EP1363893A1 - Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates - Google Patents
Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathratesInfo
- Publication number
- EP1363893A1 EP1363893A1 EP01985145A EP01985145A EP1363893A1 EP 1363893 A1 EP1363893 A1 EP 1363893A1 EP 01985145 A EP01985145 A EP 01985145A EP 01985145 A EP01985145 A EP 01985145A EP 1363893 A1 EP1363893 A1 EP 1363893A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- warfarin
- acid
- pure
- process according
- aqueous phase
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
Definitions
- the invention relates to a synthesis of pure warfarin acid and derivatives thereof.
- the invention relates to a commercially feasible, large scale process for purification of warfarin acid and the preparation of warfarin sodium, warfarin sodium 2- propanol clathrate, warfarin potassium and warfarin lithium 2-propanol clathrate therefrom, in high, pharmacopoeial grades of purity.
- Warfarin sodium, warfarin sodium 2-propanol clathrate, warfarin potassium and warfarin lithium 2-propanol clathrate are highly potent anticoagulants, generally administered orally and used extensively as active pharmaceutical ingredients (APIs). These compounds are also widely used as rodenticides in different dosages and formulations.
- APIs preferably uses systems and processes capable of providing high quality, pure intermediates and products complying with pharmacopoeial requirements. Numerous procedures for the synthesis of warfarin acid, its salts and clathrates exist, but there is still a need by the pharmaceutical industry for methods of preparing these compounds in high quality as both intermediates and products and particularly for the preparation of high purity warfarin acid.
- Warfarin acid and its alkali metal salts are coumarinic type derivatives having powerful anticoagulant properties. They are useful, established vitamin K related anticoagulant pharmaceuticals for the treatment of humans and animals.
- Warfarin sodium and its 2-propanol clathrate is marketed under various commercial names like Coumadin; Marevan; Prothromadin; Tintorane; Warfarin sodium; Warfilone; Waran.
- Warfarin potassium salt is available under the name Athrombin K. These substances are also the active component in common rodenticide agents.
- Warfarin acid known chemically as racemic 4-hydroxy-3-(3-oxo-phenylbutyl)-2H-l- benzopyran-2-one or 3-(cc-acetonylbenzyl)-4-hydroxycoumarin, is typically prepared by the Michael addition reaction of commercially available or in situ prepared 4-hydroxycoumarin to 4-phenyl-3-buten-2-one (benzalacetone).
- a wide range of conditions for example, variations in solvents, variation of acidic and basic catalysts, varying temperatures, etc., have been used in synthetic procedures described in the literature.
- warafarin acid is a well known chemical entity, a simple, commercially feasible and direct preparation of warfarin acid in the pure state has not been significantly addressed.
- Earlier purification methods described by Ikawa et al. U.S. Patent No. 2,427,578, see also, J. Am. Chem Soc. 1944, 66, 902) or by Siedman et al. (J. Am. Chem. Soc. 1950, 72, 5193), as well as many others, recrystallize the crude acid from acetone-water mixtures.
- U.S. Patent No. 2,777,859 to Link et al. describes a process of preparing an aqueous solution of warfarin alkali metal derivatives by adding an aqueous alkali metal hydroxide to an excess of water wet warfarin acid, warming and removing the excess of warfarin acid by filtration.
- U.S. Patent No. 3,077,481 to Schroeder et al. describes a process of purifying colored warfarin sodium by dissolving the amorphous salt in warm 2-propanol, cooling the resulting solution and recovering the crystalline warfarin sodium 2-propanol clathrate product.
- U.S. Pat. No. 3,192,232 to Schroeder and Link describes a process for preparing warfarin sodium and warfarin potassium salts by reacting a slurry or warfarin acid in acetone-water with less than an equivalent of sodium hydroxide or potassium hydroxide in water at room temperature.
- the solution of the crude salt is purified by stirring with active charcoal and isolating of the salt by evaporation to dryness, spray drying, or drum drying.
- U.S. Pat. No. 3,246,013 to Weiner et al. describes a process for preparing crystalline warfarin sodium 2-propanol clathrate through neutralization of a warfarin acid/2 -propanol slurry to a pH of about 9-10 using sodium hydroxide or, as an alternative to avoid the color usually present, using selected sodium alkoxides at about 50-80°C.
- Ohnishi et al. have described a method for preparing warfarin alkali metal salts by dissolving warfarin acid in an aqueous solution containing an equivalent amount of the respective alkali metal hydroxide (lithium, sodium, potassium, rubidium and cesium). Biosci. Biotech. Biochem.
- the present invention is a process for preparing pure warfarin acid from crude warfarin acid by suspending the crude acid in a water immiscible solvent, preferably toluene, extracting the acid into an aqueous solution of dilute base, separating the resulting aqueous phase and diluting it with a lower alkyl alcohol, for example, methanol, ethanol or, preferably, 2-propanol.
- a lower alkyl alcohol for example, methanol, ethanol or, preferably, 2-propanol.
- the aqueous solution is filtered before being diluted with the lower alkyl alcohol.
- the lower alkyl alcohol is preferably added to a concentration of about 50%.
- the solution is acidified to a pH of about 2 to 5 using a suitable acid, such as hydrochloric, sulfuric or phosphoric acid and the like.
- the resulting suspension is stirred at a temperature of from about 20°C to about 60°C, preferably about 40°C to about 50°C, cooling the suspension below room temperature, preferably to about 5°C to about 10°C, filtering the pure warfarin acid and drying.
- the crude warfarin acid for use in the purification is preferably prepared by hydrolyzing cyclocoumarol using about 2% to about 10% of an acidic catalyst which is preferably 4-toluene sulfonic acid, to a solution of cyclocoumarol in a mixture of a polar water miscible solvent and water at a temperature of from about room temperature to about the boiling point of the solvent. Less than 2% acid catalyst is usually ineffeicient while more than 10-15% may impurify the product and be uneconmical.
- the reaction is preferably conducted in butanone or acetone containing about 35% to about 65% of water, preferably about 40%) to about 50% water, and is most preferably conducting at reflux temperatures.
- the invention is a process for the preparation of warfarin sodium 2- propanol clathrate comprising reacting pure warfarin acid with sodium carbonate in 2- propanol.
- the 2-propanol preferably contains between about 0.5% and about 5% of water by volume, and more preferably from about 1% to about 3% of water by volume.
- the molar ratio of sodium carbonate to warfarin acid is preferably between about 0.9 and about 2, and more preferably between about 1.0 and about 1.3, to ensure yield and quality of the final product.
- the preparation of warfarin sodium 2-propanol clathrate is preferably conducted at a temperature of from about room temperature to about the boiling point of the solvent. More preferably, the reaction is carried out at reflux temperatures.
- the reaction is typically complete in a time of from about 1 to about 5 hours, and more preferably is completed in from about 2 hours to about 3 hours.
- the solids remaining after the reaction is complete which consist primarily of unreacted sodium carbonate, are removed by filtration.
- Water is removed by azeotropic distillation by either a binary or ternary system.
- the preferred binary azeotropic system is 2-propanol and water.
- Preferred ternary azeotropic distillation systems are 2-propanol-cyclohexane-water, 2-propanol- hexane-water or 2-propanol-heptane-water, preferably 2-propanol-hexane-water.
- the pure warfarin 2- propanol clathrate precipitates from the reaction mixture as a crystalline pure solid, which is collected by filtration.
- the invention is a method for preparing warfarin potassium by reacting pure warfarin acid with potassium carbonate in place of sodium carbonate.
- the reaction parameters for potassium salt formation are similar to those for warfarin sodium 2- propanol clathrate formation.
- the invention is a process for preparing warfarin lithium 2-propanol clathrate comprising reacting pure warfarin acid with a solution of lithium 2-propoxide in anhydrous 2-propanol. Preferred parameters are otherwise identical to those for the preparation of warfarin sodium 2-propanol clathrate, although the 2-propanol must be anhydrous.
- the invention is a process for preparing warfarin sodium comprising reacting pure warfarin acid with sodium carbonate in a water miscible polar solvent other than 2-propanol.
- a water miscible polar solvent is acetone, ethanol, acetonitrile or butanone, and is most preferably butanone.
- the pure warfarin sodium is collected by solvent removal or addition of a low polarity solvent, for example, hexane, heptane or cycloheptane.
- the present invention succeeds where previous efforts have failed by providing a convenient synthesis of pure warfarin acid.
- the invention is particularly advantageous in providing for the preparation of warfarin derivatives from the pure warfarin acid allowing use of the derivatives without additional purification.
- This invention solves a previously unrecognized problem and provides a method for the preparation of pure warfarin acid enabling the production of higher quality salts and clathrates without the need for additional purification.
- This invention presents an improved synthesis of warfarin acid and its derivatives in a crowded and mature art by providing a method for preparing warfarin acid in a pure form not readily obtainable by use of existing methods without additional purification.
- This invention provides advantages that were not previously appreciated such as the more efficient synthesis of high purity warfarin alkali metal salts and clathrates.
- the invention provides an advantage in producing warfarin acid in the form of large crystals that are more easily filtered, facilitate ease of drying and shorten drying times.
- This invention satisfies a long felt need for a convenient, industrially useful synthesis of pure warfarin acid and sodium, potassium and lithium salts and clathrates prepared therefrom.
- Pure refers to a substance that meets at least one of the standards of the U.S. Pharmacopoeia (USP), British Pharmacopoeia, European Pharmacopoeia (Ph.Eur).
- EPCRS refers to the European Pharmacopoeial Commission of Reference Substances and
- USPRS refers to U.S. Pharmacopoeial Reference Standards.
- the EPCRS and USPRS provide reference standards for warfarin sodium and warfarin acid.
- Non-limiting examples of suitable nonpolar solvents include aliphatic and aromatic hydrocarbons, for example, hexane, heptane, cyclohexane, toluene and benzene. Toluene is particularly preferred.
- Non-limiting examples of water miscible solvents include lower molecular weight alcohols (methanol, ethanol, isopropanol, etc.), acetonitrile, ketones (acetone, methylethyl ketone, etc.), and ethers (tetrahydorfuran, 1,4-dioxane, etc.).
- the procedure for preparing pure warfarin acid according to the invention comprises the following: 1) Preparation of a cyclocoumarol derivative by the Michael addition reaction of
- a preferred acid catalyst is 4- toluene sulfonic acid.
- the acid concentration is preferably about 2% to about 10% and more preferably about 3%> to about 6%>. Less than 2% acid is generally inefficient, and greater than 10%o- 15% leads to increased impurities and may be uneconomical.
- the butanone or acetone contains about 30% to about 60%, preferably about 40% to about 50%, water.
- the reaction may be conducted at a temperature from about room temperature to the reflux temperature of the solvent. Preferably, the reaction is conducted at about reflux temperature.
- Novel, improved preparation of pure warfarin acid by suspension of the crude acid in a low polarity, water immiscible solvent, dissolution and extraction of the warfarin acid into an aqueous alkaline phase as the warfarin salt, separation, and optionally filtration, of the aqueous alkaline solution followed by dilution with a lower alkyl alcohol, preferably above room temperature.
- the low polarity water immiscible solvent is preferably non- chlorinated and is most preferably toluene.
- the alkaline solution is preferably an aqueous solution of a dilute base, for example, sodium hydroxide.
- a preferred lower alkyl alcohol solvent is 2-propanol, although other lower alkyl alcohols, for example, methanol or ethanol, may be used.
- the pure, crystalline warfarin acid is preferably isolated by filtration of the precipitated substance.
- the acid used to precipitate the warfarin acid may be an aqueous acid selected from hydrochloric acid, sulfuric acid, phosphoric acid and the like. Sulfuric acid is preferred. It has surprisingly been found that the conditions for dilution of the aqueous salt solution and precipitation of the purified warfarin acid are instrumental in obtaining high purity warfarin acid without the need for additional purification procedures which tend to be costly and time consuming.
- dilution of the aqueous solution with a lower alkyl alcohol is critical. Accordingly, prior to the addition of the acid, the solution is stirred, preferably at a temperature of from about 20°C to about 60°C, more preferably from about 40°C to about 50°C.
- the lower alkyl alcohol preferably 2-propanol, is added at a temperature at or above room temperature.
- the resultant solution preferably contains from about 30%o to about 60% isopropanol, more preferably between about 40%> and about 50% isopropanol, to prevent loss of the pure acid.
- the acid is then added to a pH of about 2-5 at or above room temperature. Precipitation at or above temperature is critical and results in the generation of warfarin acid with higher purity and larger crystals.
- Warfarin derivatives particularly include warfarin sodium, warfarin sodium 2-propanol clathrate, warfarin potassium and warfarin lithium 2-propanol clathrate, from the pure warfarin acid previously described. It will be appreciated that warfarin salts of other ions may be formed and clathrates incorporating solvents other than 2- propanol may be prepared according to the invention.
- Warfarin sodium is prepared by refluxing the pure warfarin acid with an excess of sodium carbonate in a polar solvent such as acetone or butanone, which may be either anhydrous or contain from about 1%> to about 10% water.
- a polar solvent such as acetone or butanone
- the unreacted sodium carbonate is preferably removed by filtration.
- the product is isolated by evaporating the solvent to dryness or by precipitating the salt by addition of a nonpolar solvent such as hexane, cyclohexane, heptane and the like, and filtering and drying the precipitate.
- Warfarin sodium 2-propanol clathrate is prepared by refluxing the pure warfarin acid with an equivalent amount or an excess of sodium carbonate in 2-propanol.
- the 2-propanol may be anhydrous or may contain about 0.5% to about 10% water, preferably about 1% to about 3% water.
- the molar ratio of sodium carbonate to warfarin acid is between about 0.9 and about 2, and is preferably between about 1.0 and about 1.3.
- the reaction may be conducted at a temperature ranging from room temperature to the boiling point of the solvent for a time of from about 1 hour to about 5 hours. Preferably, the reaction is conducted at reflux temperature and the preferred reaction time is from about 2 hours to about 3 hours.
- the unreacted carbonate is removed by filtration while the excess water is removed by binary (2-propanol/water) or ternary (heptane, cyclohexane or, preferably, hexane with 2-propanol and water) azeotropic distillation.
- the precipitated pure warfarin sodium 2-propanol clathrate is further isolated as a pure crystalline solid by filtration and drying.
- Warfarin potassium salt is prepared by refluxing the pure warfarin acid with potassium carbonate in 2-propanol. Reaction conditions are similar to those for warfarin sodium 2-propanol clathrate. However, when preparing the potassium salt, a clathrate is not formed. The salt is precipitated directly from the reaction medium upon cooling, and is isolated by filtration and drying.
- Warfarin lithium-2-propanol clathrate is prepared by reacting pure warfarin acid with a small excess of lithium-2-propoxide in 2-propanol (prepared in situ from lithium strips or rods). The product is isolated by cooling, precipitation, filtration and drying.
- Warfarin derivatives prepared according to the present invention may be made into pharmaceutical dosage forms with appropriate pharmaceutically acceptable carriers or diluents.
- pharmaceutical dosage forms may be formulated into preparations including, but not limited to, solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols, in the usual ways for their respective route of administration. Methods known in the art can be utilized to prevent release or absorption of the warfarin derivative until it reaches the target organ or to ensure time-release of the composition.
- a pharmaceutically- acceptable form should be employed which does not ineffectuate the compositions of the present invention.
- the compositions may be used alone or in appropriate association, as well as in combination with, other pharmaceutically-active compounds.
- reaction solution was then concentrated to about half of its initial volume by azeotropic distillation of butanone/water, wherein the crude warfarin acid began to precipitate.
- the suspension was gradually cooled and the crude, wet warfarin acid was obtained by filtration and washed with cold butanone and water.
- the aqueous filtrate was returned to the vessel and gently warmed to 40-50°C.
- 2- Propanol (4 L) was added and the solution stirred for about l ⁇ hour while maintaining the temperature.
- Sulfuric acid (20% solution in water) was then added slowly in portions to the warm, stirred solution, until a constant acidic pH was achieved.
- a total of about 1.5-2 L of sulfuric acid solution was needed, while the pure warfarin acid precipitated as a bright-white crystalline solid.
- the thick suspension was stirred for an additional V% hour, then cooled to below 10°C for another hour.
- the cold suspension was filtered, thoroughly washed with demineralized water and finally with cold 2-propanol.
- the pure warfarin was obtained as a white crystalline powder upon drying in a vacuum oven for 8-10 hours.
- a three-neck, round bottom flask provided with mechanical stirrer, thermometer and reflux/distillation condenser was successively charged with pure warfarin acid, (308 g, 1 mole), sodium carbonate (Merck, art. 106398) (106 g, 1 mole) and butanone (MEK, CP, 3100 ml).
- Warfarin sodium was isolated as a white powder by suction filtration, washing and drying to constant weight in a vacuum oven at 35-40°C and 1 mm Hg. Yield: 298 g (90%) Clarity of the alkaline solution: clear and colorless (complies with Ph.Eur and USP). Color (phenolic ketones) by UV absorption: ⁇ 0.1 AU (complies with Ph.Eur and USP).
- EXAMPLE 4 Preparation of Warfarin Potassium A mixture of pure warfarin acid (31 g, 0.1 mole) and potassium carbonate (99%) (10.4 g, 0.75 mole) in 2-propanol (CP grade, 160 ml) was stirred at 20-25°C for 2 hours, in a suitable glass flask under a nitrogen atmosphere.
- the unclear solution was filtered using suction and the filtrate was cooled to below 5°C for 4-6 hours.
- a solution of lithium 2-propoxide in 2-propanol was prepared by reacting lithium rods, (0.42 g, 0.06 at.-g) with excess 2-propanol (CP anhydrous, 10 ml). This solution was added dropwise to a stirred suspension of pure warfarin acid (15.4 g, 0.05 mole) in 2- propanol (60 ml), under a nitrogen atmosphere.
- ⁇ -NMR test pattern practically identical to an authentic warfarin sodium clathrate sample, but the integral of the protons relative to the respective methyl groups suggested an equimolar content of IP A in clathrate.
- IPA content by GC: 15.1%
- Thermal analysis by DSC: typical endotherm, similar to those observed with an authentic warfarin sodium 2-propanol clathrate sample appeared around 160°C, suggesting the existence of a clathrate.
- a suitable glass vessel provided with a distillation column and fraction separator was charged with pure warfarin acid (1000 g, 3.25 mole), sodium carbonate (CP, 260 g, 2.45 mole) and 2-propanol (technical grade, 5000 ml).
- the mixture was heated to reflux for two hours and then cooled to room temperature.
- Demineralized water 500 ml was added and the reaction mixture stirred for l A hour at room temperature, cooled to below 10°C and rapidly filtered by suction. The clear, uncolored solution was returned to the vessel, hexane (1500 ml) was added and the mixture heated to boiling with stirring.
- a ternary azeotropic mixture began to distill and water was gradually removed from the mixture. Hexane was then removed by a binary azeotropic distillation and warfarin sodium 2-propanol clathrate precipitated. The solution was filtered with suction, the solids washed with cold 2-propanol, and dried for about 8 hours (vacuum oven, 45-50°C, 10 mm Hg) to yield the pure product as a white crystalline solid.
- the product complied with the pharmacopeial requirements.
- a suitable glass vessel provided with a distillation column was successively charged with 2-propanol (technical grade, 7.7 L), pure warfarin acid, (1.54 kg, 5 mole), sodium carbonate (0.34 kg , 3.2 mole) and demineralized water (0.22 L). The mixture was reflux ed for two hours with stirring.
- EXAMPLE 8 Preparation of Warfarin Sodium 2-Propanol Clathrate A suitable glass flask provided with a distillation column was charged with 2- propanol (8 L, technical grade or recovered) containing about ⁇ %-2% water (v/v), sodium carbonate (CP, 175 g, 1.65 mole) and pure warfarin acid (1 kg, 3.25 mole).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27173701P | 2001-02-28 | 2001-02-28 | |
US271737P | 2001-02-28 | ||
PCT/US2001/050438 WO2002070503A1 (en) | 2001-02-28 | 2001-12-28 | Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1363893A1 true EP1363893A1 (en) | 2003-11-26 |
Family
ID=23036855
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01985145A Withdrawn EP1363893A1 (en) | 2001-02-28 | 2001-12-28 | Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP1363893A1 (en) |
CN (1) | CN1505620A (en) |
BR (1) | BR0116919A (en) |
CA (1) | CA2439488A1 (en) |
IL (1) | IL157555A0 (en) |
MX (1) | MXPA03007769A (en) |
RU (1) | RU2003129000A (en) |
WO (1) | WO2002070503A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IN2012CN10302A (en) * | 2010-05-20 | 2015-06-12 | Apotex Pharmachem Inc | |
WO2011145007A1 (en) | 2010-05-20 | 2011-11-24 | Alembic Pharmaceuticals Limited | A process for the preparation of amorphous warfarin sodium |
CN109369450B (en) * | 2018-10-31 | 2021-07-27 | 江苏省农用激素工程技术研究中心有限公司 | Refining method of tralkoxydim |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2777859A (en) * | 1953-02-05 | 1957-01-15 | Wisconsin Alumni Res Found | Warfarin-alkali metal derivatives and processes of preparing the same |
US2765321A (en) * | 1955-05-27 | 1956-10-02 | Wisconsin Alumni Res Found | Process of making crystalline warfarin sodium |
FR1397213A (en) * | 1963-05-14 | 1965-04-30 | Frosst & Co Charles E | New method of preparing warfarin sodium |
US4113744A (en) * | 1974-08-13 | 1978-09-12 | Nasri W. Badran | Microcrystalline 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin (warfarin) and methods of making |
US4826689A (en) * | 1984-05-21 | 1989-05-02 | University Of Rochester | Method for making uniformly sized particles from water-insoluble organic compounds |
US5696274A (en) * | 1995-12-28 | 1997-12-09 | Hoechst Celanese Corporation | Syntheses based on 2-hydroxyacetophenone |
-
2001
- 2001-12-28 RU RU2003129000/04A patent/RU2003129000A/en unknown
- 2001-12-28 BR BR0116919-0A patent/BR0116919A/en not_active IP Right Cessation
- 2001-12-28 WO PCT/US2001/050438 patent/WO2002070503A1/en not_active Application Discontinuation
- 2001-12-28 MX MXPA03007769A patent/MXPA03007769A/en unknown
- 2001-12-28 IL IL15755501A patent/IL157555A0/en unknown
- 2001-12-28 CA CA002439488A patent/CA2439488A1/en not_active Abandoned
- 2001-12-28 EP EP01985145A patent/EP1363893A1/en not_active Withdrawn
- 2001-12-28 CN CNA018231594A patent/CN1505620A/en active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO02070503A1 * |
Also Published As
Publication number | Publication date |
---|---|
MXPA03007769A (en) | 2005-07-01 |
CA2439488A1 (en) | 2002-09-12 |
RU2003129000A (en) | 2005-05-10 |
IL157555A0 (en) | 2004-03-28 |
WO2002070503A1 (en) | 2002-09-12 |
BR0116919A (en) | 2004-10-13 |
CN1505620A (en) | 2004-06-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR20180127428A (en) | Improved method for the manufacture of sugarmaxes | |
US6512005B2 (en) | Process for synthesis of pure warfarin acid, warfarin alkali metal salts and corresponding clathrates | |
JP2004527577A (en) | Synthesis of 4-phenylbutyric acid | |
JP3913329B2 (en) | Optical resolution method of (±) -chromancarboxylic acid | |
CN108947946B (en) | Brain injury resistant deuterated compound and medical application thereof | |
JP2000510864A (en) | Method for producing 4,6-dihydroxypyrimidine | |
WO2002070503A1 (en) | Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates | |
CN101336228B (en) | Process for the manufacture of iohexol | |
AU2002234122A1 (en) | Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates | |
EP1768980B1 (en) | Improved process for the manufacture of mirtazapine | |
CA1305150C (en) | Derivatives of spiro (4,5) decane, process for their preparation and pharmaceutical compositions containing the same | |
US6673944B2 (en) | Preparation of warfarin sodium from warfarin acid | |
CN1092178C (en) | Methods for preparation of benzophenone derivatives | |
JP6670744B2 (en) | Polymorphic forms of sodium hyodeoxycholate (NaHDC) and methods for their preparation | |
SU1491336A3 (en) | Method of producing crystalline monohydrate of 1-(3ъ,4ъ-diethoxybenzyl)-6,7-diethoxy-3,4-dihydroisoquinolinitheophylline-7-acetate | |
EP0390496B1 (en) | Intermediates useful for the synthesis of delphinidin chloride | |
EP0862570B1 (en) | Process for the preparation of 9- (2-hydroxyethoxy)methyl]guanine | |
US4698432A (en) | Process for the resolution of (±) 2-[2'-(p-fluorophenyl)-5'-benzoxazolyl]-propionic acid | |
JP3264750B2 (en) | Xanthone derivatives and their production and use | |
JPS59219275A (en) | Pharmaceutical composition containing compound having flavanone structure, manufacture and novel compound | |
CN118221681A (en) | Preparation method of allopurinol | |
CN116410138A (en) | Synthesis method of topiramate intermediate | |
EA005618B1 (en) | Method for purifying 20(s)-camptothecin | |
AU2002231294A1 (en) | Preparation of warfarin sodium warfarin acid | |
JPH11130768A (en) | Production of optically active 5-hydroxy-2-decenoic acid and optically active massoia lactone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20030922 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK RO SI |
|
17Q | First examination report despatched |
Effective date: 20031217 |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: BERCOVICI, SORIN Inventor name: ULANENKO, KONSTANTIN Inventor name: SASSON, SABAR Inventor name: JAKOEL, MIRELA Inventor name: FUXMAN, OSVALDO Inventor name: EVRON, YUVAL |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20070703 |