CLIAMS:
1. A process for the preparation of dimer of zoledronic acid of formula II, a pharmaceutically acceptable salt, or a hydrate thereof,

which comprises reaction of imidazole diacid with phosphorylating agent at elevated temperature.

2. The process of claim 1, wherein the elevated temperature is about 60 to about 90 °C.

3. The process of claim 1, wherein the phosphorylating agent is orthophosphorous acid and phosphorous oxychloride.

4. The process of claim 1, wherein the reaction is conducted in the presence of acid.

5. The process of claim 1, wherein the reaction is conducted in the presence of hydrochloric acid.

6. The process of claim 1, wherein the hydrate is monohydrate.

7. The process of claim 1, wherein the dimer of zoledronic acid is having purity greater than or equal to 95%.

8. A process for the preparation of monohydrate of zoledronic acid dimer or a pharmaceutically acceptable salt thereof, which comprises:

a) reaction of imidazole diacid with phosphorylating agent in the presence of acid at elevated temperature to provide phosphorylated compound of formula II; and
b) suspension of the compound of formula II with water to provide monohydrate of zoledronic acid dimer or a pharmaceutically acceptable salt thereof.
,TagSPECI:Field of Invention

The present invention provides a chemical process for preparing zoledronic acid dimer, a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is useful as reference marker. The dimer of Formula II is represented as structural formula II:

Formula II

Background of the invention

Zoledronic acid, chemically known as (1-Hydroxy-2-imidazol-1-yl- phosphonoethyl) phosphonic acid, is a bisphosphonate derivative and represented as structural formula I:

Formula I

Zoledronic acid is a third generation bisphosphonate derivative characterized by a side chain that includes an imidazole ring. It inhibits osteoclast bone resorption and is used for the treatment of tumor-induced hypercalcemia. It is commercially available in products sold under the brand name ZOMET and RECLAST in vials as a sterile powder or solution for intravenous infusion.

Various synthetic routes for preparing Zoledronic acid, its salts thereof and the intermediates thereof were previously described in US 4,939,130, US 5,510,517, US 2010/0130746, WO 2005/063717, WO 03/093282, WO 2006/134603, WO 03/097655.

The disclosed process of WO 2005/063717 yields an undesirably high amount of the diacid impurity. However, none of the prior art is provided any feasible process to prepare dimer of zoledronic acid, a pharmaceutically acceptable salt thereof, or a hydrate thereof in its pure state.

The dimer of zoledronic acid of the formula II, a pharmaceutically acceptable salt thereof, or a hydrate thereof can be used as potential impurity to analyse pure zoledronic acid and also can be used as reference marker in its pure state.

Scientists of drug manufacturing research and development understand that a compound in a relatively pure state, which is different from API, can be used as a "reference standard." A reference standard is similar to a reference marker, which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. (Strobel p. 924, Snyder p. 549, Snyder, L. R.; Kirkland, J. J. Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response.

The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. (Strobel p. 894). For this purpose, the reference standard is added directly to the mixture, and is known as an "internal standard." (Strobel p. 925, Snyder p. 552).

In this application the reference marker is dimer of zoledronic acid. Detection or quantification of the reference marker serves to establish the level of purity of the API. The compound must be substantially pure compound to use as a reference marker.

Therefore, there is a need to develop a simple, industrially feasible and inexpensive process to prepare compound of formula II, a pharmaceutically acceptable salt thereof, or a hydrate thereof in its pure form.

Summary of the invention

The present inventors relates to a simple, conventional and industrially feasible process to provide compound of Formula II, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

In an aspect, the present invention provides a process for the preparation of dimer of zoledronic acid of formula II, a pharmaceutically acceptable salt, or a hydrate thereof,

Formula II

which comprises reaction of imidazole diacid with phosphorylating agent at elevated temperature.

In another aspect, the present invention provides a process for preparing pure dimer of zoledronic acid or a pharmaceutically acceptable salt thereof, which comprises:
a) providing solution of the reaction mixture consisting dimer of zoledronic acid in water; and
b) adding ketone solvent at below 20 °C to the solution of step a) to provide pure compound of formula II or its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the preparation of monohydrate of zoledronic acid dimer or a pharmaceutically acceptable salt thereof, which comprises:

a) reaction of imidazole diacid with phosphorylating agent in the presence of acid at elevated temperature to provide phosphorylated compound of formula II; and
b) suspension of the compound of formula II with water to provide monohydrate of zoledronic acid dimer or a pharmaceutically acceptable salt thereof.

The compound of formula II, a pharmaceutically acceptable salt thereof, or a hydrate thereof obtained from the process of the present invention is useful as reference marker. The impurity II of the present invention is also useful as intermediate to provide pure zoledronic acid.

Detailed description of the invention

The term “pure” as used herein, unless otherwise defined, refers to dimer of zoledronic acid, its pharmaceutically acceptable salt, or hydrate thereof that has purity of greater than about 90 % or greater than about 95%.

The salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.

In an aspect, the present invention provides a process for the preparation of dimer of zoledronic acid of formula II, a pharmaceutically acceptable salt, or a hydrate thereof,

Formula II
which comprises reaction of imidazole diacid with phosphorylating agent at elevated temperature.

The phosphorylating agents, which can be single or complex compounds or reagents, are known in the art and typically are phosphorous acid, orthophosphorous acid and/or a halophosphorous compound. The halophosphorous compounds includes phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride and the like; and mixtures thereof.

In an embodiment, the phosphorylating agent comprises orthophosphorous acid and phosphorous oxychloride.

The elevated temperature can be about 40 °C or above. The suitable temperature for the reaction is about 40 °C to about 100 °C. In an embodiment of the invention, the elevated temperature comprises 60 to about 90 °C.

The reaction of phosphorylation may be maintained at elevated temperature for a period of about 5 to 10 hours to complete the reaction without affecting the formation of other by-products.

The reaction may be performed in presence of an acid. The acid used for the reaction is selected from the inorganic acid and organic acid. The inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, and the like; the organic acid includes acetic acid, formic acid and the like.

After completion of the reaction, the reaction mixture may be filtered and then the resultant filtrate may be concentrated or subjected for precipitation by using suitable technique.

In another aspect, the present invention provides a process for preparing pure dimer of zoledronic acid or a pharmaceutically acceptable salt thereof, which comprises:
a) providing solution of the reaction mixture consisting dimer of zoledronic acid in water; and
b) adding ketone solvent at below 20 °C to the solution of step a) to provide pure compound of formula II or its pharmaceutically acceptable salt.

The reaction mixture which consisting dimer of zoledronic acid obtained from the reaction mixture or solid of dimer of zoledronic acid is dissolved in water at a temperature of about 20 to about 35 °C.

The obtained solution may be cooled to below 15 °C and may be maintained the solution for a period of about 30 minutes to 2 hours. The solution may be filtered to avoid the particles of the compound.

The ketone solvent used for precipitation of solid includes but are not limited to acetone, methylethyl ketone, and the like. The ketone solvent may be added at a temperature below 15 °C and then maintained the reaction mixture for 1 to 2 hours to increase the precipitation of pure compound of formula II or its pharmaceutically acceptable salt.

The solid obtained from the step b) of the present invention may have the purity greater than or equal to 95 %.

In another aspect, the present invention provides a process for the preparation of monohydrate of zoledronic acid dimer or a pharmaceutically acceptable salt thereof, which comprises:
a) reaction of imidazole diacid with phosphorylating agent in the presence of acid at elevated temperature to provide phosphorylated compound of formula II; and
b) suspension of the compound of formula II with water to provide monohydrate of zoledronic acid dimer or a pharmaceutically acceptable salt thereof.

In an embodiment, phosphoryating agents comprise orthophosphorous acid and phosphorous oxychloride.

The elevated temperature can be about 40 °C or above. The preferred elevated temperature is about 60 to about 90 °C. The reaction of phosphorylation may be maintained at elevated temperature for a period of about 5 to 10 hours.

The acid used for the reaction is selected from the inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.

After completion of the reaction, the reaction mixture may be filtered and then the resultant filtrate may be concentrated or subjected for precipitation by using suitable technique such as anti-solvent technique.

The process for precipitation comprises dilution of reaction mixture containing dimer of zoledronic acid or its salt with water and precipitating the solid by the addition of ketone solvent at 0 °C to 10 °C. The ketone solvent used for precipitation of solid is acetone.

The resultant dimer of zoledronic acid or pharmaceutically acceptable salt is converted to monohydrate of zoledronic acid dimer by the treatment of the compound of step a) with water. The step b) may be carried out at a temperature of about 20 to about 35 °C.

The step b) may be maintained at stirring for a period of 30 minutes to about 2 hours to form the monohydrate of the zoledronic acid dimer.
The resultant compound of Formula II, a pharmaceutically acceptable salt, or a hydrate thereof of the present invention may have the purity greater than 95% determined by HPLC.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLE:

Example-1: Process for preparing dimer of zoledronic acid

Imidazole diacid (10 gm) was charged to orthophosphorous acid (65 gm) and heated to 65-80 °C. To the reaction mass added phosphorous oxychloride (73 gm) and stirred at 70-90 °C for the period of 8-14 hours. To the resulting dark yellow coloured highly viscous reaction mass added dilute hydrochloric acid (95 mL) dropwise. The reaction mass was stirred further for 10-16 hours. The reaction mass was then filtered and washed with water. To the filtrate, charged acetone at the temperature of 0-10 °C and then stirred for 1-4 hours. After precipitation of solid compound, reaction mixture was filtered, washed with water followed by acetone. The crude zoledronic acid dimer obtained was then charged to water (60 mL) and stirred for 2-4 hours to obtain zoledronic acid dimer monohydrate. Then it was filtered out and washed with water.
Pure compound thus obtained was dried in an oven under vacuum at 45-65 °C.

Dry Wet: 7.0 gm.
HPLC purity: 96%