WO2006063666A1 - Process for the preparation of galanthamine hydrobromide - Google Patents
Process for the preparation of galanthamine hydrobromide Download PDFInfo
- Publication number
- WO2006063666A1 WO2006063666A1 PCT/EP2005/012521 EP2005012521W WO2006063666A1 WO 2006063666 A1 WO2006063666 A1 WO 2006063666A1 EP 2005012521 W EP2005012521 W EP 2005012521W WO 2006063666 A1 WO2006063666 A1 WO 2006063666A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- galanthamine
- hydrobromide
- solvent
- mixture
- butyl
- Prior art date
Links
- 0 C[C@](CN(C)C1)[C@]2(C=C3)c4c1ccc(*)c4OC[C@@]2CC3O Chemical compound C[C@](CN(C)C1)[C@]2(C=C3)c4c1ccc(*)c4OC[C@@]2CC3O 0.000 description 1
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the invention relates to the purification of tetracylic alkaloids, in particular to the purification of galanthamine.
- Galanthamine is used for the treatment of narrow-angle glaucoma, intoxications, nicotine and alcohol dependency and different pathologies of the nervous system, such as the Alzheimer's syndrome. For clinical purposes, it is administered in the form of hydrobromide, whose preparation was first described in the fifties (N.F. Proskumina et al., Zhur.Obshchei Khim. 22, 1899 (1952)).
- Galanthamine can be prepared by total synthesis, but due to the presence of three chiral centres, the metodologies are particularly complicated. More commonly, galanthamine is isolated from plants of the Amaryllidaceae family, for example plants of the genus Galanthus, Crinum, Leucojum and Narcissus, which also contain several galanthamine-related compounds. In these plants galanthamine can be present in traces or in the maximum amount of 0.3%. However, many of these plants are protected species and therefore the recovery of galanthamine on an industrial scale requires the use of biomasses obtained from cultivations.
- the presence of a relevant number of galanthamine structurally-related compounds makes it troublesome and often expensive to recover galanthamine in a purity suitable for the pharmaceutical use, in particular for the preparation of galanthamine hydrobromide.
- the preparation of mixtures of galanthamine and related compounds from plant materials is generally carried out using conventional methods for the extraction of alkaloids, which comprise wetting the plant material with alkali solutions suitable for hydrolysing the alkaloid salts contained in the biomass to free bases and extracting with solvents wherein the alkaloid bases are soluble.
- the alkali solutions are solutions of inorganic bases such as sodium, calcium, potassium hydroxide or carbonate or solutions of ammonium hydroxide.
- Water-miscible solvents such as methanol, ethanol and acetone, or water-immiscible solvents, such as aliphatic and aromatic hydrocarbons or esters, for example ethyl acetate, can be used as extraction solvents. Extractions can be carried out at temperatures ranging from 20 0 C to the boiling temperature of the solvent.
- concentrated aqueous solutions of sodium carbonate can be used for the hydrolysis of the alkaloid bases; for the extractions, toluene at temperatures ranging from 20 to 7O 0 C can be used.
- toluene has the advantage of satisfactorily exhausting the alkaloids while avoiding the extraction of polar constituents which would make the subsequent purification steps troublesome.
- the alkaloids contained in the toluene extracts can be separated from the non-alkaloid components by extraction with an acidic aqueous solution, for example a 2% sulfuric acid solution, followed by alkalinization with sodium or potassium hydroxide, or sodium or potassium carbonate and single re-extraction with toluene, whereby the alkaloid components are obtained as a mixture.
- hydrobromide from an alkaloids mixture containing galanthamine obtained from a plant belonging to the Amaryllidaceae family, hydrolysing the hydrobromide and extracting galanthamine with a suitable solvent.
- the invention relates to a process comprising the following steps: a) addition of hydrobromic acid to a mixture of alkaloids containing galanthamine obtained from a plant of the Amaryllidaceae family; b) recovery of the precipitate; c) dissolution of the precipitate in a basic aqueous solution; d) extraction with a solvent of general formula (II)
- the preparation of the alkaloids mixture can be carried out according to conventional methods, for example according to what described in the background of the invention.
- the precipitation of galanthamine hydrobromide from the alkaloids mixture is carried out preferably with aqueous hydrobromic acid in an alcoholic solvent, for example in methanol, ethanol, propanol or iso-propanol, preferably ethanol.
- the salification is carried out keeping the temperature from -20 to 20 0 C, preferably from 0 to 5°C during the addition of hydrobromic acid, using 5 to 7 volumes of solvent compared with the weight of the alkaloids mixture and a 5-10% excess of hydrobromic acid to the stoichiometric amount, assuming that the alkaloids have the same molecular weight as galanthamine (287 m.u.).
- the precipitation of galanthamine hydrobromide allows to increase the purity from 30-40% to 85-90%, with substantially quantitative recovery, since the mother liquors contain only traces of galanthamine hydrobromide.
- the alkali aqueous solutions used for dissolving the precipitate are preferably aqueous solutions at pH >8, containing for example sodium carbonate, potassium carbonate or ammonium hydroxide.
- galanthamine hydrobromide from galanthamine obtained according to the process of the present invention can be carried out with conventional methods generally used for the salification of alkaloids.
- galanthamine is dissolved in a suitable solvent, preferably acetone, or an alcohol, preferably 95% ethanol, and added at 0 to 5°C with a stoichiometric amount of aqueous hydrobromic acid.
- the hydrobromide can be prepared without isolating galanthamine. After extraction with r ⁇ -butyl acetate the combined organic extracts are concentrated to about 1/16 of the volume, then the solvent and hydrobromic acid are added as described above. After filtration and crystallization from water, galanthamine hydrobromide is obtained with purity higher than 99%, the content of each impurity being lower than 0.1%. The product is therefore suitable for pharmaceutical use.
- the following examples illustrate the invention in greater detail.
- Ground vegetable material 500 kg containing 0.3% galanthamine is added with 850 1 of 10% w/v aqueous sodium carbonate and extracted with 7 x 1000 1 toluene operating at 65-70 0 C.
- the extracts are combined and concentrated under vacuum to a volume of 300 1.
- the concentrated solution is treated with 50 1 of 2% sulfuric acid and the aqueous phase is collected.
- the aqueous phase is adjusted to pH 9 by addition of ammonium hydroxide and the resulting solution is extracted with 4 x 50 1 of toluene.
- the combined organic phases are concentrated to dryness under vacuum. 3.5 kg of total alkaloids are obtained containing 40% galanthamine (HPLC analysis).
- the resulting 88% galanthamine hydrobromide is suspended in 7.6 1 of water.
- the suspension is cooled to 0 0 C and diluted, keeping the temperature from 0 to 5 0 C, with 5.2 1 of 10% sodium carbonate.
- Five extractions with 5 1 of r ⁇ -butyl acetate are obtained, the organic phases are pooled and washed with 2.5 1 of salted water.
- the organic phases are concentrated under vacuum to a volume of 4 1 and allowed to crystallize at room temperature.
- the crystals are filtered and dried under vacuum at 70 0 C.
- 1.2 kg of galanthamine are obtained with chemical- physical and spectroscopical characteristics consistent with those reported in the literature (P. Carroll et al., Bull. Soc. CUm. Fr. (1990), 127, 769).
- Total alkaloids (3.5 kg) containing 40% galanthamine, obtained according to example 1, are dissolved in 24 1 of isopropanol.
- the mixture is left under stirring at room temperature for three hours, then filtered and the solid is washed with some isopropanol and dried under vacuum at 70 0 C. 2.28 kg of galanthamine hydrobromide having HPLC purity of 85% are obtained.
- the resulting solid is suspended in 8 1 of water, cooled to 0 0 C and diluted with 5.5 1 of 10% sodium carbonate.
- the mixture is left to stand for four hours and filtered, washing the precipitate with 1.5 1 of 95% ethanol.
- the wet solid is dissolved at 5O 0 C in 18 1 of 30% aqueous ethanol and the solution is concentrated under vacuum to a volume of 6 1 and left to crystallize overnight.
- the crystallized solid is filtered, washed with 1.9 1 of water and dried under vacuum at 5O 0 C. 1.9 kg of galanthamine hydrobromide having HPLC purity higher than 99% are obtained, each impurity being lower than 0.1%.
- the resulting 88% galanthamine hydrobromide is suspended in 7.6 1 of water.
- the suspension is cooled to 0 0 C and diluted with 5.2 1 of 10% sodium carbonate, keeping the temperature from 0 to 5 0 C and extracted with 5 x 5 1 of n -butyl- acetate.
- the organic phases are pooled, washed with 2.5 1 of salted water, concentrated under vacuum to a volume of 1.6 1 and then added with 8.4 1 of 95% ethanol.
- the solution is cooled to O 0 C and added under stirring with 0.56 1 of 48% hydrobromic acid, keeping the temperature at 0-5 0 C.
- the mixture is allowed to stand for four hours and filtered, washing the precipitate with 1.1 1 of 95% ethanol.
- the wet solid is dissolved at 5O 0 C in 13.2 1 of 30% aqueous ethanol, the solution is concentrated under vacuum to a volume of 4.4 1 and left to crystallize overnight.
- the resulting crystals are filtered, washed with 1.4 1 of water and dried under vacuum at 5O 0 C. 1.4 kg of galanthamine hydrobromide having HPLC purity higher than 99% is obtained, each impurity being lower than 0.1%.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2005315960A AU2005315960B2 (en) | 2004-12-17 | 2005-11-23 | Process for the preparation of galanthamine hydrobromide |
US11/793,097 US8013151B2 (en) | 2004-12-17 | 2005-11-23 | Process for the preparation of galanthamine hydrobromide |
KR1020077013259A KR101291446B1 (en) | 2004-12-17 | 2005-11-23 | Process for the preparation of galanthamine hydrobromide |
JP2007545863A JP5166878B2 (en) | 2004-12-17 | 2005-11-23 | Method for producing galantamine hydrobromide |
AT05808194T ATE440607T1 (en) | 2004-12-17 | 2005-11-23 | METHOD FOR PRODUCING GALANTHAMIN HYDROBROMIDE |
CA2592288A CA2592288C (en) | 2004-12-17 | 2005-11-23 | Process for the preparation of galanthamine hydrobromide |
EP05808194A EP1861105B1 (en) | 2004-12-17 | 2005-11-23 | Process for the preparation of galanthamine hydrobromide |
DK05808194T DK1861105T3 (en) | 2004-12-17 | 2005-11-23 | Process for the preparation of galanthamine hydrobromide |
PL05808194T PL1861105T3 (en) | 2004-12-17 | 2005-11-23 | Process for the preparation of galanthamine hydrobromide |
DE602005016308T DE602005016308D1 (en) | 2004-12-17 | 2005-11-23 | PROCESS FOR THE PREPARATION OF GALANTHAMINE HYDROBROMIDE |
CN2005800429800A CN101080231B (en) | 2004-12-17 | 2005-11-23 | Method for preparing galantamine hydrobromide |
IL183933A IL183933A0 (en) | 2004-12-17 | 2007-06-14 | Process for the preparation fo galanthamine hydrobromide |
NO20073053A NO338724B1 (en) | 2004-12-17 | 2007-06-15 | Process for the preparation of galantamine hydrobromide |
HK08102754.4A HK1113306A1 (en) | 2004-12-17 | 2008-03-10 | Process for the preparation of galanthamine hydrobromide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT002413A ITMI20042413A1 (en) | 2004-12-17 | 2004-12-17 | PROCESS FOR THE PREPARATION OF BROMIDRATE GALANTAMINE |
ITMI2004A002413 | 2004-12-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006063666A1 true WO2006063666A1 (en) | 2006-06-22 |
Family
ID=35784718
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/012521 WO2006063666A1 (en) | 2004-12-17 | 2005-11-23 | Process for the preparation of galanthamine hydrobromide |
Country Status (20)
Country | Link |
---|---|
US (1) | US8013151B2 (en) |
EP (1) | EP1861105B1 (en) |
JP (1) | JP5166878B2 (en) |
KR (1) | KR101291446B1 (en) |
CN (1) | CN101080231B (en) |
AT (1) | ATE440607T1 (en) |
AU (1) | AU2005315960B2 (en) |
CA (1) | CA2592288C (en) |
DE (1) | DE602005016308D1 (en) |
DK (1) | DK1861105T3 (en) |
ES (1) | ES2330127T3 (en) |
HK (1) | HK1113306A1 (en) |
IL (1) | IL183933A0 (en) |
IT (1) | ITMI20042413A1 (en) |
NO (1) | NO338724B1 (en) |
PL (1) | PL1861105T3 (en) |
PT (1) | PT1861105E (en) |
RU (1) | RU2387656C2 (en) |
SI (1) | SI1861105T1 (en) |
WO (1) | WO2006063666A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010025485A1 (en) * | 2008-09-04 | 2010-03-11 | Sanochemia Pharmazeutika Ag | Use of galanthaminium bromide for producing ophthalmic formulations for treating glaucoma |
EP2462941A1 (en) | 2010-09-20 | 2012-06-13 | R&D Ltd. | Method and instalation for extraction of plant raw material |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8247405B2 (en) * | 2008-12-10 | 2012-08-21 | Conopco, Inc. | Skin lightening compositions with acetylcholinesterase inhibitors |
CN101787028B (en) * | 2010-01-12 | 2012-01-04 | 恩施清江生物工程有限公司 | Method for extracting galanthamine from lycoris aurea |
BG66818B1 (en) * | 2013-03-07 | 2019-01-31 | Berbee Beheer B. V. | Composition of hippeastrum papilio extract for the production of medicines and nutritional supplements |
CN104177368B (en) * | 2014-05-27 | 2016-06-08 | 天津梅花医药有限公司 | A kind of galanthamine hydrobromide compound, preparation method and pharmaceutical composition thereof |
CN103980284B (en) * | 2014-05-30 | 2016-03-09 | 天津梅花医药有限公司 | A kind of galanthamine hydrobromide compound and preparation method thereof |
CN107462656A (en) * | 2017-07-04 | 2017-12-12 | 上海市农业科学院 | A kind of method of galanthamine content in quick detection amrallid |
BG67337B1 (en) | 2018-05-23 | 2021-06-15 | Софарма Ад | Method for preparation of purified galantamine hydrobromide |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB938767A (en) * | 1961-12-13 | 1963-10-09 | Vni Chimico Pharmatsevtichesky | The preparation of galanthamine from the amaryllidaceae and its separation from associated alkaloids |
GB942200A (en) * | 1959-03-02 | 1963-11-20 | Chimiko Pharmazevtitschen Zd | A method of obtaining galanthamine hydrobromide |
US20020028802A1 (en) * | 1995-03-17 | 2002-03-07 | Thomas Hille | Process for the isolation of galanthamine |
US20030092700A1 (en) * | 1996-04-19 | 2003-05-15 | Laszlo Czollner | Benzazepine derivatives, medicaments containing the same and their use to prepare medicaments |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1261434C (en) * | 2003-07-28 | 2006-06-28 | 浙江一新制药股份有限公司 | Method for separating high-purity galanthamine from short-tube lycoris crude extract |
DE102006033591B4 (en) | 2006-07-18 | 2008-10-16 | Thüringisches Institut für Textil- und Kunststoff-Forschung e.V. | Process for stabilizing the spinning solution in the production of cellulosic composite moldings |
-
2004
- 2004-12-17 IT IT002413A patent/ITMI20042413A1/en unknown
-
2005
- 2005-11-23 PL PL05808194T patent/PL1861105T3/en unknown
- 2005-11-23 RU RU2007122353/04A patent/RU2387656C2/en active
- 2005-11-23 US US11/793,097 patent/US8013151B2/en not_active Expired - Fee Related
- 2005-11-23 KR KR1020077013259A patent/KR101291446B1/en active IP Right Grant
- 2005-11-23 PT PT05808194T patent/PT1861105E/en unknown
- 2005-11-23 SI SI200530788T patent/SI1861105T1/en unknown
- 2005-11-23 JP JP2007545863A patent/JP5166878B2/en active Active
- 2005-11-23 DK DK05808194T patent/DK1861105T3/en active
- 2005-11-23 ES ES05808194T patent/ES2330127T3/en active Active
- 2005-11-23 WO PCT/EP2005/012521 patent/WO2006063666A1/en active Application Filing
- 2005-11-23 AU AU2005315960A patent/AU2005315960B2/en active Active
- 2005-11-23 EP EP05808194A patent/EP1861105B1/en active Active
- 2005-11-23 DE DE602005016308T patent/DE602005016308D1/en active Active
- 2005-11-23 CN CN2005800429800A patent/CN101080231B/en active Active
- 2005-11-23 AT AT05808194T patent/ATE440607T1/en active
- 2005-11-23 CA CA2592288A patent/CA2592288C/en active Active
-
2007
- 2007-06-14 IL IL183933A patent/IL183933A0/en active IP Right Grant
- 2007-06-15 NO NO20073053A patent/NO338724B1/en unknown
-
2008
- 2008-03-10 HK HK08102754.4A patent/HK1113306A1/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB942200A (en) * | 1959-03-02 | 1963-11-20 | Chimiko Pharmazevtitschen Zd | A method of obtaining galanthamine hydrobromide |
GB938767A (en) * | 1961-12-13 | 1963-10-09 | Vni Chimico Pharmatsevtichesky | The preparation of galanthamine from the amaryllidaceae and its separation from associated alkaloids |
US20020028802A1 (en) * | 1995-03-17 | 2002-03-07 | Thomas Hille | Process for the isolation of galanthamine |
US20030092700A1 (en) * | 1996-04-19 | 2003-05-15 | Laszlo Czollner | Benzazepine derivatives, medicaments containing the same and their use to prepare medicaments |
Non-Patent Citations (2)
Title |
---|
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ZHENG, YAJIN ET AL: "Method for separation of high-purity galanthamine from Lycoris radiata crude extract", XP002336902, retrieved from STN Database accession no. 2005:401473 * |
HAN, S. Y. ET AL: "Chemical and pharmacological characterization of galanthamine, an acetylcholinesterase inhibitor, and its derivatives. A potential application in Alzheimer's disease?", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY , 27(7), 673-87 CODEN: EJMCA5; ISSN: 0223-5234, vol. 27, 1992, pages 673 - 687, XP002368420 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010025485A1 (en) * | 2008-09-04 | 2010-03-11 | Sanochemia Pharmazeutika Ag | Use of galanthaminium bromide for producing ophthalmic formulations for treating glaucoma |
EP2462941A1 (en) | 2010-09-20 | 2012-06-13 | R&D Ltd. | Method and instalation for extraction of plant raw material |
Also Published As
Publication number | Publication date |
---|---|
DK1861105T3 (en) | 2009-11-16 |
HK1113306A1 (en) | 2008-10-03 |
IL183933A0 (en) | 2007-10-31 |
EP1861105A1 (en) | 2007-12-05 |
RU2387656C2 (en) | 2010-04-27 |
PL1861105T3 (en) | 2010-02-26 |
PT1861105E (en) | 2009-10-22 |
JP5166878B2 (en) | 2013-03-21 |
SI1861105T1 (en) | 2009-12-31 |
US8013151B2 (en) | 2011-09-06 |
DE602005016308D1 (en) | 2009-10-08 |
KR101291446B1 (en) | 2013-07-30 |
EP1861105B1 (en) | 2009-08-26 |
AU2005315960A1 (en) | 2006-06-22 |
US20090043092A1 (en) | 2009-02-12 |
NO338724B1 (en) | 2016-10-10 |
CA2592288C (en) | 2014-05-06 |
CN101080231A (en) | 2007-11-28 |
JP2008524125A (en) | 2008-07-10 |
CA2592288A1 (en) | 2006-06-22 |
CN101080231B (en) | 2010-11-17 |
ES2330127T3 (en) | 2009-12-04 |
KR20070095897A (en) | 2007-10-01 |
NO20073053L (en) | 2007-06-15 |
ATE440607T1 (en) | 2009-09-15 |
AU2005315960B2 (en) | 2012-01-12 |
ITMI20042413A1 (en) | 2005-03-17 |
RU2007122353A (en) | 2008-12-20 |
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