Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
  • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

• TITLE AN IMPROVED PROCESS FOR PREPARATION OF MINODRONIC ACID FIELD OF THE INVENTION
• the present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Minodronic acid.
• the bisphosponic acids and their pharmaceutically acceptable salts are an important class of medicaments that act as specific inhibitor of Osteoclast-mediated bone resorption and are useful in the treatment of bone disorders such as Paget's disease and osteoporosis.
• Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxy-apatite found in the bone.
• Minodronic acid is a compound represented by the following formula (I), which has excellent bone resorption inhibitory activity, anti-inflammatory activity and analgesic- antipyretic activity and is useful for the treatment of diseases in which increased bone resorption participates, such as Paget's disease, hypercalcemia, bone metastasis of cancer and osteoporosis, as well as progress in the bone resorption (induction of osteoporosis) caused by inflammatory joint diseases such as rheumatoid arthritis and the like
• CNl 02020676 also disclose process for preparation of Minodronic
• the synthesis are based on reacting a carboxylic acid with a mixture of phosphorous acid and one of the following phosphorus halides: phosphorus trichloride (PCI3), phosphorus oxychloride (POCI3), phosphorus pentachloride (PCI5), phosphorus tribromide (PBr 3 ), phosphorus oxybromide (POBr 3 ) or phosphorus pentabromide (PBr 5 ), then quenching the reaction mixture with water or a non-oxidizing aqueous acid, followed by heating to hydrolyze the phosphorus intermediates to the final product.
• PCI3 phosphorus trichloride
• POCI3 phosphorus oxychloride
• PCI5 phosphorus pentachloride
• PBr 3 phosphorus tribromide
• POBr 3 phosphorus oxybromide
• PBr 5 phosphorus pentabromide
• U.S. Pat. No. 4,407,761 describes the synthesis of 4-amino-l-hydroxybutylidene-l ,l - bisphosphonic acid (alendronic acid) and other bisphosphonic acids.
• the reaction has been carried out in the presence of diluent, e.g. chlorinated hydrocarbons, especially chlorobenzene, which does not solubilize the reaction components and serves only as a heat carrier.
• the reaction starts as a two-phase system, in which the melted phase gradually thickens into a non-stirrabie mass. This semi solid sticky mass finally turns into a hard, rigid material, thereby coating the walls of the reaction vessel and thus preventing the smooth heat transfer and complicating the product work-up.
• the overall yield of this process is variable i.e. 45% to 56%.
• the solvent i.e. chlorobenzene used in the reaction is carcinogenic in nature and thus not recommendable for industrial scale.
• US. Pat. No. 5,908,959 employs poly alkylene glycols as reaction solvent for synthesizing bisphosphonates.
• the use of poly alkylene glycols on industrial scale is not very feasible as they are difficult to recover in pure form for reuse.
• US Patent Application No. 20040043967 Al describes the preparation of bisphosphonic acids by using the diluents other than halogenated hydrocarbons, but overall yield of the process is 56% to 80%.
• U.S. Pat. No. 6,562,974 describes the preparation of bisphosphonates in an overall yield of 77% by using phosphorous acid as a reactant/solvent in presence of base. The disadvantage of this process is that the reaction mixture becomes very viscous without a solvent.
• the present inventors have focused on the problems associated with the prior art process and has developed an improved process for the preparation of Minodronic acid.
• present invention provides a process for preparing Minodronic acid or a salt thereof, comprising a step of converting a compound of formula II in to compound of formula III which is further converted in to compound of formula (VI), wherein Rl is a halogen or a carboxy-activating group and R2 is CI -C6 alkoxy, aralkoxy or phenoxy (both optionally substituted with C1C6 alkyl or alkoxy);
• the present invention provides process for producing a bisphosphonic acid compound which process comprises reaction of a carboxylic acid compound or as salt thereof with phosphorous acid and phosphorous trichloride in presence of tetramethylurea as a solvent.
• the present invention provides a purification process for crude Minodronic acid which comprises acid base treatment with crude Minodronic acid.
• the present invention provides a process to obtain pure Minodronic acid using acid base treatment and also provides the process to obtain pure crystal D of Minodronic acid.
• the present inventors have found that employing process of the present invention for the preparation of Minodronic acid, overcomes the drawbacks of the prior art and may be prepared and subsequently converted to Minodronic acid in high yield and purity.
• Fig 1 is the SS-NMR of the crystalline Minodronic acid hydrate before micronisation.
• Fig 2 is the SS-NMR of the crystalline Minodronic acid hydrate after micronisation.
• a further significant advantage of the present invention relates to achievement of purity of the final compound as per JP grade by using simple acid base treatment with high yield.
• present invention provides process where Imidazo [l,2-a]pyridine reacts with oxalyl derivative in presence of suitable solvent.
• Oxalyl derivative may contain on one end any halogen such as CI, Br or I or any leaving group such as mesyl, tosyl , etc at the other end any ester group such as substituted or unsubstituted alkyl, aryl or aralkyl group which can subsequently convert in to acid group.
• Suitable solvents used during reaction are high boiling non polar solvents like toluene, xylene etc. Reaction is carried out at a temperature of 50-150°C, more preferably 100-110°C. The reaction time may between 5 hour to 50 hours, specifically about 20 hours to 30 hours.
• the acylated compound of formula III is isolated from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti solvent to the solution, evaporation, vacuum distillation or a combination thereof.
• the reaction mass containing the acylated compound of formula III obtained is concentrated and then taken for next step.
• the base used in step -(b) is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, sodium hydride, lithium hydride, potassium hydride, sodamide, lithium amide, potassium amide, sodium methoxide, potassium tert- butoxide, sodium tert-butoxide, sodium tert-pentoxide, lithium tert butoxide.
• hydrolysis of ester group Wolff-Kishner reduction is carried out with hydrazine hydrate in presence of base. Reaction is carried out at reflux temperature and its required long time about 20 to 30 hrs for completion.
• Imidazo [1, 2-a] pyridine-3yl acetic acid is isolated as hydrochloride salt in a pure form which is an important intermediate of Minodronic acid.
• the solvent used in step -(c) is selected from the group consisting of aprotic polar solvents such as ⁇ , ⁇ '-dimethylethyleneurea (DMEU), N,N'-dimethyl propylene urea (DMPU), l-methyl-2-pyrrolidone (NMP), Tetramethylurea (TMU) , acetonitrile or a mixture of two or more thereof.
• aprotic polar solvents such as ⁇ , ⁇ '-dimethylethyleneurea (DMEU), N,N'-dimethyl propylene urea (DMPU), l-methyl-2-pyrrolidone (NMP), Tetramethylurea (TMU) , acetonitrile or a mixture of two or more thereof.
• Minodronic acid The most often used reaction of obtaining Minodronic acid is the reaction of Imidazo [1, 2-a] pyridine-3yl acetic acid with the phosphonating agent such as H 3 PO 3 /PCI 3 or H 3 PO 3 /POCI 3 .
• the number of publications implicates the problem of dense and heterogenic reaction mass that is not even stirrable which is solved by use of suitable solvents.
• the use of those solvents deteriorates the profitability of the process, makes isolation and purification of the product more difficult which results in complication of process implementation into the industrial scale.
• tetramethylurea as a solvent leads to obtaining Minodronic acid and simultaneously ensuring the stirrable reaction mixture. Moreover, such solution allows for simplification of the process to a greater extent, which is advantageous for implementation in to the industrial scale. Additionally, tetramethylurea is a higher boiling, less toxic solvent and can be recoverable solvent.
• Minodronic acid provides end product with more non-polar impurities which is difficult to remove and requires additional purification, thereby not suitable for commercial point of view.
• the same has been avoided by the present invention by simple acid base treatment.
• Minodronic acid hydrate The Three main known impurities of Minodronic acid hydrate are:
• Impurity-II is detected and resolved from Minodronic acid hydrate by HPLC with a relative retention time (hereafter referred as RRT) of 1.64.
• RRT relative retention time
• Impurity-II Imidazo [1,2-a] pyridine-3-yl acetic acid hydrochloride
• Impurity-II is detected and resolved from Minodronic acid hydrate by HPLC with an RRT of 2.77.
• the impurity-III is detected and resolved from Minodronic acid hydrate by HPLC with an RRT of 5.31.
• Minodronic acid obtained from this present invention contain less than 1% particularly less than 0.5% of impurity and more particularly less than 0.1% of total impurity.
• the present invention provides the robust process to eliminate the non polar impurities particularly at 1.28 RRT which is otherwise requires additional purification. Accordingly the present invention provides a purification process for crude Minodronic acid which comprises acid base treatment with crude Minodronic acid.
• process for purifying Minodronic acid involves preparation of disodium salt by stirring wet crude Minodronic acid with NaOH solution at pH 6.5-7.0. Stirring with methanol and then filtering product which removes all impurities in filterate. Pure disodium salt is now converted in to Minodronic acid by refluxing with HC1 solution.
• present invention gives process to prepare only crystal D.
• the method according to this invention involves dissolving Minodronic acid in dilute HC1 solution (4.0 lit.) at reflux temperature and then cooling 70-80°C very slowly. Further allowing it to stir at this temperature for more than 5 hrs at 100-110 RPM and then slowly cooling to room temperature gives pure crystal D.
• Minodronic acid hydrate obtained as per the present invention can be further micronized, milled or sieved to get the desired particle size required for pharmaceutical composition to achieve the desired dissolution profile.
• Example-I preparation of Imidazo[l,2-a]pyridine.
• Tetramethylurea 600 ml
• Phosphorous acid 115.68 g
• process water 30.0ml
• Imidazo [1, 2-a] pyridine-3yl acetic acid hydrochloride 100.0 g
• the LC system used for method development and forced degradation studies and method validation was Waters-Alliance (manufactured by Waters India Ltd) LC system with a photo diode detector. The out put signal was monitored and processed using Empower software system (designed by Waters India) on IBM computer (Digital Equipment Co).
• the chromatographic column used was a waters make X-bridge CI 8 (250 mm x 4.6 mm) with 5.0 ⁇ particles.
• the mobile phase consists 32.3 g of dipotassium hydrogen phosphate anhydrous, 3.0 g of EDTA-disodium salt, and 2.0 g Tetrabutyl ammonium dihydrogen phosphate into a suitable container. Dissolve the contents in 800 mL of water. Pipette out 2.0 mL of concentrated Hydrochloric acid into the same container, dissolve and mix well. Adjust the pH of the solution to 7.5. Transfer the contents to 1000 mL measuring cylinder and dilute to 960 mL with water. Transfer the contents to a suitable container and mix well.
• Reference solution - (a) preparation (Minodronic acid hydrate and each impurity is @ 0.1%).
• Spiked solution (Minodronic acid hydrate + 0.10% of each Known impurity spiked solution) @ 280 nm.

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• Chemical & Material Sciences (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• Molecular Biology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 2013
  • 2013-12-09 IN IN3517MU2012 patent/IN2012MU03517A/en unknown
  • 2013-12-09 WO PCT/IB2013/060737 patent/WO2014091386A2/en active Application Filing

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