EP1963345A2 - Verfahren zur herstellung reiner zoledronsäure - Google Patents

Verfahren zur herstellung reiner zoledronsäure

Info

Publication number
EP1963345A2
EP1963345A2 EP06831707A EP06831707A EP1963345A2 EP 1963345 A2 EP1963345 A2 EP 1963345A2 EP 06831707 A EP06831707 A EP 06831707A EP 06831707 A EP06831707 A EP 06831707A EP 1963345 A2 EP1963345 A2 EP 1963345A2
Authority
EP
European Patent Office
Prior art keywords
zoledronic acid
salts
acid
reaction
phosphorous
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Withdrawn
Application number
EP06831707A
Other languages
English (en)
French (fr)
Inventor
Ram Prasad Yadav
Zakir Gafoor Shaikh
Siddiqui Mohammad Jaweed Mukarram
Yatendra Kumar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wockhardt Ltd
Original Assignee
Wockhardt Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Wockhardt Ltd filed Critical Wockhardt Ltd
Publication of EP1963345A2 publication Critical patent/EP1963345A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the field of the invention relates to processes for the preparation of pure zoledronic acid or pharmaceutically acceptable salts thereof.
  • the invention also relates to pharmaceutical compositions that include the pure zoledronic acid.
  • Zoledronic acid a bisphosphonic acid
  • Zoledronic acid is an inhibitor of osteoclastic bone resorption indicated in the treatment of hypercalcemia of malignancy. It is also indicated for the treatment of multiple myeloma and bone metastases of solid tumors.
  • Zoledronic acid is chemically, (l-Hydroxy-2-imidazol-l-yl-phosphonoethyl)phosphonic acid monohydrate of structural Formula I.
  • a process for the preparation of zoledronic acid is disclosed for example, in U.S. Patent number 4,939,130 and Izv. Akad. Nauk. USSR, Ser. KUm., 1987, 2, 433-437.
  • the process involves the treatment of imidazol-1-yl acetic acid hydrochloride with phosphoric acid and phosphorous trichloride in chlorobenzene as solvent at 100 0 C.
  • the reaction mass becomes very thick. This leads to incomplete reaction and results in a low overall yield and impure product.
  • US Application No. 2004/0230076 provides a process for the purification of zoledronic acid.
  • the process includes obtaining a clear solution of crude zoledronic acid by raising the pH of an aqueous suspension; lowering the pH of the solution; and isolating the zoledronic acid from the solution.
  • US Application No. 2005/0054616 provides processes for the preparation of crystalline and amorphous forms of zoledronic acid.
  • the process involves the use of chlorobenzene or toluene as solvent along with silicon oil, polyethylene glycol or diatomaceous earth compounds such as celite, keisulgurh etc. as diluents to keep the reaction mass stirrable.
  • the product is not obtained in high purity.
  • zoledronic acid when prepared as per the processes reported in the prior art is not pure and yields are low. It also was observed by the present inventors that the reaction mass becomes thick and is very difficult to stir. [0007] The present inventors have found that there is no need to use solvent in the condensation reaction between imidazole- 1-yl acetic acid or salts thereof and phosphorous acid in presence of phosphorous trichloride to get zoledronic acid. A small excess of phosphorous acid can act as a solvent and the reaction mass remains homogeneous and is easily stirrable. Further, the inventors have also found that the reaction can be accomplished at temperatures less than 80 0 C in less than 10 hours reaction time. The yield of zoledronic acid obtained is about 80% with purity in excess of 99%. This significantly improves the process economics and commercial viability.
  • phosphorous oxychloride can be used in place of phosphorous trichloride without compromising on safety because commercially available phosphorous oxychloride (POCl 3 ) does not contain free phosphorous. Additionally, the boiling point Of POCl 3 is about 105 0 C, which is well above the reaction temperature, and therefore the disadvantages such as addition at reflux temperature can also be taken care off. [0010] Accordingly, in one general aspect there is provided a process for preparing pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC.
  • the process includes reacting imidazol-1-yl acetic acid or salts thereof with phosphorous acid at 8O 0 C or less to obtain a homogeneous solution; adding phosphorous trichloride at 80 0 C or less; and isolating the zoledronic acid or salts thereof from the reaction mass thereof.
  • Embodiments of the process may include one or more of the following features.
  • the reaction of imidazol-1-yl acetic acid or salt thereof with phosphorous acid may be carried out without any solvent.
  • the reaction may be carried out in the presence of one or more solvents.
  • the solvent may be one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil.
  • the process may include further purification of the product obtained. [0012] The process may include further drying of the product obtained. [0013] The process may produce the pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC. In particular, it may produce the pure zoledronic acid or salts thereof having purity more than 99.9% by HPLC.
  • a process for preparing pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC includes reacting imidazol-1-yl acetic acid or salts thereof with phosphorous acid at 80 0 C or less to obtain a homogeneous solution; adding phosphorous oxychloride at 80 0 C or less; and isolating the zoledronic acid or salts thereof from the reaction mass thereof.
  • Embodiments of the process may include one or more of the following features.
  • the reaction of imidazol-1-yl acetic acid or salt thereof with phosphorous acid may be carried out without any solvent.
  • the reaction may be carried out in the presence of one or more solvents.
  • the solvent may be one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil.
  • a pharmaceutical composition that includes a therapeutically effective amount of pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Figure 1 is an X-Ray Diffraction Pattern of zoledronic acid. Detailed Description of the Invention
  • a first aspect of the present invention provides a process for preparing pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC.
  • the process includes the steps of: (a) reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid at 80 0 C or less to obtain a homogeneous solution;
  • Imidazole 1-yl acetic acid or salts thereof may be treated with phosphorous acid and the resultant mass may be heated to get a homogeneous solution.
  • Phosphorous trichloride may be added to this homogeneous solution under controlled rate of addition at a temperature less than 8O 0 C.
  • This reaction may be carried out in the absence of a solvent. Such reactions are normally termed as "neat reactions".
  • the reaction may be carried out in the presence of one or more solvents.
  • a suitable solvent may include one or more of chlorobenzene, polyethylene glycol, toluene, and silicon oil.
  • the reaction may be continued at the same temperature until completion of the reaction. In general, it may be required to maintain the reaction temperature for about 10 hours.
  • reaction mass may be acidified.
  • the acidified mixture may be further heated for about 8-15 hours. It may be treated with activated charcoal and filtered.
  • the filtrate may be treated with acetone or any other suitable anti-solvent to precipitate zoledronic acid from the solution.
  • the precipitated mass may be filtered and dried suitably.
  • the product may be further or additionally dried to achieve the desired moisture values.
  • the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the zoledronic acid has a purity of more than purity 99% when measured by HPLC. More particularly, the purity is more than 99.7%, for example more than 99.9%.
  • a second aspect of the present invention provides a process for preparing zoledronic acid or salts thereof. The process includes the steps of:
  • Imidazol-1-yl acetic acid to be used as the starting material can be prepared the resultant by any process known in the literature. In particular, it can be prepared by reacting imidazole with alkyl haloacetate in the absence of a phase transfer catalyst to get imidazole- 1-yl acetate.
  • a third aspect of the present invention provides a process for preparing zoledronic acid or salt thereof.
  • the process includes the steps of: a) reacting imidazole with alkyl haloacetate in one or more organic solvents in the absence of a phase transfer catalyst, to get alkyl imidazole- 1-yl acetate; b) hydrolyzing the alkyl imidazole- 1-yl acetate in water to get imidazol-1-yl acetic acid; c) treating imidazol-1-yl acetic acid or salts thereof with phosphorous acid and phosphorous trichloride optionally in the presence of one or more solvents; and d) isolating the zoledronic acid or salts thereof from the reaction mass thereof.
  • the reaction of imidazole and alkyl haloacetate may be carried out in the presence of one or more suitable solvents.
  • suitable solvents include, for example, halogenated hydrocarbons, non-polar aprotic solvents, polar aprotic solvents, and mixtures thereof.
  • the reaction may also be carried out in the presence of a base.
  • the base can be selected from carbonates, bicarbonates, hydroxide or alkoxides of metals. Additionally metal halides such as potassium iodide can be effectively used as catalysts to accelerate the rate of reaction.
  • base, imidazole and catalyst are mixed with solvent and to this stirred mixture is added alkyl haloacetate at controlled rate.
  • the resultant mass after stirring for approximately 30 to 45 minutes can be heated to reflux. After completion of the reaction, the resultant mass can be cooled to room temperature and filtered to remove inorganics. The organic layer containing the product can be then concentrated under reduced pressure to get crude mass of methyl /ethyl imidazol-1-yl acetate. This crude mass can be purified suitably or can be used as such for its hydrolysis to get imidazol-1-yl acetic acid or salt thereof. [0028]
  • the hydrolysis of methyl/ethyl imidazol-1-yl acetate can be carried out under aqueous conditions at higher temperature.
  • the ester can be mixed with water and the resultant mass can be heated to reflux for about 4 to 10 hours, and cooled.
  • a fourth aspect of the present invention provides a process for the purification of zoledronic acid or salts thereof.
  • the process includes the steps of: a) obtaining a solution of zoledronic acid or salts thereof in water by heating; b) cooling the solution; and c) recovering the pure zoledronic acid or salts thereof having purity more than 99.7% from the solution thereof by the removal of water.
  • the solution of zoledronic acid may be obtained by dissolving zoledronic acid in water.
  • a solution may be obtained directly from a reaction in which zoledronic acid is formed.
  • the mixture containing zoledronic acid may be heated to obtain a solution. It can be heated from about 30 0 C to about reflux temperature of the solvent used, for example from about 30 0 C to about 100 0 C.
  • the resultant solution can be clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities.
  • the clear solution is cooled to a temperature of 30 °C or less and an optionally pre-cooled anti-solvent is added to it.
  • the anti-solvent is characterized by the fact that zoledronic acid is insoluble, practically insoluble or very slightly soluble in the anti- solvent.
  • the terms insoluble, practically insoluble or very slightly soluble have their ordinary meanings as defined in United States Phamacopoeia 2002.
  • the term "obtaining” includes dissolving, slurrying, stirring or a combination thereof.
  • the pure zoledronic acid may be recovered from the solution by a technique/which includes, for example, distillation, distillation under vacuum, filtration, filtration under vacuum, evaporation, decantation and centrifugation. The product may be further or additionally dried to achieve the desired moisture values.
  • the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the zoledronic acid has a purity of more than purity 99.7% when measured by HPLC. More particularly, the purity is more than 99.9%.
  • the pure zoledronic acid may be in its monohydrate form and has a moisture content of about 6 to 8% w/w.
  • a fifth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising as its active ingredient pure zoledronic acid or salts thereof having purity more than 99.7% by HPLC.
  • the pharmaceutical composition includes one or more pharmaceutically acceptable excipients/diluents.
  • the pharmaceutical composition of the present invention may be in the form of a solid or liquid dosage forms for oral, parenteral or topical use and may have immediate or sustained release characteristics.-
  • the dosage forms possible include tablets, capsules, powders, granules, creams, lotions, ointments, injectables, ophthalmic or otic solutions, suspensions, elixirs, and the like.
  • Example- 2 Preparation of imidazol-1-yl acetic acid Water (500 ml) was added to methyl imidazol-1-yl acetate (235 gm) and the resultant mass was refluxed for 4 to 8 hours. After completion of the reaction, it was cooled. The organic layer was separated and discarded. The aqueous layer was treated with activated charcoal, filtered to remove charcoal and concentrated under reduced pressure to get a residue. The residue obtained was treated with methanol (250 ml) and the resultant mixture was stirrejl for 2 hours and filtered.
  • Example- 4 Purification of zoledronic acid

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP06831707A 2005-12-16 2006-12-14 Verfahren zur herstellung reiner zoledronsäure Withdrawn EP1963345A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN1584MU2005 2005-12-16
IN278MU2006 2006-02-28
PCT/IB2006/003603 WO2007069049A2 (en) 2005-12-16 2006-12-14 Processes for the preparation of pure zoledronic acid

Publications (1)

Publication Number Publication Date
EP1963345A2 true EP1963345A2 (de) 2008-09-03

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP06831707A Withdrawn EP1963345A2 (de) 2005-12-16 2006-12-14 Verfahren zur herstellung reiner zoledronsäure

Country Status (2)

Country Link
EP (1) EP1963345A2 (de)
WO (1) WO2007069049A2 (de)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8071574B2 (en) 2005-02-22 2011-12-06 John Dennis Bobyn Implant improving local bone formation
WO2007125521A2 (en) * 2006-05-02 2007-11-08 Ranbaxy Laboratories Limited Polymorphic form of zoledronic acid and processes for their preparation
PL213599B1 (pl) 2008-10-31 2013-03-29 Politechnika Gdanska Sposób otrzymywania kwasu [1-hydroksy-2-(1H-imidazol-1-ilo)-etylideno] bisfosfonowego
NO2459176T3 (de) 2009-07-31 2018-02-24
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US20160016982A1 (en) 2009-07-31 2016-01-21 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
CN102070668B (zh) * 2010-12-23 2013-07-24 蚌埠丰原医药科技发展有限公司 一种利用相转移催化剂制备唑来膦酸及其钠盐的方法
WO2017208070A1 (en) 2016-05-31 2017-12-07 Grünenthal GmbH Bisphosphonic acid and coformers with lysin, glycin, nicotinamide for treating psoriatic arthritis
CN106699809A (zh) * 2016-12-07 2017-05-24 河北仁合益康药业有限公司 一种唑来膦酸的合成工艺

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7038083B2 (en) * 2002-05-17 2006-05-02 Teva Pharmaceutical Industries, Ltd. Process for making bisphosphonic acids using diluents other than halogenated hydrocarbons
WO2005005447A2 (en) * 2003-07-03 2005-01-20 Teva Pharmaceutical Industries Ltd. Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation
CA2551230A1 (en) * 2003-12-23 2005-07-14 Lyogen Limited A process for the preparation of alkyl- and aryl-diphosphonic acids and salts thereof
WO2005063717A1 (en) * 2003-12-26 2005-07-14 Natco Pharma Limited An improved process for the preparation of zoledronic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007069049A2 *

Also Published As

Publication number Publication date
WO2007069049A2 (en) 2007-06-21
WO2007069049A3 (en) 2009-04-16

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