CA2689504A1

CA2689504A1 - Processes for manufacturing bisphosphonic acids

Info

Publication number: CA2689504A1
Application number: CA002689504A
Authority: CA
Inventors: Yunqi Liu; Aaron J. Delaup
Original assignee: Individual
Current assignee: Albemarle Corp
Priority date: 2007-06-19
Filing date: 2008-06-05
Publication date: 2008-12-24
Also published as: WO2008157050A1

Abstract

Processes are provided for preparing bisphosphonic acids, wherein phosphorous acid and phosphorous halide compound are fed into composition comprising imidazole-1 - ylacetic acid, or the like, and polar solvent; the reaction mixture remains stirrable and is quenched by inputting into water; and after cooling, bisphosphonic acid can be isolated, wherein R1 comprises: i) CH3 , Formulae ii), iii), iv), v), vi), vii), viii) and ix).

Description

~
WO Zoos~U`s~oSSES FOR MANUFACTURING BISPHOSPHOvIV/~VOU`/065842 BACKGROUND
[0001] The present invention relates to processes for the preparation of bisphosphonic acids and their pharmacologically active salts, and in particular, 1-hydroxy-2-(imidazole-1-yl)ethylidene-l,l-bisphosphonic acid, commonly referred to as zoledronic acid. The bisphosphonic acids described herein are suitable for treatment of diseases of the skeletal system and in cases when bone formation andior calcium metabolism have been disturbed, such as in the therapy of bone metastases.

[0002] The bisphosphonic acids described herein have the following structure:
Q '/M i R1 o p FI \0 -----M2 p \
~ I
m 4 wherein !1/11, M2, M3 and M4 each independently can comprise hydrogen or monovalent cation and R1 can comprise the ligands shown in Table I to give the acids shown in Table 10 Table 1 R1 Acid CH3 Etidronic acid N
Zoledronic acid WO 2008/157050 RI PCT~/CI 2~008/065842 Risedronic acid N

()N Minodronic acid N

CHz Pamidronic acid ~H2 NHZ Alendronic acid Neridronic acid N CH2 Olpadronic acid CH lbandronic acid [0003] U.S. Patents iVo. 4,939,130 and 4,777,163 disclose processes for making bisphosphonic acids based upon a known method published by Kabachnick et al.
[Izv.
Akad. Nauk. USSR, Ser. Khim., 2, 433-437, (1987)]. The synthesis basically consists of reacting the appropriate w-amino acid with a mixture of phosphorous acid and one of the three phosphorus chlorides, phosphorus trichloride, phosphorus oxychloride, or phosphorus pentachloride, then quenching the reaction mixture with water or a non-oxidizing aqueous acid followed by heating to hydrolyse the phospnorous intermeaiate to the final product.

[0004] One problem associated with this process involves the solidification of the reaction melt. The reaction starts as a two-phase system that gradually thickens into a non-stirrable mass. This problem was acknowledged in CA Patent Nos. 2,018,477 and 2,044,923 wherein the inventors utilized methanesulfonic acid to solubilize the reaction components and keep it fluid up to completion of the reaction. Unfortunately, methanesulfonic acid reacts with phosphorus trichloride and under adiabatic conditions the reaction becomes self-heating at 85 C and an uncontrolled exotherm occurs at >140 C.

[0005] Others have tried to address the solidification problem utilizing various solvent systems. For example, US Patent No. 6,201,148 describes a process that utilizes N-protected derivatives and phosphoric acid as a solvent; US Patent No.

6,573,401 describes a process that uses methanesulfonic anhydride; and US Patent Application Publication 2005/0288509 describes the use of ionic solvents comprising ammonium, sulphonium or phosphonium. US Patent No. 5,908,959 describes another solvent system that addresses the solidification problem during the preparation of alendronic acid via a process utilizing a high molecular weight polyalkylene glycol, or its derivatives. However, these systems present various drawbacks including commercial suitability, high costs, product contamination concerns, and/or additional processing steps.
[0006] One way of making zoledronic acid is to react imidazole-1-ylacetic acid, phosphoric acid or phosphorous acid with PCI3, PCI5 or P CI3. Various solvents such as chlorobenzene, toluene, alkanes, PEG, diglyme, chloroform, EDC and many others have been applied in such reactions, but a non-stirrable solid mass tends to form, which results in poor heat transfer, poor reaction conversion, and a reaction that is not suitable for commercial scale up. Although methanesulfonic acid as reaction medium can give a homogeneous, stirrable mixture, the reaction becomes self-heating at 85 C
and uncontrollable at 140 C. In addition, low reaction yield (31 / ) has been reported in the literature when methanesulfonic acid was used in production of 2-(3-imidazoyl)-1-hydroxyethylidene)bisphosphonic acid, an isomer of zoledronic acid (G. R.
Kieczykowski et al., J. Org. Chem, 1995, 60, 8310 - 8312).

[0007] Thus, even in view of these and other published solvent systems and processes, there remains a need for solvent systems and processes that produce bisphosphonic acids with commercially suitable purity and in commercially suitable yields.

THE INVENTION

[0008] This invention meets the above-described needs by providing processes for preparation of bisphosphonic acids and in particular zoledronic acid. While the description that follows relates specifically to the manufacture of zoledronic acid, the process may be easily adapted to manufacture other bisphosphonic acids by selecting the appropriate starting materials, as will be familiar to those skilled in the art.

[0009] In particular, this invention provides processes for preparing bisphosphonic acid having the structure 0 /m1 R, I I P'~ 0 Ho \ _____M2 P~o / o I

~
Nf3 wherein RT comprises:
i CFi3 ~ N ~cH2 \__j ii) iii) N

N
iv) cH2 v) H2N

vi) HzN/ CH2 \JH~
vii) H2N

N
viii) 1 or \ CH2 N
ix) and M1, M2, M3, and M4 each independently comprise hydrogen or monovalent cation, the process comprising: combining R,-C 2N, wherein R, is as previously described, and polar solvent to form a mixture; feeding a first stream comprising phosphorous acid and a second stream comprising phosphorous halide compound into the mixture to form a reaction mixture; feeding the reaction mixture into water to form a quenched reaction mixture; and isolating the bisphosphonic acid from the quenched reaction mixture. Also provided are such processes (i) wherein the first stream comprising phosphorous acid and the second stream comprising phosphorous halide compound are alternately fed into the mixture, or (ii) wherein the first stream comprising phosphorous acid and the second stream comprising phosphorous halide compound are co-fed into the mixturee In such processes the mixture can be at a temperature of from about 55 C to about 80 C. Such processes are provided wherein the R1-C 2N
comprises imidazole-1-ylacetic acid, the polar solvent comprises sulfolane, N-methylpyrrolidone, or diglyme and the phosphorous halide compound comprises phosphorous trichloride, phosphorous pentachloride, phosphoroxidchloride, phosphorous tribromide, phosphorous pentabromide, or phosphoroxidbromide. In such processes, the isolating of bisphosphonic acid can comprise adding composition compriseng anii salvent to the quenched reaction mixture; the anti-sv ve St c an csomprise acetone, methyl alcohol, or ethyl alcohol. Such processes are provided wherein the water is at ambient temperature or wherein the water is pre-heated up to a temperature of about 85 C.

[0010] Also provided are processes for preparing bisphosphonic acid having the structure ~

p H \0 ~P\
m 4 ~

wherein R1 comprises:
i) CH3 N N___-cH2 ii) \__j ~-' iii) N

\ N \

iv) vi) HzN CI-12 vii) \ ~~2 N

viii) or N

ix) and Ml, M2, M3, and M4 each independently comprise hydrogen or monovalent cation, the process comprising: combining Ri-CO2H, wherein R, is as previously described, and polar solvent to form a mixture; alternately feeding a first stream comprising phosphorous acid and a second stream comprising phosphorous halide compound into the mixture to form a reaction mixture; feeding the reaction mixture into water to form a quenched reaction mixture; and isolating the bisphosphonic acid from the quenched reaction mixture.

[0011] Also provided are processes for preparing zoledronic acid comprising:
combining imidazole-1-ylacetic acid and polar solvent to form a mixture;
alternately feeding a first stream comprising phosphorous acid and a second stream comprising phosphorous halide compound into the mixture to form a reaction mixture;
feeding the reaction mixture into water to form a quenched reaction mixture; and isolating the zoledronic acid from the quenched reaction mixture. Such processes are provided wherein the polar solvent comprises sulfolane, N-methylpyrrolidone, or diglyme; or wherein the phosphorous halide compound comprises phosphorous trichloride, phosphorous pentachloride, phosphoroxidchloride, phosphorous tribromide, phosphorous pentabromide, or phosphoroxidbromide.

[0012] We have discovered that difficulties with published methods for converting imidazole-1-ylacetic acid to zoledronic acid can be overcome by preparing a slurry of imidazole-1-ylacetic acid in polar (hydrophilic) solvent, such as sulfolane, at elevated temperature and then separately feeding phosphorous acid (H3PO3) and phosphorous halide compound, such as phosphorous trichloride (PC13), into the slurry.
Suitable phosphorous halide compounds include PCI3, phosphorous pentachloride (PCIS), phosphoroxidchloride (POC13), phosphorous tribromide (PBr3), phosphorous pentabromide (PBr5), phosphoroxidbromide (POBr3), and the like. Suitable polar solvents include sulfolane, N-methylpyrrolidone (NMP), diglyme, and the like.

SurpWOngiy~ tne ~esulting reaction mixture remains a stirrable fine siuTr~in rougnout the course of the reaction. The reaction mixture can then be input into water to quench the reaction. After cooling and addition of acetone, zoledronic acid can be isolated as an off-white, crystalline product. Commercially suitable reaction conversion and yields can be realized due to the improved mixing over published methods.

irnidazole-1-ylacetic acid [0013] lmidazole-1-ylacetic acid for use in this invention can be purchased or produced according to any suitable method. Broadly, acids R1-CO2H, wherein R1 is as previously described can be used in this invention.

[0014] For example, t-butyl imidazoleacetate can be prepared from imidazole and t-butyl chloroacetate, e.g., as described in US Patent No. 4,584,008, which is incorporated herein by reference in its entirety to the extent allowed by applicable law.
Such a process can be illustrated as follows:

~~NH + 0 CH3 CHCI3 NL ~ \ r--- ~' C~ H3G CH3 [0015] In this process, reaction temperature may range from about 0 C to about 100 C, or from about 50 C to about 70 C. The reaction mass may be stirred and/or refluxed from about 1 to about 24 hours. From about 0.5 to about 5 moles, or from about 2 to about 3 moles, of the imidazole can be used per mole of t-butyl chloroacetate. The reaction can take piace in suitable inert inorganic solvent, for example, chloroform. Other suitable inert organic solvents that can be used for this step include, for example, methylene chloride, carbon tetrachloride, benzene, toluene, and the like and compatible mixtures thereof.

[0016] Upon completion, the reaction mass can be cooled to about ambient temperature and the organic phase extracted, washed, and stripped under reduced pressure to yield t-butyl imidazole-1 acetate.

[0017] The t-butyl imidazole-1 acetate can be hydrolysed to imidazole-1-ylacetic acid.
Such a hydrolysis process can be illustrated as follows:

o CH3 Water OH
N
LjN N3C CH3 N
/

[0018] The t-butyl imidazole-1-ylacetate can be hydrolyzed by dissolving in about 20 to about 40, or about 30 to about 35, molar equivalents of water and heating to about 100 C. The byproduct, t-butanol, is driven off and upon cooling the reaction mixture to about ambient temperature and stripping of the reaction mixture under vacuum, imidazole-l- ylacetic acid remains as a solid product, i.e., the imidazole-l-ylacetic acid is isolated. If desired, the imidazole-1- ylacetic acid can be used without being isolated.

Converting imidazole-1-ylacetic acid to zoledronic acid [0019] In processes according to this invention, phosphorous acid and phosphorous halide compound such as PC13 are separately fed into a slurry of imidazole-l-ylacetic acid in sulfolane at temperature of from about 55 C to slightly higher than the boiling point temperature of PCI3, or from about 55 C to about 80 C, or from about 60 C to about 65 C. The molar ratio imidazole-1-ylacetic acid to H3PO3 can range from 1:1 to 1.6. The molar ratio of imidazole-1-ylacetic acid to PC13 can range from 1:1 to 1:6. The phosphorous acid and PCI3 can be fed into the slurry via separate streams. The feeding can be done alternately, i.e., solely phosphorous acid is fed, then feeding of phosphorous acid is temporarily stopped and solely PCI3 is fed, then feeding of PCI3 is temporarily stopped and solely phosphorous acid is fed, and so on until the desired amounts of phosphorous acid and PCI3 have been added to the slurry. Otherwise, the separate streams of phosphorous acid and PCI3 can be co-fed into the slurry.
The phosphorous acid and the phosphorous halide compound can be added in any suitable form. For example, at least a portion of the phosphorous acid can be added in solid form or in solution; or all of it can be added either as a solid or in solution. Similarly, at least a portion of the phosphorous halide compound can be added in solid form, in liquid form, or in solution; or all of it can be added either as a solid, as a liquid, or in solution. The reaction mixture can then quenched (cooled), e.g., with water.
The reaction mixture can be fed into water for quenching. The water can be potable water at arwo 2ooKis?o5oature. Alternatively, the reaction mixture can bePCT/us2008ro65842,at has been pre-heated up to a temperature of about 85 C9 for example, pre-heated water from another process in the plant at a temperature from about 75 C to about 85 C can be used. After cooling of the reaction mixture and, optionally, addition of anti-solvent, such as acetone, zoledronic acid can be isolated. The isolated zoledronic acid can be an off-white, crystalline product. Suitable anti-solvents include acetone, methyl alcohol, ethyl alcohol, and the like.

[0020] This invention is particularly advantageous in that the reaction mixture remains a stirrable slurry and can be quenched by adding the reaction mixture to water. This is operationally advantageous in that a usable product is obtained much more efficiently as compared to published methods in which the reaction mixture as least partially solidifies and, therefore, must be quenched by addition of water to the reaction mixture.
EXAMPLES

[0021] The following examples are illustrative of the principles of this invention. It is understood that this invention is not limited to any one specific embodiment exemplified herein, whether in the examples or the remainder of this patent application.

Example 1 [0022] An oven-dried 250 mL 4-neck RB flask was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet and two 1/8 inch polytetrafluoroethylene (PTFE) feeding lines. The system was flushed with nitrogen for 30 minutes. Under nitrogen protection, imidazole-1-ylacetic acid (15.97 g, 0.13 mole), sulfolane (70 mL) and phosphorous acid (2.67 g, 0.033 mol) were charged to the RB
flask. The reaction mixture was mixed at 210 RPM and heated to 60 C. PCI3 (9.18 g, 0.067mol) was added slowly (1.3 mL/min) via a masterfiex tubing pump. Five minutes were allowed for mixing. Alternately fed were 26 wt lQ phosphorous acid sulfolane solution (30.7 g, 10.23 g each addition at 1.6 mL/min) and PCI3 (27.5 g, 9.18 g each portion at 1.3 mL/min). Three to five minutes of mixing were allowed between additions. The addition took 1 hr 3 min and temperature was maintained between and 67 C. After addition was complete, the temperature of the reaction mixture was raised to 80 C and was held at this temperature for 4 hours. Then the temperature of the reaction mixture was raised to 88 C and held for 30 minutes. Ambient temperature water (50 g) was added in to quench the reaction. The solution was refluxed for 3 hrs rg/i065842 at 10u 20nen cooled to room temperature. After being left overnigniTai fOor temperature, the product was vacuum-filtered and rinsed with 38 g of acetone.
Zoledronic acid was obtained as a white crystalline solid (24.1 g, 95.3wt%
purity by quantitative NMR, 65% yield).

Example 2 [0023] An oven-dried 250 mL 4-neck RB flask was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet and two 1/8 inch PTFE
feeding lines. The system was flushed with nitrogen for 30 minutes. Under nitrogen protection, imidazole-1-ylacetic acid (15.97 g, 0.13 mole), sulfolane (70 mL) and phosphorous acid (2.67 g, 0.033 mol) were charged to the RB flask. The reaction mixture was mixed at 300 RPM and heated to 60 C. PC13 (9.18 g, 0.067mol) was added in slowly (1.3 mL/min) via a masterflex tubing pump. Five minutes were allowed for mixing.
Alternately fed were 26 wt% phosphorous acid sulfolane solution (30.7 g, 10.23 g each addition at 1.6 mL/min) and PCI3 (27.5 g, 9.18 g each portion at 1.3 mL/min.
Three to five minutes of mixing were allowed between additions. The addition took 1 hr 6 min and temperature was maintained between 54 and 64 C. After addition was complete, the temperature of the reaction mixture was raised to 80 C and held for 4 hours. Then the temperature of the reaction mixture was raised to 88 C and held for 30 minutes.
This slurry was transferred via 3/8" PTFE tubing using nitrogen pressure into 100 mL of pre-heated (80 C) water under mixing. The resultant water solution was heated to refluxing and held at that temperature for 4 hr. It was then slowly cooled to room temperature then to 1-2 C and held for 1.5 hr at this temperature. The product was collected via vacuum filtration. The cake was rinsed with acetone (20 g) and zoledronic acid was obtained as a white crystalline solid (19.1 g, 98.3 wt% purity by quantitative NMR, 53% yield).

Example 3 [0024] An oven-dried 250 mL 4-neck RB flask was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet and two 1/8 inch PTFE
feeding lines. The system was flushed with nitrogen for 30 minutes. Under nitrogen protection, imidazole-1-ylacetic acid (15.9 g, 0.13 mole), sulfolane (70 mL) and phosphorous acid (2.67 g, 0.033 mol) were charged to the RB flask. The reaction mixture was mixed and heated to 60 C. PCI3 (36.7 g, 0.267 mol) and phosphorous acid (8.0 g, 0.098 mol) in sulfo docoos~io7y were co-fed over a course of 19 minutes at 1.3 rcTius2oosro6ssa2 IL0111111 dIIV I.V
mL/min respectively. Reaction temperature remained between 60 C and 67 C
during feeding. After addition of PCI3 and phosphorous acid, the reaction slurry was heated to 80 C and held at that temperature for 4 hours. This slurry was then transferred via 3/8' PTFE tubing using nitrogen pressure into 50 mL of pre-heated (80 C) water under mixing. The resultant water solution was heated to refluxing and held at that temperature for 4 hr. It was then slowly cooled to 48-50 C. Acetone (200 mL) was added in slowly and then it was cooled to 1-2 C and held for 2 hr at this temperature.
The product was collected via vacuum filtration. The cake was rinsed with acetone (35 g) and zoledronic acid was obtained as a white crystalline solid (22.1 g, 98.6 wt% purity by quantitative IVIVIR, 61 % yield).

Example 4 [0025] A 2.5 L resin-kettle was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet, two 1/8 inch PTFE tubing as PC13 and phosphorous acid sulfolane solution feeding lines. The system was dried under a stream of nitrogen. Under nitrogen, imidazoleacetic acid (79.92 g, 0.63 mol), phosphorous acid (13.90 g, 0.17 mol) and sulfolane (350 mL) were added to the resin-kettle and mixed at 200 RPM. The mixture was heated to 62 C then PCI3 (36.7 g, 0.267 mol) was added in slowly (1.3 mL/min) using a masterfiex tubing pump.
The slurry was mixed for 5 minutes. Phosphorous acid (40.0 g, 0.49 mol) was dissolved in 114.0 g of sulfolane at 50 C. Alternately, this solution (30.8 g each time at 1.6 mL/min) and 147 g (1.07 mol) of PCI3 (29.5 g each portion at 1.3 mL/min) were fed into the reactor while the reaction temperature was maintained at 60-64 C. Three to five minutes mixing time was allowed between each addition. Toward the second half of the alternate addition, addition rates were increased to 2.0 mL/min for PCf3 and 2.5 mL/min for phosphorous acid solution respectively. The addition took 3 hr and minutes. After the addition was complete, the phosphorous acid line was rinsed with 30 mL of sulfolane and this was added into the resin-kettle reactor. The reaction temperature was then raised to 80 C and maintained for 4 hours. The resulting slurry was then quenched into 250 g of water pre-heated to 80 C under mixing. The aqueous solution was refluxed for 4 hours and cooled slowly to room temperature resulting in a s[urryo Acetone (1 L) was added slowly into the slurry and the mixture was cooled further to 1-2 C. After mixing for 2 hours at this temperature, the product was vacuum filterea~in e 08c~Ke50was rinsed with acetone (150 g) and dried under pu rg~4 ~r 1 hour. Zoledronic acid was obtained as a white, crystalline solid (109.6 g).

[0026] It is to be understood that the reactants and components referred to by chemical name or formula anywhere in the specification or claims hereof, whether referred to in the singular or plural, are identified as they exist prior to being combined with or coming into contact with another substance referred to by chemical name or chemical type (e.g., another reactant, a solvent, or etc.)o It matters not what chemical changes, transformations and/or reactions, if any, take place in the resulting mixture or solution or reaction medium as such changes, transformations and/or reactions are the natural result of bringing the specified reactants and/or components together under the conditions called for pursuant to this disclosure. Thus the reactants and components are identified as ingredients to be brought together in connection with performing a desired chemical reaction or in forming a mixture to be used in conducting a desired reaction. Accordingly, even though the claims hereinafter may refer to substances, components and/or ingredients in the present tense ("comprises", "is", etc.), the reference is to the substance, component or ingredient as it existed at the time just before it was first contacted, combined, blended or mixed with one or more other substances, components and/or ingredients in accordance with the present disclosure.
Whatever transformations, if any, which occur in situ as a reaction is conducted is what the claim is intended to cover. Thus the fact that a substance, component or ingredient may have lost its original identity through a chemical reaction or transformation during the course of contacting, combining, blending or mixing operations, if conducted in accordance with this disclosure and with the application of common sense and the ordinary skill of a chemist, is thus wholly immaterial for an accurate understanding and appreciation of the true meaning and substance of this disclosure and the claims thereof. As will be familiar to those skilled in the art, the terms "combined", "combining", and the like as used herein mean that the components that are "combined" or that one is "combining" are put into a container with each other.
Likewise a"combination' of components means the components having been put together in a container.

[0027] While the present invention has been described in terms of one or more preferred embodiments, it is to be understood that other modifications may be made without departing from the scope of the invention, which is set forth in the claims below.

Claims

1. A process for preparing bisphosphonic acid having the structure wherein R1 comprises:

i) CH3, and M1, M2, M3, and M4 each independently comprise hydrogen or monovalent cation, the process comprising:
- combining R1-CO2H, wherein R1 is as previously described, and polar solvent to form a mixture;
- feeding a first stream comprising phosphorous acid and a second stream comprising phosphorous halide compound into the mixture to form a reaction mixture;
- feeding the reaction mixture into water to form a quenched reaction mixture;
and - isolating the bisphosphonic acid from the quenched reaction mixture.

2. The process of claim1 wherein the first stream comprising phosphorous acid and the second stream comprising phosphorous halide compound are alternately fed into the mixture.

3. The process of claim 1 wherein the first stream comprising phosphorous acid and the second stream comprising phosphorous halide compound are co-fed into the mixture.

4. The process of claim 1 wherein the mixture is at a temperature of from about 55°C to about 80°C.

5. The process of claim 1 wherein the R1-CO2H comprises imidazole-1-ylacetic acid, the polar solvent comprises sulfolane, N-methylpyrrolidone, or diglyme and the phosphorous halide compound comprises phosphorous trichloride, phosphorous pentachloride, phosphoroxidchloride, phosphorous tribromide, phosphorous pentabromide, or phosphoroxidbromide.

6. The process of claim 1 wherein the isolating of bisphosphonic acid comprises adding composition comprising anti-solvent to the quenched reaction mixture.

7. The process of claim 6 wherein the anti-solvent comprises acetone, methyl alcohol, or ethyl alcohol.

8. The process of claim 1 wherein the water is at ambient temperature.

9. The process of claim 1 wherein the water is pre-heated up to a temperature of about 85°C.

10. A process for preparing bisphosphonic acid having the structure wherein R1 comprises:

i) CH3, and M1, M2, M3, and M4 each independently comprise hydrogen or monovalent cation, the process comprising:
- combining R1-CO2H, wherein R1 is as previously described, and polar solvent to form a mixture;
- alternately feeding a first stream comprising phosphorous acid and a second stream comprising phosphorous halide compound into the mixture to form a reaction mixture;
- feeding the reaction mixture into water to form a quenched reaction mixture;
and - isolating the bisphosphonic acid from the quenched reaction mixture.

11. A process for preparing zoledronic acid comprising:
- combining imidazole-1-ylacetic acid and polar solvent to form a mixture;
- alternately feeding a first stream comprising phosphorous acid and a second stream comprising phosphorous halide compound into the mixture to form a reaction mixture;
- feeding the reaction mixture into water to form a quenched reaction mixture;
and - isolating the zoledronic acid from the quenched reaction mixture.

12. The process of claim 11 wherein the polar solvent comprises sulfolane, N-methylpyrrolidone, or diglyme.

13. The process of claim 11 wherein the phosphorous halide compound comprises phosphorous trichloride, phosphorous pentachloride, phosphoroxidchloride, phosphorous tribromide, phosphorous pentabromide, or phosphoroxidbromide.

14. The process of claim 11 wherein the mixture is at a temperature of from about 55°C to about 80°C.

15. The process of claim 11 wherein the water is pre-heated up to a temperature of about 85°C.

16. The process of claim 11 wherein the isolating of zoledronic acid comprises adding composition comprising anti-solvent to the quenched reaction mixture.

17. The process of claim 16 wherein the anti-solvent comprises acetone, methyl alcohol, or ethyl alcohol.

18