FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF ZOLEDRONIC ACID THEREOF IN HIGH PURITY AND IMPROVED YIELD
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an efficient process for the preparation of zoledronic acid or pharmaceutically acceptable salt thereof in high purity and improved yields.
The following specification particularly describes the invention and the manner in
which it is to be performed.
4. DESCRIPTION
The present invention relates to an efficient process for the preparation of zoledronic acid or pharmaceutically acceptable salt thereof in high purity and improved yields.
Zoledronic acid, a bisphosphonic acid, is an inhibitor of osteoclastic bone resorption indicated in the treatment of hypercalcemia of malignancy. It is also indicated for treatment of multiple myeloma and bone metastases of solid tumors. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl)phosphonic acid monohydrate having structure depicted in Formula I.

584
11 6 DEC 2005

MUM


US Patent number 4,939,130 (the '130 Patent) and Kabachnick et al, Izv. Akad. Nauk. USSR, Ser. Khim., 2, 433-437 (1987) provides process for preparation of zoledronic acid or salt thereof. The process involves treatment of imidazol-1-yl acetic acid hydrochloride with phosphoric acid and phosphorous trichloride in chlorobenzene as solvent at 100°C. During the reaction, the reaction mass becomes non-stirable and therefore results in lower yields and impure product.
US Application No 2004-0230076 provides process for purification of zoledronic acid which involves (a) raising the pH of an aqueous suspension of crude zoledronic acid until a clear solution is obtained; (b) lowering the pH of the solution obtained in (a) until zoledronic acid precipitates out of solution; and (c) isolating the zoledronic acid that has precipitated from the solution in (b).
US Application No 2005-0054616 provides crystalline and amorphous forms of zoledronic acid or salt thereof and processes for their preparation. The process adopted uses chlorobenzene or toluene as solvent along with silicon oil, polyethylene glycol or diatomaceous earth compounds such as celite, keisulgurh etc as diluent to keep the reaction mass stirable. However, the purity obtained is similar to that reported in the '130 Patent.
The present inventors have surprisingly 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 acts as a solvent and the reaction mass remains stirable. The yield of crude zoledronic acid is about 80% with purity in excess of 99%. Further the inventors have also noticed that the said reaction can be accomplished at
2

temperature less than 80°C in less than 10 hours reaction time. This significantly improved process economics and scalability at commercial scale.
In one of the aspect of the present invention there is provided a process for preparation of zoledronic acid or salt thereof, wherein the said process comprises of reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid and phosphorous trichloride to get zoledronic acid or salt thereof wherein the reaction is characterized by fact that no solvent is used in the reaction.
In another aspect of the present invention there is provided a process for preparation of zoledronic acid or salt thereof wherein the process comprises of heating together imidazol-1-yl acetic acid or salt thereof, phosphorous acid and phosphorous trichloride optionally in presence of solvent at a temperature less than 80°C for less than 10 hours.
In yet another aspect of the present invention there is provided a process for preparation of zoledronic acid or salt thereof wherein the said process comprises of,
a) reacting imidazole with alky! haloacetate wherein alkyl group is selected from methyl or ethyl in presence of an organic solvent in absence of phase transfer catalyst to get alkyl imidazole-1-yl acetate,
b) hydrolyzing alkyl imidazole-1-yl acetate in presence of 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 presence of solvent to get zoledronic acid or salt thereof.
A yet another aspect of the present invention provides a process for purification of zoledronic acid wherein the said process comprises of
a) heating zoledronic acid with 10 to 30 volumes of water at a temperature above 80°C,
b) cooling the resultant mixture to a temperature less than 15°C,
c) isolating zoledronic acid from the reaction mixture thereof.
3

A yet another aspect of the present invention provides zoledronic acid or salt thereof having purity 997% or more when measured by HPLC.
Imidazole 1-yl acetic acid or salts thereof is treated with phosphorous acid and the resultant mass is heated to get homogeneous solution. To this homogeneous solution is added under controlled rate of addition phosphorous trichloride at a temperature less than 80°C. This reaction is carried out in absence of the solvent. Such reactions are normally termed as "neat reactions". The reaction mass is enough stirable and do not pose any problems. Solvent such as chlorobenzene, polyethylene glycol, toluene, silicon oil can also be used for enhancing the stirability. The reaction is continued at the same temperature for time not exceeding 10 hours followed by acidification of the reaction mass. The acidified mixture is further heated under reflux for about 8-15 hours, treated with activated carbon and filtered. The filtrate is treated with acetone or suitable anti-solvent to precipitate zoledronic acid from the solution. The precipitated mass is filtered and dried suitably to get zoledronic acid having purity greater than 99% when measured by HPLC in about 75 to 85% yield. The purity is obtained is in the range of 99.7% to 99.95%.
The zoledronic acid so obtained having purity greater than 99% w/w can be further purified by mixing it in 10 to 30 volumes of its weight of water and heating the resultant mixture at temperature above 80°C. The resultant solution can be treated with activated charcoal while hot and after removing the charcoal it is cooled to temperature less than 15°C wherein zoledronic acid precipitates out from the mixture. The pure zoledronic acid thus obtained can be filtered and dried to get above 80% yield and purity exceeding 99.7% by HPLC. The so obtained zoledronic acid is in its monohydrate form has moisture content of about 6 to 8% w/w.
lmidazol-1-yl acetic acid or salts thereof used as starting material for preparation of zoledronic acid can be in turn prepared by reacting imidazole with alkyl haloacetate in presence of solvent and a base. It was found that there is no need to use phase transfer catalyst in this reaction. The alkyl haloacetate can be methyl chloroacetate or ethyl bromoacetate. The solvent can be selected from halogenated hydrocarbons, non-polar aprotic solvents, polar aprotic solvents or the mixture thereof. The base can
4

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. For practical purpose, 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 reaction the resultant mass can be cooled to room temperature and filtered to remove inorganics. The organic layer containing the product is 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.
The hydrolysis of methyl/ethyl imidazol-1-yl acetate is carried out under aqueous conditions at higher temperature. The ester is mixed with water and the resultant mass is heated to reflux for about 4 to 10 hours, cooled. The aqueous layer can be treated with activated carbon and concentrated under reduced pressure to get a residue, which upon addition of suitable anti-solvent such as methanol or isopropanol gives imidazol-1-yl acetic acid as precipitated solid. The solid are filtered and dried suitably to get imidazoM-yl acetic acid.
While the present invention has been described in terms of its specific embodiments, 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 invention.
EXAMPLE 1 Preparation of methyl imidazol-1-yl acetate
To the suspension of potassium carbonate (400 gm) and potassium iodide (5 gm) in dichloromethane (2 Lit) were added imidazole (100 gm) and the mixture was stirred vigorously. To this were added methyl chloroacetate (205 gm) slowly and the mass was stirred further for 30 minutes followed by heating to reflux for 6-8 hours. The mass was cooled to ambient temperature and filtered. The residue was washed with
5

dichloromethane (500 ml) and the washings were combined with filtrate. The combined dichloromethane layers were distilled under reduced pressure to get title compound. Yield: 235 gm
EXAMPLE 2
Preparation of imidazol-1-yl acetic acid
To methyl imidazol-1-yl acetate (235 gm) was added water (500 ml) and the resultant mass was refluxed for 4 to 8 hours. After completion of reaction, it is cooled. The organic layers were discarded and the aqueous layer was treated with charcoal, filtered to remove charcoal and concentrated under reduced pressure to get a residue. The crude residue was treated with methanol (250 ml) and the resultant mixture was stirred for 2 hours and filtered. The solid obtained were washed with methanol (100 ml) and dried at 70-80°C to get title compound as solid. Yield: 158 gm
EXAMPLE 3
Preparation of zoledronic acid
A mixture of imidazol-1-yl acetic acid (100 gm) and phosphorous acid (324 gm) was heated under stirring to about 60-80°C to get a homogeneous solution. To this were added phosphorous trichloride (324 gm) slowly at a temperature of about 75°C. The resultant mass was stirred for 6 hours and cooled. A solution of hydrochloric acid (9N, 465 ml) was added over 30 minutes and the entire mass was heated at 75-80°C for about 12 hours, treated with activated carbon (3.8 gm) and filtered. Acetone (1200 ml) was added to the filtrate and the resultant mixture was cooled to 15-20°C. After complete precipitation of the product, the mass was filtered and the cake was washed with acetone (300 ml) and dried at 50-60°C to get title compound as white crystalline solid.
Yield: 161 gm Purity: 99.92%
6

EXAMPLE 4
Purification of zoledronic acid
Zoledronic acid (100 gm) was added to water (2.4 Lit) and the resultant mixture was heated at temperature of about 90°C. The hot solution was treated with activated charcoal and filtered to remove charcoal. The filtrate was cooled to 5-10°C under stirring and filtered. The wet cake was washed with water (100 ml) and dried at 50-60°C to get title compound in white crystalline form. Yield: 82 gm Purity: 99.99%
7

WE CLAIM:
1. A process for preparation of zoledronic acid or salt thereof, wherein the said process comprises of reacting imidazol-1-yl acetic acid or salt thereof with phosphorous acid and phosphorous trichloride to get zoledronic acid or salt thereof wherein the reaction is characterized by fact that no solvent is used in the reaction.
2. A process of claim 1 wherein the reaction is carried out at a temperature less than 80°C.
3. A process of claim 1 wherein the product obtained is zoledronic acid monohydrate.
4. A process for preparation of zoledronic acid or salt thereof wherein the process comprises of heating together imidazol-t-yl acetic acid or salt thereof, phosphorous acid and phosphorous trichloride optionally in presence of solvent at a temperature less than 80°C for less than 10 hours.
5. A process of claim 4 wherein the solvent used is chlorobenzene, toluene, polyethylene glycol, silicon oil or mixture thereof.
6. A process for preparation of zoledronic acid or salt thereof wherein the said process comprises of,

a) reacting imidazole with a Iky I haloacetate wherein alkyl group is selected from methyl or ethyl in presence of an organic solvent in absence of phase transfer catalyst to get alkyl imidazole-1-yl acetate,
b) hydrolyzing alkyl-1-yl acetate in presence of water to get imidazol-1-yl acetic acid,
c) treating imidazol-1-yl acetic acid or salt thereof with phosphorous acid and phosphorous trichloride optionally in presence of solvent to get zoledronic acid or salt thereof.
8

7. A process of claim 6 wherein alkyl haloacetate is methyl chloroacetate or ethyl bromoacetate.
8. A process for purification of zoledronic acid wherein the said process comprises of

a) heating zoledronic acid with 10 to 30 volumes of water at a temperature above 80°C,
b) cooling the resultant mixture to a temperature less than 15°C,
c) isolating zoledronic acid from the reaction mixture thereof.
9. Zoledronic acid or salt thereof having purity 99.7% w/w or more.
10. Zoledronic acid or salt thereof having purity 99.9% w/w or more.

Dated this 16TH day of December, 2005.

For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory