WO1999036390A1 - Purification of tramadol - Google Patents
Purification of tramadol Download PDFInfo
- Publication number
- WO1999036390A1 WO1999036390A1 PCT/GB1999/000013 GB9900013W WO9936390A1 WO 1999036390 A1 WO1999036390 A1 WO 1999036390A1 GB 9900013 W GB9900013 W GB 9900013W WO 9936390 A1 WO9936390 A1 WO 9936390A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tramadol
- preparation
- salt
- crude
- hydrochloride
- Prior art date
Links
Classifications
-
- 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
- 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
- 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
Definitions
- 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.
- the invention is concerned with the separation and purification of the selected isomer to achieve a substantially increased yield of same.
- the desired product ( ⁇ ) -trans-2-dimethylaminomethyl-l- (3- methoxyphenyl ) cyclohexanol, (Tramadol) is difficult to isolate by distillation because the mixed geometric cis and trans isomers boil around 138°C - 140°C.
- 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.
- Tramadol hydrochloride as described in GB-A-997,399 involves a Grignard reaction to produce mixed cis-and trans-isomers of 2-dimethylaminomethyl-l- (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 trans-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 trans 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.
- 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.
- 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.
- 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.
- 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
- 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.
- 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.
- the bromide is found to be very suitable for the purposes of the invention and is preferred.
- alcohols such as isopropanol are found to be suitable for the present purpose.
- the salt is recovered as a precipitate, e.g. by filtering before the re-crystallisation step.
- 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% hydrobromic acid or 47% hydriodic acid.
- Tramadol hydrobromide or hydriodide can then be readily converted to a preferred pharmaceutically acceptable form for example Tramadol 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.
- 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.
- a high resolution of product can surprisingly be obtained by only one re-crystallisation step.
- 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% 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%) .
- This invention is applicable in the production of Tramadol which is useful therapeutically as a non-additive analgesic.
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU20637/99A AU744938B2 (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
IL13695799A IL136957A0 (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
NZ505129A NZ505129A (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
KR1020007007604A KR20010034010A (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
SK1035-2000A SK10352000A3 (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
CA002316991A CA2316991A1 (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
PL99341712A PL341712A1 (en) | 1998-01-14 | 1999-01-14 | Tramadole purification process |
EP99901000A EP1047662A1 (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
Applications Claiming Priority (2)
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 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999036390A1 true WO1999036390A1 (en) | 1999-07-22 |
Family
ID=10825209
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1999/000013 WO1999036390A1 (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) |
Cited By (8)
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 |
EP1346978A1 (en) * | 2002-03-21 | 2003-09-24 | Jubilant Organosys Limited | Process for preparing tramadol hydrochloride and/or tramadol monohydrate |
US6649783B2 (en) | 2001-10-03 | 2003-11-18 | Euro-Celtique, S.A. | Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols |
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 |
US7470816B2 (en) | 2005-11-14 | 2008-12-30 | Ipac 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 |
WO2014154747A1 (en) | 2013-03-26 | 2014-10-02 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Extraction of tramadol from nauclea latifolia smith |
WO2020039456A1 (en) * | 2018-08-20 | 2020-02-27 | Mylan Laboratories Limited | Tramadol hbr-celecoxib co-crystal |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USD828429S1 (en) | 2015-02-23 | 2018-09-11 | Samsung Electronics Co., Ltd. | Digital camera |
Citations (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 |
US5414129A (en) * | 1992-09-08 | 1995-05-09 | Chemagis, Ltd. | Process for the purification of 2-[(dimethylamino)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 AU AU20637/99A patent/AU744938B2/en not_active Ceased
- 1999-01-14 PL PL99341712A patent/PL341712A1/en unknown
- 1999-01-14 SK SK1035-2000A patent/SK10352000A3/en unknown
- 1999-01-14 KR KR1020007007604A patent/KR20010034010A/en not_active Application Discontinuation
- 1999-01-14 WO PCT/GB1999/000013 patent/WO1999036390A1/en not_active Application Discontinuation
- 1999-01-14 EP EP99901000A patent/EP1047662A1/en not_active Withdrawn
- 1999-01-14 IL IL13695799A patent/IL136957A0/en unknown
- 1999-01-14 TR TR2000/02022T patent/TR200002022T2/en unknown
- 1999-01-14 NZ NZ505129A patent/NZ505129A/en unknown
- 1999-01-14 HU HU0100356A patent/HUP0100356A3/en unknown
- 1999-01-14 CA CA002316991A patent/CA2316991A1/en not_active Abandoned
Patent Citations (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 |
US5414129A (en) * | 1992-09-08 | 1995-05-09 | Chemagis, Ltd. | Process for the purification of 2-[(dimethylamino)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 |
Cited By (11)
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 |
US6784319B2 (en) | 2001-10-03 | 2004-08-31 | Euro-Celtique, S.A. | Synthesis of (±)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols |
WO2003078380A2 (en) * | 2002-03-20 | 2003-09-25 | Jubilant Organosys Ltd | Process for preparing tramadol hydrochloride and/or tramadol momohydrate |
EP1346978A1 (en) * | 2002-03-21 | 2003-09-24 | Jubilant Organosys Limited | Process for preparing tramadol hydrochloride and/or tramadol monohydrate |
WO2003078380A3 (en) * | 2002-03-21 | 2004-03-11 | Jubilant Organosys Ltd | Process for preparing tramadol hydrochloride and/or tramadol momohydrate |
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 |
US7470816B2 (en) | 2005-11-14 | 2008-12-30 | Ipac 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 |
WO2014154747A1 (en) | 2013-03-26 | 2014-10-02 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Extraction of tramadol from nauclea latifolia smith |
WO2020039456A1 (en) * | 2018-08-20 | 2020-02-27 | Mylan Laboratories Limited | Tramadol hbr-celecoxib co-crystal |
Also Published As
Publication number | Publication date |
---|---|
NZ505129A (en) | 2001-11-30 |
GB9800656D0 (en) | 1998-03-11 |
AU2063799A (en) | 1999-08-02 |
IL136957A0 (en) | 2001-06-14 |
EP1047662A1 (en) | 2000-11-02 |
CA2316991A1 (en) | 1999-07-22 |
PL341712A1 (en) | 2001-04-23 |
TR200002022T2 (en) | 2000-11-21 |
AU744938B2 (en) | 2002-03-07 |
HUP0100356A2 (en) | 2002-05-29 |
HUP0100356A3 (en) | 2002-08-28 |
KR20010034010A (en) | 2001-04-25 |
SK10352000A3 (en) | 2001-02-12 |
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