparation of Tramadol according to Claim 2, 4, 5, 6, 7 or 8 wherein the salt forming process from the crude Tramadol free base is operated at or about pH 1.0, using an acid solution of 47% hydriodic acid.
12. A process for the preparation of Tramadol according to Claims 1, 3, 5, 6, 7, 8, 9 or 10 wherein the resulting Tramadol hydrobromide is further converted to a pharmaceutically acceptable form.
13. A process for the preparation of Tramadol according to Claim 12 wherein the pharmaceutically acceptable form is Tramadol hydrochloride.
14. A process for the preparation of Tramadol according to Claim 12 wherein the resulting Tramadol hydrobromide is converted to Tramadol hydrochloride by mixing Tramadol base prepared from the Tramadol hydrobromide in absolute alcohol, diisopropyl ether and hydrochloride gas.
15. A Tramadol hydrobromide product formed by the process of any one of Claims 1, 3, 5, 6, 7, 8, 9 or 10.
16. A pharmaceutically acceptable Tramadol hydrochloride product formed according to the process of any one of Claims 11, 12 or 13.
17. A process for the preparation of Tramadol according to Claims 2, 4, 5, 6, 7, 8, 9 or 11 wherein the resulting Tramadol hydriodide is further converted to a pharmaceutically acceptable form.
18. A process for the preparation of Tramadol according to Claim 17 wherein the pharmaceutically acceptable form is Tramadol hydrochloride.
19. A process for the preparation of Tramadol according to Claim 17 wherein the resulting Tramadol hydriodide is converted to Tramadol hydrochloride by mixing Tramadol base prepared from the Tramadol hydriodide in absolute alcohol, diisopropyl ether and hydrochloride gas.
20. A Tramadol hydriodide product formed by the process of any one of Claims 2, 4, 5, 6, 7, 8, 9 or 11.
21. A pharmaceutically acceptable Tramadol hydrochloride product formed according to the process of any one of Claims 17, 18 or 19.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9800656.2A GB9800656D0 (en) | 1998-01-14 | 1998-01-14 | Improved purification process |
| GB9800656.2 | 1998-01-14 | ||
| PCT/GB1999/000013 WO1999036390A1 (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2316991A1 true CA2316991A1 (en) | 1999-07-22 |
Family
ID=10825209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002316991A Abandoned CA2316991A1 (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP1047662A1 (en) |
| KR (1) | KR20010034010A (en) |
| AU (1) | AU744938B2 (en) |
| CA (1) | CA2316991A1 (en) |
| GB (1) | GB9800656D0 (en) |
| HU (1) | HUP0100356A3 (en) |
| IL (1) | IL136957A0 (en) |
| NZ (1) | NZ505129A (en) |
| PL (1) | PL341712A1 (en) |
| SK (1) | SK10352000A3 (en) |
| TR (1) | TR200002022T2 (en) |
| WO (1) | WO1999036390A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100342919B1 (en) * | 1999-10-21 | 2002-07-04 | 박노중 | A preparation and purification for trans isomer of tramadol hydrochloride |
| US6649783B2 (en) | 2001-10-03 | 2003-11-18 | Euro-Celtique, S.A. | Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols |
| EP1346978A1 (en) * | 2002-03-21 | 2003-09-24 | Jubilant Organosys Limited | Process for preparing tramadol hydrochloride and/or tramadol monohydrate |
| DE10236510A1 (en) * | 2002-08-09 | 2004-02-19 | Grünenthal GmbH | 2-((Dimethylamino)-methyl)-1-(3-methoxyphenyl)-cyclohexanol preparation, by Grignard reaction in presence of lithium salt and dialkoxyalkane to give high yield of the analgesic trans-isomer tramadol |
| EP1785412A1 (en) | 2005-11-14 | 2007-05-16 | IPCA Laboratories Limited | Tramadol recovery process |
| WO2010032254A1 (en) * | 2008-09-22 | 2010-03-25 | Kamud Drugs Pvt . Ltd . | Industrial process for cis(+m-2-r(dimethylamino)-methyl-1-(3- methoxyphenyl) cyclohexanol hydrochloride |
| EP2978739A1 (en) | 2013-03-26 | 2016-02-03 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Extraction of tramadol from nauclea latifolia smith |
| USD828429S1 (en) | 2015-02-23 | 2018-09-11 | Samsung Electronics Co., Ltd. | Digital camera |
| CA3110155A1 (en) * | 2018-08-20 | 2020-02-27 | Mylan Laboratories Limited | Tramadol hbr-celecoxib co-crystal |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3652589A (en) * | 1967-07-27 | 1972-03-28 | Gruenenthal Chemie | 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols |
| 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 |
| 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 |
-
1998
- 1998-01-14 GB GBGB9800656.2A patent/GB9800656D0/en not_active Ceased
-
1999
- 1999-01-14 TR TR2000/02022T patent/TR200002022T2/en unknown
- 1999-01-14 SK SK1035-2000A patent/SK10352000A3/en unknown
- 1999-01-14 AU AU20637/99A patent/AU744938B2/en not_active Ceased
- 1999-01-14 IL IL13695799A patent/IL136957A0/en unknown
- 1999-01-14 KR KR1020007007604A patent/KR20010034010A/en not_active Application Discontinuation
- 1999-01-14 NZ NZ505129A patent/NZ505129A/en unknown
- 1999-01-14 EP EP99901000A patent/EP1047662A1/en not_active Withdrawn
- 1999-01-14 HU HU0100356A patent/HUP0100356A3/en unknown
- 1999-01-14 PL PL99341712A patent/PL341712A1/en unknown
- 1999-01-14 WO PCT/GB1999/000013 patent/WO1999036390A1/en not_active Application Discontinuation
- 1999-01-14 CA CA002316991A patent/CA2316991A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010034010A (en) | 2001-04-25 |
| AU744938B2 (en) | 2002-03-07 |
| NZ505129A (en) | 2001-11-30 |
| GB9800656D0 (en) | 1998-03-11 |
| TR200002022T2 (en) | 2000-11-21 |
| HUP0100356A2 (en) | 2002-05-29 |
| PL341712A1 (en) | 2001-04-23 |
| SK10352000A3 (en) | 2001-02-12 |
| EP1047662A1 (en) | 2000-11-02 |
| AU2063799A (en) | 1999-08-02 |
| IL136957A0 (en) | 2001-06-14 |
| HUP0100356A3 (en) | 2002-08-28 |
| WO1999036390A1 (en) | 1999-07-22 |
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