AU744938B2 - Purification of tramadol - Google Patents
Purification of tramadol Download PDFInfo
- Publication number
- AU744938B2 AU744938B2 AU20637/99A AU2063799A AU744938B2 AU 744938 B2 AU744938 B2 AU 744938B2 AU 20637/99 A AU20637/99 A AU 20637/99A AU 2063799 A AU2063799 A AU 2063799A AU 744938 B2 AU744938 B2 AU 744938B2
- Authority
- AU
- Australia
- Prior art keywords
- tramadol
- preparation
- salt
- crude
- hydrobromide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
WO 99/36390 PCT/GB99/00013 1 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 (±)-trans-2-dimethylaminomethyl-l-(3methoxyphenyl)cyclohexanol, (Tramadol) is difficult to isolate by distillation because the mixed geometric cis and trans isomers boil around 1380C 1400C. 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 trans-isomers of 2-dimethylaminomethyl-l-(3methoxyphenyl)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.
lu~ u r i lr-il ~~vi i- i. I y WO 99/36390 PCT/GB99/00013 2 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.
WO 99/36390 PCT/GB99/00013 3 Separation may be achievable during the subsequent two recrystallisation steps mentioned therein, the conditions for which are not described in the patent, but the unwanted isomer still remains at 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 recrystallisation 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.
-§>trh ~r P:\OPER\MalU0637-99 claims b.doc-04/102 4 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 hydrobromide comprising reacting 2- (dimethylaminomethyl)cyclo-hexanone with the Grignard reagent, 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base of Tramadol, introducing the crude base to a solvent, contacting the crude base with hydrobromic acid to form a salt thereof, and subjecting the salt to a recrystallisation step to obtain the product Tramadol 15 hydrobromide.
According to another, aspect of the invention there is provided a process for the preparation of Tramadol hydriodide comprising reacting 2-(dimethylaminomethyl)cyclo- 20 hexanone with the Grignard reagent, 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base of Tramadol, introducing the crude base to a solvent, 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 is a matter of convenient choice, such as the chloride, bromide or iodide.
Aowever, the bromide is found to be very suitable for the L rurposes of the invention and is preferred.
.g9~ S< .4<C<ff.~.ozs P:\OPER\MalI\20637-99 caims b.doc-04/0Ij2 4A 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.
S*
S
S S WO 99/36390 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% 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) cycloiexanone 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 (150ml).
2 Charge 48% hydrobromic acid to pH 1.0 and stir until crystallisation begins.
3 Stir mixture at 15°C to 25 0 C for a period of 1 hour.
4 Cool to 2 0 C to 5 0 C and stir for a further period of 1 hour.
Filter and wash with isopropanol (50ml) and acetone (50ml), to obtain damp cake typically 99.1%(RR,SS) 0.4%(RS,SR). This forms the crude damp hydrobromide.
i;l ~i WO 99/36390 PCT/GB99/00013 6 6 Take damp cake up in isopropanol (155ml) and water (8ml) 7 Stir the mixture until crystallisation starts and continue at 15 0 C to 250C for a period of 1 hour.
8 Cool to -100C to -15 0 C and stir for a further period of one hour.
9 Filter and wash with isopropanol (40ml) and acetone and dry product.
Typical yield is 53g of Tramadol hydrobromide, [99.7%(RR,SS) 0.03%(RS,SR)].
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,trans-2-dimethylaminomethyl-l-(3-methoxyphenyl)- ?~ir yr 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 15 only obtain about 50% and that is only obtained by recrystallising 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 eoo 20 achieve a material with an unwanted isomer of 0.3%) go Industrial Applicability
S".
This invention is applicable in the production of Tramadol which is useful therapeutically as a non-addictive analgesic.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
c-li ir
Claims (25)
1. A process for the preparation of Tramadol hydrobromide comprising reacting 2-(dimethylaminomethyl)cyclo- hexanone with the Grignard reagent, 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base of Tramadol, introducing the crude base to a solvent, 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 hydrobromide according to claim 1 wherein the halogen is bromide. 15 3. A process for the preparation of Tramadol hydrobromide according to claim 1 or 2 wherein the salt is recovered as a precipitate. S 4. A process for the preparation of Tramadol hydrobromide according to any one of claims 1 to 3 wherein the salt 20 is recovered by filtering before the re-crystallisation step. A process for the preparation of Tramadol hydrobromide 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
6. A process for the preparation of Tramadol hydrobromide according to any one of claims 1 to 5 wherein the salt R forming process from the crude Tramadol free base is operated at or about pH 1.0, using acid solutions of k- r g P:\OPER\MaMl20637-99 claims b.doc-04/01/02 9 about 40 to 60% strength of the appropriate acids.
7. A process for the preparation of Tramadol hydrobromide 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 strength of the appropriate acids.
8. A process for the preparation of Tramadol hydrobromide according to any one of claims 1 to 7 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.
9. A Tramadol hydrobromide product formed by the process of any one of claims 1 to 8.
10. A process for the preparation of Tramadol or other 15 pharmaceutically acceptable salt forms thereof wherein the Tramadol hydrobromide product according to claim 9 is further converted to Tramadol or a pharmaceutically acceptable form thereof.
11. A process according to claim 10 wherein the e: 20 pharmaceutically acceptable salt form of Tramadol is Tramadol hydrochloride.
12. A process for the preparation of Tramadol hydrochloride according to claim 11 wherein the Tramadol hydrobromide product as defined in claim 9 is converted to Tramadol hydrochloride by mixing Tramadol base prepared from the Tramadol hydrobromide product in absolute alcohol, Sdiisopropyl ether and hydrochloride gas. s '43- *10 P:\OPER\Mal20637-99 claimsb.doc-0401/02
13. A pharmaceutically acceptable salt form of Tramadol prepared according to the process of claim
14. A pharmaceutically acceptable salt form of Tramadol according to claim 13 which is Tramadol hydrochloride.
15. Tramadol prepared according to the process of claim
16. A process for the preparation of Tramadol hydriodide comprising reacting 2-(dimethylaminomethyl)cyclo- hexanone with the Grignard reagent, 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base of Tramadol, introducing the crude base to a solvent, 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 Shydriodide. *9 99
17. A process for the preparation of Tramadol according to claim 16 wherein the halogen is bromide.
18. A process for the preparation of Tramadol hydriodide according to claim 16 or 17 wherein the salt is So recovered as a precipitate. S 20 19. A process for the preparation of Tramadol hydriodide according to any one of claims 16 to 18 wherein the salt is recovered by filtering before the re- crystallisation step. A process for the preparation of Tramadol hydriodide according to any one of claims 16 to 19 wherein the salt forming process from the crude Tramadol free base R is operated at or about pH S-I P:\OPER\Mal\20637-99 claims b.doo-04I/)02 11
21. A process for the preparation of Tramadol hydriodide according to any one of claims 16 to 20 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.
22. A process for the preparation of Tramadol hydriodide according to claim 21 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 strength of the appropriate acids.
23. A process for the preparation of Tramadol hydriodide according to any one of claims 16 to 22 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. **o
24. A Tramadol hydriodide product formed by the process of any one of claims 16 to 23.
25. A process for the preparation of Tramadol or other pharmaceutically acceptable salt forms thereof wherein the Tramadol hydriodide product according to claim 24 is further converted to Tramadol or a pharmaceutically acceptable form thereof.
26. A process according to claim 25 wherein the pharmaceutically acceptable form of Tramadol is Tramadol hydrochloride.
27. A process for the preparation of Tramadol hydrochloride Raccording to claim 26 wherein the Tramadol hydriodide product as defined in claim 24 is converted to Tramadol P:\OPER\Ma20637-99 claims b.doc-04f 1/02 12 hydrochloride by mixing Tramadol base prepared from the Tramadol hydriodide product in absolute alcohol, diisopropyl ether and hydrochloride gas.
28. A pharmaceutically acceptable salt form of Tramadol prepared according to the process of claim
29. A pharmaceutically acceptable salt form of Tramadol according to claim 28 which is Tramadol hydrochloride Tramadol prepared according to the process of claim
31. A process for the preparation of Tramadol hydriodide and Tramadol hydrobromide substantially as hereinbefore described with reference to the Examples. a a 15 DATED this 7th day of January, 2002 Macfarian Smith Limited SBy DAVIES COLLISON CAVE 20 Patent Attorneys for the Applicants oo*
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 | 1998-01-14 | ||
| PCT/GB1999/000013 WO1999036390A1 (en) | 1998-01-14 | 1999-01-14 | Purification of tramadol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2063799A AU2063799A (en) | 1999-08-02 |
| AU744938B2 true AU744938B2 (en) | 2002-03-07 |
Family
ID=10825209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU20637/99A Ceased AU744938B2 (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 |
| US20160039742A1 (en) | 2013-03-26 | 2016-02-11 | Universite Joseph Fourier - Grenoble 1 | 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 KR KR1020007007604A patent/KR20010034010A/en not_active Application Discontinuation
- 1999-01-14 NZ NZ505129A patent/NZ505129A/en unknown
- 1999-01-14 HU HU0100356A patent/HUP0100356A3/en unknown
- 1999-01-14 IL IL13695799A patent/IL136957A0/en unknown
- 1999-01-14 SK SK1035-2000A patent/SK10352000A3/en unknown
- 1999-01-14 TR TR2000/02022T patent/TR200002022T2/en unknown
- 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 EP EP99901000A patent/EP1047662A1/en not_active Withdrawn
- 1999-01-14 CA CA002316991A patent/CA2316991A1/en not_active Abandoned
- 1999-01-14 PL PL99341712A patent/PL341712A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1047662A1 (en) | 2000-11-02 |
| GB9800656D0 (en) | 1998-03-11 |
| PL341712A1 (en) | 2001-04-23 |
| TR200002022T2 (en) | 2000-11-21 |
| NZ505129A (en) | 2001-11-30 |
| AU2063799A (en) | 1999-08-02 |
| WO1999036390A1 (en) | 1999-07-22 |
| SK10352000A3 (en) | 2001-02-12 |
| IL136957A0 (en) | 2001-06-14 |
| KR20010034010A (en) | 2001-04-25 |
| HUP0100356A3 (en) | 2002-08-28 |
| HUP0100356A2 (en) | 2002-05-29 |
| CA2316991A1 (en) | 1999-07-22 |
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