WO1997025330A1 - Process for the preparation of galanthamine - Google Patents
Process for the preparation of galanthamine Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- enriched
- galanthamine
- enantiomerically
- process according
- Prior art date
Links
Classifications
-
- 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
Landscapes
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Glass Compositions (AREA)
- Apparatus For Radiation Diagnosis (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK97900276T DK0880525T3 (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 |
AU13867/97A AU700997B2 (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 |
CA002239814A CA2239814C (en) | 1996-01-04 | 1997-01-06 | Process for the preparation of galanthamine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9600080.7A GB9600080D0 (en) | 1996-01-04 | 1996-01-04 | Resolution process |
GB9600080.7 | 1996-01-04 |
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 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 |
---|---|---|---|---|
WO2001074339A2 (en) * | 2000-04-03 | 2001-10-11 | Janssen Pharmaceutica N.V. | 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 |
US20050191349A1 (en) * | 2003-12-31 | 2005-09-01 | Garth Boehm | Galantamine formulations |
WO2006013546A2 (en) * | 2004-07-28 | 2006-02-09 | Ranbaxy Laboratories Limited | Process for the preparation of pure galantamine |
WO2015108634A1 (en) | 2014-01-15 | 2015-07-23 | Exxonmobil Chemical Patents Inc. | Propylene-based impact copolymers |
CN111093931B (en) | 2017-09-11 | 2022-04-19 | 埃克森美孚化学专利公司 | Articles comprising polypropylene impact copolymer and methods of making the same |
CN116157429A (en) | 2020-07-17 | 2023-05-23 | 埃克森美孚化学专利公司 | Polymers having 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 EP EP97900276A patent/EP0880525B1/en not_active Expired - Lifetime
- 1997-01-06 PT PT97900276T patent/PT880525E/en unknown
- 1997-01-06 WO PCT/GB1997/000023 patent/WO1997025330A1/en active IP Right Grant
- 1997-01-06 DK DK97900276T patent/DK0880525T3/en active
- 1997-01-06 ZA ZA9700081A patent/ZA9781B/en unknown
- 1997-01-06 DE DE69717076T patent/DE69717076T2/en not_active Expired - Lifetime
- 1997-01-06 US US09/101,174 patent/US6087495A/en not_active Expired - Lifetime
- 1997-01-06 AT AT97900276T patent/ATE227725T1/en active
- 1997-01-06 ES ES97900276T patent/ES2186862T3/en not_active Expired - Lifetime
- 1997-01-06 AU AU13867/97A patent/AU700997B2/en not_active Expired
- 1997-01-06 CA CA002239814A patent/CA2239814C/en not_active Expired - Lifetime
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 (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001074339A2 (en) * | 2000-04-03 | 2001-10-11 | Janssen Pharmaceutica N.V. | A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease |
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 |
DE69717076D1 (en) | 2002-12-19 |
DE69717076T2 (en) | 2003-07-17 |
AU700997B2 (en) | 1999-01-14 |
PT880525E (en) | 2003-03-31 |
EP0880525B1 (en) | 2002-11-13 |
EP0880525A1 (en) | 1998-12-02 |
GB9600080D0 (en) | 1996-03-06 |
ES2186862T3 (en) | 2003-05-16 |
ZA9781B (en) | 1998-01-06 |
CA2239814C (en) | 2006-08-29 |
AU1386797A (en) | 1997-08-01 |
CA2239814A1 (en) | 1997-07-17 |
DK0880525T3 (en) | 2003-03-03 |
US6087495A (en) | 2000-07-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
IE862802L (en) | Crystalline paroxetine | |
EP0880525B1 (en) | Process for the preparation of galanthamine | |
AU709080B2 (en) | Process for preparing galanthamine derivatives by asymmetric reduction | |
SU1282815A3 (en) | Method of producing optically active trans-1-n-propyl-6-oxo-hydroquinolines | |
EP1670767B2 (en) | Resolution of a narwedine amide derivative | |
EP1692118B1 (en) | A process for the resolution of nefopam | |
AU2005212390A1 (en) | Resolution of racemates of methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)-(2-chlorophenil)acetate | |
KR101648468B1 (en) | Process for preparing Crystalline Form I of Donepezil Hydrochloride Salt | |
KR100523125B1 (en) | Process for preparing single enantiomer narwedine | |
EP0879225B1 (en) | Resolution of 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid | |
HU184233B (en) | Process for preparing 4-amino-substituted-2-piperidino-quinazoline derivatives | |
NZ237002A (en) | Method for resolving cis 3-amino-4-(2-(2-furyl)eth-1-yl)-1-methoxycarbonylmethyl-azetidin-2-one into its enantiomers and the resolved keto-l-gulonic acid hydrate salt thereof | |
US5892093A (en) | Resolution | |
CA3169745A1 (en) | Process for producing 4,5-dihydro-1h-pyrazoles and intermediates | |
KR20100044027A (en) | Method for preparing cis-dimecrotic acid and salt thereof | |
KR20060125218A (en) | The optical resolution method of benzoxazine derivative | |
CA2503146A1 (en) | Resolution of mefloquine with o,o-di-p-aroyltartaric acid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1997900276 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2239814 Country of ref document: CA Ref country code: CA Ref document number: 2239814 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09101174 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: JP Ref document number: 97524965 Format of ref document f/p: F |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1997900276 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 1997900276 Country of ref document: EP |