Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-28
2003-01-28
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S286000
Reexamination Certificate
active
06512005
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a synthesis of pure warfarin acid and derivatives thereof. In particular, the invention relates to a commercially feasible, large scale process for purification of warfarin acid in high, pharmacopoeial grades of purity.
2. Background
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.
The commercial production of 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. For example:
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-1 -benzopyran-2-one or 3-(∝-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. Although 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. Pat. 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. Pat. No. 4,113,744 to Badran et al., describes a method for preparation of pure, microcrystalline warfarin acid by dissolution of the commercial impure acid into a special amine buffered-water system, filtration and reprecipitation of the pure, microcrystalline acid by pH readjustment of the filtrate.
Bush and Trage described a procedure for the preparation of pure warfarin acid, comprising ether extraction of the crude acid, back-extraction with dilute sodium hydroxide, filtration of the alkaline solution, and reprecipitation with 5 N HCl solution. (
J. of Pharm. Sci.
1983, 72 (7), 830-831.) The pure acid is obtained by further recrystallization from acetone-water.
More recent references (for example, Ivanov et al.,
Arch. Pharm
(Weinheim) 1990, 323, 521-522; Uwaydah et al. WO 97/24347) describe extraction/recrystallization procedures using glacial acetic acid or ethyl acetate.
Warfarin alkali salts, chemically known as 4-hydroxy-3-(3-oxo-phenylbutyl)2H-1-benzopyran-2-one alkali salts or 3-(∝-acetonylbenzyl)-4-hydroxycoumnarin sodium, potassium or lithium salts, are usually prepared by reacting warfarin acid with a molar equivalent or less of the respective alkali metal bases in aqueous medium, or with the metal alkoxides in lower alkyl alcohols.
U.S. Pat. No. 2,765,321 to Schroeder et al. describes a process of preparing crystalline warfarin sodium by reacting an aqueous sodium hydroxide solution with an excess of warfarin acid, followed by removal of the acid excess by addition of ethanol and filtration. The final warfarin sodium salt is obtained through a salting out procedure using lithium chloride addition into the ethanol-water solution of the warfarin sodium salt, cooling and recovering the precipitated warfarin sodium by filtration.
U.S. Pat. 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. Pat. 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.
In French Patent 1.397.213, Yates and Thomson describe an improved preparation of warfarin sodium by reacting a suspension of warfarin acid in an anhydrous lower alkyl alcohol with a solution containing a molar equivalent of sodium hydroxide dissolved in the same solvent. The crude product is isolated as a syrup upon solvent evaporation and must be further purified and subjected to thorough drying or lyophilization. The product is normally not of pharmaceutical quality. The warfarin sodium may be purified by dissolving in 2-propanol from which the crystalline clathrate is isolated by filtration. The 2-propanol trapped may be removed by evaporation to dryness in vacuo of the crystalline salt solutions in methanol, ethanol or acetone. Further purification is required in order to obtain a pharmaceutical grade substance.
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.
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
. 1995, 59(6), 995-1006 (cf. CA 123: 105246 (1996)) The respective salts are isolated by lyophilization.
In a recent patent publication, WO 97/24347 (published Jul. 10, 1997), Uwaydah et al. describe a comprehensive process for warfarin alkali salts (sodium and potassium) and clathrate preparation starting from 2-hydroxyacetophenone and a carbonate ester. The hydroxycoumarin thus obtained is further reacted with benzalacetone in the presence of a phase transfer catalyst to give warfarin acid in a procedure similar to those of Ivanov (see reference above). The latter intermediate is further reacted with sodium or potassium hydroxide or carbonate, or preferably with sodium or potassium methoxide or ethoxide in anhydrous ethanol or 2-propanol to ultimately yield the desired product.
As can be seen from the description of existing preparations, there is a great deal of interest in this field, and a number of synthetic routes for the preparation of warfarin acid and its salts exist. However, the need remains for an economical, industrially feasible procedure to produce a high quality, pharmacopeial grade of warfarin acid and related salts.
SUMMARY OF THE INVENTION
Further objectives and advantages will become apparent from a consideration of the description, and nonlimiting examples described therein.
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
Bercovici Sorin
Evron Yuval
Fuxman Osvaldo
Jakoel Mirela
Sasson Sbar
Gollin Michael A.
Haddaway Keith G.
Owens Amelia
Taro Pharmaceutical Industries Ltd.
Venable
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