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

• Zoledronic acid is an active pharmaceutical ingredient that inhibits bone resorption and is used in certain oncology treatments and in treating Paget's disease of bone.
• Zoledronic acid is chemically (l -hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid and can be represented by the general formula (1).
• Biphosphonic acids including zoledronic acid have generally been made by reacting a corresponding acid in a solvent (or in a diluent) at enhanced temperatures with a phosphonation agent followed by hydrolysis to form the biphosphonic acid.
• the phosphonation agent may be, inter alia, a mixture of phosphorous acid and a halophosphorous compound (such as phosphorous trichloride PCl 3 , phosphorous pentachloride PCl 5 , phosphorous oxychloride POCI 3 , and the like).
• the result of the phosphonation is generally believed to be a complex mixture of cyclic pyrophosphonate intermediates (the nature of which has been suggested, e.g., in US 5,510,517).
• the hydrolysis is typically performed by heating the mixture with water or a non-oxidizing aqueous acid to form the corresponding biphosphonic acid.
• the obtained biphosphonic acid is then optionally isolated, or is optionally converted into a corresponding salt and then isolated.
• corresponding starting acid is an imidazo-substituted acetic acid of the formula (2)
• V / O ( 2 )
• chlorinated solvents are not suitable for an industrial process because of extreme toxicity of them; these solvents are classified as compounds, the presence of which in the manufactured product must be extremely low. Therefore, specific means must be applied in the elaboration of the reaction mixture and purification of the product, for to minimize the content of traces of solvents under the prescribed limits.
• WO 03/093282 is focused on solving the problem of bad stirrability of the reaction mixture by using ionic solvents.
• this process suffers from very low yields (25 %, see Ex 2) and is thus not optimal for industrial scale.
• WO 2006/134603 shows the use of aliphatic hydrocarbons or water miscible cyclic ethers such as n-octane or 1,4-dioxane, respectively. But the yields of the zoledronic acids are reduced, being about 60% (n-octane) or about 50% (dioxane).
• WO 03/097,655 uses a silicon fluid or an aromatic hydrocarbon as a diluent for the reaction.
• the yields vary from 60 to 80%.
• long reaction times (1 1 to 34 hours in the phosphonation step, 16 to 19 hours in the hydrolysis step) are less desirable in a large scale reaction process as it limits the overall capacity of the reaction equipment
• the present invention provides a useful process for making zoledronic acid including salts and/or hydrates thereof.
• a first aspect of the present invention relates to a process, which comprises: reacting in a solvent/diluent a compound of formula (2) or a salt thereof
• said solvent/diluent comprises a mixture of (i) a polyalkylene glycol and (ii) a cyclic carbonate of the formula (3)
• n is an integer from 2 to 4 and R 1 and R 2 each independently represent a hydrogen or a C1-C4 alkyl group.
• the compound of formula (3) is a propylene carbonate of the formula (3a) and the polyalkylene glycol is a polyethylene glycol, particularly of the relative molecular mass between about 200 to about 1000.
• the ratio of the compound (3) and the polyalkylene glycol is from 5: 1 to 1 :2 (v/v), preferably from 4: 1 to 1 : 1 (v/v) and most preferably from 3:1 to 4:3 (v/v).
• the phosphonation agent is typically a combination of phosphorous acid and a halophosphorous compound, preferably phosphorous trichloride.
• the reaction temperature is generally from about 4O 0 C to 8O 0 C, more preferably around 50-65 0 C.
• the relative amount of the solvent is advantageously 2 to 10 volumes based on weight of the acid of the formula (2); e.g., 2-10 ml/g of formula (2).
• the hydrolyzing step comprises contacting the intermediates with water, preferably at a temperature higher than 50 0 C.
• the process typically further comprises isolating the compound of formula ( 1 ) or a salt or hydrate thereof, such as by precipitation.
• Another aspect of the invention relates to the use of the compound (2) with less than 0.5 % of the dicarboxylic impurity of the formula (2b)
• the present invention is based, in part, on the discovery that a mixture of a polyalkylene glycol and a cyclic carbonate of formula (3) can provide an advantageous solvent/diluent in which to carry out the phosphonation reaction step in the preparation of zoledronic acid.
• the advantages of the solvent/diluent system can include low cost, low toxicity and ease of availability.
• the reaction mixture can remain an easily stirrable fluid throughout the reaction, thus allowing for good control of the reaction, easy upscaling, and simple isolation resulting in good yields and purity of the product.
• the solvent/diluent system of the present invention comprises a mixture of the compound of the formula (3) and a liquid polyalkylene glycol.
• n represents an integer from 2 to 4, and R 1 and R 2 each independently represent a hydrogen or a C1-C4 alkyl group.
• R 1 and R 2 each independently represent a hydrogen or a C1-C4 alkyl group.
• the alkyl group can be any of methyl, ethyl, propyl, or butyl (the last two including branched as well as straight chain forms), generally the alkyl is methyl.
• the polyalkylene glycol used in the present invention is typically a polyethylene glycol (PEG).
• PEG polyethylene glycol
• the PEG used will generally have an average value of the relative molecular mass from about 200 to about 1000 or, alternatively, will have a melting point of between -40 0 C to + 40 0 C.
• a typical PEG for use in the solvent/diluent is PEG 400.
• the ratio of the compound (3), typically of the compound (3a), to the polyalkylene glycol is generally in the range from 5: 1 to 1 :2 (v/v), more typically from 4: 1 to 1 : 1 (v/v) and usually from 3:1 to 4:3 (v/v), respectively.
• the solvent/diluent can comprise additional solvents and/or diluents, but conveniently consists of the compound of formula (3) and the polyalkylene glycol components. When additional solvents/diluents are present, the amount thereof is typically less than 30%, more typically less than 20%, and usually less than 10%, and preferably less than 5% of the total volume of the solvent/diluent composition.
• the solvent/diluent composition or system of the present invention is a liquid, at least at the intended phosphonation reaction temperature.
• the composition can serve as both a solvent, i.e., reactants and products can be dissolved therein, and as a diluent, i.e., reactants and products can be suspended therein.
• the solvent/diluent system of the present invention provides a good reaction medium for carrying out the synthesis of zoledronic acid and salts thereof.
• the solvent/diluent system can provide good solubility of the reaction components at the beginning of the reaction and can prevent formation and/or accumulation of sticky and/or semisolid precipitates in later stages of the reaction, which can build up on the equipment.
• reaction mixture remains a well stirrable suspension at later stages of the reaction. Since the formation and/or accumulation of semi-solid material in the course of phosphonation reaction is reduced and preferably avoided, the process can be easier, safer, and more economical on industrial scale, allowing for high yields and short reaction times.
• the compound (2) may also be used in its ester form.
• the ester is typically derived from a condensing reaction with an aliphatic alcohol having 1 to 8 carbon atoms, resulting in a C1-C8 alkyl group.
• the subsequent hydrolysis step optionally further including an additional hydrolysis treatment, can hydrolyze the ester group and thus remove the C1-C8 alkyl moiety.
• the compound of the formula (2) may be prepared by a process comprising the following sequence:
• the compound (2) should preferably be essentially free (preferably less than 0.5%) of a diacid impurity (2b)
• the known process for making the compound (2) disclosed in WO2005/063717 yields an undesirably high amount of the diacid impurity. It has been found that the origin of the diacid impurity is particularly caused by the nature of the base used for the condensation of imidazole with the haloester. Weak bases such as amines or alkali metal carbonates are less suitable for this reaction. Preferred bases are strong bases that are able to convert essentially completely the imidazole compound into an imidazole anion, i.e., an imidazolide. Such a strong base includes a metal alcoholate, for instance potassium tert. butoxide, and a metal hydride, e.g. a sodium or lithium hydride.
• the phosphonation agents which can be single or complex compounds or reagents, are known in the art and typically are phosphorous acid and/or a halophosphorous compound; the latter is advantageously phosphorous trichloride PCl 3 , phosphorous pentachloride PCIs, phosphorous oxychloride POCl 3 and the like; and mixtures thereof.
• PCl 3 has an advantage over using POCl 3 (or other P v chlorinated reagents) in higher total amount of P 1 " species needed for the phosphonation reaction.
• phosphorous trichloride is the preferred halophosphorous compound.
• the preferred molar ratio between the acid of the formula (2), phosphorous acid, and the halophosphorous compound is about 1 : (1-5): (2-5), more preferably about 1 : 3-4: 3-4.
• the solvent/diluent system of the present invention comprising the mixture of the alkylene carbonate and the polyalkylene glycol, particularly the propylene carbonate and the polyethylene glycol, may be used in any practical amount, and advantageously is used in 2 to 10 volumes based on weight of the acid of the formula (2); i.e., 2-10 ml of solvent/diluent system per 1 g of acid of formula (2) or more simply 2-10ml/g.
• the reaction between the compound of the formula (2) defined above and the phosphonation agent in the solvent/diluent system in the process of the present invention proceeds optimally at about 40 0 C to 80 0 C, more preferably at 50-65 0 C.
• the structure of the compounds produced by the reaction is not entirely clear and thus for simplicity is referred to herein as the "phosphonated intermediates.”
• the phosphonated intermediates are a complex mixture of cyclic pyrophosphonate intermediates as suggested in US 5,510,517.
• the phosphonated intermediates are subjected to a hydrolytic reaction, which can be carried out in one or more treatments/conditions.
• a hydrolytic reaction e.g., a TLC or HPLC
• the entire reaction mixture is subjected to a hydrolytic reaction by contacting the reaction mixture with water.
• various reagents, particularly the halophosphorous compounds are also decomposed.
• the above mixture of intermediates is treated by water at an enhanced temperature (advantageously higher than 5O 0 C including reflux temperature) and for a prolonged time (e.g., for at least 2 hours).
• the reaction mixture may also be treated with a mixture of water and alcohol.
• a homogeneous organic/aqueous mixture is generally formed after the hydrolysis, wherein the product of the formula (1) stays dissolved in the mixture.
• the phosphonated intermediates can be isolated first from the reaction mixture and then subjected to hydrolysis to form the compound of formula (1).
• aqueous reaction mixture may be isolated from the reaction mixture after hydrolysis in solid state by a suitable precipitation process; advantageously, the aqueous reaction mixture is treated with a water miscible organic solvent, e.g. an alcohol, preferably methanol or ethanol; the temperature of the treatment is essentially ambient.
• a water miscible organic solvent e.g. an alcohol, preferably methanol or ethanol; the temperature of the treatment is essentially ambient.
• a monohydrate of zoledronic acid exhibits very low solubility in such system and precipitates from the reaction mixture as a solid.
• the reaction mixture may be also neutralized and/or alkalinized by a molar equivalent or a slight molar excess of an alkali (e.g., sodium/potassium hydroxide or carbonate), preferably to a pH of between 3.5 and 5.
• an alkali e.g., sodium/potassium hydroxide or carbonate
• the biphosphonic acid (1) is isolated from the aqueous phase. dependent on the pH, as a solid hydrated acid or as a solid monovalent alkali metal (monosodium or monopotassium) salt by precipitation thereof after adding a water miscible organic liquid (an antisolvent) such as an aliphatic alcohol in which the salt is less soluble.
• the precipitated solid product is filtered from the liquid medium, washed and optionally dried.
• the acid of formula (1) and/or its salts may be typically isolated in hydrated forms, which are preferably crystalline. If necessary and/or desirable, the isolated crude solid product (an acid or a salt thereof) is then purified by a suitable process, e.g., by a recry stall ization or by an extraction. It may be also converted into another acid/salt/ester form, including any of its hydrated or solvated forms.
• a suitable process of a purification of crude zoledronic acid monohydrate is, e.g., a recrystall ization thereof from water, or, preferably, a dissolution thereof in water under action of an alkali (preferably alkali metal hydroxide or carbonate) to form a solution of a zoledronic acid salt, optionally treating the solution with a surface active material, and conversion of the zoledronic acid salt back to zoledronic acid, which precipitates from the solution, by an action of an acid.
• alkali preferably alkali metal hydroxide or carbonate
• Potassium t-butoxide 34.46 g was dissolved in 90 ml of dry tetrahydrofurane under nitrogen. To this solution imidazole (21.95 g) in 75 ml of T ⁇ F was added gradually. Resulted potassium imidazolide was stirred at 40 0 C. To the suspension, 25.6 ml of methyl chloroacetate was added in three portions. Reaction mixture was heated to 40°C for 140 minutes. Formed inorganic salts were filtered off and washed with 20 ml of T ⁇ F. To the combined filtrates 30 ml of water and 8 ml of 4M HCl were added. The mixture was heated to ebullition and organic solvents were distilled off .
• Imidazole (200 g) was dissolved in tetrahydrofuran (600 ml). Jacketed reactor (4 L) was flushed with nitrogen and tetrahydrofuran (1 060 ml) was added. Potassium ?-butoxide (339.9 g) was added through a funnel. The funnel and walls of the reactor were rinsed with tetrahydrofuran (140 ml). Content of the reactor was stirred for 15 minutes, cooled down to 0 0 C and the imidazole solution was slowly added. Temperature of the reaction mixture was adjusted to 7°C and methyl chloroacetate (302.9 g) was slowly added. The reaction mixture was stirred at 20- 25°C for 2 hours.
• Lithium hydride (2.58 g) was suspended in 50 ml of dry tetrahydrofurane under nitrogen. To this suspension a solution of imidazole (20.25 g) in T ⁇ F (100 ml) was added gradually within 35 minutes. Lithium imidazolide was alkylated by addition of 26 ml of methyl chloroacetate solution in 45 ml T ⁇ F. Following ⁇ PLC analysis showed monoalkylation of imidazole. Content of diester was ⁇ .1 %
• the mixture was then heated to 95- 100 0 C and stirred at this temperature for 4 hours.
• the mixture was cooled down to 4O 0 C at which point very viscous difficult-to-stir solution was formed.
• Water (80 ml) was slowly added and resulting mixture was heated to 80 0 C. The mixture was stirred at this temperature for 4 hours.
• a 4L jacketed reactor was charged with water (350 ml) and reaction mixture from the first reactor was transferred to this reactor.
• the 2L reactor was rinsed with water (450 ml) and the rinse was added to the 4L reactor.
• the mixture was heated to 83°C and then stirred at 80-85 0 C for 3 hours.
• the reaction mixture was then cooled down to 25 0 C.
• Ethanol (1 500 ml) was added over 45-60 min. Resulting suspension was cooled down to 10 0 C and was then stirred at 8-12 0 C for 120 minutes.
• Product was then filtered, washed with ethanol (2x200 ml). Wet cake was dried at 57-62°C to give 105 g of zoledronic acid monohydrate. Water content 7.69%, ⁇ PLC purity 99.6%, assay by alkalimetric titration 100.9%.
• Opalescent solution of zoledronic acid prepared from 130.86 g zoledronic acid monohydrate, 61 g of sodium hydroxide and 1 100 ml of water was boiled with 10 g of charcoal for 5 minutes. The charcoal was then filtered off and the filter cake was washed with hot water (100 ml). The solution of 36% hydrochloric acid (260 ml) was quickly added to combined filtrates. Formed suspension was cooled down to 5 0 C, the pH of suspension was adjusted to pH 1 by addition of sodium hydroxide pearls, and stirred for additional two hours at 5°C. The product was then filtered, washed on filter with water (100 ml). The product was then dried at 5O 0 C for 24 hours to give 108.13 g (82.6%) of zoledronic acid monohydrate.
• Zoledronic acid monohydrate (6.0 g) was suspended in water (100 ml) and the mixture was heated to reflux. Formed solution was cooled down to 20 0 C and resulting crystalline suspension was stirred at 19-23°C for additional 1.5 hours. Product was the filtered, washed with ethanol (10 ml) and dried at 60 0 C to give 5.21 g (86.8%) of zoledronic acid monohydrate.

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  • 2009-11-24 WO PCT/EP2009/008424 patent/WO2010060619A1/en active Application Filing
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