WO1997025330A1 - Process for the preparation of galanthamine - Google Patents
Process for the preparation of galanthamine Download PDFInfo
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- WO1997025330A1 WO1997025330A1 PCT/GB1997/000023 GB9700023W WO9725330A1 WO 1997025330 A1 WO1997025330 A1 WO 1997025330A1 GB 9700023 W GB9700023 W GB 9700023W WO 9725330 A1 WO9725330 A1 WO 9725330A1
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- Prior art keywords
- salt
- enriched
- galanthamine
- enantiomerically
- process according
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- 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.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
Definitions
- This invention relates to processes for the manufacture of enantiomerically-enriched forms of galanthamine, in free base or salt form.
- (-) -Galanthamine and derivatives thereof are useful compounds for the treatment of Alzheimer's disease and related illnesses.
- galanthamine is usually obtained by extraction from natural sources, such as daffodil or snowdrop bulbs.
- the yields of these extractive procedures are low, resulting in high costs and limited supplies of naturally obtained galanthamine.
- single enantiomer galanthamine (2) can be prepared from racemic narwedine (1) through resolution followed by reduction of the enone function, as depicted in Scheme l, below.
- the present invention is based on the surprising discovery of processes for the separation of the enantiomers of galanthamine by direct crystallisation techniques.
- a process for the preparation of an enantiomerically- enriched galanthamine salt, in which the counterion is achiral comprises seeding a supersaturated solution of the racemic salt with an enantiomerically-enriched form of the salt, and recovering the salt form that crystallises out of solution.
- a process for increasing the enantiomeric excess of an enantiomerically-enriched galanthamine salt, in which the counterion is achiral comprises crystallisation of a solution of the said enantiomerically-enriched salt, and recovery of the salt form that crystallises out of solution.
- the solution can be seeded with an enantiomerically-enriched form of the salt.
- this process for enhancing enantiomeric enrichment can be used subsequent to any process capable of producing enantiomerically-enriched galanthamine, to achieve very high enantiomeric excess.
- both the processes of the present invention have the advantage of simplicity and cost effectiveness.
- the processes are employed to manufacture salt forms enriched in (-)-galanthamine, which can then be used directly in pharmaceutical formulations, provided of course that the salt counterion is pharmaceutically-acceptable, or converted to the free base form of galanthamine, eg. by reaction with an appropriate base.
- both processes can adequately be used to prepare salt forms enriched in (+)-galanthamine, or the free base thereof, if this is desired.
- enantiomerically-enriched typically we mean at least 10% ee, more typically at least 20% ee, upto what may be considered substantially single enantiomer form, for instance at least 80% ee, and typically at least 90% ee, or higher.
- the salt used in the present invention can be any salt which is capable of giving the desired result.
- the salt is pharmaceutically-acceptable, thereby allowing direct incorporation into pharmaceutical formulations, as mentioned above.
- the salt is the hydrogen bromide salt, as this is the form in which (-)-galanthamine is currently marketed.
- racemic galanthamine hydrobromide exists as a conglomerate of its enantiomers rather than the more common case where racemates crystallise in space groups containing both enantiomeric forms.
- Evidence for the presence of a conglomerate is that the racemate and the pure enantiomer have identical IR spectra; see Jacques, Enantiomers, Racemates and Resolutions, Krieger, Florida, 1991, p 53.
- (-)-galanthamine hydrobromide shows much lower solubility than racemic hydrobromide salt in methanol, their respective solubilities being 6 mg/ml and 17 mg/ml.
- racemic galanthamine salt for use in the process according to the first aspect of the present invention can be manufactured using standard chemical techniques, in which racemic galanthamine is reacted with a moiety providing the salt counterion. Racemic galanthamine can be made by, for instance, reduction of racemic narwedine.
- the enantiomerically-enriched salt employed as the seed in the crystallisation process can be prepared from enantiomerically-enriched galanthamine obtained from natural sources, or from other synthetic procedures, as only a small amount of this is required.
- the enantiomeric excess of the seed is preferably high, for instance at least 90% ee, or higher, ie. substantially single enantiomer form.
- the enantiomeric excess that is obtained is dependent upon the process conditions employed, with optimisation of conditions such as temperature, concentration and solvent allowing higher enantiomeric excess to be achieved.
- the process according to the second aspect of the invention can be used to increase the enantiomeric excess of enantiomerically-enriched material obtained by way of the process according to the first aspect of the invention, or by any other method for preparing enantiomerically- enriched galanthamine, such as classical resolution or reduction of racemic or enantiomerically-enriched narwedine, and conversion to the appropriate salt form.
- (-)-narwedine can be carried out using any suitable reducing agent, such as lithium aluminium hydride as described by Barton and Kirby, although this has the disadvantage that epigalanthamine is also formed, or L- Selectride, although this reagent tends to be expensive and is only available in pilot plant quantities.
- Asymmetric reduction of racemic narwedine is described in WO-A- 9631453, also in the name of the present Applicant.
- a seed can be added to aid crystallisation.
- the seed should be enriched in the desired enantiomer, to direct the crystallisation to that enantiomer.
- the enantiomeric excess of the seed can be the same as or different to that of the salt solution to which it is added, but preferably it is of high enantiomeric excess, eg. at least 90% ee, or higher.
- the processes of the invention may be applicable to galanthamine derivatives also.
- Example 1 illustrates the process according to the first aspect of the present invention, and Examples 2 to 5 the process according to the second aspect of the invention.
- Example 1 Racemic galanthamine hydrobromide (101 mg) was dissolved in methanol (4.5 ml) at 60°C and the solution allowed to cool to 20°C. Seed crystals of (-) -galanthamine hydrobromide (1 mg) were added and the mixture stirred at 20°C for 4 hours. The mixture was filtered to afford (-)- galanthamine hydrobromide (17 mg) with an enantiomeric excess of 19%.
- Example 2 Example 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Glass Compositions (AREA)
- Apparatus For Radiation Diagnosis (AREA)
Abstract
The present invention comprises a process for the preparation of enantiomerically-enriched galanthamine from racemic galanthamine, and a process for increasing the enantiomeric excess of enantiomerically-enriched galanthamine, by direct crystallisation of galanthamine salts.
Description
PROCESS FOR THE PREPARATION OF GALANTHAMINE
Field of the Invention
This invention relates to processes for the manufacture of enantiomerically-enriched forms of galanthamine, in free base or salt form. Background to Invention
(-) -Galanthamine and derivatives thereof are useful compounds for the treatment of Alzheimer's disease and related illnesses. Currently galanthamine is usually obtained by extraction from natural sources, such as daffodil or snowdrop bulbs. However, the yields of these extractive procedures are low, resulting in high costs and limited supplies of naturally obtained galanthamine. It is known that single enantiomer galanthamine (2) can be prepared from racemic narwedine (1) through resolution followed by reduction of the enone function, as depicted in Scheme l, below. Usefully, since the enantiomers of narwedine (1) readily equilibrate (racemise) by way of reversible ring opening to a dienone, coupled to the fact that crystals of racemic (1) exist as a conglomerate of enantiomers, a dynamic resolution of (l) can be carried out by crystallisation with entrainment by crystals of the desired isomer (see Barton and Kirby, J. Chem. Soc. (C) (1962) 806) . However, in respect of a total synthesis, racemic narwedine itself is not readily available. Scheme 1
(»/- narwedine (-J-narweoine (-hgaβntnamine ( 1 ) ( 2 )
Several procedures have been developed for the resolution of galanthamine. One procedure involves formation of a diastereomeric salt with di-p-toluoyl tartaric acid and separation of the mixture by recrystallisation; see Kametani et aJ., Heterocycles, 1976, 1111. However, the need for the unnatural form of tartaric acid to access the desired, therapeutically-active, (-)- galanthamine renders this process costly.
Another resolution procedure involves the formation of diastereomeric esters with (-)-camphanic chloride and separation of the mixture by recrystallisation; see Szewczyk et al., J Het. Chem. (1995) 3_2: 195. The resultant product is then converted into (-)-galanthamine by reduction in a process which destroys the chiral auxiliary group, so rendering this process impractical for economic production. Summary of the Invention
The present invention is based on the surprising discovery of processes for the separation of the enantiomers of galanthamine by direct crystallisation techniques.
According to a first aspect of the present invention, a process for the preparation of an enantiomerically- enriched galanthamine salt, in which the counterion is achiral, comprises seeding a supersaturated solution of the racemic salt with an enantiomerically-enriched form of the salt, and recovering the salt form that crystallises out of solution.
According to a second aspect of the present invention, a process for increasing the enantiomeric excess of an enantiomerically-enriched galanthamine salt, in which the counterion is achiral, comprises crystallisation of a solution of the said enantiomerically-enriched salt, and recovery of the salt form that crystallises out of solution. Optionally, the solution can be seeded with an enantiomerically-enriched form of the salt. Advantageously, this process for enhancing enantiomeric
enrichment can be used subsequent to any process capable of producing enantiomerically-enriched galanthamine, to achieve very high enantiomeric excess.
Both the processes of the present invention have the advantage of simplicity and cost effectiveness. Preferably, the processes are employed to manufacture salt forms enriched in (-)-galanthamine, which can then be used directly in pharmaceutical formulations, provided of course that the salt counterion is pharmaceutically-acceptable, or converted to the free base form of galanthamine, eg. by reaction with an appropriate base. However, both processes can adequately be used to prepare salt forms enriched in (+)-galanthamine, or the free base thereof, if this is desired. Description of the Invention
In the context of the present Application, by enantiomerically-enriched typically we mean at least 10% ee, more typically at least 20% ee, upto what may be considered substantially single enantiomer form, for instance at least 80% ee, and typically at least 90% ee, or higher.
The salt used in the present invention can be any salt which is capable of giving the desired result. Preferably, the salt is pharmaceutically-acceptable, thereby allowing direct incorporation into pharmaceutical formulations, as mentioned above. Most preferably, the salt is the hydrogen bromide salt, as this is the form in which (-)-galanthamine is currently marketed.
Without being bound by theory, it seems that racemic galanthamine hydrobromide exists as a conglomerate of its enantiomers rather than the more common case where racemates crystallise in space groups containing both enantiomeric forms. Evidence for the presence of a conglomerate is that the racemate and the pure enantiomer have identical IR spectra; see Jacques, Enantiomers, Racemates and Resolutions, Krieger, Florida, 1991, p 53. Furthermore, (-)-galanthamine hydrobromide shows much lower
solubility than racemic hydrobromide salt in methanol, their respective solubilities being 6 mg/ml and 17 mg/ml. Processes for the separation of conglomerates are well described in the literature (see, for instance, Crosby, Chirality in Industry, Wiley, Chichester, 1992 p 24-27) . The racemic galanthamine salt for use in the process according to the first aspect of the present invention can be manufactured using standard chemical techniques, in which racemic galanthamine is reacted with a moiety providing the salt counterion. Racemic galanthamine can be made by, for instance, reduction of racemic narwedine. The enantiomerically-enriched salt employed as the seed in the crystallisation process can be prepared from enantiomerically-enriched galanthamine obtained from natural sources, or from other synthetic procedures, as only a small amount of this is required. The enantiomeric excess of the seed is preferably high, for instance at least 90% ee, or higher, ie. substantially single enantiomer form. To a degree, the enantiomeric excess that is obtained is dependent upon the process conditions employed, with optimisation of conditions such as temperature, concentration and solvent allowing higher enantiomeric excess to be achieved. The process according to the second aspect of the invention can be used to increase the enantiomeric excess of enantiomerically-enriched material obtained by way of the process according to the first aspect of the invention, or by any other method for preparing enantiomerically- enriched galanthamine, such as classical resolution or reduction of racemic or enantiomerically-enriched narwedine, and conversion to the appropriate salt form. Examples of classical resolution procedures have been given above. Reduction of (-)-narwedine can be carried out using any suitable reducing agent, such as lithium aluminium hydride as described by Barton and Kirby, although this has the disadvantage that epigalanthamine is also formed, or L-
Selectride, although this reagent tends to be expensive and is only available in pilot plant quantities. Asymmetric reduction of racemic narwedine is described in WO-A- 9631453, also in the name of the present Applicant. Optionally, a seed can be added to aid crystallisation. The seed should be enriched in the desired enantiomer, to direct the crystallisation to that enantiomer. The enantiomeric excess of the seed can be the same as or different to that of the salt solution to which it is added, but preferably it is of high enantiomeric excess, eg. at least 90% ee, or higher.
The increases in enantiomeric excess that are possible using this process again depend to a degree on process condition optimisation, but can be up to 50% ee or more, providing at least 90% ee, preferably at least 98% ee, or higher, in the final product.
The processes of the invention may be applicable to galanthamine derivatives also.
The present invention is now illustrated by way of the following Examples. Example 1 illustrates the process according to the first aspect of the present invention, and Examples 2 to 5 the process according to the second aspect of the invention. Example 1 Racemic galanthamine hydrobromide (101 mg) was dissolved in methanol (4.5 ml) at 60°C and the solution allowed to cool to 20°C. Seed crystals of (-) -galanthamine hydrobromide (1 mg) were added and the mixture stirred at 20°C for 4 hours. The mixture was filtered to afford (-)- galanthamine hydrobromide (17 mg) with an enantiomeric excess of 19%. Example 2
(-)-Galanthamine (6.11 g, 68% ee) was dissolved in EtOH (18 ml) by warming to 35°C. 48% HBr (3 ml, 1.2 equiv. ) in EtOH (3 ml) was added, giving a white precipitate. After cooling in ice the solid was collected by filtration. Yield = 6.01 g, (77%), 90% ee.
5.0 g of the (-)-galanthamine.HBr salt obtained was dissolved in H->0 (10 ml) on heating. (-)-Galanthamine.HBr seed crystals (3 mg) were added and the mixture cooled to room temperature. The resulting solid was collected by filtration. Yield = 1.7 g (34%), >98% ee. Example 3
(-)-Galanthamine.HBr (3.0 g) (90% ee) was slurried in EtOH (30 ml) at reflux. After 60 min. the mixture was cooled to room temperature, and stirred for 16 hours. Filtration yielded (-)-galanthamine.HBr (2.28 g, 76%) of >98% ee. Example 4
(-)-Galanthamine (18.0 g, 81% ee) was dissolved in EtOH (65 ml) by warming. 48% HBr (8.4 ml) in EtOH (10 ml) was added dropwise. The resulting white solid was collected by filtration. Yield = 22.06 g (96%).
This solid was dissolved in 3:1 IMS:H20 (200 ml) on heating to reflux, and then cooled to 5°C giving a white solid. Recovery of the solid yielded (-)-galanthamine.HBr (17.34 g, 79%), of >99.5% ee. Example 5
(-)-Galanthamine (41.5 g, 44% ee) was dissolved in
EtOH (170 ml). 48% HBr (19.4 ml) in EtOH (20 ml) was added dropwise to the solution, giving a white precipitate. This was collected by filtration. Yield of (-)-galanthamine.HBr
= 48.7 g, 91%.
This material was recrystallised from 3:1 IMS:H20 to give a white solid. Yield = 28.8 g (54%), of 92% ee.
Claims
1. A process for the preparation of an enantiomerically- enriched galanthamine salt, in which the counterion is achiral, comprising seeding a supersaturated solution of the racemic salt with an enantiomerically-enriched form of the salt, and recovering the salt form that crystallises out of solution.
2. A process according to claim 1, for the preparation of a salt enriched in the (-)-enantiomer, wherein seeding is with a salt form enriched in the (-) enantiomer.
3. A process according to claim 1, for the preparation of a salt enriched in the (+)-enantiomer, wherein seeding is with a salt form enriched in the (+)-enantiomer.
4. A process for increasing the enantiomeric excess of a first enantiomerically-enriched galanthamine salt, in which the counterion is achiral, comprising crystallisation of a solution of the said first enantiomerically-enriched salt, and recovery of the salt form that crystallises out of solution.
5. A process according to claim 4, wherein the solution is enriched in the (-)-enantiomer of the salt.
6. A process according to claim 4, wherein the solution is enriched in the (+)-enantiomer of the salt.
7. A process according to any of claims 4 to 6, further comprising seeding the salt solution with a second enantiomerically-enriched form of the salt, enriched in the desired enantiomer.
8. A process according to any of claims 4 to 7, wherein the said first enantiomerically-enriched salt is prepared by a process as defined in any of claims 1 to 3.
9. A process according to any of claims 4 to 7, wherein the said first enantiomerically-enriched salt is prepared by classical resolution of racemic galanthamine, and conversion to the salt form.
10. A process according to any of claims 4 to 7, wherein the said first enantiomerically-enriched salt is prepared by asymmetric reduction of racemic narwedine to give enantiomerically-enriched galanthamine, and conversion to the salt form.
11. A process according to any of claims 4 to 7, wherein the said first enantiomerically-enriched salt is prepared by reduction of enantiomerically-enriched narwedine to give enantiomerically-enriched galanthamine, and conversion to the salt form.
12. A process according to any preceding claim, wherein the salt is the hydrobromide.
13. A process for preparing enantiomerically-enriched galanthamine, comprising forming an enantiomerically- enriched galanthamine salt using a process according to any preceding claim, and converting the salt to galanthamine.
14. A process according to claim 13, for preparing galanthamine enriched in the (-)-enantiomer, comprising forming the salt by a process as defined in claim 2 or claim 5 or any claim dependant therefrom.
15. A process according to claim 13, for preparing galanthamine enriched in the (+)-enantiomer, comprising forming the salt by a process as defined in claim 3 or claim 6 or any claim dependant therefrom.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002239814A CA2239814C (en) | 1996-01-04 | 1997-01-06 | Process for the preparation of galanthamine |
| DE69717076T DE69717076T2 (en) | 1996-01-04 | 1997-01-06 | METHOD FOR PRODUCING GALANTHANINE |
| DK97900276T DK0880525T3 (en) | 1996-01-04 | 1997-01-06 | Process for the preparation of galanthamine |
| AU13867/97A AU700997B2 (en) | 1996-01-04 | 1997-01-06 | Process for the preparation of galanthamine |
| EP97900276A EP0880525B1 (en) | 1996-01-04 | 1997-01-06 | Process for the preparation of galanthamine |
| US09/101,174 US6087495A (en) | 1996-01-04 | 1997-01-06 | Process for the preparation of galanthamine |
| AT97900276T ATE227725T1 (en) | 1996-01-04 | 1997-01-06 | METHOD FOR PRODUCING GALANTHANIN |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9600080.7 | 1996-01-04 | ||
| GBGB9600080.7A GB9600080D0 (en) | 1996-01-04 | 1996-01-04 | Resolution process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997025330A1 true WO1997025330A1 (en) | 1997-07-17 |
Family
ID=10786571
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1997/000023 Ceased WO1997025330A1 (en) | 1996-01-04 | 1997-01-06 | Process for the preparation of galanthamine |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US6087495A (en) |
| EP (1) | EP0880525B1 (en) |
| AT (1) | ATE227725T1 (en) |
| AU (1) | AU700997B2 (en) |
| CA (1) | CA2239814C (en) |
| DE (1) | DE69717076T2 (en) |
| DK (1) | DK0880525T3 (en) |
| ES (1) | ES2186862T3 (en) |
| GB (1) | GB9600080D0 (en) |
| PT (1) | PT880525E (en) |
| WO (1) | WO1997025330A1 (en) |
| ZA (1) | ZA9781B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001074339A3 (en) * | 2000-04-03 | 2002-09-12 | Janssen Pharmaceutica Nv | A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease |
| CN102050826A (en) * | 2010-12-21 | 2011-05-11 | 浙江工业大学 | Method for separating galanthamine |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005065662A1 (en) * | 2003-12-31 | 2005-07-21 | Actavis Group Hf | Solid dosage formulations of galantamine |
| WO2005065661A2 (en) * | 2003-12-31 | 2005-07-21 | Actavis Group Hf | Immediate, controlled and sustained release formulations of galanthamine |
| WO2006013546A2 (en) * | 2004-07-28 | 2006-02-09 | Ranbaxy Laboratories Limited | Process for the preparation of pure galantamine |
| KR101834104B1 (en) | 2014-01-15 | 2018-03-02 | 엑손모빌 케미칼 패턴츠 인코포레이티드 | Propylene-based impact copolymers |
| US11370902B2 (en) | 2017-09-11 | 2022-06-28 | Exxonmobil Chemical Patents Inc. | Articles comprising polypropylene impact copolymers and methods of making the same |
| WO2022015627A2 (en) | 2020-07-17 | 2022-01-20 | Exxonmobil Chemical Patents Inc. | Polymers with low levels of volatile organic compounds and methods of making such polymers |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5428159A (en) * | 1994-04-08 | 1995-06-27 | Ciba-Geigy Corporation | Method of manufacture of (-)-galanthamine in high yield and purity substantially free of epigalanthamine |
-
1996
- 1996-01-04 GB GBGB9600080.7A patent/GB9600080D0/en active Pending
-
1997
- 1997-01-06 CA CA002239814A patent/CA2239814C/en not_active Expired - Lifetime
- 1997-01-06 ZA ZA9700081A patent/ZA9781B/en unknown
- 1997-01-06 DK DK97900276T patent/DK0880525T3/en active
- 1997-01-06 AU AU13867/97A patent/AU700997B2/en not_active Expired
- 1997-01-06 ES ES97900276T patent/ES2186862T3/en not_active Expired - Lifetime
- 1997-01-06 US US09/101,174 patent/US6087495A/en not_active Expired - Lifetime
- 1997-01-06 EP EP97900276A patent/EP0880525B1/en not_active Expired - Lifetime
- 1997-01-06 AT AT97900276T patent/ATE227725T1/en active
- 1997-01-06 DE DE69717076T patent/DE69717076T2/en not_active Expired - Lifetime
- 1997-01-06 PT PT97900276T patent/PT880525E/en unknown
- 1997-01-06 WO PCT/GB1997/000023 patent/WO1997025330A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5428159A (en) * | 1994-04-08 | 1995-06-27 | Ciba-Geigy Corporation | Method of manufacture of (-)-galanthamine in high yield and purity substantially free of epigalanthamine |
Non-Patent Citations (3)
| Title |
|---|
| J.J. COLLET; S.H. WILEN: "Enantiomers, racemates and resolutions", 1991, KRIEGER PUBLISHING COMPANY, FLORIDA, XP002015080 * |
| KAMETANI ET AL.: "The optical resolution of (+-)-galanthamine", HETEROCYCLES, vol. 4, no. 6, 1976, AMSTERDAM NL, pages 1111 - 1114, XP000603575 * |
| W. SHIEH AND J.A. CARLSON: "Asymetric transformation of either enantiomer of narwedine", JOURNAL OF ORGANIC CHEMISTRY, vol. 59, no. 18, 1994, EASTON US, pages 5463 - 5465, XP000562837 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001074339A3 (en) * | 2000-04-03 | 2002-09-12 | Janssen Pharmaceutica Nv | A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease |
| CN102050826A (en) * | 2010-12-21 | 2011-05-11 | 浙江工业大学 | Method for separating galanthamine |
| CN102050826B (en) * | 2010-12-21 | 2012-11-14 | 浙江工业大学 | Method for separating galanthamine |
Also Published As
| Publication number | Publication date |
|---|---|
| ATE227725T1 (en) | 2002-11-15 |
| EP0880525B1 (en) | 2002-11-13 |
| US6087495A (en) | 2000-07-11 |
| AU700997B2 (en) | 1999-01-14 |
| PT880525E (en) | 2003-03-31 |
| GB9600080D0 (en) | 1996-03-06 |
| DE69717076D1 (en) | 2002-12-19 |
| DK0880525T3 (en) | 2003-03-03 |
| CA2239814A1 (en) | 1997-07-17 |
| AU1386797A (en) | 1997-08-01 |
| EP0880525A1 (en) | 1998-12-02 |
| ES2186862T3 (en) | 2003-05-16 |
| DE69717076T2 (en) | 2003-07-17 |
| CA2239814C (en) | 2006-08-29 |
| ZA9781B (en) | 1998-01-06 |
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