NZ505129A - Purification of tramadol - Google Patents
Purification of tramadolInfo
- Publication number
- NZ505129A NZ505129A NZ505129A NZ50512999A NZ505129A NZ 505129 A NZ505129 A NZ 505129A NZ 505129 A NZ505129 A NZ 505129A NZ 50512999 A NZ50512999 A NZ 50512999A NZ 505129 A NZ505129 A NZ 505129A
- Authority
- NZ
- New Zealand
- Prior art keywords
- tramadol
- preparation
- salt
- hydrochloride
- crude
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the preparation of Tramadol via Tramadol hydroiodide and/or Tramadol hydrobromide is disclosed. The process involves a Grignard reaction of 2-(dimethylaminomethyl)cyclo-hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen. This forms a crude base, which is then contacted with hydrobromic acid or hydroiodic acid to form a salt, which is re-crystallized to give Tramadol hydroiodide or Tramadol hydrobromide respectively. This final product can then be converted to Tramadol.
Description
<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 505129 <br><br>
WO-99/36390 <br><br>
1 <br><br>
Purification of Tramadol <br><br>
PCT/GB99/00013 <br><br>
Technical Field This invention relates to the production of a pharmaceutical product obtained through a process which 5 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. <br><br>
10 Background Art <br><br>
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. However the target 15 compound can be obtained through subsequent re-crystallisation steps by converting the crude base to the hydrochloride salt as described m US-A-3,652,589 and GB-A-997,399. <br><br>
The production of Tramadol hydrochloride as described in GB-A-997,399 involves a Grignard reaction to produce mixed 20 cis-and trans-isomers of 2-dimethylaminomethyl-l-(3- <br><br>
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 25 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 30 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. <br><br>
Printed from Mimosa <br><br>
WO 99/36390 PCT/GB99/00013 <br><br>
2 <br><br>
The commercial production of Tramadol is believed to have always followed the process described m GB-A-997,399 but certain disadvantages of the process described have caused the acceptability of such a process to be questioned. One such 5 disadvantage lies in that the solvent used m that process is dioxane which is now considered as an unacceptable toxic compound for which the tolerance set for its residual content m the product is extremely low, of the order of several parts per billion. Furthermore dioxane is considered to be a health 10 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. <br><br>
15 There is also the need to improve the original method because the high vacuum distillation of the isomers prior to their isolation is undesirable. <br><br>
A further method for purification and separation of Tramadol hydrochloride is proposed m US-A-5,414,129 wherein 20 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 m a low molecular weight alcohol or with gaseous hydrogen chloride m the presence of an organic 25 solvent selected from medium molecular weight alcohols, <br><br>
ketones, esters, and ethers or aromatic ethers, to effect the selective precipitation of Tramadol hydrochloride. <br><br>
Although suggesting that alternative solvents to dioxane are very hard to find, a large number of solvents, including 30 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. <br><br>
Printed from Mimosa <br><br>
WO 99/36390 PCT/GB99/00013 <br><br>
3 <br><br>
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 5 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. <br><br>
More recently published EP-A-0 778 262 proposes an 10 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 m a solvent with acid to selectively dehydrate the unwanted isomer. Subsequently the 15 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 20 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 <br><br>
Therefore currently, it remains the position that as for 25 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. <br><br>
30 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. <br><br>
Printed from Mimosa <br><br>
50 <br><br>
WO 99/36390 PCT/GB99/00013 <br><br>
4 <br><br>
Disclosure of Invention <br><br>
Surprisingly it is now found that remarkable improvements in production of Tramadol are obtainable by forming salts using hydrobromic or hydriodic acids. <br><br>
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, which product may be converted to Tramadol or a pharmaceutically acceptable salt form thereof. <br><br>
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, which product may be converted to Tramadol or a pharmaceutically acceptable salt form thereof. <br><br>
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. <br><br>
A variety of solvents for the crude base are available, but alcohols, such as isopropanol are found to be suitable for the present purpose. <br><br>
Preferably the salt is recovered as a precipitate, e.g. by filtering before the re-crystallisation step. <br><br>
WO 99/36390 PCT/GB99/000J3 <br><br>
5 <br><br>
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. <br><br>
Modes for Carrying out the Invention The invention will now be further described by way of the following illustrative examples. <br><br>
Examples: <br><br>
10 Tramadol base <br><br>
In the present invention firstly a preparation of a crude Tramadol base is necessary. This follows traditional Grignard conditions which are well understood m the art. Here the Grignard reaction is between 2-(dimethylaminomethyl) 15 cyclohexanone and 3-methoxyphenylmagnesium bromide to achieve the target base. The quality of the crude base is typically 7 4.8 %(RR,S S) : 15.6%(RS,SR) . <br><br>
Secondly resolution of the base using hydrobromic or hydriodic acid is carried out by conducting the following 20 steps. <br><br>
Tramadol hydrobromide <br><br>
1 Charge Tramadol base (crude, 65g) to vessel with isopropanol (150ml). <br><br>
2 Charge 48% hydrobromic acid to pH 1.0 and stir until 25 crystallisation begins <br><br>
3 Stir mixture at 15°C to 25°C for a period of 1 hour. <br><br>
4 Cool to 2°C to 5°C and stir for a further period of 1 hour. <br><br>
5 Filter and wash with isopropanol (50ml) and acetone 30 (50ml), to obtain damp cake typically 99.1%(RR,SS) : <br><br>
0.4%(RS,SR). This forms the crude damp hydrobromide. <br><br>
Printed from Mimosa <br><br>
WO 99/36390 PCT/GB99/00013 <br><br>
6 <br><br>
6 Take damp cake up m isopropanol (155ml) and water (8ml). <br><br>
7 Stir the mixture until crystallisation starts and continue at 15°C to 25°C for a period of 1 hour. <br><br>
8 Cool to —10°C to -15°C and stir for a further period of 5 one hour. <br><br>
9 Filter and wash with isopropanol (40ml) and acetone (40ml), and dry product. <br><br>
10 Typical yield is 53g of Tramadol hydrobromide, [99.7%(RR,SS) : 0.03%(RS,SR)]. <br><br>
10 This represents a recovery of >80% of recoverable (RR,SS) <br><br>
is ome r. <br><br>
Tramadol hydriodide <br><br>
The above described resolution procedure is repeated using 47% hydriodic acid m place of hydrobromic acid to again 15 achieve excellent resolution. <br><br>
Optional processing steps <br><br>
The thus highly purified Tramadol hydrobromide or hydriodide can then be readily converted to a preferred pharmaceutically acceptable form for example Tramadol 20 hydrochloride. For producing the hydrochloride the product of the purification process is converted to the base, mixed with absolute alcohol, dusopropyl ether and hydrochloride gas. It will be understood that no additional resolution benefits are achieved on converting to the hydrochloride, since a 25 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 m solvent and hydrochloride gas. <br><br>
30 Whereas for many years the method of choice for purifying <br><br>
(±)-cis,trans-2-dimethylaminomethyl-l-(3-methoxyphenyl)- <br><br>
Printed from Mimosa <br><br></p>
</div>
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, which product may be converted to Tramadol or a pharmaceutically acceptable salt form thereof.<br><br>
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, which product may be converted to Tramadol or a pharmaceutically acceptable salt form thereof.<br><br>
3. A process for the preparation of Tramadol according to Claim 1 wherein the halogen (X) is bromide.<br><br>
4. A process for the preparation of Tramadol according to Claim 2 wherein the halogen (X) is bromide.<br><br>
5. A process for the preparation of Tramadol according to Claim 1, 2, 3 or 4 wherein the salt is recovered as a precipitate.<br><br>
6. A process for the preparation of Tramadol according to Claim 5 wherein the salt is recovered by filtering before the re-crystallisation step.<br><br>
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 1.0.<br><br> 50 5 |<br><br> WO 99/36390 PCT/GB99/0001J<br><br> 9<br><br>
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.<br><br>
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.<br><br>
10. A process for the preparation of Tramadol according to Claim 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.<br><br>
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.<br><br>
12. A process for the preparation of Tramadol according to Claim 1, 3, 5, 6, 7, 8, 9 or 10 wherein the resulting Tramadol hydrobromide is further converted to a pharmaceutically acceptable form.<br><br>
13. A process for the preparation of Tramadol according to Claim 12 wherein the pharmaceutically acceptable form is Tramadol hydrochloride.<br><br>
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.<br><br>
15. A Tramadol hydrobromide product formed by the process of any one of Claims 1, 3, 5, 6, 7, 8, 9, and 10.<br><br> WO 99/36390<br><br> 10<br><br>
16. A pharmaceutically acceptable Tramadol hydrochloride product formed according to the process of any one of Claims 12, 13, and 14.<br><br>
17. A process for the preparation of Tramadol according to Claim 2, 4, 5, 6, 7, 8, 9 or 11 wherein the resulting Tramadol hydriodide is further converted to a pharmaceutically acceptable form.<br><br>
18. A process for the preparation of Tramadol according to Claim 17 wherein the pharmaceutically acceptable form is Tramadol hydrochloride.<br><br>
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.<br><br>
20. A Tramadol hydriodide product formed by the process of any one of Claims 2, 4, 5, 6, 7, 8, 9, and 11.<br><br>
21. A pharmaceutically acceptable Tramadol hydrochloride product formed according to the process of any one of Claims 17, 18, and 19.<br><br> </p> </div>
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9800656.2A GB9800656D0 (en) | 1998-01-14 | 1998-01-14 | Improved purification process |
PCT/GB1999/000013 WO1999036390A1 (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ505129A true NZ505129A (en) | 2001-11-30 |
Family
ID=10825209
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ505129A NZ505129A (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 |
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 |
USD828429S1 (en) | 2015-02-23 | 2018-09-11 | Samsung Electronics Co., Ltd. | Digital camera |
US20210317086A1 (en) * | 2018-08-20 | 2021-10-14 | 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 EP EP99901000A patent/EP1047662A1/en not_active Withdrawn
- 1999-01-14 AU AU20637/99A patent/AU744938B2/en not_active Ceased
- 1999-01-14 WO PCT/GB1999/000013 patent/WO1999036390A1/en not_active Application Discontinuation
- 1999-01-14 KR KR1020007007604A patent/KR20010034010A/en not_active Application Discontinuation
- 1999-01-14 IL IL13695799A patent/IL136957A0/en unknown
- 1999-01-14 NZ NZ505129A patent/NZ505129A/en unknown
- 1999-01-14 SK SK1035-2000A patent/SK10352000A3/en unknown
- 1999-01-14 CA CA002316991A patent/CA2316991A1/en not_active Abandoned
- 1999-01-14 HU HU0100356A patent/HUP0100356A3/en unknown
- 1999-01-14 TR TR2000/02022T patent/TR200002022T2/en unknown
- 1999-01-14 PL PL99341712A patent/PL341712A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
HUP0100356A2 (en) | 2002-05-29 |
PL341712A1 (en) | 2001-04-23 |
IL136957A0 (en) | 2001-06-14 |
GB9800656D0 (en) | 1998-03-11 |
HUP0100356A3 (en) | 2002-08-28 |
AU744938B2 (en) | 2002-03-07 |
TR200002022T2 (en) | 2000-11-21 |
EP1047662A1 (en) | 2000-11-02 |
WO1999036390A1 (en) | 1999-07-22 |
AU2063799A (en) | 1999-08-02 |
KR20010034010A (en) | 2001-04-25 |
CA2316991A1 (en) | 1999-07-22 |
SK10352000A3 (en) | 2001-02-12 |
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