PREPARATION OF BIPHOSPHONIC ACIDS AND SALTS THEREOF

Description

Field of the invention

[0001] The present invention relates to a process for preparing bisphosphonic acids and their pharmacologically active salts.

State of the art

[0002] The bisphosphonic acids and their salts, which form the subject of the present patent application are compounds described by the following structural formula:

in which M₁, M₂, M₃, M₄ are selected from H, and a monovalent cation.

[0003] Belonging to this class of molecules are the following compounds used in the treatment of osteoporosis (see Table 1) according to the different meaning that R₁ may assume.

TABLE 1:

R1= CH3,	Etidronic acid
	Zoledronic acid
	Risedronic acid
	Minodronic acid
	Pamidronic acid
	Alendronic acid
	Neridronic acid
	Olpadronic acid
	Ibandronic acid

[0004] As regards the methods of synthesis, these compounds are synthesized starting from the corresponding carboxylic acid according to the synthetic scheme appearing in Diagram 1

[0005] Starting from the acid, by subsequent salification of the acid protons, the various salts may be obtained.

[0006] A problem that is commonly encountered in the preparation of these compounds is the formation, during the reaction, of very dense unstirrable masses, which render the industrial synthesis of these substances problematical.

[0007] In the literature various documents have been published which describe techniques of synthesis of the compounds listed in Table 1.

[0008] US4621077, which regards alendronic acid and neridronic acid, describes the use of chlorobenzene as the solvent in the synthesis. The application of this technique leads to obtaining solid and unstirrable masses in the course of the reaction. A series of other patents (US4407761, US4327039, US4304734, US4267108, US4054598) envisages the use of chlorobenzene as reaction solvent, but also in these cases the drawback described above is again met with.

[0009] US4922007, US5019651 and US5510517, as well as J. Org. Chem. 60, 8310, (1995), envisage the use of methanesulphonic acid as reaction solvent. This makes it possible to obtain stirrable masses in the course of the reaction. However, this technique, as reported in J. Org. Chem. 60, 8310, (1995), involves risks of safety in that this solvent gives rise to uncontrollable reactions in the reaction conditions, when the temperature of the reacting mixtures exceeds 85°C.

[0010] WO9834940 employs polyalkylene glycols as reaction solvents for synthesizing alendronic acid; however, these solvents have a high cost and are difficult to eliminate from the finished product, given their high boiling point

[0011] In WO0049026, starting from a nitrogen-protected derivative of β-aminopropionic acid to prevent the known problems of stirrability of the reaction mixture, use is made of orthophosphoric acid as the reaction means. The derivatization of the starting product in any case renders the method of synthesis unwieldy and involves the need for introducing additional steps for protection and deprotection.

[0012] US5792885 synthesizes pamidronic acid starting from a nitrogen-protected derivative of γ-aminobutyric acid, in aromatic hydrocarbons as the reaction solvents. This method presents the same drawbacks illustrated for the method described in WO0049026.

[0013] WO0110874 regards the use of methanesulphonic anhydride as the solvent for producing alendronic acid, but the high cost of the solvent renders the method difficult to apply at an industrial level.

[0014] WO 0157052, example 2 discloses:

"Bisphosphorylation of 3-PAA HCl to give 1-Hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid

[0015] 

[0016] The mixture of 5 eq. phosphorous acid, 1.5 eq. pyridineHCl and 3-PAA is melted together until a uniform melt is formed (80-90°C). Then 2.1 eq. of pyridine are added. The reaction is cooled to about 70°C and 2 eq. of PCl₃ are slowly added. The mixture is heated at about 70°C for 3.5 hours. Water and HCl are added, the reaction hydrolyzed for about 30 to about 45 minutes at 75° C to yield risedronate after crystallization from aqueous acid/IPA."

Technical problem

[0017] The need was thus felt to have available a general process for preparing the compounds described in Table 1 which would not present the drawbacks of the processes known to the art.

Summary of the invention

[0018] The present applicant has now unexpectedly found that, using as the reaction solvents in the synthesis of the compounds described in Diagram 1 the so-called ionic liquids of the following formulas it is possible to convert the raw materials into the desired products, avoiding the drawbacks of the processes known to the prior art:



in which each R may be independently H, a linear or branched C₁-C₂₀ alkyl group, a cycloalkyl containing from 5 to 6 carbon atoms, alkylene aryl, or aryl; R₂ is H or a linear or branched C₁-C18 alkyl group, X^- is an anion selected from the group consisting of halogenide, BF₄^-, PF₆^- or AlCl₄^-. Particularly preferred is tributylammonium chloride, which melts at approximately 60°C.

[0019] In addition, the solvent used is economically advantageous and easy to recover and recycle.

[0020] Consequently, forming the subject of the present invention are processes for preparing the active principles described in Table 1, comprising the reaction of the appropriate raw materials with phosphorous acid and phosphorus trichloride, subsequent treatment with acid water and possible final treatment with an aqueous solution of a hydroxide of an alkaline metal, characterized in that the reaction is conducted in ionic liquids at a temperature of between 15°C and 120°C.

Detailed description of the invention

[0021] M₁-M₄ are preferably selected from the cations of the alkaline metals, H, cations of aliphatic or cyclolaliphatic amines, and more preferably are sodium and/or H.

[0022] The temperature at which the aforesaid ionic solvents are liquid is preferably between 20°C and 100°C.

[0023] The solvents are moreover easy to prepare with methods of a conventional type, do not create problems of safety in so far as they do not cause uncontrollable reactions, and moreover afford the undoubted advantages that they may be recovered and re-used for several production cycles.

[0024] The following examples are provided by way of non-limiting illustrations of the process that forms the subject of the present invention.

EXAMPLE 1A

Formation of the reaction solvent (tributylammonium chloride)

[0025] A 3-litre reactor provided with a Dean-Stark trap and drip funnel is charged with 150 ml of toluene and 334.3 g of tributylamine. The solution is cooled to 25-30°C -and from the drip funnel there are added 152.6 ml of 33%-aqueous- hydrochloric acid, in the meantime controlling that the temperature does not exceed 40°C. The homogeneous solution -thus obtained is then distilled in vacuum conditions (50 mmHg) until the internal temperature reaches 80°C and no more liquid is distilled from the reactor. The mixture thus obtained consists of tributylammonium chloride and is ready for use in the subsequent reactions of formation of bisphosphonic acids.

EXAMPLE 1B

Preparation of sodium alendronate

[0026] To the liquid phase obtained in Example 1, kept at 70°C, there are added 79.5 g of phosphorous acid and subsequently 100 g of γ-aminobutyric acid. The temperature of the mixture is brought to 60°C, and from the drip funnel there are added 266.4 g of phosphorus trichloride during an interval of approximately one hour, maintaining the internal temperature between 60°C and 65°C. Subsequently, the reaction mixture is kept under stirring for two hours at 60°C, and then is cooled to 20°C. There are added 410 ml of deionized water, keeping the temperature of the reaction mixture below 40°C. At the end of addition, the temperature is brought up to 90°C and kept in these conditions for 2 hours. After cooling to 10°C, 1093 ml of 30% aqueous sodium hydroxide are added to the reaction mixture, until the final pH is 11-12. The resulting top layer, consisting of tributylamine is separated off. The tributylamine may be subsequently treated with aqueous hydrochloric acid, as described in Example 1A, to re-obtain tributylammonium chloride as the reaction solvent.

[0027] The aqueous phase is treated with 33% aqueous hydrochloric acid to bring the pH of the solution to 4.3 ± 0.1. The aqueous phase is then dripped on 7000 ml of methanol under stirring, causing the separation of a heavy precipitate, which is then filtered and washed with 500 ml of methanol.

[0028] There are obtained 1366 g of crude sodium alendronate, which is then dissolved at 75°C in 3600 ml of deionized water. The solution is then filtered at 75°C and left to crystallize by means of slow cooling, until the mixture reaches 5°C. The crystalline solid obtained is filtered and washed with 2 x 100 ml of deionized water and then dried at 50°C for 12 hours, to obtain 97.8 g of sodium alendronate (31% yield).

EXAMPLE 2

Preparation of zoledronic acid

[0029] 20 of tributylammonium chloride, prepared as in Example 1A, are put into a 100-ml flask provided with coolant, magnetic stirrer, drip funnel and thermometer. The solid is melted at 60°C, then 3.2 g of phosphorous acid and 5.0 g of 2-(1-imidazyl)-acetic acid are added. The temperature of the mixture is then brought up to 65-70°C, and from the drip funnel there are slowly added 10.9 g of PCl₃. Once the addition is completed, the mixture is brought up to 80°C and kept under these conditions for two hours, at the end of which 20 ml of deionized water are added. The mixture is brought to 90°C and is kept under these conditions for 2 hours. It is then cooled down to room temperature, and 50 ml of 33% NaOH are added to the mixture, until a pH of the mixture ≥ 12 is reached. The two phases that have formed are separated, and 20 ml of toluene are added to the aqueous bottom phase, stirring the mixture for 15 min. The phases are once more separated, and the aqueous phase is brought to pH 1 by addition of 33% HCl. The aqueous solution is then dripped on 300 ml of methanol. The solid that precipitates is filtered and washed with 50 ml of methanol.

[0030] To the filtered solid there are added 70 ml of deionized water, and the mixture is heated to 80°C and kept under these conditions for 1 hour. Then the solution is cooled to room temperature. A white solid precipitates, which is filtered and washed with 20 ml of deionized water to obtain 4.2 g of the desired product, which is dried at 50°C under vacuum for 6 hours. The weight of the dry product is 2.8 g.

EXAMPLE 3

Preparation of risedronic acid

[0031] The same procedure of preparation as the one described in Example 3 is followed, using 5.4 g of 2.-(3-pyridyl)-acetic acid instead of 2-(1-imidazyl)-acetic acid; 3.5 g of the desired product are obtained.

EXAMPLE 4

Preparation of sodium pamidronate

[0032] The same procedure of preparation as the one described in Example 1 is followed, using 86.4 g of β-aminopropionic acid instead of γ-aminobutyric acid; 81.5 g of the desired product are obtained.

Claims

1. A process for preparing bisphosphonic acids and their salts of formula (1),

in which R₁ has the meanings indicated in the following Table 1:

R1= CH3,	Etidronic acid
	Zoledronic acid
	Risedronic acid
	Minodronic acid
	Pamidronic acid
	Alendronic acid
	Neridronic acid
	Olpadronic acid
	Ibandronic acid

and in which M₁, M₂, M₃, M₄ are selected from H, and a monovalent cation, comprising the reaction of acids of formula R₁-CO₂H, in which R₁ has the aforesaid meanings, with acids and phosphorus trichloride, characterized in that the reaction is conducted at a temperature of between 15 °C and 120 °C in a solvent consisting of one or a mixture of ionic liquids selected from the group:



in which each R may be independently a linear or branched C₁-C₂₀ alkyl group, a cycloalkyl containing from 5 to 6 carbon atoms, alkylene aryl, or aryl; R₂ is H or a linear or branched C₁-C₁₈ alkyl group, X^- is an anion selected the group consisting of halogenide, BF₄^-, PF₆^-, and AlCl₄^-.

2. The process according to Claim 1, characterized in that the temperature at which the aforesaid ionic solvents are liquids is between 20 °C and 100 °C.

3. The process according to any one of Claims 1-2, characterized in that M₁-M₄ are selected from the cations of an alkaline metal, H or the cations of aliphatic or cycloaliphatic amines.

4. The process according to Claim 3, characterized in that M₁-M₄ are selected from H and/or sodium.

Ansprüche

1. Verfahren zum Herstellen von Bisphosphonsäuren und ihren Salzen gemäß der Formel (1),

worin R₁ die in der nachfolgenden Tabelle 1 gezeigten Bedeutungen aufweist:

R1=CH3,	Etidronsäure
	Zoledronsäure
	Risedronsäure
	Minodronsäure
	Pamidronsäure
	Alendronsäure
	Neridronsäure
	Olpadronsäure
	Ibandronsäure

und worin M₁, M₂, M₃, M₄ aus H und einem monovalenten Kation ausgewählt werden, wobei das Verfahren die Reaktion von Säuren der Formel R₁-CO₂H, worin R₁ die zuvor genannten Bedeutungen aufweist, mit Säuren und Phosphortrichlorid umfasst, dadurch gekennzeichnet, dass die Reaktion bei einer Temperatur zwischen 15 °C und 120 °C in einem Lösungsmittel durchgeführt wird, welches aus einer ionischen Flüssigkeit oder aus einer Mischung von ionischen Flüssigkeiten besteht, die aus der Gruppe ausgewählt wird/werden, welche besteht aus:



worin jeder R unabhängig voneinander eine lineare oder verzweigte C₁-C₂₀-Alkylgruppe, ein 5 bis 6 Kohlenstoffatome enthaltendes Cycloalkyl, Alkylenaryl oder Aryl sein kann, R₂ H oder eine lineare oder verzweigte C₁-C₁₈-Alkylgruppe ist und X^- ein Anion ist, welches aus der Gruppe ausgewählt wird, welche aus Halogenid, BF₄-, PF₆- und AlCl₄- besteht.

2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Temperatur, bei der die zuvor genannten ionischen Lösungsmittel Flüssigkeiten sind, zwischen 20 °C und 100 °C beträgt

3. Verfahren nach einem der Ansprüche 1 bis 2, dadurch gekennzeichnet, dass M₁ bis M₄ aus den Kationen eines Alkalimetalls, H oder den Kationen von aliphatischen oder cycloaliphatischen Aminen ausgewählt werden.

4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, dass das M₁ bis M₄ aus H und/oder Natrium ausgewählt werden.

Revendications

1. Procédé pour préparer des acides bisphophoniques et leurs sels de formule (1),

dans laquelle R₁ a les significations indiquées dans le tableau 1 suivant :

R1= CH3,	Acide étidronique
	Acide zolédronique
	Acide risédronique
	Acide minodronique
	Acide pamidronique
	Acide alendronique
	Acide néridronique
	Acide olpadronique
	Acide ibandronique

et dans laquelle M₁, M₂, M₃, M₄ sont choisis parmi H et un cation monovalent, comportant la réaction d'acides de formule R₁-CO₂H, dans laquelle R₁ a les significations susmentionnées, avec des acides et du trichlorure phosphoreux, caractérisé en ce que la réaction est conduite à une température entre 15 °C et 120 °C dans un solvant constitué d'un liquide ionique ou d'un mélange de liquides ioniques choisis parmi le groupe :



dans lequel chaque R peut être indépendamment un groupe alkyle en C₁ à C₂₀ linéaire ou ramifié, un cycloalkyle contenant de 5 à 6 atomes de carbone, un aryle d'alkylène ou un aryle, R₂ est H ou un groupe alkyle en C₁ à C₁₈ linéaire ou ramifié, X^- est un anion choisi parmi le groupe constitué d'un halogénure, de BF₄^-, de PF₆^- et d'AlCl₄^-.

2. Procédé selon la revendication 1, caractérisé en ce que la température à laquelle lesdits solvants ioniques susmentionnés sont des liquides, se situe entre 20°C et 100°C.

3. Procédé selon l'une quelconque des revendications 1 à 2, caractérisé en ce que M₁ à M₄ sont choisis parmi les cations d'un métal alcalin, H ou les cations d'amines aliphatiques ou cycloaliphatiques.

4. Procédé selon la revendication 3, caractérisé en ce que M₁ à M₄ sont choisis parmi H et/ou le sodium.